Back to resultsA Study Evaluating TAS-102 Plus Nivolumab in Patients With MSS CRC
Primary Purpose
Refractory Metastatic Colorectal Cancer
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
TAS-102
nivolumab
Sponsored by
About this trial
This is an interventional treatment trial for Refractory Metastatic Colorectal Cancer focused on measuring Refractory, Metastatic, Colorectal cancer, TAS-102, Nivolumab, Microsatellite Stable, Programmed cell death protein1 (PD 1)
Eligibility Criteria
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.
Sites / Locations
- Sarah Cannon Research Institute at HealthONE
- Florida Cancer Specialists
- Sarah Cannon Research Institute
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
TAS-102 + Nivolumab
Arm Description
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).
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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
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.
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.
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).
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.
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.
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.
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.
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.
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02860546
Brief Title
A Study Evaluating TAS-102 Plus Nivolumab in Patients With MSS CRC
Official Title
A Phase 2 Study With Safety Lead-in, Evaluating TAS-102 Plus Nivolumab in Patients With Microsatellite Stable Refractory Metastatic Colorectal Cancer
Study Type
Interventional
2. Study Status
Record Verification Date
July 2021
Overall Recruitment Status
Completed
Study Start Date
August 29, 2016 (Actual)
Primary Completion Date
August 2017 (Actual)
Study Completion Date
September 7, 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Taiho Oncology, Inc.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
A Phase 2 Study with Safety Lead-in, Evaluating TAS-102 Plus Nivolumab in Participants with Microsatellite Stable Refractory Metastatic Colorectal Cancer
Detailed Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Refractory Metastatic Colorectal Cancer
Keywords
Refractory, Metastatic, Colorectal cancer, TAS-102, Nivolumab, Microsatellite Stable, Programmed cell death protein1 (PD 1)
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
18 (Actual)
8. Arms, Groups, and Interventions
Arm Title
TAS-102 + Nivolumab
Arm Type
Experimental
Arm Description
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).
Intervention Type
Drug
Intervention Name(s)
TAS-102
Other Intervention Name(s)
Lonsurf®
Intervention Description
One Arm Only (of TAS 102 plus nivolumab)
Intervention Type
Drug
Intervention Name(s)
nivolumab
Other Intervention Name(s)
Opdivo®
Intervention Description
One Arm Only (of TAS 102 plus nivolumab)
Primary Outcome Measure Information:
Title
Immune-Related Overall Response Rate (irORR)
Description
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.
Time Frame
From first dose of study treatment up to 30 days after the last dose of study treatment (up to 53 weeks)
Secondary Outcome Measure Information:
Title
Number of Participants With Dose Limiting Toxicities (DLTs)
Description
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
Time Frame
Cycle 1 (each cycle is of 4 weeks)
Title
Recommended Phase 2 Dose (RP2D)
Description
RP2D of TAS-102 was evaluated based on the safety and tolerability of the combination therapy of TAS-102 and Nivolumab.
Time Frame
Cycle 1 (each cycle is of 4 weeks)
Title
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
Description
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.
Time Frame
From first dose of study treatment up to 30 days after the last dose of study treatment (up to 53 weeks)
Title
Number of Participants With Grade 3 or Higher Laboratory Tests Abnormalities
Description
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).
Time Frame
From first dose of study treatment up to 30 days after the last dose of study treatment (up to 53 weeks)
Title
Overall Response Rate (ORR)
Description
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.
Time Frame
From first dose of study treatment up to 30 days after the last dose of study treatment (up to 53 weeks)
Title
Progression-Free Survival (PFS) Based on Immune Related Response-Criteria (irRC)
Description
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.
Time Frame
From the first dose of study treatment to disease progression or death (up to 53 weeks)
Title
Progression-Free Survival (PFS) Based on RECIST Criteria
Description
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.
Time Frame
From the first dose of study treatment to disease progression or death (up to 53 weeks)
Title
Disease Control Rate (DCR) Based on irRC Criteria
Description
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.
Time Frame
From first dose of study treatment up to 30 days after the last dose of study treatment (up to 53 weeks)
Title
Disease Control Rate (DCR) Based on RECIST Criteria
Description
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.
Time Frame
From first dose of study treatment up to 30 days after the last dose of study treatment (up to 53 weeks)
Title
Overall Survival (OS)
Description
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.
Time Frame
From first dose of study treatment up to 30 days after the last dose of study treatment (up to 53 weeks)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Facility Information:
Facility Name
Sarah Cannon Research Institute at HealthONE
City
Denver
State/Province
Colorado
ZIP/Postal Code
80218
Country
United States
Facility Name
Florida Cancer Specialists
City
Sarasota
State/Province
Florida
ZIP/Postal Code
34232
Country
United States
Facility Name
Sarah Cannon Research Institute
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37203
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Study results using compiled efficacy and safety data will be published at congress or to a journal, without any identification of the patients.
Citations:
PubMed Identifier
33544407
Citation
Patel MR, Falchook GS, Hamada K, Makris L, Bendell JC. A phase 2 trial of trifluridine/tipiracil plus nivolumab in patients with heavily pretreated microsatellite-stable metastatic colorectal cancer. Cancer Med. 2021 Feb;10(4):1183-1190. doi: 10.1002/cam4.3630. Epub 2021 Feb 5.
Results Reference
derived
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A Study Evaluating TAS-102 Plus Nivolumab in Patients With MSS CRC
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