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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
76
Given PO
Given PO
Children's Hospital of Alabama
Birmingham, Alabama, United States
Children's Hospital Los Angeles
Los Angeles, California, United States
Children's Hospital of Orange County
Orange, California, United States
UCSF Medical Center-Parnassus
San Francisco, California, United States
UCSF Medical Center-Mission Bay
San Francisco, California, United States
Children's Hospital Colorado
Aurora, Colorado, United States
Children's National Medical Center
Washington D.C., District of Columbia, United States
Children's Healthcare of Atlanta - Egleston
Atlanta, Georgia, United States
Lurie Children's Hospital-Chicago
Chicago, Illinois, United States
Riley Hospital for Children
Indianapolis, Indiana, United States
...and 14 more locations
Maximum Tolerated Dose (MTD)
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.
Time frame: Up to 21 days
Number of Participants With Cycle 1 DLT
To define and describe the toxicities of AZD1755 (MK-1775) in combination with oral irinotecan administered on this schedule.
Time frame: Up to 21 days
Pharmacokinetic (PK) Parameters of Adavosertib in Terms of Systemic Exposure, AUC
The PK parameters will be summarized by means and standard deviations
Time frame: Cycle 1 day 1 prior to the irinotecan infusion, prior to the adavosertib dose, 4 hours after the dose of adavosertib is given, and prior to the irinotecan dose on day 2
Pharmacokinetic (PK) Parameters of Adavosertib in Terms of Systemic Exposure, Cmax
The PK parameters will be summarized by means and standard deviations
Time frame: Cycle 1 day 1 prior to the irinotecan infusion, prior to the adavosertib dose, 4 hours after the dose of adavosertib is given, and prior to the irinotecan dose on day 2
Pharmacokinetic (PK) Parameters of Adavosertib in Terms of Systemic Exposure, HL-Lambda (Half Life)
The PK parameters will be summarized by means and standard deviations
Time frame: Cycle 1 day 1 prior to the irinotecan infusion, prior to the adavosertib dose, 4 hours after the dose of adavosertib is given, and prior to the irinotecan dose on day 2
Pharmacokinetic (PK) Parameters of Adavosertib in Terms of Systemic Exposure, Tmax
The PK parameters will be summarized by means and standard deviations
Time frame: Cycle 1 day 1 prior to the irinotecan infusion, prior to the adavosertib dose, 4 hours after the dose of adavosertib is given, and prior to the irinotecan dose on day 2
Number and Percentage of Participants With Best Overall Response With Partial or Complete Response
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).
Time frame: Up to 1 year
Mean Fold Change in Gamma H2AX in Peripheral Blood Mono Nuclear Cells
Mean (SD) of the increase in gamma H2AX at 4 hours versus baseline among patients in Part A stratified by dose level.
Time frame: Up to 1 day
Number and Percentage of Part B Neuroblastoma Participants With MYCN Amplification
Frequency (%) of Part B Neuroblastoma participants with MYCN amplification.
Time frame: Assessed at Baseline
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