Efficacy and Safety Study of Idelalisib in Participants With Indolent B-Cell Non-Hodgkin Lymphomas

Study Overview
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Brief Summary
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The primary objective will be to assess the overall response rate and to evaluate the efficacy and safety of idelalisib (IDELA; GS-1101) in participants with previously treated indolent Non-Hodgkin Lymphoma (iNHL) that is refractory both to rituximab and to alkylating-agent-containing chemotherapy. Eligible participants will initiate oral therapy with idelalisib at a starting dose of 150 mg taken twice per day. Treatment with idelalisib can continue in compliant participants as long as the study is still ongoing and the participants appear to be benefiting from treatment with acceptable safety.

Official Title
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A Phase 2 Study to Assess the Efficacy and Safety of Idelalisib in Subjects With Indolent B-Cell Non-Hodgkin Lymphomas Refractory to Rituximab and Alkylating Agents

Conditions
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Follicular Lymphoma, Small Lymphocytic Lymphoma, Lymphoplasmacytic Lymphoma, Marginal Zone Lymphoma

Intervention / Treatment
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* Drug: Idelalisib


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Karnofsky performance status of ≥ 60 (Eastern Cooperative Oncology Group [ECOG] performance score of 0, 1, or 2) Histologically confirmed diagnosis of B-cell iNHL, with histological subtype limited to the following: Follicular lymphoma (FL) Small lymphocytic lymphoma (SLL) with absolute lymphocyte count < 5 x 10^9/L at the time of diagnosis and on baseline laboratory assessment performed within 4 weeks prior to the start of study drug administration Lymphoplasmacytic lymphoma (LPL), with or without associated Waldenstroms Macroglobulinemia (WM) Marginal zone lymphoma (MZL) (splenic, nodal, or extranodal) Prior treatment with ≥ 2 prior chemotherapy-based or immunotherapy-based regimens for iNHL Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy Prior treatment with rituximab and with an alkylating agent (eg, bendamustine, cyclophosphamide, ifosfamide, chlorambucil, melphalan, busulfan, nitrosoureas) for iNHL Lymphoma that is refractory to rituximab and to an alkylating agent Discontinuation of all other therapies for treatment of iNHL ≥ 3 weeks before Visit 2 For men and women of childbearing potential, willingness to abstain from sexual intercourse or employ an effective method of contraception during the study drug administration and follow-up periods Willingness and ability to provide written informed consent and to comply with the protocol requirements Key Exclusion Criteria: Central nervous system or leptomeningeal lymphoma Known histological transformation from iNHL to diffuse large B-cell lymphoma History of a non-lymphoma malignancy except for the following: adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, localized prostate cancer, other adequately treated Stage 1 or 2 cancer currently in complete remission, or any other cancer that has been in complete remission for ≥ 5 years Evidence of ongoing systemic bacterial, fungal, or viral infection (excluding viral upper respiratory tract infections) at the time of initiation of study treatment Pregnancy or breastfeeding Ongoing alcohol or drug addiction Known history of drug-induced liver injury, chronic active hepatitis B infection, chronic active hepatitis C infection, alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, ongoing extrahepatic obstruction caused by stones, cirrhosis of the liver, or portal hypertension History of prior allogeneic bone marrow progenitor cell or solid organ transplantation Ongoing immunosuppressive therapy, including systemic corticosteroids. Participant may be using topical or inhaled corticosteroids. Prior therapy with idelalisib Exposure to another investigational drug within 3 weeks prior to start of study treatment Concurrent participation in another therapeutic treatment trial Prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, ECG finding, or laboratory abnormality that, in the investigator's opinion, could affect the safety of the participant, alter the absorption, distribution, metabolism or excretion of the study drug, or impair the assessment of study results 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Idelalisib<br>Treatment with idelalisib will be continued until tumor progression or development of unacceptable toxicity. | Drug: Idelalisib<br>* Idelalisib 150 mg tablet administered orally twice daily<br>* Other names: IDELA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Overall response rate (ORR) was assessed based on the International Working Group Revised Response Criteria for Malignant Lymphoma (Cheson, 2007), and was defined as the percentage of participants achieving a complete response (CR) or partial response (PR; or minor response [MR] for participants with WM) as assessed by the study independent review committee (IRC). CR was defined as the complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease. PR was defined as a ≥ 50% reduction in the sum of the products of the longest perpendicular diameters of all index lesions, with no new lesions. For WM only, response was defined as a reduction in immunoglobulin M (IgM) of ≥ 50% decrease for PR, and ≥ 25% decrease for MR; no increase from baseline in the sum of the products of the longest perpendicular diameters of all index lesions, with no new lesions or signs and symptoms of active disease (Owen, 2013) | Start of Treatment to End of Treatment (up to 81 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response | Duration of Response (DOR) was defined as the interval from the first documentation of CR or PR (or MR for participants with WM) to the earlier of the first documentation of disease progression as assessed by the study IRC or death from any cause. DOR was analyzed using Kaplan-Meier (KM) estimates. | Start of Treatment to End of Treatment (up to 81 months) | 
| Lymph Node Response Rate | Lymph node response (LNR) was defined as the percentage of participants who achieved a ≥ 50% decrease from baseline in the sum of the product of the perpendicular diameters (SPD) of measurable index lesions as assessed by the study IRC. | Start of Treatment to End of Treatment (up to 81 months) | 
| Time to Response | Time to response (TTR) was defined as the interval from the start of idelalisib treatment to the first documentation of CR or PR (or MR for participants with WM) as assessed by the study IRC. | Start of Treatment to End of Treatment (up to 81 months) | 
| Progression-Free Survival | Progression-free survival (PFS) was defined as the interval from the start of idelalisib treatment to the earlier of the first documentation of disease progression as assessed by the study IRC or death from any cause. PFS was analyzed using KM estimates. | Start of Treatment to End of Treatment (up to 81 months) | 
| Overall Survival | Overall survival (OS) was defined as the time interval from the start of idelalisib treatment to death from any cause. OS was analyzed using KM estimates. | Start of Treatment to Last Long-Term Follow-Up Visit (up to maximum of 7 years) | 
| Change in Health-Related Quality of Life Using the Functional Assessment of Cancer Therapy: Lymphoma Subscale (FACT-LymS) | Change in health-related quality of life events were reported by participants using the Functional Assessment of Cancer Therapy: Lymphoma Subscale (FACT-LymS) assessment tool. Results are presented as the mean (SD) best change from baseline. The best change from baseline was defined as the highest change score (improvement) after baseline. The FACT-LymS is on a scale from 0-60, with higher scores associated with a better quality of life. It incorporates values from 15 questions, each rated 0-4, related to study indications. | Baseline to End of Treatment (up to 81 months) | 
| Change in Karnofsky Performance Status | The change in Karnofsky performance status was reported as the best (highest change score) and worst (lowest change score) change from baseline using the Karnofsky performance criteria. The Karnofsky score classified participants according to their functional impairment. Scores are on a scale from 0-100, the lower the score, the worse the survival for most serious illnesses. | Baseline to End of Treatment (up to 81 months) | 
| Changes in Plasma Concentrations of Disease-Associated Chemokines and Cytokines | Analysis of the cytokine/chemokine was planned to be performed on a subset of samples from this study along with a subset of samples from other studies. Therefore, data for this Outcome Measure are not reported here because the analysis population includes participants who were not enrolled in this study. ClinicalTrials.gov is designed for reporting results from only those participants who were enrolled in the study and described in the Participant Flow and Baseline Characteristics modules. | Enrollment to End of Treatment (up to 81 months) | 
| Safety and Tolerability of Idelalisib Assessed as the Number of Participants Experiencing Adverse Events (AEs) or Abnormalities in Vital Signs, Laboratory Tests, or Electrocardiograms | This composite endpoint measured the safety and tolerability profile of idelalisib. Clinically meaningful abnormalities in vital signs and electrocardiograms (ECG) were as determined by the investigator. | Start of Treatment to End of Treatment (up to 81 months) plus 30 days | 
| Study Drug Exposure | The average idelalisib exposure was summarized. | Start of Treatment to End of Treatment (up to 81 months) | 
| Idelalisib Plasma Concentration |  | Predose and at 1.5 hours (± 5 minutes) postdose on Day 29 | 
| PK Parameter: Cmax | Cmax at Days 1 and 29 was analyzed. Cmax is defined as the maximum concentration of drug. | Predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours postdose on Days 1 and 29 | 
| PK Parameter: Tmax | Tmax at Days 1 and 29 was analyzed. Tmax is defined as the time of Cmax (the maximum concentration of drug). | Predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours postdose on Days 1 and 29 | 
| PK Parameter: AUClast | AUClast at Days 1 and 29 was analyzed. AUClast is defined as the concentration of drug from time zero to the last observable concentration | Predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours postdose on Days 1 and 29 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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indolent Non-Hodgkin Lymphoma, Non-Hodgkin Lymphoma, iNHL, NHL, GS-1101, CAL-101, PI3K, Phosphatidylinositol 3-kinase, Follicular Lymphoma (FL), Small lymphocytic lymphoma (SLL), Lymphoplasmacytoid lymphoma (LPL), Marginal zone lymphoma (MZL)