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.

Number and Percentage of Part B Neuroblastoma Participants With MYCN Amplification

Overall Study

Germ Cells Tumors

Malignant Germ Cell Tumor

Natriuretic Agents

Anti-Infective Agents

Amino Acids

Carboplatin

Melphalan

Mannitol

Sodium thiosulfate

Mechlorethamine

Nitrogen Mustard Compounds

Antidotes

Antineoplastic Agents, Alkylating

Alkylating Agents

Immunosuppressive Agents

Immunologic Factors

Diuretics

Protective Agents

Antioxidants

Antitubercular Agents

Anti-Bacterial Agents

Chelating Agents

Phenylalanine

Alanine

Patients receive mannitol IA over 30 seconds, melphalan IA over 10 minutes, and carboplatin IA over 10 minutes. Patients then receive sodium thiosulfate IV over 15 minutes at 4 and 8 hours after carboplatin. Treatment repeats every 4-6 weeks for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

Quality-of-Life Assessment

Questionnaire Administration

Sodium Thiosulfate

Edward A Neuwelt

This phase I/II trial studies the side effects and best dose of melphalan when given together with carboplatin, mannitol, and sodium thiosulfate, and to see how well they work in treating patients with central nervous system (CNS) embryonal or germ cell tumors that is growing, spreading, or getting worse (progressive) or has come back (recurrent). Drugs used in chemotherapy, such as melphalan and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Osmotic blood-brain barrier disruption (BBBD) uses mannitol to open the blood vessels around the brain and allow cancer-killing substances to be carried directly to the brain. Sodium thiosulfate may help lessen or prevent hearing loss and toxicities in patients undergoing chemotherapy with carboplatin and BBBD. Giving melphalan together with carboplatin, mannitol, and sodium thiosulfate may be an effective treatment for recurrent or progressive CNS embryonal or germ cell tumors.

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of intra-arterial (IA) melphalan given with IA carboplatin, osmotic BBBD and delayed intravenous (IV) sodium thiosulfate (STS) in subjects with recurrent or progressive embryonal and germ cell tumors of the CNS. (Phase I) II. To estimate the response rate in subjects with recurrent or progressive CNS embryonal and germ cell tumors treated with IA carboplatin, IA melphalan, osmotic BBBD and delayed IV STS. (Phase II)

SECONDARY OBJECTIVES:

I. To describe 2-year progression-free survival (PFS) and overall survival (OS) rates in subjects with recurrent or progressive CNS embryonal and germ cell tumors treated with IA carboplatin, IA melphalan, osmotic BBBD and delayed IV STS. (Phase II) II. To describe neuropsychological and audiology outcomes in subjects with recurrent or progressive CNS embryonal and germ cell tumors treated with IA carboplatin, IA melphalan, osmotic BBBD and delayed IV STS. (Phase II) III. To describe the overall toxicity of IA carboplatin and IA melphalan in conjunction with osmotic BBBD and delayed STS chemoprotection in subjects with recurrent or progressive CNS embryonal or germ cell tumors. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of melphalan followed by a phase II study.

Patients receive mannitol IA over 30 seconds, melphalan IA over 10 minutes, and carboplatin IA over 10 minutes. Patients then receive sodium thiosulfate IV over 15 minutes at 4 and 8 hours after carboplatin. Treatment repeats every 4-6 weeks for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year, every 6 months for 1 year, and then annually for 3 years.

Melphalan, Carboplatin, Mannitol, and Sodium Thiosulfate in Treating Patients With Recurrent or Progressive CNS Embryonal or Germ Cell Tumors

Phase I/II Study of Intra-Arterial Melphalan Given With Intra-Arterial Carboplatin, Osmotic Blood-Brain Barrier Disruption and Delayed Otoprotective Sodium Thiosulfate for Patients With Recurrent or Progressive CNS Embryonal or Germ Cell Tumors

Will be assessed based on the incidence of dose-limiting toxicity, graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. All toxicities will be tabulated by event and by overall. The toxicities will also be tabulated by highest grade. The recovery from toxicities (i.e. hematologic toxicities) will also be summarized.

Descriptive statistics will be estimated.

Estimation made using Kaplan-Meier product limit estimation. A Cox proportional hazards regression model will be fit to the data to estimate the association of progression free survival and overall survival with baseline demographic and disease characteristics.

Quantitative scores, whenever possible, will be derived from each measure and converted to measure-specific Z scores using normative data. Post-treatment Z scores will be subtracted from pre-treatment Z scores to calculate absolute change in neuropsychological test performance. Significant change will be defined as change of 1 standard deviation. These data will be summarized descriptively.

Will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Estimated using proportions with associated confidence intervals.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Adavosertib and Irinotecan Hydrochloride in Treating Younger Patients With Relapsed or Refractory Solid Tumors	NCT02095132	Central Nervous... Central Nervous... Central Nervous... Embryonal Tumor... Pineoblastoma Primary Central... Recurrent Child... Recurrent Malig... Recurrent Medul... Recurrent Neuro... Recurrent Rhabd... Refractory Mali... Refractory Medu... Refractory Neur... Refractory Rhab...	Adavosertib Irinotecan Hydr...	1 Year - 21 Years	National Cancer Institute (NCI)
Melphalan, Carboplatin, Mannitol, and Sodium Thiosulfate in Treating Patients With Recurrent or Progressive CNS Embryonal or Germ Cell Tumors	NCT00983398	Central Nervous... Embryonal Tumor... Germ Cell Tumor Medulloblastoma Medulloepitheli... Primitive Neuro... Recurrent Child... Recurrent Malig... Recurrent Medul... Recurrent Primi...	Carboplatin Mannitol Melphalan Quality-of-Life... Questionnaire A... Sodium Thiosulf...	18 Years - 45 Years	OHSU Knight Cancer Institute

Spots Global Cancer Trial Database for recurrent childhood central nervous system embryonal neoplasm