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

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

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.

Study Overview

• Status: Terminated
• Conditions: Chronic Lymphocytic Leukemia (CLL); Small Lymphocytic Lymphoma (SLL)
• Intervention / Treatment: Drug: Idelalisib; Drug: Rituximab

• Study Type: Interventional
• Enrollment (Actual): 105
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • La Jolla, California, United States, 92093-0820
      • University of California, San Diego, Moores Cancer Center
    • Stanford, California, United States, 94304
      • Stanford University School of Medicine
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10032
      • Columbia University - Herbert Irving Pavilion
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute
  • Texas
    • Houston, Texas, United States, 77030
      • The Universtity of Texas MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years and older (Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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.

Drug: Idelalisib; Idelalisib 150 mg tablets administered orally twice daily; Other Names: Zydelig®; GS-1101; CAL-101; Drug: Rituximab; Rituximab 375 mg/m^2 administered intravenously once weekly x 8 weeks; Other Names: Rituxan

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Gilead Sciences

Publications and helpful links

General Publications

• O'Brien SM, Lamanna N, Kipps TJ, Flinn I, Zelenetz AD, Burger JA, Keating M, Mitra S, Holes L, Yu AS, Johnson DM, Miller LL, Kim Y, Dansey RD, Dubowy RL, Coutre SE. A phase 2 study of idelalisib plus rituximab in treatment-naive older patients with chronic lymphocytic leukemia. Blood. 2015 Dec 17;126(25):2686-94. doi: 10.1182/blood-2015-03-630947. Epub 2015 Oct 15.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2010
• Primary Completion (Actual): August 1, 2015
• Study Completion (Actual): June 1, 2016

Study Registration Dates

• First Submitted: September 15, 2010
• First Submitted That Met QC Criteria: September 16, 2010
• First Posted (Estimate): September 17, 2010

Study Record Updates

• Last Update Posted (Actual): November 16, 2018
• Last Update Submitted That Met QC Criteria: October 19, 2018
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: Rituxan; Rituximab; CLL; SLL; CAL-101; GS-1101; Phosphatidylinositol 3-kinase (PI3K)
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, B-Cell; Lymphoma; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab; Idelalisib
• Other Study ID Numbers: 101-08

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified external researchers may request IPD for this study after study completion. For more information, please visit our website at http://www.gilead.com/research/disclosure-and-transparency.
• IPD Sharing Time Frame: 18 months after study completion
• IPD Sharing Access Criteria: A secured external environment with username, password, and RSA code.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No