Rituximab, Idelalisib, and Venetoclax in Relapsed/Refractory CLL/SLL

NCT03639324 | Withdrawn Phase 1 DMC FDA Drug

• 2 other identifiers: MCC-15-12310NCI-2018-01661
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

To determine the recommended phase 2 dose (RP2D) of idelalisib and venetoclax in combination with rituximab in patients with relapsed or refractory Chronic lymphocytic leukemia/ Small lymphocytic lymphoma (CLL/SLL) following a lead-in period with idelalisib and rituximab

Conditions

Chronic Lymphocytic Leukemia; CLL; Relapsed CLL; Refractory Chronic Lymphocytic Leukemia; Relapsed Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; SLL; Relapsed Small Lymphocytic Lymphoma; Refractory Small Lymphocytic Lymphoma

Keywords

venetoclax; idelalisib; rituximab

Outcome Measures

Primary Outcomes (1)

• Find the RP2D of idelalisib and venetoclax in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL)

  Determine the recommended phase 2 dose of idelalisib and venetoclax in combination with rituximab in patients with relapsed or refractory CLL/SLL following a lead-in period with idelalisib and rituximab.

  41 Months

Secondary Outcomes (7)

• Safety Evaluation: Determine adverse events (AEs) reported using criteria in the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0

  63 Months

• Determination of cumulative complete response (CR) rate.

  52 Months

• Summarize the objective response rate.

  52 Months

• Minimal residual disease (MRD) rate

  52 Months

• Overall Survival Rate

  63 Months

Study Arms (6)

Dose Combination 1-1

EXPERIMENTAL

idelalisib + venetoclax

Drug: Dose combination 1-1

Dose Combination 1-2

EXPERIMENTAL

idelalisib + venetoclax

Drug: dose combination 1-2

Dose Combination 1-3

EXPERIMENTAL

idelalisib + venetoclax

Drug: Dose combination 1-3

Dose Combination 1-4

EXPERIMENTAL

idelalisib + venetoclax

Drug: dose combination 1-4

Sub-Trial Dose Combination 2-1

EXPERIMENTAL

idelalisib + venetoclax

Drug: Sub-Trial: Dose combination 2-1

Sub-Trial Dose Combination 2-2

EXPERIMENTAL

idelalisib + venetoclax

Drug: Sub-Trial: Dose combination 2-2

Interventions

Dose combination 1-1 DRUG

100 mg QD of idelalisib + 100 mg QD of venetoclax

Dose Combination 1-1

dose combination 1-2 DRUG

100 mg QD of idelalisib + 200 mg QD of venetoclax

Dose Combination 1-2

Dose combination 1-3 DRUG

100 mg BID of idelalisib + 200 mg QD of venetoclax

Dose Combination 1-3

dose combination 1-4 DRUG

150 mg BID of idelalisib + 200 mg QD of venetoclax

Dose Combination 1-4

Sub-Trial: Dose combination 2-1 DRUG

100 mg BID of idelalisib + 100 mg QD of venetoclax

Sub-Trial Dose Combination 2-1

Sub-Trial: Dose combination 2-2 DRUG

150 mg BID of idelalisib + 100 mg QD of venetoclax

Sub-Trial Dose Combination 2-2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years of age. Relapsed or refractory B-cell CLL or biopsy-proven SLL. Treatment required in the opinion of the investigator
• Must have had at least one standard treatment with a regimen containing at least one of the following agents/classes of agents; and where specified, must also meet the treatment duration, progression, and/or relapse criteria for that class of agent:
• Fludarabine
• An alkylator (eg, chlorambucil, bendamustine)
• A BTK inhibitor (eg, ibrutinib, acalabrutinib); and must have progressed or relapsed \> 6 months after last BTK inhibitor treatment
• An anti-CD20 monoclonal antibody (eg, rituximab, obinutuzumab)
• A BCL-2-family protein inhibitor (eg, venetoclax, navitoclax); and
• if best response is \< CR with BCL-2-family protein inhibitor treatment
• must have had ≥ 1 year of BCL-2-family protein inhibitor treatment; and
• must have progressed \> 6 months after last BCL-2-family protein inhibitor treatment
• if best response is CR with BCL-2-family protein inhibitor treatment
• must have relapsed ≥ 1 year after last BCL-2-family protein inhibitor treatment
• A PI3K inhibitor (eg, idelalisib, duvelisib, TGR-1202, copanlisib, buparlisib); and must have progressed or relapsed \> 6 months after last treatment with the PI3K inhibitor (NOTE THAT THIS CRITERION IS NOT APPLICABLE TO 2ND-STEP REGISTRATION)
• Prior allogeneic stem cell transplant allowed provided the following criteria are met:
• ≥ 12 months have elapsed since allogeneic transplant

You may not qualify if:

• Known histologic transformation from CLL/SLL to an aggressive lymphoma (ie, Richter's transformation).
• Known history of drug-induced pneumonitis History of inflammatory bowel disease. Central nervous system involvement Clinically significant infection including active hepatitis B or hepatitis C requiring active treatment, or active CMV infection Known human immunodeficiency virus (HIV) seropositivity. \* Note: HIV testing is not required.
• Vaccination within 4 weeks prior to initiation of rituximab \*Note: Review vaccination status. Patients should, if possible, be brought up-to-date with all immunizations in agreement with current immunization guidelines at least 4 weeks prior to initiating rituximab.•Ongoing requirement for warfarin (due to potential drug-drug interactions that may increase the exposure of warfarin and ensuing complications).
• Has received any of the following within 14 days prior to initiation of study treatment:(NOTE THAT THIS CRITERION IS NOT APPLICABLE TO 2ND-STEP REGISTRATION)
• Anti-cancer therapy
• Investigational therapy Has not recovered to ≤ grade 1 toxicity(s) from prior therapy, except for chronic residual toxicities that in the opinion of the investigator are not clinically relevant given the known safety/toxicity profiles of the study regimen (eg, alopecia). (NOTE THAT THIS CRITERION IS NOT APPLICABLE TO 2ND-STEP REGISTRATION) Has not recovered to ≤ grade 1 toxicity(s) from idelalisib and rituximab, except for chronic residual toxicities that in the opinion of the investigator are not clinically relevant given the known safety/toxicity profiles of the study regimen (eg, alopecia). (NOTE THAT THIS CRITERION IS NOT APPLICABLE TO 1ST-STEP REGISTRATION)
• Ongoing or planned treatment with any of the following:
• Steroid therapy for anti-neoplastic intent
• Strong or moderate CYP3A inhibitor or inducer, and/or a narrow-therapeutic sensitive substrate
• P-gp inhibitor or narrow-therapeutic sensitive P-gp substrate If any of these agents have been used, patients must be off them for ≥ 1 week before initiation of study treatment.
• Prior intolerance to any component of study regimen that, in the opinion of the investigator would preclude study treatment.
• A cardiovascular disability status of New York Heart Association Class ≥ II Diagnosis or treatment for another malignancy within 1 year of study registration, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, any in situ malignancy, or low-risk prostate cancer after curative therapy Active liver disease other than lymphoid involvement, inflammatory bowel disease, or Crohn's disease Malabsorption syndrome or other condition that precludes enteral route of administration.
• Exhibits evidence of other clinically significant uncontrolled condition(s) including, but not limited to:
• Uncontrolled infection (viral, bacterial, or fungal)
• Grade 3 or greater neutropenic fever within 1 week prior to initiation of study treatment Active autoimmune cytopenias (for 2 or more weeks), including autoimmune hemolytic anemia (AIHA) and idiopathic thrombocytopenic purpura.

Sponsors & Collaborators

• Virginia Commonwealth University: lead
• Gilead Sciences: collaborator

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Victor Y Yazbek, MD, MS

  Massey Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Patients will start on dose level 1 of venetoclax in combination with rituximab and idelalisib, then escalate or de-escalate (if lower dose is available) based upon the estimated probabilities of toxicity from an extension of the continual reassessment method for 2 agents.

Study Record Dates

• First Submitted: August 8, 2018
• First Posted: August 21, 2018
• Study Start: October 2, 2020
• Primary Completion: October 18, 2021
• Study Completion: October 18, 2021
• Last Updated: November 9, 2021

Record last verified: 2021-11

Data Sharing

• IPD Sharing: Will not share