A Study Using Olaparib Tablets for Subjects With Advanced Solid Tumours.

A Phase 1, Randomised, Open-label, 4-Period Crossover Study to Develop an In Vitro-In Vivo Correlation for Olaparib Tablets in Subjects With Solid Tumors

This is a phase 1 open label, 4 treatment, 4 sequence and 4 period crossover study in subjects with solid tumours no longer responding to, or eligible for standard therapies, and for whom there are no additional standard therapies likely to benefit the subject.

The study is an open-label, randomised, 4-period, 4-sequence crossover pharmacokinetic study designed to generate in vivo PK data from tablet variants with different size/geometry and dose, to correlate with their corresponding in vitro dissolution profiles. The duration of each dosing period is 7 days including the washout period. Subjects will be randomised to a treatment sequence, following a balanced Latin Squares design. Twelve subjects who meet inclusion/exclusion criteria and have provided informed consent will be randomly assigned to the treatment sequences: ABCD, BDAC, CADB, or DCBA.

On Day 1 of each period, subjects will receive a single dose of either Treatment A, B, C, or D, according to the randomisation schedule. Serial blood samples for determination of olaparib in plasma will be collected for up to 72 hours.

Cancer subjects with advanced solid tumours are required for this study, as pre-clinical toxicology data preclude the use of olaparib in healthy volunteers. The olaparib doses chosen will deliver exposure at or below that which has been previously demonstrated to be acceptable and tolerated in cancer subjects.

Inclusion Criteria:

1. Provision of informed consent prior to any study specific procedures.

2. Female or male subject, aged > 18 years.

3. Histologically or, where appropriate, cytologically confirmed malignant solid tumour refractory or resistant to standard therapy for which no suitable effective standard therapy is available and in the opinion of the investigator might benefit from olaparib therapy.

4. Subjects must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below:

   • Haemoglobin ≥ 100 g/L 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.
   • Subjects must have creatinine clearance estimated of ≥51 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test:

   Estimated creatinine clearance =[(140-age [years]) x weight (kg) x 1.2] (x F)a serum creatinine (μmol/L) a where F=0.85 for females and F=1 for males

5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.

6. Subjects must have a life expectancy ≥ 16 weeks.

7. 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.

8 Male subjects 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 subjects should also use a highly effective form of contraception if they are of childbearing potential.

9 Subjects must have normal GI tract anatomy and function (see exclusion criteria for specifics).

10 Subjects is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations.

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 randomisation in the present study.
3. Participation in another clinical study with an investigational product during the last 1 month.
4. Any previous treatment with a PARP inhibitor, including olaparib.
5. Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation > 500 ms, electrolyte disturbances, etc.) or subjects with congenital long QT syndrome.
6. Subjects receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment.
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 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.
9. Persistent toxicities (Common Terminology Criteria for Adverse Event (CTCAE) > grade 2) caused by previous cancer therapy, excluding alopecia.
10. Subjects with myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of MDS/AML.
11. Subjects with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required. The subject 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. Subjects with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days
12. Major surgery within 2 weeks of starting study treatment and subjects must have recovered from any effects of any major surgery.
13. Subjects 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 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.
14. Subjects unable to swallow orally administered medication and subjects with gastrointestinal disorders likely to interfere with absorption of the study medication including surgery on the upper GI tract and small bowel, malabsorptive disorders, inflammatory bowel disease, GI motility disorders, chronic diarrhea (more than 3 loose bowel movements per day) chronic constipation (no bowel movement for more than two days), recent (in last week) vomiting.
15. Pregnant or breastfeeding women.
16. Immunocompromised subjects, e.g., subjects who are known to be serologically positive for human immunodeficiency virus (HIV).
17. Subjects with a known hypersensitivity to olaparib or any of the excipients of the product.
18. Subjects with known active hepatitis (i.e. Hepatitis B or C) due to risk of transmitting the infection through blood or other body fluids.
19. Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).