| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 10036714 |
| E.1.2 | Term | Primary mediastinal large B-cell lymphoma refractory |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 | 10012822 |
| E.1.2 | Term | Diffuse large B-cell lymphoma refractory |
| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- Evaluate safety, tolerability, and pharmacokinetics (PK) of idelalisib during an initial 3-week course of idelalisib monotherapy in pediatric subjects 1 to less than 18 years of age with relapsed or refractory DLBCL or MBCL
- Establish the safety, tolerability, and preliminary efficacy (complete response (CR)/partial response (PR) utilizing the International Pediatric Non-Hodgkin Lymphoma Response Criteria of idelalisib monotherapy and idelalisib in combination with RICE (rituximab, ifosfamide, carboplatin and etoposide) chemoimmunotherapy
- Establish recommended Phase 2 doses of idelalisib in combination with RICE |
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| E.2.2 | Secondary objectives of the trial |
- Evaluate the PK of idelalisib during combination therapy
- Perform exploratory biomarker analyses during idelalisib monotherapy
- Evaluate palatability and acceptability of idelalisib 10-mg dispersible tablets in pediatric subjects |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Male or female subjects 1 to less than 18 years of age
2) Histologically confirmed diagnosis of DLBCL, or MBCL established by the World Health Organization 2008 classification of tumors of hematopoietic and lymphoid tissues
3) Relapsed or refractory DLBCL or MBCL
a) Refractory disease is defined as a < 50% decrease in lesion size with first-line therapy.
b) Relapsed reflects progressive disease or the appearance of new lesions after attainment of complete or partial remission.
c) Subjects who fail first line therapy may be categorized into 3 distinct groups: those who relapsed after complete remission, partial response with persistent disease and refractory.
4) Measurable or evaluable disease based on imaging, bone marrow examination.
5) Karnofsky ≥ 60% for patients > 16 years of age or Lansky ≥ 60 for patients ≤ 16 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
6) A negative serum pregnancy test is required for female subjects of child bearing potential.
7) Male subjects and female subjects of child bearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception as described in Appendix 5 of the protocol.
8) Lactating females must agree to discontinue nursing before idelalisib is administered
9) Adequate bone marrow function defined as:
a) For subjects without bone marrow involvement:
o Peripheral absolute neutrophil count (ANC) ≥ 1,000/μL, in the absence of growth factors
o Platelet count ≥ 100,000/μL (transfusion independent)
o Hemoglobin ≥ 8.0 gm/dL (RBC transfusion independent)
b) For subjects with bone marrow involvement (requires BM documentation):
o Platelet count ≥ 20,000/μL (may receive platelet transfusions or thrombopoietic growth factors)
o Hemoglobin ≥ 8.0 gm/dL (may receive RBC transfusions or erythropoietic growth factors)
10) Adequate renal function defined as: Estimated creatinine clearance (CrCL) ≥ 70 mL/min/1.73m2 (using the Schwartz formula; =k x L/sCr) ([k is proportionality constant: for children 1-12 years old or adolescent females ≥ 12 years old, k=0.55, and for adolescent males ≥ 12 years old, k=0.70]; L is height in centimeters [cm]; and sCr is serum creatinine [mg/dL])
11) Parent/legal guardian must provide written informed consent prior to screening evaluations.
Subject will provide assent/consent if applicable. |
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| E.4 | Principal exclusion criteria |
1) Prior PI3K inhibitor therapy
2) Prior ICE therapy, with or without an anti-CD20 antibody, or history of hypersensitivity to any components of RICE
3) Disease progression within 6 months from last anti-CD20 therapy
4) Ongoing toxicity from prior cytotoxic therapy (last dose at least 3 weeks prior to study entry)
5) Less than 4 half-lives from the last dose of previous targeted therapy and ongoing acute toxicity of prior targeted therapy
6) Known active central nervous system or leptomeningeal lymphoma or within 4 weeks from the last intrathecal therapy prior to the required diagnostic LP for this study
7) Active infection with HIV, HBV, HCV or CMV based on screening serology and PCR results
8) Evidence of uncontrolled systemic bacterial, fungal, or viral infection at the time of treatment start (Day 1)
9) Ongoing or history of drug-induced pneumonitis
10) Ongoing or history of inflammatory bowel disease
11) Pregnancy or breastfeeding
12) Currently receiving other anti-cancer agents or other investigational drug
13) Prior solid organ transplantation
14) Prior allogeneic stem cell transplantation within 60 days or active acute graft versus host disease (GVHD) grade 3 or higher (see Appendix 6 for GVHD grading)
15) Known hypersensitivity to idelalisib, the metabolites, or formulation excipients
16) Urinary outflow obstruction or inflammation of the urinary bladder (cystitis)
17) Any other clinical condition or prior therapy that, in the opinion of the Investigator, would make the subject unsuitable for the study or unable to comply with the study requirements |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
- Incidence rate of Dose Limiting Toxicities (DLTs)
- Overall safety profile of idelalisib as measured by the incidence of AEs, serious AEs (SAEs), AEs leading to idelalisib interruption, idelalisib dose reduction, premature discontinuation of idelalisib, or death |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Subjects will be seen in the clinic at least once per week during Weeks 1 through 4. Subsequent visits will occur at least every 3 weeks through EOS. Subjects will be assessed for safety at each visit. Subjects will be assessed for disease status by continuous utilization of a single modality including CT or MRI at screening, at Day 21 (or earlier if there is evidence of clinical progression), and up to 1 week prior to Day 1 of Cycles 3, 5, 8, 11, and 14 to evaluate response to study treatment. EOS imaging will be done only if imaging was not performed within 9 weeks of the EOS visit. Subjects with bone marrow involvement at baseline will require marrow evaluation at each response assessment time point. |
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| E.5.2 | Secondary end point(s) |
- Rate of Grade ≥ 3 transaminase elevations based on laboratory findings
- Overall response rate (ORR) – defined as the proportion of subjects who achieve a best response of Complete Response (CR) or Partial Response (PR) after the first dose of idelalisib (either as a result of monotherapy or in combination with RICE chemoimmunotherapy). The screening imaging study will serve as the reference for ORR.
- Overall Survival (OS) – defined as the interval from the first dose date of idelalisib to death from any cause.
- Progression-Free Survival (PFS) – defined as the interval from the start date of RICE to the earlier of the first documentation of disease progression or death from any cause. CT/MRI scan at the conclusion of idelalisib monotherapy will serve as the reference for progression.
- Pharmacokinetic parameters (Cmax, Ctrough and AUC) for idelalisib and metabolite GS-563117
- Optional exploratory biomarkers (eg pAKT, pS6 ribosomal protein) on bone marrow samples at baseline and Day 21, for subjects with marrow involvement at baseline
- Acceptability and palatability of idelalisib 10-mg dispersible tablet at Day 1 of idelalisib monotherapy and at Day 1, Cycle 1 of idelalisib in combination with RICE chemoimmunotherapy |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Subjects will be seen in the clinic at least once per week during Weeks 1 through 4. Subsequent visits will occur at least every 3 weeks through EOS. Subjects will be assessed for safety at each visit. Subjects will be assessed for disease status by continuous utilization of a single modality including CT or MRI at screening, at Day 21 (or earlier if there is evidence of clinical progression), and up to 1 week prior to Day 1 of Cycles 3, 5, 8, 11, and 14 to evaluate response to study treatment. EOS imaging will be done only if imaging was not performed within 9 weeks of the EOS visit. Subjects with bone marrow involvement at baseline will require marrow evaluation at each response assessment time point. |
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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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Paediatric study to investigate safety in children |
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| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| 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 | No |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 48 |
| 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 |
| Czech Republic |
| France |
| Italy |
| Poland |
| Spain |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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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| For each subject, end-of-study assessments will be completed once it has been determined that the subject will discontinue all study assessments. Survival follow-up will be conducted annually for a period of 5 years. The end of the study is defined when the last subject reaches the last scheduled follow-up time point, is lost to follow-up, withdraws from the study, dies or the time at which the sponsor closes the study. |
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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 | 6 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
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