Efficacy and Safety of Idelalisib in Combination With Bendamustine and Rituximab in Adults With Previously Untreated Chronic Lymphocytic Leukemia

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the progression-free survival in participants with previously untreated chronic lymphocytic leukemia (CLL) who would otherwise be suitable for bendamustine and rituximab treatment as standard of care. An increased rate of deaths and serious adverse events (SAEs) among participants with front-line CLL and early-line indolent non-Hodgkin lymphoma (iNHL) treated with idelalisib in combination with standard therapies was observed by the independent data monitoring committee (DMC) during regular review of 3 Gilead Phase 3 studies. Gilead reviewed the unblinded data and terminated this study in agreement with the DMC recommendation and in consultation with the US Food and Drug Administration (FDA).

Official Title
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A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Idelalisib in Combination With Bendamustine and Rituximab for Previously Untreated Chronic Lymphocytic Leukemia

Conditions
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Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: Idelalisib
* Drug: Bendamustine
* Drug: Rituximab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Documented diagnosis of B-cell CLL, with diagnosis established according to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) No prior therapy for CLL other than corticosteroids for disease complications CLL that warrants treatment Presence of measurable lymphadenopathy Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 Key Exclusion Criteria: Known histological transformation from CLL to an aggressive lymphoma (ie, Richter transformation) Known presence of myelodysplastic syndrome Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of randomization Ongoing liver injury History of non-infectious pneumonitis Ongoing inflammatory bowel disease History of prior allogeneic bone marrow progenitor cell or solid organ transplantation Ongoing immunosuppressive therapy other than corticosteroids Received last dose of study drug on another therapeutic clinical trial within 30 days prior to randomization Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Idelalisib+bendamustine+rituximab<br>Participants will receive idelalisib for 96 weeks plus bendamustine+rituximab for 21 weeks. | Drug: Idelalisib<br>* 150 mg tablet administered orally twice daily<br>* Other names: CAL-101;Drug: Bendamustine<br>* Administered intravenously at a starting dose of 90 mg/m^2 for up to 6 cycles. Dosing will be based on mg/m^2 of body surface area.<br>Drug: Rituximab<br>* Single-use vials administered intravenously weekly starting at 375 mg/m^2 on Day 1 (Week 0) and 500 mg/m^2 thereafter for a total of 6 infusions<br>|
| Placebo Comparator: Placebo+bendamustine+rituximab<br>Participants will receive placebo to match idelalisib for 96 weeks plus bendamustine+rituximab for 21 weeks. | Drug: Bendamustine<br>* Administered intravenously at a starting dose of 90 mg/m^2 for up to 6 cycles. Dosing will be based on mg/m^2 of body surface area.<br>Drug: Rituximab<br>* Single-use vials administered intravenously weekly starting at 375 mg/m^2 on Day 1 (Week 0) and 500 mg/m^2 thereafter for a total of 6 infusions<br>Drug: Placebo<br>* Placebo to match idelalisib administered orally twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival | Progression-free survival (PFS) is defined as the interval from randomization to the first documentation of definitive disease progression or death from any cause. Definitive disease progression is CLL progression based on standard criteria, excluding lymphocytosis alone. PFS was to be assessed by an independent review committee (IRC). | Up to 22 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Overall response rate (ORR) is defined as the proportion of participants who achieve a confirmed complete or partial response. ORR was to be assessed by an IRC. | Up to 22 months | 
| Nodal Response Rate | Nodal response rate is defined as the proportion of participants who achieve a 50% decrease from baseline in the sum of the products of the greatest perpendicular diameters of index lesions. Nodal response rate was to be assessed by an IRC. | Up to 22 months | 
| Complete Response Rate | Complete response rate is defined as the proportion of participants who achieve a confirmed complete response. Complete response rate was to be assessed by an IRC. | Up to 22 months | 
| Overall Survival | Overall survival is defined as the interval from randomization to death from any cause. Overall survival was to be assessed by an IRC. | Up to 22 months | 
| Minimal Residual Disease Negativity Rate at Week 36 | Minimal residual disease (MRD) negativity rate is defined as the proportion of participants with MRD < 10^-4 assessed by flow cytometry in bone marrow at Week 36 after therapy initiation or at least 12 weeks after the last dose of rituximab or bendamustine (whichever is later) for participants receiving the final dose of rituximab after the original scheduled date. MRD negativity rate was to be assessed by an IRC. | Up to 22 months |