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

Study Overview
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Brief Summary
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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]).

Official Title
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A Phase 2, Open-Label Study Evaluating the Efficacy, Safety, Tolerability, and Pharmacodynamics of GS-9973 in Combination With Idelalisib in Subjects With Relapsed or Refractory Hematologic Malignancies

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

Intervention / Treatment
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* Drug: Entospletinib
* Drug: Idelalisib


Participation Criteria
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Eligibility Criteria
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Key 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Entospletinib + idelalisib<br>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. | Drug: Entospletinib<br>* Entospletinib tablets administered orally twice daily<br>* Other names: GS-9973;Drug: Idelalisib<br>* Idelalisib tablets administered orally twice daily<br>* Other names: Zydelig®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | 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. | Start of treatment to end of treatment (Up to 18 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing Treatment-Emergent Adverse Events | 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. | First dose date up to the last dose date plus 30 days (maximum duration: 19 months) | 
| Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | 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. | First dose date up to the last dose date plus 30 days (maximum: 18 months) | 
| Maximum Tolerated Dose Level | 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. | First dose (entospelinib + idelalisib) date up to 6 months | 
| Progression-free Survival (PFS) | 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. | Start of treatment to end of treatment (Up to 18 months) | 
| Duration of Response (DOR) | 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. | Start of treatment to end of treatment (Up to 18 months) | 
| Time to Response (TTR) | 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. | Start of treatment to end of treatment (Up to 18 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GS-US-339-0103, SYK inhibitor, PI3K inhibitor, GS-9973, GS 9973, GS-1101, GS 1101, Cal-101, Cal 101, idelalisib, leukemia, lymphoma, CLL, MCL, DLBCL, iNHL, FL, MZL, LPL, SLL, WM, Waldenström's macroglobulinemia