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Clinical trial information and results are updated daily from ClinicalTrials.gov. The latest data update was conducted on 01/26/2021.

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

Clinicaltrials.gov identifier NCT03924245

Recruitment Status Recruiting

First Posted April 23, 2019

Last update posted June 5, 2020

Study Description

Brief summary:

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.

  • Condition or Disease: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
  • Intervention/Treatment: Drug: Entinostat
    Drug: Olaparib
  • Phase: Phase 1/Phase 2
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.

Study Design
  • Study Type: Interventional
  • Estimated Enrollment: 73 participants
  • Intervention Model: Single Group Assignment
  • Masking: None (Open Label) ()
  • Primary Purpose: Treatment
  • 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
  • Actual Study Start Date: September 2019
  • Estimated Primary Completion Date: September 2023
  • Estimated Study Completion Date: September 2025
Arms and interventions
Arm Intervention/treatment
Experimental: Treatment (entinostat, olaparib)
Patients 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
Drug: Entinostat
Given by mouth

Drug: Olaparib
Given by mouth
Outcome Measures
  • Primary Outcome Measures: 1. Maximum tolerated dose (phase I) [ Time Frame: 28 days ]
  • 2. Objective response rate (phase II) [ Time Frame: Approximately 60 days ]
  • Secondary Outcome Measures: 1. Clinical benefit rate [ Time Frame: 3 years ]
  • 2. Best overall response [ Time Frame: 3 years ]
  • 3. Progression free survival [ Time Frame: 3 years ]
  • 4. Overall survival [ Time Frame: 3 years ]
  • 5. Duration of response [ Time Frame: 3 years ]
  • 6. 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 ]
Eligibility Criteria
  • Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
  • Sexes Eligible for Study: Female
  • Accepts Healthy Volunteers: No
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 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

Contacts and Locations
Contacts

Contact: Vanderbilt-Ingram Service for Timely Access 800-811-8480 cip@vanderbilt.edu

Locations

United States, Tennessee
Vanderbilt-Ingram Cancer Center
Nashville

Sponsors and Collaborators

Vanderbilt-Ingram Cancer Center

AstraZeneca

Syndax Pharmaceuticals

Investigators

Principal Investigator: Marta Crispens, MD Vanderbilt Medical Center

More Information
  • Responsible Party: Vanderbilt-Ingram Cancer Center
  • ClinicalTrials.gov Identifier: NCT03924245 History of Changes
  • Other Study ID Numbers: VICC GYN 1842, NCI-2019-02322
  • First Posted: April 23, 2019 Key Record Dates
  • Last Update Posted: June 5, 2020
  • Last Verified: June 2020
  • Individual Participant
    Data (IPD) Sharing
    Statement:
  • Plan to Share IPD: No
  • 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.: Yes
  • Additional relevant MeSH terms: Carcinoma
    Adenocarcinoma
    Fallopian Tube Neoplasms
    Endometrial Neoplasms
    Cystadenocarcinoma, Serous
    Carcinoma, Endometrioid
    Carcinosarcoma
    Mixed Tumor, Mullerian
    Adenocarcinoma, Clear Cell