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

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ClinicalTrials.gov Identifier: NCT01796470
Recruitment Status : Terminated (Study was terminated due to safety measures.)
First Posted : February 21, 2013
Results First Posted : June 2, 2020
Last Update Posted : June 2, 2020
Sponsor:
Information provided by (Responsible Party):
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]).

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukemia Mantle Cell Lymphoma Diffuse Large B-cell Lymphoma Indolent Non-Hodgkin's Lymphoma Drug: Entospletinib Drug: Idelalisib Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 66 participants
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : June 20, 2013
Actual Primary Completion Date : January 2015
Actual Study Completion Date : December 22, 2016


Arm Intervention/treatment
Experimental: Entospletinib + 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.

Drug: Entospletinib
Entospletinib tablets administered orally twice daily
Other Name: GS-9973

Drug: Idelalisib
Idelalisib tablets administered orally twice daily
Other Names:
  • GS-1101
  • GS 1101
  • Cal-101
  • Cal 101
  • Zydelig®




Primary Outcome Measures :
  1. Objective Response Rate (ORR) [ Time Frame: 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 :
  1. Percentage of Participants Experiencing Treatment-Emergent Adverse Events [ Time Frame: 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.

  2. Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities [ Time Frame: 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.

  3. Maximum Tolerated Dose Level [ Time Frame: 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.

  4. Progression-free Survival (PFS) [ Time Frame: 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.

  5. Duration of Response (DOR) [ Time Frame: 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.

  6. Time to Response (TTR) [ Time Frame: 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.



Information from the National Library of Medicine

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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 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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01796470


Locations
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United States, California
UC San Diego Moores Cancer Center
La Jolla, California, United States, 92093
Pacific Shores Medical Group
Long Beach, California, United States, 90813
Ventura County Hematology Oncology Specialists
Oxnard, California, United States, 93030
Cancer Center of Santa Barbara
Santa Barbara, California, United States, 93105
United States, District of Columbia
Georgetown University Medical Center
Washington, District of Columbia, United States, 20007
United States, Florida
Collaborative Research Group LLC
Boynton Beach, Florida, United States, 33435
United States, New York
Weill Cornell Medical College
New York, New York, United States, 10021
University of Rochester, James P. Wilmot Cancer Center
Rochester, New York, United States, 14642
United States, Ohio
Signal Point Clinical Research Center, LLC
Middletown, Ohio, United States, 45042
United States, Oregon
Oregon Health and Science University
Portland, Oregon, United States, 97239
United States, South Carolina
Charleston Hematology Oncology
Charleston, South Carolina, United States, 29414
United States, Texas
MD Anderson Cancer Center
Houston, Texas, United States, 77030
United States, Washington
Northwest Medical Specialties
Tacoma, Washington, United States, 98405
Sponsors and Collaborators
Gilead Sciences
Investigators
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Study Director: Gilead Study Director Gilead Sciences
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT01796470    
Other Study ID Numbers: GS-US-339-0103
First Posted: February 21, 2013    Key Record Dates
Results First Posted: June 2, 2020
Last Update Posted: June 2, 2020
Last Verified: May 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Gilead Sciences:
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
Additional relevant MeSH terms:
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Lymphoma
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, Mantle-Cell
Lymphoma, Large B-Cell, Diffuse
Hematologic Neoplasms
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia
Lymphoma, Non-Hodgkin
Leukemia, Lymphoid
Leukemia, B-Cell
Lymphoma, B-Cell
Neoplasms by Site
Hematologic Diseases
Idelalisib
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action