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.
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
- Ideal body weight will be used, unless actual weight is less than ideal
- 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. 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
- 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.
- 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
