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

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

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.

Study Overview

• Status: Completed
• Conditions: Unresectable or Metastatic Microsatellite Stable (MSS) Solid Tumor; Microsatellite Stable (MSS) Colon Cancer
• Intervention / Treatment: Drug: Copanlisib; Drug: Nivolumab

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Sidney Kimmel Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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 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.	3 years
Progression Free Survival (PFS)	Number of months from treatment to disease progression (PD)	3 years
Overall Survival (OS)	Number of months from the date of first treatment until death or end of follow-up.	3 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.	51 months

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: Bristol-Myers Squibb; Bayer
• Investigators: Principal Investigator: Nilofer Azad, MD, Johns Hopkins Medical Institution

Publications and helpful links

General Publications

• Morschhauser F, Machiels JP, Salles G, Rottey S, Rule SAJ, Cunningham D, Peyrade F, Fruchart C, Arkenau HT, Genvresse I, Liu L, Kochert K, Shen K, Kneip C, Pena CE, Grevel J, Zhang J, Cisternas G, Reschke S, Granvil C, Awada A. On-Target Pharmacodynamic Activity of the PI3K Inhibitor Copanlisib in Paired Biopsies from Patients with Malignant Lymphoma and Advanced Solid Tumors. Mol Cancer Ther. 2020 Feb;19(2):468-478. doi: 10.1158/1535-7163.MCT-19-0466. Epub 2019 Oct 16.

Study record dates

Study Major Dates

• Study Start (Actual): January 17, 2019
• Primary Completion (Actual): June 14, 2022
• Study Completion (Actual): June 30, 2025

Study Registration Dates

• First Submitted: October 15, 2018
• First Submitted That Met QC Criteria: October 15, 2018
• First Posted (Actual): October 18, 2018

Study Record Updates

• Last Update Posted (Estimated): September 16, 2025
• Last Update Submitted That Met QC Criteria: August 27, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: Nivolumab; Immunotherapy; Antibody; Metastatic; Unresectable; PD-1; Solid Tumors; Colon Cancer; Copanlisib; MSS; Microsatellite stable; P13K; Mismatch-repair proficient
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pathologic Processes; Neoplasms by Site; Neoplasms; Genetic Diseases, Inborn; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colorectal Neoplasms; Intestinal Neoplasms; Neurodegenerative Diseases; Colonic Diseases; Neoplastic Processes; Heredodegenerative Disorders, Nervous System; Spinal Cord Diseases; Cerebellar Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Colonic Neoplasms; Neoplasm Metastasis; Spinocerebellar Degenerations; Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Nivolumab; copanlisib
• Other Study ID Numbers: J1887; IRB00175864 (Other Identifier: JHM IRB); CA209-8LC (Other Identifier: Bristol-Myers Squibb)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No