Clinical Trials /

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

NCT03840967

Description:

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.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Esophageal Adenocarcinoma
  • Gastric Adenocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: HCRN ESO17-325
  • NCT ID: NCT03840967

Conditions

  • Esophageal Cancer
  • Gastric Cancer
  • Adenocarcinoma

Interventions

DrugSynonymsArms
NiraparibZejulaNiraparib

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
NiraparibOther
  • Niraparib

Eligibility 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. Participant last treatment with platinum-based chemotherapy was ≤ 12 weeks from
             initiation of protocol therapy.

          5. 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 alone
             or with radiation

             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.

          6. 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.

          7. 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).

          8. 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. Patients are eligible if they
             have a deleterious alteration in one of these pre-specified HR genes, including:
             BRCA1/2, PALB2, ATM, BARD1, BRIP1, CDK12, CHEK2, FANCA, RAD51, RAD51B, RAD51C, RAD51D,
             RAD54L, NBN, ARID1A and GEN1.

             NOTE: Prior 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 prior
             genetic results are not available, subject must have archival tissue or fresh tissue
             (by new biopsy) for testing. Blood will also be required for germline mutation
             analyses. Central confirmation of all results will be performed but are not mandated
             for eligibility.

             NOTE: Both primary tumor tissue and metastatic site sample biopsies are allowed.

          9. 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)

               -  0 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.

         10. Prior cancer treatment must be completed at least 28 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.

         11. 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

               -  Serum 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*

         12. 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.

         13. Females of childbearing potential and males must be willing to abstain from
             heterosexual activity or to use 2 forms of effective methods of contraception from the
             time of informed consent until 150 days after treatment discontinuation. The two
             contraception methods can be comprised of two barrier methods, or a barrier method
             plus a hormonal method.

         14. Participant must agree to not breastfeed during the study or for 180 days after the
             last dose of study treatment.

         15. 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.

         16. 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 platinum-based chemotherapy (platinum
             refractory).

          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.

          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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate
Time Frame:2 years
Safety Issue:
Description: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

Measure:Assess adverse events
Time Frame:2 years
Safety Issue:
Description:Evaluate the safety and tolerability of niraparib as defined by CTCAE v5.
Measure:Progression free survival
Time Frame:3 years
Safety Issue:
Description: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.
Measure:Disease Control Rate
Time Frame:2 years
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Shadia Jalal, MD

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