Talazoparib Plus Irinotecan With or Without Temozolomide in Children With Refractory or Recurrent Solid Malignancies
Condition: Childhood Solid Tumors
MeSH terms: Neoplasms
Study type: Interventional
Phase: Phase 1

Summary: 
      The drug, talazoparib, seems to work against cancer in test tubes and animals by preventing
      DNA repair in damaged cells leading to their death. Investigators do not know if talazoparib
      combined with irinotecan will work in humans. Talazoparib has been used in only a small
      number of adults and children, and there is much not yet known about it.

      In Arm A of this study, investigators seek to find the safest dose of irinotecan to give with
      talazoparib to children and young adults. In a phase I study, different dose levels of drug
      may be tested. The first 2 or 3 patients will be given a dose, and if none of them has a bad
      side-effect, the next 2 or 3 patients will be given a higher dose. No temozolomide will be
      given in in Arm A.

      The experimental drug combination of talazoparib and irinotecan will be tested in the hopes
      of finding a treatment that may be effective against recurrent or refractory solid tumors.
      The goals of study Arm A are:

        -  To determine whether the combination of talazoparib and irinotecan is a beneficial
           treatment for your cancer;

        -  To learn what kind of side effects talazoparib can cause;

        -  To learn what kind of side effects talazoparib in combination with irinotecan can cause;

        -  To learn more about the biology of talazoparib in children diagnosed with solid tumors.

      The purpose of Arm B is to to find the safest doses of irinotecan and temozolomide to give
      with talazoparib to children and young adults with a solid malignancy.. Talazoparib belongs
      to a family of drugs called "poly ADP ribose polymerase or PARP inhibitors." Irinotecan and
      temozolomide belong to a family of drugs called "DNA damaging agents."

      There are two arms of this trial, A and B. In this study, investigators hope that irinotecan
      (administered in Arm A) and irinotecan plus temozolomide (administered in Arm B) will damage
      the DNA of the cancer cells. Then, talazoparib (which is a PARP inhibitor) will block the
      repair of the cancer cell's damaged DNA, causing the cancer cell to die (a process called
      "apoptosis").

      There are different types of cancers found in children and young adults which appear to be
      vulnerable to the combination of chemotherapy agents that will be given in this study. Work
      carried out in the lab show that these agents may be very promising in the treatment of ewing
      sarcoma, germ cell tumors, wilms tumor, medulloblastoma and possibly neuroblastoma.
    

Detailed description: 
      In Arm A of this study, talazoparib will be administered orally on day 1 either once or twice
      per day depending on the dose level of the enrolled participant. Both oral talazoparib and
      intravenous (IV) irinotecan will then be administered daily, on days 2-6. Each cycle will
      last 21 days.

      Once the maximum tolerated doses (MTDs) for talazoparib and irinotecan are determined, a
      second arm of the study (Arm B) will open administering talazoparib, irinotecan and
      temozolomide. Talazoparib will be given orally, on days 1-6. Intravenous irinotecan and oral
      temozolomide will be given on days 2-6. The study will estimate the maximum tolerated doses,
      describe the toxicities of therapy, estimate the response rate and characterize the
      pharmacokinetics of the combined talazoparib plus irinotecan with or without temozolomide.

      This study is a traditional dose escalation study using a standard 3+3 phase I design. In Arm
      A, six or more dose levels will be evaluated for the combination of talazoparib and
      irinotecan. Once the MTDs of Arm A are determined, Arm B will open and evaluate the
      combination of talazoparib, irinotecan and temozolomide.

      PRIMARY OBJECTIVES - ARM A

        -  To estimate the maximum tolerated doses (MTDs) of talazoparib (daily, days 1-6) combined
           with irinotecan (daily, days 2-6) given every 21 days in children with refractory or
           recurrent solid malignancies.

        -  To identify and describe the dose limiting toxicities of talazoparib and irinotecan
           administered in combination to patients with refractory or recurrent solid malignancies.

      PRIMARY OBJECTIVES - ARM B

        -  To estimate the maximum tolerated dose (MTD) of temozolomide (given daily, days 2-6)
           when combined with talazoparib (daily, days 1-6) and irinotecan (daily, days 2-6) given
           every 21 days in children with refractory or recurrent solid malignancies.

        -  To identify and describe the dose limiting toxicities of temozolomide, talazoparib and
           irinotecan administered in combination to patients with refractory or recurrent solid
           malignancies.

      SECONDARY OBJECTIVES

        -  To estimate the response rate, within the confines of a phase I study, to talazoparib
           plus irinotecan and talazoparib plus irinotecan and temozolomide administered in
           combination in pediatric patients with refractory or recurrent solid malignancies.

        -  To characterize the pharmacokinetics of talazoparib plus irinotecan and talazoparib plus
           irinotecan and temozolomide when given in combination to children with refractory or
           recurrent solid malignancies.
    

Intervention name(s): Talazoparib; Irinotecan; Temozolomide; Filgrastim; Peg-filgrastim
Intervention type(s): Drug; Drug; Drug; Drug; Drug
Intervention description(s): Given orally once or twice on day 1 (depending on the dose level), then daily on days 2-6.; Given intravenously daily, days 2-6 immediately following the talazoparib dose.; Given orally daily. Dose to be determined after MTD established with talazoparib plus irinotecan.; Given subcutaneously (SubQ) once per day starting 24-36 hours after last dose of chemotherapy and continuing until post-nadir ANC is >2,000/μL, unless peg-filgrastim is given.; Given subcutaneously (SubQ) once per day starting 24-36 hours after last dose of chemotherapy and continuing until post-nadir ANC is >2,000/μL, unless filgrastim is given.
Other intervention name(s): BMN 673; Camptosar®; Temodar; G-CSF; Neupogen®; Pegylated filgrastim; Neulasta®
Intervention MeSH terms: Irinotecan; Temozolomide; Talazoparib; Lenograstim
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment