Olaparib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Defects in DNA Damage Repair Genes (A Pediatric MATCH Treatment Trial)

Phase 2

Completed

Conditions: Low Grade Glioma
Recurrent Childhood Central Nervous System Neoplasm
Recurrent Neuroblastoma
Refractory Glioma
Refractory Primary Central Nervous System Neoplasm
Advanced Malignant Solid Neoplasm
Recurrent Childhood Ependymoma
Recurrent Childhood Non-Hodgkin Lymphoma
Recurrent Childhood Soft Tissue Sarcoma
Recurrent Langerhans Cell Histiocytosis

Interventions: Drug: Olaparib

Registration Number: NCT03233204

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This phase II Pediatric MATCH trial studies how well olaparib works in treating patients with solid tumors, non-Hodgkin lymphoma, or histiocytic disorders with defects in deoxyribonucleic acid (DNA) damage repair genes that have spread to other places in the body (advanced) and have come back (relapsed) or do not respond to treatment (refractory). Olaparib is an inhibitor of PARP, an enzyme that helps repair DNA when it becomes damaged. Blocking PARP may help keep cancer cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy.

Detailed Description: PRIMARY OBJECTIVE:

I. To determine the objective response rate (ORR; complete response + partial response) in pediatric patients treated with olaparib with advanced solid tumors (including central nervous system \[CNS\] tumors), non-Hodgkin lymphomas or histiocytic disorders that harbor activating genetic alterations in the deleterious genetic alterations in the DNA damage repair (DDR) pathway.

SECONDARY OBJECTIVES:

I. To estimate the progression free survival in pediatric patients treated with olaparib with advanced solid tumors including non-Hodgkin lymphomas, CNS tumors, and histiocytosis that harbor deleterious genetic alterations in the DDR pathway.

II. To obtain information about the tolerability of olaparib in children and adolescents with relapsed or refractory cancer.

III. To provide preliminary estimates of the pharmacokinetics of olaparib in children and adolescents with relapsed or refractory cancer.

EXPLORATORY OBJECTIVE:

I. To explore approaches to profiling changes in tumor genomics over time through the evaluation of circulating tumor DNA.

OUTLINE:

Patients receive olaparib orally (PO) twice daily (BID) on days 1-28. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 6

Inclusion Criteria

Patient must have enrolled onto APEC1621SC (NCT03155620) and must have been given a treatment assignment to Molecular Analysis for Therapy Choice (MATCH) to APEC1621H based on the presence of an actionable mutation
Patients must be >= than 12 months and =< 21 years of age at the time of study enrollment
Patients must have a body surface area >= 0.65 m^2 at enrollment
Patients must have radiographically measurable disease at the time of study enrollment; patients with neuroblastoma who do not have measurable disease but have iobenguane (MIBG) positive (+) evaluable disease are eligible; measurable disease in patients with CNS involvement is defined as tumor that is measurable in two perpendicular diameters on magnetic resonance imaging (MRI) and visible on more than one slice
- Note: The following do not qualify as measurable disease:
  - Malignant fluid collections (e.g., ascites, pleural effusions)
  - Bone marrow infiltration except that detected by MIBG scan for neuroblastoma
  - Lesions only detected by nuclear medicine studies (e.g., bone, gallium or positron emission tomography [PET] scans) except as noted for neuroblastoma
  - Elevated tumor markers in plasma or cerebrospinal fluid (CSF)
  - Previously radiated lesions that have not demonstrated clear progression post radiation
  - Leptomeningeal lesions that do not meet the measurement requirements for Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
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 therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment; if after the required timeframe, the numerical eligibility criteria are met, e.g. blood count criteria, the patient is considered to have recovered adequately
- Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive
  - >= 21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days if prior nitrosourea)
- Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the last dose of agent
- Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1
- Corticosteroids: If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
- Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth factor (e.g. pegfilgrastim) or 7 days for short-acting growth factor; for growth factors 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 and the study-assigned research coordinator
- Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors)
- Stem cell infusions (with or without total body irradiation [TBI]):
  - Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor lymphocyte infusion (DLI) or boost infusion: >= 84 days after infusion and no evidence of graft versus host disease (GVHD)
  - Autologous stem cell infusion including boost infusion: >= 42 days
- Cellular therapy: >= 42 days after the completion of any type of cellular therapy (e.g. modified T cells, natural killer [NK] cells, dendritic cells, etc.)
- Radiation therapy (XRT)/external beam irradiation including protons: >= 14 days after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation to >= 50% of the pelvis; >= 42 days if other substantial bone marrow (BM) radiation
  - Note: Radiation may not be delivered to "measurable disease" tumor site(s) being used to follow response to subprotocol treatment
- Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131iodine [I]-MIBG): >= 42 days after systemically administered radiopharmaceutical therapy
- Patients must not have received prior exposure to olaparib, veliparib, niraparib, rucaparib, talazoparib or other poly adenosine diphosphate ribose polymerase inhibitors (PARPi)
For patients with solid tumors without known bone marrow involvement: peripheral absolute neutrophil count (ANC) >= 1000/mm^3 (within 7 days prior to enrollment)
For patients with solid tumors without known bone marrow involvement: platelet count >= 100,000/mm^3 (within 7 days prior to enrollment) (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts (may receive platelet or packed red blood cells [pRBC] transfusions provided they are not known to be refractory to red cell or platelet transfusions); these patients will not be evaluable for hematologic toxicity
Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 (within 7 days prior to enrollment) or
A serum creatinine based on age/gender as follows (within 7 days prior to enrollment):
- Age 1 to < 2 years: maximum serum creatinine 0.6 mg/dL for male and 0.6 mg/dL for female
- Age 2 to < 6 years: maximum serum creatinine 0.8 mg/dL for male and 0.8 mg/dL for female
- Age 6 to < 10 years: maximum serum creatinine 1 mg/dL for male and 1 mg/dL for female
- Age 10 to < 13 years: maximum serum creatinine 1.2 mg/dL for male and 1.2 mg/dL for female
- Age 13 to < 16 years: maximum serum creatinine 1.5 mg/dL for male and 1.4 mg/dL for female
- Age >= 16 years: maximum serum creatinine 1.7 mg/dL for male and 1.4 mg/dL for female
Patients with solid tumors: bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment)
Patients with solid tumors: serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (within 7 days prior to enrollment); (for the purpose of this study, the ULN for SGPT is 45 U/L)
Patients with solid tumors: serum albumin >= 2 g/dL (within 7 days prior to enrollment)
Activated partial thromboplastin time (aPTT) =< 1.5 x ULN (within 7 days prior to enrollment)
International normalized ratio (INR) =< 1.5 (within 7 days prior to enrollment)
Patients must be able to swallow intact tablets
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

Exclusion Criteria

Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies; pregnancy tests must be obtained in girls who are post-menarchal; women of child-bearing potential and their partners should agree to use two (2) highly effective forms of contraception throughout study participation and for at least one (1) month after the last dose of olaparib; male study participants should avoid fathering a child or donating sperm during the study and for three (3) months after the last dose of olaparib
Concomitant medications
- Corticosteroids: 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; if used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
- Investigational drugs: patients who are currently receiving another investigational drug are not eligible
- Anti-cancer agents: patients who are currently receiving other anti-cancer agents are not eligible
- Anti-GVHD agents post-transplant: 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
- CYP3A/CYP3A4 agents: patients who are currently receiving drugs that are strong and moderate inducers or inhibitors of CYP3A or CYP3A4 are not eligible; strong inducers or inhibitors of CYP3A4 should be avoided from 21 days prior to enrollment to the end of the study
Patients who have an uncontrolled infection are not eligible
Patient who are known to be serologically positive for human immunodeficiency virus (HIV)
Patients with known active hepatitis (i.e. hepatitis B or C)
Patients who have received a prior solid organ transplantation are not eligible
Patients with symptomatic uncontrolled brain metastases; a scan to confirm the absence of brain metastases is not required; the patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 4 weeks prior to enrollment; patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days
Patients with known symptomatic Fanconi anemia (FA), ataxia-telangiectasia (A-T) syndrome, Bloom syndrome (BS) and Nijmegen breakage syndrome (NBS) are not eligible (asymptomatic carriers are acceptable)
Major surgery must not have occurred within 2 weeks prior to enrollment and patients must have recovered from any effects of any major surgery
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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (olaparib)	Olaparib	Patients receive olaparib PO BID on days 1-28. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Objective Response Rate (Complete Response/Partial Response)	Up to 2 years from study entry	A responder is defined as a patient who achieves a best response of partial response or complete response on the study. Response rates will be calculated as the percent of evaluable patients who are responders, and confidence intervals will be constructed using the Wilson score interval method. The revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) was used to determine response and progression in this study, with specific criteria outlined for the different subtypes of tumors (e.g., 2-dimensional measurements for central nervous system (CNS) tumors).

Secondary Outcome Measures

Name	Time	Method
Progression Free Survival (PFS)	Up to 6 months from study entry	The Kaplan-Meier method will be used to estimate the 6 month PFS. PFS is defined as time from initiation of protocol treatment to disease progression, recurrence, death from any cause, or date of last contact.
Percentage of Patients Experiencing Treatment-related Grade 3 or Higher Adverse Events	Up to 2 years from study entry	Percentage of patients experiencing treatment-related grade 3 or higher adverse events will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
Pharmacokinetics (PK) of Olaparib, Area Under the Curve (AUC)	Up to day 8 of cycle 1	The mean (sd) of the AUC.

Trial Locations

Locations (113): Sinai Hospital of Baltimore
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Baltimore, Maryland, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
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Baltimore, Maryland, United States
Children's Healthcare of Atlanta - Egleston
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Atlanta, Georgia, United States
University of Illinois
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Chicago, Illinois, United States
University of Chicago Comprehensive Cancer Center
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Chicago, Illinois, United States
Children's Hospital of Pittsburgh of UPMC
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Pittsburgh, Pennsylvania, United States
Cleveland Clinic Foundation
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Cleveland, Ohio, United States
Seattle Children's Hospital
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Seattle, Washington, United States
Riley Hospital for Children
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Indianapolis, Indiana, United States
University Medical Center of Southern Nevada
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Las Vegas, Nevada, United States
Alliance for Childhood Diseases/Cure 4 the Kids Foundation
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Las Vegas, Nevada, United States
Cincinnati Children's Hospital Medical Center
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Cincinnati, Ohio, United States
Children's Hospitals and Clinics of Minnesota - Minneapolis
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Minneapolis, Minnesota, United States
University of Minnesota/Masonic Cancer Center
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Minneapolis, Minnesota, United States
Duke University Medical Center
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Durham, North Carolina, United States
Children's Hospital of San Antonio
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San Antonio, Texas, United States
Methodist Children's Hospital of South Texas
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San Antonio, Texas, United States
Children's Hospital of Alabama
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Birmingham, Alabama, United States
UCSF Medical Center-Mission Bay
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San Francisco, California, United States
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
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Denver, Colorado, United States
University of Oklahoma Health Sciences Center
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Oklahoma City, Oklahoma, United States
Legacy Emanuel Children's Hospital
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Portland, Oregon, United States
Oregon Health and Science University
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Portland, Oregon, United States
Primary Children's Hospital
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Salt Lake City, Utah, United States
Albany Medical Center
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Albany, New York, United States
Mission Hospital
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Asheville, North Carolina, United States
NYU Langone Hospital - Long Island
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Mineola, New York, United States
Roswell Park Cancer Institute
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Buffalo, New York, United States
New York Medical College
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Valhalla, New York, United States
Carolinas Medical Center/Levine Cancer Institute
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Charlotte, North Carolina, United States
Scott and White Memorial Hospital
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Temple, Texas, United States
University of Wisconsin Carbone Cancer Center - University Hospital
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Madison, Wisconsin, United States
Madigan Army Medical Center
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Tacoma, Washington, United States
Mayo Clinic in Rochester
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Rochester, Minnesota, United States
University of Nebraska Medical Center
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Omaha, Nebraska, United States
Children's Hospital of Wisconsin
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Milwaukee, Wisconsin, United States
The Steven and Alexandra Cohen Children's Medical Center of New York
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New Hyde Park, New York, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
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New York, New York, United States
University of Rochester
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Rochester, New York, United States
Memorial Sloan Kettering Cancer Center
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New York, New York, United States
State University of New York Upstate Medical University
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Syracuse, New York, United States
Saint Joseph's Hospital/Children's Hospital-Tampa
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Tampa, Florida, United States
Banner University Medical Center - Tucson
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Tucson, Arizona, United States
Banner Children's at Desert
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Mesa, Arizona, United States
Children's Hospital Los Angeles
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Los Angeles, California, United States
Kaiser Permanente Downey Medical Center
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Downey, California, United States
Miller Children's and Women's Hospital Long Beach
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Long Beach, California, United States
Valley Children's Hospital
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Madera, California, United States
Kaiser Permanente-Oakland
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Oakland, California, United States
UCSF Benioff Children's Hospital Oakland
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Oakland, California, United States
Children's Hospital Colorado
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Aurora, Colorado, United States
Alfred I duPont Hospital for Children
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Wilmington, Delaware, United States
Children's National Medical Center
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Washington, District of Columbia, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
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Miami, Florida, United States
Nemours Children's Clinic-Jacksonville
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Jacksonville, Florida, United States
Nicklaus Children's Hospital
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Miami, Florida, United States
Nemours Children's Clinic - Pensacola
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Pensacola, Florida, United States
Saint Luke's Cancer Institute - Boise
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Boise, Idaho, United States
Saint Jude Midwest Affiliate
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Peoria, Illinois, United States
Southern Illinois University School of Medicine
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Springfield, Illinois, United States
University of Iowa/Holden Comprehensive Cancer Center
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Iowa City, Iowa, United States
Blank Children's Hospital
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Des Moines, Iowa, United States
Eastern Maine Medical Center
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Bangor, Maine, United States
Bronson Methodist Hospital
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Kalamazoo, Michigan, United States
University of Mississippi Medical Center
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Jackson, Mississippi, United States
Washington University School of Medicine
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Saint Louis, Missouri, United States
Cardinal Glennon Children's Medical Center
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Saint Louis, Missouri, United States
Mercy Hospital Saint Louis
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Saint Louis, Missouri, United States
Children's Hospital and Medical Center of Omaha
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Omaha, Nebraska, United States
Hackensack University Medical Center
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Hackensack, New Jersey, United States
Morristown Medical Center
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Morristown, New Jersey, United States
NYP/Weill Cornell Medical Center
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New York, New York, United States
Novant Health Presbyterian Medical Center
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Charlotte, North Carolina, United States
Sanford Broadway Medical Center
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Fargo, North Dakota, United States
Dayton Children's Hospital
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Dayton, Ohio, United States
Nationwide Children's Hospital
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Columbus, Ohio, United States
ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital
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Toledo, Ohio, United States
Children's Hospital of Philadelphia
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Philadelphia, Pennsylvania, United States
Saint Jude Children's Research Hospital
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Memphis, Tennessee, United States
BI-LO Charities Children's Cancer Center
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Greenville, South Carolina, United States
Sanford USD Medical Center - Sioux Falls
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Sioux Falls, South Dakota, United States
Vanderbilt University/Ingram Cancer Center
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Nashville, Tennessee, United States
Cook Children's Medical Center
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Fort Worth, Texas, United States
UT Southwestern/Simmons Cancer Center-Dallas
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Dallas, Texas, United States
Medical City Dallas Hospital
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Dallas, Texas, United States
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
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Houston, Texas, United States
M D Anderson Cancer Center
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Houston, Texas, United States
Children's Hospital of The King's Daughters
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Norfolk, Virginia, United States
Providence Sacred Heart Medical Center and Children's Hospital
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Spokane, Washington, United States
University Pediatric Hospital
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San Juan, Puerto Rico
Loma Linda University Medical Center
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Loma Linda, California, United States
Prisma Health Richland Hospital
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Columbia, South Carolina, United States
West Virginia University Healthcare
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Morgantown, West Virginia, United States
Geisinger Medical Center
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Danville, Pennsylvania, United States
Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
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New Brunswick, New Jersey, United States
Arkansas Children's Hospital
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Little Rock, Arkansas, United States
East Tennessee Childrens Hospital
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Knoxville, Tennessee, United States
Providence Alaska Medical Center
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Anchorage, Alaska, United States
San Jorge Children's Hospital
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San Juan, Puerto Rico
Summerlin Hospital Medical Center
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Las Vegas, Nevada, United States
University of Vermont and State Agricultural College
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Burlington, Vermont, United States
AdventHealth Orlando
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Orlando, Florida, United States
Yale University
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New Haven, Connecticut, United States
C S Mott Children's Hospital
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Ann Arbor, Michigan, United States
Nemours Children's Hospital
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Orlando, Florida, United States
Arnold Palmer Hospital for Children
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Orlando, Florida, United States
Norton Children's Hospital
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Louisville, Kentucky, United States
Children's Mercy Hospitals and Clinics
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Kansas City, Missouri, United States
University of Florida Health Science Center - Gainesville
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Gainesville, Florida, United States
Children's Hospital New Orleans
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New Orleans, Louisiana, United States
Ochsner Medical Center Jefferson
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New Orleans, Louisiana, United States
Dell Children's Medical Center of Central Texas
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Austin, Texas, United States
Virginia Commonwealth University/Massey Cancer Center
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Richmond, Virginia, United States