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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Unresectable or Metastatic Microsatellite Stable (MSS) Solid Tumor Along With Microsatellite Stable (MSS) Colon Cancer, Colon Cancer

Intervention / Treatment
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* Drug: Copanlisib
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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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.

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I - Copanlisib and Nivolumab (De-Escalation)<br> | Drug: Copanlisib<br>* 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<br>* Other names: Bay 80-6946;Drug: Nivolumab<br>* 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<br>* Other names: OPDIVO, Bay 80-6946;|
| Experimental: Phase II /Arm A-P13K mutation/Copanlisib and Nivolumab<br> | Drug: Copanlisib<br>* 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<br>* Other names: Bay 80-6946;Drug: Nivolumab<br>* 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<br>* Other names: OPDIVO, Bay 80-6946;|
| Experimental: Phase II/Arm B -P13K wild type /Copanlisib and Nivolumab<br> | Drug: Copanlisib<br>* 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<br>* Other names: Bay 80-6946;Drug: Nivolumab<br>* 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<br>* Other names: OPDIVO, Bay 80-6946;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 28 days | 
| 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. | 6-months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 6-months | 
| Duration of Response (DOR) | Number of months from the first documentation of a response to date of disease progression. | 2 years | 
| Progression Free Survival (PFS) | Number of months from treatment to disease progression (PD) | 2 years | 
| Overall Survival (OS) | Number of months from the date of first treatment until death or end of follow-up. | 2 years | 
| 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. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunotherapy, Nivolumab, Copanlisib, Unresectable, Metastatic, PD-1, P13K, Antibody, Solid Tumors, Colon Cancer, MSS, Mismatch-repair proficient, Microsatellite stable