A Study of Idelalisib and Rituximab in Elderly Patients With Untreated CLL or SLL

Study Overview
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Brief Summary
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This study is to evaluate the safety and clinical activity of idelalisib alone and in combination with rituximab in patients with CLL or SLL. This Phase 2 study will be the first time that idelalisib is administered to previously untreated patients with hematologic malignancies. Idelalisib has demonstrated clinical activity as a single agent in relapsed or refractory CLL and SLL with acceptable toxicity, which supports its evaluation in previously untreated patients. The study population is limited to patients over 65 years of age because younger patients are generally appropriate for standard immunochemotherapy regimens that are highly active. Since the mechanism of action of idelalisib is distinct from rituximab, it is hypothesized that the combination will be more active than either agent alone. This study will establish initial safety and clinical activity of idelalisib in combination with rituximab in patients with CLL or SLL. Cohort 2 of this study will establish safety and clinical activity of idelalisib alone in subjects with untreated CLL or SLL.

Official Title
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A Phase 2 Single Arm Study to Investigate the Safety and Clinical Activity of Idelalisib Alone and in Combination With Rituximab in Elderly Subjects With Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Conditions
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Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL)

Intervention / Treatment
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* Drug: Idelalisib
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Histologically or cytologically confirmed CLL or SLL. Age ≥ 65 Presence of measurable lymphadenopathy (defined as the presence of ≥1 nodal lesion that measures ≥ 1.5 cm in the longest diameter (LD) and ≥ 1.0 cm in the longest perpendicular diameter (LPD) as assessed by physical exam, computed tomography (CT) or magnetic resonance imaging (MRI)). CLL - Binet Stage C or Rai Stage III or IV or has active disease defined by meeting at least one of the following criteria: Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia Massive (ie, > 6 cm below the left costal margin) or progressive or symptomatic splenomegaly Massive nodes (ie, > 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time of less than 6 months Autoimmune anemia and/or thrombocytopenia poorly responsive to corticosteroids or other standard therapy At least one of the following disease-related symptoms: Unintentional weight loss ≥ 10% within the previous 6 months Significant fatigue Fevers > 100.4 F for ≥ 2 weeks without other evidence of infection Night sweats for ≥ 1 month without evidence of infection SLL - has active disease as defined above for CLL, except the lymphocytosis criterion does not apply World Health Organization (WHO) Performance Status of ≤ 2 For men of child-bearing potential, willing to use adequate methods of contraception for the entire duration of the study Able to provide written informed consent Key Exclusion Criteria: Prior therapy for CLL or SLL, except corticosteroids for symptom relief Treatment with a short course of corticosteroids for symptom relief within 1-week prior to Visit 1 Known active central nervous system involvement of the malignancy Ongoing active, serious infection requiring systemic therapy. Patients may be receiving prophylactic antibiotics and antiviral therapy at the discretion of the treating physician. Serum creatinine ≥ 2.0 mg/dL Serum bilirubin ≥ 2 mg/dL (unless due to Gilbert's syndrome) or serum transaminases (ie, aspartate aminotransferase (AST), alanine aminotransferase (ALT)) ≥ 2 x upper limit of normal Positive test for human immunodeficiency virus (HIV) antibodies Active hepatitis B or C (confirmed by ribonucleic acid (RNA) test). Patients with serologic evidence of prior exposure are eligible. History of a non-CLL malignancy except for the following: adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for ≥ 1 year prior to study entry, 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. Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 65 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>This arm consists of 2 cohorts. Participants in Cohort 1 will receive idelalisib for up to twelve 28-day cycles (or development of unacceptable toxicity) plus rituximab (8 doses through the end of Cycle 2). Upon completion of twelve 28-cycles, participants are eligible to remain on idelalisib in a continuation protocol. Participants in Cohort 2 will receive idelalisib until disease progression or development of unacceptable toxicity. | Drug: Idelalisib<br>* Idelalisib 150 mg tablets administered orally twice daily<br>* Other names: CAL-101;Drug: Rituximab<br>* Rituximab 375 mg/m^2 administered intravenously once weekly x 8 weeks<br>* Other names: Rituxan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR was assessed based on standardized International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria as specifically modified for this study to reflect current recommendations which consider the mechanism of action of idelalisib and similar drugs, and was defined as the proportion of participants achieving a complete response (CR) or partial response (PR) as assessed by the investigator. Based on the CLL response definition in the protocol (modified Hallek 2008), the parameters of lymphadenopathy, liver and/or spleen size, constitutional symptoms, polymorphonuclear leukocytes, circulating clonal B-lymphocytes, platelet count, hemoglobin, and marrow were assessed. CR: meeting all defined criteria PR: meeting at least 2 of the criteria of circulating lymphocytes, lymphadenopathy, liver, spleen, or bone marrow (or only lymphadenopathy if liver and spleen normal at baseline) and at least 1 of the criteria for polymorphonuclear leukocytes, platelet count, or hemoglobin. | Up to 28 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Safety of Idelalisib | The overall safety of idelalisib was assessed as the percentage of participants experiencing treatment-emergent adverse events (AEs; Serious AEs, Grade ≥ 3 AEs, AEs related to idelalisib, and AEs leading to discontinuation of idelalisib). | Up to 28 Months | 
| Lymphadenopathy Response Rate | Lymphadenopathy response rate was defined as the percentage of participants with a ≥ 50% reduction from baseline in the sum of the perpendicular diameters of all measurable lesions while receiving study therapy. | Baseline and up to 28 Months | 
| Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions |  | Baseline; Weeks 8, 16, 24, 36, 48, 60, 72, 84, 96, 108, and 120 | 
| Duration of Response | Duration of response (DOR) was defined as the interval from the first documentation of CR or PR to the earlier of the first documentation of disease progression or death from any cause. | Up to 28 Months | 
| Progression-Free Survival | Progression-free survival (PFS) was defined as the interval from the first dose date of drug to the earlier of the first documentation of definitive disease progression or death from any cause. Progression was defined using the Standardized IWCLL criteria as specifically modified for this study to consider the mechanism of action of idelalisib and similar drugs. The occurrence of any of the following events indicated progression: Evidence of any new disease Evidence of worsening of index lesions, spleen or liver, or non-index disease Decrease in platelet count or hemoglobin that is attributable to CLL and is confirmed by bone marrow biopsy | Up to 28 Months | 
| Idelalisib Plasma Concentrations (Cohort 1) |  | Predose and 1.5 hours postdose at Weeks 0, 4, and 24 | 
| Idelalisib Plasma Concentrations (Cohort 2) |  | Predose and 1.5 hours postdose at Weeks 0 and 4 and predose at Weeks 8 and 20 | 
| Changes in Potential Pharmacodynamic Markers of Drug Activity in Plasma and Whole Blood | Changes in potential pharmacodynamic markers of drug activity will include assessments of chemokine and cytokine concentrations, effects on the activity of PI3K and related pathways, and effect on cell migration and other functional outcomes. This endpoint will be assessed at the following time points: Idelalisib+Rituximab (Cohort 1): Predose and 1.5 hour postdose on Day 1 and predose on Days 15, 29, 57, 113, and 169 Idelalisib (Cohort 2): Predose on Days 1, 29, 57, 141 | Up to 169 days | 
| Overall Survival | Overall survival (OS) is defined as the interval from the start of study treatment to death from any cause. | Up to 28 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CLL, SLL, GS-1101, CAL-101, Phosphatidylinositol 3-kinase (PI3K), Rituximab, Rituxan