Clinical Trials /

Copanlisib Plus Venetoclax in R/R DLBCL

NCT04572763

Description:

This research study is evaluating the combination of two drugs, copanlisib and venetoclax, as a possible treatment for trelapsed/refractory diffuse large B-cell lymphoma (DLBCL) The names of the study drugs involved in this study are: - Copanlisib - Venetoclax

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

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Copanlisib Plus Venetoclax in R/R DLBCL
  • Official Title: A Phase I/II Study of Copanlisib Plus Venetoclax for the Treatment of Relapsed/Refractory Diffuse Large B-cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 20-069
  • NCT ID: NCT04572763

Conditions

  • Diffuse Large B Cell Lymphoma
  • Relapsed Diffuse Large B-Cell Lymphoma
  • Refractory Diffuse Large B-Cell Lymphoma

Interventions

DrugSynonymsArms
CopanlisibAliqopaDose Escalation Copanlisib + Venetoclax
VenetoclaxVenclextaDose Escalation Copanlisib + Venetoclax

Purpose

This research study is evaluating the combination of two drugs, copanlisib and venetoclax, as a possible treatment for trelapsed/refractory diffuse large B-cell lymphoma (DLBCL) The names of the study drugs involved in this study are: - Copanlisib - Venetoclax

Detailed Description

      This study is an open-label, multi-center, non-randomized phase I/II study of the combination
      treatment copanlisib + venetoclax in patients with relapsed/refractory (R/R) diffuse large
      B-cell lymphoma (DLBCL).

      Phase I clinical trials test the safety of investigational drugs, and also try to define the
      appropriate dose of the investigational drugs to use for further studies. Phase II clinical
      trials test the safety and effectiveness of investigational drugs to learn whether the drugs
      work in treating a specific disease."Investigational" means that the drugs are being studied.

      Copanlisib is an IV medication that is approved by the U.S. Food and Drug Administration
      (FDA) for the treatment of adult patients with relapsed follicular lymphoma who have received
      at least two prior therapies. Venetoclax is an oral medication that is approved by the U.S.
      FDA for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small
      lymphocytic lymphoma (SLL) and certain patients with acute myeloid leukemia (AML). The FDA
      has not approved copablisib or venetoclax for the treatment of DLBCL or the combination of
      copanlisib and venetoclax as a treatment for any disease.

      In the phase I portion of this study, the investigators are looking to determine the dose of
      venetoclax that is safe to give with copanlisib and to see what the side effects are of this
      combination.

      In the phase II trial, the investigators will be determining how effective venetoclax and
      copanlisib are for the treatment of R/R DLBCL. Data from laboratory suggest that some subsets
      of DLBCL are enriched for mutations that make them sensitive to the combination of copanlisib
      plus venetoclax. This study will look at genetic changes in your cancer and determine if
      abnormalities in specific genes make these drugs more or less effective.

      It is expected that about 48 people will take part in this research study.

      Bayer, a pharmaceutical company, is supporting this research study by providing the study
      drug copanlisib and funding for this study. Abbvie, a pharmaceutical company, is supporting
      this research study by providing the study drug venetoclax and funding for this study.
    

Trial Arms

NameTypeDescriptionInterventions
Dose Escalation Copanlisib + VenetoclaxExperimentalPhase 1 Dose escalation will occur using a 3+3 design Copanlisib will be administered IV on days 1, 8 and 15 in 28 day cycle Venetoclax will be administered orally daily for each 28-day cycle. During cycle 1, a venetoclax dose ramp-up is performed in the outpatient setting
  • Copanlisib
  • Venetoclax
Recommended phase II dose (RP2D) Copanlisib + VenetoclaxExperimentalPatients will be treated with copanlisib in combination with venetoclax, administered at the Recommended phase II dose (RP2D).
  • Copanlisib
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          -  A confirmed diagnosis of DLBCL according to the 2016 WHO classification. Patients with
             high-grade B-cell lymphoma with translocations of MYC and BCL-2 and/or BCL-6 are
             eligible

          -  Relapsed after autologous stem cell transplantation or chimeric antigen receptor (CAR)
             T-cell therapy or not a candidate for these therapies

          -  Willingness to undergo a pre-treatment biopsy. If considered unsafe to proceed with
             biopsy, archival tissue samples may be utilized after discussion with the PI. Archival
             samples performed within 90 days and without intervening therapy are also acceptable
             if they meet the criteria as specified in the laboratory manual.

          -  ECOG performance status < 2

          -  Age ≥ 18 years

          -  Patients must meet the following hematologic criteria at screening:

               -  Absolute neutrophil count ≥1000 cells/mm3 (0.5 x 109/L), with no white-blood cell
                  growth factor use for at least 7 days prior to screening.

               -  Platelet count ≥75,000 cells/mm3 (75 x 109/L) or ≥50,000 cells/mm3 (50 x 109/L if
                  documented disease involvement of the bone marrow), without platelet transfusion
                  within 7 days of screening

               -  Hemoglobin (Hb) ≥ 8 g/dL, without blood transfusion within 7 days of screening

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 x
             ULN for patients with liver involvement by lymphoma)

          -  Lipase ≤ 1.5 x ULN

          -  Total bilirubin ≤ 1.5 x ULN (< 3 x ULN for patients with Gilbert's syndrome, patients
             with cholestasis due to compressive adenopathies of the hepatic hilum or documented
             liver involvement or with biliary obstruction due to lymphoma)

          -  Adequate renal function defined by serum creatinine ≤1.5 x ULN or creatinine clearance
             (by Cockroft-Gault) ≥ 50 ml/min

          -  Women of childbearing potential (WOCBP) and men must agree to use effective
             contraception when sexually active. This applies for the time period between signing
             of the informed consent form and 6 months for WOCBP and for men after the last
             administration of study treatment. A woman is considered of childbearing potential,
             i.e. fertile, following menarche and until becoming post-menopausal unless permanently
             sterile. Permanent sterilization methods include but are not limited to hysterectomy,
             bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined
             as no menses for continuous 12 months without an alternative medical cause. A high
             follicle stimulating hormone (FSH) level in the postmenopausal range may be used to
             confirm a post-menopausal state in women not using hormonal contraception or hormonal
             replacement therapy. The investigator or a designated associate is requested to advise
             the patient how to achieve highly effective birth control, e.g. intrauterine device
             (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion,
             vasectomized partner, use of two forms of birth control, and sexual abstinence. The
             use of condoms by male patients is required unless the female partner is permanently
             sterile.

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

        Exclusion Criteria:

          -  Patients receiving cancer therapy (i.e., chemotherapy, radiation therapy,
             immunotherapy, biologic therapy, hormonal therapy, surgery and/or tumor embolization)
             within 2 weeks of Cycle 1/Day 1 with the following exceptions:

               -  Limited palliative radiation is allowed if completed > 1 week of C1D1

          -  Systemic corticosteroid therapy at a daily dose higher than 15 mg prednisone or
             equivalent. Previous corticosteroid therapy must be stopped or reduced to the allowed
             dose at least 7 days prior to C1D1.

          -  History of other malignancies, except:

               -  Malignancy treated medically or surgically with curative intent and with no known
                  active disease present for ≥2 years before the first dose of study drug

               -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
                  of disease

               -  Adequately treated carcinoma in situ without evidence of disease.

               -  Localized prostate cancer and low-risk prostate cancer on active surveillance

          -  Within three months of autologous stem cell transplantation at time of starting study
             treatment

          -  Within six months of allogeneic stem cell transplantation at time of starting study
             treatment or active graft vs. host disease requiring systemic treatment or prophylaxis
             within 6 weeks of starting study treatment

          -  Vaccinated with live, attenuated vaccines of any kind <4 weeks before first dose of
             study drug

          -  History of or active autoimmune disease requiring systemic immunosuppression

          -  Recent infection requiring intravenous antibiotics that was completed ≤7 days before
             the first dose of study drug, or any uncontrolled active systemic infection

          -  Patients with ongoing use of prophylactic antibiotics are eligible as long as there is
             no evidence of active infection and the antibiotic is not included on the list of
             prohibited medications

          -  Known bleeding disorders (eg, von Willebrand's disease) or hemophilia

          -  History of stroke or intracranial hemorrhage within 3 months prior to enrollment

          -  Known history of Human Immunodeficiency Virus (HIV) infection. All patients must be
             screened for HIV up to 28 days prior to study drug start using a blood test for HIV
             according to local regulations.

          -  Hepatitis B (HBV) or hepatitis C (HCV). All patients must be screened for HBV and HCV
             up to 28 days prior to study drug start. Patients positive for HBsAg or HBcAb will be
             eligible if they are negative for HBV-DNA, these patients should receive prophylactic
             antiviral therapy. Patients positive for anti-HCV antibody will be eligible if they
             are negative for HCV-RNA.

          -  CMV PCR positive at baseline

          -  Major surgery within 4 weeks of first dose of study drug

          -  Any life-threatening illness, medical condition, or organ system dysfunction that, in
             the investigator's opinion, could compromise the subject's safety at undue risk

          -  Uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New
             York Heart Association Functional Classification; or a history of myocardial
             infarction, unstable angina, or acute coronary syndrome within 6 months prior to
             randomization

          -  Unable to swallow capsules or malabsorption syndrome, disease significantly affecting
             gastrointestinal function, or resection of the stomach or small bowel currently
             affecting absorption, symptomatic inflammatory bowel disease or ulcerative colitis, or
             partial or complete bowel obstruction

          -  History of or concurrent condition of interstitial lung disease of any severity and/or
             severely impaired lung function (as judged by the investigator)

          -  Concurrent diagnosis of pheochromocytoma

          -  Lactating or pregnant. Women of child bearing potential must have a pregnancy test
             prior performed a maximum of 7 days before the start of treatment, and a negative
             result must be documented

          -  Patients receiving any other anti-cancer study agents

          -  Known lymphomatous involvement of the central nervous system

          -  Seizure disorder requiring medication

          -  Patients who require warfarin or other vitamin K antagonists for anticoagulation
             (other anticoagulants are allowed after consultation with the overall study chair).

          -  Concurrent administration of medications or foods that are strong inhibitors or
             inducers of CYP3A taken within 7 days of starting study treatment (Table 3).

          -  Herbal medications excluded within 7 days of starting study treatment (Section 5.5.1).

          -  Uncontrolled arterial hypertension despite optimal medical management

          -  Type 1 or type 2 diabetes mellitus with a HbA1c > 8.5%

          -  Known hypersensitivity to any of the test drugs, test drug classes, or excipients in
             the formulation
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose of venetoclax in combination with copanlisib (recommended phase II dose (RP2D) - Phase 1
Time Frame:28 Days up to 1 year
Safety Issue:
Description:The highest dose of the drug combination that does not cause unacceptable side effects as assessed by protocol-specified DLT criteria.

Secondary Outcome Measures

Measure:Partial response Rate (PR)
Time Frame:28 Days
Safety Issue:
Description:Per Lugano criteria
Measure:Complete response Rate (CR)
Time Frame:28 Days
Safety Issue:
Description:Per Lugano criteria
Measure:Duration of response (DOR)
Time Frame:Every 3 months to 1 year
Safety Issue:
Description:Legnth of time the patients respond to therapy
Measure:Progression-free survival (PFS)
Time Frame:Time from randomization (or registration) to the date of first documented progression or date of death from any cause, whichever comes first, for up to 5 years.
Safety Issue:
Description:The time from randomization (or registration) to progression or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation.
Measure:Overall survival (OS)
Time Frame:Time from randomization (or registration) to the date of death from any cause, assessed for up to 5 years.
Safety Issue:
Description:The time from randomization (or registration) to death due to any cause or censored at date last known alive.
Measure:Exome sequencing
Time Frame:Up to 1 year
Safety Issue:
Description:A genomic classifier will be applied to whole exome sequencing (WES) of DLBCL biopsy samples to determine genomic cluster.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • Diffuse Large B Cell Lymphoma
  • Relapsed Diffuse Large B-Cell Lymphoma
  • Refractory Diffuse Large B-Cell Lymphoma

Last Updated

September 28, 2020