Study to Evaluate Efficacy, Safety, Tolerability, and Pharmacodynamics of Entospletinib in Adults With Relapsed or Refractory Hematologic Malignancies

Chronic Lymphocytic Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01799889
• Other study ID #: GS-US-339-0102
• Status: Terminated
• Phase: Phase 2
• Start date: March 14, 2013
• Est. completion date: January 30, 2020

Study information

• Verified date: November 2020
• Source: Gilead Sciences
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary objective of the study is to evaluate efficacy of entospletinib in participants with relapsed or refractory hematologic malignancies. Participants with the following relapsed or refractory hematologic malignancies will be enrolled into the study: relapsed or refractory chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), or non-FL indolent non-Hodgkin lymphomas (iNHL; including lymphoplasmacytoid lymphoma/ Waldenström macroglobulinemia [LPL/WM], small lymphocytic lymphoma [SLL], or marginal zone lymphoma [MZL]).

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 326
• Est. completion date: January 30, 2020
• Est. primary completion date: September 14, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Key Inclusion Criteria:

• Diagnosis of B-cell iNHL, DLBCL, MCL, or 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®) ; individuals with malignancies being studied in these protocols must have failed screening in the respective idelalisib protocol

• Prior treatment for lymphoid malignancy requiring treatment for progressive disease

• Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy

• 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 non-Hodgkin lymphoma (ie, Richter transformation) except if the CLL participant is enrolling in the BCR previously treated cohort

• Known active central nervous system or leptomeningeal lymphoma

• Presence of known intermediate- or high-grade myelodysplastic syndrome

• 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.

Related Conditions & MeSH terms

• Chronic Lymphocytic Leukemia
• Diffuse Large B-cell Lymphoma
• Follicular Lymphoma
• Hematologic Neoplasms
• Leukemia, Lymphocytic, Chronic, B-Cell
• Lymphoma
• Lymphoma, Large B-Cell, Diffuse
• Lymphoma, Mantle-Cell
• Mantle Cell Lymphoma
• Non-FL Indolent Non-Hodgkin's Lymphoma

Intervention

Drug:
• Entospletinib MM
Entospletinib MM tablet administered orally
• Entospletinib SDD
Entospletinib SDD tablet administered orally

Locations

Country	Name	City	State
Canada	Royal Victoria Regional Health Centre	Barrie	Ontario
Canada	Sir Mortimer B. Davis-Jewish General Hospital	Montreal	Quebec
United States	University of Michigan Health System	Ann Arbor	Michigan
United States	Northside Hospital	Atlanta	Georgia
United States	Texas Oncology-Austin Midtown	Austin	Texas
United States	Hematology Oncology Clinic, PLLC	Baton Rouge	Louisiana
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Tufts Medical Center	Boston	Massachusetts
United States	Rocky Mountain Cancer Centers, LLP	Boulder	Colorado
United States	Gabrail Cancer Center Research	Canton	Ohio
United States	University of North Carolina	Chapel Hill	North Carolina
United States	University of Chicago	Chicago	Illinois
United States	Oncology Hematology Care	Cincinnati	Ohio
United States	Cleveland Clinic	Cleveland	Ohio
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Texas Oncology-Medical City Dallas	Dallas	Texas
United States	Kaiser Permanente of Colorado	Denver	Colorado
United States	Karmanos Cancer Institute	Detroit	Michigan
United States	City of Hope National Medical Center	Duarte	California
United States	Virginia Cancer Specialists, PC	Fairfax	Virginia
United States	Summit Medical Group, P.A.	Florham Park	New Jersey
United States	Florida Cancer - Colonial	Fort Myers	Florida
United States	Center for Cancer and Blood Disorders	Fort Worth	Texas
United States	Jones Clinic PC	Germantown	Tennessee
United States	Hattiesburg Clinic	Hattiesburg	Mississippi
United States	Memorial Cancer Institute	Hollywood	Florida
United States	Indiana University Simon Cancer Center	Indianapolis	Indiana
United States	Columbia Basin Hematology and Oncology	Kennewick	Washington
United States	Gwinnett Hospital System Dba The Center for Cancer Care	Lawrenceville	Georgia
United States	One Medical Center Drive	Lebanon	New Hampshire
United States	Northwest Georgia Oncology Center	Marietta	Georgia
United States	Minnesota Oncology Hematology, PA	Minneapolis	Minnesota
United States	Tennessee Oncology, PLLC	Nashville	Tennessee
United States	Clinical Research Alliance	New York	New York
United States	Illinois Cancer Specialists	Niles	Illinois
United States	Ocala Oncology Center	Ocala	Florida
United States	Oncology Hematology West PC dba Nebraska Cancer Specialists	Omaha	Nebraska
United States	Virginia Cancer Institute	Richmond	Virginia
United States	Cancer Care Center of South Texas	San Antonio	Texas
United States	Cancer Care Network of South Texas	San Antonio	Texas
United States	Sharp Memorial Hospital	San Diego	California
United States	University of Washington	Seattle	Washington
United States	Cancer Center of Central Connecticut	Southington	Connecticut
United States	Williamette Valley Cancer Center and Research Institute	Springfield	Oregon
United States	Arizona Oncology Associates	Tucson	Arizona
United States	Northwest Cancer Specialists, PC	Vancouver	Washington
United States	Prairie Lakes Health Care System, Inc.	Watertown	South Dakota
United States	Yakima Valley Memorial Hospital North Star Lodge	Yakima	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Gilead Sciences

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-Free Survival (PFS) Rate of Participants With CLL After BCR Targeted Therapy, MCL, and DLBCL at Week 16	PFS rate was assessed by Independent Review Committee (IRC) and defined per standardized criteria (2007 Cheson criteria) (for NHL) and International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria (for CLL), as the percentage of participants not experiencing definitive progression or death. Disease progression was defined per standardized criteria as: evidence of any new disease; worsening of nodal or extra-nodal index lesions; unequivocal increase in the size of non-index lesions or non-measurable disease, size of the liver, spleen, or other organ; and a = 25% increase from nadir in either monoclonal immunoglobulin M (IgM) concentration or total serum IgM quantitation. Disease progression was defined per standardized IWCLL criteria as: evidence of any new disease; worsening of index lesions, spleen or liver, or non-index disease; and decrease in platelet count or hemoglobin that is attributable to CLL. PFS rate was analyzed using Kaplan-Meier (KM) estimates.	Week 16
Primary	PFS Rate of Participants With CLL (Including CLL, Prior BCR Inhibitor Naive Participants), FL, and Non-FL iNHL at Week 24	PFS rate was assessed by IRC and defined per standardized criteria (2007 Cheson criteria) (for NHL) and IWCLL criteria (for CLL), as the percentage of participants not experiencing definitive progression or death. Disease progression was defined per standardized criteria (2007 Cheson criteria) as: evidence of any new disease; worsening of nodal or extra-nodal index lesions; unequivocal increase in the size of non-index lesions or non-measurable disease, size of the liver, spleen, or other organ; and a = 25% increase from nadir in either monoclonal IgM concentration or total serum IgM quantitation. Disease progression was defined per standardized IWCLL criteria as: evidence of any new disease; worsening of index lesions, spleen or liver, or non-index disease; and decrease in platelet count or hemoglobin that is attributable to CLL. PFS rate was analyzed using KM estimates.	Week 24
Secondary	Percentage of Participants Experiencing Treatment-Emergent Adverse Events	A treatment-emergent Adverse Event (AE) was defined as an AE that occurs in the period from the first dose of study treatment to 30 days after the last dose of study treatment or leads to discontinuation of study treatment. Participants were assessed for AEs according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03.	First dose date up to the last dose date plus 30 days (maximum: 78.4 months)
Secondary	Percentage of Participants With Hematology Postbaseline Toxicity Grade 3 or Higher	Hematology toxicity at any time postbaseline was summarized according to the NCI CTCAE, version 4.03. The most severe graded abnormality was counted for each participant per test.; ANC = absolute neutrophil count; Hb = hemoglobin; WBC = white blood cells	First dose date up to the last dose date plus 30 days (maximum: 78.4 months)
Secondary	Percentage of Participants With Serum Chemistry Toxicity Postbaseline Grade 3 or Higher	Serum chemistry toxicity at anytime postbaseline was summarized according to the NCI CTCAE, version 4.03. The most severe graded abnormality was counted for each participant per test. ALT = alanine aminotransferase; ALP = alkaline phosphatase; AST = aspartate aminotransferase	First dose date up to the last dose date plus 30 days (maximum: 78.4 months)
Secondary	Objective Response Rate (ORR), as Assessed by IRC Per Standardized Criteria (2007 Cheson Criteria) (for NHL) and IWCLL Criteria (for CLL)	ORR: percentage of participants with complete response (CR) or partial response (PR) (or very good PR [VGPR] or minor response [MR] for participants with LPL/WM). Per 2007 Cheson criteria, CR: complete resolution of all disease-related radiological abnormalities; PR: =50% reduction in sum of products (SPD) of the longest diameters of all index lesions, no new lesions; VGPR: >90% decrease from baseline (DFB) in IgM, and other criteria for CR met; MR: =25% but <50% DFB in IgM, no increase from baseline (IFB) in SPD of lesions, no new lesions. Per IWCLL, CR: lymphocytes (Ly) <4*10^9/L, no lymphadenopathy, normal spleen and liver size, absence of disease, absolute neutrophil count (ANC) >1.5*10^9/L, platelets =100*10^9/L, hemoglobin (Hb) >110 g/L, bone marrow at least normocellular for age; PR: =2 of these: =50% decrease in Ly, lymphadenopathy, size of liver and spleen, bone marrow infiltrates; and =1 of these: ANC >1500/µL, platelets =100,000/µL, Hb >11 g/dL.	From first dose date until first occurrence of CR or PR (or VGPR or MR for participants with LPL/WM) (up to approximately 7 years)
Secondary	Duration of Response (DOR), as Assessed by IRC Per Standardized Criteria (2007 Cheson Criteria) (for NHL) and IWCLL Criteria (for CLL)	DOR was defined as the interval from first documentation of CR or PR (or VGPR or MR for participants with LPL/WM) to earlier of first documentation of definitive disease progression or death from any cause. Per 2007 Cheson criteria, CR: complete resolution of all disease-related radiological abnormalities; PR: =50% reduction in SPD of longest diameters of all index lesions, no new lesions; VGPR: >90% DFB in IgM, and other criteria for CR met; MR: =25% but <50% DFB in IgM, no IFB in SPD of lesions, no new lesions. Per IWCLL criteria, CR: Ly <4*10^9/L, no lymphadenopathy, normal spleen and liver size, absence of disease, ANC >1.5*10^9/L, platelets =100*10^9/L, Hb >110 g/L, bone marrow at least normocellular for age; PR: =2 of these: =50% decrease in Ly, lymphadenopathy, size of liver and spleen, bone marrow infiltrates; and =1 of these: ANC>1500/µL, platelets =100,000/µL, Hb >11 g/dL. Disease progression: as defined in Outcome measure 1. DOR was analyzed using KM estimates.	From the date of first documentation of CR or PR (or VGPR or MR for participants with LPL/WM) to disease progression or death from any cause (up to approximately 7 years)
Secondary	Time to Response (TTR), as Assessed by IRC Per Standardized Criteria (2007 Cheson Criteria) (for NHL) and IWCLL Criteria (for CLL)	TTR was defined as the interval from the first dose of study drug to the first documentation of CR or PR (or VGPR or MR for participants with LPL/WM). Per 2007 Cheson criteria, CR: complete resolution of all disease-related radiological abnormalities; PR: = 50% reduction in SPD of the longest diameters of all index lesions, no new lesions; VGPR: >90% DFB in IgM, and other criteria for CR met; MR: =25% but <50% DFB in IgM, no IFB in SPD of lesions, no new lesions. Per IWCLL criteria, CR: Ly <4*10^9/L, no lymphadenopathy, normal spleen and liver size, absence of disease, ANC >1.5*10^9/L, platelets =100*10^9/L, Hb >110 g/L, bone marrow at least normocellular for age; PR: =2 of these: =50% decrease in Ly, lymphadenopathy, size of liver and spleen, bone marrow infiltrates; and =1 of these: ANC >1500/µL, platelets =100,000/µL, Hb >11 g/dL.	From the first dose of study drug to the first documentation of CR or PR (or VGPR or MR for participants with LPL/WM) (up to approximately 7 years)