Study of Idelalisib in Combination With BI 836826 in Participants With Chronic Lymphocytic Leukemia

• ClinicalTrials.gov Identifier: NCT02538614
• Recruitment Status: Terminated
• First Posted: September 2, 2015
• Results First Posted: November 25, 2020
• Last Update Posted: November 25, 2020
• Sponsor: Gilead Sciences
• Collaborator: Boehringer Ingelheim
• Information provided by (Responsible Party): Gilead Sciences

Study Description

Brief Summary:

This study consists of 2 parts: Phase 1b and Phase 2. Phase 1b will evaluate the safety and tolerability of the combination of idelallisib with the anti-CD37 monoclonal antibody BI 836826 in participants with relapsed/refractory chronic lymphocytic leukemia (R/R CLL), and establish the high recommended Phase 2 combination dose (highRP2D) as well as an alternate lower recommended Phase 2 combination dose (lowRP2D). Phase 2 will determine the rates of complete response (CR) and of minimal residual disease (MRD) negativity with the combination at the highRP2D and the lowRP2D in participants with R/R CLL.

Condition or disease	Intervention/treatment	Phase
Chronic Lymphocytic Leukemia (CLL)	Drug: Idelalisib; Drug: BI 836826	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 2 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Phase 1b: sequential assignment, Phase 2: parallel assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1b/2 Study of Idelalisib in Combination With BI 836826 in Subjects With Chronic Lymphocytic Leukemia
• Actual Study Start Date: December 29, 2015
• Actual Primary Completion Date: July 5, 2017
• Actual Study Completion Date: July 5, 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: Phase 1b: Idelalisib + BI 836826; Participants will receive escalating dose of idelalisib at dose levels, 50 mg, 100 mg, and 150 mg + BI 836826 10 mg on Day 8, 50 mg on Day 9 and Day 15, and 100 mg on Day 22, every 2 weeks through Week 18, and every 4 weeks through Week 46. 2 dose combinations (highRP2D and lowRP2D) will be determined for further evaluations in Phase 2.	Drug: Idelalisib; Tablets administered orally twice daily; Other Names: GS-1101; CAL-101; Zydelig®; Drug: BI 836826; Intravenous administration as a rate-controlled infusion
Experimental: Phase 2 Idelalisib + BI 836826; Participants will be randomly assigned to receive 1 of the 2 dose combinations selected from Phase 1b.	Drug: Idelalisib; Tablets administered orally twice daily; Other Names: GS-1101; CAL-101; Zydelig®; Drug: BI 836826; Intravenous administration as a rate-controlled infusion

Outcome Measures

Primary Outcome Measures :

1. Phase 1b: Percentage of Participants Experienced Dose Limiting Toxicities (DLTs) During the First 7 Weeks of Study Therapy [ Time Frame: Up to 7 weeks ]
   DLTs refer to toxicities experienced during the final 6 weeks of 7-week study treatment that have been judged to be clinically significant and related to study treatment. Events occurring during the initial 7-day idelalisib monotherapy run-in period and resolving by Day 8 were not included.
2. For Phase 2: Complete Response Rate (CRR) [ Time Frame: Up to 18 months ]
   CRR was defined as the percentage of participants who achieve a complete response (CR). 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.
3. For Phase 2: Minimal Residual Disease (MRD) Negativity Rate in Bone Marrow by Week 50 [ Time Frame: Week 50 ]
   MRD defined as the percentage of participants with MRD < 10^-4, assessed by flow cytometry in bone marrow, achieved by Week 50.

Secondary Outcome Measures :

1. Phase 1b: Percentage of Participants Experienced DLTs During the Treatment Period [ Time Frame: Up to 18 months ]
   DLTs refer to toxicities experienced during the final 6 weeks of 7-week study treatment that have been judged to be clinically significant and related to study treatment. Events occurring during the initial 7-day idelalisib monotherapy run-in period and resolving by Day 8 were not included.
2. For Phase 1b and Phase 2: Number of Participants Experiencing Any Serious Adverse Events (SAE) [ Time Frame: Up to 18 months ]
   An SAE is defined as an event that, at any dose, results in the following: death, life-threatening, in-patient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, a congenital anomaly/birth defect or a medically important event or reaction.
3. For Phase 1b and Phase 2: Number of Participants Who Permanently Discontinued Study Treatment Due to an Adverse Event [ Time Frame: Up to 18 months ]
   An AE is any untoward medical occurrence in a clinical study participant administered a medicinal product, which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The severity of AEs was graded using the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03.
4. For Phase 2: Overall Response Rate (ORR) [ Time Frame: Up to 18 months ]
   ORR was defined as the percentage of participants achieving a complete response (CR) or partial response (PR). 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.
5. For Phase 2: Duration of Complete Response (DCR) [ Time Frame: Up to 18 months ]
   DCR was defined as the interval from the first documentation of CR to the earlier of the first documentation of definitive disease progression or death from any cause. 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.
6. For Phase 2: Duration of Response (DOR) [ Time Frame: Up to 18 months ]
   DOR was defined as the interval from the first documentation of CR or PR to the earlier of the first documentation of definitive disease progression or death from any cause. 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.
7. For Phase 2: Progression-Free Survival (PFS) [ Time Frame: Up to 18 months ]
   PFS was defined as the interval from randomization to the earlier of the first documentation of definitive disease progression or death from any cause. Definitive disease progression was defined as evidence of any new disease, worsening of index lesions, spleen or liver, or non-index disease, decrease in platelet count or hemoglobin that is attributable to chronic lymphocytic leukemia (CLL) or more than 4 weeks after the discontinuation of idelalisib: an increase in the number of blood lymphocytes by 50% or more.
8. For Phase 2: Overall Survival (OS) [ Time Frame: Up to 18 months ]
   OS was defined as the interval from the randomization to the date of death from any cause.
9. For Phase 2: MRD Negativity Rate in Blood at Any Time [ Time Frame: Up to 18 months ]
   MRD negativity rate in blood was defined as the percentage of participants with MRD < 10^-4, assessed by flow cytometry in blood, at any time on study.
10. For Phase 2: MRD Negativity Rate in Bone Marrow at Any Time [ Time Frame: Up to 18 months ]
    MRD negativity rate in bone marrow was defined as the percentage of participants with MRD < 10^-4, assessed by flow cytometry in bone marrow, at any time on study.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Key Inclusion Criteria:

• Diagnosis of B-cell CLL, established according to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria and having received at least 2 prior treatment regimens
• CLL that warrants treatment

• Clinically quantifiable disease burden defined as:

  • For Phase 1b individuals: absolute lymphocyte count (ALC) > 5000/μL in peripheral blood.

  • For Phase 2 individuals either:

    • At least 1 node ≥ 2 cm on computed tomography (CT) or magnetic resonance imaging (MRI) or
    • bone marrow exam is performed at screening and demonstrates quantifiable CLL.
• Discontinuation of all cytotoxic chemotherapy and anti-CD20 antibody therapy for ≥ 4 weeks, alemtuzumab for ≥ 8 weeks, targeted therapy for ≥ 2 weeks, and investigational therapy for ≥ 3 weeks before enrollment (Phase 1b) or randomization (Phase 2). For individuals with relapsed CLL most recently treated with B-cell receptor (BCR) pathway inhibitors who, in the opinion of the investigator, will not tolerate waiting 3 weeks, a washout period of > 5 half-lives is allowed. If on a systemic corticosteroid, the dose must be stable for the previous 4 weeks.
• Eastern Cooperative Oncology Group (ECOG) score of ≤ 2

Key Exclusion Criteria:

• Known histological transformation from CLL to an aggressive lymphoma (ie, Richter transformation)
• Known presence of myelodysplastic syndrome
• 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 enrollment, other adequately treated Stage 1 or 2 cancer currently in complete remission, or any other cancer that has been in complete remission for ≥ 2 years.
• Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of enrollment
• Ongoing drug-induced liver injury, chronic active hepatitis C (HCV), chronic active hepatitis B (HBV), alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or portal hypertension.
• History of drug-induced pneumonitis
• Ongoing inflammatory bowel disease
• Ongoing alcohol or drug addiction
• History of prior allogeneic bone marrow progenitor cell or solid organ transplantation
• Ongoing systemic immunosuppressive therapy other than corticosteroids
• History of prior therapy with any phosphatidylinositol 3-kinase (PI3K) inhibitor (including idelalisib), or any anti-CD37 agent
• Ongoing infection with, or treatment or prophylaxis for, CMV within the past 28 days.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Contacts and Locations

Locations

United States, Ohio

Ohio State University

Columbus, Ohio, United States

United States, Utah

University of Utah

Salt Lake City, Utah, United States

Sponsors and Collaborators

Gilead Sciences

Boehringer Ingelheim

Investigators

• Study Director: Gilead Study Director; Gilead Sciences

  Study Documents (Full-Text)

Documents provided by Gilead Sciences:

Study Protocol  [PDF] June 15, 2017

Statistical Analysis Plan  [PDF] November 28, 2017

More Information

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT02538614
• Other Study ID Numbers: GS-US-312-1579
• First Posted: September 2, 2015
• Results First Posted: November 25, 2020
• Last Update Posted: November 25, 2020
• Last Verified: November 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Qualified external researchers may request IPD for this study after study completion. For more information, please visit our website at https://www.gilead.com/science-and-medicine/research/clinical-trials-transparency-and-data-sharing-policy
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• Time Frame: 18 months after study completion
• Access Criteria: A secured external environment with username, password, and RSA code.
• URL: https://www.gilead.com/science-and-medicine/research/clinical-trials-transparency-and-data-sharing-policy

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, B-Cell; Chronic Disease; Disease Attributes; Pathologic Processes; Idelalisib; BI 836826; Antineoplastic Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Immunological