Selumetinib and Olaparib in Solid Tumors

NCT03162627 | Active Not Recruiting Phase 1 FDA Drug

• 2 other identifiers: 2016-1129NCI-2018-01205
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

Brief Summary

This study has 2 phases: Phase 1 (dose escalation) and Phase 2 (dose expansion). The goal of Phase 1 of this clinical research study is to find the highest tolerable dose combination of selumetinib and olaparib that can be given to patients who have solid tumors that are advanced or recurrent (has returned after treatment). The goal of Phase 2 is to learn if the highest tolerable dose combination found in Phase 1 can help to control advanced or recurrent solid tumors. The safety of the study drug combination will also be studied in both parts. This is an investigational study. Selumetinib is not FDA approved or commercially available. It is currently being used for research purposes only. Olaparib is FDA approved and commercially available for the treatment of ovarian cancer that has a certain type of genetic mutation (change). It is considered investigational to use selumetinib in combination with olaparib to treat advanced or recurrent cancer. The study doctor can explain how the study drugs are designed to work. Up to 90 participants will be enrolled in this study. All will take part at MD Anderson.

Conditions

Malignant Neoplasm of Breast; Malignant Neoplasms of Digestive Organs; Malignant Neoplasms of Female Genital Organs; Malignant Neoplasms of Male Genital Organs; Malignant Neoplasms of Thyroid and Other Endocrine Glands

Keywords

Malignant neoplasm of breast; Malignant neoplasms of digestive organs; Malignant neoplasms of female genital organs; Malignant neoplasms of male genital organs; Malignant neoplasms of thyroid and other endocrine glands; Solid tumors; Ras Pathway Alterations; Ovarian Tumors with PARP Resistance; Selumetinib; AZD6244; Olaparib; Lynparza

Outcome Measures

Primary Outcomes (1)

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

  MTD defined by dose limiting toxicities (DLTs) that occur during the first 4 weeks of therapy and are related to the study medications. Grading of DLTs follow the guidelines provided in the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

  28 days

Secondary Outcomes (3)

• Determination of Drug Concentration in Selumetinib and Olaparib

  Day 1,8, and 15 of Cycle 1, and Day 1 of Cycle 2.

• Comparison of Baseline Expression Values with Differing Treatment Responses of Selumetinib and Olaparib

  Day 1,8,15,22 of Cycle 1, Day 1 of Cycle 2.,Day 1 of Cycle 3, and 7 days after last dose of study drugs.

• Anti-Tumor Activity Evaluation by RECIST v1.1

  4 months

Study Arms (5)

Selumetinib + Olaparib

EXPERIMENTAL

Dose Escalation Phase: Participants take both Selumetinib and Olaparib by mouth 2 times each day, about 12 hours apart at the Starting Dose Level. Treatment cycle is 28 days. When maximum tolerated dose reached, Dose Expansion Phase begins.

Drug: Selumetinib; Drug: Olaparib

Ovarian Cancer with RPA

EXPERIMENTAL

Dose Expansion Phase: Selumetinib + Olaparib taken at the maximum tolerated dose from Dose Escalation Phase.

Drug: Selumetinib; Drug: Olaparib

Endometrial Cancer with RPA

EXPERIMENTAL

Dose Expansion Phase: Selumetinib + Olaparib taken at the maximum tolerated dose from Dose Escalation Phase.

Drug: Selumetinib; Drug: Olaparib

Ovarian Cancer-Progression-prior PARP Treatment

EXPERIMENTAL

Dose Expansion Phase: Selumetinib + Olaparib taken at the maximum tolerated dose from Dose Escalation Phase.

Drug: Selumetinib; Drug: Olaparib

Solid Tumors that Harbor Somatic RPA

EXPERIMENTAL

Dose Expansion Phase: Selumetinib + Olaparib taken at the maximum tolerated dose from Dose Escalation Phase.

Drug: Selumetinib; Drug: Olaparib

Interventions

Selumetinib DRUG

Dose Escalation Phase Starting Dose: 50 mg by mouth twice a day on Days 1-28. Dose Expansion Phase Starting Dose: Maximum tolerated dose from Dose Escalation Phase.

Also known as: AZD6244

Endometrial Cancer with RPA; Ovarian Cancer with RPA; Ovarian Cancer-Progression-prior PARP Treatment; Selumetinib + Olaparib; Solid Tumors that Harbor Somatic RPA

Olaparib DRUG

Dose Escalation Phase Starting Dose: 150 mg by mouth twice a day on Days 1-28. Dose Expansion Phase Starting Dose: Maximum tolerated dose from Dose Escalation Phase.

Also known as: Lynparza

Endometrial Cancer with RPA; Ovarian Cancer with RPA; Ovarian Cancer-Progression-prior PARP Treatment; Selumetinib + Olaparib; Solid Tumors that Harbor Somatic RPA

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent obtained from the subject prior to performing any protocol-related procedures, including screening evaluations.
• Age \>/= 18 years at time of study entry
• 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.
• Patients may have unlimited prior chemotherapy treatments.
• 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.
• For dose expansion phase, patients must have at least one site of measurable disease as defined by RECIST criteria (Version 1.1).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• 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).
• Life expectancy of \>/= 16 weeks.
• 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)/\[72\*serum creatinine (mg/dL)\].
• 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.
• 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).
• Female patients of childbearing potential must use two highly effective forms of contraception.
• 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.
• 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.

You may not qualify if:

• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
• Previous enrollment in the present study.
• Participation in another clinical study with an investigational product during the 4 weeks prior to therapy initiation.
• 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.
• Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment initiation.
• 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.
• 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.
• 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.
• 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.
• 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.
• Any unresolved toxicity (\>/= CTCAE grade 2) from previous anti-cancer therapy, excluding alopecia.
• 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.
• Known myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of MDS/AML.
• Female subjects who are pregnant/breast-feeding or who are of reproductive potential and not employing acceptable methods of birth control.
• 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;

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• AstraZeneca: collaborator

Study Sites (1)

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Sun C, Fang Y, Labrie M, Li X, Mills GB. Systems approach to rational combination therapy: PARP inhibitors. Biochem Soc Trans. 2020 Jun 30;48(3):1101-1108. doi: 10.1042/BST20191092.

  PMID: 32379297 DERIVED

Related Links

• University of Texas MD Anderson Cancer Center Website

MeSH Terms

Conditions

Breast Neoplasms

Interventions

AZD 6244; olaparib

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Shannon Westin, MD

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 18, 2017
• First Posted: May 22, 2017
• Study Start: August 4, 2017
• Primary Completion (Estimated): August 30, 2026
• Study Completion (Estimated): August 30, 2026
• Last Updated: April 15, 2026

Record last verified: 2026-04

Locations

US (1)