E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Lymphocytic Leukemia (CLL) |
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E.1.1.1 | Medical condition in easily understood language |
Chronic Lymphocytic Leukemia (CLL) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10008958 |
E.1.2 | Term | Chronic lymphocytic leukaemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the effect of the addition of idelalisib (GS-1101) to ofatumumab on progression-free survival (PFS) in subjects with previously treated chronic lymphocytic leukemia (CLL) |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the effect of the addition of idelalisib to ofatumumab on the onset, magnitude, and duration of tumor control • To evaluate the effect of the addition of idelalisib to ofatumumab for subjects with 17p deletion and/or TP53 mutation • To assess the effect of the addition of idelalisib 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 idelalisib to ofatumumab on disease-associated biomarkers and to evaluate potential mechanisms of resistance to idelalisib • To characterize the effect of ofatumumab on idelalisib exposure through evaluation of idelalisib plasma concentrations over time • To describe the safety profile observed with the addition of idelalisib to ofatumumab • To estimate health resource utilization associated with the addition of idelalisib to ofatumumab |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 diameter [LD] and ≥1.0 cm in the longest perpendicular diameter [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 cytotoxic 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 child-bearing potential, willingness to use a protocol-recommended method of contraception from the screening visit (Visit 1) throughout the study 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 child-bearing potential having intercourse with females of childbearing potential, willingness to use a protocol-recommended method of contraception from the randomization visit (Visit 2) throughout the study 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. |
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E.4 | Principal 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 idelalisib 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 idelalisib), or spleen tyrosine kinase (SYK). 15) Prior participation in a idelalisib clinical trial. 16) Concurrent participation in another therapeutic clinical trial. 17) 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. |
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E.5 End points |
E.5.1 | 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 other than lymphocytosis alone |
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E.5.1.1 | Timepoint(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 drug(s) 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.
The proportion of subjects who are progression-free at 24 and 48 weeks from randomization will be presented. |
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E.5.2 | Secondary end point(s) |
Five endpoints are designated as secondary endpoints for which sequential testing will be performed to control Type 1 error rate. Secondary endpoints will be ORR, lymph node response rate, PFS in 17p deleted and/or TP53 mutated subjects,OS and CR rate. All other endpoints will be considered exploratory.
Tumor Control • Overall response rate (ORR) – defined as the proportion of subjects who achieve a complete response (CR) or partial response (PR) • Lymph node response rate – defined as the proportion of subjects who achieve a ≥50% decrease from baseline in the sum of the products of the greatest perpendicular diameters (SPD) of index lesions • CR rate – defined as the proportion of subjects who achieve a CR • PFS in subjects with 17p deletion and/or TP53 mutation • 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 • Percent change in lymph node area – defined as the percent change from baseline in the SPD of index lesions • Splenomegaly response rate – defined as the proportion of subjects with a 50% decrease from baseline (minimum decrease of 2 cm) in the enlargement of the spleen in its LVD or to ≤ 12 cm by imaging • Hepatomegaly response rate – defined as the proportion of subjects with a decrease by ≥50% from baseline in the enlargement of the liver in its LVD or decrease to < 18 cm by imaging • 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 onstudy 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]<1.5 x 109/L) who achieve an ANC ≥1.5 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 from baseline in HRQL domain and symptom scores based on the Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu) (see Appendix 2) • Changes from baseline in Karnofsky performance status (see Appendix 2) 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 diseaseassociated 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 idelalisib plasma concentrations as assessed by a validated bioanalytical method Safety • Overall safety profile of each 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 drug(s) 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 life-year) |
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E.5.2.1 | Timepoint(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 drug(s) 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. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 52 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If 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 |
Poland |
Spain |
Sweden |
United Kingdom |
United States |
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E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |