Copanlisib and Nivolumab in Treating Participants With Richter's Transformation or Transformed Indolent Non-Hodgkin's Lymphoma
Copanlisib and Nivolumab in Treating Participants With Richter's Transformation or Transformed Indolent Non-Hodgkin's Lymphoma
This phase I trial studies best dose and how well copanlisib when given together with
 nivolumab works in treating participants with Richter's transformation or transformed
 indolent non-Hodgkin's lymphoma. Copanlisib may stop the growth of tumor cells by blocking
 some of the enzymes needed for cell growth. Monoclonal antibodies, such as nivolumab, may
 interfere with the ability of tumor cells to grow and spread. Giving copanlisib and nivolumab
 may work better in treating participants with Richter's transformation or transformed
 non-Hodgkin's lymphoma.
PRIMARY OBJECTIVES:

 I. To evaluate the maximum-tolerated dose (MTD) of copanlisib administered in combination
 with nivolumab in patients with transformed chronic lymphocytic leukemia (CLL)/non-Hodgkin's
 lymphoma (NHL).

 SECONDARY OBJECTIVES:

 I. To evaluate the preliminary efficacy of copanlisib administered in combination with
 nivolumab in patients with transformed CLL/NHL.

 EXPLORATORY OBJECTIVES:

 I. To evaluate the T-cell repertoire and activation patterns following dual targeting of PI3K
 and PD-1.

 II. To establish if PD-1/PD-L 1 expression correlates with response to the combination of
 copanlisib and nivolumab.

 OUTLINE: This is a dose-escalation study of copanlisib.

 Participants receive copanlisib intravenously (IV) over 60 minutes on days 1, 8, and 15 and
 nivolumab IV over 30 minutes on days 1 and 15. Courses repeat every 28 days for 12 courses in
 the absence of disease progression or unacceptable toxicity.

 After completion of study treatment, participants are followed up every 3 months for 1 year
 and then every 4-6 months thereafter.
Inclusion Criteria:

 -  Diagnosis of Richter syndrome (RS; transformed CLL), or indolent non-Hodgkin's
 lymphoma (NHL) (follicular lymphoma [FL], lymphoplasmacytic lymphoma [LPL], marginal
 zone lymphoma [MZL]) in transformation. Only patients who have diffuse large B-cell
 lymphoma (DLBCL) histology are eligible.

 -  Participants with RS must have received at least 2 cycles of prior systemic therapy
 for either RS or underlying CLL

 -  Participants with FL and other indolent lymphomas in transformation must have
 underwent ≥ 1 prior chemo-immunotherapy regimen (e.g., R-CHOP or similar) administered
 for ≥2 cycles and have had either documented disease progression to the most recent
 treatment regimen, or refractory disease and must not be candidates for or planning to
 pursue autologous stem cell transplant, or must have relapsed following autologous
 stem cell transplant which took place at least 3 months prior to study therapy.

 -  Radiographically measurable lymphadenopathy (>= 1.5 cm) or measurable extra-nodal
 disease.

 -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2.

 -  Direct bilirubin =<2 x institutional upper limit of normal (ULN) Aspartate
 aminotransferase (AST) or alanine aminotransferase (ALT) less than 2.5 x institutional
 ULN.

 -  Estimated creatinine clearance (CrCL) using the Cockcroft-Gault equation >= 50 mL/min
 or creatinine < 1.5 mg/dL.

 -  Platelets >= 75,000/mm^3 (>=25,000/mm^3 if due to disease involvement in the bone
 marrow.

 -  Absolute neutrophil count >= 1000/mm^ (>= 500/mm^ if due to disease involvement in the
 bone marrow.

 -  Female participants who:

 -  Are postmenopausal for at least 1 year before the screening visit, or

 -  Are surgically sterile, or

 -  Participants of childbearing potential must have a negative serum beta-human
 chorionic gonadotropin at screening and:

 -  Agree to practice 1 highly effective method and 1 additional effective
 (barrier) method of contraception at the same time, from the time of signing
 the informed consent through 1 month after the last dose of copanlisib, or 5
 months after the last dose of nivolumab, whichever is later, or

 -  Agree to practice true abstinence, when this is in line with the preferred
 and usual lifestyle of the subject. (Periodic abstinence [eg, calendar,
 ovulation, symptothermal, post-ovulation methods] withdrawal, spermicides
 only, and lactational amenorrhea are not acceptable methods of
 contraception. Female and male condoms should not be used together.).

 -  Male patients, even if surgically sterilized (i.e., status post-vasectomy) must:

 -  Agree to practice effective barrier contraception during the entire study treatment
 period and through 1 month after the last dose of copanlisib, OR

 -  Agree to practice true abstinence, when this is in line with the preferred and usual
 lifestyle of the subject (Periodic abstinence [e.g., calendar, ovulation,
 symptothermal, post-ovulation methods for the female partner] withdrawal, spermicides
 only, and lactational amenorrhea are not acceptable methods of contraception. Female
 and male condoms should not be used together.).

 -  Ability to understand and the willingness to sign a written informed consent document.

 Exclusion Criteria:

 -  History of allogeneic bone marrow or organ transplant.

 -  Prior therapeutic intervention with any of the following:

 -  Therapeutic anti-cancer antibodies within 4 weeks.

 -  Radio- or toxin-immunoconjugates within 10 weeks.

 -  All other chemotherapy, radiation therapy within 30 days prior to initiation of
 study therapy.

 -  Targeted therapy - within 6 half-lives (for example, 36 hours for ibrutinib).

 -  History of prior malignancy except:

 -  Malignancy treated with curative intent and no known active disease present for
 >= 2 years prior to initiation of therapy on current study.

 -  Adequately treated non-melanoma skin cancer or lentigo maligna (melanoma in situ)
 without evidence of disease.

 -  Adequately treated in situ carcinomas (e.g., cervical, esophageal, etc.) without
 evidence of disease.

 -  Asymptomatic prostate cancer managed with "watch and wait" strategy.

 -  Inadequate recovery from adverse events related to prior therapy to grade =< 1
 (excluding grade 2 alopecia and neuropathy).

 -  Chronic use of corticosteroids in doses which exceed 15 mg of prednisone per day, or
 the equivalent.

 -  Uncontrolled immune hemolysis or thrombocytopenia.

 -  A history of human immunodeficiency virus (HIV) infection. HIV-positive participants
 on combination antiretroviral therapy are ineligible because of the potential for
 pharmacokinetic interactions with copanlisib and/or nivolumab. In addition, these
 participants are at increased risk of lethal infections when treated with
 marrow-suppressive therapy. Appropriate studies will be undertaken in participants
 receiving combination antiretroviral therapy when indicated.

 -  Major surgery (under general anesthesia) within 30 days prior to therapy.

 -  Inability to swallow and retain an oral medication.

 -  Evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV), or history of
 HCV.

 -  Live vaccine within 30 days.

 -  Prior PD1, PD-L 1 or checkpoint inhibitors including CTLA4, Lag3, 41BB etc.

 -  Subjects with an active, known or suspected autoimmune disease. Subjects with type I
 diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders
 (such as vitiligo, psoriasis) not requiring systemic treatment, well controlled asthma
 and/or mild allergic rhinitis (seasonal allergies) are eligible.

 -  Evidence of central nervous system (CNS) involvement.

 -  Use of strong CYP3A4 inhibitors or inducers within 2 weeks prior to starting study
 therapy.

 -  History or concurrent condition of interstitial lung disease and/or severely impaired
 lung function.

 -  Patients with hemoglobin (Hb) A1c > 8.5% at screening.

 -  Uncontrolled arterial hypertension despite optimal medical management (per
 investigator's assessment).

 -  Patients with uncontrolled coagulopathy or bleeding disorder.

 -  Arterial or venous thrombotic or embolic events such as cerebrovascular accident
 (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism
 within 3 months prior to the start of study treatment.

 -  The following cardiovascular abnormalities:

 -  Congestive heart failure >= class 3 New York Heart Association (NYHA) class.

 -  Unstable angina (angina symptoms at rest), new-onset angina (onset within the
 last 3 months).

 -  Myocardial infarction less than 6 months before start of study treatment.

 -  Left ventricular ejection fraction (LVEF) less than 45%.

 -  QT interval (QTc) > 480 msec.

 -  Females who are pregnant or nursing. Pregnant individuals are excluded from this study
 because copanlisib and nivolumab have the potential to cause fetal harm based on
 relevant animal studies (Refer to the appropriate prescribing information). Because
 there is an unknown but potential risk for adverse events in nursing infants,
 breast-/chest-feeding should be discontinued prior to treatment with copanlisib and
 nivolumab.