A Phase I/II Study for the Safety and Efficacy of Panitumumab in Combination With TAS-102 for Patients With Colorectal Cancer

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the combination of panitumumab and Triflridine/Tipiracil (FTD/TPI; TAS-102) in patients with RAS wild-type metastatic colorectal cancer (CRC) refractory to standard chemotherapy (oxaliplatin, fluoropyrimidines, irinotecan and angiogenesis inhibitors).

Detailed Description
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The purpose of this study is to evaluate the combination of panitumumab and TAS-102 in patients with RAS wild-type metastatic colorectal cancer (CRC) refractory to standard chemotherapy (oxaliplatin, fluoropyrimidines, irinotecan and angiogenesis inhibitors). Patients who are judged eligible for the study based on the inclusion and exclusion criteria will be received panitumumab (6 mg/kg) every 2 weeks and TAS-102 (35 mg/m² given orally twice a day in a 28-day) in 2-week cycle of 5 days of treatment followed by a 2-day rest period, and then a 14-day rest period. A maximum of 58 participants will be enrolled.

Official Title
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A Phase I/II Study for the Safety and Efficacy of Panitumumab in Combination With TAS-102 for Patients With RAS (KRAS, NRAS) Wild-type, Unresectable, Advanced/Recurrent Colorectal Cancer

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: Panitumumab + TAS-102


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Investigator and subinvestigator judge a candidate is understand clinical trial and comply this protocol. Participants who have given written consent to take part in the study after detailed explanation of the study prior to enrollment Aged ≥20 to <75 years at the time of informed consent Participants with unresectable adenocarcinoma originating in the large intestine (excluding carcinoma of the appendix and anal canal cancer) Participants with lesion(s) that can be evaluated. It is essential to be evaluated the tumor according to the Response Evaluation Criteria in Solid Tumors (RECIST) ver. 1.1. Participants who have received chemotherapies for metastatic colorectal cancer and are refractory to or failing those chemotherapies* including; fluoropyrimidines, irinotecan, oxaliplatin, and an angiogenesis inhibitors. *: Refractory to or failing those chemotherapies are defied as following; If recurrence is observed by imaging during neoadjuvant/adjuvant therapy, or within 6 months of the completion of adjuvant therapy. If imaging or clinical progression is observed during or within 3 months of the last dose of chemotherapy for advanced cancer. When it is determined that the drugs (ie, fluropyrimidines, oxaliplatin, irinotecan, and angiogenesis inhibitors) are not allowed to be resume due to intolerable AE toxicities (eg, serious allergic reaction and accumulative neuropathy). Participants classified as KRAS/NRAS wild-type** by KRAS/NRAS testing*. *: KRAS/NRAS test will be performed using the in vitro diagnostic listed in the National Health Insurance. **: Participants with no mutation in any of the codons shown below are considered wild type. KRAS: EXON2 (codon 12, 13), EXON3 (codon 59, 61), EXON4 (codon 117, 146) NRAS：EXON2 (codon 12, 13), EXON3 (codon 59, 61),EXON4 (codon 117, 146) Participants are able to take medications orally. Participants who satisfy the following criteria for the major organ function in tests performed within 14 days prior to enrollment Neutrophil count ≥1.5×10^3/µL Platelet count ≥1.0×10^4/µL Hemoglobin ≥8.0 g/dL Total bilirubin ≤1.5 mg/dL Aspartate aminotransferase (AST) ≤ 100 IU/L ( ≤200 IU/L if liver metastases are present) Alanine aminotransferase (ALT) ≤ 100 IU/L ( ≤200 IU/L if liver metastases are present) Serum creatinine ≤ 1.5 mg/dL Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 Life expectancy of ≥ 3 months (90 days) after enrollment Exclusion Criteria: Has received anti-EGFR antibodies (cetuximab or panitumumab), regorafenib, or TAS-102. Has had treatment with radiotherapy and/or chemotherapy within 2 weeks (14 days) prior to study drug administration (except for limited field radiation in order to rescue of pain). Known brain metastasis or strongly suspected of brain metastasis Synchronous cancers or metachronous cancers with a disease-free period of ≥ 5 years (excluding colorectal cancer) excluding mucosal cancers cured or be possibly cured by regional resection (esophageal, stomach, and cervical cancer, non-melanoma skin cancer, bladder cancer, etc.). Body cavity fluid that requires treatment (pleural effusion, ascites, pericardial effusion, etc.) Participants who do not want to use contraception to prevent pregnancy, and women who are pregnant or breast-feeding, or test positive for pregnancy Any investigational agent received within prior 4 weeks (28 days). Disease requiring systemic steroids for treatment (excluding topical steroids) History or obvious and extensive CT findings of interstitial pulmonary disease (interstitial pneumonia, pulmonary fibrosis, etc.) Intestinal paralysis, gastrointestinal obstruction, or uncontrollable diarrhea (incapacitating symptoms despite adequate treatment. Serious drug hypersensitivity (without allergy to oxaliplatin) Local or systemic active infection requiring treatment, or fever indicating infection NYHA class II or higher heart failure or serious heart disease Active hepatitis B Known HIV infection Adverse event due to previous treatment that has not recovered to Grade 1 (Grade 2 for peripheral sensory neuropathy) by CTCAE (Japanese edition JCOG version 4.03) (excluding hemoglobin content) Known BRAF mutation Other participants judged by the investigator or subinvestigator to be ineligible for enrollment in the study (such as patients who were coerced to give consent)

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 74 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: panitumumab + TAS-102 combination therapy<br>Panitumumab 6 mg/kg every 2 weeks, plus TAS-102 35 mg/m² given orally twice a day in 5 days followed by a 2-day rest period for 2-week cycle, and then a 14-day rest period (28 days per 1 course). | Drug: Panitumumab + TAS-102<br>* panitumumab + TAS-102 combination therapy<br>* Other names: Panitumumab + Triflridine/Tipiracil (FTD/TPI);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicity (DLT) With Panitumumab Plus TAS-102 Combination Therapy | DLT was evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and was defined as any of the following events: 1. Grade 4 neutropenia for more than 7 days under maximum supportive therapy; 2. Febrile neutropenia; 3. Platelet counts decreased of Grade 3 requiring platelet transfusion or blood platelet decreased of Grade 4; 4. If Course 2 was not initiated within 14 days due to AE related to the protocol treatment; 5. Grade 3 or higher non-hematologic toxicity that was considered clinically significant, except the following cases, Grade 3 gastrointestinal symptoms that could be controlled with supportive therapy (eg, appropriate use of antiemetics, antidiarrheals), and Grade 3 or higher electrolyte abnormalities that were not deemed clinically significant. | Up to approximately 1 month | 
| Progression Free Survival (PFS) Rate at 6 Months | PFS rate at 6 months was defined as the crude rate of surviving participants who survived or were not determined as progressive at 6 months from the day of enrollment. Although the subjects who had no imaging data on progression at 6 months after enrollment or the subjects who had lost to follow-up were included in the denominator, these subjects were not handled as progression-free. Progression included both progression disease (PD) based on diagnostic imaging assessed according to response evaluation criteria in solid tumors (RECIST) ver 1.1 and primary disease progression that cannot be confirmed by diagnostic imaging (clinical progression). PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS was defined as the period from the day of enrollment until death by all causes. | From date of enrollment until the death, assessed up to approximately 29 months | 
| Progression Free Survival (PFS) | PFS was defined as the period from the day of enrollment until the day of documented progression or the day of death due to all causes whichever comes earlier. Progression included both PD based on diagnostic imaging assessed according to response evaluation criteria in solid tumors (RECIST) ver 1.1 and primary disease progression that cannot be confirmed by diagnostic imaging (clinical progression). PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). | From date of enrollment until the date of progression or death, assessed up to approximately 29 months | 
| Response Rate (RR) | RR was defined as the percentage of participants who had shown complete response (CR) or partial response (PR) as the best overall response in accordance with the RECIST 1.1 criteria. The best overall response was CR, followed by PR, stable disease (SD), progressive disease (PD), and not evaluable (NE). CR: disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to <10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters as the best overall response after randomization., SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). | From date of enrollment until the end of follow-up period, assessed up to approximately 29 months | 
| Duration of Response (DOR) | DOR means that the period from the day when either CR or PR is first confirmed until the day of documented PD or the day of death due to all causes, whichever occurs earlier. | From date of CR or PR until the date of PD or death, assessed up to approximately 29 months | 
| Disease Control Rate (DCR) | DCR was defined as the percentage of participants who had shown CR, PR, or SD as the best overall response in accordance with the RECIST version 1.1 criteria. | From date of enrollment until the end of follow-up period, assessed up to approximately 29 months | 
| Time to Treatment Failure (TTF) | TTF was defined as the time from the date of enrollment to the date of the decision to discontinue the protocol treatment, the date of documented progression during the protocol treatment, or the date of death from any cause, whichever had come earlier. | From date of enrollment until the date of the protocol treatment discontinuation, progression or death, assessed up to approximately 29 months | 
| Number of Participants Reporting One or More Treatment-Emergent Adverse Events (TEAEs) | Adverse events (AEs) were any unfavorable medical events encountered in a participant treated with a drug. They were not limited to the events with clear causal relationship with treatment with the concerned drug. Treatment-emergent adverse events (TEAEs) were defined as AEs that had occurred after the initiation of protocol treatment. | From first dose of the study drug through 30 days after the last dose of study drug or start of subsequent antineoplastic therapy, assessed up to approximately 29 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic colorectal cancer, Panitumumab, TAS-102