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

Sponsor

Gilead Sciences (Industry)

Overall Status

Withdrawn

CT.gov ID

NCT03349346

Collaborator

(none)

Enrollment

Locations

Arms

80.1

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

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)

Condition or Disease	Intervention/Treatment	Phase
Diffuse Large B-Cell Lymphoma Mediastinal B-cell Lymphoma	Drug: Idelalisib Drug: Rituximab Drug: Ifosfamide Drug: Carboplatin Drug: Etoposide	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Anticipated Study Start Date :

Jun 1, 2019

Anticipated Primary Completion Date :

Feb 1, 2021

Anticipated Study Completion Date :

Feb 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1- Participants 12 to less than 18 years of age 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.	Drug: Idelalisib Tablet (s) or dispersible tablets for suspension administered orally twice daily Other Names: Zydelig® Drug: Rituximab 375 mg/m^2 administered intravenously Drug: Ifosfamide 3 mg/m^2 administered intravenously Drug: Carboplatin 635 mg/m^2 administered intravenously Drug: Etoposide 100 mg/m^2 administered intravenously
Experimental: Cohort 2- Participants 1 to less than 12 years of age 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.	Drug: Idelalisib Tablet (s) or dispersible tablets for suspension administered orally twice daily Other Names: Zydelig® Drug: Rituximab 375 mg/m^2 administered intravenously Drug: Ifosfamide 3 mg/m^2 administered intravenously Drug: Carboplatin 635 mg/m^2 administered intravenously Drug: Etoposide 100 mg/m^2 administered intravenously

Arm

Intervention/Treatment

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

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.

Drug: Idelalisib

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

Other Names:

Zydelig®

Drug: Rituximab

375 mg/m^2 administered intravenously

Drug: Ifosfamide

3 mg/m^2 administered intravenously

Drug: Carboplatin

635 mg/m^2 administered intravenously

Drug: Etoposide

100 mg/m^2 administered intravenously

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

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.

Drug: Idelalisib

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

Other Names:

Zydelig®

Drug: Rituximab

375 mg/m^2 administered intravenously

Drug: Ifosfamide

3 mg/m^2 administered intravenously

Drug: Carboplatin

635 mg/m^2 administered intravenously

Drug: Etoposide

100 mg/m^2 administered intravenously

Outcome Measures

Primary Outcome Measures

Incidence Rate of Dose Limiting Toxicities (DLTs) [Up to Day 21]
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) [Up to 12 months]
Proportion of Participants Experiencing Serious Adverse Events (SAEs) [Up to 12 months]
Proportion of Participants Experiencing Adverse Events (AEs) Leading to Idelalisib Interruption, Idelalisib Dose Reduction, Premature Discontinuation of Idelalisib, or Death [Up to 12 months]

Secondary Outcome Measures

Rate of Grade ≥ 3 Transaminase Elevations Based on Laboratory Findings [Up to 12 months]
Overall Response Rate (ORR) [Up to 12 months]
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) [Up to 5 years]
Overall Survival (OS) is defined as the interval from the first dose date of idelalisib to death from any cause.
Progression-Free Survival (PFS) [Up to 12 months]
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 [Predose and up to 24 hours postdose on Day 1 and Cycle 1, Day 5 of idelalisib + RICE combination therapy]
Cmax is defined as the maximum observed concentration of drug.
Pharmacokinetic Parameter: Cmax of GS-563117 [Predose and up to 24 hours postdose on Day 1 and Cycle 1, Day 5 of idelalisib + RICE combination therapy]
GS-563117 is the metabolite of idelalisib. Cmax is defined as the maximum observed concentration of drug.
Pharmacokinetic Parameter: Ctrough of Idelalisib [Predose and up to 24 hours postdose on Day 1 and Cycle 1, Day 5 of idelalisib + RICE combination therapy]
Ctrough is defined as the plasma concentration at the end of the dosing interval.
Pharmacokinetic Parameter: Ctrough of GS-563117 [Predose and up to 24 hours postdose on Day 1 and Cycle 1, Day 5 of idelalisib + RICE combination therapy]
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 [Predose and up to 24 hours postdose on Day 1 and Cycle 1, Day 5 of idelalisib + RICE combination therapy]
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 [Predose and up to 24 hours postdose on Day 1 and Cycle 1, Day 5 of idelalisib + RICE combination therapy]
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 [Baseline and Day 21]
Acceptability and Palatability of Idelalisib 10-mg Dispersible Tablet [Day 1 of idelalisib monotherapy and at Day 1, Cycle 1 of idelalisib in combination with RICE chemoimmunotherapy]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Year to 18 Years

Sexes Eligible for Study:

All

Accepts 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.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Centre Hospitalier Régional Universitaire de Lille	Lille	France	59000
2	Istituto Giannina Gaslini	Genova	Italy	16147
3	Ospedale Pediatrico Bambino Gesu	Roma	Italy	00165
4	Infantile Regina Margherita Hospital	Torino	Italy	10126
5	Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wroclawiu	Wrocław	Poland	50-556
6	Hospital Vall d´Hebrón	Barcelona	Spain	08035
7	Hospital Universitario HM Monteprincipe	Madrid	Spain	28660