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

Primary Purpose

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

Status

Terminated

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Idelalisib

Rituximab

About this trial

This is an interventional treatment trial for Chronic Lymphocytic Leukemia (CLL) focused on measuring CLL, SLL, GS-1101, CAL-101, Phosphatidylinositol 3-kinase (PI3K), Rituximab, Rituxan

Eligibility Criteria

65 Years - undefined (Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

University of California, San Diego, Moores Cancer Center
Stanford University School of Medicine
Columbia University - Herbert Irving Pavilion
Memorial Sloan Kettering Cancer Center
Sarah Cannon Research Institute
The Universtity of Texas MD Anderson Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Idelalisib

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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).

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.

Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions

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.

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

Idelalisib Plasma Concentrations (Cohort 1)

Idelalisib Plasma Concentrations (Cohort 2)

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

Overall Survival

Overall survival (OS) is defined as the interval from the start of study treatment to death from any cause.

Full Information

NCT ID

NCT01203930

First Posted

September 15, 2010

Last Updated

October 19, 2018

Sponsor

Gilead Sciences

1. Study Identification

Unique Protocol Identification Number

NCT01203930

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2017

Overall Recruitment Status

Terminated

Study Start Date

October 2010 (Actual)

Primary Completion Date

August 2015 (Actual)

Study Completion Date

June 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Gilead Sciences

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

Keywords

CLL, SLL, GS-1101, CAL-101, Phosphatidylinositol 3-kinase (PI3K), Rituximab, Rituxan

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

105 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Idelalisib

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Idelalisib

Other Intervention Name(s)

Zydelig®, GS-1101, CAL-101

Intervention Description

Idelalisib 150 mg tablets administered orally twice daily

Intervention Type

Drug

Intervention Name(s)

Rituximab

Other Intervention Name(s)

Rituxan

Intervention Description

Rituximab 375 mg/m^2 administered intravenously once weekly x 8 weeks

Primary Outcome Measure Information:

Title

Overall Response Rate (ORR)

Description

Time Frame

Up to 28 Months

Secondary Outcome Measure Information:

Title

Overall Safety of Idelalisib

Description

Time Frame

Up to 28 Months

Title

Lymphadenopathy Response Rate

Description

Time Frame

Baseline and up to 28 Months

Title

Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions

Time Frame

Baseline; Weeks 8, 16, 24, 36, 48, 60, 72, 84, 96, 108, and 120

Title

Duration of Response

Description

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.

Time Frame

Up to 28 Months

Title

Progression-Free Survival

Description

Time Frame

Up to 28 Months

Title

Idelalisib Plasma Concentrations (Cohort 1)

Time Frame

Predose and 1.5 hours postdose at Weeks 0, 4, and 24

Title

Idelalisib Plasma Concentrations (Cohort 2)

Time Frame

Predose and 1.5 hours postdose at Weeks 0 and 4 and predose at Weeks 8 and 20

Title

Changes in Potential Pharmacodynamic Markers of Drug Activity in Plasma and Whole Blood

Description

Time Frame

Up to 169 days

Title

Overall Survival

Description

Overall survival (OS) is defined as the interval from the start of study treatment to death from any cause.

Time Frame

Up to 28 Months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Gilead Study Director

Organizational Affiliation

Gilead Sciences

Official's Role

Study Director

Facility Information:

Facility Name

University of California, San Diego, Moores Cancer Center

City

La Jolla

State/Province

California

ZIP/Postal Code

92093-0820

Country

United States

Facility Name

Stanford University School of Medicine

City

Stanford

State/Province

California

ZIP/Postal Code

94304

Country

United States

Facility Name

Columbia University - Herbert Irving Pavilion

City

New York

State/Province

New York

ZIP/Postal Code

10032

Country

United States

Facility Name

Memorial Sloan Kettering Cancer Center

City

New York

State/Province

New York

ZIP/Postal Code

10065

Country

United States

Facility Name

Sarah Cannon Research Institute

City

Nashville

State/Province

Tennessee

ZIP/Postal Code

37203

Country

United States

Facility Name

The Universtity of Texas MD Anderson Cancer Center

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing 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 URL

http://www.gilead.com/research/disclosure-and-transparency

Citations:

PubMed Identifier

26472751

Citation

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.

Results Reference

derived

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

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