Back to resultsEntospletinib in Combination With Idelalisib in Adults With Relapsed or Refractory Hematologic Malignancies
Primary Purpose
Chronic Lymphocytic Leukemia, Mantle Cell Lymphoma, Diffuse Large B-cell Lymphoma
Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Entospletinib
Idelalisib
Sponsored by
About this trial
This is an interventional treatment trial for Chronic Lymphocytic Leukemia focused on measuring 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
Eligibility 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.
Sites / Locations
- UC San Diego Moores Cancer Center
- Pacific Shores Medical Group
- Ventura County Hematology Oncology Specialists
- Cancer Center of Santa Barbara
- Georgetown University Medical Center
- Collaborative Research Group LLC
- Weill Cornell Medical College
- University of Rochester, James P. Wilmot Cancer Center
- Signal Point Clinical Research Center, LLC
- Oregon Health and Science University
- Charleston Hematology Oncology
- MD Anderson Cancer Center
- Northwest Medical Specialties
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Entospletinib + idelalisib
Arm Description
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.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
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.
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.
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.
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.
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01796470
Brief Title
Entospletinib in Combination With Idelalisib in Adults With Relapsed or Refractory Hematologic Malignancies
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
Study Type
Interventional
2. Study Status
Record Verification Date
May 2020
Overall Recruitment Status
Terminated
Why Stopped
Study was terminated due to safety measures.
Study Start Date
June 20, 2013 (Actual)
Primary Completion Date
January 2015 (Actual)
Study Completion Date
December 22, 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Gilead Sciences
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
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]).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Lymphocytic Leukemia, Mantle Cell Lymphoma, Diffuse Large B-cell Lymphoma, Indolent Non-Hodgkin's Lymphoma
Keywords
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
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Enrollment
66 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Entospletinib + idelalisib
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Entospletinib
Other Intervention Name(s)
GS-9973
Intervention Description
Entospletinib tablets administered orally twice daily
Intervention Type
Drug
Intervention Name(s)
Idelalisib
Other Intervention Name(s)
GS-1101, GS 1101, Cal-101, Cal 101, Zydelig®
Intervention Description
Idelalisib tablets administered orally twice daily
Primary Outcome Measure Information:
Title
Objective Response Rate (ORR)
Description
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.
Time Frame
Start of treatment to end of treatment (Up to 18 months)
Secondary Outcome Measure Information:
Title
Percentage of Participants Experiencing Treatment-Emergent Adverse Events
Description
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.
Time Frame
First dose date up to the last dose date plus 30 days (maximum duration: 19 months)
Title
Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities
Description
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.
Time Frame
First dose date up to the last dose date plus 30 days (maximum: 18 months)
Title
Maximum Tolerated Dose Level
Description
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 Frame
First dose (entospelinib + idelalisib) date up to 6 months
Title
Progression-free Survival (PFS)
Description
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.
Time Frame
Start of treatment to end of treatment (Up to 18 months)
Title
Duration of Response (DOR)
Description
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 Frame
Start of treatment to end of treatment (Up to 18 months)
Title
Time to Response (TTR)
Description
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.
Time Frame
Start of treatment to end of treatment (Up to 18 months)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gilead Study Director
Organizational Affiliation
Gilead Sciences
Official's Role
Study Director
Facility Information:
Facility Name
UC San Diego Moores Cancer Center
City
La Jolla
State/Province
California
ZIP/Postal Code
92093
Country
United States
Facility Name
Pacific Shores Medical Group
City
Long Beach
State/Province
California
ZIP/Postal Code
90813
Country
United States
Facility Name
Ventura County Hematology Oncology Specialists
City
Oxnard
State/Province
California
ZIP/Postal Code
93030
Country
United States
Facility Name
Cancer Center of Santa Barbara
City
Santa Barbara
State/Province
California
ZIP/Postal Code
93105
Country
United States
Facility Name
Georgetown University Medical Center
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20007
Country
United States
Facility Name
Collaborative Research Group LLC
City
Boynton Beach
State/Province
Florida
ZIP/Postal Code
33435
Country
United States
Facility Name
Weill Cornell Medical College
City
New York
State/Province
New York
ZIP/Postal Code
10021
Country
United States
Facility Name
University of Rochester, James P. Wilmot Cancer Center
City
Rochester
State/Province
New York
ZIP/Postal Code
14642
Country
United States
Facility Name
Signal Point Clinical Research Center, LLC
City
Middletown
State/Province
Ohio
ZIP/Postal Code
45042
Country
United States
Facility Name
Oregon Health and Science University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
Charleston Hematology Oncology
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29414
Country
United States
Facility Name
MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Northwest Medical Specialties
City
Tacoma
State/Province
Washington
ZIP/Postal Code
98405
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
26968534
Citation
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.
Results Reference
derived
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Entospletinib in Combination With Idelalisib in Adults With Relapsed or Refractory Hematologic Malignancies
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