Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

CRC043: A Phase II Study of Venetoclax in Combination With Dose-adjusted EPOCH-R for Patients With Richter's Syndrome

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: NCT03054896
Recruitment Status : Recruiting
First Posted : February 16, 2017
Last Update Posted : July 4, 2019
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
Matthew S. Davids, MD, Dana-Farber Cancer Institute

Tracking Information
First Submitted Date  ICMJE February 10, 2017
First Posted Date  ICMJE February 16, 2017
Last Update Posted Date July 4, 2019
Actual Study Start Date  ICMJE March 8, 2017
Estimated Primary Completion Date September 1, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 15, 2017)
Rate of Complete Response by 2008 IW-CLL Response Criteria [ Time Frame: 2 years ]
Complete Response Rate
Original Primary Outcome Measures  ICMJE
 (submitted: February 13, 2017)
Rate of Complete Response by 2008 IW-CLL Response Criteria [ Time Frame: 2 years ]
Change History Complete list of historical versions of study NCT03054896 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 15, 2017)
  • Partial Response Rate by 2008 IW-CLL Response Criteria [ Time Frame: 2 years ]
    Partial Response Rate
  • Progression Free Survival [ Time Frame: 2 years ]
    PFS
  • Overall Survival Rate [ Time Frame: 2 years ]
    OS
  • Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 2 years ]
    Treatment-related AEs
Original Secondary Outcome Measures  ICMJE
 (submitted: February 13, 2017)
  • Partial Response Rate by 2008 IW-CLL Response Criteria [ Time Frame: 2 years ]
  • Progression Free Survival [ Time Frame: 2 years ]
  • Overall Survival Rate [ Time Frame: 2 years ]
  • Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 2 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE CRC043: A Phase II Study of Venetoclax in Combination With Dose-adjusted EPOCH-R for Patients With Richter's Syndrome
Official Title  ICMJE Venetoclax Plus Dose-adjusted EPOCH-R for Richter's Syndrome
Brief Summary

This research study is evaluating the combination of a study drug, venetoclax, and a standard chemotherapy regimen, EPOCH-R, as a possible treatment for Richter's Syndrome.

The drugs involved in this study are:

  • Venetoclax
  • EPOCH-R:
  • Etoposide
  • Prednisone
  • Vincristine Sulfate (Oncovin)
  • Cyclophosphamide
  • Doxorubicin Hydrochloride (Hydroxydaunomycin)
  • Rituximab
Detailed Description

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.

Tumor cells from patients with Richter's Syndrome are often resistant to chemotherapy. One reason for this may be that a protein called BCL-2 can prevent cancer cells from dying after being exposed to chemotherapy. Venetoclax is an oral drug that specifically targets BCL-2. It has already been shown to be highly effective at killing tumor cells from CLL patients whose cells are resistant to chemotherapy, leading to its FDA (the U.S. Food and Drug Administration) approval for these patients. A small number of patients with Richter's Syndrome have been treated with venetoclax as a single drug, and some of these patients had improvement of their cancer with this treatment.

In this research study, the investigators are looking to see whether adding venetoclax to a standard chemotherapy regimen, R-EPOCH, will help this chemotherapy work better to more effectively kill tumor cells in patients with Richter's Syndrome. Venetoclax is not approved for Richter's Syndrome or for use in combination with chemotherapy, which is why its use in this trial is considered to be investigational.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Richter Syndrome
Intervention  ICMJE
  • Drug: Venetoclax
    Venetoclax is an Antineoplastic Agent; BCL-2 Inhibitor
    Other Name: Venclexta
  • Other: DA-EPOCH-R
    Intensive chemotherapy regiment
Study Arms  ICMJE Experimental: Venetoclax
  • Standard chemotherapy regimen, DA-EPOCH-R, with a novel oral Bcl-2 inhibitor, venetoclax will be administered to patients
  • Chemotherapy cycles will be administered approximately every 3 weeks
  • Initial venetoclax dose ramp-up will be done in a condensed fashion over approximately 5 days, followed by continuous daily dosing
Interventions:
  • Drug: Venetoclax
  • Other: DA-EPOCH-R
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: February 13, 2017)
20
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 1, 2023
Estimated Primary Completion Date September 1, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Must have a confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic lymphoma as per IW-CLL 2008 criteria (Hallek et al, 2008) with biopsy proven transformation to diffuse large B cell lymphoma (DLBCL), consistent with Richter's Syndrome.
  • Age greater than or equal to 18 years. Because CLL and Richter's Syndrome are extremely rare in persons <18 years of age, children are excluded from this study.
  • ECOG performance status <2 (see Appendix A)
  • Patients must meet the following hematologic criteria at screening, unless they have significant bone marrow involvement of their malignancy confirmed on biopsy:

    • Absolute neutrophil count ≥1000 cells/mm3 (0.5 x 109/L). Growth factor allowed to achieve
    • Platelet count ≥40,000 cells/mm3 (40 x 109/L) independent of transfusion within 7 days of screening
  • Subject must have adequate coagulation, renal, and hepatic function, per laboratory reference range at Screening as follows:

    • Activated partial thromboplastin time (aPTT) and prothrombin time (PT) not to exceed 1.5 × ULN;
    • Creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min using 24-hour urine collection for creatinine clearance
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × ULN;
    • Bilirubin ≤ 1.5 × ULN;
    • Subjects with Gilbert's Syndrome or resolving autoimmune hemolytic anemia may have a bilirubin up to 3.0 × ULN and are still eligible
    • The effects of venetoclax on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
  • Patients who have undergone prior allogeneic transplantation are eligible provided they do not have significant active graft versus host disease and that their transplant day 0 is > 6 months from their first dose of chemotherapy
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Patients with the Hodgkin variant transformation of CLL will be excluded
  • History of severe allergic or anaphylactic reactions to monoclonal antibody therapy or to the chemotherapy drugs used in this study (see Appendix D), unless the antibody can be given through a desensitization program in consultation with an allergist
  • Subject has received any of the following within 14 days or 5 drug half-lives (whichever is shortest) prior to the first dose of chemotherapy, or has not recovered to less than Grade 2 clinically significant adverse effect(s)/toxicity(s) of the previous therapy:
  • Any anti-cancer therapy including chemotherapy, biologic agents for anti-neoplastic treatment (e.g. monoclonal antibodies) or radiotherapy, investigational therapy, including targeted small molecule agents.
  • History of other malignancies, except:
  • Malignancy treated with curative intent and with no known active disease present before the first dose of study drug and felt to be at low risk for recurrence by treating physician.
  • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
  • Adequately treated carcinoma in situ without evidence of disease
  • Low-risk prostate cancer on active surveillance
  • Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc.) within 28 days of the first dose of study drug.
  • Corticosteroids are allowed, but must be dosed at prednisone 20 mg (or equivalent) or lower prior to the start of chemotherapy.
  • Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
  • Known bleeding disorders (eg, von Willebrand's disease) or hemophilia.
  • History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
  • History of human immunodeficiency virus (HIV) or active hepatitis C virus (HCV) or hepatitis B virus (HBV). Patients who are positive for hepatitis B core antibody or hepatitis B surface antigen must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded.
  • Any uncontrolled active systemic infection.
  • 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 or put the study outcomes at undue risk.
  • Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 2 or higher 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, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction at time of screening.
  • Breastfeeding or pregnant. Serum pregnancy test will be conducted.
  • Male subject who is considering fathering a child or donating sperm during the study or for approximately 90 days after the last dose of study drugs.
  • Unwilling or unable to participate in all required study evaluations and procedures. Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations)
  • Patients receiving any other study agents
  • Patients with known CNS involvement
  • Baseline QTcF >480 ms. NOTE: This criterion does not apply to patients with a left bundle branch block.
  • Patients who require warfarin or other vitamin K antagonists for anticoagulation (other anticoagulants are allowed).
  • Concurrent administration of medications or foods that are strong inhibitors or inducers of CYP3A (see Appendix B).
  • Patients with ongoing use of prophylactic antibiotics are eligible as long as there is no evidence of active infection and the antibiotic is not a prohibited medication
  • Unable to receive prophylactic treatment for pneumocystis, herpes simplex virus (HSV), and herpes zoster (VZV) at start of treatment
  • Significant co-morbid condition or disease which in the judgment of the Principal Investigator would place the patient at undue risk or interfere with the study
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: Samantha Pazienza 617-632-2328 Samantha_Pazienza@dfci.harvard.edu
Contact: Matthew S. Davids, MD, MMSc 617-632-6331 Matthew_Davids@dfci.harvard.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03054896
Other Study ID Numbers  ICMJE 16-596
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
Plan to Share IPD: No
Responsible Party Matthew S. Davids, MD, Dana-Farber Cancer Institute
Study Sponsor  ICMJE Dana-Farber Cancer Institute
Collaborators  ICMJE Genentech, Inc.
Investigators  ICMJE
Principal Investigator: Matthew S. Davids, MD, MMSc Dana-Farber Cancer Institute
PRS Account Dana-Farber Cancer Institute
Verification Date July 2019

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