Clinical Trials /

Olaparib and Ramucirumab in Treating Patients With Metastatic or Locally Recurrent Gastric or Gastroesophageal Junction Cancer That Cannot Be Removed by Surgery

NCT03008278

Description:

This pilot phase I/II trial studies the side effects and best dose of olaparib when given together with ramucirumab and how well they work in treating patients with gastric or gastroesophageal junction cancer that has spread to other places in the body, has come back, or cannot be removed by surgery. Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as ramucirumab , may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving olaparib and ramucirumab may work better in treating patients with gastric or gastroesophageal junction cancer compared to ramucirumab and paclitaxel (a chemotherapy drug) or ramucirumab alone.

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

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Olaparib and Ramucirumab in Treating Patients With Metastatic or Locally Recurrent Gastric or Gastroesophageal Junction Cancer That Cannot Be Removed by Surgery
  • Official Title: A Phase 1/2 Study of Olaparib in Combination With Ramucirumab in Metastatic Gastric and Gastroesophageal Junction Adenocarcinoma (10017760)

Clinical Trial IDs

  • ORG STUDY ID: NCI-2016-02049
  • SECONDARY ID: NCI-2016-02049
  • SECONDARY ID: 10066
  • SECONDARY ID: 10066
  • SECONDARY ID: P30CA016359
  • SECONDARY ID: UM1CA186689
  • NCT ID: NCT03008278

Conditions

  • Gastroesophageal Junction Adenocarcinoma
  • Metastatic Malignant Neoplasm in the Lymph Nodes
  • Recurrent Gastric Carcinoma
  • Stage IV Gastric Cancer AJCC v7

Interventions

DrugSynonymsArms
OlaparibAZD2281, KU-0059436, Lynparza, PARP Inhibitor AZD2281Treatment (olaparib, ramucirumab)
Ramucirumabanti-VEGFR-2 fully human monoclonal antibody IMC-1121B, Cyramza, IMC-1121B, LY3009806, Monoclonal Antibody HGS-ETR2Treatment (olaparib, ramucirumab)

Purpose

This pilot phase I/II trial studies the side effects and best dose of olaparib when given together with ramucirumab and how well they work in treating patients with gastric or gastroesophageal junction cancer that has spread to other places in the body, has come back, or cannot be removed by surgery. Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as ramucirumab, may interfere with the ability of tumor cells to grow and spread. Giving olaparib and ramucirumab may work better in treating patients with gastric or gastroesophageal junction cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the safe dose of olaparib with ramucirumab, but not to exceed olaparib dose
      of 300 mg twice daily (tablet formulation). (Phase I) II. To determine the efficacy of
      olaparib plus ramucirumab as measured by the objective response rate (ORR). (Phase II).

      SECONDARY OBJECTIVES:

      I. To estimate median progression-free survival (PFS). II. To estimate median overall
      survival (OS). III. To measure the prevalence of the BROCA-HR biomarker in our study
      population.

      IV. To determine toxicity of olaparib and ramucirumab combination. V. To evaluate the effects
      of this regimen on quality of life scores by European Organization for Research and Treatment
      of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30).

      TERTIARY OBJECTIVES:

      I. To assess the correlation between the Myriad homologous recombination deficiency (HRD)
      assay results, the signature 3 status, and mutations in BROCA-HR panel.

      II. To evaluate the association between findings from BROCA-HR panel, the Myriad HRD assay,
      and signature 3 results with response to therapy.

      III. To determine results of immunoassay for poly-ADP-ribosylated (PAR) substrates in tumor
      tissue.

      IV. To create a PDX model to study DNA repair in gastric tumors treated with PARP inhibitors
      (PARPi) from both pre-treatment biopsy and repeat biopsy after 16 weeks of treatment.

      V. Biobank additional tumor tissue for future genomic analysis. VI. Biobank peripheral blood
      for future genomic analysis and assessment of circulating tumor deoxyribonucleic acid (DNA).

      OUTLINE: This is a phase I, dose-escalation study of olaparib followed by a phase II study.

      Patients receive olaparib orally (PO) twice daily (BID) on days 1-14 and ramucirumab
      intravenously (IV) over 60 minutes on day 1. Courses repeat every 14 days in the absence of
      disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 4 weeks and then every 6
      weeks thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (olaparib, ramucirumab)ExperimentalPatients receive olaparib PO BID on days 1-14 and ramucirumab IV over 60 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
  • Olaparib

Eligibility Criteria

        Inclusion Criteria:

          -  The patient must have histologically confirmed, gastric carcinoma, including
             gastroesophageal junction (GEJ) adenocarcinoma (patients with adenocarcinoma of the
             distal esophagus are eligible if the primary tumor involves the GEJ)

          -  The patient has metastatic disease or locally recurrent, unresectable disease with
             measurable lymph node metastases

               -  For patients with nonregional lymph node metastases are eligible, but lymph node
                  metastases must be measurable by Response Evaluation Criteria in Solid Tumors
                  (RECIST) version (v)1.1

               -  For patients with locally recurrent, unresectable disease if there is at least
                  one lymph node metastasis either regional or non-regional that is measurable by
                  RECIST v1.1

               -  For patients who have received prior radiation treatment the measurable lesions
                  must be outside the radiation field

          -  The patient must have measurable disease by RECIST v1.1

          -  The patient must have experienced disease progression during or within 4 months after
             the last dose of chemotherapy for metastatic disease, or during or within 6 months
             after the last dose of adjuvant chemotherapy

          -  The patient must have experienced disease progression as outlined above after
             treatment with 1 or more prior chemotherapies

          -  All previous treatments are acceptable as long as they did not contain ramucirumab or
             PARP inhibitors

          -  Elevation in tumor markers without radiographic evidence of disease progression is not
             satisfactory for progression on previous treatment

          -  Patients who did not tolerate previous chemotherapy regimens are eligible as long as
             there is disease progression within 4 months after the last dose of therapy

          -  The patient has a life expectancy of >= 12 weeks

          -  The patient has resolution to grade =< 1 (or grade =< 2 for neuropathy) by National
             Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), of all
             clinically significant toxic effects of prior chemotherapy, surgery, radiotherapy, or
             hormonal therapy (with the exception of alopecia)

          -  Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1 (Karnofsky
             >= 60%)

          -  Leukocytes >= 3,000/mcL

          -  Absolute neutrophil count >= 1,500/mcL

          -  Platelets >= 100,000/mcL

          -  Hemologic > 9 g/dL

          -  Total bilirubin =< 1.5 x the institutional upper limit of normal (ULN)

          -  Aspartate aminotransferases (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x institutional ULN

          -  Creatinine =< 1.5 x institutional ULN OR creatinine clearance >= 60 mL/min/1.73 m^2
             for patients with creatinine levels above institutional normal

          -  Proteinuria urinary protein is =< 1+ on dipstick or routine urinalysis, or a 24-hour
             urine collection for protein < 1000 mg of protein in 24 hours

          -  Coagulation parameters (international normalized ratio [INR], activated partial
             thromboplastin time [aPTT]) =< 1.25 x institutional limits, except where a lupus
             anti-coagulant has been confirmed; patients on full dose anti-coagulation must be on a
             stable dose for at least 14 days; if receiving warfarin, the patient must have an INR
             =< 3.0 without any evidence of active bleeding within 14 days prior to first dose of
             study treatment or a pathologic condition that carries a high risk of bleeding (tumor
             involvement with major blood vessels or varices)

          -  Women of child-bearing potential and men must agree to use adequate contraception
             including hormonal, barrier, or abstinence; contraception must be started prior to
             study enrollment; female patients of childbearing potential must have a negative serum
             pregnancy test within 7 days prior to randomization; should a woman become pregnant or
             suspect she is pregnant while she or her partner is participating in this study, she
             should inform her treating physician immediately; men treated or enrolled on this
             protocol must also agree to use adequate contraception prior to the study, for the
             duration of the study participation, and for 4 months after completion of olaparib and
             ramucirumab administration

          -  Ability to understand and the willingness to sign a written informed consent document

          -  The patient must be willing to undergo a biopsy prior to treatment

          -  The patient must be willing to undergo repeat biopsy at week 16 (for the first 20
             patients in the phase 2 part of the study)

          -  Patients must be able to tolerate oral medications either by mouth or feeding tube,
             and not have a gastrointestinal illness that would preclude absorption of olaparib

          -  Adequately controlled blood pressure (BP) < 140 mmHg (systolic) and < 90 mmHg
             (diastolic) taken in the clinic setting by a medical professional within 2 weeks prior
             to starting study; patients with hypertension may be managed with up to a maximum of 3
             antihypertensive medications; a cardiologist or blood pressure specialist must
             evaluate patients who are on 3 antihypertensive medications within 4 weeks of
             enrollment

          -  Patients who have the following risk factors are considered to be at increased risk
             for cardiac toxicity and must have documented left ventricular ejection fraction
             (LVEF) by echocardiogram greater than institution's lower limit of normal (or 55% if
             threshold for normal not otherwise specified by institutional guidelines) obtained
             within 3 months

               -  Prior treatment with anthracyclines

               -  Prior treatment with trastuzumab

               -  A New York Heart Association (NYHA) classification of II controlled with
                  treatment

               -  Prior central thoracic radiation therapy (RT), including RT to the heart.

               -  History of myocardial infarction within 12 months (patients with history of
                  myocardial infarction within 6 months are excluded)

        Exclusion Criteria:

          -  Patients with untreated brain metastases are excluded from this clinical trial because
             of their poor prognosis and because they often develop progressive neurologic
             dysfunction that would confound the evaluation of neurologic and other adverse events

          -  Patients cannot have received any other investigational agents within the past 3 weeks

          -  The patient has experienced any grade 3-4 gastrointestinal bleeding within 3 months
             prior to randomization

          -  The patient has experienced any arterial thrombotic events, including but not limited
             to myocardial infarction, transient ischemic attack, cerebrovascular accident, or
             unstable angina, within 6 months prior to enrollment

          -  The patient has an ongoing or active infection, symptomatic congestive heart failure,
             unstable angina pectoris, symptomatic or poorly controlled cardiac arrhythmia,
             uncontrolled thrombotic or hemorrhagic disorder, or any other serious uncontrolled
             medical disorder in the opinion of the investigator

          -  The patient has an ongoing or active psychiatric illness or social situation that
             would limited compliance with study requirements

          -  Clinically significant peripheral vascular disease or vascular disease (abdominal
             aortic aneurysm > 5 cm) or aortic dissection; if known history of abdominal aortic
             aneurysm with >= 4 cm in diameter, all of the following must be met

               -  An ultrasound within the last 6 months required to document that it is =< 5 cm

               -  Patient must be asymptomatic from the aneurysm

               -  Blood pressure must be well controlled as defined in this protocol

          -  The patient has uncontrolled or poorly controlled hypertension despite standard
             medical management as defined in this protocol

          -  NYHA classification of III or IV

          -  History of hypertensive crisis or hypertensive encephalopathy within 3 years

          -  A major surgical procedure, open biopsy, non-healing wound, ulcer or significant
             traumatic injury within 28 days prior to starting ramucirumab (percutaneous,
             endobronchial, and endoscopic biopsies are allowed)

          -  The patient has received chemotherapy, radiotherapy, immunotherapy, or targeted
             therapy for gastric cancer within 2 weeks of enrollment

          -  The patient has received any investigational therapy within 4 weeks of enrollment

          -  The patient has received prior therapy with ramucirumab or any PARP inhibitor

          -  Patients must not have evidence of coagulopathy or bleeding diathesis; therapeutic
             anticoagulation for prior thromboembolic events is permitted; the clinical indication
             for therapeutic anticoagulation must be clearly documented prior to enrollment and
             must be discussed with the principal investigator (PI); patients on greater than or
             equal to 2 anti-thrombotic agents, including but not limited to anti-platelet agents
             (nonsteroidal anti-inflammatory drugs [NSAIDS]/aspirin, clopidogrel), heparin, low
             molecular weight heparin, warfarin and a direct thrombin inhibitor will be excluded

          -  The patient has elective or planned major surgery to be performed during the course of
             the clinical trial

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to olaparib and ramucirumab

          -  Pregnant women are excluded from this study; breastfeeding should be discontinued if
             the mother is treated with olaparib and ramucirumab

          -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
             therapy are ineligible

          -  The patient has known and active alcohol or drug dependency

          -  The patient has a concurrent active malignancy other than treated non-melanoma skin
             cancers or in situ neoplasm; a patient with a prior history of malignancy is eligible,
             provided that they have been free of disease for > 3 years

          -  Patients may not have features suggestive of myelodysplastic syndrome (MDS) or acute
             myelogenous leukemia (AML) on peripheral blood smear or bone marrow biopsy, if
             clinically indicated

          -  Patients may not have current signs and/or symptoms of bowel obstruction within 1
             month prior to starting study drugs, except if it was a temporary incident (improved
             within < 24 hours [hr] with medical management)

          -  History of hemoptysis within the last 1 month

          -  History of abdominal fistula, intra-abdominal abscess, or gastrointestinal perforation
             within the last 3 months

          -  Dependency on IV hydration > 1 day per week

          -  Participants receiving any medications or substances that are strong inhibitors or
             inducers of CYP3A4 are ineligible; dihydropyridine calcium-channel blockers are
             permitted for management of hypertension

          -  Current use of natural herb products or other complementary alternative medications;
             if used previously, patients must have at least 1-week washout and must stop using
             them while participating in this study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose limiting toxicity and maximum tolerated dose of oloparib assessed by NCI CTCAE version 4.0 (Phase I)
Time Frame:Up to 14 days
Safety Issue:
Description:Will be estimated using the 95% confidence interval (CI) based on Wilson's method. The Wilcoxon rank sum test and Fisher's exact test will be applied to study the association between the response status and the continuous and categorical variables, respectively. The generalized non-linear model and logistic regression will be applied for multivariable data analysis. The adjusted p-value and 95% CI of the odds ration will be reported.

Secondary Outcome Measures

Measure:Progression free survival
Time Frame:From start of treatment to time of progression or death, whichever occurs first, assessed up to 1 year
Safety Issue:
Description:Will be compared for duration of response survival with Kaplan-Meier estimates and log-rank tests. The Rothman CI will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease of the PFS data. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.
Measure:Overall survival
Time Frame:Up to 1 year
Safety Issue:
Description:Will be compared for duration of response survival with Kaplan-Meier estimates and log-rank tests. The Rothman CI will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.
Measure:BROCA-HR status
Time Frame:Up to 1 year
Safety Issue:
Description:Will be compared for duration of response survival with Kaplan-Meier estimates and log-rank tests. The Rothman CI will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.
Measure:Incidence of adverse events assessed by NCI CTCAE version 4.0
Time Frame:Up to 30 days of last dose administration
Safety Issue:
Description:Will be tabulated by type and grade and compared to established rates for ramucirumab monotherapy. Ninety-five percent confidence intervals will be calculated for each of these.
Measure:EORTC QLQ-C30 scores
Time Frame:Up to 112 days
Safety Issue:
Description:Will be compared between groups using two-sample t-tests. Also, will examine whether there is a difference in these measures based on response using 2-way analysis of variance models where group and response will be factors and the measures will be the outcome.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

March 2, 2018