Adavosertib and Irinotecan Hydrochloride in Treating Younger Patients With Relapsed or Refractory Solid Tumors
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|ClinicalTrials.gov Identifier: NCT02095132|
Recruitment Status : Recruiting
First Posted : March 24, 2014
Last Update Posted : September 16, 2019
|Condition or disease||Intervention/treatment||Phase|
|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||Drug: Adavosertib Drug: Irinotecan Drug: Irinotecan Hydrochloride||Phase 1 Phase 2|
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.
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 18 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up periodically.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||154 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||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|
|Actual Study Start Date :||March 27, 2014|
|Estimated Primary Completion Date :||April 30, 2021|
Experimental: Treatment (irinotecan hydrochloride, adavosertib)
Patients receive irinotecan hydrochloride PO and adavosertib PO on days 1-5. Treatment repeats every 21 days for 18 cycles in the absence of disease progression or unacceptable toxicity.
Drug: Irinotecan Hydrochloride
- Maximum tolerated dose (MTD) [ Time Frame: 21 days ]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.
- Pharmacokinetic (PK) parameters of adavosertib in terms of systemic exposure [ 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 ]The PK parameters will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).
- PK parameters of adavosertib in terms of drug clearance [ 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 ]The PK parameters will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).
- Response rate [ Time Frame: Up to 1 year ]Will be assessed according to Response Evaluation Criteria in Solid Tumors. Response rates will be calculated as the percent of patients whose best response is a complete response (CR) or partial response (PR) and confidence intervals will be constructed according to the method of Chang. A responder is defined as a patient who achieves a best confirmed response of PR or CR on the study.
- Change in phosphorylated-cyclin-dependent kinase 1 (p-CDK1) levels [ Time Frame: Baseline up to 1 year ]Decreased p-CDK1 indicating Wee1 inhibition by adavosertib will be investigated. These analyses will be descriptive and exploratory and hypotheses generating in nature.
- Predictive biomarkers of adavosertib sensitivity [ Time Frame: Up to 1 year ]These analyses will be descriptive and exploratory and hypotheses generating in nature.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02095132
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|Principal Investigator:||Kristina A Cole||COG Phase I Consortium|