A Phase 3, Randomised, Double-Blind, Placebo-Controlled Study of GS-1101 in Combination with Bendamustine and Rituximab for Previously Treated CLL

INTERVENTION: Product Name: NA Product Code: GS‐1101 Pharmaceutical Form: Tablet CAS Number: 870281‐82‐6 Current Sponsor code: GS‐1101 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 150‐ Pharmaceutical form of the placebo: Tablet Route of administration of the placebo: Oral use Trade Name: MABTHERA*EV 2F 10ML 100MG Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed INN: RITUXIMAB CAS Number: 174722‐31‐7 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 100‐ Trade Name: MABTHERA*EV 1FL 50ML 500MG Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed INN: RITUXIMAB CAS Number: 174722‐31‐7 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 500‐ Trade Name: LEVACT*10FL 25MG 2,5MG/ML Pharmaceutical Form: Powder for solution for infusion INN or Proposed INN: BENDAMUSTINE HYDROCHLORIDE CAS Number: 3543‐75‐7 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 25‐ Trade Name: LEVACT*5FL 100MG 2,5MG/ML Pharmaceutical Form: Powder for solution for infusion INN or Proposed INN: BENDAMUSTINE HYDROCHLORIDE CAS Number: 3543‐75‐7 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 100‐ Product Name: NA Product Code: GS‐1101 Pharmaceutical Form: Tablet CAS Number: 870281‐82‐6 Current Sponsor code: GS‐1101 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 100‐ Pharmaceutical form of the placebo: Tablet Route of administration of the placebo: Oral use CONDITION: Chronic Lymphocytic Leukemia (CLL) ; MedDRA version: 15.0 Level: SOC Classification code 10029104 Term: Neoplasms benign, malignant and unspecified (incl cysts and polyps) System Organ Class: 10029104 ‐ Neoplasms benign, malignant and unspecified (incl cysts and polyps) ; MedDRA version: 15.0 Level: PT Classification code 10008958 Term: Chronic lymphocytic leukaemia System Organ Class: 10029104 ‐ Neoplasms benign, malignant and unspecified (incl cysts and polyps) Therapeutic area: Diseases [C] ‐ Cancer [C04] PRIMARY OUTCOME: Main Objective: To evaluate the effect of the addition of GS‐1101 to bendamustine/rituximab on progression‐free survival (PFS) in subjects with previously treated chronic lymphocytic leukemia (CLL). Primary end point(s): ‐Progression‐free survival (PFS) – defined as the interval from randomization to the earlier of the first documentation of definitive disease progression or death from any cause; definitive disease progression is CLL progression based on standard criteria and occurring for any reason (ie, increasing lymphadenopathy, organomegaly or bone marrow involvement; decreasing platelet count, hemoglobin, or neutrophil count; or worsening of disease‐related symptoms) other than lymphocytosis alone. Secondary Objective: ‐To determine the effect of the addition of GS‐1101 to bendamustine/rituximab on the onset, magnitude, and duration of tumor control; ‐To assess the effect of the addition of GS‐1101 to bendamustine/rituximab on measures of subject well‐being, including overall survival (OS), health‐related quality of life (HRQL), and performance status; ‐To assess the effects of the addition of GS‐1101 to bendamustine/rituximab on disease‐associated biomarkers and to evaluate potential mechanisms of resistance to GS‐1101; ‐To characterize exposure to study treatment as determined by treatment administration with each of the therapeutic agents and evaluation of GS‐1101 plasma concentrations over time; ‐To describe the safety profile observed with the addition of GS‐1101 to bendamustine/rituximab. Timepoint(s) of evaluation of this end point: Clinic/laboratory visits will occur every 2 weeks through Week 24 and every 6 weeks between Weeks 24 and 48. Subjects who continue on study treatment past Week 48 will have clinic visits every 12 weeks. Subjects will be assessed for safety at each clinic visit. Subjects will be assessed for CLL disease status by physical and laboratory examinations at each clinic visit and by CT or MRI at Weeks 12, 24, 36, and 48 and every 12 weeks thereafter through Week 120. For follow‐up visits after Week 120, CT or MRI is only required at the End of‐Treatment visit. SECONDARY OUTCOME: Secondary end point(s): Tumor Control ‐Overall response rate (ORR): defined as the proportion of subjects who achieve a complete response (CR) or partial response (PR); ‐Time to response (TTR): defined as the interval from randomization to the first documentation of CR or PR; ‐Duration of response (DOR): defined as the interval from the first documentation of CR or PR to the earlier of the first documentation of definitive disease progression or death from any cause; ‐Time to treatment failure (TTF): defined as the interval from randomization to the earliest of the first documentation of definitive disease progression, the permanent cessation of study drug (GS‐1101/placebo) due to an adverse event, or death from any cause; ‐Percent change in lymph node area: defined as the percent change from baseline in the sum of the products of the greatest perpendicular diameters (SPD) of index lymph nodes; ‐Lymph node response rate: defined as the proportion of subjects who achieve a =50% decrease from baseline in the SPD of index lymph nodes; ‐Splenomegaly response rate: defined as the proportion of subjects with baseline splenomegaly who achieve an on‐study normalization or a decrease by =50% from baseline in the pretreatment enlargement of the splenic longest vertical dimension (LVD) (by imaging) or in the pretreatment enlargement of the splenic LVD below the left costal margin (by palpation); ‐Hepatomegaly response rate: defined as the proportion of subjects with baseline hepatomegaly who achieve an on‐study normalization or a decrease by =50% from baseline in the pretreatment enlargement of the hepatic LVD (by imaging) or in the pretreatment enlargement of the hepatic LVD at the right midclavicular line (by percussion); ‐Hemoglobin response rate: defined as the proportion of subjects with baseline anemia (hemoglobin <110 g/L [11.0 g/dL]) who achieve an on‐study hemoglobin =110 g/L (11.0 g/dL) or demonstrate a =50% increase in hemoglobin from baseline; ‐Overall survival (OS): defined as the interval from randomization to death from any cause. Timepoint(s) of evaluation of this end point: Clinic/laboratory visits will occur every 2 weeks through Week 24 and every 6 weeks between Weeks 24 and 48. Subjects who continue on study treatment past Week 48 will have clinic visits every 12 weeks. Subjects will be assessed for safety at each clinic visit. Subjects will be assessed for CLL disease status by physical and laboratory examinations at each clinic visit and by CT or MRI at Weeks 12, 24, 36, and 48 and every 12 weeks thereafter through Week 120. For follow‐up visits after Week 120, CT or MRI is only required at the End‐of‐Treatment visit. INCLUSION CRITERIA: ‐Diagnosis of B‐cell CLL, with diagnosis established according to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria and documented within medical records; ‐CLL that warrants treatment (consistent with accepted IWCLL criteria for initiation of therapy); ‐Presence of measurable lymphadenopathy (defined as the presence of =1 nodal lesion that measures =2.0 cm in the longest dimension [LD] and =1.0 cm in the longest perpendicular dimension [LPD] as assessed by computed tomography [CT] or magnetic resonance imaging [MRI]); ‐Prior treatment for CLL comprising: a) =2 cycles of a regimen containing a purine analog (eg, fludarabine, pentostatin, cladribine) or bendamustine, and b) =2 doses with a regimen containing an anti‐CD20 monoclonal antibody (eg, rituximab, ofatumumab, GA‐101) 6) Documentation of CLL progression <36 months since the completion of the last prior therapy for CLL; ‐Discontinuation of all therapy (including radiotherapy, chemother