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

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.

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