| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Lymphocytic Leukemia (CLL) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Lymphocytic Leukemia (CLL) |
|
| 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 | 16.1 |
| 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) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To evaluate the effect of the addition of idelalisib to
bendamustine/rituximab on progression-free survival (PFS) in
subjects with previously treated chronic lymphocytic leukemia
(CLL) |
|
| E.2.2 | Secondary objectives of the trial |
• To determine the effect of the addition of idelalisib to bendamustine/rituximab on the onset, magnitude, and duration of tumor control
• To assess the effect of the addition of idelalisib 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 idelalisib to
bendamustine/rituximab on disease-associated biomarkers and to evaluate potential mechanisms of resistance to idelalisib
• To characterize the effect of bendamustine/rituximab on idelalisib exposure through evaluations of idelalisib plasma concentration over time
• To describe the safety profile observed with the addition of idelalisib to bendamustine/rituximab
• To estimate health resource utilization associated with the addition of idelalisib to bendamustine/rituximab |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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)
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:
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.
7) Discontinuation of all therapy (including radiotherapy, chemotherapy, immunotherapy, or investigational therapy) for the treatment of CLL ≥3 weeks before randomization. Note subjects may receive 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 [Grades 1 or 2 permitted]).
9) Karnofsky performance score of ≥60
10) Required baseline laboratory data (within 4 weeks prior to randomization) as shown in the protocol
11) For female subjects of childbearing potential, willingness to use a protocol-recommended method of contraception from the screening visit (Visit 1) throughout the study treatment period and for 30 days following the last dose of study drug or > 12 months from she last dose of rituximab (whichever is later). Note: A female subject is considered to be of childbearing potential unless she has had a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; has medically documented ovarian failure (with serum estradiol and folliclestimulating hormone [FSH] levels within the institutional postmenopausal range and a negative serum or urine βHCG); or is menopausal (amenorrhea for >12 months or amenorrhea for >6 months with serum estradiol and FSH levels within the institutional postmenopausal range)
12) For male subjects of childbearing 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 treatment period until ≥6 months following the last dose of bendamustine or ≥90 days following the last dose of study (whichever is later) and to refrain from sperm donation from randomization (Visit 2) throughout the study and until ≥6 months following the last dose of bendamustine or ≥90 days following the last dose of study drug (whichever is later). Note: A male subject is considered able to father a child unless he has had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy, or has ongoing testicular suppression with a depot luteinizing hormone- releasing hormone (LH-RH) agonist (eg. goserelin acetate [Zoladex®]), leuprolide acetate [Lupron®]), or triptorelin pamoate [Trelstar®]).
13) In the judgment of the investigator, participation in the protocol offers an acceptable benefit-to-risk ratio when considering current CLL disease status, prior treatment history, medical condition, and the potential benefits and risks of alternative treatments for CLL.
Note: Investigators should consider whether a study subject is an
appropriate candidate for bendamustine-containing therapy based
on the number and severity of comorbid conditions; subjects with
a baseline Cumulative Illness Rating Scale (CIRS) score of ≤6
may be particularly appropriate candidates for this trial
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.4 | Principal exclusion criteria |
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 ≥5 years.
4) 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. 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.
5) 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.
6) Ongoing drug-induced pneumonitis.
7) Ongoing inflammatory bowel disease.
8) Ongoing alcohol or drug addiction.
9) Pregnancy or breastfeeding.
10) History of prior allogeneic bone marrow progenitor cell or solid organ transplantation.
11) 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 rituximab infusions or as needed for treatment-emergent comorbid conditions.
12) In a subject with a history of prior bendamustine therapy, a time interval from the last dose of bendamustine to the subsequent CLL progression of <6 months.
13) 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).
14) History of anaphylaxis in association with previous administration of monoclonal antibodies.
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.5.1 | 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 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.5.1.1 | 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. |
|
| E.5.2 | 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 SPD of index lymph nodes
• 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, or regression to a spleen LVD of ≤0 cm by physical examination
• Hepatomegaly response rate – defined as the proportion of subjects with a 50% decrease (minimum decrease of 2 cm) from baseline in the enlargement of the liver in its LVD or to ≤18 cm by imaging, or regression to a liver LVD of ≤15 cm by physical examination
• ALC response rate – defined as the proportion of subjects with baseline lymphocytosis (ALC≥4 x 109/L) who achieve an on-study 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 from baseline in HRQL domain and symptom scores based
on the Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu)
• Changes from baseline in Karnofsky performance status
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 life-year)
|
|
| E.5.2.1 | 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. For follow-up visits after Week 120, CT or MRI is only required at the End-of-Treatment visit. |
|
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | Yes |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 99 |
| 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 |
| Belgium |
| Canada |
| France |
| Greece |
| Ireland |
| Italy |
| Austria |
| Croatia |
| New Zealand |
| Portugal |
| Romania |
| Argentina |
| Australia |
| Brazil |
| Czech Republic |
| Germany |
| Hungary |
| Spain |
| Israel |
| Poland |
| Russian Federation |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
|
| 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
|
| It is expected that the final analysis of the study will take place after a minimum of 24 months of follow-up. The final analysis will be conducted after the 260th event (definitive CLL progression or death) or 36 months from the time the last subject is enrolled (whichever occurs first). Once outstanding data queries have been resolved, the database will be locked, the blind will be broken, and the final analysis of the study will be performed. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 8 |
| 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 | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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