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    Summary
    EudraCT Number:2012-001236-65
    Sponsor's Protocol Code Number:GS-US-312-0119
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-06-03
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2012-001236-65
    A.3Full title of the trial
    A Phase 3, Randomized, Controlled Study Evaluating the Efficacy and Safety of GS-1101 (CAL-101) in Combination with Ofatumumab for Previously Treated Chronic Lymphocytic Leukemia
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3 Study with GS-1101 in Combination with Ofatumumab for Previously Treated CLL
    A.4.1Sponsor's protocol code numberGS-US-312-0119
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01659021
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorGilead Sciences, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportGilead Sciences, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGilead Sciences, Inc.
    B.5.2Functional name of contact pointMedical Monitor
    B.5.3 Address:
    B.5.3.1Street Address199 East Blaine Street
    B.5.3.2Town/ citySeattle, WA
    B.5.3.3Post code98102
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1206256 4939
    B.5.5Fax number+1206832 2012
    B.5.6E-mailronald.dubowy@gilead.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code GS-1101
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNGS-1101 (INN not available)
    D.3.9.1CAS number 870281-82-6
    D.3.9.2Current sponsor codeGS-1101
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typeOral, small molecule inhibitor
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code GS-1101
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNGS-1101 (INN not available)
    D.3.9.1CAS number 870281-82-6
    D.3.9.2Current sponsor codeGS-1101
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typeOral, small molecule inhibitor
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Arzerra (ofatumumab) injection, for intravenous infusion
    D.2.1.1.2Name of the Marketing Authorisation holderGlaxo Group Ltd
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNOFATUMUMAB
    D.3.9.1CAS number 679818-59-8
    D.3.9.4EV Substance CodeSUB25221
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Arzerra (ofatumumab) injection, for intravenous infusion
    D.2.1.1.2Name of the Marketing Authorisation holderGlaxo Group Ltd
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNOFATUMUMAB
    D.3.9.1CAS number 679818-59-8
    D.3.9.4EV Substance CodeSUB25221
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Chronic Lymphocytic Leukemia (CLL)
    E.1.1.1Medical condition in easily understood language
    Chronic Lymphocytic Leukemia (CLL)
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.0
    E.1.2Level PT
    E.1.2Classification code 10008958
    E.1.2Term Chronic lymphocytic leukaemia
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the effect of the addition of GS-1101 to ofatumumab on progression-free survival (PFS) in subjects with previously treated chronic lymphocytic leukemia (CLL)
    E.2.2Secondary objectives of the trial
    • To evaluate the effect of the addition of GS-1101 to ofatumumab on the onset, magnitude, and duration of tumor control
    • To assess the effect of the addition of GS-1101 to ofatumumab 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 ofatumumab 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 ofatumumab
    • To estimate health resource utilization associated with the addition of GS-1101 to ofatumumab
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects must meet all of the following inclusion criteria to be eligible for participation in this study:
    1) Male or female ≥18 years of age.
    2) Diagnosis of B-cell CLL, with diagnosis established according to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria and documented within medical records.
    3) CLL that warrants treatment (consistent with accepted IWCLL criteria for initiation of therapy). Any of the following conditions constitute CLL that warrants treatment:
    a) Evidence of progressive marrow failure as manifested by the onset or worsening of anemia and/or thrombocytopenia, or
    b) Massive (ie, lower edge of spleen ≥6 cm below the left costal margin), progressive, or symptomatic splenomegaly, or
    c) Massive (ie, ≥10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy, or
    d) Progressive lymphocytosis in the absence of infection, with an increase in blood absolute lymphocyte count (ALC) ≥50% over a 2-month period or lymphocyte doubling time of
    <6 months (as long as initial ALC was ≥30,000/L), or
    e) Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy, or
    f) Constitutional symptoms, defined as any one or more of the following disease-related symptoms or signs occurring in the absence of evidence of infection:
    i) Unintentional weight loss of ≥10% within the previous
    6 months, or
    ii) Significant fatigue (≥Grade 2), or
    iii) Fevers >100.5°F or 38.0°C for ≥2 weeks, or
    iv) Night sweats for >1 month.
    4) 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]).
    5) Prior treatment for CLL comprising therapy with either of the following types of drugs given alone or in combination:
    a) A purine analog (eg, fludarabine, pentostatin, cladribine) administered for ≥2 cycles of treatment
    b) Bendamustine administered for ≥2 cycles of treatment
    6) Documentation of CLL progression <24 months since the completion of the last prior therapy for CLL.
    7) Discontinuation of all therapy (including radiotherapy, chemotherapy, immunotherapy, or investigational therapy) for the treatment of CLL ≥6 weeks before randomization. Note: Subjects
    may be receiving corticosteroids to manage CLL manifestations.
    8) All acute toxic effects of any prior antitumor therapy resolved to Grade ≤1 before randomization (with the exception of alopecia [Grade 1 or 2 permitted], neurotoxicity [Grade 1 or 2 permitted],
    or bone marrow parameters [any of Grade 1, 2, 3, or 4 permitted]).
    9) Karnofsky performance score of ≥60.
    10) Required baseline laboratory data (within 4 weeks prior to randomization) as shown in the table located in the study protocol synopsis.
    11) For female subjects of childbearing potential, willingness to abstain from heterosexual intercourse or use a protocolrecommended method of contraception from the screening visit (Visit 1) throughout the study treatment period, and to 30 days from the last dose of study drug or 12 months from the last dose of ofatumumab (whichever is later).
    12) For male subjects of childbearing potential having intercourse with females of childbearing potential, willingness to abstain from heterosexual intercourse or use a protocol-recommended
    method of contraception from the randomization visit (Visit 2) throughout the study treatment period and for 90 days following the last dose of study drug and to refrain from sperm donation from randomization (Visit 2) throughout the study treatment period and for 90 days following the last dose of study drug.
    13) In the judgment of the investigator, participation in the protocol offers an acceptable benefit-to-risk ratio when considering current CLL disease status, medical condition, and the potential benefits and risks of alternative treatments for CLL.
    14) Willingness and ability to comply with scheduled visits, drug administration plan, imaging studies, laboratory tests, other study procedures, and study restrictions. Note: Psychological, social,
    familial, or geographical factors that might preclude adequate study participation should be considered.
    15) Evidence of a personally signed informed consent indicating that the subject is aware of the neoplastic nature of the disease and has been informed of the procedures to be followed, the experimental nature of the therapy, alternatives, potential benefits, possible side effects, potential risks and discomforts, and other pertinent aspects of study participation.
    E.4Principal exclusion criteria
    Subjects who meet any of the following exclusion criteria are not to be enrolled in this study:
    1) Known histological transformation from CLL to an aggressive lymphoma (ie, Richter transformation). Note: Biopsy documentation of the absence or presence of transformation is
    not required.
    2) Known presence of intermediate- or high-grade myelodysplastic syndrome (ie, subjects are excluded who have ≥5 bone marrow blasts; karotypic abnormalities other than normal, Y deletion, 5q
    deletion, or 20q deletion; or ≥2 lineages of cytopenias due to myelodysplasia).
    3) History of a non-CLL malignancy except for the following: adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for ≥1 year prior to randomization, other adequately treated Stage 1 or 2 cancer currently in complete remission, or any other cancer that has been in complete remission for ≥2 years.
    4) Known hypersensitivity or intolerance to any of the active substances or excipients in the formulations for either GS-1101 or ofatumumab
    5) Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of randomization (Visit 2). Note: Subjects with localized fungal infections of skin or nails are eligible. Subjects may be receiving prophylactic antiviral or antibacterial therapies at the discretion of the investigator; anti-pneumocystis prophylaxis is encouraged. For subjects who are at substantial risk of an infection (eg, influenza) that may be prevented by immunization, consideration should be given to providing the
    vaccine prior to initiation of protocol therapy.
    6) Ongoing drug-induced liver injury, chronic active hepatitis C (HCV), chronic active hepatitis B (HBV), alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or portal hypertension.
    7) Ongoing drug-induced pneumonitis.
    8) Ongoing inflammatory bowel disease.
    9) Ongoing alcohol or drug addiction.
    10) Pregnancy or breastfeeding.
    11) History of prior allogeneic bone marrow progenitor cell or solid organ transplantation.
    12) Ongoing immunosuppressive therapy other than corticosteroids. Note: Subjects may use topical, enteric, inhaled, or systemic corticosteroids as therapy for manifestations of CLL, comorbid conditions, or autoimmune anemia and/or thrombocytopenia. During study participation, subjects may receive systemic or other corticosteroids as pretreatment for ofatumumab infusions or as needed for treatment-emergent comorbid conditions.
    13) In a subject with a history of prior ofatumumab therapy, the time from the last dose of ofatumumab to documented CLL progression is <6 months.
    14) History of prior therapy with any inhibitor of AKT, Bruton tyrosine kinase (BTK), Janus kinase (JAK), mammalian target of rapamycin (mTOR), phosphatidylinositol 3-kinase (PI3K) (including GS-1101), or spleen tyrosine kinase (SYK).
    15) Concurrent participation in another therapeutic clinical trial.
    16) Prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, electrocardiogram (ECG) finding, or laboratory abnormality that, in the investigator’s opinion, could adversely affect the safety of the subject or impair the assessment of study results.
    E.5 End points
    E.5.1Primary 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
    E.5.1.1Timepoint(s) of evaluation of this end point
    Clinic/laboratory visits will occur weekly for Weeks 1 through 8, every 4 weeks at Weeks 12, 16, 20, and 24, and every 6 weeks between Weeks 24 and 48. Subjects continuing on study treatment past Week 48 will have clinic visits every 12 weeks. Subjects will be assessed for safety at each visit. Subjects will be assessed for CLL disease status by physical and laboratory examinations at each visit and by CT or MRI at Weeks 8, 16, 24, 36, 48 and every 12 weeks thereafter through Week 96. For follow-up visits after Week 96, CT or MRI is only required at the end-of-therapy visit.

    The proportion of subjects who are progression-free at 24 and 48 weeks from randomization will be presented.
    E.5.2Secondary 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 GS-1101 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 vertical splenic dimension
    • 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)
    • ALC response rate – defined as the proportion of subjects with baseline lymphocytosis (ALC≥4 x 109/L) who achieve an onstudy ALC <4 x 109/L or demonstrate a ≥50% decrease in ALC from baseline
    • Platelet response rate – defined as the proportion of subjects with baseline thrombocytopenia (platelet count <100 x 109/L) who achieve an on-study platelet count ≥100 x 109/L or demonstrate a
    ≥50% increase in platelet count from baseline
    • 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
    • Neutrophil response rate – defined as the proportion of subjects with baseline neutropenia (absolute neutrophil count [ANC]<1 x 109/L) who achieve an ANC ≥1 x 109/L or demonstrate a ≥50%
    increase in ANC from baseline

    Patient Well-Being
    • Overall survival (OS) – defined as the interval from randomization to death from any cause
    • Change in HRQL domain and symptom scores based on the Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu)
    • Changes in Karnofsky performance status – defined as the change from baseline in the performance status and the time to definitive performance status improvement or worsening; time to definitive performance status improvement (better than baseline) is the interval from randomization to the first timepoint when the performance status is consistently better than at baseline (including that timepoint as well as all the subsequent timepoints) in a subject whose last performance status score is better than at baseline; and time to definitive performance status worsening (worse than baseline) is the interval from randomization until the earliest of death or the first timepoint when the performance status is consistently worse than at baseline (including that timepoint as well as all the subsequent timepoints) in a subject whose last performance status score is worse than at baseline

    Pharmacodynamic Markers of Drug Activity and Resistance
    • Changes from baseline in PI3K/Akt/mTOR pathway activation as a measure of PI3Kδ pathway activity
    • Changes from baseline in the plasma concentrations of disease-associated chemokines and cytokines

    Exposure
    • Study drug administration as assessed by prescribing records and compliance as assessed by quantification of used and unused drug
    • Trough (pre-dose) and peak (1.5-hour samples) of GS-1101 plasma concentrations as assessed by a validated bioanalytical method

    Safety
    • Overall safety profile of each study treatment regimen characterized by the type, frequency, severity, timing of onset, duration, and relationship to study therapy of any adverse events or abnormalities of laboratory tests; serious adverse events; or adverse events leading to discontinuation of study treatment

    Pharmacoeconomics
    • Change in health status – defined as the change from baseline in overall health and single-item dimension scores as assessed using the EuroQoL Five-Dimension (EQ-5D) utility measure
    • Health resource measures, including resource utilization, total costs, and measures of cost per unit of benefit (eg, cost per additional progression-free month, cost per quality-adjusted lifeyear)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Clinic/laboratory visits will occur weekly for Weeks 1 through 8, every 4 weeks at Weeks 12, 16, 20, and 24, and every 6 weeks between Weeks 24 and 48. Subjects continuing on study treatment past Week 48 will have clinic visits every 12 weeks. Subjects will be assessed for safety at each visit. Subjects will be assessed for CLL disease status by physical and laboratory examinations at each visit and by CT or MRI at Weeks 8, 16, 24, 36, 48 and every 12 weeks thereafter through Week 96. For follow-up visits after Week 96, CT or MRI is only required at the end-of-therapy visit.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic Yes
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA43
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Belgium
    Canada
    Denmark
    France
    Ireland
    Netherlands
    Norway
    Poland
    Spain
    Sweden
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    It is expected that the final analysis of the study will take place after a minimum of 12 months of follow-up. The analysis will be conducted after the 129th event (definitive CLL progression or death) or 18 months from the time the last subject is enrolled (whichever occurs first). Once outstanding data queries have been resolved, the database will be locked and the final analysis of the study will be performed.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months1
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 65
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 145
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 113
    F.4.2.2In the whole clinical trial 210
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    After a patient has completed/terminated their study participation, long term care for the participant will remain the responsibility of their primary treating physician.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-12-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-05-06
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-08-15
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