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Antineoplastic Agents

All Drugs and Chemicals

Nivolumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

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).

TAS-102

nivolumab

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

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.

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

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

Study results using compiled efficacy and safety data will be published at congress or to a journal, without any identification of the patients.

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.

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

RP2D of TAS-102 was evaluated based on the safety and tolerability of the combination therapy of TAS-102 and Nivolumab.

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.

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).

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.

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.

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.

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.

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.

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.

Taiho Oncology, Inc.

Analysis was performed on safety population.

Participants received a dose of 35 mg/m\^2 of TAS-102 tablets orally 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 mg/kg/dose Nivolumab I.V infusion over 60 minutes every 14 days (on Day 1 and Day 15 of each 4-week cycle).

TAS-102 + Nivolumab

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Baseline population included all enrolled participants who received at least 1 dose of study drug.

After interim analysis, per study design plan, the trial was stopped for futility before enrollment into Stage 2.

Taiho Central

Efficacy population included all participants in the safety population (all participants who received at least 1 dose of study drug) who completed at least 6 months of tumor follow-up, unless the participant progressed or died before the 6-month follow-up.

Immune-Related Overall Response Rate (irORR)

DLT Evaluable (DLTE) population included all participants in the safety population in Stage 1, prior to confirming the recommended dose, who completed at least 1 cycle (28 days) of study treatment with at least 80% of the study treatment administered, unless the treatment was interrupted because of a DLT.

Number of Participants With Dose Limiting Toxicities (DLTs)

DLTE population included all participants in the safety population in Stage 1, prior to confirming the recommended dose, who completed at least 1 cycle (4 weeks) of study treatment with at least 80% of the study treatment administered, unless the treatment was interrupted because of a DLT.

Recommended Phase 2 Dose (RP2D)

Participants with TEAEs

Participants with TESAEs

Safety population included all participants who received at least 1 dose of study drug.

Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

Grade 4: Neutropenia (neutrophils low)

Grade 4: Anemia (hemoglobin low)

Grade 4: Leukopenia (leukocytes low)

Grade 4: Lymphopenia (lymphocytes low)

Grade 4: Thrombocytopenia (platelets low)

Grade 4: Bilirubin High

Grade 4: Glucose High

Grade 4: Sodium Low

Grade 3: Neutropenia (neutrophils low)

Grade 3: Anemia (hemoglobin low)

Grade 3: Leukopenia (leukocytes low)

Grade 3: Lymphopenia (lymphocytes low)

Grade 3: Thrombocytopenia (platelets low)

Grade 3: Bilirubin High

Grade 3: Glucose High

Grade 3: Sodium Low

Number of Participants With Grade 3 or Higher Laboratory Tests Abnormalities

Efficacy population included all participants in the safety population who completed at least 6 months of tumor follow-up, unless the participant progressed or died before the 6-month follow-up.

Overall Response Rate (ORR)

Radiologic progression of disease only

Radiologic + clinical progression of disease

Progression-Free Survival (PFS) Based on Immune Related Response-Criteria (irRC)

Progression-Free Survival (PFS) Based on RECIST Criteria

Disease Control Rate (DCR) Based on irRC Criteria

Disease Control Rate (DCR) Based on RECIST Criteria

Safety population included all participants who received at least 1 dose of study drug. Overall number of participants analyzed is 0 because data were not collected for the outcome measure at particular time point.

Spots Global Cancer Trial Database for programmed cell death protein1 (pd 1)