Selumetinib and Olaparib in Solid Tumors

Recruitment & Eligibility

Status: Active, not recruiting

Sex: All

Target Recruitment: Not specified

Inclusion Criteria

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. Know

Exclusion Criteria

Not provided

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Maximum Tolerated Dose (MTD) for Combination of Selumetinib and Olaparib in Participants with Advanced or Recurrent Solid Tumors

Secondary Outcome Measures

Name	Time	Method
Determination of Drug Concentration in Selumetinib and Olaparib;Comparison of Baseline Expression Values with Differing Treatment Responses of Selumetinib and Olaparib;Anti-Tumor Activity Evaluation by RECIST v1.1

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