Entospletinib in Combination With Idelalisib in Adults With Relapsed or Refractory Hematologic Malignancies

Phase 2

Terminated

Conditions: Chronic Lymphocytic Leukemia
Indolent Non-Hodgkin's Lymphoma
Mantle Cell Lymphoma
Diffuse Large B-cell Lymphoma

Interventions: Drug: Entospletinib
Drug: Idelalisib

Registration Number: NCT01796470

Lead Sponsor: Gilead Sciences

Brief Summary: This study will evaluate the efficacy of the combination entospletinib and idelalisib in participants with relapsed or refractory hematologic malignancies. Participants will be enrolled who have one of the following hematological tumor types: chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), or indolent non-Hodgkin lymphomas (iNHL; including follicular lymphoma (FL) and lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia \[LPL/WM\], small lymphocytic lymphoma \[SLL\], or marginal zone lymphoma \[MZL\]).

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 66

Inclusion Criteria

Diagnosis of B-cell indolent non-Hodgkin lymphoma (iNHL),diffuse large B-cell lymphoma (DLBCL),mantle cell lymphoma (MCL), or chronic lymphocytic leukemia (CLL) as documented by medical records and with histology based on criteria established by the World Health Organization
For institutions that have Phase 3 or Phase 4 protocols studying idelalisib (Zydelig®; GS-1101); individuals with malignancies being studied in these protocols must have failed screening and be registered as a screen failure in the respective idelalisib protocol
Prior treatment for lymphoid malignancy
Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy
Discontinuation of all therapy for the treatment of cancer ≥ 3 weeks before the start of study drug
All acute toxic effects of any prior antitumor therapy resolved to Grade ≤ 1 before the start of study drug
Karnofsky performance status of ≥ 60
Life expectancy of at least 3 months

Key

Exclusion Criteria

Known histological transformation from iNHL or CLL to an aggressive form of NHL (ie, Richter transformation)
Known active central nervous system or leptomeningeal lymphoma
Presence of known intermediate- or high-grade myelodysplastic syndrome
Current therapy with agents that reduce gastric acidity, including but not limited to antacids, H2 inhibitors, and proton pump inhibitors
Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of start of study drug
Ongoing liver injury
Ongoing or recent hepatic encephalopathy
Ongoing drug-induced pneumonitis
Ongoing inflammatory bowel disease
Ongoing alcohol or drug addiction
Pregnancy or breastfeeding
History of prior allogeneic bone marrow progenitor cell or solid organ transplantation
Ongoing immunosuppressive therapy
Concurrent participation in an investigational drug trial with therapeutic intent

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Entospletinib + idelalisib	Entospletinib	Entospletinib plus idelalisib at one of 4 dose combinations (400 mg/100 mg; 600 mg/100 mg; 800 mg/100 mg; 800 mg/150 mg). After discontinuation of entospletinib+idelalisib combination therapy, and following a washout period, participants may continue to receive entospletinib 400 mg monotherapy.
Entospletinib + idelalisib	Idelalisib	Entospletinib plus idelalisib at one of 4 dose combinations (400 mg/100 mg; 600 mg/100 mg; 800 mg/100 mg; 800 mg/150 mg). After discontinuation of entospletinib+idelalisib combination therapy, and following a washout period, participants may continue to receive entospletinib 400 mg monotherapy.

Primary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	Start of treatment to end of treatment (Up to 18 months)	ORR assessed by the Independent Review Committee (IRC), was based on the International Working Group Revised Response Criteria (Cheson, 2012) and investigator's response, defined as the percentage of participants achieving a complete response (CR) or partial response (PR) (or very good partial response \[VGPR\] or minor response \[MR\] for participants with LPL/WM). 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. VGPR and MR were defined as ≥ 90% and ≥ 25% but \< 50% decrease from baseline in serum monoclonal immunoglobulin M (IgM) concentration by serum protein electrophoresis (SPEP) respectively.

Secondary Outcome Measures

Name	Time	Method
Duration of Response (DOR)	Start of treatment to end of treatment (Up to 18 months)	DOR was defined as the interval from the first-time response (CR or PR \[or VGPR or MR for participants with LPL/WM\]) is achieved 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. VGPR and MR were defined as ≥ 90% and ≥ 25% but \< 50% decrease from baseline in serum monoclonal IgM concentration by SPEP respectively.
Progression-free Survival (PFS)	Start of treatment to end of treatment (Up to 18 months)	PFS was defined as the interval from the first dose of study drug to the earlier of the first documentation of definitive disease progression or death from any cause.
Percentage of Participants Experiencing Treatment-Emergent Adverse Events	First dose date up to the last dose date plus 30 days (maximum duration: 19 months)	A treatment-emergent Adverse Event (AE) was defined as any AE with an onset date of on or after the study drug start date and no later than 30 days after permanent discontinuation of study drugs or an AE leading to premature discontinuation of study drug. An AE is any untoward medical occurrence in a clinical investigation where participants administered a medicinal product, and which does not necessarily have a causal relationship with this treatment.
Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities	First dose date up to the last dose date plus 30 days (maximum: 18 months)	A treatment-emergent laboratory (Hematology, Serum Chemistry and Urinalysis) abnormality was defined as an abnormality that, compared to baseline, worsens by ≥ 1 grade in the period from the first dose of study drug. Safety as assessed by grading of laboratory values and AEs according to the National Cancer Institutes' Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. Grade 0 = none, Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening or disabling. If baseline data are missing, then any graded abnormality (i.e., an abnormality that is Grade ≥ 1 in severity) will be considered treatment-emergent. The percentage of participants in each worst postbaseline grade is reported.
Maximum Tolerated Dose Level	First dose (entospelinib + idelalisib) date up to 6 months	Maximum tolerated dose (MTD) is defined as the highest dose level that was consistently well tolerated without dose limiting toxicity (DLT) for the majority of participants time on treatment (ie,\> 50%) as determined by the investigator for each participant. DLTs are defined as Grade 4 hematological toxicities persisting for ≥ 14 days or Grade ≥ 3 toxicities of other types.
Time to Response (TTR)	Start of treatment to end of treatment (Up to 18 months)	TTR was defined as the interval from the first dose of entospletinib/idelalisib to the time response (CR or PR \[or VGPR or MR for participants with LPL/WM\]) is first achieved. 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. VGPR and MR were defined as ≥ 90% and ≥ 25% but \< 50% decrease from baseline in serum monoclonal IgM concentration by SPEP respectively.

Trial Locations

Locations (13): University of Rochester, James P. Wilmot Cancer Center
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Rochester, New York, United States
Northwest Medical Specialties
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Tacoma, Washington, United States
Signal Point Clinical Research Center, LLC
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Middletown, Ohio, United States
UC San Diego Moores Cancer Center
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La Jolla, California, United States
Oregon Health and Science University
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Portland, Oregon, United States
MD Anderson Cancer Center
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Houston, Texas, United States
Pacific Shores Medical Group
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Long Beach, California, United States
Collaborative Research Group LLC
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Boynton Beach, Florida, United States
Ventura County Hematology Oncology Specialists
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Oxnard, California, United States
Charleston Hematology Oncology
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Charleston, South Carolina, United States
Cancer Center of Santa Barbara
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Santa Barbara, California, United States
Georgetown University Medical Center
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Washington, District of Columbia, United States
Weill Cornell Medical College
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New York, New York, United States