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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)

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ClinicalTrials.gov Identifier: NCT03233204
Recruitment Status : Active, not recruiting
First Posted : July 28, 2017
Last Update Posted : February 8, 2023
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Study Description
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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.

Condition or disease Intervention/treatment Phase
Advanced Malignant Solid Neoplasm Ann Arbor Stage III Childhood Non-Hodgkin Lymphoma Ann Arbor Stage IV Childhood Non-Hodgkin Lymphoma Low Grade Glioma Malignant Glioma Recurrent Childhood Central Nervous System Neoplasm Recurrent Childhood Ependymoma Recurrent Childhood Malignant Germ Cell Tumor Recurrent Childhood Non-Hodgkin Lymphoma Recurrent Childhood Rhabdomyosarcoma Recurrent Childhood Soft Tissue Sarcoma Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor Recurrent Glioma Recurrent Hepatoblastoma Recurrent Langerhans Cell Histiocytosis Recurrent Malignant Solid Neoplasm Recurrent Medulloblastoma Recurrent Neuroblastoma Recurrent Osteosarcoma Refractory Childhood Malignant Germ Cell Tumor Refractory Ependymoma Refractory Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor Refractory Glioma Refractory Hepatoblastoma Refractory Langerhans Cell Histiocytosis Refractory Malignant Glioma Refractory Malignant Solid Neoplasm Refractory Medulloblastoma Refractory Neuroblastoma Refractory Non-Hodgkin Lymphoma Refractory Osteosarcoma Refractory Primary Central Nervous System Neoplasm Refractory Rhabdomyosarcoma Refractory Soft Tissue Sarcoma Rhabdoid Tumor Wilms Tumor Drug: Olaparib Phase 2

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 49 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice)- A Phase 2 Subprotocol of Olaparib in Patients With Tumors Harboring Defects in DNA Damage Repair Genes
Actual Study Start Date : July 24, 2017
Estimated Primary Completion Date : March 31, 2024
Estimated Study Completion Date : March 31, 2024

Resource links provided by the National Library of Medicine

Drug Information available for: Olaparib

Arms and Interventions
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Arm Intervention/treatment
Experimental: Treatment (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.
 Drug: Olaparib
Given PO
Other Names:
  • AZD 2281
  • AZD-2281
  • AZD2281
  • KU-0059436
  • Lynparza
  • PARP Inhibitor AZD2281


Outcome Measures
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Primary Outcome Measures :
  1. Objective response rate (complete response/partial response) [ Time Frame: Up to 4 years ]
    Determined using Response Evaluation Criteria in Solid Tumors version 1.1. 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.


Secondary Outcome Measures :
  1. Progression free survival (PFS) [ Time Frame: From the initiation of protocol treatment to the occurrence of disease progression, disease recurrence, or death from any cause, assessed up to 4 years ]
    PFS along with the confidence intervals will be estimated using the Kaplan-Meier method.

  2. Incidence of toxicity [ Time Frame: Up to 4 years ]
    Evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Toxicity tables will be constructed to summarize the observed incidence by type of toxicity and grade. A patient will be counted only once for a given toxicity for the worst grade of that toxicity reported for that patient. Toxicity information recorded will include the type, severity, time of onset, time of resolution, and the probable association with the study regimen.

  3. Pharmacokinetics (PK) of olaparib [ Time Frame: Pre-dose on day 1, and pre-dose, 1, 2, 4, and 6-8 hours after morning dose on day 8 of cycle 1 ]
    A descriptive analysis of PK parameters will be performed to define systemic exposure, drug clearance, and other pharmacokinetic parameters. The PK parameters will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).


Other Outcome Measures:
  1. Change in tumor genomic profile [ Time Frame: Cycle 5 day 1 to 4 years ]
    Approaches to profiling changes in tumor genomics over time through evaluation of circulating tumor deoxyribonucleic acid will be explored. Descriptive analysis will be performed and will be summarized with simple summary statistics.


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   12 Months to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations
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Information from the National Library of Medicine

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): NCT03233204


Locations
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Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Julia Glade-Bender Children's Oncology Group
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03233204    
Other Study ID Numbers: NCI-2017-00766
NCI-2017-00766 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
APEC1621H
APEC1621H ( Other Identifier: Children's Oncology Group )
APEC1621H ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
First Posted: July 28, 2017    Key Record Dates
Last Update Posted: February 8, 2023
Last Verified: October 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lymphoma
Neoplasms
Sarcoma
Lymphoma, Non-Hodgkin
Glioma
Neuroblastoma
Neoplasms, Germ Cell and Embryonal
Osteosarcoma
Rhabdomyosarcoma
Ependymoma
Sarcoma, Ewing
Medulloblastoma
Neuroectodermal Tumors
Neuroectodermal Tumors, Primitive
Wilms Tumor
 Neuroectodermal Tumors, Primitive, Peripheral
Rhabdoid Tumor
Nervous System Neoplasms
Hepatoblastoma
Central Nervous System Neoplasms
Histiocytosis, Langerhans-Cell
Histiocytosis
Recurrence
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Disease Attributes
Pathologic Processes