Adavosertib and Irinotecan Hydrochloride in Treating Younger Patients With Relapsed or Refractory Solid Tumors
Condition: Central Nervous System Embryonal Tumor With Rhabdoid Features; Central Nervous System Embryonal Tumor, Not Otherwise Specified; Central Nervous System Ganglioneuroblastoma; Embryonal Tumor With Multilayered Rosettes, C19MC-Altered; Pineoblastoma; Primary Central Nervous System Neoplasm; Recurrent Childhood Central Nervous System Embryonal Neoplasm; Recurrent Malignant Solid Neoplasm; Recurrent Medulloblastoma; Recurrent Neuroblastoma; Recurrent Rhabdomyosarcoma; Refractory Malignant Solid Neoplasm; Refractory Medulloblastoma; Refractory Neuroblastoma; Refractory Rhabdomyosarcoma
MeSH terms: Neoplasms; Neuroblastoma; Rhabdomyosarcoma; Medulloblastoma; Nervous System Neoplasms; Central Nervous System Neoplasms; Pinealoma; Neoplasms, Germ Cell and Embryonal; Ganglioneuroblastoma; Recurrence
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      This phase I/II trial studies the side effects and best dose of adavosertib and irinotecan
      hydrochloride in treating younger patients with solid tumors that have come back (relapsed)
      or that have not responded to standard therapy (refractory). Adavosertib and irinotecan
      hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for
      cell growth.
    

Detailed description: 
      PRIMARY OBJECTIVES:

      I. To estimate the maximum tolerated dose (MTD) and/or recommended phase 2 dose of
      adavosertib (AZD1755 [MK-1775]) administered on days 1 through 5 every 21 days, in
      combination with oral irinotecan (irinotecan hydrochloride), to children with recurrent or
      refractory solid tumors.

      II. To define and describe the toxicities of AZD1755 (MK-1775) in combination with oral
      irinotecan administered on this schedule.

      III. To characterize the pharmacokinetics of AZD1755 (MK-1775) in children with refractory
      cancer.

      SECONDARY OBJECTIVES:

      I. To preliminarily define the antitumor activity of AZD1755 (MK-1775) and irinotecan within
      the confines of a Phase 1 study.

      II. To obtain initial phase 2 efficacy data on the anti-tumor activity of AZD1755 (MK-1775)
      in combination with irinotecan administered to children with relapsed or refractory
      neuroblastoma, in children with relapsed or refractory medulloblastoma/CNS PNET (central
      nervous system primitive neuroectodermal tumor) and in children with relapsed or refractory
      rhabdomyosarcoma.

      III. To investigate checkpoint over-ride by AZD1755 (MK-1775) via the mechanism-based
      pharmacodynamic (PD) biomarker of decreased cyclin-dependent kinase 1 (CDK1) phosphorylation
      in correlative and exploratory studies.

      IV. To evaluate potential predictive biomarkers of AZD1755 (MK-1775) sensitivity, including
      v-myc avian myelocytomatosis viral oncogene homolog (MYC), v-myc avian myelocytomatosis viral
      oncogene neuroblastoma derived homolog (MYCN), phosphorylated-WEE1 G2 checkpoint kinase
      (p-Wee1), enhancer of zeste homolog 2 (Drosophila) (EZH2) and gamma-H2A histone family,
      member gamma-(H2AX) in tumor tissues in correlative and exploratory studies.

      OUTLINE: This is a phase I, dose-escalation followed by a phase II study.

      Patients receive irinotecan hydrochloride orally (PO) and adavosertib PO on days 1-5.
      Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up periodically.
    

Intervention name(s): Adavosertib; Irinotecan Hydrochloride
Intervention type(s): Drug; Drug
Intervention description(s): Given PO; Given PO
Other intervention name(s): AZD-1775; AZD1775; MK-1775; MK1775; Campto; Camptosar; Camptothecin 11; Camptothecin-11; CPT 11; CPT-11; Irinomedac; Irinotecan Hydrochloride Trihydrate; Irinotecan Monohydrochloride Trihydrate; U-101440E
Intervention MeSH terms: Irinotecan; Camptothecin; Adavosertib
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment