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Duvelisib and Venetoclax in Relapsed or Refractory CLL or SLL or RS

Primary Purpose

Chronic Lymphocytic Leukemia, Richter Syndrome

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Duvelisib
Venetoclax
Sponsored by
Dana-Farber Cancer Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Lymphocytic Leukemia focused on measuring chronic lymphocytic leukemia (CLL), Richter's Syndrome, Richter's Transformation

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Must have a confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic lymphoma requiring therapy, as per IW-CLL 2008 criteria OR Biopsy proven transformation to diffuse large B cell lymphoma (DLBCL), consistent with Richter's Syndrome
  • Disease that has progressed during or relapsed after at least one previous CLL/SLL therapy - If Richter's Syndrome, this criterion is not applicable
  • Age greater to or equal to 18 years
  • ECOG performance status ≤2 (Karnofsky ≥60%)
  • Patients must meet the following hematologic criteria at screening, unless they have significant bone marrow involvement of CLL confirmed on biopsy:

    • Absolute neutrophil count ≥500 cells/mm3 (0.5 x 109/L). Growth factor is allowed in order to achieve this
    • Platelet count ≥25,000 cells/mm3 (25 x 109/L) independent of transfusion within 7 days of screening
  • Adequate hepatic function defined as:

    --Serum aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x upper limit of normal (ULN), bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin

  • Adequate renal function as defined as:

    --Serum creatinine ≤1.5 times the upper limit of normal or creatinine clearance ≥ 50 mL/min using a 24-hour urine collection

  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal, barrier method or abstinence) prior to study entry and for the duration of study participation
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Previous treatment with venetoclax or duvelisib
  • Patients receiving cancer therapy (i.e., chemotherapy, radiation therapy, immunotherapy, biologic therapy, surgery within 2 weeks of Cycle 1/Day 1 with the following exceptions:

    • For patients on targeted therapies, a washout of least five half lives is required
    • Patients who experience clinical deterioration may start therapy after a shorter washout period with prior approval by the PI
    • Corticosteroid therapy (prednisone or equivalent <20 mg daily) is allowed
  • Confirmed central nervous system involvement
  • Allogeneic hematologic stem cell transplant within 6 months of starting study treatment or active graft vs. host disease (GVHD) requiring treatment or prophylaxis
  • History of active malignancy requiring therapy with the exception of hormonal therapy
  • Any active systemic infection requiring IV antibiotics or uncontrolled, active infections
  • Known history of human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV)
  • Major surgery within 4 weeks of first dose of study drug
  • Currently active gastrointestinal disease, including colitis, inflammatory bowel disease and diarrhea requiring therapy
  • Currently active, clinically significant cardiovascular disease, such as 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
  • 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
  • Use of Coumadin for anticoagulation (other anticoagulants permitted)
  • Lactating or pregnant
  • Concurrent administration of medications or foods that are strong inhibitors or inducers of CYP3A (see Appendix D) . The concomitant use of drugs or foods that are strong or moderate inhibitors or inducers of CYP3A are not allowed beginning 1 week prior to the first dose of duvelisib.
  • 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
  • Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction resulting in malabsorption or chronic diarrhea
  • Active abuse of alcohol
  • History of chronic liver disease or veno-occlusive disease/sinusoidal obstruction syndrome
  • History or concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function
  • Known hypersensitivity to duvelisib and/or its excipients
  • History of tuberculosis treatment within the 2 years prior to initiation of therapy

Sites / Locations

  • University of Miami- Sylvester Comprehensive Cancer CenterRecruiting
  • Northern Light Eastern Maine Medical CenterRecruiting
  • Massachusetts General Hospital
  • Boston Medical Center
  • Beth Israel Deaconess Medical Center
  • Dana Farber Cancer InstituteRecruiting
  • Berkshire Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Duvelisib +Venetoclax,

Arm Description

Duvelisib will be given alone for the first seven days. On day 8 Venetoclax will be added. Duvelisib will be administered orally twice daily Venetoclax will be administered orally daily All patients will be admitted for administration of the initial dose of venetoclax at each dose escalation

Outcomes

Primary Outcome Measures

Maximum Tolerated Dose of Venetoclax When Administered with Duvelisib
As assessed by protocol-specified DLT criteria (phase I)
Rate of complete remission
By IW-CLL criteria (phase II)

Secondary Outcome Measures

Cmax
Cmax
Half-life
Half-life
Volume of Distribution
Volume of Distribution
Objective response rate
By IW-CLL Criteria
Duration of response
By IW-CLL Criteria
Progression free survival
By IW-CLL Criteria
Rate of minimal residual disease negativity
By IW-CLL Criteria

Full Information

First Posted
May 2, 2018
Last Updated
July 31, 2023
Sponsor
Dana-Farber Cancer Institute
Collaborators
Secura Bio, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT03534323
Brief Title
Duvelisib and Venetoclax in Relapsed or Refractory CLL or SLL or RS
Official Title
A Phase I/II Study of Duvelisib and Venetoclax in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma or Patients With Richter's Syndrome
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
July 12, 2018 (Actual)
Primary Completion Date
July 1, 2024 (Anticipated)
Study Completion Date
July 1, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Dana-Farber Cancer Institute
Collaborators
Secura Bio, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This research study is assessing a new drug, duvelisib, in combination with a drug that is already FDA approved, venetoclax, as a possible treatment for participants with CLL or those with Richter's Syndrome
Detailed Description
This is a Phase I/II clinical trial. A Phase I clinical trial tests the safety of an investigational drugs and also tries to define the appropriate dose of the investigational drugs to use for further studies. "Investigational" means that the drugs are being studied together for the first time. This phase I study tests the safety of the drug duvelisib when used in combination with the drug venetoclax. Duvelisib is still being studied, but the FDA (the U.S. Food and Drug Administration) has approved the use of Duvelisib in patients with CLL/SLL with relapsed or refractory CLL after having received 2 or more prior therapies. Duvelisib is a drug that is given in capsule form and taken by mouth. This drug is designed to stop cancer growth by blocking a protein called phosphatidylinositide 3-kinase (PI3K), which is important for the survival of CLL cells. In laboratory studies and in other clinical trials that included participants with CLL, duvelisib was effective at killing CLL cells. Venetoclax is a tablet that is taken by mouth. Venetoclax targets a protein called BCL-2, which helps cancer cells survive. Venetoclax is an effective treatment for many participants with CLL who do not respond to chemotherapy or other approved drugs or who have relapsed after prior therapy.Venetoclax is FDA approved for participants with CLL who have never had therapy before or whose CLL has worsened after prior therapy. In the phase I portion of this study, the investigators are looking to determine the dose of venetoclax that is safe to give with duvelisib and to see what the side effects are of this combination. In the phase II portion of this study, we are looking to determine how effective thecombination of duvelisib and venetoclax is for patients with CLL or Richter's Syndrome

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Lymphocytic Leukemia, Richter Syndrome
Keywords
chronic lymphocytic leukemia (CLL), Richter's Syndrome, Richter's Transformation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
67 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Duvelisib +Venetoclax,
Arm Type
Experimental
Arm Description
Duvelisib will be given alone for the first seven days. On day 8 Venetoclax will be added. Duvelisib will be administered orally twice daily Venetoclax will be administered orally daily All patients will be admitted for administration of the initial dose of venetoclax at each dose escalation
Intervention Type
Drug
Intervention Name(s)
Duvelisib
Other Intervention Name(s)
IPI-145
Intervention Description
This drug is designed to stop cancer growth by blocking a protein called phosphatidylinositide 3-kinase (PI3K), which is important for the survival of CLL cells.
Intervention Type
Drug
Intervention Name(s)
Venetoclax
Other Intervention Name(s)
Venclexta
Intervention Description
Venetoclax targets a protein called BCL-2, which helps cancer cells survive.
Primary Outcome Measure Information:
Title
Maximum Tolerated Dose of Venetoclax When Administered with Duvelisib
Description
As assessed by protocol-specified DLT criteria (phase I)
Time Frame
Up to 7 weeks
Title
Rate of complete remission
Description
By IW-CLL criteria (phase II)
Time Frame
2 years
Secondary Outcome Measure Information:
Title
Cmax
Description
Cmax
Time Frame
Up to 7 weeks
Title
Half-life
Description
Half-life
Time Frame
Up to 7 weeks
Title
Volume of Distribution
Description
Volume of Distribution
Time Frame
Up to 7 weeks
Title
Objective response rate
Description
By IW-CLL Criteria
Time Frame
2 years
Title
Duration of response
Description
By IW-CLL Criteria
Time Frame
2 years
Title
Progression free survival
Description
By IW-CLL Criteria
Time Frame
2 years
Title
Rate of minimal residual disease negativity
Description
By IW-CLL Criteria
Time Frame
2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Must have a confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic lymphoma requiring therapy, as per IW-CLL 2008 criteria OR Biopsy proven transformation to diffuse large B cell lymphoma (DLBCL), consistent with Richter's Syndrome Disease that has progressed during or relapsed after at least one previous CLL/SLL therapy - If Richter's Syndrome, this criterion is not applicable Age greater to or equal to 18 years ECOG performance status ≤2 (Karnofsky ≥60%) Patients must meet the following hematologic criteria at screening, unless they have significant bone marrow involvement of CLL confirmed on biopsy: Absolute neutrophil count ≥500 cells/mm3 (0.5 x 109/L). Growth factor is allowed in order to achieve this Platelet count ≥25,000 cells/mm3 (25 x 109/L) independent of transfusion within 7 days of screening Adequate hepatic function defined as: --Serum aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x upper limit of normal (ULN), bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin Adequate renal function as defined as: --Serum creatinine ≤1.5 times the upper limit of normal or creatinine clearance ≥ 50 mL/min using a 24-hour urine collection Women of child-bearing potential and men must agree to use adequate contraception (hormonal, barrier method or abstinence) prior to study entry and for the duration of study participation Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Previous treatment with venetoclax or duvelisib Patients receiving cancer therapy (i.e., chemotherapy, radiation therapy, immunotherapy, biologic therapy, surgery within 2 weeks of Cycle 1/Day 1 with the following exceptions: For patients on targeted therapies, a washout of least five half lives is required Patients who experience clinical deterioration may start therapy after a shorter washout period with prior approval by the PI Corticosteroid therapy (prednisone or equivalent <20 mg daily) is allowed Confirmed central nervous system involvement Allogeneic hematologic stem cell transplant within 6 months of starting study treatment or active graft vs. host disease (GVHD) requiring treatment or prophylaxis History of active malignancy requiring therapy with the exception of hormonal therapy Any active systemic infection requiring IV antibiotics or uncontrolled, active infections Known history of human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV) Major surgery within 4 weeks of first dose of study drug Currently active gastrointestinal disease, including colitis, inflammatory bowel disease and diarrhea requiring therapy Currently active, clinically significant cardiovascular disease, such as 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 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 Use of Coumadin for anticoagulation (other anticoagulants permitted) Lactating or pregnant Concurrent administration of medications or foods that are strong inhibitors or inducers of CYP3A (see Appendix D) . The concomitant use of drugs or foods that are strong or moderate inhibitors or inducers of CYP3A are not allowed beginning 1 week prior to the first dose of duvelisib. 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 Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction resulting in malabsorption or chronic diarrhea Active abuse of alcohol History of chronic liver disease or veno-occlusive disease/sinusoidal obstruction syndrome History or concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function Known hypersensitivity to duvelisib and/or its excipients History of tuberculosis treatment within the 2 years prior to initiation of therapy
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Celeste Celeste
Phone
857-215-1646
Email
celeste_carey@dfci.harvard.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Matthew S Davids, MD
Organizational Affiliation
Dana-Farber Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Miami- Sylvester Comprehensive Cancer Center
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alvaro Alencar, MD
First Name & Middle Initial & Last Name & Degree
Nathalie Luis
Facility Name
Northern Light Eastern Maine Medical Center
City
Brewer
State/Province
Maine
ZIP/Postal Code
04412
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Bhandari Shruti, MD
First Name & Middle Initial & Last Name & Degree
Laurie Lewis
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Individual Site Status
Active, not recruiting
Facility Name
Boston Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02118
Country
United States
Individual Site Status
Completed
Facility Name
Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Individual Site Status
Completed
Facility Name
Dana Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Matthew Davids, MD
Phone
617-632-6331
First Name & Middle Initial & Last Name & Degree
Matthew S Davids, MD
Facility Name
Berkshire Medical Center
City
Pittsfield
State/Province
Massachusetts
ZIP/Postal Code
01201
Country
United States
Individual Site Status
Completed

12. IPD Sharing Statement

Plan to Share IPD
No

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Duvelisib and Venetoclax in Relapsed or Refractory CLL or SLL or RS

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