- Email: [email protected]
IIa trial of the mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) administered orally in patients with refractory or advanced malignancies and sarcoma†
original articles
19. Hensley ML, Maki R, Venkatraman E et al.. Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial. J Clin Oncol 2002; 20: 2824–2831. 20. Pautier P, Genestie C, Fizazi K et al.. Cisplatin-based chemotherapy regimen (DECAV) for uterine sarcomas. Int J Gynecol Cancer 2002; 12: 749–754. 21. Le Cesne A, Antoine E, Spielmann M et al.. High-dose ifosfamide: circumvention of resistance to standard-dose ifosfamide in advanced soft tissue sarcomas. J Clin Oncol 1995; 13: 1600–1608. 22. Van Glabbeke M, van Oosterom AT, Oosterhuis JW et al.. Prognostic factors for the outcome of chemotherapy in advanced soft tissue sarcoma: an analysis of 2,185 patients treated with anthracycline-containing first-line regimens—an European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol 1999; 17: 150–157. 23. Hempling RE, Piver MS, Baker TR. Impact on progression-free survival of adjuvant cyclophosphamide, vincristine, doxorubicin (Adriamycine), and dacarbazine (CYVADIC) chemotherapy for stage I uterine sarcoma. Am J Clin Oncol 1995; 18: 282–286. 24. Buchsbaum HJ, Lifshitz S, Blythe JG. Prophylactic chemotherapy in stages I and II uterine sarcoma. Gynecol Oncol 1979; 8: 346–348. 25. Hannigan EV, Freedman RS, Rutledge FN. Adjuvant chemotherapy in early uterine sarcoma. Gynecol Oncol 1983; 15: 56–64. 26. Van Nagell JR, Hanson MB, Donaldson ES et al.. Adjuvant vincristine, dactinomycin, and cyclophosphamide in stage I uterine sarcomas: a pilot study. Cancer 1986; 57: 1451–1454. 27. Hensley ML, Ishill N, Soslow R et al.. Adjuvant gemcitabine plus docetaxel for completely resected stages I-IV high grade uterine leiomyosarcoma: results of a prospective study. Gynecol Oncol 2009; 112: 563–567.
Annals of Oncology 24: 1104–1111, 2013 doi:10.1093/annonc/mds602 Published online 4 December 2012
Phase I/IIa trial of the mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) administered orally in patients with refractory or advanced malignancies and sarcoma† M. M. Mita1*, E. Poplin2, C. D. Britten3, W. D. Tap3,4, E. H. Rubin5, B. B. Scott5, L. Berk6, V. M. Rivera6, J. W. Loewy6, P. Dodion6, F. Haluska6, J. Sarantopoulos1, A. Mita1 & A. Tolcher1 1 Cancer Therapy Research Center, Institute for Drug Development, San Antonio; 2Gastrointestinal/Hepatobiliary Program, Cancer Institute of New Jersey, New Brunswick; 3Division of Medical Oncology, David Geffen School of Medicine, University of California, Los Angeles; 4Sarcoma Oncology, Memorial Sloan-Kettering Cancer Center, New York; 5Merck Sharp & Dohme Corp., Whitehouse Station; 6ARIAD Pharmaceuticals, Inc., Cambridge, USA
Received 22 June 2012; revised 12 October 2012; accepted 15 October 2012
Background: Ridaforolimus is an inhibitor of mTOR with evidence of antitumor activity in an I.V. formulation. This multicenter, open-label, 3 + 3 design nonrandomized, dose-escalation, phase I/IIa trial was conducted to determine the *Correspondence to: Dr M. Mita, Experimental Therapeutics Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, SCCT Mezzanine MS 35, Los Angeles, CA 90048, USA. Tel: +1-310-248-6729; Fax: +1-310-248-6740; E-mail: [email protected] †
This article was presented in part at ASCO 2008, CTOS 2008. AACR-NCI-EORTC 2008.
© The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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10. Omura GA, Major FJ, Blessing JA et al.. A randomized study of adriamycin with and without dimethyl triazinoimidazole carboxamide in advanced uterine sarcomas. Cancer 1983; 52: 626–632. 11. Gershenson DM, Kavanagh JJ, Copeland LJ et al.. High-dose doxorubicin infusion therapy for disseminated mixed mesodermal sarcoma of the uterus. Cancer 1987; 59: 1264–1267. 12. Sutton G, Blessing J, Barrett R et al.. Phase II trial of ifosfamide and mesna in leimyosarcoma of the uterus: a Gynecologic Oncologic Group study. Am J Obstet Gynecol 1992; 166: 556–559. 13. Sutton GP, Blessing JA, Rosenheim N et al.. Phase II trial of ifosfamide and mesna in mixed mesodermal tumors of the uterus. Am J Obstet Gynecol 1989; 161: 309–312. 14. Thigpen JT, Blessing JA, Beecham J et al.. Phase II trial of cisplatin as first line chemotherapy in patients with advanced or recurrent uterine sarcomas (a Gynecologic Oncologic Group study). J Clin Oncol 1991; 9: 1962–1966. 15. Thigpen JT, Blessing JA, Orr JW, Jr et al.. Phase II trial of cisplatin in treatment of patients with advanced or recurrent mixed mesodermal sarcomas of the uterus: a Gynecologic Oncologic Group study. Cancer Treat Rep 1986; 70: 271–274. 16. Piver MS, Deeulis TG, Lele SB et al.. Cyclophosphamide, vincristine, adriamycine, and dimethyl-triazeno imidazole carboxamide (CYVADIC) for sarcomas of the female genital tract. Gynecol Oncol 1982; 14: 319–323. 17. Sutton G, Blessing JA, Malfetano JH. Ifosfamide and doxorubicine in the treatment of advanced leiomyosarcomas of the uterus: a Gynecologic Oncology Group Study. Gynecol Oncol 1996; 2: 226–229. 18. Muss HB, Bundy B, disaia PJ et al.. Treatment of recurrent or advanced uterine sarcoma : a randomized trial of doxorubicine versus doxorubicine and cyclophosphamide (a phase III trial of the Gynecologic Oncology Group). Cancer 1985; 55: 1648–1653.
Annals of Oncology
original articles
Annals of Oncology
introduction
materials and methods
The mammalian target of rapamycin (mTOR) is a central regulator in a number of signaling pathways involved in cell growth, division, metabolism, and angiogenesis [1, 2]. Growth and nutrient stimuli activate mTOR through PI3K/AKT signaling [3]. In turn, mTOR activates downstream effectors including p70 S6kinase 1 (S6K1) and the eukaryotic initiation factor 4E binding protein 1 (4E-BP1), two important proteins involved in the regulation of ribosomal biosynthesis and the translation of mRNA species involved in cell cycle regulation [4]. The PI3K/AKT/pathway has been linked to oncogenesis in a number of different human cancers [3, 5, 6]. Inhibition of mTOR results in disruption of cell cycle progression and cell growth providing further validation for mTOR as an anticancer target [7–9]. Several rapamycin analogs with improved solubility and stability have been developed, including temsirolimus (CCI-779) and everolimus (RAD001), which received regulatory approval for the treatment of renal cell carcinoma and pancreatic neuroendocrine tumors [10, 11]. Ridaforolimus (AP23573/MK-8669) is an orally available nonprodrug analog of rapamycin and is a potent and selective mTOR inhibitor demonstrated by its ability to prevent downstream activation of S6K1 and 4E-BP1 [12, 13] and inhibits proliferation of a number of different tumor cell lines and xenografts [14]. Phase I studies with I.V. ridaforolimus indicated that it was well tolerated and had promising antitumor activity in a number of different malignancies including sarcoma [12, 15]. This study was a phase I/IIa, open-label, dose-escalation trial of oral ridaforolimus in metastatic or unresectable solid tumors. The primary objective of the study was to determine the safety, tolerability, and maximum tolerated dose (MTD) of oral ridaforolimus. Although not prespecified, the study was enriched for patients with sarcoma based on prior clinical observations [12]. The secondary objectives included assessment of antitumor activity, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of ridaforolimus.
patient selection
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Patients with a histological diagnosis of metastatic or unresectable solid tumors were enrolled. Additional eligibility criteria were as follows: age ≥18 years; an ECOG performance status of 0–2; adequate renal, hepatic, and bone marrow function; serum cholesterol ≤350 mg/dl or triglycerides ≤400 mg/dl; ≥4 weeks from prior anticancer or radiation therapy; no active CNS malignancies or metastases; no prior treatment with mTOR inhibitors; no hypersensitivity to macrolide antibiotics; no significant cardiovascular disease, medical problems, or pregnancy. All study participants provided written informed consent. The protocol was approved by the relevant Institutional Review Boards and carried out according to the guidelines of good clinical practice and with ethical standards for human experimentation.
trial design phase I dosing regimen and escalation This was an open-label, 3 + 3 design nonrandomized, multicenter, phase I/IIa dose-escalation trial to establish safety, tolerability, and MTD of oral ridaforolimus (10-mg enteric-coated tablets). Seven dosing regimens, all on a 28-day cycle, were examined (Table 1). For each regimen, three patients were initially enrolled. In the absence of a dose-limiting toxicity (DLT) during cycle 1 (28 days) of study treatment, enrollment into the next dose level cohort commenced. In the event that one of the three patients experienced a DLT, then three additional patients were enrolled into that cohort. In the event that two of three patients or two of six patients treated at a given dose level experienced a DLT, no further patients were enrolled at that dose level and additional patients were enrolled at the previous dose level. Patient enrollment and dose escalation proceeded until the MTD had been determined. DLTs were defined as any of the following: grade 3 nonhematologic toxicity lasting >3 days despite supportive care, with the exception of self-limiting or medically controllable toxic effects (e.g. fever without neutropenia, nausea, vomiting, fatigue, and hypersensitivity reactions); grade 4 nonhematologic toxicity; grade 4 sustained neutropenia (ANC < 500/mm3, >5 days duration); grade 3 or 4 neutropenia associated with fever (<1000/mm3; >38.5°C) thrombocytopenia (<25 000/mm3); inability, due to any toxicity thought to be associated with the study drug, to complete a total of one dosing cycle, and unresolved toxic effects that delayed retreatment for >2 weeks.
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safety, pharmacokinetic (PK) and pharmacodynamic parameters, maximum tolerated dose, and antitumor activity of oral ridaforolimus. Patients and methods: Patients with metastatic or unresectable solid tumors refractory to therapy were eligible. Seven different continuous and intermittent dosing regimens were examined. Results: One hundred and forty-seven patients were enrolled in this study among which 85 were patients with sarcoma. Stomatitis was the most common DLT observed. The dosing regimen, 40 mg QD × 5 days/week, provided the best combination of cumulative dose, dose density, and cumulative exposure, and was the recommended dosing regimen for subsequent clinical development. PK was nonlinear, with less than proportional increases in day-1 blood AUC0–∞ and Cmax, particularly with doses >40 mg. The terminal half-life estimate of ridaforolimus (QD × 5 40 mg) was 42.0 h, and the mean half-life ∼30–60 h. The clinical benefit rate, (complete response, partial response, or stable disease for ≥4 months was 24.5% for all patients and 27.1% for patients with sarcoma. Conclusion: Oral ridaforolimus had an acceptable safety profile and exhibited antitumor activity in patients with sarcoma and other malignancies. ClinicalTrials.gov Identifier: NCT00112372. Key words: mTOR, rapamycin, ridaforolimus, sarcoma
original articles
Annals of Oncology
Table 1. Maximum tolerated dose and dose-limiting toxic effects by dosing regimen Regimen
Patients treated
Dose (# of patients)
Maximum tolerated dose
QD × 4 (once weekly)
37
20 mg (3) 30 mg (4) 40 mg (10) 50 mg (15) 70 mg (4) 30 mg (14) 40 mg (24) 50 mg (7) 60 mg/ 30 mgd (7) 100 mg/50 mge (5)
Below MTD Below MTD Below MTD MTD Above MTD Below MTD MTD a Above MTDa Not formally determinedb Not formally determinedb
45
LD QD × 5 (once weekly)
12
QD × 6 (once weekly)
13
30 mg
Above MTD
QD × 21 (every 28 days)
18
10 mg (3) 15 mgc (12) 20 mg (3)
Below MTD MTD Above MTD
10 mg (14) 20 mg (4) 20 mg
MTD Above MTD Not determined
QD × 28 (every 28 days)
18
BID × 4 (once weekly)
4
Grade 3 mouth ulceration (1) Grade 3 stomatitis (2)
Grade 2 stomatitis (1) Grade 3 hyperglycemia (1) Grade 3 fatigue/asthenia (2) Grade 2 stomatitis Grade 2 mouth ulceration (2) Grade 2 stomatitis; mouth ulceration
Grade 3 stomatitis (2) Grade 3 stomatitis Grade 2 mouth ulceration (1)
Maximum tolerated dose (MTD), when determined, is shown for each dosing regimen. Loading dose 60 mg/30 mg = QD × 4 days/week: 60 mg day 1, 30 mg days 2–5. Loading dose 100 mg/50 mg = QD × 4 days/week: 100 mg day 1, 50 mg days 2–5. a The MTD of 40 mg for the QD × 5 cohort was based on clinical evidence, by the Sponsor and Principal Investigators, of the safety and tolerability data for all dose levels tested, and not strictly on the number of patients in the cohort who experienced DLTs. Only one patient in the 50 mg QD × 5 days/week cohort experienced a DLT as defined by the protocol. b The 60-mg loading dose + 30 mg days 2–5/week was well tolerated; the 100-mg loading dose + 50 mg days 2–5/week dosing regimen exceeded the MTD. c The 15 mg dose was achieved by alternating daily 10 and 20 mg doses. d Loading dose 60 mg/30 mg = QD × 5/60 mg day 1, 30 mg days 2–5. e Loading dose 100 mg/50 mg = QD × 5/100 mg day 1, 50 mg days 2–5.
patient evaluation
pharmacodynamic analyses
.Patients were screened based on medical histories and laboratory tests. At baseline and during the trial, the following evaluations were carried out: physical examinations, 12-lead ECG, chest X-ray, routine laboratory evaluations, and slit-lamp eye examination. Adverse event (AE) terms were coded according to MedDRA and severity graded according to the US NCI Common Terminology Criteria for AEs, version 3. The primary antitumor activity end point was the clinical benefit rate (CBR), determined using the modified Response Evaluation Criteria for Solid Tumors (RECIST) guidelines. Disease was assessed at baseline and every two cycles (8 weeks) by the appropriate radiologic studies, including CT scans and/or MRI. A patient was classified as having a clinical benefit if the patient experienced a complete response or partial response (PR), or had stable disease (SD) with duration of ≥4 months.
Peripheral blood mononuclear cells (PBMCs) were used to investigate the inhibitory activity of ridaforolimus on mTOR on days 1, 2, 11, 15, 16, and 22 of cycle 1 and day 1 of cycle 2. PBMC protein extracts were analyzed by western blot using an antiphospho-4E-BP1(Ser65/Thr70) [12, 15].
pharmacokinetic analyses Blood samples for PK analysis were collected at day 1, 2, 4, 8, 11, 15, 16, and 22. Samples were analyzed for ridaforolimus using a validated liquid chromatography and tandem mass spectroscopy assay. PK parameters, Cmax, AUC, Tmax, and t1/2 were calculated using WinNonLin software.
| Mita et al.
statistical methods The sample size of the trial was not predetermined and based on the standard 3 + 3 dose-escalation algorithm. Statistical analyses were descriptive in nature with no formal statistical inference. Summary statistics and analyses were provided for all patients, by dose level for each dosing regimen, and for the subgroup of patients with sarcoma. The treated population included all patients who received at least one dose of trial treatment. The first-cycle DLT was determined in those patients who received sufficient trial drug during cycle 1 of treatment to enable an adequate evaluation of the safety of the dosing regimen. An adequate exposure during cycle 1 was defined as having received ≥75% of planned trial drug doses during cycle 1, exclusive of doses missed due to treatment-related toxicity. Inability to complete cycle 1 due to toxicity was considered a DLT. Safety and antitumor activity data are reported for all patients in the treated population and for the subgroup of patients with sarcoma. Survival curves were computed using the Kaplan–Meier [ product limit] method.
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QD × 5 (once weekly)
Dose-limiting toxicity and severity (# of patients)
original articles
Annals of Oncology
results
Table 2. Patient demographics and disease characteristics
general
Characteristics
dose-limiting toxicity and maximum tolerated dose All 147 patients were assessable for toxicity assessment (Table 1). Stomatitis (including mucosal inflammation, oral pain, and mouth ulceration) was the most common DLT. Of the 12 patients with a recorded DLT, 10 experienced stomatitis. One patient each experienced a DLT of grade 3 fatigue and asthenia or grade 3 hyperglycemia. The DLTs included grade 2 events of stomatitis or mouth ulceration that were considered intolerable. All recorded DLT’s resulted in delay in dosing and/or a reduction in dosage. When delayed dosing was warranted, the delay in dosing was ≤2 weeks to allow for amelioration to grade 1 or resolution of the event. The MTD was 50 mg for the QD × 4 days/week dosing regimen, 40 mg for the QD × 5 days/week regimen, 15 mg for the QD × 21 regimen, and 10 mg for the QD × 28 regimen (Table 2). The pre-specified protocol criteria for an MTD were not reached for the QD × 5 days/week, and the recommended dose for this regimen was determined to be 40 mg by the Sponsor and Principal Investigators, considering the safety and tolerability data for all dose levels tested. One patient in the 50 mg QD × 5 days/week experienced a DLT, and two experienced grade 3 toxic effects that did not meet the definition of a DLT. None of the 24 patients receiving 40-mg ridaforolimus QD × 5 days/week experienced a DLT.
safety profile AEs were reported for 146 (99.3%) of the 147 patients in the treated population, and the most commonly encountered (≥10%) treatment-related AEs are summarized (Table 3). There was no indication of ridaforolimus-induced immunosuppression.
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All treated patients
Number of patients 147 Median age (range), years 55 (23–84) Sex, n (%) Male 65 (44.2) Female 82 (55.8) ECOG performance status, n (%) 0 45 (30.6) 1 88 (59.9) 2 13 (8.8) Missing 1 (0.7) Location of primary tumor Sarcoma 85 Soft tissue 66 Ewing 2 Other bone sarcomas 3 Uterine 14 Colorectal 10 Breast 9 Other tumor type < 5% 43 Prior anticancer treatment 0 12 Mean (SD) 3.4 (2.37) Median 3 Min–max 0–11
Treated patients with sarcoma 85 54 (23–84) 33 (38.8) 52 (12.9) 31 (36.5) 49 (57.6) 4 (4.7) 1 (1.2)
2.7 (1.80) 3 0–8
Stomatitis was frequent in this trial (Table 3) and is an AE associated with mTOR inhibitors [12, 16–19]. The majority of the oral events were mild or moderate in severity and were treated symptomatically, with typical complete resolution. Rash and dermatologic events were also common treatmentrelated AEs; however, most were mild to moderate in severity with no grade 3 or 4 events. Pneumonitis is a known AE associated with mTOR inhibitors [12, 17, 19] and a variety of pulmonary events were reported and considered by the investigator to be treatment related, including dyspnea in 10 patients (6.8%), pneumonitis in 10 patients (6.8%), cough in 4 patients (2.7%), and 1 patient with interstitial lung disease (ILD) (0.7%). Most patients diagnosed with pneumonitis or ILD had their treatment suspended for 1–3 weeks and received a short course of oral corticosteroids. Ridaforolimus was resumed in some cases without recurrence of toxicity. As observed with other rapamycin analogs, treatment-related metabolic disorder events were frequent; 15.0% of the patients experienced hypertriglyceridemia; and 18.4% experienced hypercholesterolemia. The majority of these events were mild or moderate in severity and reversible with adequate treatment. Similar to other rapamycin analogs, hematological AEs were reported; 24.5% of patients experienced anemia; 20.4% thrombocytopenia and 6.1% neutropenia that were considered treatment related. The majority of these events were grade 1 or 2. There were no apparent differences in the safety profile of ridaforolimus in the subgroup of patients with sarcoma
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A total of 147 patients received at least one dose of ridaforolimus between May 2005 and December 2008. Pretreatment characteristics are outlined (Table 2). Eighty-five patients had a diagnosis of sarcoma and 62 patients with solid tumors other than sarcoma. Most patients in the treated population (82.3%) had stage IV disease. Treated patients received study drug for a median of 53 days (range 1–1064 days). The median cumulative dose of ridaforolimus received per patient was 960 mg (range 40–20 650 mg). Patients with a diagnosis of sarcoma received ridaforolimus for a median of 56 days (range 1–591 days) and the median cumulative dose received was 1250 mg (range 40–20 650 mg). The total predicted exposure of ridaforolimus over the first cycle (AUC0–28 days) was dependent on regimen. The QD × 4 (50 mg), QD x5 (40 mg), and QD × 6 (30 mg) dosing regimens administered similar cumulative dose amounts over a 4-week cycle (800, 800, and 720 mg, respectively). The calculated total predicted exposure of ridaforolimus was similar between these groups. The QD × 21 (15 mg) and QD × 28 (10 mg) dosing groups were administered up to 315-mg cumulative dose amounts over the 4-week cycle.
original articles
Annals of Oncology
observed at most post-dose time-points analyzed throughout the 28-day cycle, including time-points 4 days after dosing. In the QD × 21 days schedule, >70% inhibition was observed at all time-points within 24 h of dosing, whereas reduced inhibition of ∼50% was observed at the time-point eight days after dosing (i.e. cycle 2 day 1) (data not shown).
compared with the other solid tumors. Besides those described above, there were no unexpected changes in hematology, chemistry, urinalysis, and ECG parameters because of exposure to ridaforolimus. Treatment-related (investigator assessment) grade 4 toxic effects were observed in 4 (2.7%) patients. These included a grade 4 cerebellar infarction, which resolved with sequelae; a grade 4 gastrointestinal fistula and grade 4 sepsis both of which resolved; a grade 4 elevated lipase level and a grade 4 anemia, which resolved after a delay in treatment. Treatment-related grade 3 toxic effects were observed in 47 (32.0%) patients, grade 2 toxic effects in 73 (49.7%) patients, and grade 1 toxic effects in 15 (10.2%) patients (Table 3). No deaths in patients who received ridaforolimus or within 30 days of last dose were considered by the investigator to be related to study drug. Seventy deaths were reported on study, most due to the progression of the underlying malignancy, of which 23 deaths occurred within 30 days of the last dose of ridaforolimus.
tumor response
pharmacokinetics and pharmacodynamics Blood samples from 129 patients were used to determine the PK parameters for ridaforolimus according to dosing regimen (Table 4). The terminal half-life estimate of ridaforolimus in the QD × 5 40 mg group was 42.0 h. The median time to achieve maximum concentration (Tmax) was approximately 3 h. The mean half-life estimate (t1/2) of ridaforolimus spanned ∼30–60 h across all dosing regimens. Oral ridaforolimus inhibited mTOR activity in PBMCs. In all 141 patients analyzed, p-4E-BP1 levels were strongly and rapidly reduced with a median level of inhibition across all patients of >90% at both 4 and 24 h after dosing. When ridaforolimus was administered on a QD × 4 days/week, QD × 5 days/week, QD × 6 days/week, or QD × 28 days schedule, median levels of at least ∼70% inhibition were Table 3. Treatment-related adverse events occurring in ≥10% of treated patients Treatment-related adverse events Fatigue Mucosal inflammation Rash Mouth ulceration Anemia Stomatitis Diarrhea Nausea Thrombocytopenia Hypercholesterolemia Anorexia Hypertriglyceridemia Aspartate aminotransferase increased Alanine aminotransferase increased Dysgeusia Hyperglycemia Vomiting Decreased appetite
| Mita et al.
All treated patients (N = 147) Total N (%) Grade 1
Grade 2
Grade 3
Grade 4
72 (49.0) 71 (48.3) 45 (30.6) 43 (29.3) 36 (24.5) 35 (23.8) 34 (23.1) 31 (21.1) 30 (20.4) 27 (18.4) 26 (17.7) 22 (15.0) 20 (13.6) 19 (12.9) 19 (12.9) 19 (12.9) 19 (12.9) 15 (10.2)
32 (21.8%) 33 (22.4%) 2 (1.4%) 11 (7.5%) 19 (12.9%) 13 (8.8%) 10 (6.8%) 7 (4.8%) 10 (6.8%) 5 (3.4) 8 (5.4) 6 (4.1) 8 (5.4) 6 (4.1) 1 (0.7) 7 (4.8) 4 (2.7) 1 (0.7)
7 (4.8%) 5 (3.4%) 0 (0.0%) 2 (1.4%) 6 (4.1%) 1 (0.7%) 1 (0.7%) 5 (3.4%) 6 (4.1%) 0 (0.0%) 2 (1.4) 2 (1.4) 2 (1.4) 1 (0.7) 0 (0.0%) 7 (4.8) 4 (2.7) 0 (0.0%)
0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
33 (22.4%) 33 (22.4%) 43 (29.3%) 30 (20.4%) 10 (6.8%) 21 (14.3%) 23 (15.6%) 19 (12.9%) 14 (9.5%) 22 (15.0) 16 (10.9) 14 (9.5) 10 (6.8) 12 (8.2) 18 (12.2) 5 (3.4) 11 (7.5) 14 (9.5)
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Across all dosing regimens for the treated population, the CBR was 24.5% for the treated population and 27.1% for the sarcoma subgroup (Table 5). The highest CBRs in subgroups with 10 patients or more were for the intermittent dosing regimens 30 mg QD × 5 days/week: 57.1% (8 of 14 patients); 30-mg QD × 6 days/week: 38.5% (5 of 13 patients) and 40-mg Qd × 5 in sarcoma 23% (3 of 13 patients with sarcoma). The best overall response was PR for 2 (1.4%) and SD for ≥8 weeks for 67 (45.6%) of the 147 patients (Table 5). The best overall response for the 85 patients in the sarcoma subgroup was PR for two patients (2.4%) and SD for 45 (52.9%). The best overall response was PR for two patients in the 40 mg QD × 5 days/week cohort, a 63-year-old female with a diagnosis of stage IV abdominal liposarcoma; and a 48-yearold female with a diagnosis of stage IV follicular dendritic cell sarcoma of the pelvis and retroperitoneum. The duration of the PR was 4 months for the first patient; and >11 months for the second patient (ongoing at the time of database lock). Across all dosing regimens, the Kaplan–Meier estimate of the median overall survival was 37.7 weeks for all patients and 42.7 weeks for the sarcoma subgroup (Figure 1a). Estimated median progression-free survival (PFS) (Kaplan–Meier estimate) for all patients was 12.1 weeks, and for the sarcoma subgroup was 17.1 weeks (Figure 1b). In the 85 patients with sarcoma across all dose levels, ridaforolimus administration resulted in a 6-month PFS rate of 29%.
original articles
Annals of Oncology
Table 4. Summary of whole-blood model-predicted pharmacokinetic parameters of ridaforolimus in male and female patients with advanced malignancy stratified by dosing regimen (N = 129) Dose (mg)
N
AUCb0–∞ (ng·h/ml)
Cbmax (ng/ml)
Tcmax (h)
td1/2 (h)
QD × 28
10 20 10 15e 20 20 30 40 50 70 20 30 40 50 60 + 30 100 + 50 30
13 3 3 11 2 2 4 8 12 5 3f 13 20 5 7 5 13
696 (523, 925) 1858 (646, 5350) 941 (201, 4410) 645 (419, 994) 1049 (91, 2100) 990 (19, 51 300) 2017 (659, 6170) 2436 (1930, 3070) 2342 (1850, 2960) 2473 (1620, 3780) 998 (510, 2890) 1397 (955, 2040) 2017 (1730, 2350) 1436 (829, 2490) 2241 (1330, 3760) 4313 (2330, 7990) 2224 (1790, 2760)
55.2 (41.6, 73.1) 105 (16.2, 675) 46.2 (11.0, 194) 38.3 (18.2, 80.4) 107 (0.7, 15 800) 96.0 (46.8, 197) 129 (96.1, 172) 162 (104, 253) 194 (140, 268) 176 (105, 295) 65.8 (23.8, 182) 92.7 (63.9, 135) 112 (84.9, 148) 101 (37.9, 269) 109 (68.9, 174) 191 (117, 313) 154 (118, 203)
3.1 (1.9, 5.6) 3.2 (0.4, 4.2) 4.4 (3.3, 4.8) 2.8 (1.6, 16.7) 3.3 (2.8, 3.9) 3.3 (3.2, 3.3) 3.7 (3.1, 4.1) 2.6 (1.6, 8.1) 2.6 (1.3, 4.4) 2.7 (2.6, 3.2) 3.4 (2.2, 4.5) 3.0 (1.9, 5.8) 3.0 (1.4, 9.8) 2.9 (1.6, 5.9) 4.2 (2.4, 6.8) 3.1 (2.5, 3.9) 2.7 (1.5, 7.1)
33.6 (31.2) 58.4 (10.9) 56.3 (32.4) 36.6 (32.1) 39.1 (19.7) 48.5 (5.2) 43.5 (27.2) 34.6 (9.0) 40.5 (19.6) 35.0 (15.6) 32.4 (4.5) 36.3 (18.7) 42.0 (17.7) 30.5 (5.4) 41.0 (22.5) 43.7 (7.2) 53.0 (27.7)
QD × 21
QD × 4/week
BID × 4/week QD × 5/week
Loading dose QD × 5/week QD × 6/week
D, day; LD, loading dose; QD, daily. Oral dosing schedules include: four consecutive daily doses followed by a 3-day rest (QD × 4); five consecutive daily doses followed by 2-day rest (QD × 5); six consecutive daily doses followed by a 1-day rest (QD × 6); daily doses for 21 days every 4 weeks (QD × 21); once daily doses without interruption (QD × 28); and a loading dose (LD) administered on the first day of every week followed by QD × 4 (LD + QD × 4). b Data presented as geometric mean (95% confidence interval). The calculated Cmax and AUC0–∞ represent the estimated Cmax and AUC0–∞ after a theoretical first dose of the described dosing schedule. c Data presented as median (min, max). d t1/2 represents the terminal t1/2 (t1/2β) from the study. Data presented as harmonic mean (pseudo SD). e Patients in the 15 mg QD × 21 dose cohort received alternating daily doses of 10 and 20 mg that started with 10 mg day 1, 20 mg on day 2, and alternating 10 and 20 mg for the rest of the cycle. f N = 2 for Cmax and AUC0–∞; one patient in the 20 mg BID cohort with no record of day 1 dosing was excluded from Cmax and AUC0–∞ calculation. a
Table 5. The best overall tumor response, according to the RECIST criteria for all treated patients (N = 147) and for the subset of patients with sarcoma (N = 85) Best overall response
Number of patients, n (%) All (N = 147) All sarcoma (N = 85)
Clinical benefit rate 95% confidence interval Partial response Progressive disease Stable disease Unable to evaluate
36 (24.5%) 17.8% to 32.3% 2 (1.4%) 47 (32.0%) 67 (45.6%) 31 (21.1%)
23 (27.1%) 18.0% to 37.8% 2 (2.4%) 21 (24.7%) 45 (52.9%) 17 (20.0%)
In the 40 mg QD × 5 days/week cohort. the Kaplan–Meier estimate of the median overall survival was 37.7 weeks across histologies; median overall survival was not reached in the sarcoma subgroup. The median PFS was 15.4 weeks (N = 24) and 16.1 weeks for the subgroup of 13 patients with sarcoma. Among the patients with sarcoma treated with this dose regimen, the 6-month PFS rate was 23%.
discussion This study investigated the safety, PK, PD, tolerability, and MTD of orally administered ridaforolimus, an mTOR
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inhibitor, in 147 patients with progressive or recurrent malignancies, including 85 patients with sarcoma. Several dosage regimens were examined in this trial. Similar to I.V. ridaforolimus [12, 15], oral ridaforolimus was associated with an acceptable safety profile during this trial with generally mild or moderate and manageable toxic effects. Stomatitis (including mucosal inflammation, oral pain, and mouth ulceration) was observed to be the most common DLT. When these AEs occurred, delayed dosing or reduction in dosage enabled the patient to remain on ridaforolimus and symptomatic treatment of oral events were employed to relieve pain and allow normal oral intake. Rash and other dermatologic events were also frequent. Based on known toxic effects associated with other rapamycin analogs (temsirolimus and everolimus), no unexpected patterns of toxic effects were observed. There were no treatment-related deaths on study. Among tolerable dosing regimens, 40 mg QD × 5 days/week provided the best combination of cumulative dose, dose density, and cumulative exposure, and was selected as the recommended phase II dose. PK parameters for ridaforolimus were nonlinear, with less than proportional increases in model-predicted day 1 blood AUC0–∞ and Cmax, particularly with oral doses >40 mg. The PD activity observed following oral administration of ridaforolimus in this trial was comparable to that seen in
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Dose regimensa
original articles
Annals of Oncology
earlier trials in with I.V. ridaforolimus [12, 15]. With both dosing routes, a median level of p-4E-BP1 inhibition of >90% across all patients was observed at the earliest time-point after the initial dose (4 and 1 h, for oral and I.V, respectively). Sustained inhibition of ≥50% was also observed following oral and I.V. administration, at all post-dose time-points. p-4E-BP1 was selected based on its simple detection in PBMCs and the relationship between ridaforolimus induced inhibition of p-4EBP1 phosphorylation in PBMCs and efficacy in preclinical models [20]. However, although ridaforolimus inhibited its target in PBMC, no correlation was observed between this PD effect and antitumor activity, consistent with findings from other mTOR inhibitors such as everolimus [12, 15, 17, 19]. Oral ridaforolimus had promising antitumor activity in patients with a broad range of advanced solid tumors, including sarcomas. While assessment of antitumor activity was not the primary end point of this study, the 6-month PFS
| Mita et al.
rate of 23% observed in 13 previously treated patients with sarcoma who received the recommended dose of 40 mg QD × 5 days/week exceeds the EORTC recommendation of a 6-month PFS rate of >14%, to identify active treatments in previously treated patients with sarcoma [21]. The median PFS in this study compares favorably with data from several large trials in patients with sarcoma with brivanib and pazopanib [22, 23]. We acknowledge the fact that around 20% of patients were not assessable for efficacy. This is not unusual in phase I studies where patients may not be able to complete two cycles of therapy in order to have restaging imaging studies due to decreased performance status, loss of follow-up, or toxicity. Nonetheless, due to the large number of patients enrolled, we were still able to determine the overall response rate and clinical benefit, therefore completing the secondary objective for this study. In summary, these results suggest that oral ridaforolimus is well tolerated and has antitumor activity in patients with a
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Figure 1. (a). The Kaplan–Meier estimate of the median overall survival for the treated population and the subgroup of patients with sarcoma are shown, for all dosing schedules and for the 40 mg/day for 5 consecutive days schedule. (b). The Kaplan–Meier estimates of the median progression-free survival (PFS) for the treated population and the subgroup of patients with sarcoma are shown, for all dosing schedules and for the 40 mg/day for 5 consecutive days schedule.
Annals of Oncology
broad range of advanced solid tumors, including sarcomas. The dosing regimen of 40 mg QD × 5 days/week is recommended for further development of oral ridaforolimus based on safety, efficacy, PK, and PD data. The activity and overall safety profile demonstrated in this study warrant further evaluation of oral ridaforolimus in patients with advanced cancer, particularly in advanced sarcoma. The dosing regimen of 40 mg QD × 5 days/week oral ridaforolimus has been used in a global, multicenter, placebo-controlled, phase III trial designed to evaluate maintenance therapy in patients with sarcoma [24]. Ridaforolimus is also being evaluated in several other combination studies in different tumor types.
acknowledgement
funding The study protocol was the responsibility of ARIAD Pharmaceuticals, Inc., Cambridge, MA, in collaboration with various health authorities. All analyses were conducted and data interpreted by scientists at ARIAD Pharmaceuticals. All authors had full access to the study data.
disclosure CDB has a received grant from Merck Sharp & Dohme. EHR is an employee of Merck Sharp & Dohme and may hold stock options in the company. BBS is an employee of Merck Sharp & Dohme and may hold stock options in the company. LB was an employee of ARIAD Pharmaceuticals at the time of the study and may hold stock options in the company. VMR is an employee of ARIAD Pharmaceuticals and may hold stock options in the company. JWL was an employee of ARIAD Pharmaceuticals at the time of the study and may hold stock options in the company. PD is an employee of ARIAD Pharmaceuticals and may hold stock options in the company. FH was an employee of ARIAD Pharmaceuticals at the time of the study and may hold stock options in the company. AT has received consulting fees from Merck Sharp & Dohme, Ariad, Abgenomics, Abraxis, Actavis, Celgene, Curis, Dendreon, Exelexis, GSK, Huya, Insert Therapeutics, Invivis, Nektar, Neumedicines, Onyx, Pfizer, PPD Development, ProNai, Regeneron, Spectrum, Supergen, Symphogen, Triphase Accelerator, Veeda, and Zygenia. He is an advisory board member for Adnexus, Ambit, Enzon, Five Prime, Galapagos, Genetech, Intellikine, Janssen, Micromet, Novartis, Otsuka, Sanofi-Aventis, and Vaccinex.
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2. Schmelzle T, Hall MN. TOR, a central controller of cell growth. Cell 2000; 103: 253–262. 3. Hennessy BT, Smith DL, Ram PT et al.. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 2005; 4: 988–1004. 4. Fingar DC, Richardson CJ, Tee AR et al.. mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol Cell Biol 2004; 24: 200–216. 5. Osaki M, Oshimura M, Ito H. PI3K-Akt pathway: its functions and alterations in human cancer. Apoptosis 2004; 9: 667–676. 6. Sansal I, Sellers WR. The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol 2004; 22: 2954–2963. 7. Blume-Jensen P, Hunter T. Oncogenic kinase signaling. Nature 2001; 411: 355–365. 8. Huang S, Houghton PJ. Targeting mTOR signaling for cancer therapy. Curr Opin Pharmacol 2003; 3: 371–377. 9. Raught B, Gingras AC, Sonenberg N. The target of rapamycin (TOR) proteins. Proc Natl Acad Sci USA 2001; 98: 7037–7044. 10. Agarwala SS, Case S. Everolimus (RAD001) in the treatment of advanced renal cell carcinoma: a review. Oncologist 2010; 15: 236–245. 11. Ciuffreda L, Di Sanza C, Incani UC et al.. The mTOR pathway: a new target in cancer therapy. Curr Cancer Drug Targets 2010; 10: 484–495. 12. Mita MM, Mita AC, Chu QS et al.. Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies. J Clin Oncol 2008; 26: 361–367. 13. Squillace RM, Miller D, Cookson M et al.. Antitumor activity of ridaforolimus and potential cell-cycle determinants of sensitivity in sarcoma and endometrial cancer models. Mol Cancer Ther 2011; 10(2): 1959–1968. 14. Rivera VM, Squillace RM, Miller D et al.. Ridaforolimus (AP23573; MK-8669), a potent mTOR inhibitor, has broad antitumor activity and can be optimally administered using intermittent dosing regimens. Mol Cancer Ther 2011; 10: 1059–1071. 15. Hartford CM, Desai AA, Janisch L et al.. A phase I trial to determine the safety, tolerability, and maximum tolerated dose of deforolimus in patients with advanced malignancies. Clin Cancer Res 2009; 15: 1428–1434. 16. Dancey JE. Therapeutic targets: MTOR and related pathways. Cancer Biol Ther 2006; 5: 1065–1073. 17. Garnock-Jones KP, Keating GM. Everolimus: in advanced renal cell carcinoma. Drugs 2009; 69: 2115–2124. 18. Sankhala K, Mita A, Kelly K et al.. The emerging safety profile of mTOR inhibitors, a novel class of anticancer agents. Target Oncol 2009; 4: 135–142. 19. Simpson D, Curran MP. Temsirolimus: in advanced renal cell carcinoma. Drugs 2008; 68: 631–638. 20. Berk L, Mita MM, Kreisberg J et al.. Analysis of the pharmacodynamic activity of the mTOR inhibitor ridaforolimus (AP23573, MK-8669) in a phase 1 clinical trial. Cancer Chemother Pharmacol 2012; 69(4): 1369–1377. 21. van Glabbeke M, Verweij J, Judson I et al.. Progression-free rate as the principal end-point for phase II trials in soft-tissue sarcomas. Eur J Cancer 2002; 38: 543–549. 22. Schwartz GK. Brivanib (BMS-582664) in advanced soft-tissue sarcoma (STS): Biomarker and subset results of a phase II randomized discontinuation trial. J Clin Oncol 2011; 29(suppl; abstr 10000). 23. Van Der Graaf WT. PALETTE: A randomized, double-blind, phase III trial of pazopanib versus placebo in patients ( pts) with soft-tissue sarcoma (STS) whose disease has progressed during or following prior chemotherapy—An EORTC STBSG Global Network Study (EORTC 62072). J Clin Oncol 2011; 26(suppl; abstr LBA10002). 24. Mita A, Britten CD, Poplin E et al.. Deforolimus trial 106—a phase I trial evaluating 7 regimens of oral Deforolimus (AP23573, MK-8669). J Clin Oncol 2008; 26(suppl; abstr 3509).
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The authors thank Jennifer Pawlowski for her editorial assistance and submission of this manuscript.
original articles
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Annals of Oncology 24: 1104–1111, 2013 doi:10.1093/annonc/mds602 Published online 4 December 2012
Phase I/IIa trial of the mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) administered orally in patients with refractory or advanced malignancies and sarcoma† M. M. Mita1*, E. Poplin2, C. D. Britten3, W. D. Tap3,4, E. H. Rubin5, B. B. Scott5, L. Berk6, V. M. Rivera6, J. W. Loewy6, P. Dodion6, F. Haluska6, J. Sarantopoulos1, A. Mita1 & A. Tolcher1 1 Cancer Therapy Research Center, Institute for Drug Development, San Antonio; 2Gastrointestinal/Hepatobiliary Program, Cancer Institute of New Jersey, New Brunswick; 3Division of Medical Oncology, David Geffen School of Medicine, University of California, Los Angeles; 4Sarcoma Oncology, Memorial Sloan-Kettering Cancer Center, New York; 5Merck Sharp & Dohme Corp., Whitehouse Station; 6ARIAD Pharmaceuticals, Inc., Cambridge, USA
Received 22 June 2012; revised 12 October 2012; accepted 15 October 2012
Background: Ridaforolimus is an inhibitor of mTOR with evidence of antitumor activity in an I.V. formulation. This multicenter, open-label, 3 + 3 design nonrandomized, dose-escalation, phase I/IIa trial was conducted to determine the *Correspondence to: Dr M. Mita, Experimental Therapeutics Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, SCCT Mezzanine MS 35, Los Angeles, CA 90048, USA. Tel: +1-310-248-6729; Fax: +1-310-248-6740; E-mail: [email protected] †
This article was presented in part at ASCO 2008, CTOS 2008. AACR-NCI-EORTC 2008.
© The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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Annals of Oncology
original articles
Annals of Oncology
introduction
materials and methods
The mammalian target of rapamycin (mTOR) is a central regulator in a number of signaling pathways involved in cell growth, division, metabolism, and angiogenesis [1, 2]. Growth and nutrient stimuli activate mTOR through PI3K/AKT signaling [3]. In turn, mTOR activates downstream effectors including p70 S6kinase 1 (S6K1) and the eukaryotic initiation factor 4E binding protein 1 (4E-BP1), two important proteins involved in the regulation of ribosomal biosynthesis and the translation of mRNA species involved in cell cycle regulation [4]. The PI3K/AKT/pathway has been linked to oncogenesis in a number of different human cancers [3, 5, 6]. Inhibition of mTOR results in disruption of cell cycle progression and cell growth providing further validation for mTOR as an anticancer target [7–9]. Several rapamycin analogs with improved solubility and stability have been developed, including temsirolimus (CCI-779) and everolimus (RAD001), which received regulatory approval for the treatment of renal cell carcinoma and pancreatic neuroendocrine tumors [10, 11]. Ridaforolimus (AP23573/MK-8669) is an orally available nonprodrug analog of rapamycin and is a potent and selective mTOR inhibitor demonstrated by its ability to prevent downstream activation of S6K1 and 4E-BP1 [12, 13] and inhibits proliferation of a number of different tumor cell lines and xenografts [14]. Phase I studies with I.V. ridaforolimus indicated that it was well tolerated and had promising antitumor activity in a number of different malignancies including sarcoma [12, 15]. This study was a phase I/IIa, open-label, dose-escalation trial of oral ridaforolimus in metastatic or unresectable solid tumors. The primary objective of the study was to determine the safety, tolerability, and maximum tolerated dose (MTD) of oral ridaforolimus. Although not prespecified, the study was enriched for patients with sarcoma based on prior clinical observations [12]. The secondary objectives included assessment of antitumor activity, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of ridaforolimus.
patient selection
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Patients with a histological diagnosis of metastatic or unresectable solid tumors were enrolled. Additional eligibility criteria were as follows: age ≥18 years; an ECOG performance status of 0–2; adequate renal, hepatic, and bone marrow function; serum cholesterol ≤350 mg/dl or triglycerides ≤400 mg/dl; ≥4 weeks from prior anticancer or radiation therapy; no active CNS malignancies or metastases; no prior treatment with mTOR inhibitors; no hypersensitivity to macrolide antibiotics; no significant cardiovascular disease, medical problems, or pregnancy. All study participants provided written informed consent. The protocol was approved by the relevant Institutional Review Boards and carried out according to the guidelines of good clinical practice and with ethical standards for human experimentation.
trial design phase I dosing regimen and escalation This was an open-label, 3 + 3 design nonrandomized, multicenter, phase I/IIa dose-escalation trial to establish safety, tolerability, and MTD of oral ridaforolimus (10-mg enteric-coated tablets). Seven dosing regimens, all on a 28-day cycle, were examined (Table 1). For each regimen, three patients were initially enrolled. In the absence of a dose-limiting toxicity (DLT) during cycle 1 (28 days) of study treatment, enrollment into the next dose level cohort commenced. In the event that one of the three patients experienced a DLT, then three additional patients were enrolled into that cohort. In the event that two of three patients or two of six patients treated at a given dose level experienced a DLT, no further patients were enrolled at that dose level and additional patients were enrolled at the previous dose level. Patient enrollment and dose escalation proceeded until the MTD had been determined. DLTs were defined as any of the following: grade 3 nonhematologic toxicity lasting >3 days despite supportive care, with the exception of self-limiting or medically controllable toxic effects (e.g. fever without neutropenia, nausea, vomiting, fatigue, and hypersensitivity reactions); grade 4 nonhematologic toxicity; grade 4 sustained neutropenia (ANC < 500/mm3, >5 days duration); grade 3 or 4 neutropenia associated with fever (<1000/mm3; >38.5°C) thrombocytopenia (<25 000/mm3); inability, due to any toxicity thought to be associated with the study drug, to complete a total of one dosing cycle, and unresolved toxic effects that delayed retreatment for >2 weeks.
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safety, pharmacokinetic (PK) and pharmacodynamic parameters, maximum tolerated dose, and antitumor activity of oral ridaforolimus. Patients and methods: Patients with metastatic or unresectable solid tumors refractory to therapy were eligible. Seven different continuous and intermittent dosing regimens were examined. Results: One hundred and forty-seven patients were enrolled in this study among which 85 were patients with sarcoma. Stomatitis was the most common DLT observed. The dosing regimen, 40 mg QD × 5 days/week, provided the best combination of cumulative dose, dose density, and cumulative exposure, and was the recommended dosing regimen for subsequent clinical development. PK was nonlinear, with less than proportional increases in day-1 blood AUC0–∞ and Cmax, particularly with doses >40 mg. The terminal half-life estimate of ridaforolimus (QD × 5 40 mg) was 42.0 h, and the mean half-life ∼30–60 h. The clinical benefit rate, (complete response, partial response, or stable disease for ≥4 months was 24.5% for all patients and 27.1% for patients with sarcoma. Conclusion: Oral ridaforolimus had an acceptable safety profile and exhibited antitumor activity in patients with sarcoma and other malignancies. ClinicalTrials.gov Identifier: NCT00112372. Key words: mTOR, rapamycin, ridaforolimus, sarcoma
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Annals of Oncology
Table 1. Maximum tolerated dose and dose-limiting toxic effects by dosing regimen Regimen
Patients treated
Dose (# of patients)
Maximum tolerated dose
QD × 4 (once weekly)
37
20 mg (3) 30 mg (4) 40 mg (10) 50 mg (15) 70 mg (4) 30 mg (14) 40 mg (24) 50 mg (7) 60 mg/ 30 mgd (7) 100 mg/50 mge (5)
Below MTD Below MTD Below MTD MTD Above MTD Below MTD MTD a Above MTDa Not formally determinedb Not formally determinedb
45
LD QD × 5 (once weekly)
12
QD × 6 (once weekly)
13
30 mg
Above MTD
QD × 21 (every 28 days)
18
10 mg (3) 15 mgc (12) 20 mg (3)
Below MTD MTD Above MTD
10 mg (14) 20 mg (4) 20 mg
MTD Above MTD Not determined
QD × 28 (every 28 days)
18
BID × 4 (once weekly)
4
Grade 3 mouth ulceration (1) Grade 3 stomatitis (2)
Grade 2 stomatitis (1) Grade 3 hyperglycemia (1) Grade 3 fatigue/asthenia (2) Grade 2 stomatitis Grade 2 mouth ulceration (2) Grade 2 stomatitis; mouth ulceration
Grade 3 stomatitis (2) Grade 3 stomatitis Grade 2 mouth ulceration (1)
Maximum tolerated dose (MTD), when determined, is shown for each dosing regimen. Loading dose 60 mg/30 mg = QD × 4 days/week: 60 mg day 1, 30 mg days 2–5. Loading dose 100 mg/50 mg = QD × 4 days/week: 100 mg day 1, 50 mg days 2–5. a The MTD of 40 mg for the QD × 5 cohort was based on clinical evidence, by the Sponsor and Principal Investigators, of the safety and tolerability data for all dose levels tested, and not strictly on the number of patients in the cohort who experienced DLTs. Only one patient in the 50 mg QD × 5 days/week cohort experienced a DLT as defined by the protocol. b The 60-mg loading dose + 30 mg days 2–5/week was well tolerated; the 100-mg loading dose + 50 mg days 2–5/week dosing regimen exceeded the MTD. c The 15 mg dose was achieved by alternating daily 10 and 20 mg doses. d Loading dose 60 mg/30 mg = QD × 5/60 mg day 1, 30 mg days 2–5. e Loading dose 100 mg/50 mg = QD × 5/100 mg day 1, 50 mg days 2–5.
patient evaluation
pharmacodynamic analyses
.Patients were screened based on medical histories and laboratory tests. At baseline and during the trial, the following evaluations were carried out: physical examinations, 12-lead ECG, chest X-ray, routine laboratory evaluations, and slit-lamp eye examination. Adverse event (AE) terms were coded according to MedDRA and severity graded according to the US NCI Common Terminology Criteria for AEs, version 3. The primary antitumor activity end point was the clinical benefit rate (CBR), determined using the modified Response Evaluation Criteria for Solid Tumors (RECIST) guidelines. Disease was assessed at baseline and every two cycles (8 weeks) by the appropriate radiologic studies, including CT scans and/or MRI. A patient was classified as having a clinical benefit if the patient experienced a complete response or partial response (PR), or had stable disease (SD) with duration of ≥4 months.
Peripheral blood mononuclear cells (PBMCs) were used to investigate the inhibitory activity of ridaforolimus on mTOR on days 1, 2, 11, 15, 16, and 22 of cycle 1 and day 1 of cycle 2. PBMC protein extracts were analyzed by western blot using an antiphospho-4E-BP1(Ser65/Thr70) [12, 15].
pharmacokinetic analyses Blood samples for PK analysis were collected at day 1, 2, 4, 8, 11, 15, 16, and 22. Samples were analyzed for ridaforolimus using a validated liquid chromatography and tandem mass spectroscopy assay. PK parameters, Cmax, AUC, Tmax, and t1/2 were calculated using WinNonLin software.
| Mita et al.
statistical methods The sample size of the trial was not predetermined and based on the standard 3 + 3 dose-escalation algorithm. Statistical analyses were descriptive in nature with no formal statistical inference. Summary statistics and analyses were provided for all patients, by dose level for each dosing regimen, and for the subgroup of patients with sarcoma. The treated population included all patients who received at least one dose of trial treatment. The first-cycle DLT was determined in those patients who received sufficient trial drug during cycle 1 of treatment to enable an adequate evaluation of the safety of the dosing regimen. An adequate exposure during cycle 1 was defined as having received ≥75% of planned trial drug doses during cycle 1, exclusive of doses missed due to treatment-related toxicity. Inability to complete cycle 1 due to toxicity was considered a DLT. Safety and antitumor activity data are reported for all patients in the treated population and for the subgroup of patients with sarcoma. Survival curves were computed using the Kaplan–Meier [ product limit] method.
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QD × 5 (once weekly)
Dose-limiting toxicity and severity (# of patients)
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Annals of Oncology
results
Table 2. Patient demographics and disease characteristics
general
Characteristics
dose-limiting toxicity and maximum tolerated dose All 147 patients were assessable for toxicity assessment (Table 1). Stomatitis (including mucosal inflammation, oral pain, and mouth ulceration) was the most common DLT. Of the 12 patients with a recorded DLT, 10 experienced stomatitis. One patient each experienced a DLT of grade 3 fatigue and asthenia or grade 3 hyperglycemia. The DLTs included grade 2 events of stomatitis or mouth ulceration that were considered intolerable. All recorded DLT’s resulted in delay in dosing and/or a reduction in dosage. When delayed dosing was warranted, the delay in dosing was ≤2 weeks to allow for amelioration to grade 1 or resolution of the event. The MTD was 50 mg for the QD × 4 days/week dosing regimen, 40 mg for the QD × 5 days/week regimen, 15 mg for the QD × 21 regimen, and 10 mg for the QD × 28 regimen (Table 2). The pre-specified protocol criteria for an MTD were not reached for the QD × 5 days/week, and the recommended dose for this regimen was determined to be 40 mg by the Sponsor and Principal Investigators, considering the safety and tolerability data for all dose levels tested. One patient in the 50 mg QD × 5 days/week experienced a DLT, and two experienced grade 3 toxic effects that did not meet the definition of a DLT. None of the 24 patients receiving 40-mg ridaforolimus QD × 5 days/week experienced a DLT.
safety profile AEs were reported for 146 (99.3%) of the 147 patients in the treated population, and the most commonly encountered (≥10%) treatment-related AEs are summarized (Table 3). There was no indication of ridaforolimus-induced immunosuppression.
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All treated patients
Number of patients 147 Median age (range), years 55 (23–84) Sex, n (%) Male 65 (44.2) Female 82 (55.8) ECOG performance status, n (%) 0 45 (30.6) 1 88 (59.9) 2 13 (8.8) Missing 1 (0.7) Location of primary tumor Sarcoma 85 Soft tissue 66 Ewing 2 Other bone sarcomas 3 Uterine 14 Colorectal 10 Breast 9 Other tumor type < 5% 43 Prior anticancer treatment 0 12 Mean (SD) 3.4 (2.37) Median 3 Min–max 0–11
Treated patients with sarcoma 85 54 (23–84) 33 (38.8) 52 (12.9) 31 (36.5) 49 (57.6) 4 (4.7) 1 (1.2)
2.7 (1.80) 3 0–8
Stomatitis was frequent in this trial (Table 3) and is an AE associated with mTOR inhibitors [12, 16–19]. The majority of the oral events were mild or moderate in severity and were treated symptomatically, with typical complete resolution. Rash and dermatologic events were also common treatmentrelated AEs; however, most were mild to moderate in severity with no grade 3 or 4 events. Pneumonitis is a known AE associated with mTOR inhibitors [12, 17, 19] and a variety of pulmonary events were reported and considered by the investigator to be treatment related, including dyspnea in 10 patients (6.8%), pneumonitis in 10 patients (6.8%), cough in 4 patients (2.7%), and 1 patient with interstitial lung disease (ILD) (0.7%). Most patients diagnosed with pneumonitis or ILD had their treatment suspended for 1–3 weeks and received a short course of oral corticosteroids. Ridaforolimus was resumed in some cases without recurrence of toxicity. As observed with other rapamycin analogs, treatment-related metabolic disorder events were frequent; 15.0% of the patients experienced hypertriglyceridemia; and 18.4% experienced hypercholesterolemia. The majority of these events were mild or moderate in severity and reversible with adequate treatment. Similar to other rapamycin analogs, hematological AEs were reported; 24.5% of patients experienced anemia; 20.4% thrombocytopenia and 6.1% neutropenia that were considered treatment related. The majority of these events were grade 1 or 2. There were no apparent differences in the safety profile of ridaforolimus in the subgroup of patients with sarcoma
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A total of 147 patients received at least one dose of ridaforolimus between May 2005 and December 2008. Pretreatment characteristics are outlined (Table 2). Eighty-five patients had a diagnosis of sarcoma and 62 patients with solid tumors other than sarcoma. Most patients in the treated population (82.3%) had stage IV disease. Treated patients received study drug for a median of 53 days (range 1–1064 days). The median cumulative dose of ridaforolimus received per patient was 960 mg (range 40–20 650 mg). Patients with a diagnosis of sarcoma received ridaforolimus for a median of 56 days (range 1–591 days) and the median cumulative dose received was 1250 mg (range 40–20 650 mg). The total predicted exposure of ridaforolimus over the first cycle (AUC0–28 days) was dependent on regimen. The QD × 4 (50 mg), QD x5 (40 mg), and QD × 6 (30 mg) dosing regimens administered similar cumulative dose amounts over a 4-week cycle (800, 800, and 720 mg, respectively). The calculated total predicted exposure of ridaforolimus was similar between these groups. The QD × 21 (15 mg) and QD × 28 (10 mg) dosing groups were administered up to 315-mg cumulative dose amounts over the 4-week cycle.
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Annals of Oncology
observed at most post-dose time-points analyzed throughout the 28-day cycle, including time-points 4 days after dosing. In the QD × 21 days schedule, >70% inhibition was observed at all time-points within 24 h of dosing, whereas reduced inhibition of ∼50% was observed at the time-point eight days after dosing (i.e. cycle 2 day 1) (data not shown).
compared with the other solid tumors. Besides those described above, there were no unexpected changes in hematology, chemistry, urinalysis, and ECG parameters because of exposure to ridaforolimus. Treatment-related (investigator assessment) grade 4 toxic effects were observed in 4 (2.7%) patients. These included a grade 4 cerebellar infarction, which resolved with sequelae; a grade 4 gastrointestinal fistula and grade 4 sepsis both of which resolved; a grade 4 elevated lipase level and a grade 4 anemia, which resolved after a delay in treatment. Treatment-related grade 3 toxic effects were observed in 47 (32.0%) patients, grade 2 toxic effects in 73 (49.7%) patients, and grade 1 toxic effects in 15 (10.2%) patients (Table 3). No deaths in patients who received ridaforolimus or within 30 days of last dose were considered by the investigator to be related to study drug. Seventy deaths were reported on study, most due to the progression of the underlying malignancy, of which 23 deaths occurred within 30 days of the last dose of ridaforolimus.
tumor response
pharmacokinetics and pharmacodynamics Blood samples from 129 patients were used to determine the PK parameters for ridaforolimus according to dosing regimen (Table 4). The terminal half-life estimate of ridaforolimus in the QD × 5 40 mg group was 42.0 h. The median time to achieve maximum concentration (Tmax) was approximately 3 h. The mean half-life estimate (t1/2) of ridaforolimus spanned ∼30–60 h across all dosing regimens. Oral ridaforolimus inhibited mTOR activity in PBMCs. In all 141 patients analyzed, p-4E-BP1 levels were strongly and rapidly reduced with a median level of inhibition across all patients of >90% at both 4 and 24 h after dosing. When ridaforolimus was administered on a QD × 4 days/week, QD × 5 days/week, QD × 6 days/week, or QD × 28 days schedule, median levels of at least ∼70% inhibition were Table 3. Treatment-related adverse events occurring in ≥10% of treated patients Treatment-related adverse events Fatigue Mucosal inflammation Rash Mouth ulceration Anemia Stomatitis Diarrhea Nausea Thrombocytopenia Hypercholesterolemia Anorexia Hypertriglyceridemia Aspartate aminotransferase increased Alanine aminotransferase increased Dysgeusia Hyperglycemia Vomiting Decreased appetite
| Mita et al.
All treated patients (N = 147) Total N (%) Grade 1
Grade 2
Grade 3
Grade 4
72 (49.0) 71 (48.3) 45 (30.6) 43 (29.3) 36 (24.5) 35 (23.8) 34 (23.1) 31 (21.1) 30 (20.4) 27 (18.4) 26 (17.7) 22 (15.0) 20 (13.6) 19 (12.9) 19 (12.9) 19 (12.9) 19 (12.9) 15 (10.2)
32 (21.8%) 33 (22.4%) 2 (1.4%) 11 (7.5%) 19 (12.9%) 13 (8.8%) 10 (6.8%) 7 (4.8%) 10 (6.8%) 5 (3.4) 8 (5.4) 6 (4.1) 8 (5.4) 6 (4.1) 1 (0.7) 7 (4.8) 4 (2.7) 1 (0.7)
7 (4.8%) 5 (3.4%) 0 (0.0%) 2 (1.4%) 6 (4.1%) 1 (0.7%) 1 (0.7%) 5 (3.4%) 6 (4.1%) 0 (0.0%) 2 (1.4) 2 (1.4) 2 (1.4) 1 (0.7) 0 (0.0%) 7 (4.8) 4 (2.7) 0 (0.0%)
0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
33 (22.4%) 33 (22.4%) 43 (29.3%) 30 (20.4%) 10 (6.8%) 21 (14.3%) 23 (15.6%) 19 (12.9%) 14 (9.5%) 22 (15.0) 16 (10.9) 14 (9.5) 10 (6.8) 12 (8.2) 18 (12.2) 5 (3.4) 11 (7.5) 14 (9.5)
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Across all dosing regimens for the treated population, the CBR was 24.5% for the treated population and 27.1% for the sarcoma subgroup (Table 5). The highest CBRs in subgroups with 10 patients or more were for the intermittent dosing regimens 30 mg QD × 5 days/week: 57.1% (8 of 14 patients); 30-mg QD × 6 days/week: 38.5% (5 of 13 patients) and 40-mg Qd × 5 in sarcoma 23% (3 of 13 patients with sarcoma). The best overall response was PR for 2 (1.4%) and SD for ≥8 weeks for 67 (45.6%) of the 147 patients (Table 5). The best overall response for the 85 patients in the sarcoma subgroup was PR for two patients (2.4%) and SD for 45 (52.9%). The best overall response was PR for two patients in the 40 mg QD × 5 days/week cohort, a 63-year-old female with a diagnosis of stage IV abdominal liposarcoma; and a 48-yearold female with a diagnosis of stage IV follicular dendritic cell sarcoma of the pelvis and retroperitoneum. The duration of the PR was 4 months for the first patient; and >11 months for the second patient (ongoing at the time of database lock). Across all dosing regimens, the Kaplan–Meier estimate of the median overall survival was 37.7 weeks for all patients and 42.7 weeks for the sarcoma subgroup (Figure 1a). Estimated median progression-free survival (PFS) (Kaplan–Meier estimate) for all patients was 12.1 weeks, and for the sarcoma subgroup was 17.1 weeks (Figure 1b). In the 85 patients with sarcoma across all dose levels, ridaforolimus administration resulted in a 6-month PFS rate of 29%.
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Annals of Oncology
Table 4. Summary of whole-blood model-predicted pharmacokinetic parameters of ridaforolimus in male and female patients with advanced malignancy stratified by dosing regimen (N = 129) Dose (mg)
N
AUCb0–∞ (ng·h/ml)
Cbmax (ng/ml)
Tcmax (h)
td1/2 (h)
QD × 28
10 20 10 15e 20 20 30 40 50 70 20 30 40 50 60 + 30 100 + 50 30
13 3 3 11 2 2 4 8 12 5 3f 13 20 5 7 5 13
696 (523, 925) 1858 (646, 5350) 941 (201, 4410) 645 (419, 994) 1049 (91, 2100) 990 (19, 51 300) 2017 (659, 6170) 2436 (1930, 3070) 2342 (1850, 2960) 2473 (1620, 3780) 998 (510, 2890) 1397 (955, 2040) 2017 (1730, 2350) 1436 (829, 2490) 2241 (1330, 3760) 4313 (2330, 7990) 2224 (1790, 2760)
55.2 (41.6, 73.1) 105 (16.2, 675) 46.2 (11.0, 194) 38.3 (18.2, 80.4) 107 (0.7, 15 800) 96.0 (46.8, 197) 129 (96.1, 172) 162 (104, 253) 194 (140, 268) 176 (105, 295) 65.8 (23.8, 182) 92.7 (63.9, 135) 112 (84.9, 148) 101 (37.9, 269) 109 (68.9, 174) 191 (117, 313) 154 (118, 203)
3.1 (1.9, 5.6) 3.2 (0.4, 4.2) 4.4 (3.3, 4.8) 2.8 (1.6, 16.7) 3.3 (2.8, 3.9) 3.3 (3.2, 3.3) 3.7 (3.1, 4.1) 2.6 (1.6, 8.1) 2.6 (1.3, 4.4) 2.7 (2.6, 3.2) 3.4 (2.2, 4.5) 3.0 (1.9, 5.8) 3.0 (1.4, 9.8) 2.9 (1.6, 5.9) 4.2 (2.4, 6.8) 3.1 (2.5, 3.9) 2.7 (1.5, 7.1)
33.6 (31.2) 58.4 (10.9) 56.3 (32.4) 36.6 (32.1) 39.1 (19.7) 48.5 (5.2) 43.5 (27.2) 34.6 (9.0) 40.5 (19.6) 35.0 (15.6) 32.4 (4.5) 36.3 (18.7) 42.0 (17.7) 30.5 (5.4) 41.0 (22.5) 43.7 (7.2) 53.0 (27.7)
QD × 21
QD × 4/week
BID × 4/week QD × 5/week
Loading dose QD × 5/week QD × 6/week
D, day; LD, loading dose; QD, daily. Oral dosing schedules include: four consecutive daily doses followed by a 3-day rest (QD × 4); five consecutive daily doses followed by 2-day rest (QD × 5); six consecutive daily doses followed by a 1-day rest (QD × 6); daily doses for 21 days every 4 weeks (QD × 21); once daily doses without interruption (QD × 28); and a loading dose (LD) administered on the first day of every week followed by QD × 4 (LD + QD × 4). b Data presented as geometric mean (95% confidence interval). The calculated Cmax and AUC0–∞ represent the estimated Cmax and AUC0–∞ after a theoretical first dose of the described dosing schedule. c Data presented as median (min, max). d t1/2 represents the terminal t1/2 (t1/2β) from the study. Data presented as harmonic mean (pseudo SD). e Patients in the 15 mg QD × 21 dose cohort received alternating daily doses of 10 and 20 mg that started with 10 mg day 1, 20 mg on day 2, and alternating 10 and 20 mg for the rest of the cycle. f N = 2 for Cmax and AUC0–∞; one patient in the 20 mg BID cohort with no record of day 1 dosing was excluded from Cmax and AUC0–∞ calculation. a
Table 5. The best overall tumor response, according to the RECIST criteria for all treated patients (N = 147) and for the subset of patients with sarcoma (N = 85) Best overall response
Number of patients, n (%) All (N = 147) All sarcoma (N = 85)
Clinical benefit rate 95% confidence interval Partial response Progressive disease Stable disease Unable to evaluate
36 (24.5%) 17.8% to 32.3% 2 (1.4%) 47 (32.0%) 67 (45.6%) 31 (21.1%)
23 (27.1%) 18.0% to 37.8% 2 (2.4%) 21 (24.7%) 45 (52.9%) 17 (20.0%)
In the 40 mg QD × 5 days/week cohort. the Kaplan–Meier estimate of the median overall survival was 37.7 weeks across histologies; median overall survival was not reached in the sarcoma subgroup. The median PFS was 15.4 weeks (N = 24) and 16.1 weeks for the subgroup of 13 patients with sarcoma. Among the patients with sarcoma treated with this dose regimen, the 6-month PFS rate was 23%.
discussion This study investigated the safety, PK, PD, tolerability, and MTD of orally administered ridaforolimus, an mTOR
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inhibitor, in 147 patients with progressive or recurrent malignancies, including 85 patients with sarcoma. Several dosage regimens were examined in this trial. Similar to I.V. ridaforolimus [12, 15], oral ridaforolimus was associated with an acceptable safety profile during this trial with generally mild or moderate and manageable toxic effects. Stomatitis (including mucosal inflammation, oral pain, and mouth ulceration) was observed to be the most common DLT. When these AEs occurred, delayed dosing or reduction in dosage enabled the patient to remain on ridaforolimus and symptomatic treatment of oral events were employed to relieve pain and allow normal oral intake. Rash and other dermatologic events were also frequent. Based on known toxic effects associated with other rapamycin analogs (temsirolimus and everolimus), no unexpected patterns of toxic effects were observed. There were no treatment-related deaths on study. Among tolerable dosing regimens, 40 mg QD × 5 days/week provided the best combination of cumulative dose, dose density, and cumulative exposure, and was selected as the recommended phase II dose. PK parameters for ridaforolimus were nonlinear, with less than proportional increases in model-predicted day 1 blood AUC0–∞ and Cmax, particularly with oral doses >40 mg. The PD activity observed following oral administration of ridaforolimus in this trial was comparable to that seen in
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Dose regimensa
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Annals of Oncology
earlier trials in with I.V. ridaforolimus [12, 15]. With both dosing routes, a median level of p-4E-BP1 inhibition of >90% across all patients was observed at the earliest time-point after the initial dose (4 and 1 h, for oral and I.V, respectively). Sustained inhibition of ≥50% was also observed following oral and I.V. administration, at all post-dose time-points. p-4E-BP1 was selected based on its simple detection in PBMCs and the relationship between ridaforolimus induced inhibition of p-4EBP1 phosphorylation in PBMCs and efficacy in preclinical models [20]. However, although ridaforolimus inhibited its target in PBMC, no correlation was observed between this PD effect and antitumor activity, consistent with findings from other mTOR inhibitors such as everolimus [12, 15, 17, 19]. Oral ridaforolimus had promising antitumor activity in patients with a broad range of advanced solid tumors, including sarcomas. While assessment of antitumor activity was not the primary end point of this study, the 6-month PFS
| Mita et al.
rate of 23% observed in 13 previously treated patients with sarcoma who received the recommended dose of 40 mg QD × 5 days/week exceeds the EORTC recommendation of a 6-month PFS rate of >14%, to identify active treatments in previously treated patients with sarcoma [21]. The median PFS in this study compares favorably with data from several large trials in patients with sarcoma with brivanib and pazopanib [22, 23]. We acknowledge the fact that around 20% of patients were not assessable for efficacy. This is not unusual in phase I studies where patients may not be able to complete two cycles of therapy in order to have restaging imaging studies due to decreased performance status, loss of follow-up, or toxicity. Nonetheless, due to the large number of patients enrolled, we were still able to determine the overall response rate and clinical benefit, therefore completing the secondary objective for this study. In summary, these results suggest that oral ridaforolimus is well tolerated and has antitumor activity in patients with a
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Figure 1. (a). The Kaplan–Meier estimate of the median overall survival for the treated population and the subgroup of patients with sarcoma are shown, for all dosing schedules and for the 40 mg/day for 5 consecutive days schedule. (b). The Kaplan–Meier estimates of the median progression-free survival (PFS) for the treated population and the subgroup of patients with sarcoma are shown, for all dosing schedules and for the 40 mg/day for 5 consecutive days schedule.
Annals of Oncology
broad range of advanced solid tumors, including sarcomas. The dosing regimen of 40 mg QD × 5 days/week is recommended for further development of oral ridaforolimus based on safety, efficacy, PK, and PD data. The activity and overall safety profile demonstrated in this study warrant further evaluation of oral ridaforolimus in patients with advanced cancer, particularly in advanced sarcoma. The dosing regimen of 40 mg QD × 5 days/week oral ridaforolimus has been used in a global, multicenter, placebo-controlled, phase III trial designed to evaluate maintenance therapy in patients with sarcoma [24]. Ridaforolimus is also being evaluated in several other combination studies in different tumor types.
acknowledgement
funding The study protocol was the responsibility of ARIAD Pharmaceuticals, Inc., Cambridge, MA, in collaboration with various health authorities. All analyses were conducted and data interpreted by scientists at ARIAD Pharmaceuticals. All authors had full access to the study data.
disclosure CDB has a received grant from Merck Sharp & Dohme. EHR is an employee of Merck Sharp & Dohme and may hold stock options in the company. BBS is an employee of Merck Sharp & Dohme and may hold stock options in the company. LB was an employee of ARIAD Pharmaceuticals at the time of the study and may hold stock options in the company. VMR is an employee of ARIAD Pharmaceuticals and may hold stock options in the company. JWL was an employee of ARIAD Pharmaceuticals at the time of the study and may hold stock options in the company. PD is an employee of ARIAD Pharmaceuticals and may hold stock options in the company. FH was an employee of ARIAD Pharmaceuticals at the time of the study and may hold stock options in the company. AT has received consulting fees from Merck Sharp & Dohme, Ariad, Abgenomics, Abraxis, Actavis, Celgene, Curis, Dendreon, Exelexis, GSK, Huya, Insert Therapeutics, Invivis, Nektar, Neumedicines, Onyx, Pfizer, PPD Development, ProNai, Regeneron, Spectrum, Supergen, Symphogen, Triphase Accelerator, Veeda, and Zygenia. He is an advisory board member for Adnexus, Ambit, Enzon, Five Prime, Galapagos, Genetech, Intellikine, Janssen, Micromet, Novartis, Otsuka, Sanofi-Aventis, and Vaccinex.
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The authors thank Jennifer Pawlowski for her editorial assistance and submission of this manuscript.
original articles