Clinical Trials /

Olaparib and Entinostat in Patients With Recurrent, Platinum-Refractory, Resistant Ovarian, Primary Peritoneal, Fallopian Tube Cancers

NCT03924245

Description:

This phase I/II trial studies the side effects and best dose of olaparib and entinostat and to see how well they work in treating patients with ovarian, primary peritoneal, or fallopian tube cancers that have come back or do not respond to platinum-based chemotherapy. Olaparib and entinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Fallopian Tube Carcinoma
  • Fallopian Tube Carcinosarcoma
  • Ovarian Carcinoma
  • Ovarian Carcinosarcoma
  • Peritoneal Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Olaparib and Entinostat in Patients With Recurrent, Platinum-Refractory, Resistant Ovarian, Primary Peritoneal, Fallopian Tube Cancers
  • Official Title: A Phase I/II Study of Olaparib With Entinostat in the Treatment of Recurrent, Platinum-Refractory or Resistant, Homologous Recombination Repair Proficient Ovarian, Primary Peritoneal, and Fallopian Tube Cancers

Clinical Trial IDs

  • ORG STUDY ID: VICC GYN 1842
  • SECONDARY ID: NCI-2019-02322
  • NCT ID: NCT03924245

Conditions

  • Fallopian Tube Cancer
  • Fallopian Tube Carcinosarcoma
  • Fallopian Tube Clear Cell Adenocarcinoma
  • Fallopian Tube Endometrioid Adenocarcinoma
  • High Grade Fallopian Tube Serous Adenocarcinoma
  • High Grade Ovarian Serous Adenocarcinoma
  • Ovarian Carcinosarcoma
  • Ovarian Clear Cell Adenocarcinoma
  • Ovarian Endometrioid Adenocarcinoma
  • Primary Peritoneal Serous Adenocarcinoma
  • Recurrent Endometrial Carcinoma
  • Recurrent Ovarian Carcinoma
  • Recurrent Primary Peritoneal Carcinoma

Interventions

DrugSynonymsArms
EntinostatTreatment (entinostat, olaparib)
OlaparibTreatment (entinostat, olaparib)

Purpose

This phase I/II trial studies the side effects and best dose of olaparib and entinostat and to see how well they work in treating patients with ovarian, primary peritoneal, or fallopian tube cancers that have come back or do not respond to platinum-based chemotherapy. Olaparib and entinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Determine the maximum tolerated dose (MTD) for the combination of olaparib and entinostat
      in the treatment of recurrent, platinum-refractory or resistant high-grade serous carcinoma
      of the ovary, fallopian tube or peritoneum. (Phase I) II. Determine the objective response
      rate in patients with recurrent, platinum-refractory or resistant, homologous repair
      proficient (HRP) high-grade carcinoma of the ovary, fallopian tube or peritoneum treated with
      the combination of olaparib and entinostat at the recommended phase 2 dose, as determined in
      phase I of this trial. (Phase II)

      SECONDARY OBJECTIVES:

      I. Assess the safety and tolerability of the combination of olaparib and entinostat in
      patients with recurrent, platinum-refractory or resistant high-grade serous carcinoma of the
      ovary, fallopian tube, or peritoneum. (Phase I) II. Further assess the nature and degree of
      toxicity of olaparib and entinostat in this cohort of patients. (Phase II) III. Determine the
      clinical benefit rate (CBR) (complete response [CR] + partial response [PR] + stable disease
      [SD]) as assessed at the time of best response to therapy). (Phase II) IV. Determine the
      progression free (PFS) and overall survival (OS). (Phase II) V. Determine the duration of
      response (DoR). (Phase II)

      EXPLORATORY OBJECTIVES:

      I. Assess the correlation between the Myriad myChoice homologous recombination pathway
      deficiency (HRD) score and the response to treatment.

      II. Assess the degree of deoxyribonucleic acid (DNA) damage in circulating tumor cells and
      tumor biopsies (optional) after cycle 2 and at the end of treatment by phosphorylated (p)HAX2
      and PAR and correlate with the response to treatment.

      III. Assess baseline cyclin E amplification in ovarian tumors by fluorescence in situ
      hybridization (FISH) and correlate with response to treatment.

      IV. Assess the expression of ki67/mib1 as a marker of cell proliferation in circulating tumor
      cells and in tumor biopsy specimens (optional) after cycle 2 of therapy and at the end of
      treatment and correlate with response to treatment.

      V. Measure cyclin E1, CDK2, E2F1, and BRD expression by immunohistochemistry in circulating
      tumor cells and in tumor biopsy specimens (optional) after cycle 2 of therapy and at the end
      of treatment and correlate with response to treatment.

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

      Patients receive entinostat orally (PO) 1 week before starting combination therapy (day -7).
      Patients then receive entinostat PO on days 1, 8, 15, and 22, and olaparib PO twice daily
      (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression and
      unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days and then every 12
      weeks.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (entinostat, olaparib)ExperimentalPatients receive entinostat PO 1 week before starting combination therapy (day -7). Patients then receive entinostat PO on days 1, 8, 15, and 22, olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression and unacceptable toxicity
  • Entinostat
  • Olaparib

Eligibility Criteria

        Inclusion Criteria:

          -  High-grade carciomas of the ovary, fallopian tube, or periteonum, based on local
             pathology review, including high grade serous carcinoma, high grade endometrioid
             carcinomas, clear cell carcinoma, and carcinosarcoma.

          -  Platinum-refractory or resistant disease, as defined by progressive disease while
             receiving platinum-based chemotherapy or with recurrent disease < 6 months after the
             completion of platinum-based chemotherapy.

          -  May have received up to 2 prior therapies for platinum-resistant ovarian cancer.

          -  Must have received prior-platinum-based chemotherapy.

          -  BRCA1, BRCA2, RAD51, BRIP1, ATM, FANCL, PALB2 and other FA/BRCA pathway gene
             wild-type.

          -  Tumor HR-proficient, as assessed by Myriad myChoice HRD Test (HRD score < 42).

          -  Provision of informed consent prior to any study specific procedures

          -  Patients must have normal organ and bone marrow function measured within 28 days prior
             to administration of study treatment as defined below:

               -  Haemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days

               -  Absolute neutrophil count (ANC) ≥ 1.5 x 109 /L

               -  Platelet count ≥ 100 x 109 /L

               -  Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)

               -  Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT))
                  / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) ≤
                  2.5 x institutional upper limit of normal unless liver metastases are present in
                  which case they must be ≤ 5x ULN

               -  Patients must have creatinine clearance estimated using the Cockcroft-Gault
                  equation of ≥51 mL/min:

        Estimated creatinine clearance = (140-age [years]) x weight (kg) (x 0.85) serum creatinine
        (mg/dL) x 72

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1

          -  Patients must have a life expectancy ≥ 16 weeks.

          -  Postmenopausal or evidence of non-childbearing status for women of childbearing
             potential: negative urine or serum pregnancy test within 28 days of study treatment
             and confirmed prior to treatment on day 1. Postmenopausal is defined as:

               -  Amenorrheic for 1 year or more following cessation of exogenous hormonal
                  treatments

               -  Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the
                  post menopausal range for women under 50

               -  Radiation-induced oophorectomy with last menses >1 year ago

               -  Chemotherapy-induced menopause with >1 year interval since last menses

               -  Surgical sterilisation (bilateral oophorectomy or hysterectomy)

          -  Patient is willing and able to comply with the protocol for the duration of the study
             including undergoing treatment and scheduled visits and examinations.

          -  At least one lesion, not previously irradiated, that can be accurately measured at
             baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must have short
             axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and
             which is suitable for accurate repeated measurements.

          -  Formalin fixed, paraffin embedded (FFPE) tumor sample or slides from the primary
             cancer must be available for myRisk HRD testing. If there is not written confirmation
             of the availability of an archived tumor sample prior to enrolment the patient is not
             eligible for the study (See Appendix E for specific specimen requirements).
             Additionally, a second FFPE tumor sample OR 10 unstained slides must be available for
             performance of correlative studies.

        The patient must provide separate informed consent to obtain the optional tumor biopsy.

        If a patient declines to participate in the optional tissue biopsy, there will be no
        penalty or loss of benefit to the patient. The patient will not be excluded from other
        aspects of the study.

        Exclusion Criteria:

          -  Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
             staff and/or staff at the study site)

          -  Previous enrollment in the present study

          -  Participation in another clinical study with an investigational product during the
             last 4 weeks.

          -  Any previous treatment with PARP inhibitor, including olaparib.

          -  Any previous treatment with an HDAC inhibitor, including entinostat.

          -  Low grade or borderline epithelial ovarian, fallopian tube, or peritoneal cancers,
             sex- cord stromal tumors of the ovary, germ cell tumors of the ovary.

          -  Patients with known germline mutations of BRCA1, BRCA1, RAD51, ATM, FANCL, PALB2, and
             other FA/BRCA pathway genes.

          -  Patients whose tumors are HR-deficient, as measured by Myriad myChoice HRD test (HRD
             score > 42).

          -  Other malignancy within the last 5 years except: adequately treated non-melanoma skin
             cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ
             (DCIS), Stage 1, grade 1 endometrial carcinoma, or other solid tumours including
             lymphomas (without bone marrow involvement) curatively treated with no evidence of
             disease for ≥5 years. Patients with a history of localised triple negative breast
             cancer may be eligible, provided they completed their adjuvant chemotherapy more than
             three years prior to registration, and that the patient remains free of recurrent or
             metastatic disease

          -  Resting ECG with QTcF > 470 msec on 2 or more time points within a 24 hour period or
             family history of long QT syndrome

          -  Patients receiving any systemic chemotherapy or radiotherapy (except for palliative
             reasons) within 3 weeks prior to study treatment.

          -  Concomitant use of known strong CYP3A inhibitors (eg. itraconazole,telithromycin,
             clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
             saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg.
             ciprofloxacin, erythromycin, diltiazem, fluconazole,verapamil). See
             https://secure.medicalletter.org/system/files/private/TML-article1491e.pdf for a more
             complete list. The required washout period prior to starting olaparib is 2 weeks.

          -  Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin,
             rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort ) or
             moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). See
             https://secure.medicalletter.org/system/files/private/TML-article-1491e.pdf for a more
             complete list. The required washout period prior to starting olaparib is 5 weeks for
             enzalutamide or phenobarbital and 3 weeks for other agents.

          -  Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) grade 2)
             caused by previous cancer therapy, excluding alopecia.

          -  Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features
             suggestive of MDS/AML

          -  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 treatment. Patients with spinal cord compression unless considered to
             have received definitive treatment for this and evidence of clinically stable disease
             for 28 days.

          -  Major surgery within 2 weeks of starting study treatment and patients must have
             recovered from any effects of any major surgery.

          -  Patients considered a poor medical risk due to a serious, uncontrolled medical
             disorder, non-malignant systemic disease or active, uncontrolled infection. Examples
             include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3
             months) myocardial infarction, uncontrolled hypertension, recent bleeding diathesis,
             uncontrolled major seizure disorder, unstable spinal cord compression, superior vena
             cava syndrome, extensive interstitial bilateral lung disease on High Resolution
             Computed Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining
             informed consent.

          -  Patients unable to swallow orally administered medication and patients with
             gastrointestinal disorders likely to interfere with absorption of the study
             medication.

          -  Breast feeding women.

          -  Patients, e.g., patients who are known to be serologically positive for human
             immunodeficiency virus (HIV).

          -  Patients with a known hypersensitivity to olaparib or any of the excipients of the
             product.

          -  Patients with a known hypersensitivity to entinostat or any of the excipients of the
             product.

          -  Patients with known active hepatitis (i.e. Hepatitis B or C) due to risk of
             transmitting the infection through blood or other body fluids

          -  Previous allogenic bone marrow transplant or double umbilical cord blood
             transplantation (dUCBT)

          -  Whole blood transfusions in the last 120 days prior to entry to the study.

          -  Patients taking warfarin
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (phase I)
Time Frame:28 days
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Clinical benefit rate
Time Frame:3 years
Safety Issue:
Description:
Measure:Best overall response
Time Frame:3 years
Safety Issue:
Description:
Measure:Progression free survival
Time Frame:3 years
Safety Issue:
Description:
Measure:Overall survival
Time Frame:3 years
Safety Issue:
Description:
Measure:Duration of response
Time Frame:3 years
Safety Issue:
Description:
Measure:Incidence of adverse events per national Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Time Frame:Up to 30 days after treatment
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Vanderbilt-Ingram Cancer Center

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