Study of Onivyde With Talazoparib or Temozolomide in Children With Recurrent Solid Tumours and Ewing Sarcoma

Titre officiel

A Randomized Phase I/II Study of Talazoparib or Temozolomide in Combination With Onivyde in Children With Recurrent Solid Malignancies and Ewing Sarcoma

Sommaire:

La partie phase I de cette étude est destinée aux enfants ou adolescents et aux jeunes adultes (AJA) chez lesquels on a diagnostiqué une tumeur solide qui a récidivé (retour après traitement) ou qui est réfractaire (n’a jamais disparu complètement). L’essai testera 2 combinaisons de traitements; les participants seront répartis de façon aléatoire dans le groupe A ou B. L’objectif de l’étude de phase I est de déterminer quelles sont les doses les plus élevées tolérables des combinaisons thérapeutiques administrées dans chaque groupe. Dans le groupe A, les enfants et les jeunes adultes atteints d’une tumeur solide récurrente ou réfractaire recevront deux médicaments, dénommés Onivyde et Talazoparib. Onivyde agit en endommageant l’ADN de la cellule cancéreuse, alors que Talazoparib agit en bloquant la réparation de l’ADN une fois que la cellule cancéreuse est endommagée. En endommageant l’ADN de la tumeur et en bloquant sa réparation, les cellules cancéreuses pourraient mourir. Dans le groupe B, les enfants et les jeunes adultes atteints d’une tumeur solide récurrente ou réfractaire recevront deux médicaments, dénommés Onivyde et Temozolomide. Ces deux médicaments agissent en endommageant l’ADN des cellules cancéreuses, ce qui peut entraîner la mort des tumeurs. Une fois que les doses les plus élevées sont atteintes dans chaque groupe, A et B, on ouvrira les « groupes élargis ». Un groupe élargi traite un plus grand nombre d’enfants et de jeunes adultes atteints d’une tumeur solide récurrente ou réfractaire aux doses les plus élevées atteintes dans l’étude de phase 1. L’objectif des groupes élargis est de vérifier si les tumeurs disparaissent chez les enfants et les jeunes adultes atteints d’une tumeur solide récurrente ou réfractaire. Il y aura trois « groupes élargis ». Dans le groupe A1, les enfants et les jeunes adultes atteints d’une tumeur solide récurrente ou réfractaire (à l’exception du sarcome d’Ewing) recevront Onivyde et Talazoparib. Dans le groupe A2, les enfants et les jeunes adultes atteints d’une tumeur solide récurrente ou réfractaire qui a un problème de réparation de l’ADN (identifié par leur médecin), recevront Onivyde et Talazoparib. Dans le groupe B1, les enfants et les adolescents atteints d’une tumeur solide récurrente ou réfractaire (à l’exception du sarcome d’Ewing) recevront Onivyde et Témozolomide. Une fois que les doses les plus élevées de médicaments utilisées dans les groupes A et B auront été déterminées, une étude de phase II sera entreprise pour les enfants ou les jeunes adultes atteints d’un sarcome d’Ewing qui a récidivé ou qui est réfractaire au traitement reçu après le diagnostic initial. L’essai testera les deux mêmes combinaisons thérapeutiques dans le groupe A et le groupe B. Durant la phase II, un participant atteint de sarcome d’Ewing sera assigné de façon aléatoire pour recevoir le traitement donné dans le groupe A ou B.

Description de l'essai

Primary Outcome:

  • Phase I:To determine the recommended phase 2 doses (RP2Ds) of Onivyde combined with talazoparib (Arm A) and Onivyde combined with temozolomide (Arm B) administered to children, adolescents and young adults with refractory or recurrent solid malignancies.
  • Phase II:To estimate the progression-free survival (PFS) of Onivyde plus talazoparib and Onivyde plus temozolomide in patients with refractory or recurrent Ewing sarcoma.
Secondary Outcome:
  • Phase I:To characterize the safety profile of the treatment regimens, Onivyde plus talazoparib (Arm A) and Onivyde plus temozolomide (Arm B)
  • To characterize the plasma pharmacokinetics of Onivyde plus talazoparib (Arm A) and Onivyde plus temozolomide (Arm B)
  • To characterize the plasma pharmacokinetics of Onivyde plus talazoparib (Arm A) and Onivyde plus temozolomide (Arm B)
  • To characterize the plasma pharmacokinetics of Onivyde plus talazoparib (Arm A) and Onivyde plus temozolomide (Arm B)
  • To characterize the plasma pharmacokinetics of Onivyde plus talazoparib (Arm A) and Onivyde plus temozolomide (Arm B)
  • To characterize the plasma pharmacokinetics of Onivyde plus talazoparib (Arm A) and Onivyde plus temozolomide (Arm B)
  • To characterize the plasma pharmacokinetics of Onivyde plus talazoparib (Arm A) and Onivyde plus temozolomide (Arm B)
  • To characterize the plasma pharmacokinetics of Onivyde plus talazoparib (Arm A) and Onivyde plus temozolomide (Arm B)
  • To characterize the plasma pharmacokinetics of Onivyde plus talazoparib (Arm A) and Onivyde plus temozolomide (Arm B)
  • To estimate the antitumour activity of Onivyde plus talazoparib (Arm A) and Onivyde plus temozolomide (Arm B)
  • To estimate the antitumour activity of Onivyde plus talazoparib (Arm A) and Onivyde plus temozolomide (Arm B)
  • To estimate the antitumour activity of Onivyde plus talazoparib (Arm A) and Onivyde plus temozolomide (Arm B)
  • To estimate the antitumour activity of Onivyde plus talazoparib (Arm A) and Onivyde plus temozolomide (Arm B)
  • To estimate the antitumour activity of Onivyde plus talazoparib (Arm A) and Onivyde plus temozolomide (Arm B)
  • Phase II: To describe the toxicity of the treatment regimens.
  • To describe the antitumour activity of Onivyde plus talazoparib (Arm A) and Onivyde plus temozolomide (Arm B)
  • To describe the antitumour activity of Onivyde plus talazoparib (Arm A) and Onivyde plus temozolomide (Arm B)
  • To describe the antitumour activity of Onivyde plus talazoparib (Arm A) and Onivyde plus temozolomide (Arm B)
  • To describe the antitumour activity of Onivyde plus talazoparib (Arm A) and Onivyde plus temozolomide (Arm B)
  • To describe the antitumour activity of Onivyde plus talazoparib (Arm A) and Onivyde plus temozolomide (Arm B)
  • To characterize the plasma pharmacokinetics Onivyde and talazoparib in children, adolescents and young adults with refractory or recurrent Ewing sarcoma.
  • To characterize the plasma pharmacokinetics Onivyde and talazoparib in children, adolescents and young adults with refractory or recurrent Ewing sarcoma.
  • To characterize the plasma pharmacokinetics Onivyde and talazoparib in children, adolescents and young adults with refractory or recurrent Ewing sarcoma.
  • To characterize the plasma pharmacokinetics Onivyde and talazoparib in children, adolescents and young adults with refractory or recurrent Ewing sarcoma.
  • To characterize the plasma pharmacokinetics Onivyde and talazoparib in children, adolescents and young adults with refractory or recurrent Ewing sarcoma.
  • To characterize the plasma pharmacokinetics Onivyde and talazoparib in children, adolescents and young adults with refractory or recurrent Ewing sarcoma
  • To characterize the plasma pharmacokinetics Onivyde and talazoparib in children, adolescents and young adults with refractory or recurrent Ewing sarcoma.
  • To characterize the plasma pharmacokinetics Onivyde and talazoparib in children, adolescents and young adults with refractory or recurrent Ewing sarcoma.
ONITT (ONIvyde, Talazoparib, Temozolomide) is a phase I/II study which will evaluate two treatment regimens; nanoliposomal irinotecan (nal-IRN, Onivyde) plus talazoparib (TAL) and Onivyde (ONI) plus temozolomide (TMZ) for the treatment of recurrent or refractory (RR) Ewing sarcoma. A dose finding phase I study will be open to patients with recurrent or refractory solid tumours. Patients will be assigned to receive either ONI plus TAL (Arm A) or ONI plus TMZ (Arm B). Once the recommended phase II doses (RP2D) of Arm A and Arm B are determined, expansion cohorts (A1, B1) will open at the RP2Ds for enrollment of non-Ewing sarcoma solid tumour patients. There will be an additional Arm A expansion cohort (A2) for patients with homologous recombination repair defects. Concurrently, the phase II study will open to patients with RR Ewing sarcoma. In the phase II study, patients with RR Ewing sarcoma will be randomized to receive either ONI plus TAL or ONI plus TMZ. The primary endpoint will be progression-free survival (PFS). PFS of both treatment arms in the phase II study will be compared to one another by using a two-arm non-inferiority design when superiority is expected. Phase I Primary Objective To determine the recommended phase 2 doses (RP2Ds) of Onivyde combined with talazoparib (Arm A) and Onivyde combined with temozolomide (Arm B) administered to children, adolescents and young adults with refractory or recurrent solid malignancies. Phase I Secondary Objectives
  • To characterize the safety profile of the drug regimens, Onivyde plus talazoparib (Arm A) and Onivyde plus temozolomide (Arm B).
  • To characterize the plasma pharmacokinetics (PK) of Onivyde and talazoparib in children, adolescents and young adults with refractory or recurrent solid malignancies.
  • To estimate the antitumour activity of Onivyde plus talazoparib and Onivyde plus temozolomide. Phase I Exploratory Objectives
  • To describe the relationship between UGT1A1 genotype status with toxicity and response.
  • To describe the molecular profile of germline and tumours, including evaluation of mutations in homologous recombination genes and their possible association to therapy response in patients with recurrent or refractory solid tumours.
  • To measure ctDNA at different time points and evaluate its relationship with response to therapy.
  • To describe the safety profile of the combination Onivyde plus talazoparib and Onivyde plus temozolomide at the determined RP2D in children, adolescents and young adults treated in the expansion cohorts.
  • To describe the palatability and ease of administration of talazoparib liquid suspension in children who are unable to swallow the capsules. Phase II Primary Objectives • To compare the progression-free survival (PFS) of Onivyde plus talazoparib and Onivyde plus temozolomide in patients with refractory or recurrent Ewing sarcoma. Phase II Secondary Objectives
  • To describe the toxicity of the treatment regimens.
  • To describe the objective response rate (ORR), disease control rate (DCR) after cycle 4, duration of response (DoR), event free survival (EFS) and overall survival (OS) for patients receiving Onivyde plus talazoparib and Onivyde plus temozolomide.
  • To characterize the plasma pharmacokinetics of Onivyde and talazoparib in children, adolescents and young adults with refractory or recurrent Ewing sarcoma. Phase II Exploratory Objectives
  • To describe the relationship between UGT1A1 genotype status with toxicity and response.
  • To describe the molecular profile of germline and tumours, including evaluation of mutations in homologous recombination genes and their possible association to chemotherapy response in patients with recurrent or refractory Ewing sarcoma.
  • To describe ctDNA at different time points and the relationship with response to therapy.
  • To describe the palatability and ease of administration of talazoparib liquid suspension in children who are unable to swallow the capsules. Phase I The phase I portion of the study will include 2 separate treatment arms, Arms A and B. Arm A will evaluate Onivyde plus talazoparib (ONI + TAL). Arm B will evaluate Onivyde plus temozolomide (ONI + TMZ). Both phase I studies will be open to patients with recurrent or refractory solid tumours who meet eligibility criteria. In Arm A, patients will receive intravenous Onivyde on Days 1 and 8. They will receive oral talazoparib twice on Day 1 and then daily on Days 2-6. In Arm B, patients will receive intravenous Onivyde on Days 1 and 8. They will receive oral temozolomide daily on Days 1-5. Pharmacokinetic testing will take place during Cycle 1. Therapy may continue for up to 24 months. Tumour assessments will be performed at baseline and repeated after cycles 2, 4, 6 and then every 4 cycles thereafter to assess disease status. If at any designated disease evaluation time point a patient develops a response that is better than the prior response (i.e. SD at Cycle 2 evaluation, then PR at Cycle 4 evaluation), an interim disease evaluation is recommended after 28 days to confirm response. Therapy will be discontinued if there is evidence of disease progression or drug-related dose limiting toxicities requiring removal from treatment. Safety and tolerability will be monitored continuously throughout study participation. Phase II Following the completion of the phase I dose finding studies, patients with recurrent or refractory Ewing sarcoma that meet eligibility criteria will be eligible for randomization into the phase II study. Arm A will evaluate Onivyde plus talazoparib (ONI + TAL). Arm B will evaluate Onivyde plus temozolomide (ONI + TMZ). In Arm A, patients will receive intravenous Onivyde on Days 1 and 8. They will receive oral talazoparib twice on Day 1 and then daily on Days 2-6. In Arm B, patients will receive intravenous Onivyde on Days 1 and 8. They will receive oral temozolomide daily on Days 1-5. Pharmacokinetic testing will take place during Cycle 1. Therapy may continue for up to 24 months. Tumour assessments will be performed at baseline and repeated after Cycles 2, 4, 6 and then every 4 cycles thereafter to assess disease status. If at any designated disease evaluation time point a patient develops a response that is better than the prior response (i.e. SD at Cycle 2 evaluation, then PR at Cycle 4 evaluation), an interim disease evaluation is recommended after 28 days to confirm response. Therapy will be discontinued if there is evidence of disease progression and/or any other condition(s) occur that do not allow treatment continuation or similar toxicities requiring removal from the trial. Safety and tolerability will be monitored continuously throughout study participation. Sample size: In the dose escalation phase I study, approximately 18 patients per arm will be enrolled for a total of 36 patients. The dose expansion phase I study will include 3 treatment cohorts. Arm A will have 2 dose expansion cohorts including 1) a non-ES solid tumour cohort (A1) and 2) a DNA repair defects/mutations cohort (A2). Arm B will have 1 dose expansion cohort including non-ES solid tumours (B1). Approximately 12 patients will enroll per expansion treatment cohort for a total of 36 patients. In the phase II study, 44 patients will be enrolled on each arm for a total of 88 patients.

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