| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Indolent Non-Hodgkin Lymphomas
•Follicular lymphoma
•Small lymphocytic lymphoma
•Lymphoplasmacytic lymphoma (with or without Waldenström macroglobulinemia)
•Marginal zone lymphoma
|
|
| E.1.1.1 | Medical condition in easily understood language |
| Indolent Non-Hodgkin Lymphomas |
|
| 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 | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10065856 |
| E.1.2 | Term | Non-Hodgkin's lymphoma unspecified histology indolent |
| 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 rituximab on progression-free survival (PFS) in subjects with previously treated indolent non-Hodgkin lymphoma (iNHL) |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the effect of the addition of idelalisib 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 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 rituximab on disease-associated biomarkers
• To characterize the effect of rituximab on idelalisib exposure through evaluation 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
Exploratory objective
• To describe the efficacy of idelalisib at 150 mg BID during the openlabel
extension |
|
| 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) Histologically confirmed diagnosis of B-cell iNHL, with histological subtype limited to the following based on criteria established by the
World Health Organization (WHO) 2008 classification of tumors of hematopoietic and lymphoid tissues:
a) FL Grade 1, 2, or 3a
b) SLL with absolute lymphocyte count <5 x 109/L at the time of diagnosis
c) Lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM)
d) Marginal zone lymphoma (MZL) (splenic, nodal, or extranodal)
3) Relapsed, radiographically measurable nodal or extranodal iNHL as determined by the IRC (defined as the presence of ≥1 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) Prior treatment for lymphoid malignancy comprising ≥1 regimen containing a therapeutic anti-CD20 antibody (eg, rituximab,
ofatumumab, GA-101) administered for ≥2 doses of antibody treatment.
Note: Prior treatments may have been administered as single agents or as components of combination therapies. Subjects may also have
received other commercially available chemotherapies, immunotherapies, or non-excluded investigational therapies. Each
repeated but separate therapeutic application of the same single-agent or combination is considered an independent regimen.
5) Discontinuation of all therapy (including radiotherapy, chemotherapy, immunotherapy, or investigational therapy) for the treatment of cancer
≥6 weeks prior to randomization. Note: Subjects may be receiving corticosteroids to manage iNHL manifestations.
6) 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]).
7) Karnofsky performance score of ≥40.
8) Required baseline laboratory data (within 4 weeks prior to randomization) as shown in the table located in the study protocol
synopsis.
9) 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 idelalisib/placebo 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, 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 (age ≥54 years with amenorrhea for at least 12
months and serum follicle stimulating hormone (FSH) level elevated to within the postmenopausal range based on the laboratory reference
range where the hormonal assay is performed).
10) For male subjects of reproductive potential having intercourse with females of childbearing potential, willingness to use a protocolrecommended
method of contraception from the randomization visit (Visit 2) throughout the study and for 90 days following the last dose of
idelalisib/placebo or 12 months from the last dose of rituximab (whichever is later) and to refrain from sperm donation from
randomization (Visit 2) throughout the study and for 90 days following the last dose of idelalisib/placebo or 12 months from the last dose of
rituximab (whichever is later). Note: A male subject is considered to be of reproductive potential 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®]).
11) In the judgment of the investigator, participation in the protocol offers an acceptable benefit-to-risk ratio when considering current iNHL
disease status, medical condition, and the potential benefits and risks of alternative treatments for the subject's iNHL.
12) 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.
13) 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.
Open-label extension entry criteria: see protocol |
|
| E.4 | Principal exclusion criteria |
Subjects who meet any of the following exclusion criteria are not to be
enrolled in this study:
1) Known central nervous system or leptomeningeal lymphoma. Note:
Imaging documentation of the absence or presence of central disease is
not required.
2) History of lymphoid malignancy other than those allowed per
Inclusion Criterion 2. Note: Biopsy documentation of the absence or
presence of high grade lymphoma is not required.
3) Known presence of intermediate- or high-grade myelodysplastic
syndrome. Note: intermediate- or high-grade myelodysplasia is defined
as the presence of ≥5% bone marrow blasts; karotypic abnormalities
other than normal, Y deletion, 5q deletion, or 20q deletion; or ≥2
lineages of cytopenias due to myelodysplasia.
4) History of a non-lymphoid 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 or
any other cancer that has been in complete remission without treatment
for ≥5 years prior to randomization.
5) Known hypersensitivity or intolerance to any of the active substances
or excipients in the formulations for either idelalisib or rituximab
6) 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 regimens (eg, anti-pneumocystis
prophylaxis) 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 randomization.
7) 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.
8) Ongoing drug-induced pneumonitis.
9) Ongoing inflammatory bowel disease.
10) Ongoing alcohol or drug addiction.
11) Pregnancy or breastfeeding.
12) History of prior allogeneic bone marrow progenitor cell or solid
organ transplantation.
13) Ongoing immunosuppressive therapy other than corticosteroids.
Note: Subjects may use topical, enteric, inhaled, or systemic
corticosteroids as therapy for manifestations of iNHL, 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.
14) Lack of at least a partial response (PR) with a rituximab-containing
regimen or occurrence of progressive disease within 6 months from the
last dose of rituximab for iNHL.
15) History of prior therapy with any inhibitor of AKT (a
serine/threonine protein kinase), Bruton tyrosine kinase (BTK), Janus
kinase (JAK), mammalian target of rapamycin (mTOR),
phosphatidylinositol 3-kinase (PI3K) (including idelalisib), or spleen
tyrosine kinase (SYK).
16) Concurrent participation in another therapeutic clinical trial.
17) Prior participation in a idelalisib clinical trial.
18) 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 iNHL disease progression or death from any cause; definitive iNHL disease progression is based on standard criteria. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Clinic/laboratory visits will occur weekly for Weeks 1 through 4, every 2 weeks for Weeks 6 through 12; at Weeks 20, 24, 28 and 36; and every 12 weeks past Week 36. Subjects will be assessed for
safety at each clinic visit.
Subjects will be assessed for iNHL disease status by physical and laboratory examinations at each visit and by CT or MRI at baseline and every 12 weeks thereafter.
The proportion of subjects who are progression-free at 24 and 48, 72, and 96 weeks from randomization will be presented. |
|
| E.5.2 | Secondary end point(s) |
Four endpoints are designated as secondary endpoints for which sequential testing will be performed to control the Type 1 error rate. Secondary endpoints will be ORR, lymph node response rate, CR rate, and OS. All other endpoints will be considered tertiary.
Tumor Control
• Overall response rate (ORR) – defined as the proportion of subjects who achieve a CR or PR [or very good partial response (VGPR) or minor response (MR) for patients with WM]
• 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
• Time to response (TTR) – defined as the interval from randomization to the first documentation of CR or PR (or VGPR or MR for patients with WM)
• Duration of response (DOR) – defined as the interval from the first documentation of CR or PR (or VGPR or MR for patients with WM) to the earlier of the first documentation of definitive disease progression or death from any cause
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: Lymphoma (FACT-Lym)
• Changes from baseline in Karnofsky performance status.
Pharmacodynamic Markers of Drug Activity and Resistance
• Changes in the plasma concentrations of disease-associated chemokines and cytokines
• Changes in peripheral blood disease-related B-cell receptors
• Changes in peripheral blood lymphoid and myeloid cell subsets
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 treatment regimen characterized by the type, frequency, severity, timing of onset, duration, and relationship to study drugs 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 lifeyear)
Exploratory Endpoints in the Open-Label Extension
• PFS – defined as the interval from the date of first idelalisib dose to the
earlier of the first documentation of definitive iNHL disease progression
or death from any cause; definitive iNHL disease progression is based on
standard criteria
• ORR – defined as the proportion of subjects who achieve a CR or PR [or
VGPR or MR for subjects with WM]
• Lymph node response rate – defined as the proportion of subjects who
achieve a ≥ 50% decrease from open-label extension baseline in the SPD
of index lesions
• CR rate – defined as the proportion of subjects who achieve a CR
• TTR – defined as the interval from the date of first idelalisib dose to
the first documentation of CR or PR (or VGPR or MR for subjects with
WM)
• DOR – defined as the interval from the first documentation of CR or PR
(or VGPR or MR for subjects with WM) during the open-label extension
to the earlier of the first documentation of definitive disease progression
or death from any cause
• OS – defined as the interval from randomization to death from any
cause |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Clinic/lab visits will occur weekly Weeks 1 - 4, every 2 weeks for Weeks 6 through 12; at Weeks 20, 24, 28 and 36; every 12 weeks past
Week 36. Subjects will be assessed for safety at each visit. Subjects will be assessed for iNHL disease status by physical and lab examinations at
each visit, by CT or MRI at baseline, every 12 weeks thereafter.
Upon IRC-confirmed DP, subjects randomized to Arm B will be offered the opportunity to receive open-label idelalisib 150 mg BID as
monotherapy. Clinic/lab visits will occur every 2 weeks through Week 12; every 4 weeks for Weeks 16 through 24; every 12 weeks thereafter. Subjects
will be assessed for iNHL disease status by physical and lab examinations at each visit, by CT or MRI every 12 weeks for the first 48
week, every 24 weeks thereafter. |
|
| 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 | No |
| E.6.11 | Pharmacogenomic | No |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 64 |
| 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 |
| Bulgaria |
| France |
| Germany |
| Italy |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Spain |
| Sweden |
| 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
|
| The final efficacy analysis will be conducted after approximately 246 events (definitive iNHL progression or death). It is expected that this number of events will occur after a minimum of 18 months of follow-up. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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