Copanlisib and Nivolumab in Treating Patients with Microsatellite Stable Relapsed, Refractory, Metastatic, or Unresectable Solid Tumors or Colorectal Cancer

Inclusion Criteria

• Be willing and able to provide written informed consent for the trial
• Have histologically confirmed metastatic or unresectable: * Mismatch-repair proficient (MSS) solid tumor (for phase I dose de-escalation) OR * Mismatch-repair proficient (MSS) colorectal cancer with known PI3K-mutation status (for expansion cohorts). Next generation sequencing (NGS) and polymerase chain reaction (PCR) based testing by a Clinical Laboratory Improvement Act (CLIA) certified lab will be used to determine PI3K status
• In terms of prior therapies: * For phase I dose de-escalation: have received all curative treatment options AND at least 2 lines of systemic therapy in the metastatic setting * For MSS colorectal cancer cohorts in phase II expansion: have received at least 2 prior lines of standard therapy including a fluoropyrimidine, oxaliplatin, and irinotecan-containing regimen. KRAS/NRAS/BRAF wild type patients must have received or refused anti-EGFR therapy
• Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
• Have biopsiable disease. If biopsy is attempted and unsuccessful (the patient undergoes an invasive procedure), the patient may still be treated. For expansion, patients must have archival tissue available
• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale at study entry
• Have a life expectancy of 3 months
• Absolute neutrophil count (ANC) >= 1500/uL (within 21 days of treatment initiation)
• Platelets >= 75 000/uL (within 21 days of treatment initiation)
• Hemoglobin >= 8.0 g/dL or >= 5.6 mmol/L (criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 1 week) (within 21 days of treatment initiation)
• Serum creatinine =< 1.5 x upper limit of normal (ULN) or glomerular filtration rate (GFR) >= 40 mL/min/1.73 (within 21 days of treatment initiation)
• Urine protein:creatinine ration (UPCR) < 3.5 on a random urine sample (within 21 days of treatment initiation)
• Total bilirubin =< 1.5 x ULN (< 2 x ULN for patients with Gilbert’s syndrome) (within 21 days of treatment initiation)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x ULN (within 21 days of treatment initiation)
• Lipase < 1.5 X ULN (within 21 days of treatment initiation)
• Hemoglobin A1c (HbA1c) =< 7%
• Glucose < 160 mg/dL (fasting) or < 200 mg/dL (non-fasting)
• International normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants (within 21 days of treatment initiation)
• Left ventricular ejection fraction (LVEF) >= 50% (within 21 days of treatment initiation)
• Male subjects must agree to use a contraception as detailed in this protocol during the treatment period and for at least 6 months after the last dose of study drug and refrain from donating sperm during this period
• Female subjects must not be pregnant (negative urine or serum test within 72 hours of first dose of study drug) or breastfeeding, and at least one of the following conditions must apply: * Not a woman of childbearing potential (WOCBP) or * A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 6 months after the last dose of study drug

Exclusion Criteria

• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137)
• Prior therapy with a PI3K inhibitor
• Has received prior chemotherapy, targeted small molecule therapy, or surgery within 4 weeks of the first dose of treatment. Participants must have recovered from all adverse events (AEs) due to previous interventions to =< grade 1 or baseline. Participants with =< grade 2 neuropathy or =< grade 2 anemia may be eligible
• Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities to =< grade 1 or baseline, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (=< 2 weeks of radiotherapy) to non-central nervous system (CNS) disease. Participants with =< grade 2 anemia may be eligible
• Is currently participating in or has participated in a study of an investigational agent or investigational device within 4 weeks prior to the first dose of study treatment. (i.e. must be 4 weeks after the last dose of the previous investigational agent)
• Has received a live vaccine within 30 days prior to the first dose of study drug. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed
• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy
• Has known CNS metastases and/or carcinomatous meningitis
• Has symptomatic ascites or has required a paracentesis in the last 12 weeks
• Has known hypersensitivity to nivolumab, copanlisib, or any ingredients in the formulation of these study drugs
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the 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. Subjects with vitiligo or resolved childhood asthma/atopy are exceptions. Intermittent use of bronchodilators or local steroid injections are not excluded. Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Autoimmune diagnoses not listed must be approved by the protocol chair
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
• Has an active infection requiring systemic therapy
• Has a known history of human immunodeficiency virus (HIV) infection
• Has a known history of hepatitis B (hepatitis B surface antigen [HBsAg] reactive) or active hepatitis C virus infection (hepatitis C antibody [HepCAb] followed by HepC ribonucleic acid [RNA] if Ab test is positive)
• Cytomegalovirus (CMV) PCR positive
• Has a history or concurrent condition of interstitial lung disease or severely impaired lung function (as judged by the investigator)
• Has type I diabetes or type II diabetes requiring treatment with a sulfonylurea, meglitinide, or insulin
• Uncontrolled cardiovascular disease * Congestive heart failure > New York Heart Association (NYHA) class 2 * Unstable angina (symptoms at rest), new-onset angina (within the last 3 months) * Myocardial infarction less than 6 months before start of test drug * Uncontrolled arterial hypertension despite optimal medical management
• 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. Examples of inhibitors of CYP3A4: ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir and saquinavir. Examples of inducers of CYP3A: rifampin, phenytoin, carbamazepine, phenobarbital, St. John’s wort
• Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism within 3 months before the start of study medication
• Non-healing wound, ulcer, or fracture
• Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event >= Common Terminology Criteria for Adverse Events (CTCAE) grade 3 within 4 weeks prior to the start of study medication
• Had a blood or platelet transfusion within 7 days of cycle 1 day 1 treatment
• Seizure disorder requiring anti-seizure medication
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 6 months after the last dose of trial treatment
• Is a prisoner or is compulsorily detained