Patient case: 45-year-old female with colon cancer; genetic feature: PIK3CA (E545K)

Clinical trial: Copanlisib and Nivolumab in Treating Patients With Metastatic Solid Tumors or Lymphoma

Summary: This phase Ib trial studies the side effects and best dose of copanlisib and nivolumab in treating patients with solid tumors that have spread to other places in the body or lymphoma. Copanlisib stops tumors from growing by blocking proteins that are known to be important for tumor cell growth. Monoclonal antibodies, such as nivolumab, may unblock the immune system so that it can recognize and attack tumor cells. Giving copanlisib and nivolumab may work better in treating patients with solid tumors or lymphoma.

Detailed description: PRIMARY OBJECTIVES:
  I. To establish the safety, tolerability, and the recommended phase 2 dose (RP2D) of copanlisib and nivolumab combination in patients with advanced solid tumors and lymphomas.
  SECONDARY OBJECTIVES:
  I. Evaluate the effect of the copanlisib and nivolumab combination on markers of anti-tumor immunity in circulating immune cells, circulating tumor cells (CTCs), and pre- and post-treatment tumor biopsies.
  II. Evaluate the effect of the combination on biomarkers of AKT inhibition, deoxyribonucleic acid (DNA) damage (gammaH2AX, pNbs1, Rad51), apoptosis, and epithelial-mesenchymal transition in CTCs and pre- and post- treatment tumor biopsies.
  III. Assess preliminary antitumor activity of the combination.
  OUTLINE: This is a dose-escalation study.
  Patients receive copanlisib intravenously (IV) over 1 hour on days 1, 8, and 15 and nivolumab IV over 30 minutes on day 1 or on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  After completion of study treatment, patients are followed up for 30 days.

Eligibility: Inclusion Criteria:
  -  Patients must have histologically documented metastatic solid tumors which have progressed after one line of therapy, or lymphoma which has progressed after all Food and Drug Administration (FDA)-approved therapy; this trial will enroll a minimum of 5 lymphoma patients
  -  Patients must have measurable or evaluable disease
  -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  -  Leukocytes >= 2,000/mcL
  -  Absolute neutrophil count >= 1,500/mcL
  -  Platelets >= 100,000/mcL
  -  Total bilirubin =<1.5 x institutional upper limit of normal (ULN)
  -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) /alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x institutional ULN
  -  Serum creatinine =< 1.5 x institutional ULN OR creatinine clearance >= 50 mL/min/1.73 m^2 by Cockcroft-Gault
  -  Amylase/lipase =< 1.5 x institutional ULN (without symptoms of pancreatitis)
  -  Any prior therapy must have been completed >= 4 weeks (6 weeks for nitrosoureas and mitomycin C) or, if known, >= 5 half-lives of the prior agent (whichever is shorter) prior to enrollment on protocol (minimum of 1 week between prior therapy and study enrollment), and the participant must have recovered to eligibility levels from prior toxicity; prior definitive radiation should have been completed >= 4 weeks or palliative radiation should have been completed >= 2 weeks prior to study enrollment and all associated toxicities resolved to eligibility levels; patients must be >= 2 weeks since any investigational agent administered as part of a phase 0 study (where a sub-therapeutic dose of drug is administered) at the principal investigator's (PI's) discretion, and should have recovered to grade 1 or baseline from any toxicities
  -  Patients who have had prior monoclonal antibody therapy must have completed that therapy >= 6 weeks (or 3 half-lives of the antibody, whichever is shorter) prior to enrollment on protocol (minimum of 1 week between prior therapy and study enrollment)
  -  Patients that have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways are eligible, unless they discontinued such therapy due to toxicity
  -  Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during the treatment portion of the study, and for a minimum of 8 after the last dose of study drug; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
  -  Ability to understand and the willingness to sign a written informed consent document
  -  Willingness to provide blood and new tumor biopsy samples for research purposes if on the expansion phase of the study
  Exclusion Criteria:
  -  Patients who are receiving any other investigational agents
  -  Patients with clinically significant illnesses which would compromise participation in the study, including but not limited to active or uncontrolled infection, immune deficiencies, hepatitis B, hepatitis C, active tuberculosis, uncontrolled asthma, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, myocardial infarction within the past 6 months, cerebral vascular accident/stroke within the past 6 months, or psychiatric illness/social situations that would limit compliance with study requirements
  -  Patients with known brain metastases or carcinomatous meningitis are excluded from this clinical trial, with the exception of patients whose brain metastatic disease status has remained stable for >= 1 month after treatment of the brain metastases; patients on anti-seizure medications may be enrolled at the discretion of the principal investigator
  -  Patients with blood oxygen saturation < 90% at rest; patients must not have symptomatic interstitial lung disease, pneumonitis, or known pulmonary fibrosis
  -  Patients with uncontrolled arterial hypertension despite optimal medical management or uncontrolled type I or II diabetes mellitus; patients with well-controlled arterial hypertension or diabetes mellitus are eligible
  -  Patients are not eligible if they have had or are planned for solid organ transplant or allogeneic hematopoietic stem cell transplant
  -  Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; however, systemic corticosteroids may be indicated after starting the study drugs to treat immune-related adverse reactions; inhaled or topical steroids and adrenal replacement doses >10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
  -  Patients should be excluded if they have had prior treatment with the combination of a PI3K inhibitor and a PD-1 inhibitor
  -  The concomitant use of strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir and saquinavir) and strong inducers of CYP3A4 (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, St. John's Wort) is not permitted; it is important to regularly consult a frequently-updated medical reference for a list of drugs to avoid or minimize use of; Patient Drug Information Handout and Wallet Card should be provided to patients; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
  -  Patients who are known to be human immunodeficiency virus (HIV)-positive at registration are eligible at the time of registration as long as:
  -  CD4+ cell count >= 250 cells/mm^3
  -  If patient is on antiretroviral therapy, there must be minimal interactions or overlapping toxicity of the antiretroviral therapy with the study drugs; once daily combinations that use pharmacologic boosters may not be used
  -  No history of non-malignancy acquired immune deficiency syndrome (AIDS)-defining conditions other than historical low CD4+ cell counts
  -  Pregnant or breastfeeding women will be excluded from participation in this trial

Relevance to patient case: not relevant