| Eligibility |
Inclusion Criteria:
1. Written informed consent obtained from the subject prior to performing any
protocol-related procedures, including screening evaluations.
2. Age >/= 18 years at time of study entry
3. Patients with advanced cancer that is refractory to standard therapy, or that has
either relapsed after standard therapy or has no standard therapy that increases
survival by at least three months.
4. Patients may have unlimited prior chemotherapy treatments.
5. For dose escalation phase, patients may have evaluable or measurable disease. For
ovarian cancer, if no measurable disease is present, patients should have assessable
disease such as pleural effusion, ascites, with CA-125 GCIG criteria.
6. For dose expansion phase, patients must have at least one site of measurable disease
as defined by RECIST criteria (Version 1.1).
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
8. All prior treatment-related toxicities must be Common Terminology Criteria for Adverse
Events (CTCAE) (Version 4.03) </= Grade 1 at the time of screening (except alopecia).
9. Life expectancy of >/= 16 weeks.
10. Adequate normal organ and marrow function as defined by: Hemoglobin >/= 10.0 g/dL with
no blood transfusion within 28 days of starting treatment; White blood cells (WBC) >3
x 10^9/L; Absolute neutrophil count (ANC) >/= 1.5 x 10^9/L (> 1500 per mm^3); Platelet
count >/= 100 x 10^9/L (>100,000 per mm^3); Serum bilirubin </= 1.5 x institutional
upper limit of normal (ULN); AST (SGOT) and ALT (SGPT) </= 2.5 x ULN unless liver
metastases are present, in which case it must be </= 5x ULN; Serum creatinine CL>50
mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine
collection for determination of creatinine clearance--Creatinine CL
(ml/min)=[Weight(kg)*(140-Age)*(0.85 for females or 1 for males)/[72*serum creatinine
(mg/dL)].
11. Subject is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
up.
12. Postmenopausal or evidence of non-childbearing status for women of childbearing
potential: negative urine or serum pregnancy test within 7 days of study treatment.
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; OR surgical sterilization (bilateral oophorectomy or
hysterectomy).
13. Female patients of childbearing potential must use two highly effective forms of
contraception.
14. Male patients must use a condom during treatment and for 3 months after the last dose
of olaparib when having sexual intercourse with a pregnant woman or with a woman of
childbearing potential. Female partners of male patients should also use a highly
effective form of contraception if they are of childbearing potential.
15. Additional criteria for escalation cohorts: A) Patients must have RPA (including KRAS,
NRAS, NF1, HRAS, and BRAF); B) Prior treatment with MEK inhibitors and/or PARP
inhibitors is allowed.
16. Additional criteria for expansion cohorts: A) Patients must have
histologically-confirmed advanced or recurrent ovarian cancer with RPA or that had
progression during prior PARP inhibitor treatment, endometrial cancer with RPA, or
other solid tumor types with RPA; B) Measurable and biopsy-accessible disease; C)
Patient must be willing to undergo biopsy procedure; D) Prior treatment with PARP
inhibitors is allowed.
Exclusion Criteria:
1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site).
2. Previous enrollment in the present study.
3. Participation in another clinical study with an investigational product during the 4
weeks prior to therapy initiation.
4. Recent major surgery within 4 weeks prior to starting study treatment. Minor surgery
within 2 weeks of starting study treatment. Patients must be recovered from effects of
surgery.
5. Patients receiving any systemic chemotherapy or radiotherapy (except for palliative
reasons) within 3 weeks prior to study treatment initiation.
6. Concomitant use of known strong (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 prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3
weeks for other agents.
7. 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 olaparib is 2 weeks.
8. Concomitant use of other anti-cancer therapy (chemotherapy, immunotherapy, hormonal
therapy (Hormone replacement therapy is acceptable), radiotherapy (except for
palliative), biological therapy or other novel agent) or live virus and live bacterial
vaccines while the patient is receiving study medication. Strong or Moderate CYP3A
inhibitors and inducers should not be taken with study treatment; however, if no other
suitable alternative concomitant medication is available, dose reductions may be
allowed under careful monitoring.
9. Known severe hypersensitivity to selumetinib or olaparib, their comparators, or
combination medications or any excipient of these medicinal products, or history of
allergic reactions attributed to compounds of similar chemical or biologic composition
to selumetinib or olaparib, or their comparator.
10. History of another primary malignancy except for: A) Malignancy treated with curative
intent and with no known active disease >/= 3 years before the first dose of study
drug and of low potential risk for recurrence; B) Adequately treated non-melanoma skin
cancer or lentigo maligna without evidence of disease; C) Adequately treated carcinoma
in situ without evidence of disease, e.g. cervical cancer in situ; D) Synchronous
endometrial and ovarian cancer is allowed, provided the endometrial cancer is presumed
Stage IA/B grade 1/2.
11. Any unresolved toxicity (>/= CTCAE grade 2) from previous anti-cancer therapy,
excluding alopecia.
12. Known or suspected brain metastases or spinal cord compression, unless the condition
has been asymptomatic, has been treated with surgery and/or radiation, and has been
stable without requiring corticosteroids nor anticonvulsant medications for at least 4
weeks prior to the first dose of study medication. Patients with history of brain
metastases should undergo brain imaging within 4 weeks of therapy initiation and at
each restaging.
13. Known myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of
MDS/AML.
14. Female subjects who are pregnant/breast-feeding or who are of reproductive potential
and not employing acceptable methods of birth control.
15. Cardiac conditions as follows: Uncontrolled hypertension (BP >/= 150/95 mmHg despite
medical therapy); Acute coronary syndrome within 6 months prior to starting treatment;
Uncontrolled Angina - Canadian Cardiovascular Society grade II-IV despite medical
therapy; Symptomatic heart failure NYHA Class II-IV, prior or current cardiomyopathy,
or severe valvular heart disease; Prior or current cardiomyopathy including but not
limited to the following: known hypertrophic cardiomyopathy or known arrhythmogenic
right ventricular cardiomyopathy; Previous moderate or severe impairment of left
ventricular systolic function (LVEF <45% on echocardiography or equivalent on MUGA)
even if full recovery has occurred; Severe valvular heart disease;
16. (Continued from previous) Baseline LVEF below the LLN measured by ECHO or
institution's LLN for MUGA; Atrial fibrillation with a ventricular rate >100 bpm on
ECG at rest; QTcF >470ms on two or more timepoints or other factors that increase the
risk of QT prolongation such as family history of long QT syndrome.
17. Ophthalmological conditions as follows: Current or past history of retinal pigment
epithelial detachment (RPED)/central serous retinopathy (CSR) or retinal vein
occlusion; or Intraocular pressure (IOP) > 21 mmHg or uncontrolled glaucoma
(irrespective of IOP)
18. Any evidence of a severe or uncontrolled systemic disease (e.g. unstable or
uncompensated respiratory, cardiac, hepatic, or renal disease, active infection
(including hepatitis B, hepatitis C, human immunodeficiency virus [HIV]), active
bleeding diatheses or renal transplant.
19. Previous allogenic bone marrow transplant or double umbilical cord blood
transplantation.
20. Whole blood transfusion in the last 120 days prior to entry to the study.
21. Patient is confirmed to have actively symptomatic pneumonitis.
22. Extensive bilateral lung disease on high-resolution computed tomography (HRCT) scan.
23. Patients unable to swallow orally administered medication and patients with
gastrointestinal disorders likely to interfere with absorption of the study
medication.
24. Immunocompromised patients, e.g. patients known to be serologically positive for HIV.
Patients do NOT need to be tested for HIV in order to enroll on study.
25. Evidence of any other significant clinical disorder or laboratory finding that, in the
opinion of the investigator, would interfere with evaluation of study treatment or
interpretation of patient safety or study results.
26. For the expansion cohorts only: Prior treatment with any MEK inhibitor is not allowed
in the expansion cohorts.
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