| 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 | 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) |
|
| 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 idelalisib (formerly GS-1101) on the onset, magnitude, and duration of tumor control
• To compare tumor control in subjects receiving rituximab alone in Study GS-US-312-0116 to that observed in the same subjects when receiving the standard dose of idelalisib alone in Study GS-US-312-0117
• To assess the effect of idelalisib on measures of subject well-being, including overall survival (OS), health related quality of life (HRQL), and performance status
• To assess the effects of idelalisib on disease associated biomarkers and to evaluate potential mechanisms of resistance to idelalisib
• To characterize exposure to idelalisib as determined by treatment administration and evaluation of idelalisib plasma concentrations over time
• To describe the safety profile observed with idelalisib
• To estimate health resource utilization associated with administration of idelalisib |
|
| E.2.2 | Secondary objectives of the trial |
| determining the effect of idelalisib on the onset, magnitude, and duration of tumor control; overall survival (OS); health-related quality of life (HRQL); changes in subject performance status; disease-associated biomarkers and potential mechanisms of resistance; treatment administration; safety; and health resource utilization. |
|
| 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) Participation in Study GS-US-312-0116.
2) Occurrence of confirmed, definitive CLL progression while receiving study drug therapy (idelalisib/placebo) in Study GS US 312 0116. Note: 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. Subjects must have confirmation by the sponsor working in collaboration with an independent review committee (IRC) that the disease has progressed on the clinical trial (Study GS-US-312-0116) before receiving secondary GS 1101 therapy on this extension trial (Study GS-US-312-0117).
3) Presence of radiographically 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 CT or MRI).
4)Permanent cessation of Study GS-US-312-0116 treatment (rituximab
and idelalisib/placebo) and no intervening or continuing therapy
(including radiotherapy, chemotherapy, immunotherapy, or
investigational therapy) for the treatment of CLL. Note: subjects may
receive corticosteroids to manage CLL manifestations.
5) The time from permanent cessation of Study GS-US-312-0116 treatment (rituximab and/or GS-1101/placebo) and the initiation of Study GS-US-312-0117 therapy is ≤12 weeks. Note: Study procedures performed as part of Study GS-US-312-0116 need not be repeated and can be used as screening procedures for Study GS-US-312-0117 if performed within 4 weeks prior to initiation of study drug therapy on Study GS-US-312-0117.
6) Karnofsky performance score of ≥40.
7) Required baseline laboratory data (within 4 weeks prior to initiation of study treatment) as shown in the table below. Note: Confirmation should be considered for out-of-range values to determine if the abnormality is real or artifactual. Values should be obtained within the screening period and should generally be the most recent measurement obtained. Subjects with any degree of neutropenia, thrombocytopenia, or anemia due to CLL or prior therapy may enroll.
8) For female subjects of childbearing potential, willingness to use a
protocol-recommended method of contraception from the screening visit
(Visit 1) throughout the study and for 30 days from the last dose of
study drug. 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 follicle-stimulating hormone [FSH] levels within the
institutional postmenopausal range and a negative serum or urine
βHCG), or is menopausal (defined as age ≥54 years with amenorrhea for >12 months or amenorrhea
for > 6 months with serum estradiol and FSH levels within the
institutional postmenopausal range).
9) For male subjects of childbearing potential having intercourse with
females of childbearing potential, willingness to use a protocolrecommended
method of contraception from the start of study drug
(Visit 2) throughout the study and for 90 days following the last dose of
study drug and to refrain from sperm donation from the start of study
drug (Visit 2) throughout the study and for 90 days following the
last dose of study drug. 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®]).
10) 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.
11) 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.
12) 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 |
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) Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of the start of study treatment (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.
3) Pregnancy or breastfeeding.
4) Intentional breaking of the blind in Study GS-US-312-0116 by the investigator or the study subject.
5) Concurrent participation in another therapeutic clinical trial.
6) 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) |
-Tumour control
-Patient well-being
-Pharmacodynamic Markers of drug activity and resistance
-Exposure
-Safety
-Pharmacoeconomics |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Tumour control
-Progression-free survival (PFS)
-Overall response rate (ORR)
-Lymph node response rate
-CR rate
-Time to response (TTR)
-Duration of response (DOR)
-Percentage change in lymph node area
-Splenomegaly response rate
-Hepatomegaly response rate
-ALC response rate
-Platelet response rate
-Hemoglobin response rate
-Neutrophil response rate
Patient Well-being
• Overall survival (OS)
• 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 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 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 drug
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 |
|
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | 19 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 65 |
| 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 |
| France |
| Germany |
| Italy |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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