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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

Tracking Information
First Submitted Date  ICMJE February 19, 2013
First Posted Date  ICMJE February 21, 2013
Results First Submitted Date  ICMJE May 18, 2020
Results First Posted Date  ICMJE June 2, 2020
Last Update Posted Date June 2, 2020
Actual Study Start Date  ICMJE June 20, 2013
Actual Primary Completion Date January 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 18, 2020)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: February 19, 2013)
Progression Free Survival [ Time Frame: up to 48 weeks ]
From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 18, 2020)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 19, 2013)
  • Safety and Tolerability [ Time Frame: up to 48 weeks ]
    Safety: all abnormal laboratory data, adverse events (AEs) and treatment-emergent AEs. Safety will be assessed by grading of laboratory values and AEs according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03
  • Efficacy [ Time Frame: up to 48 weeks ]
    • Objective response rate (ORR). ORR will be determined from the subjects' best response during GS-9973 and idelalisib therapy and will include complete response (CR) and partial response (PR).
    • Disease control rate (DCR). DCR will be defined as from the subjects' best response during GS-9973 and idelalisib therapy and will include stable disease (SD) lasting at least 16 weeks, CR, and PR.
    • Duration of response (DOR). DOR will be defined as time from the first response is achieved until the earlier of the first documentation of definitive disease progression or death from any cause.
    • Time to response (TTR). TTR will be defined as time from the first dose of GS-9973 and idelalisib to the first time the response (CR or PR) is achieved.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: February 19, 2013)
Exploratory Endpoints [ Time Frame: up to 48 weeks ]
To estimate the degree of target coverage, proximal and distal pharmacodynamic biomarkers related to SYK inhibition will be measured in peripheral blood samples and will be correlated with GS-9973 and idelalisib drug levels.
 
Descriptive Information
Brief Title  ICMJE Entospletinib in Combination With Idelalisib in Adults With Relapsed or Refractory Hematologic Malignancies
Official Title  ICMJE 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
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 Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Chronic Lymphocytic Leukemia
  • Mantle Cell Lymphoma
  • Diffuse Large B-cell Lymphoma
  • Indolent Non-Hodgkin's Lymphoma
Intervention  ICMJE
  • 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®
Study Arms  ICMJE 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.

Interventions:
  • Drug: Entospletinib
  • Drug: Idelalisib
Publications * Barr PM, Saylors GB, Spurgeon SE, Cheson BD, Greenwald DR, O'Brien SM, Liem AK, Mclntyre RE, Joshi A, Abella-Dominicis E, Hawkins MJ, Reddy A, Di Paolo J, Lee H, He J, Hu J, Dreiling LK, Friedberg JW. Phase 2 study of idelalisib and entospletinib: pneumonitis limits combination therapy in relapsed refractory CLL and NHL. Blood. 2016 May 19;127(20):2411-5. doi: 10.1182/blood-2015-12-683516. Epub 2016 Mar 11.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: August 27, 2014)
66
Original Estimated Enrollment  ICMJE
 (submitted: February 19, 2013)
200
Actual Study Completion Date  ICMJE December 22, 2016
Actual Primary Completion Date January 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01796470
Other Study ID Numbers  ICMJE GS-US-339-0103
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Gilead Sciences
Study Sponsor  ICMJE Gilead Sciences
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Gilead Study Director Gilead Sciences
PRS Account Gilead Sciences
Verification Date May 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP