A Prospective, Multicenter Phase II Study of the Efficacy and Feasibility of 15-minute Panitumumab Infusion Plus Irinotecan for Oxaliplatin- and Irinotecan-refractory, KRAS Wild-type Metastatic Colorectal Cancer (Short Infusion of Panitumumab Trial)

Accepted Manuscript A prospective, multicenter phase II study of the efficacy and feasibility of 15-min panitumumab infusion plus irinotecan for oxaliplatin- and irinotecan-refractory, KRAS wild-type metastatic colorectal cancer (SHIP) Kohei Akiyoshi, Tetsuya Hamaguchi, Kenichi Yoshimura, Naoki Takahashi, Yoshitaka Honma, Satoru Iwasa, Atsuo Takashima, Ken Kato, Yasuhide Yamada, Hisashi Onodera, Shigeyuki Takeshita, Hisateru Yasui, Gen Sakai, Sotaro Akatsuka, Kohei Ogawa, Yosuke Horita, Yushi Nagai, Yasuhiro Shimada PII:

S1533-0028(16)30169-4

DOI:

10.1016/j.clcc.2017.10.004

Reference:

CLCC 398

To appear in:

Clinical Colorectal Cancer

Received Date: 26 September 2016 Revised Date:

25 September 2017

Accepted Date: 10 October 2017

Please cite this article as: Akiyoshi K, Hamaguchi T, Yoshimura K, Takahashi N, Honma Y, Iwasa S, Takashima A, Kato K, Yamada Y, Onodera H, Takeshita S, Yasui H, Sakai G, Akatsuka S, Ogawa K, Horita Y, Nagai Y, Shimada Y, A prospective, multicenter phase II study of the efficacy and feasibility of 15-min panitumumab infusion plus irinotecan for oxaliplatin- and irinotecan-refractory, KRAS wild-type metastatic colorectal cancer (SHIP), Clinical Colorectal Cancer (2017), doi: 10.1016/j.clcc.2017.10.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Original Study A prospective, multicenter phase II study of the efficacy and feasibility of 15-min

KRAS wild-type metastatic colorectal cancer (SHIP)

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, Kenichi Yoshimura3, Naoki Takahashi1,

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Kohei Akiyoshi1,2, Tetsuya Hamaguchi1,

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panitumumab infusion plus irinotecan for oxaliplatin- and irinotecan-refractory,

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Yoshitaka Honma1, Satoru Iwasa1, Atsuo Takashima1, Ken Kato1, Yasuhide Yamada1, Hisashi Onodera4, Shigeyuki Takeshita5, Hisateru Yasui6, Gen Sakai7, Sotaro Akatsuka8,

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Kohei Ogawa9, Yosuke Horita10, Yushi Nagai1 & Yasuhiro Shimada1

Gastrointestinal Oncology Division, National Cancer Center Hospital, Tokyo;

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Department of Medical Oncology, Osaka City General Hospital, Osaka; 3Statistician,

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1

Innovative Clinical Research Center, Kanazawa University, Ishikawa; 4General Surgery

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Department, St. Luke’s International Hospital, Tokyo; 5Department of Internal Medicine, Japanese Red Cross Nagasaki Genbaku Hospital, Nagasaki; 6Medical Oncology Division, Kyoto Medical Center, Kyoto; 7Division of Gastroenterology, Saiseikai Utsunomiya Hospital, Tochigi; 8Department of Oncology, Yokohama Rosai Hospital, Kanagawa ; 9Department of Gastroenterology, Toyama University Hospital, Toyama; 10

Department of Internal Medicine, Toyama Prefectural Central Hospital, Toyama, 1

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Japan; 11Departoment of Gastroenterological Oncology, Comprehensive Cancer Center,

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Saitama Medical University International Medical Center

Correspondence to:

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Tetsuya Hamaguchi

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Department of Gastroenterological Oncology, Comprehensive Cancer Center Saitama Medical University International Medical Center 1397-1, Yamane, Hidaka-City, Saitama-Pref, Japan

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Tel: +81 429844111, Fax: +81 429844582, e-mail: [email protected]

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Running Title: Phase II study of 15-min panitumumab infusion with irinotecan

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Abstract Background: In some recently updated clinical guidelines, the fully humanized

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monoclonal antibody panitumumab, in combination with irinotecan, is recommended as an optional third-line chemotherapy for KRAS wild type metastatic colorectal cancer

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safety of short 15-min panitumumab infusions.

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(mCRC). This prospective, multicenter phase II study evaluated the effectiveness and

Patients and Methods: Between January 2011 and December 2011, patients with KRAS wild-type mCRC were enrolled at 8 centers. Key eligibility criteria were age ≥20 years, and resistance or intolerance to irinotecan, fluoropyrimidine and oxaliplatin. All

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patients received 6 mg/kg panitumumab and 150 mg/m2 or the prior tolerated dose of irinotecan, biweekly, until disease progression or unacceptable toxicity. The initial

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panitumumab infusion was 60 min, followed by a 30-min infusion, and then 15-min

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infusions. The primary endpoint was the confirmed response rate by RECIST 1.0. Secondary endpoints were progression-free survival, overall survival and toxicity. This trial is registered Clinical trial information, number UMIN 000004647. Results: Among the 43 patients, the median age (range) was 62 years (32-75 years), 58% were male, and the ECOG performance status was 0 to 1. The total response rate was 37.2% (95% confidence interval [CI], 23.0-53.3) and confirmed response rate was

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18.6% (95% confidence interval [CI], 8.4-33.4). Median progression-free and overall survival were 5.8 months (95% CI, 3.3-8.4) and 13.6 months (95% CI, 10.8-16.5),

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respectively. The most frequent Grade 3/4 toxicities were anorexia (12%), leucopenia (9%) and neutropenia (9%). Nine patients did not reach the 15-min infusion, primarily

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because to disease progression before then. No infusion-related reactions were

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observed.

Conclusion: The short 15-min panitumumab infusion regimen was well tolerated, without compromising safety or efficacy in patients with KRAS wild-type, oxaliplatinand irinotecan-refractory mCRC.

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Key words: panitumumab, short infusion, infusion-related reaction, feasibility,

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metastatic colorectal cancer,

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MicroAbstract:

This prospective, multicenter phase II study was conducted to evaluate the

feasibility of shorter, 15-min panitumumab infusions in patients with KRAS wild-type oxaliplatin- or irinotecan-refractory metastatic colorectal cancer. The findings indicate that 15-min panitumumab infusions had similar efficacy to that in previous reports, with no infusion-related reactions or increases in the frequency or severity of adverse events.

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Introduction Colorectal cancer (CRC) is the third and fourth leading cause of cancer-related

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morbidity and mortality worldwide 1. In Japan, the number of CRC cases has rapidly increased over recent years and it has become the second most common malignancy.

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Estimates suggest that 104,700 new cases of CRC are diagnosed in Japan annually 2.

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Although metastatic CRC (mCRC) is considered to be an incurable disease, cytotoxic agents and new molecularly targeted drugs have prolonged survival times. The monoclonal antibodies cetuximab and panitumumab, which both target epithelial growth factor receptor (EGFR), are recommended as first- to third- line

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standard treatment for wild-type KRAS exon 2 mCRC. Recent data suggest that patients with wild-type KRAS by extended analysis (exons 3 or 4 of KRAS or exons 2–4 of 3-5

. Panitumumab was developed

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NRAS) are likely to benefit from anti-EGFR therapy

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subsequent to cetuximab, but previous clinical trial indicate that the two antibodies have almost equivalent efficacy 6. However, there are several differences between these agents. Cetuximab is a chimeric monoclonal antibody, whereas panitumumab is a fully humanized monoclonal antibody. Therefore, infusion-related reactions are less frequent with panitumumab (0.5%) than cetuximab (5%)

7, 8

. In addition, the results of the

BOND trial suggest that the combination of cetuximab and irinotecan has higher

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efficacy than cetuximab alone as third-line treatment 9. A previous study demonstrated that the combination of panitumumab and irinotecan was effective in patients with 10

. As a consequence,

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KRAS wild-type, oxaliplatin- or irinotecan-refractory mCRC

panitumumab and irinotecan chemotherapy is recommended as an optional third-line

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chemotherapy in some updated clinical guidelines 1112.

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Another study revealed that the 60- and 30-min infusion regimens of panitumumab had a similar safety and pharmacokinetic profile, and no significant infusion-related reactions were observed

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. Although a shorter, 15-min infusion of

panitumumab has the potential to enhance patient convenience, published data on the

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feasibility of this regimen are not available. Therefore, this was a prospective, multicenter, phase II study to determine the effectiveness and safety of 15-min

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panitumumab infusions, using standard 60-min infusions as a historical control (SHIP

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trial: Short Infusion of Panitumumab).

Patients and methods Study design and eligibility criteria Between January 2011 and December 2011, 43 patients who received at least one cycle of treatment were enrolled from 8 Japanese institutions. The cut-off date for

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collection of follow-up data was December 18, 2012. The

inclusion

criteria

were

as

follows:

histologically

confirmed

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adenocarcinoma, mucinous carcinoma or signet ring-cell carcinoma; unresectable mCRC; KRAS wild type; aged between 20 and 75 years; ECOG performance status of 0,

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1 or 2; expected to survive for at least 2 months after enrollment; with at least 1

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measurable lesion according to the RECIST 1.0 criteria; resistance or intolerance to fluoropyrimidines, oxaliplatin and irinotecan; no prior anti-EGFR therapy; adequate bone marrow function (white blood cell ≥3000 count /mm3, platelets ≥7.5×104 count/mm3, haemoglobin ≥8.0g/dl), renal function (serum creatinine ≤1.5mg/dl),

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hepatic function (bilirubin ≤1.5×upper limit of normal, aspartate aminotransferase and alanine aminotransferase ≤2.5×upper limit of normal; and, the required treatment-free

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interval of at least 4 weeks since surgery, radiation or chemotherapy.

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The exclusion criteria were as follows: other active malignancies within the last 5 years; a history of severe drug hypersensitivity; clinically significant infectious disease; severe complications, including obvious bowel obstruction, interstitial lung disease, pulmonary fibrosis, uncontrolled diabetes mellitus, and heart, renal or hepatic failure; moderate to severe pleural effusion and/or ascites; symptomatic brain metastasis; blood transfusion required for gastrointestinal bleeding during the 14 days

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before enrollment; and, any other cases deemed unsuitable for enrollment by the investigator.

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The study was fully compliant with the Declaration of Helsinki. The study protocol was approved by the institutional review board of each participating institution.

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Written informed consent was obtained from all patients prior to participation.

Treatment

All patients received biweekly chemotherapy comprising panitumumab and irinotecan, as well as antiemetic premedication with 5-HT3 and dexamethasone.

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Panitumumab was administered at a dose of 6 mg/kg and irinotecan at a dose of either 150 mg/m2 or the tolerated irinotecan dose during prior treatment. All chemotherapeutic

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and antiemetic agents were administered at the approved doses in Japan (Figure 1). The

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initial panitumumab infusion was administered over 60 min, followed by a 30-min infusion, and then 15-min infusions unless infusion rerated reaction occurred. Treatment was continued until disease progression or unacceptable toxicity. Pre-emptive topical adapalen and oral minocycline was administered to all patients with acne-like skin conditions, as previously described

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. Panitumumab was stopped for a moment in the

case of Grade 2 infusion-related or hypersensitivity reactions. If the reaction resolved to

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Grade 1 or less, infusion was resumed at half the previous infusion rate. If a patient experienced a Grade 3 or worse hypersensitivity reaction, chemotherapy was

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immediately discontinued, and intramuscular injections of epinephrine, an antihistamine drug, with or without intravenous steroids and oxygen were given, according to medical

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indications, and that protocol treatment was persistently stopped.

Assessment

Tumor response was assessed with the RECIST version 1.0 after every fourth administration until disease progression or withdrawal from the trial, corresponding to

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clinical practice. Responses were confirmed at least 28 days after the criteria for response were first met. Tumor assessment was performed on the basis of each

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investigator’s judgment. Toxicity was graded according to the National Cancer Institute

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Common Toxicity Criteria (version 4.0.).

Statistical analysis

The primary outcome was assessed according to the intention-to-treat principle. The primary endpoint was the confirmed objective response rate according to RECIST 1.0. The Key Secondary endpoints were the feasibility of short 30- or 15-min infusions

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of panitumumab, progression-free survival, overall survival, total objective response and the disease control rate. Total objective response rate was defined as the sum of

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confirmed response rate and unconfirmed response rate. Unconfirmed response rate was defined as the percentage of patients who were not confirmed at least 28 days after the

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criteria for response were first met. Stable disease was defined as the assessment which

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did not turn out total objective response or progressive disease in the course of treatment. Progression-free survival was defined as the number of days from registration to disease progression or death from any cause, censored on the last day the patient was alive without evidence of progression. Overall survival was defined as the

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number of days from registration to death from any cause, censored on the last day the patient was alive. Progression-free survival and overall survival were analyzed based on

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the Kaplan-Meier method, and the event rates are presented with 95% confidence

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intervals (CIs) for each endpoint. The disease control rate was defined as the percentage of patients who achieved a complete response, a partial response and stable disease. The sample size of 40 subjects receiving panitumumab with irinotecan was based on expected and threshold response rates of 30% and 10%, respectively, as assumed from previous reports

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, and α and β errors of 0.05 and 0.1, respectively. All statistical

analyses were conducted using SAS software (version 9.1.3; SAS Institute. Cary, NC,

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USA).

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This trial is registered Clinical trial information, number UMIN 000004647.

Results

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The baseline characteristics of the study population are shown in Table 1.

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Among the 43 patients, the median age was 62 years (range: 32–75 years) and 58% were male. The ECOG performance status was 0 or 1 in all patients, the primary location were rectum in 53% of patients, and 67% of patients previously treated with bevacizumab.

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After a median follow-up of 16.8 months (range: 12.5-23.6 months), 10 patients continued on treatment, while 19 and 13 patients had discontinued due to

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disease progression and adverse events, respectively (Figure 2). With respect to disease

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responses, 16 patients had a partial response (8 responses was confirmed and 8 responses was unconfirmed), 13 patients had stable disease, 12 patients had disease progression, and 2 were not evaluable. The total response rate was 37.2% (95% CI, 23.0-53.3) and confirmed response rate was 18.6% (95% CI, 8.4-33.4), with a disease control rate of 67.4% (95% CI, 51.5-80.9). Early tumor shrinkage, defined as >30% reduction at the first evaluation, was observed in 35% of patients (Table 2).

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Unfortunately, it was not possible to confirm a partial response in 7 of the patients with early shrinkage, mainly due to inappropriate imaging follow-up. The median time from

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partial response to the next evaluation was 10.0 weeks (8.1-19.3 weeks). Median progression-free survival was 5.8 months (95% CI, 3.3-8.4; Figure 3) and median

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overall survival was 13.6 months (95% CI, 10.8-16.5; Figure 4). Twenty patients

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(47.6%) exhibited prominent tumor shrinkage during treatment (Figure 5). The 60-min infusion was administered to 43 patients for 62 doses, the 30-min infusion to 40 patients for 55 doses, and the 15-min infusion to 34 patients for 187 doses (Table 3). During protocol treatment, nine patients were unable to reach the 15-min

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infusion for the following reasons: disease progression (n=4), adverse events (n=3; diarrhea, constipation and stomatitis), patient refusal (n=1) and off-protocol (n-1). No

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infusion-related reactions were experienced at any of the three infusion times. The most

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frequent hematological toxicities were leucopenia (9%) and neutropenia (9%). Grade 3/4 non-hematological toxicities included anorexia (12%), fatigue (7%), diarrhea (7%), rash acneiform (7%), stomatitis (5%), paronychia (5%), hyponatremia (2%) and hypomagnesemia (2%; Table 4). No patients were intolerant of the 15-min infusion for any reason and needed to have the infusion duration lengthened again.

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Discussion This is the first prospective study to describe the efficacy and feasibility of

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shorter 15-min panitumumab infusions. With respect to efficacy, this study demonstrated that panitumumab with irinotecan is a promising treatment for

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oxaliplatin-/irinotecan-refractory KRAS wild-type mCRC. Progression-free survival and

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overall survival were good even though the primary endpoint of confirmed objective response rate was not met. In the GERCOR study, Andre et al. evaluated the combination of panitumumab and irinotecan in 65 patients with KRAS wild–type mCRC refractory to oxaliplatin, fluoropyrimidines, irinotecan and bevacizumab. The objective

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response rate was 35.2% and the disease control rate was 66.7%. Median progression-free and overall survival were 6.3 and 11.9 months, respectively. These data 10

. Recently updated guidelines from both the

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are similar to those in the present study

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National Comprehensive Cancer Network (NCCN) and the Japanese Society for Cancer of the Colon and Rectum (JSCCR) recommend the combination of panitumumab with irinotecan as third-line treatment for KRAS wild-type mCRC refractory to standard chemotherapy, including irinotecan

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. Because our results appear to be similar to

those reported by Andre et al., this regimen should also be considered for Japanese patients.

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With respect to feasibility, the 15-min panitumumab infusion did not induce infusion-related reactions in patients who were able to tolerate a 60-min infusion

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followed by a 30-min infusion. The observed adverse events were within the acceptable range, and the treatment was performed safely. The 15-min panitumumab infusion did

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not increase the incidence of adverse events compared with data from previous studies. Stephenson et al. evaluated the safety of an initial 60-min panitumumab infusion 13

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followed by 30-min infusions in 43 patients

. No infusion-related reactions were

reported, but a conservative post hoc analysis indicated that 4 potential infusion-related reactions occurred in 3 patients (7%). Nevertheless, panitumumab was not discontinued

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in any of the patients because of infusion-related reactions. Because panitumumab is a fully humanized monoclonal antibody, the frequency of infusion-related reactions is

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lower compared with the chimeric antibody cetuximab. The lower incidence of infusion

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and hypersensitivity reactions with panitumumab is also considered to be related to the absence of galactose-α-1,3 galactose on the Fab fragment

15

. In the case of the

monoclonal antibody bevacizumab, which is not fully humanized, the safety of 10-min infusions of bevacizumab (5 mg/kg) was investigated in 370 patients with colorectal cancer after administration of 2,311 doses. Minor infusion-related reactions occurred in 6 patients, but the results indicated that 10-min infusions of bevacizumab were safe 16.

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This led to the hypothesis that 15-min infusions of panitumumab, a fully humanized monoclonal antibody, may also be safe and feasible. In the STEPP trial, pre-emptive

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skin treatment reduced panitumumab-induced skin toxicity 17. Grade 3/4 rash acneiform were 7% in our results, 4% in STEPP trial, 32% in GERCOR study 10, 17. This was also

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an effective pre-treatment for acne-like skin care in patients administered the 15-min

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panitumumab infusion.

The present study has some limitations. In particular, a definitive conclusion on the safety of 15-min panitumumab infusions can not be made, mainly because of the small study population and an insufficient number of15-min infusion doses. To

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determine the frequency of rare adverse events (e.g., ≤0.5%), it would be necessary to include a few hundred with over 300 cases to confirm safety. Because data from fewer

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than 50 patients and 187 doses were available in the present study, additional

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information on the use of short panitumumab infusions in routine clinical practice must be accrued. Another factor is that the safety of a 15-min infusion as the first dose was not evaluated. Because infusion-related reactions to panitumumab and cetuximab tend to occur during the first or second dose, a 60-min infusion followed by a 30-min infusion may enable desensitization, and decrease the risk of infusion-related reactions during subsequent 15-min infusions. However, information on desensitization is not

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available due to the rarity of panitumumab-related infusion reactions. Desensitization to cetuximab has been successful, and a protocol is available

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. In the present study, the

study

10

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primary endpoint of objective confirmed response rate was inferior to that in a previous ; however, the proportion of patients with early tumor shrinkage and the total

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response rate was favorable. The discrepancy between confirmed response rate and total

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response rate was probably caused by delayed confirmation of responses because the median time from partial response to the next evaluation was 10 weeks, ranging from

Conclusions

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approximately 8 to 20 weeks.

Panitumumab with irinotecan was effective in patients with KRAS wild-type

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oxaliplatin- or irinotecan-refractory mCRC. Furthermore, there were no infusion-related

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reactions or obvious increases in the frequency and severity of adverse events after administration of 15-min panitumumab infusions from the third dose among patients able to tolerate a 60-min infusion followed by a 30-min infusion. The findings suggest that 15-min panitumumab infusions are both efficacious and feasible, while the shorter infusion time increases the convenience of outpatient chemotherapy.

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Clinical Practice Points


Our study demonstrated the efficacy and feasibility of short 30- and/or 15-min




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panitumumab infusions.

There were no infusion-related reactions with 60-, 30-, or 15-min panitumumab

Survival data after the shorter 15-min panitumumab infusion with irinotecan in

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infusions and no increase in the frequency and severity of adverse events.

patients with KRAS wild-type, oxaliplatin- or irinotecan-refractory mCRC were similar to those in previous reports.

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Acknowledgements

We sincerely appreciate the participation of the patients and their families. We

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would also like to thank all co-investigators for their contributions to this study: E.

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Usami, H. Orita, M. Tada and M. Kasahara (National Cancer Center Hospital).

Disclosure

This work was supported by a Grant-in-Aid for Cancer Research (20S-3) from the Ministry of Health, Labor and Welfare of Japan. T.H., A.T., H.Y. and Y.S. has received honoraria from Takeda pharmaceuticals.

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S.I. has received an institutional research funding from Takeda; outside the submitted

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work. The remaining authors have stated that they have no conflicts of interest.

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Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer.

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2010;127:2893-2917. 2.

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3.

Douillard JY, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369:1023-1034.

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Schwartzberg LS, Rivera F, Karthaus M, et al. PEAK: a randomized, multicenter

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phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal

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Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15:1065-1075.

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Price TJ, Peeters M, Kim TW, et al. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer

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(ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study.

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Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with

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Andre T, Blons H, Mabro M, et al. Panitumumab combined with irinotecan for patients with KRAS wild-type metastatic colorectal cancer refractory to standard chemotherapy: a GERCOR efficacy, tolerance, and translational molecular study.

Ann Oncol. 2013;24:412-419. 11.

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Rectum (JSCCR) Guideline 2014 for treatment of colorectal cancer. Int J Clin Oncol. 2015 13.

Stephenson JJ, Gregory C, Burris H, et al. An open-label clinical trial evaluating safety and pharmacokinetics of two dosing schedules of panitumumab in patients

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Table 1.

Patient characteristics

Sex 25 (58%) 18 (42%) 62 (32-75)

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Male Female Age, median (range) Performance status (ECOG) 0 1 2

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Tumor location Colon Rectum

23 (53%) 20 (47%) 0 ( 0%)

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20 (47%) 23 (53%)

ALP <300 IU/L >300 IU/L

12 (28%) 31 (72%)

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Prior treatment with bevacizumab Yes No

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Abbreviations: ALP, alkaline phosphatase.

29 (67%) 14 (33%)

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Table 2.

Tumor response (n=43)

Respense －no. (%) 0 (0 %)

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Complete response - Confirmed PRs - Unconfirmed PRs Stable disease

16 (37 %) 8 (19 %) 8 (19 %) 13 (30 %)

Progressive disease Not evaluated

12 (28 %) 2 (5 %)

Total response rate No. (%) 95% CI Confirmed response rate

16 (37 %) 23.0-53.3 8 (19%) 8.4-33.4

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No. (%) 95% CI Disease control rate No. (%)

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Total Partial response

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95% CI Early tumor shrinkage at first evaluation ＞30% ≦30%

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Median time from PRin to next evaluation

29 (67.4 %) 51.5-80.9 15 (35%) 28 (65%) 10.0 weeks (8.1-19.3)

Abbreviations: CI, confidential interval; PR, partial response.

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Frequencies of infusion time (n=43) Patients

Doses

60 minutes 30 minutes

43 40

62 55

15 minutes

34

187

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Administration time

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Table 3.

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Table 4.

Adverse events Grade 3/4 (%)

Leukopenia Neutropenia

27 16

(63%) (37%)

4 4

(9%) (9%)

Anemia Thrombocytopenia Febrile neutropenia

40 11 0

(93%) (26%)

6 0 0

(14%)

Fatigue Anorexia

29 25

(67%) (58%)

3 5

(7%) (12%)

Nausea

14

(33%)

1

(2%)

Stomatitis Diarrhea Rash acneiform

23 23 38

(53%) (53%) (88%)

2 3 3

(5%) (7%) (7%)

Paronychia Hand–foot syndrome Hyponatremia Hypomagnesemia

25 17 15 24

2 0 1 1

(5%)

Infusion-related reaction

0

SC

M AN U (58%) (40%) (35%) (56%)

TE D EP AC C

RI PT

Any grade (%)

0

(2%) (2%)

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Figure legends Treatment schedule

Figure 2.

Consort Diagram

Figure 3.

Kaplan-Meier Estimates of Progression-free Survival

Figure 4.

Kaplan-Meier Estimates of Overall Survival

Figure 5.

Waterfall plot of induction response of patients

AC C

EP

TE D

M AN U

SC

RI PT

Figure 1.

90 min

60 min

30 min

15 min

1

15

EP AC C

90 min

29

90 min

SC

90 min

TE D

Day

90 min

15 min

M AN U

CPT-11 150 mg/m2 Pmab 6 mg/kg

RI PT

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43

15 min

57

RI PT

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SC

Patients enrolled N = 43

TE D

M AN U

Panitumumab + CPT-11 N = 43 Treated (n = 43) Not treated (n = 0)

AC C

EP

Still on treatment (n = 10) Off treatment (n = 33) - Disease progression (n = 19) - Adverse event (n = 13) - Death (n = 0) - Other (n = 1)

AC C EP TE D M AN U

Progression Free Survival

SC

RI PT

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Time (months)

AC C EP TE D M AN U

Overall Survival

SC

RI PT

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Time (months)

AC C EP

Maximum decrease from baseline (%) -20

-40

-60

-80

TE D

80

60

40

20

0

M AN U

100

SC

RI PT

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Patient