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

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

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

Study Overview

• Status: Active, not recruiting
• Conditions: Chronic Lymphocytic Leukemia; Richter Syndrome
• Intervention / Treatment: Drug: Duvelisib; Drug: Venetoclax

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

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami- Sylvester Comprehensive Cancer Center
  • Maine
    • Brewer, Maine, United States, 04412
      • Northern Light Eastern Maine Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
    • Pittsfield, Massachusetts, United States, 01201
      • Berkshire Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1 Level 1: 100 mg Venetoclax (daily) + 25 mg Duvelisib (BID); Duvelisib will be given alone for the first seven days. On day 8 Venetoclax will be added.; Duvelisib will be administered orally twice daily of 25mg; Venetoclax will be administered orally daily of 100mg; All patients will be admitted for administration of the initial dose of venetoclax at each dose escalation	Drug: Duvelisib; 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.; Other Names: IPI-145; Drug: Venetoclax; Venetoclax targets a protein called BCL-2, which helps cancer cells survive.; Other Names: Venclexta
Experimental: Phase 1 Level 2: 200 mg Venetoclax (daily) + 25 mg Duvelisib (BID); Duvelisib will be administered orally twice daily of 25mg; Venetoclax will be administered orally daily of 200mg; All patients will be admitted for administration of the initial dose of venetoclax at each dose escalation	Drug: Duvelisib; 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.; Other Names: IPI-145; Drug: Venetoclax; Venetoclax targets a protein called BCL-2, which helps cancer cells survive.; Other Names: Venclexta
Experimental: Phase 1 Level 3: 400 mg Venetoclax (daily) + 25 mg Duvelisib (BID); Duvelisib will be administered orally twice daily of 25mg; Venetoclax will be administered orally daily of 400mg; All patients will be admitted for administration of the initial dose of venetoclax at each dose escalation	Drug: Duvelisib; 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.; Other Names: IPI-145; Drug: Venetoclax; Venetoclax targets a protein called BCL-2, which helps cancer cells survive.; Other Names: Venclexta
Experimental: Phase 2: 400 mg Venetoclax (daily) + 25 mg Duvelisib (BID); Duvelisib will be administered orally twice daily of 25mg; Venetoclax will be administered orally daily of 400mg	Drug: Duvelisib; 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.; Other Names: IPI-145; Drug: Venetoclax; Venetoclax targets a protein called BCL-2, which helps cancer cells survive.; Other Names: Venclexta

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Response Rate (CRR)	The overall response rate (ORR) was defined as the proportion of participants achieving complete response (CR) based on IWCLL 2008 and Lugano 2014 criteria for RS.	Response assessment on the end of cycle 3, 6 and 13. With 28 days per cycle.
Overall Response Rate (ORR)	The overall response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) based on IWCLL 2008 and Lugano 2014 criteria for RS.	Response assessment on the end of cycle 3, 6 and 13. With 28 days per cycle.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
12-month Progression-Free Survival (PFS) Rate	Progression-free survival based on the Kaplan-Meier method is defined as the duration between randomization and documented disease progression (PD) or death, or is censored at time of last disease assessment.	Relevant to this endpoint is at 12 month.
1-year Overall Survival (OS)	1-year OS is a probability estimated using the Kaplan-Meier method; OS is defined as the time from study entry to death, or censored at date last known alive.	Relevant to this endpoint is 1 year.
1-year MRD Negativity Rate	Defined by the proportion of participants achieved the MRD negative CR in bone marrow.	At 1 year

Collaborators and Investigators

• Sponsor: Dana-Farber Cancer Institute
• Collaborators: Secura Bio, Inc.
• Investigators: Principal Investigator: Matthew S Davids, MD, Dana-Farber Cancer Institute

Study record dates

Study Major Dates

• Study Start (Actual): July 12, 2018
• Primary Completion (Actual): December 1, 2024
• Study Completion (Estimated): July 1, 2026

Study Registration Dates

• First Submitted: May 2, 2018
• First Submitted That Met QC Criteria: May 11, 2018
• First Posted (Actual): May 23, 2018

Study Record Updates

• Last Update Posted (Actual): March 23, 2026
• Last Update Submitted That Met QC Criteria: March 2, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Richter's Transformation; Richter's Syndrome; chronic lymphocytic leukemia (CLL)
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Chronic Disease; Disease Attributes; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; Leukemia, Lymphocytic, Chronic, B-Cell; Antineoplastic Agents; venetoclax; duvelisib
• Other Study ID Numbers: 18-089

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No