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

Phase 2

Terminated

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

Interventions: Drug: Idelalisib
Drug: Rituximab

Registration Number: NCT01203930

Lead Sponsor: Gilead Sciences

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 105

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Idelalisib	Rituximab	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.
Idelalisib	Idelalisib	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.

Primary Outcome Measures

Name	Time	Method
Overall Response Rate (ORR)	Up to 28 Months	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.

Secondary Outcome Measures

Name	Time	Method
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	Up to 28 Months	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.
Progression-Free Survival	Up to 28 Months	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: 1. Evidence of any new disease 2. Evidence of worsening of index lesions, spleen or liver, or non-index disease 3. Decrease in platelet count or hemoglobin that is attributable to CLL and is confirmed by bone marrow biopsy
Idelalisib Plasma Concentrations (Cohort 1)	Predose and 1.5 hours postdose at Weeks 0, 4, and 24
Overall Safety of Idelalisib	Up to 28 Months	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).
Lymphadenopathy Response Rate	Baseline and up to 28 Months	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.
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	Up to 169 days	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
Overall Survival	Up to 28 Months	Overall survival (OS) is defined as the interval from the start of study treatment to death from any cause.

Trial Locations

Locations (6): University of California, San Diego, Moores Cancer Center
🇺🇸
La Jolla, California, United States
Columbia University - Herbert Irving Pavilion
🇺🇸
New York, New York, United States
Memorial Sloan Kettering Cancer Center
🇺🇸
New York, New York, United States
Sarah Cannon Research Institute
🇺🇸
Nashville, Tennessee, United States
The Universtity of Texas MD Anderson Cancer Center
🇺🇸
Houston, Texas, United States
Stanford University School of Medicine
🇺🇸
Stanford, California, United States