PRIMARY OBJECTIVE:
I. To evaluate whether combination treatment with temozolomide (TMZ) + olaparib shows
preliminary evidence of clinical activity among patients with advanced uterine leiomyosarcoma
(LMS) as measured by the confirmed objective response rate (ORR).
SECONDARY OBJECTIVES:
I. To evaluate the toxicity profile associated with the combination treatment. II. To
evaluate the progression free survival (PFS) associated with the combination treatment.
III. To evaluate what proportion of uterine LMS tumors exhibit homologous recombination (HR)
deficiency as measured by (1) genomic alterations in HR components at baseline and (2)
deoxyribonucleic acid (DNA) repair protein RAD51 homolog (RAD51) foci formation at baseline
and while on study treatment.
IV. To evaluate the feasibility of these assays in human tissue, and to preliminarily
evaluate for any association between presence of HR deficiency as measured by each assay and
increased clinical benefit from the study treatment.
EXPLORATORY OBJECTIVES:
I. To evaluate what proportion of uterine LMS tumors exhibit HR deficiency as measured by
Schlafen family member number 11(SLFN11) protein expression at baseline.
II. To evaluate the feasibility of these assays in human tissue, and to preliminarily
evaluate for any association between presence of HR deficiency as measured by this assay and
increased clinical benefit from the study treatment.
III. To evaluate MGMT protein expression in uterine LMS tumors, and to preliminarily evaluate
for any association between MGMT expression and increased clinical benefit from the study
treatment.
IV. To perform an optional third tissue biopsy in patients who initially benefit from study
treatment but later show early evidence of disease progression to evaluate for changes in the
status of the RAD51 foci, MGMT, and SLFN11 assays at that time.
OUTLINE:
Patients receive olaparib orally (PO) twice per day (BID) and temozolomide PO once daily (QD)
on days 1-7. Cycles repeat every 21 days in the absence of disease progression or
unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 2 years, and
then every 6 months until death or withdrawal of consent.
Inclusion Criteria:
- Patients must have histologically documented LMS of uterine origin. Pathology review
and confirmation of diagnosis will occur at the site enrolling the patient on this
study.
- Patients must have locally advanced and unresectable or metastatic disease.
- Patients must have disease which is measurable at study entry according to Response
Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria. Additionally,
patients must have a site of disease deemed accessible for biopsy at no or minimal
risk to the patient (including through the use of image-guidance). If there are
questions regarding the feasibility of biopsy, the case should be reviewed with
interventional radiology or the appropriate department at the study site prior to
registration.
- Patients must have had prior progression on, or intolerance to, at least one line of
systemic therapy for advanced LMS. Adjuvant therapy administered after curative
resection will not qualify as prior treatment. There is no upper limit on the number
of prior therapies received.
- Patients must demonstrate an Eastern Cooperative Oncology Group (ECOG) performance
status (PS) of =< 2 (Karnofsky >= 50%)
- Absolute neutrophil count >= 1,500/mcL (measured within 14 days prior to
administration of study treatment)
- Hemoglobin >= 9 g/dL (without transfusion of packed red blood cells within the past 28
days) (measured within 14 days prior to administration of study treatment)
- Platelets >= 100,000/mcL (measured within 14 days prior to administration of study
treatment)
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (measured within 14
days prior to administration of study treatment)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional ULN (measured within 14 days prior to administration of study
treatment)
- Glomerular filtration rate (GFR) >= 51 mL/min, based on a 24-hour urine test for
creatinine clearance or estimated using the Cockcroft-Gault equation (measured within
14 days prior to administration of study treatment)
- If patients have evidence of chronic hepatitis B virus (HBV) infection, HBV viral load
must be undetectable on suppressive therapy if indicated. Patients with a past or
resolved HBV infection (defined as the presence of hepatitis B core antibody and
absence of hepatitis B surface antigen [HBsAg]) are eligible.
- If patients have a history of hepatitis C virus (HCV) infection, they must be treated
with undetectable HCV viral load (polymerase chain reaction is negative for HCV
ribonucleic acid [RNA]).
- Patients must be postmenopausal or have evidence of non-childbearing status, OR, for
women of childbearing potential, must have a negative urine or serum pregnancy test
within 28 days of study treatment and confirmed again on day 1 prior to study
treatment.
- Postmenopausal is defined as:
- Amenorrheic for >= 1 year 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)
- Patients and their partners, if sexually active and of childbearing potential, must
agree to the use of two highly effective forms of contraception in combination
throughout the period of taking study treatment and for 3 months after the last dose
of study drug(s) to prevent pregnancy in the study patient or partner.
- Patients must be able to swallow orally administered medication.
- Patients must have a life expectancy >= 16 weeks.
- Patients must be able to understand and be willing to sign a written informed consent
document. Patients with impaired decision-making capacity (IDMC) will be eligible if
they have a close caregiver or legally authorized representative (LAR) available to
assist them.
- Patients must be willing and able to comply with the protocol for the duration of the
study, including undergoing treatment and attending scheduled visits and examinations.
- Patients with human immunodeficiency virus (HIV) infection may be enrolled on this
study provided: (a) they are on a stable regimen of highly active anti-retroviral
therapy (HAART) with no medications otherwise prohibited by this protocol (e.g.
drug-drug interactions) and (b) require no concurrent antibiotics or antifungals for
the prevention of opportunistic infections and (c) have a CD4 count above 250 cell/mcL
and an undetectable viral load on standard polymerase chain reaction (PCR)-based tests
within 1 month of initiation of study treatment. Other patients with clinically
significant immunosuppression, e.g. organ transplant patients, are not eligible. If
clarification is needed, this may be discussed with the medical monitor.
- Patients must be able to have temozolomide provided as a standard of care medication.
Exclusion Criteria:
- Patients must not have had any previous treatment with any poly(adenosine
diphosphate[ADP]-ribose) polymerase (PARP) inhibitors, including olaparib, or prior
treatment with dacarbazine and/or temozolomide.
- Patients must have recovered from adverse events due to prior anti-cancer therapy
(i.e., may not have residual toxicities > grade 1 or above baseline), excluding
alopecia. Patients who have endocrinopathies associated with prior immunotherapy
treatment but which are controlled with replacement therapy are eligible.
- Prior to initiating study treatment, at least 28 days must have elapsed from the last
dose of systemic anti-cancer treatment (cytotoxic, biologic or immunotherapeutic) or
radiation therapy (except for palliative radiation, in which case a 14-day washout
applies).
- Patients must not have had major surgery within 2 weeks of starting study treatment
and must have recovered from any effects of any major surgery that occurred > 2 weeks
before starting study treatment.
- Patients must not be receiving any other investigational agent.
- Patients must not have been diagnosed with another 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), any other malignant condition considered indolent and
unlikely to require active therapy.
- Patients must not have myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or
bone marrow biopsy findings consistent with MDS and/or AML.
- Patients must not have active central nervous system (CNS) or leptomeningeal disease
at the time of enrollment. Patients with a history of such disease previously treated
with curative intent (such as with surgery or radiation) that have not progressed on
subsequent imaging, have been clinically asymptomatic, and have not received systemic
corticosteroids for at least 28 days, are eligible.
- Patients must not have a history of allergic reactions attributed to compounds of
similar chemical or biologic composition to olaparib or TMZ or any of the excipients
of any study product.
- Patients must refrain from 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 for strong or moderate CYP3A inhibitors prior
to starting olaparib 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 must refrain from concomitant use of known strong CYP3A inducers (e.g.,
phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine,
carbamazepine, nevirapine and St John's wort) or moderate CYP3A inducers (e.g.,
bosentan, efavirenz, modafinil). The required washout period for strong or moderate
CYP3A inducers prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital
and 3 weeks for other agents.
- Patients must not have an uncontrolled intercurrent illness including, but not limited
to, ongoing or active infection, 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, or psychiatric illness
that would limit compliance with study requirements.
- Pregnant women are excluded from this study because olaparib is a PARP inhibitor 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 olaparib, breastfeeding should be discontinued if the mother is treated
with olaparib. These potential risks may also apply to other agents used in this
study.
- Patients must not have gastrointestinal disorders likely to interfere with absorption
of the study medication.
- Patients must not have had involvement in the planning and/or conduct of the study.
