- Email: [email protected]
Multicenter Phase 2 Trial of Gemcitabine, Carboplatin, and Sorafenib in Patients With Metastatic or Unresectable Transitional-Cell Carcinoma
Original Study
Multicenter Phase 2 Trial of Gemcitabine, Carboplatin, and Sorafenib in Patients With Metastatic or Unresectable Transitional-Cell Carcinoma Michael E. Hurwitz,1 Paul Markowski,2 Xiaopan Yao,1 Hari Deshpande,1 Jaymin Patel,1 Amir Mortazavi,3 Alessia Donadio,4 Mark N. Stein,2 William Kevin Kelly,5 Daniel Peter Petrylak,1 Janice M. Mehnert2 Abstract We studied whether the addition of sorafenib, an oral tyrosine kinase inhibitor, enhanced the antitumor activity of gemcitabine and carboplatin in 17 subjects with advanced transitional-cell carcinoma (TCC). Therapy with gemcitabine and carboplatin with sorafenib was associated with significant toxicity but had impressive responses, including durable ones. Although we do not recommend further testing of this dosage and combination of medications in metastatic TCC because of its toxicity, testing the combination of tyrosine kinase inhibitors and chemotherapy should be pursued in future studies. Background: Sorafenib, an oral tyrosine kinase inhibitor, may enhance the antitumor activity of platinum-based chemotherapy in transitional-cell carcinoma. This study investigated the safety and clinical outcome of adding sorafenib to gemcitabine and carboplatin for patients with advanced transitional-cell carcinoma. Patients and Methods: Subjects with metastatic or unresectable chemotherapy-naive TCC with Eastern Cooperative Oncology Group performance status 0 or 1 received gemcitabine (1000 mg/m2 on days 1 and 8) and carboplatin (area under the curve of 5 on day 1) with sorafenib (400 mg 2 times a day on days 22-19 every 21 days) for 6 cycles. Subjects with stable disease or partial or complete response continued to receive sorafenib until disease progression. The primary end point was progression-free survival (PFS) at 5 months with a secondary end point of response (partial or complete). Results: Seventeen subjects were enrolled. The median number of cycles of gemcitabine and carboplatin with sorafenib provided was 4.4. A total of 15, 5, and 8 subjects required reductions of gemcitabine, carboplatin, and sorafenib, respectively. Thirteen subjects (76%) required multiple dose reductions. Eleven subjects (65%) were free of progression at 5 months. The overall response rate was 54% (95% confidence interval [CI], 0.28-077), with 4 patients experiencing complete response (24%; 95% CI, 0.07-0.50) and 5 partial response (29%; 95% CI, 0.10-0.56); 7 subjects (41%) had stable disease. Median PFS was 9.5 months (95% CI, 0.43-1.26), and median overall survival was 25.2 months (95% CI, 0.96-5.65). One-year PFS was 31%, and 1-year overall survival was 72%. Eleven subjects (65%) discontinued treatment because of toxicity. There were no toxic deaths. Conclusion: Gemcitabine and carboplatin with sorafenib showed clinical activity in advanced TCC, with some prolonged progression-free intervals. However, gemcitabine and carboplatin with sorafenib was associated with significant toxicity, causing discontinuation of therapy in most patients. Clinical Genitourinary Cancer, Vol. -, No. -, 1-8 ª 2018 Elsevier Inc. All rights reserved. Keywords: Chemotherapy, First line, TCC, Tyrosine kinase inhibitor, Urothelial carcinoma
1
Yale Cancer Center, New Haven, CT Department of Medicine, Rutgers Cancer Institute of New Jersey, NJ Ohio State University Cancer Center, OH 4 St Francis Hospital and Medical Center, Hartford, CT 5 Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 2 3
Address for correspondence: Janice M. Mehnert, MD, Department of Medicine, Rutgers Cancer Institute of New Jersey, 195 Little Albany St, New Brunswick, NJ 08901 E-mail contact: [email protected]
Submitted: Jun 21, 2017; Accepted: Jul 19, 2018
1558-7673/$ - see frontmatter ª 2018 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.clgc.2018.07.021
Clinical Genitourinary Cancer Month 2018
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Phase 2 Trial of Gemcitabine, Carboplatin, and Sorafenib Introduction Metastatic transitional-cell carcinoma (TCC) is an aggressive malignancy with a very low cure rate (http://seer.cancer.gov/ statfacts/html/urinb.html). While most metastatic or locally advanced TCCs will initially respond to cisplatinum-based combination chemotherapy, these responses are usually short lived, and the disease almost always recurs.1-3 Impaired renal function, peripheral neuropathy, hearing loss, poor performance status, and inability to receive adequate hydration render approximately 30% of patients ineligible to receive cisplatin-based regimens. In these sicker patients, substitution with carboplatin-based regimens has shown encouraging efficacy and improved tolerability.4-9 Therefore, carboplatin-based regimens are an attractive backbone for clinical studies of additional agents with the aim of improving efficacy while maintaining acceptable tolerability. Specifically, the combination of gemcitabine and carboplatin has been established as effective and comparatively nontoxic.10 Unfortunately, the median survival is only approximately 10 months with gemcitabine/carboplatin— considerably lower than for cisplatin-based regimens. Addition of paclitaxel to the gemcitabine/carboplatin backbone resulted in a 68% response rate with an overall survival (OS) of 14.7 months, suggesting that improvements can be made to the gemcitabine/ carboplatin combination using the appropriate drug.11 Agents chosen for combination therapy should be based on our understanding of molecular derangements in TCC. Multiple lines of evidence suggest targeting angiogenesis may prove useful in the treatment of bladder cancer. Several studies have correlated elevated vascular endothelial growth factor (VEGF) levels with disease recurrence or progression, and increased expression of VEGF in the tissue, serum, and urine of patients with TCC has been correlated with stage and prognosis.12,13 Inhibitors of angiogenesis show activity in preclinical models of TCC.14-16 Microvessel density, a marker of angiogenesis within tumors, has also been correlated with stage, recurrence, and survival in TCC.17,18 The RTK/Ras/MAPK pathway appears to be activated in approximately 45% of muscle-invasive bladder cancers and is thought to be a major driver of TCC.19 Sorafenib is a multikinase inhibitor with high affinity for the VEGF receptors and various Raf isoforms (drug concentration causing 50% inhibition, 6-100 nM).20 On the basis of the above findings, we conducted a multicenter phase 2 study to assess response in patients with advanced or metastatic TCC treated with the combination of gemcitabine, carboplatin, and sorafenib.
Patients and Methods This multicenter study was approved by Yale’s institutional review board and was performed in accordance with the 2008 Declaration of Helsinki. Each site was individually required to have approval by their local human investigation committee and Yale’s institutional review board. All patients were required to provide written informed consent before study registration. The primary objective was to assess progression-free survival (PFS). The secondary objectives were to determine overall safety and tolerability and to define the proportion of patients who experienced complete or partial response. To be included in the study, patients had to be of any race and either gender, and > 18 years of age with histologically confirmed
2
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Clinical Genitourinary Cancer Month 2018
TCC of urothelial origin that was metastatic, locally advanced, or unresectable. An Eastern Cooperative Oncology Group performance status score of 0 or 1 was required at entry. Prior radiation was permitted if 4 weeks had elapsed before trial enrollment. Prior intravesical, neoadjuvant, and adjuvant therapies were permitted if they had been completed > 12 months from trial enrollment. The following were required at trial entry: adequate bone marrow function defined by hemoglobin 9 g/dL, absolute neutrophil count (ANC) 1500/mm3, and platelets 100 109/L; renal function by glomerular filtration rate 40 mL/min/1.73 m2 (Cockcroft-Gault); hepatic function by total bilirubin 1.5 times the upper limit of normal (ULN), alanine aminotransferase/aspartate aminotransferase 2.5 ULN, and international normalized ratio 1.5 or a prothrombin time/partial thromboplastin time within normal limits. Subjects were excluded on the basis of the following criteria: presence of brain metastases; infection with human immunodeficiency virus, chronic hepatitis B or C, or any active clinically serious infection of higher than grade 2 by Common Terminology Criteria for Adverse Events v3.0; severe cardiovascular disease; and bleeding diathesis or coagulopathy.
Treatment Schedule All patients received gemcitabine 1000 mg/m2 on days 1 and 8, carboplatin area under the curve of 5 on day 1, and sorafenib 400 mg orally twice daily on days 2 through 19 of each 21-day cycle. Standard supportive care included antiemetics, antipyretics, pain control, and prophylactic hematopoietic growth factors per American Society of Clinical Oncology guidelines.21 Patients were treated for a maximum of 6 cycles, if tolerated. Subjects with stable disease or with complete or partial response were maintained on oral sorafenib on the same schedule until there was evidence of disease progression or unacceptable toxicity.
Toxicity and Dose Modifications Sorafenib toxicity (except for skin and blood pressure) was measured by Common Terminology Criteria for Adverse Events v3.0. Dose modifications were specified on the basis of toxicity and were mandated for all grade 3/4 toxicities. Sorafenib was held for a first grade 3 toxicity until grade 2 or less for hematologic toxicity and until grade 1 or less for nonskin nonhematologic toxicity. Then treatment was resumed at the same dose level. For a second grade 3 event, sorafenib was held until grade 2 or less for hematologic toxicity and until grade 1 or less for nonskin nonhematologic toxicity, and resumed at a dose reduced by 200 mg per day (1 dose level reduction). For a third event, sorafenib was held until grade 2 or less and resumed at a dose reduced by 400 mg per day (2 dose level reductions). After a third event, sorafenib was discontinued. For a first grade 4 toxicity, sorafenib was held until grade 2 or less and resumed at a dose reduced by 200 mg per day (1 dose level reduction) or was discontinued at the discretion of the principal investigator after discussion with the study sponsor. For skin toxicity (specifically handefoot syndrome), management was per manufacturer recommendations.22 For hypertension, no action was taken at grade 1. Asymptomatic grade 2 toxicity was managed with antihypertensive monotherapy.
Michael E. Hurwitz et al For symptomatic grade 2 or 3 toxicity, multiple antihypertensives were used. Sorafenib was held until resolution of symptoms and blood pressure was controlled. Subjects were removed from the trial for grade 4 hypertension. Dose modifications for other specific nonhematologic toxicities of sorafenib are provided in Supplemental Table 1 in the online version. Patients who developed grade 3 fever/chills, grade 3 elevation of hepatic transaminases with alanine aminotransferase and aspartate aminotransferase < 10 ULN, grade 3 hyperlipasemia or hyperamylasemia without clinical or other evidence of pancreatitis, grade 3 leukopenia, or grade 3/4 lymphopenia could continue study treatment without interruption at the discretion of the investigator. For hematologic toxicity while receiving gemcitabine/carboplatin, the drugs were held on day 1 for ANC < 1500/mm3 and platelets < 100 109/L. If delayed, gemcitabine was decreased by 200 mg/m2. For a second delay, carboplatin was decreased to an area under the curve of 4. Patients were removed from the study or moved to a maintenance phase for > 2 dose reductions. On day 8, for ANC 1000 to 1499/mm3 or platelets 75 109 to 100 109, gemcitabine was reduced by 200 mg/m2. For ANC < 1000/mm3 or platelets < 75 109, treatment was held and not made up. If day 8 was held, the next cycle doses were decreased by 1 dose level. For gemcitabine/carboplatin nonhematologic toxicity, with the exception of alopecia or nausea/vomiting not optimally managed with antiemetics, dose reductions were as follows: for grade 3/4 toxicities, the dose was held until toxicity resolved to grade 2 or less and resumed at 1 dose level lower. Once the dose of gemcitabine or carboplatin was reduced, there was no dose escalation. Subjects were removed from the study if treatment was held for 21 days.
Table 1 Patient Characteristics Characteristic
Value
Age (Years) Mean
65
Range
47-86
Sex Male Female
14 (83) 3 (17)
Race White
15 (88)
African American
1 (6)
Hispanic
1 (6)
Performance Status 0
7 (41)
1
10 (59)
Baseline Creatinine Clearancea <50 mL/min/1.73 m2
6 (35)
51-60 mL/min/1.73 m2
4 (24)
> 60 mL/min/1.73 m2
7 (41)
Data are presented as n (%) unless otherwise indicated. a Creatinine clearance using Cockcroft-Gault formula adjusted for ideal body weight.
used to calculate PFS and OS. All analyses were performed by SAS 9.3 (SAS Institute, Cary, NC) and R 3.1.2 (R Foundation for Statistical Computing, Vienna, Austria; http://www.r-project.org/).
Results Patient Characteristics
Efficacy Evaluation Patients had a history, physical, toxicity assessment, complete blood count, and comprehensive metabolic panel performed monthly while receiving treatment. Response was measured by Response Evaluation Criteria in Solid Tumors v1.123 after 3 and 6 cycles of treatment, then every 3 months by computed tomography or magnetic resonance imaging for the first 18 months, followed by every 6 months for the next 18 months.
Statistical Analysis This trial followed a minimax Simon 2-stage design.24 The primary outcome was the proportion of patients who experienced PFS of 5 months. PFS was defined as time to progression or any-cause mortality, whichever came first. We assumed the standard platinum-based therapy response rate for TCC was 50%. The primary study aim was to determine if the treatment resulted in PFS of 70% at 5 months. Target enrollment was 17 patients for the first phase. If > 8 subjects were free of progression at 5 months, another 13 subjects, for a total of 30, were to be enrolled. If 19 or more (out of 30) experienced 5-month PFS, then the probability of 5-month PFS is 70%. This design provides 84% statistical power to detect a difference of 20% (70% vs. 50%), with a significance level of < .1 (type I error). Descriptive statistics were used for patient characteristics, with median and range for continuous variables and frequency and percentage for categorical variables. Kaplan-Meier estimates were
Between December 2007 and February 2010, 17 patients (14 men and 3 women) with creatinine clearance 40 mL/min/1.73 m2 were enrolled onto the study. All 17 patients were included in the final analysis for response and survival. One subject withdrew consent, but all others were treated. The baseline characteristics are summarized in Table 1. A total of 88% had metastatic disease, 6% had locally unresectable disease, and 6% were not evaluable. The study was planned as a minimax Simon 2-stage design. If 9 of 17 subjects enrolled had a PFS of 5 months, then 13 more patients were going to be enrolled, for a total of 30 patients. Although the study reached its aim of 9 subjects who experienced
Table 2 Efficacy Characteristic
N (%)
Progression-Free Survival Progression free at 5 months
11 (65)
Progression within 5 months
5 (29)
Lost to follow-up
1 (6)
Best Reported Response Stable disease
7 (41)
Partial response
5 (29)
Complete response
4 (24)
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Phase 2 Trial of Gemcitabine, Carboplatin, and Sorafenib Table 3 Site of Disease at Enrollment and Response by Site Responsea
Disease
N (%)
Metastatic disease
15 (88)
Unresectable local disease
1 (6)
Lymph node only
3 (18)
All with lymph node disease
7 (41)
4 (57%)
Bone
3 (18)
1 (33%)
Liver
2 (12)
1 (50%)
Study Treatment and Toxicity
Site
a
OS was 25.2 months (95% CI, 12.5-73.5). The 1-year PFS was 31%, and the 1-year OS was 72% (Figure 2).
Lung
3 (18)
1 (33%)
Visceral nonliver
5 (29)
3 (60%)
Percentage of lesions at these sites that responded to treatment.
a 5-month PFS, the study sponsor did not choose to continue the trial because of toxicity, so no more subjects were enrolled.
Response and Survival All 17 subjects were evaluated for response (Table 2). One patient moved away and was lost to follow-up. The overall response rate was 54% (95% confidence interval [CI], 0.28-077) with 4 complete responses (24%; CI, 0.07-0.50) and 5 partial responses (29%; 95% CI, 0.10-0.56). A total of 41% of subjects experienced stabilization of disease for at least 3 months (the earliest time that progression was assessed). No evaluable patients had disease progression at the first restaging. Sites of response included bladder, bones, lymph nodes, lungs, liver, and soft tissue (Table 3). In one subject a lung lesion became cavitary, possibly suggestive of an effect of sorafenib on tumor vasculature (Figure 1). Eleven subjects (65%) had PFS 5 months. At a median followup of 5.8 years, PFS was 9.5 months (95% CI, 5.6-16.4) and the
Seventeen patients had data evaluable for toxicity. A total of 77 cycles of gemcitabine/carboplatin were administered with a median of 4.5 cycles per patient. Fifteen, 5, and 9 subjects required dose reductions of gemcitabine, carboplatin, and sorafenib, respectively, with 13 subjects (76%) requiring multiple dose reductions; 7 (41%) were removed from the trial within 5 months because of > 3 dose reductions. Seven subjects (41%) experienced grade 3/4 neutropenia, 5 (29%) grade 3/4 anemia, and 8 (47%) grade 3/4 thrombocytopenia during gemcitabine and carboplatin with sorafenib; 1 neutropenic fever was noted. There were 4 grade 3/4 bleeding events. The most common grade 3/4 nonhematologic toxicities were fatigue (29%), hypophosphatemia (29%), infection (24%), and diarrhea (6%). There were no toxic deaths (Table 4 and Supplemental Table 1 in the online version). Sorafenib maintenance was provided for a median of six 28-day cycles (range, 2-47 cycles). Eleven subjects (65%) discontinued treatment (of all trial therapies) because of toxicity, and 5 discontinued treatment because of disease progression. Hematologic toxicity caused discontinuation of treatment in 6 patients. Other causes of treatment discontinuation are listed in Table 5.
Discussion This trial treated subjects with a combination of gemcitabine, carboplatin, and sorafenib. For a number of reasons, we do not recommend further testing of this dosage and combination of medications in metastatic TCC. First, all but one of the subjects on the trial required dose reductions, and most subjects discontinued treatment because of toxicity, regardless of whether patients were cisplatin eligible or ineligible, demonstrating that this combination of drugs at these doses is not tolerable for a large number of patients with this disease. Second, cisplatin is considered to be a better drug
Figure 1 Necrotic Response to Therapy. Chest Computed Tomographic Scan (A) before and (B) after 1 Cycle of Therapy. Subject Continued on Study Protocol for 8 Cycles Total, With Partial Response, and Came off Study by His Choice because of Inability to Tolerate Sorafenib. He Remained Free of Progression for > 1 Year
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Michael E. Hurwitz et al Figure 2 Kaplan-Meier Plots of PFS and OS. Dashed Lines Indicate 95% Confidence Intervals
Abbreviations: OS ¼ overall survival; PFS ¼ progression-free survival.
in this disease than carboplatin. In trials with cisplatin and carboplatin arms, the cisplatin arms outperform the carboplatin arms.4,25 Third, sorafenib has multiple targets, not all of which would be predicted to have activity in bladder cancer but could potentially add to toxicity. Other drugs are both less promiscuous and more potent for VEGF pathway blockade. Since this study was begun, a number of other studies using inhibitors of the VEGF pathway have been tested in TCC. As single agents, the most successful was pazopanib in the second-line setting, with a response rate of 17.1%, though the PFS was only 3.1 months.26 Other single-agent trials have been far less impressive, with 2 trials of sorafenib resulting in no responses and a trial of the VEGF trap aflibercept with a 4.5% response rate.27-29 Studies have also combined small-molecule inhibitors of VEGF with platinum-based chemotherapies. The Hoosier Oncology Group GU 04-75 trial of gemcitabine, cisplatin, and bevacizumab
enrolled 43 patients and demonstrated a response rate of 72%, median PFS of 8.2 months, OS of 19.2 months, and antiangiogenic treatmenterelated toxicities (deep-vein thrombosis/pulmonary Table 4 Reasons Subjects Went Off Study Toxicity
N
%
Total Thrombocytopenia Neutropenia Unspecified hematologic Fatigue/Failure to Thrive Cardiac Epistaxis Progression of disease Lost to follow-up
11 3 2 1 2 2 1 5 1
65
29 6
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Phase 2 Trial of Gemcitabine, Carboplatin, and Sorafenib Table 5 All Toxicities With at Least Single Grade 3/4 AE Grade 3/4 AE AE
All AE Grades
N
%
N
%
Anemia
5
29.4
13
76.5
Decreased leukocytes (total WBC)
1
5.9
4
23.5
Hematologic
Lymphopenia
1
5.9
2
11.8
Neutropenia/granulocytopenia
7
41.2
10
58.8
Thrombocytopenia
8
47.1
13
76.5
Decreased CD4 count
1
5.9
2
11.8 29.4
Nonhematologic ALT
1
5.9
5
Blood in stool
1
5.9
1
5.9
Constipation
1
5.9
12
70.6
Diarrhea
3
17.6
14
82.4
Dysphagia
1
5.9
1
5.9
Fatigue (asthenia, lethargy, malaise)
5
29.4
16
94.1
Fever (in absence of neutropenia)
1
5.9
5
29.4
Glucose, serum-high
2
11.8
5
29.4
Hypertension
2
11.8
7
41.2
Infection
4
23.5
4
23.5
Magnesium, serum-high
1
5.9
1
5.9
Muscle weakness (not due to neuropathy)
1
5.9
3
17.6
Pain—Abdomen NOS
2
11.8
7
41.2
Pain—Back
3
17.6
9
52.9
Pain—Extremityelimb
4
23.5
8
47.1
Pain—Head/headache
2
11.8
8
47.1
Phosphate, serum-low
5
29.4
9
52.9
Potassium, serum-high
2
11.8
2
11.8
Obstruction, genitourinary—Ureter
1
5.9
1
5.9
Rash
2
11.8
10
58.8 17.6
Renal/genitourinary—Other
1
5.9
3
Syncope
1
5.9
1
5.9
Thrombosis/thrombus/embolism
2
11.8
2
11.8
Urinary frequency/urgency
1
5.9
4
23.5
Weight loss
1
5.9
6
35.3
Abbreviations: AE ¼ adverse event; ALT ¼ alanine aminotransferase; NOS ¼ not otherwise specified; WBC ¼ white blood cell count.
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embolism 21%, hemorrhage 7%, hypertension 7%, proteinuria 2%)30; this regimen is being explored further in a randomized phase 3 trial comparing gemcitabine/cisplatin to gemcitabine/cisplatin/ bevacizumab (NCT00942331). Two single-arm trials, one using gemcitabine/carboplatin and bevacizumab and another using gemcitabine/cisplatin and sunitinib, had response rates of 49% and 64% and OS values of 13.9 and 12 months, respectively, similar to response rates and OS results from the standard-of-care regimens of gemcitabine/cisplatin and methotrexate, vinblastine, doxorubicin, and cisplatin.3,31,32 Small randomized phase 2 studies have also been performed. Grivas et al33 treated subjects with platinum-based regimens and then randomized 28 to receive placebo and 26 to receive sunitinib
Clinical Genitourinary Cancer Month 2018
maintenance therapy. PFS was 64% for the placebo arm versus 72% for the sunitinib arm, which was not statistically significant, although the trial was so small that it was only powered to detect very large differences. Similarly, another study treated patients with gemcitabine and cisplatin and then randomized 49 patients to receive placebo and 40 to receive sorafenib maintenance therapy.34 Response rates were 47% versus 52.5% and PFS times were 6.1 versus 6.3 months, respectively. Again, the study was small and was closed early because of slow accrual. Last, trials of second-line chemotherapy combined with VEGF inhibitors have demonstrated activity. The combination of pazopanib and paclitaxel in 28 previously treated subjects had 3 complete responses and a 54% overall response rate, with median 6.2
Michael E. Hurwitz et al months PFS and 10 months OS.35 A comparison of ramucirumab versus placebo in combination with docetaxel in the second-line setting has demonstrated a statistically significant PFS advantage for ramucirumab (5.4 vs. 2.8 months).36 Thus, it appears that among the currently tested small-molecule VEGF pathway inhibitors, single-agent therapy is unlikely to be an important strategy, whereas adding these agents to chemotherapy-based backbones might add significant benefit. A number of findings in this study are worth noting for future studies. First, out of 17 subjects, 2 had very long-term remissions (>5 years), one of which is a possible cure in a disease with a negligible cure rate from conventional chemotherapy. Furthermore, despite very few patients completing therapy, the PFS and OS compare favorably with the standard-of-care therapies of gemcitabine/cisplatin and methotrexate, vinblastine, doxorubicin, and cisplatin combination results from phase 3 studies (PFS 9.5 vs. 7.7-8.3 months, OS 25.2 vs. 14-15.2 months).3 While the number of patients treated on this study is small and one cannot directly compare phase 2 results with phase 3 results given the likely differences in patient populations, the findings of an OS of 25.2 months is intriguing. A similar trial using lower doses of chemotherapy (but possibly with cisplatin instead of carboplatin) with a more specific VEGF pathway inhibitor might provide similar benefits with much less toxicity. Forthcoming results of the NCT00942331 trial will allow a randomized trial assessment of the addition of bevacizumab to gemcitabine/cisplatin compared to gemcitabine/cisplatin alone. Furthermore, as noted above, in the second-line setting, ramucirumab in combination with docetaxel chemotherapy has been shown to have a PFS benefit compared to docetaxel alone.36 This agent or other agents might show similar improved efficacy in the first-line setting. Given the limited benefit provided by first-line chemotherapy in this disease, trying other similar combinations of chemotherapy with antiangiogenic agents is a reasonable strategy.
Clinical Practice Points A number of trials have assessed tyrosine kinase inhibitors alone
or in combination with platinum-based chemotherapy in the treatment of TCC. As single agents, response rates range from 4.5% to 17.1%. To date, no combination has yet been assessed in a randomized trial (though one is ongoing), and both the tyrosine kinase inhibitor and the chemotherapy backbone have not yet been optimized. In this trial, we treated subjects with gemcitabine/carboplatin and sorafenib in 17 subjects in the first-line setting. Sorafenib has specificity for VEGF receptors as well as several Raf isoforms and other tyrosine kinases. Carboplatin was chosen because of its better tolerability compared to cisplatin. The overall response rate was 54%. Median PFS and OS were 9.5 months and 25.2 months, respectively, and 2 subjects had responses that lasted > 5 years. However, 11 subjects (65%) discontinued treatment, and 13 subjects (76%) required multiple dose reductions because of toxicity. Thus, gemcitabine and carboplatin with sorafenib was associated with significant toxicity but demonstrated impressive survivals, including durable ones.
These results have 2 implications. First, given the poor tolerability
and our inability to treat subjects at these doses, we do not recommend going forward with this combination of agents at these doses. Second, response rates, including durable responses, are high despite the requirement for multiple dose reductions in most patients, suggesting that the combination of tyrosine kinase inhibitors and chemotherapy should be pursued in future studies. Using a tyrosine kinase inhibitor more specific to VEGFR2 and modifying its dose might produce more tolerable combinations with durable responses.
Disclosure The authors have stated that they have no conflict of interest.
Supplemental Data A supplemental table accompanying this article can be found in the online version at https://doi.org/10.1016/j.clgc.2018.07.021.
References 1. Sternberg CN, Yagoda A, Scher HI, et al. M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for advanced transitional cell carcinoma of the urothelium. J Urol 1988; 139:461-9. 2. Maase von der H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 2000; 18:3068-77. 3. Maase von der H, Sengelov L, Roberts JT, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol 2005; 23:4602-8. 4. Bellmunt J, Ribas A, Eres N, et al. Carboplatin-based versus cisplatin-based chemotherapy in the treatment of surgically incurable advanced bladder carcinoma. Cancer 1997; 80:1966-72. 5. Bellmunt J, de Wit R, Albanell J, Baselga J. A feasibility study of carboplatin with fixed dose of gemcitabine in “unfit” patients with advanced bladder cancer. Eur J Cancer 2001; 37:2212-5. 6. Linardou H, Aravantinos G, Efstathiou E, et al. Gemcitabine and carboplatin combination as first-line treatment in elderly patients and those unfit for cisplatinbased chemotherapy with advanced bladder carcinoma: phase II study of the Hellenic Co-operative Oncology Group. Urology 2004; 64:479-84. 7. Park JH, Lee SW, Kim HS, et al. Combination of gemcitabine and carboplatin as first line treatment in elderly patients or those unfit for cisplatin-based chemotherapy with advanced transitional cell carcinoma of the urinary tract. Cancer Chemother Pharmacol 2013; 71:1033-9. 8. Nogué-Aliguer M, Carles J, Arrivi A, et al. Gemcitabine and carboplatin in advanced transitional cell carcinoma of the urinary tract: an alternative therapy. Cancer 2003; 97:2180-6. 9. Bamias A, Moulopoulos LA, Koutras A, et al. The combination of gemcitabine and carboplatin as first-line treatment in patients with advanced urothelial carcinoma. A phase II study of the Hellenic Cooperative Oncology Group. Cancer 2006; 106: 297-303. 10. De Santis M, Bellmunt J, Mead G, et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol 2012; 30:191-9. 11. Hussain M, Vaishampayan U, Du W, Redman B, Smith DC. Combination paclitaxel, carboplatin, and gemcitabine is an active treatment for advanced urothelial cancer. J Clin Oncol 2001; 19:2527-33. 12. Crew JP, O’Brien T, Bicknell R, Fuggle S, Cranston D, Harris AL. Urinary vascular endothelial growth factor and its correlation with bladder cancer recurrence rates. J Urol 1999; 161:799-804. 13. Bochner BH, Cote RJ, Weidner N, et al. Angiogenesis in bladder cancer: relationship between microvessel density and tumor prognosis. J Natl Cancer Inst 1995; 87:1603-12. 14. Inoue K, Slaton JW, Davis DW, et al. Treatment of human metastatic transitional cell carcinoma of the bladder in a murine model with the antievascular endothelial growth factor receptor monoclonal antibody DC101 and paclitaxel. Clin Cancer Res 2000; 6:2635-43. 15. Inoue K, Chikazawa M, Fukata S, Yoshikawa C, Shuin T. Frequent administration of angiogenesis inhibitor TNP-470 (AGM-1470) at an optimal biological dose inhibits tumor growth and metastasis of metastatic human transitional cell carcinoma in the urinary bladder. Clin Cancer Res 2002; 8:2389-98.
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Phase 2 Trial of Gemcitabine, Carboplatin, and Sorafenib 16. Inoue K, Chikazawa M, Fukata S, Yoshikawa C, Shuin T. Docetaxel enhances the therapeutic effect of the angiogenesis inhibitor TNP-470 (AGM-1470) in metastatic human transitional cell carcinoma. Clin Cancer Res 2003; 9:886-99. 17. Dickinson AJ, Fox SB, Persad RA, Hollyer J, Sibley GN, Harris AL. Quantification of angiogenesis as an independent predictor of prognosis in invasive bladder carcinomas. Br J Urol 1994; 74:762-6. 18. Jaeger TM, Weidner N, Chew K, et al. Tumor angiogenesis correlates with lymph node metastases in invasive bladder cancer. J Urol 1995; 154:69-71. 19. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 2014; 507:315-22. 20. Wilhelm S, Carter C, Lynch M, et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 2006; 5:835-44. 21. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006; 24:3187-205. 22. Bayer Healthcare Pharmaceuticals Inc. Nexavar package insert, October 2010. 23. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-47. 24. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989; 10:1-10. 25. Petrioli R, Frediani B, Manganelli A, et al. Comparison between a cisplatincontaining regimen and a carboplatin-containing regimen for recurrent or metastatic bladder cancer patients. A randomized phase II study. Cancer 1996; 77:34451. 26. Necchi A, Mariani L, Zaffaroni N, et al. Pazopanib in advanced and platinumresistant urothelial cancer: an open-label, single group, phase 2 trial. Lancet Oncol 2012; 13:810-6. 27. Dreicer R, Li H, Stein M, et al. Phase 2 trial of sorafenib in patients with advanced urothelial cancer: a trial of the Eastern Cooperative Oncology Group. Cancer 2009; 115:4090-5.
8
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Clinical Genitourinary Cancer Month 2018
28. Sridhar SS, Winquist E, Eisen A, et al. A phase II trial of sorafenib in first-line metastatic urothelial cancer: a study of the PMH Phase II Consortium. Invest New Drugs 2011; 29:1045-9. 29. Twardowski P, Stadler WM, Frankel P, et al. Phase II study of aflibercept (VEGFTrap) in patients with recurrent or metastatic urothelial cancer, a California Cancer Consortium trial. Urology 2010; 76:923-6. 30. Hahn NM, Stadler WM, Zon RT, et al. Phase II trial of cisplatin, gemcitabine, and bevacizumab as first-line therapy for metastatic urothelial carcinoma: Hoosier Oncology Group GU 04-75. J Clin Oncol 2011; 29:1525-30. 31. Balar AV, Apolo AB, Ostrovnaya I, et al. Phase II study of gemcitabine, carboplatin, and bevacizumab in patients with advanced unresectable or metastatic urothelial cancer. J Clin Oncol 2013; 31:724-30. 32. Geldart T, Chester J, Casbard A, et al. SUCCINCT: an open-label, single-arm, non-randomised, phase 2 trial of gemcitabine and cisplatin chemotherapy in combination with sunitinib as first-line treatment for patients with advanced urothelial carcinoma. Eur Urol 2015; 67:599-602. 33. Grivas PD, Daignault S, Tagawa ST, et al. Double-blind, randomized, phase 2 trial of maintenance sunitinib versus placebo after response to chemotherapy in patients with advanced urothelial carcinoma. Cancer 2014; 120:692-701. 34. Krege S, Rexer H, Dorp vom F, et al. Prospective randomized double-blind multicentre phase II study comparing gemcitabine and cisplatin plus sorafenib chemotherapy with gemcitabine and cisplatin plus placebo in locally advanced and/ or metastasized urothelial cancer: SUSE (AUO-AB 31/05). BJU Int 2014; 113: 429-36. 35. Narayanan S, Lam A, Vaishampayan U, et al. Phase II study of pazopanib and paclitaxel in patients with refractory urothelial cancer. Clin Genitourin Cancer 2016; 14:432-7. 36. Petrylak DP, Tagawa ST, Kohli M, et al. Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: an open-label, three-arm, randomized controlled phase II trial. J Clin Oncol 2016; 34:1500-9.
Supplemental Table 1 Complete List of AEs AE Grade AE
1
2
3
4
5
Allergy/Immunology Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip)
Total No.
Grade 3/4 AE
5
0 0
5
0
0
0
0
5 3
0
Otitis, middle ear (noninfectious)
0
1
0
0
0
1
0
Tinnitus
0
2
0
0
0
Auditory/Ear
Blood/Bone Marrow 0
0
0
0
2
0
45
23
1
0
Bone marrow cellularity
1
CD4 count
0
1
0
1
0
2
1
Anemia
3
5
5
0
0
13
5
Leukocytes (total WBC)
0
3
0
1
0
4
1
Lymphopenia
0
1
1
0
0
2
1
Neutrophils/granulocytes (ANC/AGC)
1
2
6
1
0
10
7
Platelets
5
0
2
6
0
13
8
10
2
Cardiac General Cardiac general—Other (specify)
2
0
0
0
0
2
0
Hypertension
2
3
2
0
0
7
2
Hypotension
1
0
0
0
0
1
0
Coagulation International normalized ratio of prothrombin time
1
0
0
0
0
Constitutional Symptoms
1
0
1
0
36
7 0
1
0
0
0
0
1
Fatigue (asthenia, lethargy, malaise)
5
6
5
0
0
16
5
Fever (in absence of neutropenia)
4
0
1
0
0
5
1
Insomnia
1
0
0
0
0
1
0
Rigors/chills
2
1
0
0
0
3
0
Sweating (diaphoresis)
3
0
0
0
0
3
0
Weight gain
1
0
0
0
0
1
0
Weight loss
3
2
1
0
0
6
1
Dermatology/Skin
46
2
Dermatology/skin—Other (blisters—palms)
1
0
0
0
0
1
0
Dermatology/skin—Other (left arm swelling)
1
0
0
0
0
1
0
Dermatology/skin—Other (lesion/nodule on left arm)
1
0
0
0
0
1
0
Michael E. Hurwitz et al
Clinical Genitourinary Cancer Month 2018
Constitutional symptoms—Other (specify)
- 8.e1
8.e2 Clinical Genitourinary Cancer Month 2018
AE Grade AE
1
2
3
4
5
Total No.
Dermatology/skin—Other (specify)
1
0
0
0
0
1
Grade 3/4 AE 0
Dermatology/skin—Other (specify; bumps left arm)
1
0
0
0
0
1
0
Dry skin
0
2
0
0
0
2
0
Hair loss/alopecia (scalp or body)
8
1
0
0
0
9
0 0
Nail changes
2
0
0
0
0
2
10
0
0
0
0
10
0
Rash
5
3
2
0
0
10
2
Rash/desquamation
6
1
0
0
0
7
0
Ulceration
0
1
0
0
0
1
0
3
0
Pruritus/itching
Endocrine Endocrine—Other (specify)
2
0
0
0
0
2
0
Hot flashes/flushes
1
0
0
0
0
1
0
95
0
Gastrointestinal Anorexia
4
8
0
0
0
12
0
Constipation
11
0
1
0
0
12
1
Dehydration
1
2
0
0
0
3
0 3
Diarrhea
10
1
3
0
0
14
Diarrhea (result of CT scan)
0
0
1
0
0
1
1
Distension/bloating, abdominal
1
1
0
0
0
2
0
Dry mouth/salivary gland (xerostomia)
8
1
0
0
0
9
0
Dysphagia (difficulty swallowing)
0
0
1
0
0
1
1
Enteritis (inflammation of small bowel)
0
1
0
0
0
1
0
Gastrointestinal—Other (specify)
1
0
0
0
0
1
0
Heartburn/dyspepsia
7
0
0
0
0
7
0
Hemorrhoids
1
0
0
0
0
1
0
Mucositis/stomatitis (clinical exam)—Oral cavity
2
0
0
0
0
2
0
Mucositis/stomatitis (functional/symptomatic)—Oral cavity
3
0
0
0
0
3
0 0
Nausea
10
2
0
0
0
12
Taste alteration (dysgeusia
5
2
0
0
0
7
0
Vomiting
3
4
0
0
0
7
0
Phase 2 Trial of Gemcitabine, Carboplatin, and Sorafenib
Supplemental Table 1 Continued
Supplemental Table 1 Continued AE Grade AE
1
2
3
4
5
Hemorrhage/Bleeding
Total No.
Grade 3/4 AE
8
1
Hemorrhage, GU—Bladder
1
0
0
0
0
1
0
Hemorrhage, pulmonary/upper respiratory—Nose
4
1
0
0
0
5
0
Hemorrhage/Bleeding—Other (blood in stool)
0
0
1
0
0
1
1
Hemorrhage/Bleeding—Other (specify)
1
0
0
0
0
Infection
1
0
12
4 1
Infection—Other (blood culture)
0
0
1
0
0
1
Infection—Other (burning sensation)
1
0
0
0
0
1
0
Infection—Other (right molar)
0
1
0
0
0
1
0
Infection—Other (specify)
1
0
0
0
0
1
0
Infection—Other (unknown)
0
0
1
0
0
1
1
Infection with normal ANC or grade 1 or 2 neutrophils—Bronchus
0
0
1
0
0
1
1
Infection with normal ANC or grade 1 or 2 neutrophils—Eye NOS
0
1
0
0
0
1
0
Infection with normal ANC or grade 1 or 2 neutrophils—Skin (cellulitis)
0
1
0
0
0
1
0
Infection with normal ANC or grade 1 or 2 neutrophils—Urinary tract NOS
0
2
0
0
0
2
0
Infection with unknown ANC—Rectum
0
0
1
0
0
1
1
Infection with unknown ANC—Urinary tract NOS
0
1
0
0
0
1
0
Lymphatics Edema
2
0
2
0
0
0
0
0
47
12
Albumin, serumelow (hypoalbuminemia)
1
1
0
0
0
2
0
Alkaline phosphatase
2
1
0
0
0
3
0
ALT
4
0
1
0
0
5
1
AST
4
0
0
0
0
4
0
Bicarbonate, serumelow
1
0
0
0
0
1
0
Calcium, serumehigh (hypercalcemia)
1
0
0
0
0
1
0
Calcium, serumelow (hypocalcemia)
3
0
0
0
0
3
0
Creatinine
5
0
0
0
0
5
0
Metabolic/Laboratory
Glucose, serumehigh (hyperglycemia)
1
2
2
0
0
5
2
Glucose, serumelow (hypoglycemia)
1
0
0
0
0
1
0
Michael E. Hurwitz et al
Clinical Genitourinary Cancer Month 2018
2
- 8.e3
8.e4 Clinical Genitourinary Cancer Month 2018
AE Grade AE
1
2
3
4
5
Total No.
Grade 3/4 AE
Magnesium, serum-high (hypermagnesemia)
0
0
1
0
0
1
1
Magnesium, serum-low (hypomagnesemia)
0
1
0
0
0
1
0
Metabolic/laboratory—Other (specify)
1
0
0
0
0
1
0
Phosphate, serumelow (hypophosphatemia)
0
4
5
0
0
9
5
Potassium, serumehigh (hyperkalemia)
0
0
2
0
0
2
2
Potassium, serumelow (hypokalemia) 1
1
0
0
0
0
1
0
Sodium, serumelow (hyponatremia)
1
0
1
0
0
2
1
9
1
Arthritis (nonseptic)
2
0
0
0
0
2
0
Extremityeupper (function)
1
0
0
0
0
1
0
Muscle weakness (not due to neuropathy)—Extremityelower
2
0
0
0
0
2
0
Muscle weakness (not due to neuropathy)—Right-sided
1
0
0
0
0
1
0
Muscle weakness (not due to neuropathy)—Whole body/generalized
2
0
1
0
0
3
1
28
1
Confusion
0
1
0
0
0
1
0
Dizziness
5
2
0
0
0
7
0
Mood alteration—Anxiety
2
2
0
0
0
4
0
Mood alteration—Depression
3
1
0
0
0
4
0
Musculoskeletal/Soft Tissue
Neurology
Neurology—Other (specify)
1
0
0
0
0
1
0
Neurology—Other (specify, neuropathy, heals)
1
0
0
0
0
1
0
Neuropathy
9
0
0
0
0
9
0
Syncope (fainting)
0
0
1
0
0
1
1
4
0
Ocular/Visual Ocular/Visual—Other (specify)
0
1
0
0
0
1
0
Ophthalmoplegia/diplopia (double vision)
0
1
0
0
0
1
0
Visioneblurred
1
0
0
0
0
1
0
Visioneflashing lights/floaters
1
0
0
0
0
1
0
75
17
Pain—Abdomen NOS
2
3
2
0
0
7
2
Pain—Back
3
3
3
0
0
9
3
Pain
Pain—Bladder
1
0
0
0
0
1
0
Pain—Buttock
1
0
0
0
0
1
0
Phase 2 Trial of Gemcitabine, Carboplatin, and Sorafenib
Supplemental Table 1 Continued
Supplemental Table 1 Continued AE Grade AE
1
2
3
4
5
Total No.
Pain—Cardiac/heart
1
0
0
0
0
1
Grade 3/4 AE 0
Pain—Chest wall
1
0
0
0
0
1
0
Pain—Chest/thorax NOS
3
0
0
0
0
3
0
Pain—Extremityelimb
1
3
4
0
0
8
4
Pain—Head/headache
4
2
2
0
0
8
2
Pain—Joint
0
2
0
0
0
2
0
Pain—Neck
1
3
1
0
0
5
1
Pain—Neuralgia/peripheral nerve
1
0
0
0
0
1
0
Pain—Oral cavity
0
1
0
0
0
1
0
Pain—Oralegums
1
0
0
0
0
1
0
Pain—Other (flank)
0
1
0
0
0
1
0
Pain—Other (head, neck, and face)
1
0
0
0
0
1
0
Pain—Other (left flank)
1
0
1
0
0
2
1
Pain—Other (left rib)
1
0
0
0
0
1
0
1
0
0
0
0
1
0
Pain—Other (nose)
0
1
0
0
0
1
0
Pain—Other (right groin)
0
0
1
0
0
1
1
Pain—Other (right thigh)
0
0
1
0
0
1
1
Pain—Other (specify)
2
4
1
0
0
7
1
Pain—Other (specify; aches and pains)
1
0
0
0
0
1
0
Pain—Other (specify; hip and thigh)
0
1
0
0
0
1
0
Pain—Other (top of head)
1
0
0
0
0
1
0
Pain—Rectum
1
0
0
0
0
1
0
Pain—Scalp
1
1
0
0
0
2
0
Pain—Sinus
2
0
0
0
0
2
0
Pain—Stomach
0
0
1
0
0
1
1
Pain—Throat/pharynx/larynx
1
0
0
0
0
Pulmonary/Upper Respiratory
1
0
25
0
Cough
9
1
0
0
0
10
0
Dyspnea (shortness of breath)
8
1
0
0
0
9
0
Hiccoughs (hiccups, singultus)
1
0
0
0
0
1
0
Pulmonary/upper respiratory—Other (specify)
1
0
0
0
0
1
0
Voice changes/dysarthria (eg, hoarseness, loss of or alteration in voice, laryngitis)
4
0
0
0
0
4
0
Michael E. Hurwitz et al
Clinical Genitourinary Cancer Month 2018
Pain—Other (nose and ears)
- 8.e5
8.e6 Clinical Genitourinary Cancer Month 2018
AE Grade AE
1
2
3
4
5
Renal/GU
Total No.
Grade 3/4 AE
15
3
Obstruction, GU—Ureter
0
0
1
0
0
1
1
Renal/GU—Other (hematuria)
3
0
0
0
0
3
0
Renal/GU—Other (specify)
2
0
1
0
0
3
1
Renal/GU—Other (specify, neobladder)
1
0
0
0
0
1
0
Urinary frequency/urgency
3
0
1
0
0
4
1
Urine color change
3
0
0
0
0
3
0
Sexual/Reproductive Function
4
0
Erectile dysfunction
1
0
0
0
0
1
0
Libido
2
1
0
0
0
3
0
4
2
1
0
Vascular Phlebitis (including superficial thrombosis)
0
1
0
0
0
Thrombosis/thrombus/embolism
0
0
2
0
0
2
2
Vascular—Other (left knee swelling)
1
0
0
0
0
1
0
Abbreviations: AE ¼ adverse event; AGC ¼ absolute granulocyte count; ALT ¼ alanine aminotransferase; ANC ¼ absolute neutrophil count; AST ¼ aspartate aminotransferase; GU ¼ genitourinary; NOS ¼ not otherwise specified; WBC ¼ white blood cell count.
Phase 2 Trial of Gemcitabine, Carboplatin, and Sorafenib
Supplemental Table 1 Continued
Multicenter Phase 2 Trial of Gemcitabine, Carboplatin, and Sorafenib in Patients With Metastatic or Unresectable Transitional-Cell Carcinoma Michael E. Hurwitz,1 Paul Markowski,2 Xiaopan Yao,1 Hari Deshpande,1 Jaymin Patel,1 Amir Mortazavi,3 Alessia Donadio,4 Mark N. Stein,2 William Kevin Kelly,5 Daniel Peter Petrylak,1 Janice M. Mehnert2 Abstract We studied whether the addition of sorafenib, an oral tyrosine kinase inhibitor, enhanced the antitumor activity of gemcitabine and carboplatin in 17 subjects with advanced transitional-cell carcinoma (TCC). Therapy with gemcitabine and carboplatin with sorafenib was associated with significant toxicity but had impressive responses, including durable ones. Although we do not recommend further testing of this dosage and combination of medications in metastatic TCC because of its toxicity, testing the combination of tyrosine kinase inhibitors and chemotherapy should be pursued in future studies. Background: Sorafenib, an oral tyrosine kinase inhibitor, may enhance the antitumor activity of platinum-based chemotherapy in transitional-cell carcinoma. This study investigated the safety and clinical outcome of adding sorafenib to gemcitabine and carboplatin for patients with advanced transitional-cell carcinoma. Patients and Methods: Subjects with metastatic or unresectable chemotherapy-naive TCC with Eastern Cooperative Oncology Group performance status 0 or 1 received gemcitabine (1000 mg/m2 on days 1 and 8) and carboplatin (area under the curve of 5 on day 1) with sorafenib (400 mg 2 times a day on days 22-19 every 21 days) for 6 cycles. Subjects with stable disease or partial or complete response continued to receive sorafenib until disease progression. The primary end point was progression-free survival (PFS) at 5 months with a secondary end point of response (partial or complete). Results: Seventeen subjects were enrolled. The median number of cycles of gemcitabine and carboplatin with sorafenib provided was 4.4. A total of 15, 5, and 8 subjects required reductions of gemcitabine, carboplatin, and sorafenib, respectively. Thirteen subjects (76%) required multiple dose reductions. Eleven subjects (65%) were free of progression at 5 months. The overall response rate was 54% (95% confidence interval [CI], 0.28-077), with 4 patients experiencing complete response (24%; 95% CI, 0.07-0.50) and 5 partial response (29%; 95% CI, 0.10-0.56); 7 subjects (41%) had stable disease. Median PFS was 9.5 months (95% CI, 0.43-1.26), and median overall survival was 25.2 months (95% CI, 0.96-5.65). One-year PFS was 31%, and 1-year overall survival was 72%. Eleven subjects (65%) discontinued treatment because of toxicity. There were no toxic deaths. Conclusion: Gemcitabine and carboplatin with sorafenib showed clinical activity in advanced TCC, with some prolonged progression-free intervals. However, gemcitabine and carboplatin with sorafenib was associated with significant toxicity, causing discontinuation of therapy in most patients. Clinical Genitourinary Cancer, Vol. -, No. -, 1-8 ª 2018 Elsevier Inc. All rights reserved. Keywords: Chemotherapy, First line, TCC, Tyrosine kinase inhibitor, Urothelial carcinoma
1
Yale Cancer Center, New Haven, CT Department of Medicine, Rutgers Cancer Institute of New Jersey, NJ Ohio State University Cancer Center, OH 4 St Francis Hospital and Medical Center, Hartford, CT 5 Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 2 3
Address for correspondence: Janice M. Mehnert, MD, Department of Medicine, Rutgers Cancer Institute of New Jersey, 195 Little Albany St, New Brunswick, NJ 08901 E-mail contact: [email protected]
Submitted: Jun 21, 2017; Accepted: Jul 19, 2018
1558-7673/$ - see frontmatter ª 2018 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.clgc.2018.07.021
Clinical Genitourinary Cancer Month 2018
-1
Phase 2 Trial of Gemcitabine, Carboplatin, and Sorafenib Introduction Metastatic transitional-cell carcinoma (TCC) is an aggressive malignancy with a very low cure rate (http://seer.cancer.gov/ statfacts/html/urinb.html). While most metastatic or locally advanced TCCs will initially respond to cisplatinum-based combination chemotherapy, these responses are usually short lived, and the disease almost always recurs.1-3 Impaired renal function, peripheral neuropathy, hearing loss, poor performance status, and inability to receive adequate hydration render approximately 30% of patients ineligible to receive cisplatin-based regimens. In these sicker patients, substitution with carboplatin-based regimens has shown encouraging efficacy and improved tolerability.4-9 Therefore, carboplatin-based regimens are an attractive backbone for clinical studies of additional agents with the aim of improving efficacy while maintaining acceptable tolerability. Specifically, the combination of gemcitabine and carboplatin has been established as effective and comparatively nontoxic.10 Unfortunately, the median survival is only approximately 10 months with gemcitabine/carboplatin— considerably lower than for cisplatin-based regimens. Addition of paclitaxel to the gemcitabine/carboplatin backbone resulted in a 68% response rate with an overall survival (OS) of 14.7 months, suggesting that improvements can be made to the gemcitabine/ carboplatin combination using the appropriate drug.11 Agents chosen for combination therapy should be based on our understanding of molecular derangements in TCC. Multiple lines of evidence suggest targeting angiogenesis may prove useful in the treatment of bladder cancer. Several studies have correlated elevated vascular endothelial growth factor (VEGF) levels with disease recurrence or progression, and increased expression of VEGF in the tissue, serum, and urine of patients with TCC has been correlated with stage and prognosis.12,13 Inhibitors of angiogenesis show activity in preclinical models of TCC.14-16 Microvessel density, a marker of angiogenesis within tumors, has also been correlated with stage, recurrence, and survival in TCC.17,18 The RTK/Ras/MAPK pathway appears to be activated in approximately 45% of muscle-invasive bladder cancers and is thought to be a major driver of TCC.19 Sorafenib is a multikinase inhibitor with high affinity for the VEGF receptors and various Raf isoforms (drug concentration causing 50% inhibition, 6-100 nM).20 On the basis of the above findings, we conducted a multicenter phase 2 study to assess response in patients with advanced or metastatic TCC treated with the combination of gemcitabine, carboplatin, and sorafenib.
Patients and Methods This multicenter study was approved by Yale’s institutional review board and was performed in accordance with the 2008 Declaration of Helsinki. Each site was individually required to have approval by their local human investigation committee and Yale’s institutional review board. All patients were required to provide written informed consent before study registration. The primary objective was to assess progression-free survival (PFS). The secondary objectives were to determine overall safety and tolerability and to define the proportion of patients who experienced complete or partial response. To be included in the study, patients had to be of any race and either gender, and > 18 years of age with histologically confirmed
2
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Clinical Genitourinary Cancer Month 2018
TCC of urothelial origin that was metastatic, locally advanced, or unresectable. An Eastern Cooperative Oncology Group performance status score of 0 or 1 was required at entry. Prior radiation was permitted if 4 weeks had elapsed before trial enrollment. Prior intravesical, neoadjuvant, and adjuvant therapies were permitted if they had been completed > 12 months from trial enrollment. The following were required at trial entry: adequate bone marrow function defined by hemoglobin 9 g/dL, absolute neutrophil count (ANC) 1500/mm3, and platelets 100 109/L; renal function by glomerular filtration rate 40 mL/min/1.73 m2 (Cockcroft-Gault); hepatic function by total bilirubin 1.5 times the upper limit of normal (ULN), alanine aminotransferase/aspartate aminotransferase 2.5 ULN, and international normalized ratio 1.5 or a prothrombin time/partial thromboplastin time within normal limits. Subjects were excluded on the basis of the following criteria: presence of brain metastases; infection with human immunodeficiency virus, chronic hepatitis B or C, or any active clinically serious infection of higher than grade 2 by Common Terminology Criteria for Adverse Events v3.0; severe cardiovascular disease; and bleeding diathesis or coagulopathy.
Treatment Schedule All patients received gemcitabine 1000 mg/m2 on days 1 and 8, carboplatin area under the curve of 5 on day 1, and sorafenib 400 mg orally twice daily on days 2 through 19 of each 21-day cycle. Standard supportive care included antiemetics, antipyretics, pain control, and prophylactic hematopoietic growth factors per American Society of Clinical Oncology guidelines.21 Patients were treated for a maximum of 6 cycles, if tolerated. Subjects with stable disease or with complete or partial response were maintained on oral sorafenib on the same schedule until there was evidence of disease progression or unacceptable toxicity.
Toxicity and Dose Modifications Sorafenib toxicity (except for skin and blood pressure) was measured by Common Terminology Criteria for Adverse Events v3.0. Dose modifications were specified on the basis of toxicity and were mandated for all grade 3/4 toxicities. Sorafenib was held for a first grade 3 toxicity until grade 2 or less for hematologic toxicity and until grade 1 or less for nonskin nonhematologic toxicity. Then treatment was resumed at the same dose level. For a second grade 3 event, sorafenib was held until grade 2 or less for hematologic toxicity and until grade 1 or less for nonskin nonhematologic toxicity, and resumed at a dose reduced by 200 mg per day (1 dose level reduction). For a third event, sorafenib was held until grade 2 or less and resumed at a dose reduced by 400 mg per day (2 dose level reductions). After a third event, sorafenib was discontinued. For a first grade 4 toxicity, sorafenib was held until grade 2 or less and resumed at a dose reduced by 200 mg per day (1 dose level reduction) or was discontinued at the discretion of the principal investigator after discussion with the study sponsor. For skin toxicity (specifically handefoot syndrome), management was per manufacturer recommendations.22 For hypertension, no action was taken at grade 1. Asymptomatic grade 2 toxicity was managed with antihypertensive monotherapy.
Michael E. Hurwitz et al For symptomatic grade 2 or 3 toxicity, multiple antihypertensives were used. Sorafenib was held until resolution of symptoms and blood pressure was controlled. Subjects were removed from the trial for grade 4 hypertension. Dose modifications for other specific nonhematologic toxicities of sorafenib are provided in Supplemental Table 1 in the online version. Patients who developed grade 3 fever/chills, grade 3 elevation of hepatic transaminases with alanine aminotransferase and aspartate aminotransferase < 10 ULN, grade 3 hyperlipasemia or hyperamylasemia without clinical or other evidence of pancreatitis, grade 3 leukopenia, or grade 3/4 lymphopenia could continue study treatment without interruption at the discretion of the investigator. For hematologic toxicity while receiving gemcitabine/carboplatin, the drugs were held on day 1 for ANC < 1500/mm3 and platelets < 100 109/L. If delayed, gemcitabine was decreased by 200 mg/m2. For a second delay, carboplatin was decreased to an area under the curve of 4. Patients were removed from the study or moved to a maintenance phase for > 2 dose reductions. On day 8, for ANC 1000 to 1499/mm3 or platelets 75 109 to 100 109, gemcitabine was reduced by 200 mg/m2. For ANC < 1000/mm3 or platelets < 75 109, treatment was held and not made up. If day 8 was held, the next cycle doses were decreased by 1 dose level. For gemcitabine/carboplatin nonhematologic toxicity, with the exception of alopecia or nausea/vomiting not optimally managed with antiemetics, dose reductions were as follows: for grade 3/4 toxicities, the dose was held until toxicity resolved to grade 2 or less and resumed at 1 dose level lower. Once the dose of gemcitabine or carboplatin was reduced, there was no dose escalation. Subjects were removed from the study if treatment was held for 21 days.
Table 1 Patient Characteristics Characteristic
Value
Age (Years) Mean
65
Range
47-86
Sex Male Female
14 (83) 3 (17)
Race White
15 (88)
African American
1 (6)
Hispanic
1 (6)
Performance Status 0
7 (41)
1
10 (59)
Baseline Creatinine Clearancea <50 mL/min/1.73 m2
6 (35)
51-60 mL/min/1.73 m2
4 (24)
> 60 mL/min/1.73 m2
7 (41)
Data are presented as n (%) unless otherwise indicated. a Creatinine clearance using Cockcroft-Gault formula adjusted for ideal body weight.
used to calculate PFS and OS. All analyses were performed by SAS 9.3 (SAS Institute, Cary, NC) and R 3.1.2 (R Foundation for Statistical Computing, Vienna, Austria; http://www.r-project.org/).
Results Patient Characteristics
Efficacy Evaluation Patients had a history, physical, toxicity assessment, complete blood count, and comprehensive metabolic panel performed monthly while receiving treatment. Response was measured by Response Evaluation Criteria in Solid Tumors v1.123 after 3 and 6 cycles of treatment, then every 3 months by computed tomography or magnetic resonance imaging for the first 18 months, followed by every 6 months for the next 18 months.
Statistical Analysis This trial followed a minimax Simon 2-stage design.24 The primary outcome was the proportion of patients who experienced PFS of 5 months. PFS was defined as time to progression or any-cause mortality, whichever came first. We assumed the standard platinum-based therapy response rate for TCC was 50%. The primary study aim was to determine if the treatment resulted in PFS of 70% at 5 months. Target enrollment was 17 patients for the first phase. If > 8 subjects were free of progression at 5 months, another 13 subjects, for a total of 30, were to be enrolled. If 19 or more (out of 30) experienced 5-month PFS, then the probability of 5-month PFS is 70%. This design provides 84% statistical power to detect a difference of 20% (70% vs. 50%), with a significance level of < .1 (type I error). Descriptive statistics were used for patient characteristics, with median and range for continuous variables and frequency and percentage for categorical variables. Kaplan-Meier estimates were
Between December 2007 and February 2010, 17 patients (14 men and 3 women) with creatinine clearance 40 mL/min/1.73 m2 were enrolled onto the study. All 17 patients were included in the final analysis for response and survival. One subject withdrew consent, but all others were treated. The baseline characteristics are summarized in Table 1. A total of 88% had metastatic disease, 6% had locally unresectable disease, and 6% were not evaluable. The study was planned as a minimax Simon 2-stage design. If 9 of 17 subjects enrolled had a PFS of 5 months, then 13 more patients were going to be enrolled, for a total of 30 patients. Although the study reached its aim of 9 subjects who experienced
Table 2 Efficacy Characteristic
N (%)
Progression-Free Survival Progression free at 5 months
11 (65)
Progression within 5 months
5 (29)
Lost to follow-up
1 (6)
Best Reported Response Stable disease
7 (41)
Partial response
5 (29)
Complete response
4 (24)
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Phase 2 Trial of Gemcitabine, Carboplatin, and Sorafenib Table 3 Site of Disease at Enrollment and Response by Site Responsea
Disease
N (%)
Metastatic disease
15 (88)
Unresectable local disease
1 (6)
Lymph node only
3 (18)
All with lymph node disease
7 (41)
4 (57%)
Bone
3 (18)
1 (33%)
Liver
2 (12)
1 (50%)
Study Treatment and Toxicity
Site
a
OS was 25.2 months (95% CI, 12.5-73.5). The 1-year PFS was 31%, and the 1-year OS was 72% (Figure 2).
Lung
3 (18)
1 (33%)
Visceral nonliver
5 (29)
3 (60%)
Percentage of lesions at these sites that responded to treatment.
a 5-month PFS, the study sponsor did not choose to continue the trial because of toxicity, so no more subjects were enrolled.
Response and Survival All 17 subjects were evaluated for response (Table 2). One patient moved away and was lost to follow-up. The overall response rate was 54% (95% confidence interval [CI], 0.28-077) with 4 complete responses (24%; CI, 0.07-0.50) and 5 partial responses (29%; 95% CI, 0.10-0.56). A total of 41% of subjects experienced stabilization of disease for at least 3 months (the earliest time that progression was assessed). No evaluable patients had disease progression at the first restaging. Sites of response included bladder, bones, lymph nodes, lungs, liver, and soft tissue (Table 3). In one subject a lung lesion became cavitary, possibly suggestive of an effect of sorafenib on tumor vasculature (Figure 1). Eleven subjects (65%) had PFS 5 months. At a median followup of 5.8 years, PFS was 9.5 months (95% CI, 5.6-16.4) and the
Seventeen patients had data evaluable for toxicity. A total of 77 cycles of gemcitabine/carboplatin were administered with a median of 4.5 cycles per patient. Fifteen, 5, and 9 subjects required dose reductions of gemcitabine, carboplatin, and sorafenib, respectively, with 13 subjects (76%) requiring multiple dose reductions; 7 (41%) were removed from the trial within 5 months because of > 3 dose reductions. Seven subjects (41%) experienced grade 3/4 neutropenia, 5 (29%) grade 3/4 anemia, and 8 (47%) grade 3/4 thrombocytopenia during gemcitabine and carboplatin with sorafenib; 1 neutropenic fever was noted. There were 4 grade 3/4 bleeding events. The most common grade 3/4 nonhematologic toxicities were fatigue (29%), hypophosphatemia (29%), infection (24%), and diarrhea (6%). There were no toxic deaths (Table 4 and Supplemental Table 1 in the online version). Sorafenib maintenance was provided for a median of six 28-day cycles (range, 2-47 cycles). Eleven subjects (65%) discontinued treatment (of all trial therapies) because of toxicity, and 5 discontinued treatment because of disease progression. Hematologic toxicity caused discontinuation of treatment in 6 patients. Other causes of treatment discontinuation are listed in Table 5.
Discussion This trial treated subjects with a combination of gemcitabine, carboplatin, and sorafenib. For a number of reasons, we do not recommend further testing of this dosage and combination of medications in metastatic TCC. First, all but one of the subjects on the trial required dose reductions, and most subjects discontinued treatment because of toxicity, regardless of whether patients were cisplatin eligible or ineligible, demonstrating that this combination of drugs at these doses is not tolerable for a large number of patients with this disease. Second, cisplatin is considered to be a better drug
Figure 1 Necrotic Response to Therapy. Chest Computed Tomographic Scan (A) before and (B) after 1 Cycle of Therapy. Subject Continued on Study Protocol for 8 Cycles Total, With Partial Response, and Came off Study by His Choice because of Inability to Tolerate Sorafenib. He Remained Free of Progression for > 1 Year
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Clinical Genitourinary Cancer Month 2018
Michael E. Hurwitz et al Figure 2 Kaplan-Meier Plots of PFS and OS. Dashed Lines Indicate 95% Confidence Intervals
Abbreviations: OS ¼ overall survival; PFS ¼ progression-free survival.
in this disease than carboplatin. In trials with cisplatin and carboplatin arms, the cisplatin arms outperform the carboplatin arms.4,25 Third, sorafenib has multiple targets, not all of which would be predicted to have activity in bladder cancer but could potentially add to toxicity. Other drugs are both less promiscuous and more potent for VEGF pathway blockade. Since this study was begun, a number of other studies using inhibitors of the VEGF pathway have been tested in TCC. As single agents, the most successful was pazopanib in the second-line setting, with a response rate of 17.1%, though the PFS was only 3.1 months.26 Other single-agent trials have been far less impressive, with 2 trials of sorafenib resulting in no responses and a trial of the VEGF trap aflibercept with a 4.5% response rate.27-29 Studies have also combined small-molecule inhibitors of VEGF with platinum-based chemotherapies. The Hoosier Oncology Group GU 04-75 trial of gemcitabine, cisplatin, and bevacizumab
enrolled 43 patients and demonstrated a response rate of 72%, median PFS of 8.2 months, OS of 19.2 months, and antiangiogenic treatmenterelated toxicities (deep-vein thrombosis/pulmonary Table 4 Reasons Subjects Went Off Study Toxicity
N
%
Total Thrombocytopenia Neutropenia Unspecified hematologic Fatigue/Failure to Thrive Cardiac Epistaxis Progression of disease Lost to follow-up
11 3 2 1 2 2 1 5 1
65
29 6
Clinical Genitourinary Cancer Month 2018
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Phase 2 Trial of Gemcitabine, Carboplatin, and Sorafenib Table 5 All Toxicities With at Least Single Grade 3/4 AE Grade 3/4 AE AE
All AE Grades
N
%
N
%
Anemia
5
29.4
13
76.5
Decreased leukocytes (total WBC)
1
5.9
4
23.5
Hematologic
Lymphopenia
1
5.9
2
11.8
Neutropenia/granulocytopenia
7
41.2
10
58.8
Thrombocytopenia
8
47.1
13
76.5
Decreased CD4 count
1
5.9
2
11.8 29.4
Nonhematologic ALT
1
5.9
5
Blood in stool
1
5.9
1
5.9
Constipation
1
5.9
12
70.6
Diarrhea
3
17.6
14
82.4
Dysphagia
1
5.9
1
5.9
Fatigue (asthenia, lethargy, malaise)
5
29.4
16
94.1
Fever (in absence of neutropenia)
1
5.9
5
29.4
Glucose, serum-high
2
11.8
5
29.4
Hypertension
2
11.8
7
41.2
Infection
4
23.5
4
23.5
Magnesium, serum-high
1
5.9
1
5.9
Muscle weakness (not due to neuropathy)
1
5.9
3
17.6
Pain—Abdomen NOS
2
11.8
7
41.2
Pain—Back
3
17.6
9
52.9
Pain—Extremityelimb
4
23.5
8
47.1
Pain—Head/headache
2
11.8
8
47.1
Phosphate, serum-low
5
29.4
9
52.9
Potassium, serum-high
2
11.8
2
11.8
Obstruction, genitourinary—Ureter
1
5.9
1
5.9
Rash
2
11.8
10
58.8 17.6
Renal/genitourinary—Other
1
5.9
3
Syncope
1
5.9
1
5.9
Thrombosis/thrombus/embolism
2
11.8
2
11.8
Urinary frequency/urgency
1
5.9
4
23.5
Weight loss
1
5.9
6
35.3
Abbreviations: AE ¼ adverse event; ALT ¼ alanine aminotransferase; NOS ¼ not otherwise specified; WBC ¼ white blood cell count.
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embolism 21%, hemorrhage 7%, hypertension 7%, proteinuria 2%)30; this regimen is being explored further in a randomized phase 3 trial comparing gemcitabine/cisplatin to gemcitabine/cisplatin/ bevacizumab (NCT00942331). Two single-arm trials, one using gemcitabine/carboplatin and bevacizumab and another using gemcitabine/cisplatin and sunitinib, had response rates of 49% and 64% and OS values of 13.9 and 12 months, respectively, similar to response rates and OS results from the standard-of-care regimens of gemcitabine/cisplatin and methotrexate, vinblastine, doxorubicin, and cisplatin.3,31,32 Small randomized phase 2 studies have also been performed. Grivas et al33 treated subjects with platinum-based regimens and then randomized 28 to receive placebo and 26 to receive sunitinib
Clinical Genitourinary Cancer Month 2018
maintenance therapy. PFS was 64% for the placebo arm versus 72% for the sunitinib arm, which was not statistically significant, although the trial was so small that it was only powered to detect very large differences. Similarly, another study treated patients with gemcitabine and cisplatin and then randomized 49 patients to receive placebo and 40 to receive sorafenib maintenance therapy.34 Response rates were 47% versus 52.5% and PFS times were 6.1 versus 6.3 months, respectively. Again, the study was small and was closed early because of slow accrual. Last, trials of second-line chemotherapy combined with VEGF inhibitors have demonstrated activity. The combination of pazopanib and paclitaxel in 28 previously treated subjects had 3 complete responses and a 54% overall response rate, with median 6.2
Michael E. Hurwitz et al months PFS and 10 months OS.35 A comparison of ramucirumab versus placebo in combination with docetaxel in the second-line setting has demonstrated a statistically significant PFS advantage for ramucirumab (5.4 vs. 2.8 months).36 Thus, it appears that among the currently tested small-molecule VEGF pathway inhibitors, single-agent therapy is unlikely to be an important strategy, whereas adding these agents to chemotherapy-based backbones might add significant benefit. A number of findings in this study are worth noting for future studies. First, out of 17 subjects, 2 had very long-term remissions (>5 years), one of which is a possible cure in a disease with a negligible cure rate from conventional chemotherapy. Furthermore, despite very few patients completing therapy, the PFS and OS compare favorably with the standard-of-care therapies of gemcitabine/cisplatin and methotrexate, vinblastine, doxorubicin, and cisplatin combination results from phase 3 studies (PFS 9.5 vs. 7.7-8.3 months, OS 25.2 vs. 14-15.2 months).3 While the number of patients treated on this study is small and one cannot directly compare phase 2 results with phase 3 results given the likely differences in patient populations, the findings of an OS of 25.2 months is intriguing. A similar trial using lower doses of chemotherapy (but possibly with cisplatin instead of carboplatin) with a more specific VEGF pathway inhibitor might provide similar benefits with much less toxicity. Forthcoming results of the NCT00942331 trial will allow a randomized trial assessment of the addition of bevacizumab to gemcitabine/cisplatin compared to gemcitabine/cisplatin alone. Furthermore, as noted above, in the second-line setting, ramucirumab in combination with docetaxel chemotherapy has been shown to have a PFS benefit compared to docetaxel alone.36 This agent or other agents might show similar improved efficacy in the first-line setting. Given the limited benefit provided by first-line chemotherapy in this disease, trying other similar combinations of chemotherapy with antiangiogenic agents is a reasonable strategy.
Clinical Practice Points A number of trials have assessed tyrosine kinase inhibitors alone
or in combination with platinum-based chemotherapy in the treatment of TCC. As single agents, response rates range from 4.5% to 17.1%. To date, no combination has yet been assessed in a randomized trial (though one is ongoing), and both the tyrosine kinase inhibitor and the chemotherapy backbone have not yet been optimized. In this trial, we treated subjects with gemcitabine/carboplatin and sorafenib in 17 subjects in the first-line setting. Sorafenib has specificity for VEGF receptors as well as several Raf isoforms and other tyrosine kinases. Carboplatin was chosen because of its better tolerability compared to cisplatin. The overall response rate was 54%. Median PFS and OS were 9.5 months and 25.2 months, respectively, and 2 subjects had responses that lasted > 5 years. However, 11 subjects (65%) discontinued treatment, and 13 subjects (76%) required multiple dose reductions because of toxicity. Thus, gemcitabine and carboplatin with sorafenib was associated with significant toxicity but demonstrated impressive survivals, including durable ones.
These results have 2 implications. First, given the poor tolerability
and our inability to treat subjects at these doses, we do not recommend going forward with this combination of agents at these doses. Second, response rates, including durable responses, are high despite the requirement for multiple dose reductions in most patients, suggesting that the combination of tyrosine kinase inhibitors and chemotherapy should be pursued in future studies. Using a tyrosine kinase inhibitor more specific to VEGFR2 and modifying its dose might produce more tolerable combinations with durable responses.
Disclosure The authors have stated that they have no conflict of interest.
Supplemental Data A supplemental table accompanying this article can be found in the online version at https://doi.org/10.1016/j.clgc.2018.07.021.
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Phase 2 Trial of Gemcitabine, Carboplatin, and Sorafenib 16. Inoue K, Chikazawa M, Fukata S, Yoshikawa C, Shuin T. Docetaxel enhances the therapeutic effect of the angiogenesis inhibitor TNP-470 (AGM-1470) in metastatic human transitional cell carcinoma. Clin Cancer Res 2003; 9:886-99. 17. Dickinson AJ, Fox SB, Persad RA, Hollyer J, Sibley GN, Harris AL. Quantification of angiogenesis as an independent predictor of prognosis in invasive bladder carcinomas. Br J Urol 1994; 74:762-6. 18. Jaeger TM, Weidner N, Chew K, et al. Tumor angiogenesis correlates with lymph node metastases in invasive bladder cancer. J Urol 1995; 154:69-71. 19. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 2014; 507:315-22. 20. Wilhelm S, Carter C, Lynch M, et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 2006; 5:835-44. 21. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006; 24:3187-205. 22. Bayer Healthcare Pharmaceuticals Inc. Nexavar package insert, October 2010. 23. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-47. 24. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989; 10:1-10. 25. Petrioli R, Frediani B, Manganelli A, et al. Comparison between a cisplatincontaining regimen and a carboplatin-containing regimen for recurrent or metastatic bladder cancer patients. A randomized phase II study. Cancer 1996; 77:34451. 26. Necchi A, Mariani L, Zaffaroni N, et al. Pazopanib in advanced and platinumresistant urothelial cancer: an open-label, single group, phase 2 trial. Lancet Oncol 2012; 13:810-6. 27. Dreicer R, Li H, Stein M, et al. Phase 2 trial of sorafenib in patients with advanced urothelial cancer: a trial of the Eastern Cooperative Oncology Group. Cancer 2009; 115:4090-5.
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28. Sridhar SS, Winquist E, Eisen A, et al. A phase II trial of sorafenib in first-line metastatic urothelial cancer: a study of the PMH Phase II Consortium. Invest New Drugs 2011; 29:1045-9. 29. Twardowski P, Stadler WM, Frankel P, et al. Phase II study of aflibercept (VEGFTrap) in patients with recurrent or metastatic urothelial cancer, a California Cancer Consortium trial. Urology 2010; 76:923-6. 30. Hahn NM, Stadler WM, Zon RT, et al. Phase II trial of cisplatin, gemcitabine, and bevacizumab as first-line therapy for metastatic urothelial carcinoma: Hoosier Oncology Group GU 04-75. J Clin Oncol 2011; 29:1525-30. 31. Balar AV, Apolo AB, Ostrovnaya I, et al. Phase II study of gemcitabine, carboplatin, and bevacizumab in patients with advanced unresectable or metastatic urothelial cancer. J Clin Oncol 2013; 31:724-30. 32. Geldart T, Chester J, Casbard A, et al. SUCCINCT: an open-label, single-arm, non-randomised, phase 2 trial of gemcitabine and cisplatin chemotherapy in combination with sunitinib as first-line treatment for patients with advanced urothelial carcinoma. Eur Urol 2015; 67:599-602. 33. Grivas PD, Daignault S, Tagawa ST, et al. Double-blind, randomized, phase 2 trial of maintenance sunitinib versus placebo after response to chemotherapy in patients with advanced urothelial carcinoma. Cancer 2014; 120:692-701. 34. Krege S, Rexer H, Dorp vom F, et al. Prospective randomized double-blind multicentre phase II study comparing gemcitabine and cisplatin plus sorafenib chemotherapy with gemcitabine and cisplatin plus placebo in locally advanced and/ or metastasized urothelial cancer: SUSE (AUO-AB 31/05). BJU Int 2014; 113: 429-36. 35. Narayanan S, Lam A, Vaishampayan U, et al. Phase II study of pazopanib and paclitaxel in patients with refractory urothelial cancer. Clin Genitourin Cancer 2016; 14:432-7. 36. Petrylak DP, Tagawa ST, Kohli M, et al. Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: an open-label, three-arm, randomized controlled phase II trial. J Clin Oncol 2016; 34:1500-9.
Supplemental Table 1 Complete List of AEs AE Grade AE
1
2
3
4
5
Allergy/Immunology Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip)
Total No.
Grade 3/4 AE
5
0 0
5
0
0
0
0
5 3
0
Otitis, middle ear (noninfectious)
0
1
0
0
0
1
0
Tinnitus
0
2
0
0
0
Auditory/Ear
Blood/Bone Marrow 0
0
0
0
2
0
45
23
1
0
Bone marrow cellularity
1
CD4 count
0
1
0
1
0
2
1
Anemia
3
5
5
0
0
13
5
Leukocytes (total WBC)
0
3
0
1
0
4
1
Lymphopenia
0
1
1
0
0
2
1
Neutrophils/granulocytes (ANC/AGC)
1
2
6
1
0
10
7
Platelets
5
0
2
6
0
13
8
10
2
Cardiac General Cardiac general—Other (specify)
2
0
0
0
0
2
0
Hypertension
2
3
2
0
0
7
2
Hypotension
1
0
0
0
0
1
0
Coagulation International normalized ratio of prothrombin time
1
0
0
0
0
Constitutional Symptoms
1
0
1
0
36
7 0
1
0
0
0
0
1
Fatigue (asthenia, lethargy, malaise)
5
6
5
0
0
16
5
Fever (in absence of neutropenia)
4
0
1
0
0
5
1
Insomnia
1
0
0
0
0
1
0
Rigors/chills
2
1
0
0
0
3
0
Sweating (diaphoresis)
3
0
0
0
0
3
0
Weight gain
1
0
0
0
0
1
0
Weight loss
3
2
1
0
0
6
1
Dermatology/Skin
46
2
Dermatology/skin—Other (blisters—palms)
1
0
0
0
0
1
0
Dermatology/skin—Other (left arm swelling)
1
0
0
0
0
1
0
Dermatology/skin—Other (lesion/nodule on left arm)
1
0
0
0
0
1
0
Michael E. Hurwitz et al
Clinical Genitourinary Cancer Month 2018
Constitutional symptoms—Other (specify)
- 8.e1
8.e2 Clinical Genitourinary Cancer Month 2018
AE Grade AE
1
2
3
4
5
Total No.
Dermatology/skin—Other (specify)
1
0
0
0
0
1
Grade 3/4 AE 0
Dermatology/skin—Other (specify; bumps left arm)
1
0
0
0
0
1
0
Dry skin
0
2
0
0
0
2
0
Hair loss/alopecia (scalp or body)
8
1
0
0
0
9
0 0
Nail changes
2
0
0
0
0
2
10
0
0
0
0
10
0
Rash
5
3
2
0
0
10
2
Rash/desquamation
6
1
0
0
0
7
0
Ulceration
0
1
0
0
0
1
0
3
0
Pruritus/itching
Endocrine Endocrine—Other (specify)
2
0
0
0
0
2
0
Hot flashes/flushes
1
0
0
0
0
1
0
95
0
Gastrointestinal Anorexia
4
8
0
0
0
12
0
Constipation
11
0
1
0
0
12
1
Dehydration
1
2
0
0
0
3
0 3
Diarrhea
10
1
3
0
0
14
Diarrhea (result of CT scan)
0
0
1
0
0
1
1
Distension/bloating, abdominal
1
1
0
0
0
2
0
Dry mouth/salivary gland (xerostomia)
8
1
0
0
0
9
0
Dysphagia (difficulty swallowing)
0
0
1
0
0
1
1
Enteritis (inflammation of small bowel)
0
1
0
0
0
1
0
Gastrointestinal—Other (specify)
1
0
0
0
0
1
0
Heartburn/dyspepsia
7
0
0
0
0
7
0
Hemorrhoids
1
0
0
0
0
1
0
Mucositis/stomatitis (clinical exam)—Oral cavity
2
0
0
0
0
2
0
Mucositis/stomatitis (functional/symptomatic)—Oral cavity
3
0
0
0
0
3
0 0
Nausea
10
2
0
0
0
12
Taste alteration (dysgeusia
5
2
0
0
0
7
0
Vomiting
3
4
0
0
0
7
0
Phase 2 Trial of Gemcitabine, Carboplatin, and Sorafenib
Supplemental Table 1 Continued
Supplemental Table 1 Continued AE Grade AE
1
2
3
4
5
Hemorrhage/Bleeding
Total No.
Grade 3/4 AE
8
1
Hemorrhage, GU—Bladder
1
0
0
0
0
1
0
Hemorrhage, pulmonary/upper respiratory—Nose
4
1
0
0
0
5
0
Hemorrhage/Bleeding—Other (blood in stool)
0
0
1
0
0
1
1
Hemorrhage/Bleeding—Other (specify)
1
0
0
0
0
Infection
1
0
12
4 1
Infection—Other (blood culture)
0
0
1
0
0
1
Infection—Other (burning sensation)
1
0
0
0
0
1
0
Infection—Other (right molar)
0
1
0
0
0
1
0
Infection—Other (specify)
1
0
0
0
0
1
0
Infection—Other (unknown)
0
0
1
0
0
1
1
Infection with normal ANC or grade 1 or 2 neutrophils—Bronchus
0
0
1
0
0
1
1
Infection with normal ANC or grade 1 or 2 neutrophils—Eye NOS
0
1
0
0
0
1
0
Infection with normal ANC or grade 1 or 2 neutrophils—Skin (cellulitis)
0
1
0
0
0
1
0
Infection with normal ANC or grade 1 or 2 neutrophils—Urinary tract NOS
0
2
0
0
0
2
0
Infection with unknown ANC—Rectum
0
0
1
0
0
1
1
Infection with unknown ANC—Urinary tract NOS
0
1
0
0
0
1
0
Lymphatics Edema
2
0
2
0
0
0
0
0
47
12
Albumin, serumelow (hypoalbuminemia)
1
1
0
0
0
2
0
Alkaline phosphatase
2
1
0
0
0
3
0
ALT
4
0
1
0
0
5
1
AST
4
0
0
0
0
4
0
Bicarbonate, serumelow
1
0
0
0
0
1
0
Calcium, serumehigh (hypercalcemia)
1
0
0
0
0
1
0
Calcium, serumelow (hypocalcemia)
3
0
0
0
0
3
0
Creatinine
5
0
0
0
0
5
0
Metabolic/Laboratory
Glucose, serumehigh (hyperglycemia)
1
2
2
0
0
5
2
Glucose, serumelow (hypoglycemia)
1
0
0
0
0
1
0
Michael E. Hurwitz et al
Clinical Genitourinary Cancer Month 2018
2
- 8.e3
8.e4 Clinical Genitourinary Cancer Month 2018
AE Grade AE
1
2
3
4
5
Total No.
Grade 3/4 AE
Magnesium, serum-high (hypermagnesemia)
0
0
1
0
0
1
1
Magnesium, serum-low (hypomagnesemia)
0
1
0
0
0
1
0
Metabolic/laboratory—Other (specify)
1
0
0
0
0
1
0
Phosphate, serumelow (hypophosphatemia)
0
4
5
0
0
9
5
Potassium, serumehigh (hyperkalemia)
0
0
2
0
0
2
2
Potassium, serumelow (hypokalemia) 1
1
0
0
0
0
1
0
Sodium, serumelow (hyponatremia)
1
0
1
0
0
2
1
9
1
Arthritis (nonseptic)
2
0
0
0
0
2
0
Extremityeupper (function)
1
0
0
0
0
1
0
Muscle weakness (not due to neuropathy)—Extremityelower
2
0
0
0
0
2
0
Muscle weakness (not due to neuropathy)—Right-sided
1
0
0
0
0
1
0
Muscle weakness (not due to neuropathy)—Whole body/generalized
2
0
1
0
0
3
1
28
1
Confusion
0
1
0
0
0
1
0
Dizziness
5
2
0
0
0
7
0
Mood alteration—Anxiety
2
2
0
0
0
4
0
Mood alteration—Depression
3
1
0
0
0
4
0
Musculoskeletal/Soft Tissue
Neurology
Neurology—Other (specify)
1
0
0
0
0
1
0
Neurology—Other (specify, neuropathy, heals)
1
0
0
0
0
1
0
Neuropathy
9
0
0
0
0
9
0
Syncope (fainting)
0
0
1
0
0
1
1
4
0
Ocular/Visual Ocular/Visual—Other (specify)
0
1
0
0
0
1
0
Ophthalmoplegia/diplopia (double vision)
0
1
0
0
0
1
0
Visioneblurred
1
0
0
0
0
1
0
Visioneflashing lights/floaters
1
0
0
0
0
1
0
75
17
Pain—Abdomen NOS
2
3
2
0
0
7
2
Pain—Back
3
3
3
0
0
9
3
Pain
Pain—Bladder
1
0
0
0
0
1
0
Pain—Buttock
1
0
0
0
0
1
0
Phase 2 Trial of Gemcitabine, Carboplatin, and Sorafenib
Supplemental Table 1 Continued
Supplemental Table 1 Continued AE Grade AE
1
2
3
4
5
Total No.
Pain—Cardiac/heart
1
0
0
0
0
1
Grade 3/4 AE 0
Pain—Chest wall
1
0
0
0
0
1
0
Pain—Chest/thorax NOS
3
0
0
0
0
3
0
Pain—Extremityelimb
1
3
4
0
0
8
4
Pain—Head/headache
4
2
2
0
0
8
2
Pain—Joint
0
2
0
0
0
2
0
Pain—Neck
1
3
1
0
0
5
1
Pain—Neuralgia/peripheral nerve
1
0
0
0
0
1
0
Pain—Oral cavity
0
1
0
0
0
1
0
Pain—Oralegums
1
0
0
0
0
1
0
Pain—Other (flank)
0
1
0
0
0
1
0
Pain—Other (head, neck, and face)
1
0
0
0
0
1
0
Pain—Other (left flank)
1
0
1
0
0
2
1
Pain—Other (left rib)
1
0
0
0
0
1
0
1
0
0
0
0
1
0
Pain—Other (nose)
0
1
0
0
0
1
0
Pain—Other (right groin)
0
0
1
0
0
1
1
Pain—Other (right thigh)
0
0
1
0
0
1
1
Pain—Other (specify)
2
4
1
0
0
7
1
Pain—Other (specify; aches and pains)
1
0
0
0
0
1
0
Pain—Other (specify; hip and thigh)
0
1
0
0
0
1
0
Pain—Other (top of head)
1
0
0
0
0
1
0
Pain—Rectum
1
0
0
0
0
1
0
Pain—Scalp
1
1
0
0
0
2
0
Pain—Sinus
2
0
0
0
0
2
0
Pain—Stomach
0
0
1
0
0
1
1
Pain—Throat/pharynx/larynx
1
0
0
0
0
Pulmonary/Upper Respiratory
1
0
25
0
Cough
9
1
0
0
0
10
0
Dyspnea (shortness of breath)
8
1
0
0
0
9
0
Hiccoughs (hiccups, singultus)
1
0
0
0
0
1
0
Pulmonary/upper respiratory—Other (specify)
1
0
0
0
0
1
0
Voice changes/dysarthria (eg, hoarseness, loss of or alteration in voice, laryngitis)
4
0
0
0
0
4
0
Michael E. Hurwitz et al
Clinical Genitourinary Cancer Month 2018
Pain—Other (nose and ears)
- 8.e5
8.e6 Clinical Genitourinary Cancer Month 2018
AE Grade AE
1
2
3
4
5
Renal/GU
Total No.
Grade 3/4 AE
15
3
Obstruction, GU—Ureter
0
0
1
0
0
1
1
Renal/GU—Other (hematuria)
3
0
0
0
0
3
0
Renal/GU—Other (specify)
2
0
1
0
0
3
1
Renal/GU—Other (specify, neobladder)
1
0
0
0
0
1
0
Urinary frequency/urgency
3
0
1
0
0
4
1
Urine color change
3
0
0
0
0
3
0
Sexual/Reproductive Function
4
0
Erectile dysfunction
1
0
0
0
0
1
0
Libido
2
1
0
0
0
3
0
4
2
1
0
Vascular Phlebitis (including superficial thrombosis)
0
1
0
0
0
Thrombosis/thrombus/embolism
0
0
2
0
0
2
2
Vascular—Other (left knee swelling)
1
0
0
0
0
1
0
Abbreviations: AE ¼ adverse event; AGC ¼ absolute granulocyte count; ALT ¼ alanine aminotransferase; ANC ¼ absolute neutrophil count; AST ¼ aspartate aminotransferase; GU ¼ genitourinary; NOS ¼ not otherwise specified; WBC ¼ white blood cell count.
Phase 2 Trial of Gemcitabine, Carboplatin, and Sorafenib
Supplemental Table 1 Continued