Symptoms and General Pathology

All Conditions

Neoplasms

Nervous System Diseases

Rare Diseases

Recurrence

Neuroblastoma

Central Nervous System Neoplasms

Medulloblastoma

Nervous System Neoplasms

Ganglioneuroblastoma

Rhabdomyosarcoma

Pinealoma

Neoplasms, Germ Cell and Embryonal

Disease Attributes

Neuroectodermal Tumors, Primitive, Peripheral

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Neuroepithelial

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Myosarcoma

Neoplasms, Connective and Soft Tissue

Sarcoma

Glioma

Brain Neoplasms

Brain Diseases

Central Nervous System Diseases

Pineoblastoma

Embryonal Tumor With Multilayered Rosettes

Pineocytoma

Neuroepithelioma

Soft Tissue Sarcoma

Antineoplastic Agents

All Drugs and Chemicals

Irinotecan

Camptothecin

Adavosertib

Topoisomerase I Inhibitors

Enzyme Inhibitors

Patients receive irinotecan hydrochloride 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.

Irinotecan Hydrochloride

Kristina A Cole

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.

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.

Adavosertib and Irinotecan Hydrochloride in Treating Younger Patients With Relapsed or Refractory Solid Tumors

A Phase 1/2 Study of AZD1775 (MK-1775) in Combination With Oral Irinotecan in Children, Adolescents, and Young Adults With Relapsed or Refractory Solid Tumors

MTD is defined as the maximum doses of adavosertib and irinotecan hydrochloride at which fewer than one-third of patients experience dose limiting toxicities when receiving this combination.

To define and describe the toxicities of AZD1755 (MK-1775) in combination with oral irinotecan administered on this schedule.

The PK parameters will be summarized by means and standard deviations

Frequency (%) of response-evaluable patients with best overall response of partial or complete response as determined by revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1).

Mean (SD) of the increase in gamma H2AX at 4 hours versus baseline among patients in Part A stratified by dose level.

Frequency (%) of Part B Neuroblastoma participants with MYCN amplification.

National Cancer Institute (NCI)

Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study.

Patients with relapsed or refractory solid tumors, including patients with primary or metastatic CNS tumors treated at 70 mg/m2 Irinotecan (IRIN) and 50 mg/m2 AZD1775 (MK-1775)

Part A, Dose Level 1

Patients with relapsed or refractory solid tumors, including patients with primary or metastatic CNS tumors treated at 70 mg/m2 Irinotecan (IRIN) and 65 mg/m2 AZD1775 (MK-1775)

Part A, Dose Level 2

Patients with relapsed or refractory solid tumors, including patients with primary or metastatic CNS tumors treated at 90 mg/m2 Irinotecan (IRIN) and 65 mg/m2 AZD1775 (MK-1775)

Part A, Dose Level 3

Patients with relapsed or refractory solid tumors, including patients with primary or metastatic CNS tumors treated at 90 mg/m2 Irinotecan (IRIN) and 85 mg/m2 AZD1775 (MK-1775)

Part A, Dose Level 4

Patients with relapsed or refractory solid tumors, including patients with primary or metastatic CNS tumors treated at 90 mg/m2 Irinotecan (IRIN) and 110 mg/m2 AZD1775 (MK-1775)

Part A, Dose Level 5

Patients with relapsed or refractory solid tumors, including patients with primary or metastatic CNS tumors treated at the MTD/RP2D of 90 mg/m2 Irinotecan (IRIN) and 110 mg/m2 AZD1775 (MK-1775)

Part A, PK Expansion

Patients with relapsed or refractory neuroblastoma treated at the MTD/RP2D of 90 mg/m2 Irinotecan (IRIN) and 85 mg/m2 AZD1775 (MK-1775)

Part B, Neuroblastoma

Patients with relapsed or refractory Medulloblastoma/CNS PNET treated at the MTD/RP2D of 90 mg/m2 Irinotecan (IRIN) and 85 mg/m2 AZD1775 (MK-1775)

Part C, Medulloblastoma/CNS PNET

Patients with relapsed or refractory Rhabdomyosarcoma treated at the MTD/RP2D of 90 mg/m2 Irinotecan (IRIN) and 85 mg/m2 AZD1775 (MK-1775)

Part D, Rhabdomyosarcoma

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Results Reporting Coordinator

Irinotecan (IRIN)

AZD1775 (MK-1775)

Part A Patients with relapsed or refractory solid tumors, including patients with primary or metastatic CNS tumors treated with Irinotecan (IRIN) and AZD1775 (MK-1775)

Part A

All Part A patients contributed to determining MTD. Only Toxicity evaluable patients were accounted.

Maximum Tolerated Dose (MTD)

Number of Participants With Cycle 1 DLT

Patients with relapsed or refractory solid tumors, including patients with primary or metastatic CNS tumors treated at 70 mg/m2 Irinotecan (IRIN) and 50 mg/m2 AZD1775 (MK-1775

Summary statistics for PK parameter for patients in Part A. Per study protocol, PK measures were not required for Parts B, C, or D, therefore, data were not and will not be collected.

Pharmacokinetic (PK) Parameters of Adavosertib in Terms of Systemic Exposure, AUC

Pharmacokinetic (PK) Parameters of Adavosertib in Terms of Systemic Exposure, Cmax

Pharmacokinetic (PK) Parameters of Adavosertib in Terms of Systemic Exposure, HL-Lambda (Half Life)

Pharmacokinetic (PK) Parameters of Adavosertib in Terms of Systemic Exposure, Tmax

Patients with complete response or partial response among response-evaluable patients.

Number and Percentage of Participants With Best Overall Response With Partial or Complete Response

Part A patients with data available. Per study protocol, pharmacodynamics were not required for Parts B, C, or D, therefore, data were not collected and will not be collected.

Mean Fold Change in Gamma H2AX in Peripheral Blood Mono Nuclear Cells

Only Part B eligible patients. Per study protocol, data for Parts A, C, and D were not and will not ever be collected.

Spots Global Cancer Trial Database for central nervous system embryonal tumor, not otherwise specified