A Study Evaluating TAS-102 Plus Nivolumab in Patients With MSS CRC

Study Overview
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Brief Summary
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A Phase 2 Study with Safety Lead-in, Evaluating TAS-102 Plus Nivolumab in Participants with Microsatellite Stable Refractory Metastatic Colorectal Cancer

Detailed Description
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This is a multicenter, single arm, safety lead-in, Phase 2 study, using Simon's 2 stage design evaluating the safety and efficacy of TAS-102 plus nivolumab in participants with Microsatellite-stable refractory metastatic colorectal cancer Stage 1: Participants will be enrolled and after Cycle 1 treatment, they will be evaluated for the safety and tolerability of the combination therapy. Assuming a tolerated dose is confirmed additional participants evaluable for response will be enrolled and followed for a minimum of 6 months and there will be an interim analysis to assess the safety and efficacy to determine whether the second stage will open for enrollment. Stage 2: Additional participant evaluable for response assessment will be enrolled and followed for a minimum of 6 months.

Official Title
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A Phase 2 Study With Safety Lead-in, Evaluating TAS-102 Plus Nivolumab in Patients With Microsatellite Stable Refractory Metastatic Colorectal Cancer

Conditions
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Refractory Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: TAS-102
* Drug: nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has provided written informed consent. Participants with confirmed histologically proven metastatic or locally advanced colorectal adenocarcinoma who are microsatellite stable (MSS) (ie, not microsatellite instable [MSI]) based on either an analysis of tissue from a prior biopsy or based on tissue from a new biopsy. Participants with the presence of at least 1 lesion with measurable disease as defined by 10 millimeters (mm) in the longest diameter for a soft tissue lesions or 15 mm in the short axis for a lymph node by response evaluation criteria in solid tumors (RECIST) and immune related response-criteria (irRC) for a response assessment. Participants has received at least 2 prior lines of standard chemotherapies for metastatic colorectal cancer (mCRC) and is refractory to or failing those chemotherapies. Age greater than or equal to (>=) 18 years. Eastern Cooperative Oncology Group performance status of 0 to 1 Life expectancy of >=4 months. Has adequate organ function. Women of childbearing potential must have a negative pregnancy test (urine or serum) within 7 days before starting study drugs. Is able to take medications orally. Is able to take medications orally. Exclusion Criteria: Has a serious illness or medical condition. Treatment with any of the following within the specified time frame before enrollment: Major surgery within the past 4 weeks (the surgical incision should be fully healed before study drug administration). Any anticancer therapy within the past 3 weeks before enrollment. Extended field radiation within the past 4 weeks or limited field radiation within the past 2 weeks before enrollment. Any investigational drug/device received within the past 4 weeks or 5 times the half-life (whichever is shorter) before enrollment. Previous treatment with TAS-102. Prior treatment with anti-programmed cell death-1 (anti-PD-1), anti-programmed cell death ligand (anti-PD-L1), anti programmed cell death ligand 2, anti-CD137, anti-OX-40, anti CD40, anti cytotoxic T lymphocyte associated antigen-4 antibodies, or any other immune checkpoint inhibitors. Unresolved toxicity of >=Common Terminology Criteria for Adverse Events version (CTCAE) version 4.03 grade 2 attributed to any prior therapies (excluding anemia, alopecia, skin pigmentation, and platinum induced neurotoxicity). Prior events of immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune mediated nephritis and renal dysfunction, immune mediated rash, immune mediated encephalitis, and history of infusion reactions to nivolumab. Known or assumed hypersensitivity to TAS-102 or nivolumab or any of its ingredients, including polysorbate 80-containing infusion. Previous severe hypersensitivity reaction to treatment with another mAb. Pregnant or lactating female. Inappropriate for entry into this study in the judgment of the investigator.

Ages Eligible for Study
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Minimum Age: 18 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: TAS-102 + Nivolumab<br>Participants received a dose of 35 milligrams per meter square (mg/m^2) of TAS-102 tablets orally twice per day (BID) within 1 hour after completion of morning and evening meals, in 4-week cycle. In each 4-week cycle, TAS-102 was administered for 2 weeks, as 5 days a week with 2 days rest, followed by a 14-day rest. Also participants received 3 milligrams per kilogram per dose (mg/kg/dose) Nivolumab intravenous (I.V) infusion over 60 minutes every 14 days (on Day 1 and Day 15 of each 4-week cycle). | Drug: TAS-102<br>* One Arm Only (of TAS 102 plus nivolumab)<br>* Other names: Lonsurf®;Drug: nivolumab<br>* One Arm Only (of TAS 102 plus nivolumab)<br>* Other names: Opdivo®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune-Related Overall Response Rate (irORR) | irORR was defined as the percentage of participants achieving a complete response (irCR) or partial response (irPR) based on irRC criteria. Per irRC criteria, Complete Response (irCR) was defined as the disappearance of all tumor lesions (measurable or not, and no new lesions)., Partial Response (irPR) was defined as a decrease in the sum of the products of the two largest perpendicular diameters (SPD) by 50 percent (%) or greater by a consecutive assessment at least 4 weeks after first documentation, Stable Disease (irSD) was defined as the failure to meet criteria for irCR or irPR in absence of progressive disease (irPD), irPD was defined as at least 25% increase in SPD relative to nadir. | From first dose of study treatment up to 30 days after the last dose of study treatment (up to 53 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities (DLTs) | DLT: defined as occurrence of any of the following- Hematological toxicities: Grade 4 neutropenia lasting greater than(>)7 days Grade 4 febrile neutropenia and fever greater than or equal to (>=)38 degree celsius for over 1 hour Grade 4 thrombocytopenia or grade 3 thrombocytopenia associated with bleeding or requiring transfusions Non-hematological toxicities: Grade 3 or grade 4 non-hematologic toxicity (excluding alopecia, nausea, vomiting, diarrhea) Grade 3 or grade 4 nausea/vomiting lasting >48 hours and uncontrolled by aggressive anti-emetic therapy, including serotonin 5-HT3 receptor antagonists (e.g, ondansetron) Grade 3 or grade 4 diarrhea lasting > 48 hours and unresponsive to antidiarrheal medication Drug-related toxicities: Any drug-related toxicity resulting in > 2 weeks delay in initiation of Cycle 2 (i.e, cannot start Cycle 2 until Day 43 or later) Any drug-related toxicity that prevents completion of 80% compliance for either drug in Cycle 1 | Cycle 1 (each cycle is of 4 weeks) | 
| Recommended Phase 2 Dose (RP2D) | RP2D of TAS-102 was evaluated based on the safety and tolerability of the combination therapy of TAS-102 and Nivolumab. | Cycle 1 (each cycle is of 4 weeks) | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | An adverse event (AE) was defined as any untoward medical condition that occurs in a participants while participating in a clinical study and does not necessarily have a causal relationship with the use of the study treatment. A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. TEAEs: AEs that developed or worsened during the on-treatment period which was defined as the period from the time of first dose of study treatment until 30 days after the last dose of study treatment. | From first dose of study treatment up to 30 days after the last dose of study treatment (up to 53 weeks) | 
| Number of Participants With Grade 3 or Higher Laboratory Tests Abnormalities | Hematological and chemistry laboratory tests abnormalities were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03. as: Grade 1 (Mild, asymptomatic or mild symptoms); Grade 2 (Moderate, minimal, local or noninvasive intervention indicated); Grade 3 (Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated); Grade 4 (Life-threatening consequences, urgent intervention indicated); Grade 5 (Death related to AE). | From first dose of study treatment up to 30 days after the last dose of study treatment (up to 53 weeks) | 
| Overall Response Rate (ORR) | ORR was defined as the percentage of participants with objective evidence of complete response (CR) or partial response (PR) per response evaluation criteria in solid tumors (RECIST) version 1.1.CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to less than (<)10 millimeters (mm). PR was defined as at least a 30 % decrease in the sum of diameters of the target lesions, taking as a reference the baseline sum diameters. | From first dose of study treatment up to 30 days after the last dose of study treatment (up to 53 weeks) | 
| Progression-Free Survival (PFS) Based on Immune Related Response-Criteria (irRC) | Immune-related progression free survival was defined as the time (in months) from the date of first dose of study treatment until the date of the investigator-assessed radiological disease progression (based on irRC) or death due to any cause. Participants who were alive with no disease progression at the moment of the analysis cut-off date was censored at the date of the last tumor assessment. Per irRC criteria disease progression defined as at least 25% increase in SPD relative to nadir. Analysis was performed using Kaplan-Meier estimates. | From the first dose of study treatment to disease progression or death (up to 53 weeks) | 
| Progression-Free Survival (PFS) Based on RECIST Criteria | Progression free survival was defined as the time (in months) from the date of first dose of study treatment until the date of the investigator-assessed radiological disease progression (based on RECIST 1.1) or death due to any cause. Per RECIST criteria disease progression defined as least 20% increase in the sum of diameters of the target lesions, taking as a reference the smallest sum on study, including the baseline sum. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Definitive new lesion presence also indicated progression. | From the first dose of study treatment to disease progression or death (up to 53 weeks) | 
| Disease Control Rate (DCR) Based on irRC Criteria | DCR was defined as the percentage of participants with objective evidence of radiologic complete response (CR), partial response (PR), or stable disease (SD) and was based on the overall best response from each participant as determined from investigator response assessments and following irRC criteria. Per irRC criteria, CR was defined as the disappearance of all tumor lesions (measurable or not, and no new lesions). PR was defined as a decrease in the sum of the products of the two largest perpendicular diameters by 50% or greater by a consecutive assessment at least 4 weeks after first documentation. SD was defined as the failure to meet criteria for irCR or irPR in absence of in absence of irPD. | From first dose of study treatment up to 30 days after the last dose of study treatment (up to 53 weeks) | 
| Disease Control Rate (DCR) Based on RECIST Criteria | DCR was defined as the percentage of participants with objective evidence of radiologic CR, PR, or SD and was based on the overall best response from each participant as determined from investigator response assessments and following RECIST Criteria version 1.1. Per RECIST Criteria CR defined as disappearance of all target lesions. Reduction in any pathological lymph nodes in short axis to <10 mm. PR defined as at least a 30% decrease in the sum of diameters of the target lesions, taking as a reference the baseline sum diameters. SD defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as a reference the smallest sum diameters during study. | From first dose of study treatment up to 30 days after the last dose of study treatment (up to 53 weeks) | 
| Overall Survival (OS) | OS was defined as the time from the first dose of the study treatment to the death in the safety population. Participants alive at the time of the study discontinuation were censored. Analysis was performed using Kaplan-Meier estimates. | From first dose of study treatment up to 30 days after the last dose of study treatment (up to 53 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Refractory, Metastatic, Colorectal cancer, TAS-102, Nivolumab, Microsatellite Stable, Programmed cell death protein1 (PD 1)