PRIMARY OBJECTIVE:
I. To assess the safety of abemaciclib plus olaparib in patients with platinum-resistant
ovarian cancer by determining the maximum tolerated dose and recommended phase 2 dose.
SECONDARY OBJECTIVE:
I. To observe and record anti-tumor activity using overall response rate (ORR) and duration
of response (DoR) with abemaciclib and olaparib, given in combination, in patients with
platinum-resistant ovarian cancer.
EXPLORATORY OBJECTIVES:
I. To assess proof of mechanism (RB, phosphoRB, cleaved caspase 3, Ki67, geminin, gamma-H2AX,
RAD51 nuclear foci, pNBS multiplex, Myc transcriptional targets ODC1 and LDHA, homologous
recombination genes BRCA1, BRCA2, RAD51, serum thymidine kinase), plasma and tumor
pharmacokinetics, and subgroups of response (immunohistochemistry [IHC] for Myc, cyclin E;
next generation sequencing [NGS]/whole exome sequencing [WES] for DCAF, hormone receptor [HR]
repair gene alterations, Myc, and CCNE1; ribonucleic acid sequencing [RNAseq] for Myc and
CCNE1).
II. To contribute genetic analysis data from de-identified biospecimens to Genomic Data
Commons (GDC), a well annotated cancer molecular and clinical data repository, for current
and future research; specimens will be annotated with key clinical data, including
presentation, diagnosis, staging, summary treatment, and if possible, outcome.
III. To bank formalin-fixed, paraffin-embedded (FFPE) tissue, blood (for cell-free DNA
analysis), and nucleic acids obtained from patients at the Experimental Therapeutics Clinical
Trials Network (ETCTN) Biorepository at Nationwide Children's Hospital.
OUTLINE: This is a dose-escalation study of abemaciclib.
Patients receive olaparib orally (PO) twice daily (BID) on days 1-28 and abemaciclib PO BID
on days 8-28 of cycle 1 and days 1-28 of subsequent cycles. Cycles repeat every 28 days in
the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days.
Inclusion Criteria:
- Patients must have histologically confirmed recurrent platinum-resistant epithelial
ovarian carcinoma (EOC) of any histology, as defined by progression within 6 months of
the last dose of platinum-based chemotherapy. Both primary platinum resistant and
acquired platinum resistant patients are allowed
- High-grade serous histology is required (for the dose expansion cohort only)
- Patients must have received 1-3 prior systemic therapies
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
- Hemoglobin >= 10 g/dL (within 28 days prior to administration of study treatment)
- Patients may receive erythrocyte transfusions to achieve this hemoglobin level at
the discretion of the investigator. Initial treatment must not begin earlier than
the day after the erythrocyte transfusion
- Absolute neutrophil count >= 1,500/mcL (within 28 days prior to administration of
study treatment)
- Platelets >= 100,000/mcL (within 28 days prior to administration of study treatment)
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 28 days
prior to administration of study treatment)
- Patients with Gilbert's syndrome with a total bilirubin =< 2.0 times ULN and
direct bilirubin within normal limits are permitted
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) /
alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3 x
institutional ULN, unless liver metastases are present in which case they must be =< 5
x ULN (within 28 days prior to administration of study treatment)
- Patients must have creatinine clearance estimated of >= 51 mL/min using the
Cockcroft-Gault equation or based on a 24-hour urine test (within 28 days prior to
administration of study treatment)
- Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 unless data exists supporting
safe use at lower kidney function values, no lower than 30 mL/min/1.73 m^2 (within 28
days prior to administration of study treatment). Estimated GFR calculated using
Cockcroft-Gault equation
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
load must be undetectable on suppressive therapy, if indicated
- Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen
(HBsAg) result. Patients with a past or resolved HBV infection (defined as the
presence of hepatitis B core antibody and absence of HBsAg) are eligible
- Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load.
- Patients positive for hepatitis C virus (HCV) antibody are eligible only if
polymerase chain reaction is negative for HCV ribonucleic acid (RNA)
- Patients with treated brain metastases are eligible if patient is stable for at least
4 weeks status post (s/p) radiation therapy and off corticosteroids, as ascertained by
clinical examination and brain imaging (magnetic resonance imaging [MRI] or computed
tomography [CT] scan) during the screening period
- Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association Functional Classification. To be
eligible for this trial, patients should be class 2B or better
- Postmenopausal or evidence of non-childbearing status, a 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
postmenopausal 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 sterilization (bilateral oophorectomy or hysterectomy)
- The effects of abemaciclib and olaparib on the developing human fetus are unknown. For
this reason and because CDK-and PARP-inhibiting agents are known to be teratogenic,
women of child-bearing potential and their partners, who are sexually active, must
agree to the use of one highly effective form of contraception and their partner must
use a male condom prior to study entry, for the duration of study participation, and
for 1 month after the last dose of study treatment. 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
- For the dose expansion cohort, patients must have disease amenable to biopsy for
correlative studies, specifically at least 1 tumor accessible and safe for biopsy on
office exam or tumor that a radiologist deems is safe for biopsy in interventional
radiology department based on imaging (dose expansion cohort only). For the dose
escalation cohort, patients with evaluable disease are acceptable
- For inclusion in i) the optional genetic research and ii) the optional biomarker
research, patients must fulfill the following criteria:
- Provision of informed consent for genetic research prior to collection of sample
- Provision of informed consent for biomarker research prior to collection of
sample
- If a patient declines to participate in the optional exploratory genetic research
or the optional biomarker research, there will be no penalty or loss of benefit
to the patient. The patient will not be excluded from other aspects of the study
- Patients may not have received prior CDK 4/6 inhibitors. Previous PARP inhibitor use
is allowed in front-line treatment but not for recurrent disease
- Patients who received chemotherapy must have recovered (Common Terminology Criteria
for Adverse Events [CTCAE] grade =< 1) from the acute effects of chemotherapy except
for residual alopecia or grade 2 peripheral neuropathy prior to randomization. A
washout period of at least 21 days is required between last chemotherapy dose and
randomization (provided the patient did not receive radiotherapy)
- Patients who received radiotherapy must have completed and fully recovered from the
acute effects of radiotherapy. A washout period of at least 28 days is required
between end of radiotherapy and randomization
- For agents other than chemotherapy, a 4 week washout period is required. Previous
bevacizumab use is allowed
- Ability to understand and the willingness to sign a written informed consent document.
Participants with impaired decision-making capacity (IDMC) who have a
legally-authorized representative (LAR) and/or family member available will also be
eligible
Exclusion Criteria:
- Patients who are receiving any other investigational agents
- History of allergic reaction or hypersensitivity attributed to compounds of similar
chemical or biologic composition to abemaciclib, olaparib or any of the excipients of
these products
- Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin,
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g.
ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout
period prior to starting study treatment is 2 weeks. Because the lists of these agents
are constantly changing, it is important to regularly consult a frequently-updated
medical reference. As part of the enrollment/informed consent procedures, the patient
will be counseled on the risk of interactions with other agents, and what to do if new
medications need to be prescribed or if the patient is considering a new
over-the-counter medicine or herbal product
- Patients with psychiatric illness/social situations that would limit compliance with
study requirements
- Pregnant women are excluded from this study because abemaciclib is a CDK-inhibiting
agent and olaparib is a PARP inhibiting agent with the potential for teratogenic or
abortifacient effects. Because there is an unknown but potential risk for adverse
events in nursing infants secondary to treatment of the mother with abemaciclib and
olaparib, breastfeeding should be discontinued if the mother is treated with
abemaciclib and olaparib
- Other malignancy unless curatively treated with no evidence of disease for >= 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
- Resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible
cardiac conditions, as judged by the investigator (e.g., unstable ischemia,
uncontrolled symptomatic arrhythmia, congestive heart failure, corrected QT [QTcF]
prolongation > 500 ms, electrolyte disturbances, ventricular tachycardia and
ventricular fibrillation), or sudden cardiac arrest, etc.), or patients with
congenital long QT syndrome
- Patients with myelodysplastic syndrome/acute myeloid leukemia or with features
suggestive of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML)
- Patients considered a poor medical risk due to a serious, uncontrolled medical
disorder, non-malignant systemic disease or active, uncontrolled infection that, in
the judgment of the investigator, would preclude participation in this study. Examples
include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3
months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal
cord compression, superior vena cava syndrome, extensive interstitial bilateral lung
disease on high resolution computed tomography (HRCT) scan, severe dyspnea at rest or
requiring oxygen therapy, severe renal impairment [e.g. estimated creatinine clearance
< 30 ml/min], history of major surgical resection involving the stomach or small
bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic
condition resulting in baseline grade 2 or higher diarrhea)
- Patients unable to swallow orally administered medication and patients with
gastrointestinal disorders likely to interfere with absorption of the study medication
- Major surgery within 2 weeks of starting study treatment and patients must have
recovered from any effects of any major surgery
- Previous allogenic bone marrow transplant or double umbilical cord blood
transplantation (dUCBT)
- Patients with an active systemic fungal infection
