Microsatellite Stable (MSS) Colon Cancer, Unresectable or Metastatic Microsatellite Stable (MSS) Solid Tumor
Conditions
Keywords
Immunotherapy, Nivolumab, Copanlisib, Unresectable, Metastatic, PD-1, P13K, Antibody, Solid Tumors, Colon Cancer, MSS, Mismatch-repair proficient, Microsatellite stable
Brief summary
A phase I/II study of PI3Kinase inhibition (copanlisib) and anti-PD-1 antibody nivolumab in relapsed/refractory solid tumors with expansions in mismatch-repair proficient (MSS) colorectal cancer.
Interventions
DRUGCopanlisib
Copanlisib will be administered as a 60 minute IV infusion (-5min/+10min) at a dose of 45 mg - 60 mg IV. Copanlisib will be administered once a week (days 1, 8, and 15 or Day 1 and Day 15 of each 28 day cycle). Drug: 45 or 60 mg IV
DRUGNivolumab
Nivolumab 480 mg will be administered as a 30 minute IV infusion (-5min/+10min) on Day 1 of each 28 day cycle. Drug: 480 mg IV
Sponsors
Bayer
Bristol-Myers Squibb
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥18 years. * Ability to understand and willingness to sign a written informed consent document. * Phase I: Must have received all curative treatment options and at least 2 lines of systemic therapy. * Phase II: Must have received at least 2 lines of systemic therapy including a fluoropyrimidine, oxaliplatin, and irinotecan-containing regimen. KRAS/NRAS/BRAF wildtype patients must have received or refused anti-EGR. * Must have received all curative treatment options and at least 2 lines of systemic and standard therapy. * Must have measurable disease based on RECIST 1.1 * Must have biopsiable disease. * Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 * Life expectancy of greater than 3 months. * Patients must have adequate organ and marrow function defined by study-specified laboratory tests within 21 days of initial study drug. * Men must use acceptable form of birth control while on study. * Woman of childbearing potential must have a negative pregnancy test and follow contraceptive guidelines as defined per protocol.
Exclusion criteria
* Prior treatment with immunotherapy agents (including, anti-PD-1, anti-PD-L1, anti- PD-L2, anti-CTLA4, etc.). * Prior therapy with a PI3K inhibitor * Chemotherapy, target small molecule therapy, investigational therapy, or surgery within 4 weeks prior to first dose of treatment. * Has received prior radiotherapy within 2 weeks prior to the start of treatment. * Patient who is receiving or have received any other investigational agents within 4 weeks prior to the first dose of treatment. * Has received a live vaccine 30 days prior to the first dose of study drug. * Has known additional malignancy that is progressing or requires active treatment.. * Has known central nervous system (CNS) metastases and/or carcinomatous meningitis. * Has symptomatic ascites or has required a paracentesis in the last 12 weeks. * Hypersensitivity reaction to study drug. * Patients diagnosed of immunodeficiency or are on any immunosuppressive agents within 7 days prior to first dose of study drug. * Has active autoimmune disease that has required systemic treatment in the past 12 months, or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. * Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis. * Has an active infection requiring systemic therapy. * Infection with HIV or hepatitis B or C. * Cytomegalovirus polymerase chain reaction (CMV PCR) positive. * Known history or concurrent interstitial lung disease. * Type I diabetes or Type II diabetes requiring treatment with a sulfonylurea, meglitinide, or insulin at screening. * Uncontrolled cardiovascular disease. * Patient with uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Use of anti-arrhythmic therapy (beta blockers or digoxin are permitted). * Use of CYP3A4 inhibitors and inducers within 2 weeks of starting study drug and throughout treatment. * Any arterial or venous thrombotic or embolic events within 3 months of start of study drug. * Non-healing wound, ulcer, or fracture. * Patients with evidence or history of bleeding condition. * Had a blood or platelet transfusion within 7 days of Cycle 1 Day 1 treatment. * Seizure disorder requiring anti-seizure medication. * Conditions, including alcohol or drug dependence, intercurrent illness, or lack of sufficient peripheral venous access, that would affect the patient's ability to comply with study visits and procedures. * Are pregnant or breastfeeding. * Unwilling or unable to follow the study schedule for any reason.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing a Dose Limiting Toxicity | 28 days | Number of participants experiencing a Dose Limiting Toxicity (DLT) in each dose level. DLT is defined as any of the following study drug-related toxicities occurring during the first cycle of study drug on study: * Grade 4 anemia * Grade ≥ 3 neutropenia lasting ≥ 14 days * Grade ≥ 3 febrile neutropenia * Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with clinically significant bleeding * Treatment-related ≥ grade 4 AEs, except transient hyperglycemia * Grade ≥ 3 Pneumonitis or recurrent Grade 2 pneumonitis * Grade ≥ 3 Nephritis * Grade ≥ 3 elevated AST or ALT * Grade ≥ 2 eye pain or reduction of visual acuity that does not respond to topical therapy, improve to ≤ grade 1 within 2 weeks of topical therapy, or requires systemic therapy * Any other Grade ≥ 3 toxicities (with certain exceptions for transient AEs or asymptomatic labs) |
| 6-month Objective Response Rate (ORR) of Patients Treated With Copanlisib and Nivolumab | 6-months | The proportion of subjects with partial response (PR) or complete response (CR) as defined by Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Per RECIST 1.1, complete response is defined as disappearance of all target lesions, and partial response is defined as at least a 30% decrease in the sum of diameters of target lesions. Lesions are assessed by CT or MRI. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) Status at 6 Months. | 6-months | Percentage of participants achieving stable disease (SD) or better (SD + PR + CR). Per RECIST 1.1, complete response is defined as disappearance of all target lesions, partial response is defined as at least a 30% decrease in the sum of diameters of target lesions, stable disease occurs when there is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (at least 20% increase). Lesions are assessed by CT or MRI. |
| Duration of Response (DOR) | 3 years | Number of months from the first documentation of a partial or complete response by RECIST 1.1 to date of disease progression. Responses may be documented at any time on the study, including patients responding after the 6-month evaluation used for the primary outcome. |
| Progression Free Survival (PFS) | 3 years | Number of months from treatment to disease progression (PD) |
| Overall Survival (OS) | 3 years | Number of months from the date of first treatment until death or end of follow-up. |
| Number of Participants Experiencing Study Drug-related Toxicities | 51 months | Number of participants experiencing study drug-related adverse events Grade 3 or higher as defined by CTCAE v5.0. |
Countries
United States
Participant flow
Pre-assignment details
9 participants (1 from Phase 1, 4 from Phase 2 Cohort A and 4 from Phase 2 Cohort B) were excluded from analysis because they did not receive the study drug.
Participants by arm
| Arm | Count |
|---|---|
| Phase I - Dose Finding Copanlisib: Copanlisib will be administered as a 60 minute IV infusion (-5min/+10min) at one of three dose levels:
Dose Level 1: 60mg on Day 1, 8, and 15
Dose Level -1: 60mg on Day 1 and 15
Dose Level -2: 45 mg on Day 1 and 15
Nivolumab: Nivolumab 480 mg will be administered as a 30 minute IV infusion (-5min/+10min) on Day 1 of each cycle.
Cycle length is 28 days.
Only Dose Level 1 was tested. | 6 |
| Phase II /Cohort A - PI3K Mutation Copanlisib 60 mg will be administered as a 60-minute IV infusion (-5min/+10min) on Day 1, 8, and 15 of each 28-day cycle.
Nivolumab 480 mg will be administered as a 30-minute IV infusion (-5min/+10min) on Day 1 of each 28-day cycle. | 21 |
| Phase II/Cohort B - PI3K Wild Type Copanlisib 60 mg will be administered as a 60-minute IV infusion (-5min/+10min) on Day 1, 8, and 15 of each 28-day cycle.
Nivolumab 480 mg will be administered as a 30-minute IV infusion (-5min/+10min) on Day 1 of each 28-day cycle. | 12 |
| Total | 39 |
Baseline characteristics
| Characteristic | Phase I - Dose Finding | Phase II /Cohort A - PI3K Mutation | Phase II/Cohort B - PI3K Wild Type | Total |
|---|---|---|---|---|
| Age, Continuous | 59.5 years | 57 years | 58.5 years | 58 years |
| Eastern Cooperative Oncology Group (ECOG) Classification of Participants ECOG 0 | 3 Participants | 11 Participants | 4 Participants | 18 Participants |
| Eastern Cooperative Oncology Group (ECOG) Classification of Participants ECOG 1 | 3 Participants | 10 Participants | 8 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 20 Participants | 11 Participants | 37 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 5 Participants | 1 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 15 Participants | 10 Participants | 30 Participants |
| Region of Enrollment United States | 6 Participants | 21 Participants | 12 Participants | 39 Participants |
| Sex: Female, Male Female | 2 Participants | 15 Participants | 4 Participants | 21 Participants |
| Sex: Female, Male Male | 4 Participants | 6 Participants | 8 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 6 | 14 / 21 | 9 / 12 |
| other Total, other adverse events | 6 / 6 | 21 / 21 | 12 / 12 |
| serious Total, serious adverse events | 3 / 6 | 11 / 21 | 6 / 12 |
Outcome results
Primary
6-month Objective Response Rate (ORR) of Patients Treated With Copanlisib and Nivolumab
The proportion of subjects with partial response (PR) or complete response (CR) as defined by Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Per RECIST 1.1, complete response is defined as disappearance of all target lesions, and partial response is defined as at least a 30% decrease in the sum of diameters of target lesions. Lesions are assessed by CT or MRI.
Time frame: 6-months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I - Dose Finding (Dose Level 1) | 6-month Objective Response Rate (ORR) of Patients Treated With Copanlisib and Nivolumab | 0 Participants |
| Phase II /Cohort A- PI3K Mutation | 6-month Objective Response Rate (ORR) of Patients Treated With Copanlisib and Nivolumab | 2 Participants |
| Phase II /Cohort B- PI3K Wild Type | 6-month Objective Response Rate (ORR) of Patients Treated With Copanlisib and Nivolumab | 0 Participants |
Primary
Number of Participants Experiencing a Dose Limiting Toxicity
Number of participants experiencing a Dose Limiting Toxicity (DLT) in each dose level. DLT is defined as any of the following study drug-related toxicities occurring during the first cycle of study drug on study: * Grade 4 anemia * Grade ≥ 3 neutropenia lasting ≥ 14 days * Grade ≥ 3 febrile neutropenia * Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with clinically significant bleeding * Treatment-related ≥ grade 4 AEs, except transient hyperglycemia * Grade ≥ 3 Pneumonitis or recurrent Grade 2 pneumonitis * Grade ≥ 3 Nephritis * Grade ≥ 3 elevated AST or ALT * Grade ≥ 2 eye pain or reduction of visual acuity that does not respond to topical therapy, improve to ≤ grade 1 within 2 weeks of topical therapy, or requires systemic therapy * Any other Grade ≥ 3 toxicities (with certain exceptions for transient AEs or asymptomatic labs)
Time frame: 28 days
Population: Per protocol, Dose Limiting Toxicities (DLTs) were only assessed in Phase I subjects in order to determine the Phase II dose of copanlisib. Since no subjects experienced DLTs in Dose Level 1, this was the only dose level tested.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I - Dose Finding (Dose Level 1) | Number of Participants Experiencing a Dose Limiting Toxicity | 0 Participants |
Secondary
Disease Control Rate (DCR) Status at 6 Months.
Percentage of participants achieving stable disease (SD) or better (SD + PR + CR). Per RECIST 1.1, complete response is defined as disappearance of all target lesions, partial response is defined as at least a 30% decrease in the sum of diameters of target lesions, stable disease occurs when there is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (at least 20% increase). Lesions are assessed by CT or MRI.
Time frame: 6-months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I - Dose Finding (Dose Level 1) | Disease Control Rate (DCR) Status at 6 Months. | 0 Participants |
| Phase II /Cohort A- PI3K Mutation | Disease Control Rate (DCR) Status at 6 Months. | 5 Participants |
| Phase II /Cohort B- PI3K Wild Type | Disease Control Rate (DCR) Status at 6 Months. | 3 Participants |
Secondary
Duration of Response (DOR)
Number of months from the first documentation of a partial or complete response by RECIST 1.1 to date of disease progression. Responses may be documented at any time on the study, including patients responding after the 6-month evaluation used for the primary outcome.
Time frame: 3 years
Population: Only patients who had a partial or complete response by RECIST were evaluable for duration of response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase II /Cohort A- PI3K Mutation | Duration of Response (DOR) | 20.6 months |
| Phase II /Cohort B- PI3K Wild Type | Duration of Response (DOR) | 13.1 months |
Secondary
Number of Participants Experiencing Study Drug-related Toxicities
Number of participants experiencing study drug-related adverse events Grade 3 or higher as defined by CTCAE v5.0.
Time frame: 51 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I - Dose Finding (Dose Level 1) | Number of Participants Experiencing Study Drug-related Toxicities | 5 Participants |
| Phase II /Cohort A- PI3K Mutation | Number of Participants Experiencing Study Drug-related Toxicities | 16 Participants |
| Phase II /Cohort B- PI3K Wild Type | Number of Participants Experiencing Study Drug-related Toxicities | 10 Participants |
Secondary
Overall Survival (OS)
Number of months from the date of first treatment until death or end of follow-up.
Time frame: 3 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I - Dose Finding (Dose Level 1) | Overall Survival (OS) | 5.61 months |
| Phase II /Cohort A- PI3K Mutation | Overall Survival (OS) | 6.77 months |
| Phase II /Cohort B- PI3K Wild Type | Overall Survival (OS) | 10.26 months |
Secondary
Progression Free Survival (PFS)
Number of months from treatment to disease progression (PD)
Time frame: 3 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I - Dose Finding (Dose Level 1) | Progression Free Survival (PFS) | 1.64 months |
| Phase II /Cohort A- PI3K Mutation | Progression Free Survival (PFS) | 1.68 months |
| Phase II /Cohort B- PI3K Wild Type | Progression Free Survival (PFS) | 1.82 months |