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

Study Purpose

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 or that have not responded to standard therapy. Adavosertib and irinotecan hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Recruitment Criteria

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

Accepts Healthy Volunteers
No

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Study Type
Interventional
Eligible Ages 1 Year - 21 Years
Gender All
More Inclusion & Exclusion Criteria

Inclusion Criteria:

- Patients must have had histologic verification of malignancy at original diagnosis or relapse except in patients with intrinsic brain stem tumors, optic pathway gliomas, or patients with pineal tumors and elevations of cerebrospinal fluid (CSF) or serum tumor markers including alpha-fetoprotein or beta-human chorionic gonadotropin (HCG) - Part A: Patients with relapsed or refractory solid tumors, including patients with primary or metastatic CNS tumors - Part B: Patients with relapsed or refractory neuroblastoma - Part C: Patients with relapsed or refractory medulloblastoma or CNS embryonal tumors formally classified as PNET (pineoblastoma, CNS neuroblastoma, CNS ganglioneuroblastoma, embryonal tumor with multi-layered rosettes, medulloepithelioma, CNS embryonal tumor with rhabdoid features (INI1 intact) and CNS embryonal tumor, not otherwise specified) - Part D: Patients with relapsed or refractory rhabdomyosarcoma - Patients must have a body surface area >= 0.35 m^2 at the time of study enrollment if enrolling on dose levels 1-5; patients must have a body surface area >= 0.46 m^2 at the time of study enrollment if enrolling on dose level 0 - Part A: Patients must have either measurable or evaluable disease - Part B: Patients must have either measurable disease or must be evaluable for MIBG response without evidence of Response Evaluation Criteria in Solid Tumors (RECIST) measurable lesions; patients with neuroblastoma in bone marrow only are not eligible - Part C: Patients must have measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) - Part D: Patients must have measurable disease for Part D - Patient's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life - Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age; note: neurologic deficits in patients with CNS tumors must have been relatively stable for at least 7 days prior to study enrollment; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score - Patients must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy - At least 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea) - At least 14 days after the last dose of a long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth factor; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair - At least 7 days after the last dose of a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair - At least 42 days after the completion of any type of immunotherapy, e.g. tumor vaccines - >= 21 days must have elapsed from infusion of lase dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1 - At least 14 days after local palliative radiation therapy (XRT) (small port); at least 150 days must have elapsed if prior traumatic brain injury (TBI), craniospinal XRT or if >= 50% radiation of pelvis; at least 42 days must have elapsed if other substantial bone marrow radiation, including therapeutic doses of Iobenguane (MIBG) - Stem cell Infusion without TBI: no evidence of active graft vs.host disease and at least 84 days must have elapsed after transplant or stem cell infusion - Patients previously treated with irinotecan are eligible for this study - For patients with solid tumors without known bone marrow involvement: peripheral absolute neutrophil count (ANC) >= 1000/mm^3 - For patients with solid tumors without known bone marrow involvement: platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) - For patients with solid tumors without known bone marrow involvement: hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) - Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions); these patients will not be evaluable for hematologic toxicity; at least 2 of every cohort of 3 patients must be evaluable for hematologic toxicity for Part A, the dose escalation part of the study; if dose-limiting hematologic toxicity is observed, all subsequent patients enrolled must be evaluable for hematologic toxicity - Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows: - Age 1 to < 2 years: 0.6 mg/dL - Age 2 to < 6 years: 0.8 mg/dL - Age 6 to < 10 years: 1 mg/dL - Age 10 to < 13 years: 1.2 mg/dL - Age 13 to < 16 years: 1.5 mg/dL (males), 1.4 mg/dL (females) - Age >= 16 years: 1.7 mg/dL (males), 1.4 mg/dL (females) - Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age - Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L; for the purpose of this study, the ULN for SGPT is 45 U/L - Serum albumin >= 2 g/dL - Correct QT interval (QTc) =< 480 msec; Note: Patients should avoid concomitant medication known or suspected to prolong QTc interval or cause torsades de pointes; if possible, alternative agents should be considered; patients who are receiving drugs that prolong the QTc are eligible if the drug is necessary and no alternatives are available - Patients with seizure disorder may be enrolled if on non-enzyme inducing anticonvulsants and well controlled - Nervous system disorders (Common Terminology Criteria for Adverse Events version 5.0 [CTCAE v5.0]) resulting from prior therapy must be =< grade 2, with the exception of decreased tendon reflex (DTR); any grade of DTR is eligible - All patients and/or their parents or legally authorized representatives must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines - Tissue blocks or slides must be sent if available, with exclusions; if tissue blocks or slides are unavailable, the study chair must be notified prior to study enrollment - Patients must be able to swallow capsules

Exclusion Criteria:

- Pregnant or breast-feeding women may not be entered on this study; pregnancy tests must be obtained in girls who are post-menarchal - Males or females of reproductive potential may not participate unless they have agreed to use an effective double barrier contraceptive method for the entire duration of protocol therapy and for 3 months (males) and 1 month (females) after study drug discontinuation - Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible - Patients who are currently receiving another investigational drug are not eligible - Patients who are currently receiving other anti-cancer agents are not eligible - Patients who are currently receiving drugs that are strong or moderate inhibitors and/or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) or sensitive CYP3A4 substrates and CYP3A4 substrates with a narrow therapeutic range are not eligible; the use of aprepitant as an antiemetic is prohibited; caution should be exercised with concomitant administration of AZD1755 (MK-1775) and agents that are sensitive substrates of cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8), 2C9 and 2C19, or substrates of this enzyme with narrow therapeutic ranges, as well as agents that are inhibitors or substrates of permeability glycoprotein (P-gp) - Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial - Patients must not have received enzyme inducing anticonvulsants for at least 14 days prior to enrollment - Patients with cardiac diseases ongoing or in the past 6 months (e.g. congestive heart failure, acute myocardial infarction, significant uncontrolled arrhythmias) are not eligible for this trial - Patients who have an uncontrolled infection are not eligible - Patients who have received a prior solid organ transplantation are not eligible - Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible - Patients with a history of allergic reaction to irinotecan, cephalosporins or a severe penicillin allergy are not eligible - Patients unable to swallow capsules whole are not eligible; nasogastric or gastric (G) tube administration is not allowed

Trial Details

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

Trial ID:
NCT02095132

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Phase
Phase 1/Phase 2

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

Lead Sponsor
National Cancer Institute (NCI)

The person who is responsible for the scientific and technical direction of the entire clinical study.

Principal Investigator
Kristina A Cole
Principal Investigator Affiliation COG Phase I Consortium

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

Agency Class
NIH
Overall Status Recruiting
Countries Canada, United States

The disease, disorder, syndrome, illness, or injury that is being studied.

Conditions
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
Additional Details

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 18 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically.

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

Children's Hospital of Wisconsin, Milwaukee, Wisconsin

Status

Suspended

Address

Children's Hospital of Wisconsin

Milwaukee, Wisconsin, 53226

Seattle Children's Hospital, Seattle, Washington

Status

Recruiting

Address

Seattle Children's Hospital

Seattle, Washington, 98105

Site Contact

Site Public Contact

ctsucontact@westat.com

888-823-5923

Houston, Texas

Status

Recruiting

Address

Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center

Houston, Texas, 77030

Site Contact

Site Public Contact

burton@bcm.edu

713-798-1354

St. Jude Children's Research Hospital, Memphis, Tennessee

Status

Recruiting

Address

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105

Site Contact

Site Public Contact

ctsucontact@westat.com

888-823-5923

Pittsburgh, Pennsylvania

Status

Suspended

Address

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, 15224

Children's Hospital of Philadelphia, Philadelphia, Pennsylvania

Status

Suspended

Address

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104

Oregon Health and Science University, Portland, Oregon

Status

Suspended

Address

Oregon Health and Science University

Portland, Oregon, 97239

Cincinnati, Ohio

Status

Recruiting

Address

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229

Site Contact

Site Public Contact

ctsucontact@westat.com

888-823-5923

New York, New York

Status

Recruiting

Address

NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center

New York, New York, 10032

Site Contact

Site Public Contact

nr2616@cumc.columbia.edu

212-305-6361

Washington University School of Medicine, Saint Louis, Missouri

Status

Recruiting

Address

Washington University School of Medicine

Saint Louis, Missouri, 63110

Site Contact

Site Public Contact

info@siteman.wustl.edu

800-600-3606

Minneapolis, Minnesota

Status

Recruiting

Address

University of Minnesota/Masonic Cancer Center

Minneapolis, Minnesota, 55455

Site Contact

Site Public Contact

ctsucontact@westat.com

888-823-5923

C S Mott Children's Hospital, Ann Arbor, Michigan

Status

Recruiting

Address

C S Mott Children's Hospital

Ann Arbor, Michigan, 48109

Site Contact

Site Public Contact

ctsucontact@westat.com

888-823-5923

Dana-Farber Cancer Institute, Boston, Massachusetts

Status

Recruiting

Address

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215

Site Contact

Site Public Contact

877-442-3324

Riley Hospital for Children, Indianapolis, Indiana

Status

Recruiting

Address

Riley Hospital for Children

Indianapolis, Indiana, 46202

Site Contact

Site Public Contact

800-248-1199

Lurie Children's Hospital-Chicago, Chicago, Illinois

Status

Suspended

Address

Lurie Children's Hospital-Chicago

Chicago, Illinois, 60611

Atlanta, Georgia

Status

Recruiting

Address

Children's Healthcare of Atlanta - Egleston

Atlanta, Georgia, 30322

Site Contact

Site Public Contact

ctsucontact@westat.com

888-823-5923

Children's National Medical Center, Washington, District of Columbia

Status

Recruiting

Address

Children's National Medical Center

Washington, District of Columbia, 20010

Site Contact

Site Public Contact

ctsucontact@westat.com

888-823-5923

Children's Hospital Colorado, Aurora, Colorado

Status

Suspended

Address

Children's Hospital Colorado

Aurora, Colorado, 80045

UCSF Medical Center-Mission Bay, San Francisco, California

Status

Recruiting

Address

UCSF Medical Center-Mission Bay

San Francisco, California, 94158

Site Contact

Site Public Contact

877-827-3222

UCSF Medical Center-Parnassus, San Francisco, California

Status

Active, not recruiting

Address

UCSF Medical Center-Parnassus

San Francisco, California, 94143

Children's Hospital of Orange County, Orange, California

Status

Recruiting

Address

Children's Hospital of Orange County

Orange, California, 92868

Site Contact

Site Public Contact

ctsucontact@westat.com

888-823-5923

Children's Hospital Los Angeles, Los Angeles, California

Status

Suspended

Address

Children's Hospital Los Angeles

Los Angeles, California, 90027

Children's Hospital of Alabama, Birmingham, Alabama

Status

Recruiting

Address

Children's Hospital of Alabama

Birmingham, Alabama, 35233

Site Contact

Site Public Contact

ctsucontact@westat.com

888-823-5923

International Sites

Hospital for Sick Children, Toronto, Ontario, Canada

Status

Active, not recruiting

Address

Hospital for Sick Children

Toronto, Ontario, M5G 1X8

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