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A Study Evaluating Safety and Efficacy of Niraparib in Patients With Previously Treated Metastatic Esophageal/Gastroesophageal Junction/Proximal Gastric Adenocarcinoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03840967
Recruitment Status : Recruiting
First Posted : February 15, 2019
Last Update Posted : May 24, 2022
Sponsor:
Collaborators:
GlaxoSmithKline
Indiana University School of Medicine
Information provided by (Responsible Party):
Shadia Jalal, MD, Hoosier Cancer Research Network

Brief Summary:
Patients can be prescreened for the study at the time of diagnosis of locally advanced or metastatic disease by determining presence of LOH high status and/or deleterious alterations in HR pathway genes in the most recent available tumor tissue sample or in blood if they are found to have germline mutations. Patients with either somatic or germline mutations will be allowed. At the time of disease progression, patients with high LOH or deleterious alterations in HR pathway genes and satisfying all other inclusion criteria will be enrolled on the study. Patients will be treated with niraparib (flat dose) orally every day for 28 days until disease progression, unacceptable side effects, withdrawal of consent, or death. CT of the chest/abdomen/pelvis will be performed every 2 months and response will be assessed by RECIST 1.1.

Condition or disease Intervention/treatment Phase
Esophageal Cancer Gastric Cancer Adenocarcinoma Drug: Niraparib Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 43 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study Evaluating Safety and Efficacy of Niraparib in Patients With Previously Treated Homologous Recombination (HR) Defective or Loss of Heterozygosity (LOH) High Metastatic Esophageal/Gastroesophageal Junction/Proximal Gastric Adenocarcinoma
Actual Study Start Date : July 9, 2019
Estimated Primary Completion Date : November 2023
Estimated Study Completion Date : November 2024


Arm Intervention/treatment
Niraparib Drug: Niraparib
Niraparib will be administered as a flat-fixed daily dose depending on weight and platelet count. Subjects will take orally on a daily basis for 28 days. Each cycle = 28 days
Other Name: Zejula




Primary Outcome Measures :
  1. Objective Response Rate [ Time Frame: 2 years ]
    Determine objective response rate (ORR) with niraparib in patients with metastatic esophageal/gastroesophageal junction (GEJ)/proximal gastric adenocarcinoma previously treated with platinum containing chemotherapy and harboring high genome wide loss of heterozygosity (LOH) or defective homologous recombination noted through deleterious alterations in HR genes.


Secondary Outcome Measures :
  1. Assess adverse events [ Time Frame: 2 years ]
    Evaluate the safety and tolerability of niraparib as defined by CTCAE v5.

  2. Progression free survival [ Time Frame: 3 years ]
    PFS is defined as the time from D1 of treatment until the criteria for disease progression is met as defined by RECIST 1.1 or death as a result of any cause, whichever occurs first.

  3. Disease Control Rate [ Time Frame: 2 years ]
    Disease control rate is defined as the proportion of all subjects with stable disease (SD) for 8 weeks, or partial response (PR), or complete response (CR) according to RECIST 1.1.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
  2. Age ≥ 18 years at the time of consent.
  3. ECOG Performance Status of 0-1 within 14 days prior to registration.
  4. Locally advanced esophageal adenocarcinoma or proximal gastric adenocarcinoma or metastatic adenocarcinoma originating from esophagus, GE junction, or proximal stomach who progress/recur beyond 2 months of receiving a platinum- containing regimen

    NOTE: Patients can be pre-screened for study at any time including after surgical resection for locally advanced esophageal cancer, at presentation with metastatic disease and potentially during chemotherapy and radiation prior to surgery.

  5. A subject with symptomatic brain metastasis may be considered if they have completed their treatment for brain metastasis at least 4 weeks prior to study registration, have been off of corticosteroids for ≥ 2 weeks, and are asymptomatic. Patients with asymptomatic brain mets that are untreated will be allowed.
  6. Must not have received more than 1 prior line of chemotherapy in the metastatic setting (could have received immunotherapy, VEGF directed therapy, and/or trastuzumab which does not count as chemotherapy).
  7. One of the following genetic results is required for eligibility:

    • High LOH in tissue OR
    • HR mutation in tissue OR
    • Germline mutation (blood)

    NOTE: Mutations, deletions or loss by fusions are the acceptable alterations in HR genes as long as they are deleterious. Patients are eligible if they have a mutation in pre-specified HR genes BRCA1/2, PALB2, ATM, BARD1, BRIP1, CDK12, CHEK2, FANCA, RAD51, RAD51B, RAD51C, RAD51D, RAD54L, NBN, ARID1A and GEN1. Deleterious mutations in HR genes are defined as those that have been previously characterized to be loss-of-function/pathogenic/or likely pathogenic as specified per the following databases: Clinvar, OncoKB, or BRCAExchange. Mutations or small insertions or deletions that results in truncation, frameshift, stop codon loss, or stop codon gain will also be considered deleterious irrespective of their presence in the aforementioned databases unless previously characterized to be benign. Copy number losses or disruption by fusion will also be considered deleterious irrespective of their presence in the aforementioned databases. Gene amplifications or variants of unknown significance will not be eligible for inclusion.

    NOTE: Genetic testing results from a CLIA certified lab that confirm one of the following: high LOH in tissue, HR mutation in tissue or germline mutation in blood are required and can be used to meet eligibility. Even if subject has met eligibility with one of the criteria above, results from the other analysis is required if available.

    If prior genetic results are not available, subject must have archival tissue or fresh tissue (by new biopsy) for testing. Both primary tumor tissue and metastatic site sample biopsies are allowed. Blood will also be required for germline mutation analyses. Central confirmation of all results will be performed but are not mandated for eligibility. If a subject has met eligibility with prior genetic results but does not have sufficient archival tissue for central confirmation, a biopsy is not required.

  8. Presence of measurable disease by RECIST v1.1, defined as:

    • Tumor lesions that must be accurately measured in at least one dimension (longest diameter in the plane of measurement is to be recorded) with a minimum size of:

      • 10 mm by CT scan (CT scan slice thickness no greater than 5 mm)
      • 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured with calipers should be recorded as non-measurable)
      • 20 mm by chest X-ray
    • Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed.
  9. Prior cancer treatment must be completed at least 14 days prior to registration and the subject must have recovered from all reversible acute toxic effects of the regimen (other than alopecia) to ≤ Grade 1 or baseline.
  10. Demonstrate adequate organ function as defined in the table below; all screening labs to be obtained within 14 days prior to registration.

    • Absolute Neutrophil Count (ANC) ≥ 1.5 K/mm3
    • Hemoglobin (Hgb) ≥ 9 g/dL
    • Platelet Count (Plt) ≥ 100 K/ mm3
    • Creatinine ≤ 1.5 X upper limit of normal (ULN)
    • Bilirubin ≤ 1.5× ULN ((≤2.0 in patients with known Gilberts syndrome))
    • Aspartate aminotransferase (AST) ≤ 2.5× ULN*
    • Alanine aminotransferase (ALT) ≤ 2.5 × ULN*
  11. Females of childbearing potential must have a negative pregnancy test within 7 days prior to study treatment. Urine or serum βhCG if clinically appropriate. If a urine test is done and it is positive or cannot be confirmed as negative, a serum pregnancy test will be required. NOTE: Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months.
  12. Females of childbearing potential must be willing to abstain from heterosexual intercourse or use adequate contraception as described in the protocol. Males must be willing to abstain from heterosexual intercourse or use adequate contraception as described in the protocol.
  13. Participants must agree to not breastfeed during the study or for 30 days after the last dose of study treatment.
  14. As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study.
  15. Participant must agree to not donate blood during the study or for 90 days after the last dose of study treatment.

Exclusion Criteria:

  1. Prior therapy with a PARP inhibitor
  2. Disease progression during first 2 months of standard dose platinum-based chemotherapy (platinum refractory). This excludes low dose platinum based therapy that is given in a chemotherapy-radiation regimen for locally advanced esophageal cancer.
  3. Participant must not be simultaneously enrolled in any other interventional clinical trial.
  4. Participant must not have had major surgery ≤ 3 weeks prior to initiating protocol therapy and participant must have recovered from any surgical effects.
  5. Participant must not have received investigational therapy ≤ 4 weeks, or within a time interval less than at least 5 half-lives of the investigational agent, whichever is shorter, prior initiating protocol therapy.
  6. Participant has had radiation therapy encompassing >20% of the bone marrow within 2 weeks; or any radiation therapy within 1 week prior to Day 1 of protocol therapy.
  7. Participant must not have a known hypersensitivity to niraparib components or excipients including tartrazine.
  8. Participant must not have received a transfusion (platelets or red blood cells) ≤ 4 weeks prior to initiating protocol therapy.
  9. Participant must not have received colony stimulating factors (e.g., granulocyte colony-stimulating factor, granulocyte macrophage colony stimulating factor, or recombinant erythropoietin) within 4 weeks prior initiating protocol therapy.
  10. Participant has had any known Grade 3 or 4 anemia, neutropenia or thrombocytopenia due to prior chemotherapy that persisted > 4 weeks and was related to the most recent treatment.
  11. Participant must not have any known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
  12. Participant must not have a serious, uncontrolled medical disorder, nonmalignant systemic disease, or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent.
  13. No active secondary cancer

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): NCT03840967


Contacts
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Contact: Shadia Jalal, MD 317-274-3658 sjalal@iu.edu
Contact: Rae Richards 317-634-5842 ext 38 rrichards@hoosiercancer.org

Locations
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United States, Florida
Moffitt Cancer Center Completed
Tampa, Florida, United States, 33612
United States, Indiana
Indiana Univeristy Melvin and Bren Simon Cancer Center Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Jessica Norfleet    317-278-5646    jnorflee@iu.edu   
Principal Investigator: Shadia Jalal, MD         
United States, Michigan
University of Michigan Health System Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Tracy Wojciechowski    734-936-0860    tgura@med.umich.edu   
Principal Investigator: Thomas Enzler, MD         
United States, New York
Roswell Park Cancer Institute Recruiting
Buffalo, New York, United States, 14263
Contact: Deeponpaul Singh    716-845-8270    Deeponpaul.Singh@RoswellPark.org   
Principal Investigator: Christos Fountzilas, MD         
Sponsors and Collaborators
Shadia Jalal, MD
GlaxoSmithKline
Indiana University School of Medicine
Investigators
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Principal Investigator: Shadia Jalal, MD Indiana University Melvin and Bren Simon Cancer Center
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Responsible Party: Shadia Jalal, MD, Sponsor-Investigator, Hoosier Cancer Research Network
ClinicalTrials.gov Identifier: NCT03840967    
Other Study ID Numbers: HCRN ESO17-325
First Posted: February 15, 2019    Key Record Dates
Last Update Posted: May 24, 2022
Last Verified: May 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
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Niraparib
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents