Clinical Trials /

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

NCT03884998

Description:

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.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
  • Richter Syndrome
  • Transformed Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Copanlisib and Nivolumab in Treating Participants With Richter's Transformation or Transformed Indolent Non-Hodgkin's Lymphoma
  • Official Title: A Phase I Study of PI3Kα,δ Inhibitor Copanlisib in Combination With PD-1 Antagonist Nivolumab in Patients With Transformed Chronic Lymphocytic Leukemia (Richter's Transformation) or Non-Hodgkin Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: STUDY00018655
  • SECONDARY ID: HEM-18125-L
  • SECONDARY ID: NCI-2018-01880
  • NCT ID: NCT03884998

Conditions

  • Chronic Lymphocytic Leukemia
  • Richter Syndrome
  • Diffuse Large B Cell Lymphoma
  • Follicular Lymphoma
  • Indolent Non-hodgkin Lymphoma
  • Loss of Chromosome 17p
  • Lymphoplasmacytic Lymphoma
  • Marginal Zone Lymphoma
  • TP53 Gene Mutation

Interventions

DrugSynonymsArms
Copanlisib1032568-63-0, BAYTreatment (copanlisib and nivolumab)
Nivolumab946414-94-4, BMS-936558, MDX-1106, NIVO, NIVOLUMAB, Nivolumab, ONO-4538, OpdivoTreatment (copanlisib and nivolumab)

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (copanlisib and nivolumab)ExperimentalParticipants receive copanlisib 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.
  • Copanlisib
  • Nivolumab

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of dose-limiting toxicities of copanlisib in combination with nivolumab
Time Frame:Up to day 28
Safety Issue:
Description:Will be summarized for the safety population by dose level. All adverse events (AEs) will be coded by system organ class, Medical Dictionary for Regulatory Activities (MedDRA) preferred term, and severity grade using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.

Secondary Outcome Measures

Measure:Overall response rate (ORR) or complete response (CR) + partial response (PR)
Time Frame:Up to 48 weeks
Safety Issue:
Description:Will be summarized with 95% confidence intervals.
Measure:Duration of response
Time Frame:Up to 48 weeks
Safety Issue:
Description:Will be summarized descriptively using means and standard deviation along with 95% confidence interval.
Measure:Progression-free survival (PFS)
Time Frame:Date of first study treatment and the date of objective signs of disease progression, subsequent anti-leukemic therapy, or death, whichever is reported first, assessed up to 48 weeks
Safety Issue:
Description:Will be summarized descriptively using the Kaplan-Meier estimate along with 95% confidence interval. We will also perform subset analysis with subjects who were treated at the maximum tolerated dose (MTD).
Measure:Overall survival
Time Frame:Up to 48 weeks
Safety Issue:
Description:Will be summarized descriptively using the Kaplan-Meier estimate along with 95% confidence interval. We will also perform subset analysis with subjects who were treated at the MTD.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:OHSU Knight Cancer Institute

Last Updated

November 27, 2019