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.
