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Idelalisib With Rituximab, Ifosfamide, Carboplatin, Etoposide (RICE) in Children and Adolescents

Primary Purpose

Diffuse Large B-Cell Lymphoma, Mediastinal B-cell Lymphoma

Status

Withdrawn

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

Idelalisib

Rituximab

Ifosfamide

Carboplatin

Etoposide

About this trial

This is an interventional treatment trial for Diffuse Large B-Cell Lymphoma

Eligibility Criteria

1 Year - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Key Inclusion Criteria:

Histologically confirmed diagnosis of DLBCL or MBCL established by the World Health Organization (WHO) 2008 classification of tumors of hematopoietic and lymphoid tissues
Relapsed or refractory disease
Measurable or evaluable disease based on imaging or bone marrow examination
Karnofsky ≥ 60% for participants > 16 years of age or Lansky ≥ 60 for participants ≤ 16 years of age. Participants 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.
A negative serum pregnancy test is required for females of child bearing potential.
Participants of child bearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception .
Lactating females must agree to discontinue nursing before idelalisib is administered
Adequate bone marrow function as defined in the protocol
Adequate renal function as defined in the protocol

Key Exclusion Criteria:

Prior ifosfamide, carboplatin, etoposide (ICE) therapy, with or without an anti-CD20 antibody, or history of hypersensitivity to any components of RICE
Known active central nervous system or leptomeningeal lymphoma or within 4 weeks from the last intrathecal therapy prior to the required diagnostic lumbar puncture (LP) for this study
Disease progression within 6 months from last anti-CD20 therapy
Ongoing toxicity from prior cytotoxic therapy (last dose at least 3 weeks prior to study entry)
Less than 4 half-lives from the last dose of previous targeted therapy and ongoing acute toxicity of prior targeted therapy
Active infection with human immunodeficiency virus (HIV), cytomegalovirus (CMV), hepatitis B virus (HBV), or hepatitis C virus (HCV) based on screening serology and polymerase chain reaction (PCR) results
Evidence of systemic bacterial, fungal, or viral infection at the time of treatment start (Day 1)
Ongoing or history of drug-induced pneumonitis
Ongoing or history of inflammatory bowel disease
Pregnancy or breastfeeding
Currently receiving other anti-cancer or other investigational drug
Prior solid organ transplantation
Prior allogeneic stem cell transplantation within 60 days or active acute graft versus host disease (GVHD) Grade 3 or higher
Known hypersensitivity to idelalisib, the metabolites, or formulation excipients
Any other clinical condition or prior therapy that, in the opinion of the Investigator, would make the participant unsuitable for the study or unable to comply with the study requirements

NOTE: Other protocol defined Inclusion/ Exclusion criteria may apply.

Sites / Locations

Centre Hospitalier Régional Universitaire de Lille
Istituto Giannina Gaslini
Ospedale Pediatrico Bambino Gesu
Infantile Regina Margherita Hospital
Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wroclawiu
Hospital Vall d´Hebrón
Hospital Universitario HM Monteprincipe

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Cohort 1- Participants 12 to less than 18 years of age

Cohort 2- Participants 1 to less than 12 years of age

Arm Description

Participants will receive idelalisib monotherapy (from day 1 to day 21), followed by combination therapy with RICE. Upon enrollment, participants will be assigned to one of the 3 dose levels during idelalisib monotherapy (Dose level 1 = 55 mg/m^2 twice daily (BID), Dose level 2 = 85 mg/m^2 BID, Dose level 3 = 125 mg/m^2 BID) administered as 50 mg, 100 mg or 150 mg tablets as appropriate, or as 10 mg dispersible tablets for oral suspension for participants who cannot swallow tablets. Day 1: single dose of idelalisib Day 2 up to Day 21: initiate and continue idelalisib BID dosing Day 22 for up to 12 months: idelalisib twice per day in combination with RICE. Cycles of RICE will be administered over 5 days every 3 weeks (Day 1: rituximab; Day 3: rituximab, ifosfamide, carboplatin, etoposide; Days 4 and 5: ifosfamide, etoposide) starting day 22 (or earlier if there is evidence of clinical progression while on idelalisib monotherapy) for up to 12 months.

Participants will receive one of the 3 doses of idelalisib monotherapy (from day 1 to day 21) followed by combination therapy with RICE. Idelalisib will be administered as as 50 mg, 100 mg or 150 mg tablets as appropriate, or as 10 mg dispersible tablets for oral suspension for participants who cannot swallow tablets. Participants will will be enrolled at dose level 1 once tolerability is demonstrated in the older cohort (Cohort 1). Thereafter, both age cohorts will be dose escalated independently. Day 1: single dose of idelalisib Day 2 up to Day 21: initiate and continue idelalisib BID Day 22 for up to 12 months: idelalisib twice per day in combination with RICE. Cycles of RICE will be administered over 5 days every 3 weeks (Day 1: rituximab; Day 3: rituximab, ifosfamide, carboplatin, etoposide; Days 4 and 5: ifosfamide, etoposide) starting day 22 (or earlier if there is evidence of clinical progression while on idelalisib monotherapy) for up to 12 months.

Outcomes

Primary Outcome Measures

Incidence Rate of Dose Limiting Toxicities (DLTs)

DLTs refer to toxicities experienced during the first 21 days of study treatment that have been judged to be clinically significant and related to study treatment.

Proportion of Participants Experiencing Adverse Events (AEs)

Proportion of Participants Experiencing Serious Adverse Events (SAEs)

Proportion of Participants Experiencing Adverse Events (AEs) Leading to Idelalisib Interruption, Idelalisib Dose Reduction, Premature Discontinuation of Idelalisib, or Death

Secondary Outcome Measures

Rate of Grade ≥ 3 Transaminase Elevations Based on Laboratory Findings

Overall Response Rate (ORR)

Overall response rate (ORR) is defined as the proportion of participants 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)

Overall Survival (OS) is defined as the interval from the first dose date of idelalisib to death from any cause.

Progression-Free Survival (PFS)

Progression-Free Survival (PFS) is 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. Computed tomography/ magnetic resonance imaging (CT/MRI) scan at the conclusion of idelalisib monotherapy will serve as the reference for progression.

Pharmacokinetic Parameter: Cmax of Idelalisib

Cmax is defined as the maximum observed concentration of drug.

Pharmacokinetic Parameter: Cmax of GS-563117

GS-563117 is the metabolite of idelalisib. Cmax is defined as the maximum observed concentration of drug.

Pharmacokinetic Parameter: Ctrough of Idelalisib

Ctrough is defined as the plasma concentration at the end of the dosing interval.

Pharmacokinetic Parameter: Ctrough of GS-563117

Ctrough is defined as the plasma concentration at the end of the dosing interval.

Pharmacokinetic Parameter: Area Under the Concentration-Time Curve (AUC) of Idelalisib

AUC is defined as the plasma concentration at the end of the dosing interval.

Pharmacokinetic Parameter: Area Under the Concentration-Time Curve (AUC) of GS-563117

AUC is defined as the plasma concentration at the end of the dosing interval.

Levels of Optional Exploratory Biomarkers on Bone Marrow Samples (eg pAKT, pS6 ribosomal protein) and plasma cytokines

Acceptability and Palatability of Idelalisib 10-mg Dispersible Tablet

For participants who cannot swallow a whole tablet, the investigator will ask if the tablet administered as a suspension is palatable and will observe if the participant is able to swallow the dosage form. The acceptability and palatability of idelalisib dispersible tablets administered as an oral suspension (for participants unable to swallow the tablet) will be evaluated by a questionnaire administered to the participant and/or the parent/legal guardian.

Full Information

NCT ID

NCT03349346

First Posted

November 17, 2017

Last Updated

December 7, 2018

Sponsor

Gilead Sciences

1. Study Identification

Unique Protocol Identification Number

NCT03349346

Brief Title

Idelalisib With Rituximab, Ifosfamide, Carboplatin, Etoposide (RICE) in Children and Adolescents

Official Title

Phase 1b Trial Evaluating Idelalisib in Children and Adolescents With Relapsed or Refractory Diffuse Large B-cell Lymphoma or Mediastinal B-cell Lymphoma in Combination With RICE

Study Type

Interventional

2. Study Status

Record Verification Date

December 2018

Overall Recruitment Status

Withdrawn

Why Stopped

The European Medical Agency granted a Paediatric Investigational Product-specific waiver on the grounds that idelalisib is likely to be unsafe in paediatrics

Study Start Date

June 2019 (Anticipated)

Primary Completion Date

February 2021 (Anticipated)

Study Completion Date

February 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Gilead Sciences

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

5. Study Description

Brief Summary

The primary objectives of this study are to evaluate safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of idelalisib; and to establish recommended phase 2 doses (RP2D) of idelalisib in combination with rituximab, ifosfamide, carboplatin, etoposide (RICE) in children and adolescents with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or mediastinal B-cell lymphoma (MBCL)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Diffuse Large B-Cell Lymphoma, Mediastinal B-cell Lymphoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Cohort 1- Participants 12 to less than 18 years of age

Arm Type

Experimental

Arm Description

Arm Title

Cohort 2- Participants 1 to less than 12 years of age

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Idelalisib

Other Intervention Name(s)

Zydelig®

Intervention Description

Tablet (s) or dispersible tablets for suspension administered orally twice daily

Intervention Type

Drug

Intervention Name(s)

Rituximab

Intervention Description

375 mg/m^2 administered intravenously

Intervention Type

Drug

Intervention Name(s)

Ifosfamide

Intervention Description

3 mg/m^2 administered intravenously

Intervention Type

Drug

Intervention Name(s)

Carboplatin

Intervention Description

635 mg/m^2 administered intravenously

Intervention Type

Drug

Intervention Name(s)

Etoposide

Intervention Description

100 mg/m^2 administered intravenously

Primary Outcome Measure Information:

Title

Incidence Rate of Dose Limiting Toxicities (DLTs)

Description

DLTs refer to toxicities experienced during the first 21 days of study treatment that have been judged to be clinically significant and related to study treatment.

Time Frame

Up to Day 21

Title

Proportion of Participants Experiencing Adverse Events (AEs)

Time Frame

Up to 12 months

Title

Proportion of Participants Experiencing Serious Adverse Events (SAEs)

Time Frame

Up to 12 months

Title

Proportion of Participants Experiencing Adverse Events (AEs) Leading to Idelalisib Interruption, Idelalisib Dose Reduction, Premature Discontinuation of Idelalisib, or Death

Time Frame

Up to 12 months

Secondary Outcome Measure Information:

Title

Rate of Grade ≥ 3 Transaminase Elevations Based on Laboratory Findings

Time Frame

Up to 12 months

Title

Overall Response Rate (ORR)

Description

Time Frame

Up to 12 months

Title

Overall Survival (OS)

Description

Overall Survival (OS) is defined as the interval from the first dose date of idelalisib to death from any cause.

Time Frame

Up to 5 years

Title

Progression-Free Survival (PFS)

Description

Time Frame

Up to 12 months

Title

Pharmacokinetic Parameter: Cmax of Idelalisib

Description

Cmax is defined as the maximum observed concentration of drug.

Time Frame