| 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 | 14.1 |
| 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 (formerly GS-1101) to rituximab on progression-free survival (PFS) in subjects with previously treated chronic lymphocytic leukemia (CLL). |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the effect of the addition of idelalisib (formerly GS-1101) to rituximab on the onset, magnitude,
and duration of tumor control
• To assess the effect of the addition of idelalisib to rituximab on measures of subject wellbeing,
including OS, HRQL, and performance status
• To assess the effects of the addition of idelalisib to rituximab on disease-associated
biomarkers and to evaluate potential mechanisms of resistance to idelalisib
• To characterize the effect of rituximab on idelalisib exposure through
evluations of idelalisib plasma concentrations over time
• To describe the safety profile observed with the addition of idelalisib to rituximab
• To estimate health resource utilization associated with the addition of idelalisib to
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 IWCLL criteria
[Hallek 2008] and documented within medical records.
3) CLL that warrants treatment (consistent with accepted IWCLL criteria for initiation of therapy [Hallek 2008]).
4) 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).
5) Prior treatment for CLL
6) In a subject whose last prior therapy contained an anti-CD20 antibody (eg, rituximab,
ofatumumab, GA-101), evidence of disease improvement during that therapy or
documentation of CLL progression ≥6 months after completion of that therapy. Note:
Subjects who did not receive a therapeutic anti-CD20 antibody (eg, rituximab,
ofatumumab, GA-101) as a component of the last prior therapy need not have
experienced disease improvement or may have relapsed <6 months from the completion
of the prior regimen.
7) Documentation of CLL progression <24 months since the completion of the last prior
therapy for CLL.
8) 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.
9) 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, 2, 3, or 4 permitted).
10) Karnofsky performance score of ≥40.
11) Appropriate for non-cytotoxic-containing therapy.
12) Required baseline laboratory data (within 4 weeks prior to randomization) 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.
13) 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 the 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 renge). See Section 5.6.4
for information regarding recommendations for contraception.
14) For male subjects of childbearing potential and having intercourse
with females of childbearing potential, willingness to use a protocolrecommended
method 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. 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®]).
15) 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.
16) Willingness 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.
17) 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) 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) [Greenberg 1997].
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 initiation
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.
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, or inhaled, or systemic
corticosteroids as therapy for manifestations of CLL, comorbid conditions
and 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) Prior therapy with any inhibitor of Bruton tyrosine kinase (BTK), Janus kinase (JAK),
mammalian target of rapamycin (mTOR), phosphatidylinositol 3 kinase (PI3K)
(including GS 1101), or spleen tyrosine kinase (Syk).
13) History of anaphylaxis in association with previous administration of monoclonal
antibodies
14) Concurrent participation in another therapeutic clinical trial.
15) 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 other than lymphocytosis alone |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Four 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, OS and CR rate.
• 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 summary of the products of the greatest perpendicular diameters (SPD) of index lymph nodes
• Overall survival (OS) -defined as the interval from randomization to death from any cause
• CR rate - defined as the proportion of subjects whoc achieve a Complete Response
• Splenomegaly response rate – defined as the proportion of subjects with a 50% decrease (minimum 2 cm) from baseline in the enlargement of the spleen in its LVD or decrease to <12 cm by imaging
• Hepatomegaly response rate – defined as the proportion of subjects with a 50% decrease (minimum 2 cm) 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 on-study ALC < 4 x 109/L or demostrate 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 onstudy 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 10^9/L) who achieve an ANC ≥1.5 x 10^9/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 3) 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 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
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) | 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 | 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
|
| It is expected that the final efficacy analysis of the study will take place approximately after the 119th event (definitive CLL progression or death) or earlier if the decision is made to stop the trial due to overwhelming efficacy based upon interim analysis results. 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 | 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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