Efficacy and Safety of Idelalisib in Combination With Obinutuzumab Compared to Chlorambucil in Combination With Obinutuzumab for 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 effects of idelalisib with obinutuzumab versus the combination of chlorambucil and obinutuzumab on progression-free survival (PFS) in participants with previously untreated chronic lymphocytic leukemia (CLL). 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 those studies in agreement with the DMC recommendation and in consultation with the US Food and Drug Administration (FDA). All front-line studies of idelalisib, including this study, were also terminated.

Official Title
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A Phase 3, Randomized, Open-Label Study Evaluating the Efficacy and Safety of Idelalisib in Combination With Obinutuzumab Compared to Chlorambucil in Combination With Obinutuzumab for Previously Untreated Chronic Lymphocytic Leukemia

Conditions
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Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: Idelalisib
* Drug: Chlorambucil
* Drug: Obinutuzumab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Not a candidate for fludarabine therapy based on either: creatinine clearance < 70 mL/min, or Cumulative Illness Rating Scale score > 6, by assessment of the investigator 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 Ongoing drug-induced pneumonitis Ongoing inflammatory bowel disease History of prior allogeneic bone marrow progenitor cell or solid organ transplantation Ongoing immunosuppressive therapy other than corticosteroids Concurrent participation in another therapeutic clinical trial Undergone major surgery within 30 days prior to randomization Known hypersensitivity or intolerance to any of the active substances or excipients in the formulations for idelalisib, obinutuzumab, or chlorambucil History of non-infectious pneumonitis 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
Interventional Model Description: Safety Run-In Phase: Single Group; Randomized Phase: Parallel
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Safety Run-In: Idelalisib+obinutuzumab<br>Participants will receive idelalisib for 96 weeks and obinutuzumab over 21 weeks. Following 4 weeks of treatment, safety data will be reviewed by an independent data monitoring committee (DMC). If acceptable tolerability is observed, the randomized portion of the study will begin. | Drug: Idelalisib<br>* 150 mg tablet administered orally twice daily<br>* Other names: Zydelig®;Drug: Obinutuzumab<br>* 1000 mg/40 mL single-use vials administered intravenously for a total of 8 doses over 21 weeks<br>|
| Experimental: Randomized: Idelalisib+obinutuzumab<br>Participants will receive idelalisib for 96 weeks and obinutuzumab over 21 weeks. | Drug: Idelalisib<br>* 150 mg tablet administered orally twice daily<br>* Other names: Zydelig®;Drug: Obinutuzumab<br>* 1000 mg/40 mL single-use vials administered intravenously for a total of 8 doses over 21 weeks<br>|
| Active Comparator: Randomized: Obinutuzumab+chlorambucil<br>Participants will receive obinutuzumab over 21 weeks and chlorambucil over 23 weeks. | Drug: Chlorambucil<br>* 2 mg tablets administered at a dose of 0.5 mg/kg orally every other week for a total of 12 doses<br>Drug: Obinutuzumab<br>* 1000 mg/40 mL single-use vials administered intravenously for a total of 8 doses over 21 weeks<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 11 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 11 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 11 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 11 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 11 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. For participants receiving the final dose of obinutuzumab after the original scheduled date, the MRD assessment was performed no less than 12 weeks after the last dose of obinutuzumab. MRD negativity rate was to be assessed by an IRC. | Up to 11 months |