Copanlisib and Nivolumab in Treating Patients With Richter's Transformation or Transformed Indolent Non-Hodgkin Lymphoma

  • STATUS
    Recruiting
  • End date
    Jul 16, 2023
  • participants needed
    21
  • sponsor
    City of Hope Medical Center
Updated on 9 April 2022
cancer
stem cell transplantation
cyclophosphamide
lymphoma
hodgkin's disease
rituximab
vincristine
monoclonal antibodies
waldenstrom's macroglobulinemia
prednisone
direct bilirubin
doxorubicin
neutrophil count
tumor cells
monoclonal antibody therapy
nivolumab
follicular lymphoma
conjugated bilirubin
monoclonal protein
diffuse large b-cell lymphoma
b-cell lymphoma
copanlisib
marginal zone lymphoma
beta human chorionic gonadotrophin
large b-cell lymphoma
r-chop
richter syndrome
lymphadenopathy
indolent lymphoma
indolent non-hodgkin lymphoma
chop regimen

Summary

This phase I trial studies the best dose and how well copanlisib when given together with nivolumab works in treating patients with Richter's transformation or transformed indolent non-Hodgkin lymphoma. Copanlisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving copanlisib and nivolumab may work better in treating patients with Richter's transformation or transformed non-Hodgkin lymphoma.

Description

PRIMARY OBJECTIVE:

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 OBJECTIVE:

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.

Patients receive copanlisib intravenously (IV) over 60 minutes on days 1, 8, and 15 and nivolumab IV over 30 minutes on days 1 and 15. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year.

Details
Condition Chronic Lymphocytic Leukemia, Diffuse Large B-Cell Lymphoma, Follicular Lymphoma, Indolent Non-Hodgkin Lymphoma, Lymphoplasmacytic Lymphoma, Marginal Zone Lymphoma, Richter Syndrome
Treatment Nivolumab, Copanlisib
Clinical Study IdentifierNCT03884998
SponsorCity of Hope Medical Center
Last Modified on9 April 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Diagnosis of Richter syndrome (RS; transformed CLL), or indolent 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 in transformation are eligible (for example, patients with transformation into Hodgkin lymphoma subtype are not 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., rituximab/cyclophosphamide/doxorubicin/prednisone/vincristine [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\
Total bilirubin =< 2 x institutional upper limit of normal (ULN)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than 2.5 x institutional ULN
Estimated creatinine clearance (CrCL) using the Cockroft-Gault equation >= 30 mL/min
Platelets >= 75,000/mm^3 (>= 25,000/mm^3 if due to disease involvement in the bone marrow; transfusion is not permitted to achieve this level)
Female participants who
Absolute neutrophil count >= 1000/mm^3 (>= 500/mm^3 if due to disease involvement in the bone marrow)
Are surgically sterile (i.e. tubal ligation), 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 [e.g., 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 2 weeks
Radio- or toxin-immunoconjugates within 10 weeks
Radiation therapy within 2 weeks
Targeted therapy - within 6 half-lives (for example, 36 hours for ibrutinib)
History of prior malignancy except
All other chemotherapy within 3 weeks prior to initiation of study therapy
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
Chronic use of corticosteroids in doses which exceed 15 mg of prednisone per day, or the equivalent
Any adverse event related to prior therapy that has not recovered to =< grade 1
Uncontrolled immune hemolysis or thrombocytopenia
(excluding grade 2 alopecia and grade 2 neuropathy)
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
Evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV), or history of HCV
Live vaccine within 30 days
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
Prior PD1, PD-L 1 or checkpoint inhibitors including CTLA4, Lag3, 41BB etc. within 2 years, or at any time if administered with the intent to treat Richter syndrome
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
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%
Corrected QT interval (QTc) > 480 msec (if echocardiogram performed during screening)
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
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