Colorectal Cancer
Conditions
Brief summary
The purpose of this study is to learn if combination of the two drugs regorafenib and nivolumab is an effective treatment for pMMR - MSS colorectal cancer, a special type of cancer of the colon or rectum (pMMR stands for proficient Mismatch Repair; MSS stands for Microsatellite Stable) and whether it is safe for patients. Regorafenib works by blocking several different proteins involved in tumor growth. Nivolumab is an immunotherapy drug encouraging the body's own immune system to attack cancer cells. Both drugs have been approved, but not for how they are being used as combination therapy in this study. Brand name of regorafenib is Stivarga; brand name of nivolumab is Opdivo.
Interventions
DRUGRegorafenib (Stivarga, BAY73-4506)
Regorafenib administered as oral tablets given every day for 3 weeks of each 28 days treatment cycle (i.e., 3 weeks on, 1 week off)
BIOLOGICALNivolumab (Opdivo)
Administered on day 1 of every treatment cycle.
Sponsors
Bristol-Myers Squibb
Bayer
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histological or cytological confirmed advanced, metastatic, or progressive pMMR/MSS adenocarcinoma of colon or rectum * Participant must have progressed or be intolerant to prior systemic chemotherapy including fluoropyrimidines, irinotecan, oxaliplatin, anti-vascular endothelial growth factor (VEGF) therapy, and, if extended rat sarcoma viral oncogene homolog (RAS) wild type, an anti-epidermal growth factor receptor (EGFR) therapy. Exceptions may apply * Participants must have adequate organ and marrow function defined by protocol-specified laboratory tests * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 * Measurable disease as determined by response evaluation criteria in solid tumors (RECIST) v1.1 * Provision of recently obtained tumor tissue as per protocol specified requirement * Anticipated life expectancy greater than 3 months * Be able to swallow and absorb oral tablets
Exclusion criteria
* Participants with Mismatch repair deficient (dMMR) / microsatellite instable-high (MSI-H) colorectal cancer * Prior therapy with regorafenib, anti-programmed cell death protein 1 (PD-1), programmed cell death protein 1 ligand 1 (PD-L1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, or any form of immunotherapy to treat cancer * Presence of active central nervous system (CNS) metastases; participants with stable CNS disease or previously treated lesions are eligible for study entry * Poorly controlled hypertension, defined as a blood pressure consistently above 150/90 mmHg despite optimal medical management * Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks) within 6 months before the start of study medication. Active pulmonary emboli or deep vein thrombosis that are significant or not adequately controlled on anticoagulation regimen * Any hemorrhage or bleeding event ≥ National Cancer Institute - Common terminology criteria for adverse events (NCI-CTCAE) Grade 3 within 28 days prior to the start of study medication * Participants with an active, known or suspected autoimmune disease * History of interstitial lung disease or pneumonitis * Known history of human immunodeficiency virus (HIV) infection or current chronic or active hepatitis B or C infection * Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 Assessed by Investigator | Through database cut-off date of 11-NOV-2020 (Primary Completion Date) (up to 13 months) | ORR was defined as the percentage of participants with overall response of complete response (CR) or partial response (PR). CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have decreased in size to have a short axis of \< 10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) | Through last patient last visit (LPLV) at date of 28 MAR 2022 (up to 30 months) | DOR was defined for responders only as the time from first documentation of response (i.e. CR or PR) until disease progression or death (if death without documented disease progression). CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have decreased in size to have a short axis of \< 10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. |
| Disease Control Rate (DCR) at 8 and 16 Weeks | At 8, 16, 24, 32 and 40 weeks | DCR was defined as the percentage of participants with tumor response of complete response (CR), partial response (PR) or stable disease (SD). CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have decreased in size to have a short axis of \< 10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. |
| Progression-free Survival (PFS) | Through last patient last visit (LPLV) at date of 28 MAR 2022 (up to 30 months) | PFS was the time from first dose of study medication to disease progression or death, whichever was earlier. |
| Overall Survival (OS) | Through last patient last visit (LPLV) at date of 28 MAR 2022 (up to 30 months) | OS was defined as time from first dose of the study treatment to death. For patients who did not die, OS was censored at the last time point at which the survival status was known to be alive. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Different Severity Types of TEAEs Per Common Terminology Criteria for Adverse Events (CTCAE) v5 | 30 days after last dose of regorafenib and 100 days after last dose of nivolumab until study completion (up to 30 months) | TEAEs were started during treatment or within the post-treatment time window (30 days after last dose of regorafenib and 100 days after last dose of nivolumab.). TEAEs were summarized by system organ class (SOC) and preferred term, severity (based on CTCAE v5 grades). Laboratory data considered as AE were graded according to CTCAE v5. Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death related to AE. |
Countries
United States
Participant flow
Recruitment details
Study was conducted at 12 centers (of which at least one participant was treated) in the United States between 14-OCT-2019 (first participant first visit) and 28-MAR-2022 (last participant last visit).
Pre-assignment details
A total of 94 participants were screened to enter the study; 21 participants were screening failures and 3 participants discontinued before completion of screening (2 participants withdrew consent and 1 participant died during screening). A total of 70 participants were assigned to treatment and received at least one dose of study treatment.
Participants by arm
| Arm | Count |
|---|---|
| Regorafenib Plus Nivolumab Regorafenib was administrated 2x40 mg once daily (q.d.) on cycle 1 and up to 3x40 mg q.d. from cycle 2 onward for 3 weeks of each 28 days treatment cycle (21 days on/7 days off).
Nivolumab was administrated 480 mg on day 1 of each 28 days treatment cycle (Q4W). | 70 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Active Follow-up Period | Death | 13 |
| Active Follow-up Period | Other Reasons | 1 |
| Active Follow-up Period | Progressive Disease - Clinical Assessment | 4 |
| Active Follow-up Period | Withdrawal by Subject | 2 |
| Long-term Follow-up Period | Death | 22 |
| Long-term Follow-up Period | Ongoing with Long Term Follow-up | 6 |
| Long-term Follow-up Period | Withdrawal by Subject | 1 |
| Treatment Period | Adverse Event | 8 |
| Treatment Period | Death | 1 |
| Treatment Period | Other Reasons | 2 |
| Treatment Period | Physician Decision | 5 |
| Treatment Period | Progressive Disease - Clinical Assessment | 7 |
| Treatment Period | Progressive Disease - Radiological Progression | 47 |
Baseline characteristics
| Characteristic | Regorafenib Plus Nivolumab |
|---|---|
| Age, Continuous | 57.9 years STANDARD_DEVIATION 10.7 |
| Baseline ECOG Performance Status 0 - Fully Active | 36 participants |
| Baseline ECOG Performance Status 1 - Restricted Activity | 34 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 61 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 7 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants |
| Race (NIH/OMB) More than one race | NA Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 50 Participants |
| Sex: Female, Male Female | 29 Participants |
| Sex: Female, Male Male | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 40 / 70 |
| other Total, other adverse events | 66 / 70 |
| serious Total, serious adverse events | 34 / 70 |
Outcome results
Primary
Overall Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 Assessed by Investigator
ORR was defined as the percentage of participants with overall response of complete response (CR) or partial response (PR). CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have decreased in size to have a short axis of \< 10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters.
Time frame: Through database cut-off date of 11-NOV-2020 (Primary Completion Date) (up to 13 months)
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Regorafenib Plus Nivolumab | Overall Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 Assessed by Investigator | 7.1 percentage (%) of participants |
p-value: 0.272195% CI: [2.4, 15.9]Exact Binomial Test
Secondary
Disease Control Rate (DCR) at 8 and 16 Weeks
DCR was defined as the percentage of participants with tumor response of complete response (CR), partial response (PR) or stable disease (SD). CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have decreased in size to have a short axis of \< 10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study.
Time frame: At 8, 16, 24, 32 and 40 weeks
Population: Full Analysis Set (FAS)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Regorafenib Plus Nivolumab | Disease Control Rate (DCR) at 8 and 16 Weeks | Disease Control Rate at 8 weeks | 38.6 percentage (%) of participants |
| Regorafenib Plus Nivolumab | Disease Control Rate (DCR) at 8 and 16 Weeks | Disease Control Rate at 16 weeks | 38.6 percentage (%) of participants |
| Regorafenib Plus Nivolumab | Disease Control Rate (DCR) at 8 and 16 Weeks | Disease Control Rate at 40 weeks | 38.6 percentage (%) of participants |
| Regorafenib Plus Nivolumab | Disease Control Rate (DCR) at 8 and 16 Weeks | Disease Control Rate at 24 weeks | 38.6 percentage (%) of participants |
| Regorafenib Plus Nivolumab | Disease Control Rate (DCR) at 8 and 16 Weeks | Disease Control Rate at 32 weeks | 38.6 percentage (%) of participants |
Secondary
Duration of Response (DOR)
DOR was defined for responders only as the time from first documentation of response (i.e. CR or PR) until disease progression or death (if death without documented disease progression). CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have decreased in size to have a short axis of \< 10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters.
Time frame: Through last patient last visit (LPLV) at date of 28 MAR 2022 (up to 30 months)
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Regorafenib Plus Nivolumab | Duration of Response (DOR) | NA weeks |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Different Severity Types of TEAEs Per Common Terminology Criteria for Adverse Events (CTCAE) v5
TEAEs were started during treatment or within the post-treatment time window (30 days after last dose of regorafenib and 100 days after last dose of nivolumab.). TEAEs were summarized by system organ class (SOC) and preferred term, severity (based on CTCAE v5 grades). Laboratory data considered as AE were graded according to CTCAE v5. Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death related to AE.
Time frame: 30 days after last dose of regorafenib and 100 days after last dose of nivolumab until study completion (up to 30 months)
Population: Full Analysis Set (FAS)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Regorafenib Plus Nivolumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Different Severity Types of TEAEs Per Common Terminology Criteria for Adverse Events (CTCAE) v5 | Serious AEs | 34 participants |
| Regorafenib Plus Nivolumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Different Severity Types of TEAEs Per Common Terminology Criteria for Adverse Events (CTCAE) v5 | Worst grade: Grade 1 | 3 participants |
| Regorafenib Plus Nivolumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Different Severity Types of TEAEs Per Common Terminology Criteria for Adverse Events (CTCAE) v5 | Worst grade: Grade 3 | 38 participants |
| Regorafenib Plus Nivolumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Different Severity Types of TEAEs Per Common Terminology Criteria for Adverse Events (CTCAE) v5 | Worst grade: Grade 4 | 7 participants |
| Regorafenib Plus Nivolumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Different Severity Types of TEAEs Per Common Terminology Criteria for Adverse Events (CTCAE) v5 | Worst grade: Grade 3 or 4 | 45 participants |
| Regorafenib Plus Nivolumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Different Severity Types of TEAEs Per Common Terminology Criteria for Adverse Events (CTCAE) v5 | Grade 5 (death) between Day 31 and Day 100 | 0 participants |
| Regorafenib Plus Nivolumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Different Severity Types of TEAEs Per Common Terminology Criteria for Adverse Events (CTCAE) v5 | Any AEs | 69 participants |
| Regorafenib Plus Nivolumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Different Severity Types of TEAEs Per Common Terminology Criteria for Adverse Events (CTCAE) v5 | Worst grade: Grade 2 | 18 participants |
| Regorafenib Plus Nivolumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Different Severity Types of TEAEs Per Common Terminology Criteria for Adverse Events (CTCAE) v5 | Worst grade: Grade 5 (death) | 3 participants |
| Regorafenib Plus Nivolumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Different Severity Types of TEAEs Per Common Terminology Criteria for Adverse Events (CTCAE) v5 | Worst grade: Grade 1 or 2 | 21 participants |
| Regorafenib Plus Nivolumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Different Severity Types of TEAEs Per Common Terminology Criteria for Adverse Events (CTCAE) v5 | Worst grade: Grade 3, 4, or 5 | 48 participants |
| Regorafenib Plus Nivolumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Different Severity Types of TEAEs Per Common Terminology Criteria for Adverse Events (CTCAE) v5 | Grade 5 (death) between Day X+1 and Day 30 | 3 participants |
Secondary
Overall Survival (OS)
OS was defined as time from first dose of the study treatment to death. For patients who did not die, OS was censored at the last time point at which the survival status was known to be alive.
Time frame: Through last patient last visit (LPLV) at date of 28 MAR 2022 (up to 30 months)
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Regorafenib Plus Nivolumab | Overall Survival (OS) | 51.86 weeks |
Secondary
Progression-free Survival (PFS)
PFS was the time from first dose of study medication to disease progression or death, whichever was earlier.
Time frame: Through last patient last visit (LPLV) at date of 28 MAR 2022 (up to 30 months)
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Regorafenib Plus Nivolumab | Progression-free Survival (PFS) | 8.00 weeks |
Post Hoc
Duration of Stable Disease
Duration of stable disease was measured from the start of the treatment until the criteria for progression were met.
Time frame: Through last patient last visit (LPLV) at date of 28 MAR 2022 (up to 30 months)
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Regorafenib Plus Nivolumab | Duration of Stable Disease | 29.86 weeks |