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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03884998
Recruitment Status : Recruiting
First Posted : March 21, 2019
Last Update Posted : August 5, 2020
Sponsor:
Collaborators:
Oregon Health and Science University
National Cancer Institute (NCI)
Information provided by (Responsible Party):
City of Hope Medical Center

Tracking Information
First Submitted Date  ICMJE March 19, 2019
First Posted Date  ICMJE March 21, 2019
Last Update Posted Date August 5, 2020
Actual Study Start Date  ICMJE March 18, 2019
Estimated Primary Completion Date January 6, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 19, 2019)
  • Incidence of dose-limiting toxicities of copanlisib in combination with nivolumab [ Time Frame: Up to day 28 ]
    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.
  • Incidence of adverse events as assessed by CTCAE v5 [ Time Frame: Up to 48 weeks ]
    All adverse events will be tabulated and summarized by major organ category, grade, anticipation, and drug attribution. Serious adverse events (SAE) specific incidence and exact 95% confidence interval will be provided where appropriate.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 19, 2019)
  • Overall response rate (ORR) or complete response (CR) + partial response (PR) [ Time Frame: Up to 48 weeks ]
    Will be summarized with 95% confidence intervals.
  • Duration of response [ Time Frame: Up to 48 weeks ]
    Will be summarized descriptively using means and standard deviation along with 95% confidence interval.
  • 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 ]
    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).
  • Overall survival [ Time Frame: Up to 48 weeks ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: March 19, 2019)
  • Tumor response [ Time Frame: Up to 48 weeks ]
    Will explore the association between tumor PD-L1 expression.
  • T cell repertoire after treatment [ Time Frame: Up to 48 weeks ]
    Evaluation of T-cell repertoire of patients with transformed chronic lymphocytic leukemia (CLL)/non-Hodgkin's lymphoma (NHL) after receiving nivolumab
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Copanlisib and Nivolumab in Treating Participants With Richter's Transformation or Transformed Indolent Non-Hodgkin's Lymphoma
Official Title  ICMJE 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
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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
Intervention  ICMJE
  • Drug: Copanlisib
    Given IV
    Other Name: 1032568-63-0, BAY
  • Biological: Nivolumab
    Given IV
    Other Name: 946414-94-4, BMS-936558, MDX-1106, NIVO, NIVOLUMAB, Nivolumab, ONO-4538, Opdivo
Study Arms  ICMJE Experimental: Treatment (copanlisib and nivolumab)
Participants 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.
Interventions:
  • Drug: Copanlisib
  • Biological: Nivolumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 19, 2019)
15
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 6, 2023
Estimated Primary Completion Date January 6, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Alexey Danilov, MD 626-359-8111 adanilov@coh.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03884998
Other Study ID Numbers  ICMJE 20066
HEM-18125-L ( Other Identifier: OHSU Knight Cancer Institute )
NCI-2018-01880 ( Other Grant/Funding Number: National Cancer Institute )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party City of Hope Medical Center
Study Sponsor  ICMJE City of Hope Medical Center
Collaborators  ICMJE
  • Oregon Health and Science University
  • National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Alexey Danilov, MD City of Hope Medical Center
PRS Account City of Hope Medical Center
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP