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

NCT03924245 | Terminated Phase 1 DMC FDA Drug

• 2 other identifiers: VICC GYN 1842NCI-2019-02322
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 2

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.

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

Outcome Measures

Primary Outcomes (2)

• Maximum tolerated dose (phase I)

  28 days

• Objective response rate (phase II)

  Approximately 60 days

Secondary Outcomes (6)

• Clinical benefit rate

  3 years

• Best overall response

  3 years

• Progression free survival

  3 years

• Overall survival

  3 years

• Duration of response

  3 years

Study Arms (1)

Treatment (entinostat, olaparib)

EXPERIMENTAL

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; Drug: Olaparib

Interventions

Entinostat DRUG

Given by mouth

Treatment (entinostat, olaparib)

Olaparib DRUG

Given by mouth

Treatment (entinostat, olaparib)

Eligibility Criteria

• Age: 18 Years+
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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
• If the first ECG shows QTcF \> 470 msec, a second ECG within 24 hours would need to be completed
• 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.

Sponsors & Collaborators

• Vanderbilt-Ingram Cancer Center: lead
• AstraZeneca: collaborator
• Syndax Pharmaceuticals: collaborator

Study Sites (2)

University of Kansas Cancer Center

Kansas City, Kansas, 66160, United States

Location

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, 37232, United States

Location

MeSH Terms

Conditions

Fallopian Tube Neoplasms; Endometrial Neoplasms; Ovarian Neoplasms

Interventions

entinostat; olaparib

Condition Hierarchy (Ancestors)

Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Fallopian Tube Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Uterine Neoplasms; Uterine Diseases; Endocrine Gland Neoplasms; Ovarian Diseases; Endocrine System Diseases; Gonadal Disorders

Study Officials

• Marta Crispens, MD

  Vanderbilt Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Sponsor Investigator

Study Record Dates

• First Submitted: April 18, 2019
• First Posted: April 23, 2019
• Study Start: October 1, 2020
• Primary Completion: February 4, 2022
• Study Completion: February 4, 2022
• Last Updated: April 4, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)