Testing the Use of the Combination of Selumetinib and Olaparib or Selumetinib Alone Targeted Treatment for RAS Pathway Mutant Recurrent or Persistent Ovarian and Endometrial Cancers, A ComboMATCH Treatment Trial
Study Details
Study Description
Brief Summary
This phase II trial compares selumetinib plus olaparib to selumetinib alone in women with endometrial or ovarian cancer that has come back (recurrent) or that remains despite treatment (persistent) and harbors a mutation in the RAS pathway. Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Olaparib is an inhibitor of PARP, an enzyme that helps repair deoxyribonucleic acid (DNA) when it becomes damaged. Blocking PARP may help keep tumor cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. The addition of olaparib to selumetinib could increase the percentage of tumors that shrink as well as lengthen the time that the tumors remain stable (without progression) as compared to selumetinib alone.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
PRIMARY OBJECTIVES:
- Compare progression free survival of combination of olaparib and selumetinib sulfate (selumetinib) to selumetinib alone in patients with RAS mutant ovarian cancer. (Cohort 1) II. Compare progression free survival of combination of olaparib and selumetinib to selumetinib alone in patients with RAS mutant endometrial cancer. (Cohort 2)
SECONDARY OBJECTIVES:
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Determine safety of both arms per Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0.
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Compare objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 between the two arms.
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Determine rate of objective response per RECIST 1.1 in those patients that crossover from the single agent arm to the combination arm.
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Report duration of response of the two treatment arms. V. To assess concordance between the diagnostic tumor mutation profile generated by the designated laboratories, the pre-treatment biopsy mutation profile, and the pre-treatment circulating tumor (ct)DNA mutation profile from plasma, as described in ComboMATCH Registration protocol.
TRANSLATIONAL OBJECTIVE:
- To assess association of baseline genomic and transcriptomic status with response and resistance to therapy.
OUTLINE: Patients in both cohorts are randomized to 1 of 2 arms.
ARM I: Patients receive selumetinib orally (PO) twice daily (BID) on days 1-28 of each cycle and olaparib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo a tumor biopsy at baseline and an optional one at end of treatment, blood collection at baseline and optional collection after the first 28 days, as well as computed tomography (CT) scans every 8 weeks. Patients may undergo bone marrow aspiration or biopsy as clinically indicated.
ARM II: Patients receive selumetinib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience progression may elect to cross over to Arm I provided they have not had dose limiting toxicities to monotherapy selumetinib. Patients undergo a tumor biopsy at baseline and an optional one at end of treatment, blood collection at baseline and optional collection after the first 28 days, as well as CT scans every 8 weeks. Patients may undergo bone marrow aspiration or biopsy as clinically indicated.
After completion of study treatment, patients are followed up at 30 days, every 3 months for 2 years, and then every 6 months for 3 years.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Arm I (selumetinib, olaparib) Patients receive selumetinib PO BID on days 1-28 of each cycle and olaparib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo a tumor biopsy at baseline and an optional one at end of treatment, blood collection at baseline and optional collection after the first 28 days, as well as CT scans every 8 weeks. Patients may undergo bone marrow aspiration or biopsy as clinically indicated. |
Procedure: Biopsy
Undergo tumor biopsy
Other Names:
Procedure: Biospecimen Collection
Undergo blood collection
Other Names:
Procedure: Bone Marrow Aspiration and Biopsy
Undergo bone marrow aspiration or biopsy
Procedure: Computed Tomography
Undergo CT scan
Other Names:
Drug: Olaparib
Given PO
Other Names:
Drug: Selumetinib Sulfate
Given PO
Other Names:
|
| Active Comparator: Arm II (selumetinib) Patients receive selumetinib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience progression may elect to cross over to Arm I provided they have not had dose limiting toxicities to monotherapy selumetinib. Patients undergo a tumor biopsy at baseline and an optional one at end of treatment, blood collection at baseline and optional collection after the first 28 days, as well as CT scans every 8 weeks. Patients may undergo bone marrow aspiration or biopsy as clinically indicated. |
Procedure: Biopsy
Undergo tumor biopsy
Other Names:
Procedure: Biospecimen Collection
Undergo blood collection
Other Names:
Procedure: Bone Marrow Aspiration and Biopsy
Undergo bone marrow aspiration or biopsy
Procedure: Computed Tomography
Undergo CT scan
Other Names:
Drug: Selumetinib Sulfate
Given PO
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Progression-free survival (PFS) [The duration of time from enrollment to the date of progression or death, whichever occurs first, assessed up to 5 years]
Disease progression will be defined using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria, as determined by the treating physician. The primary analyses will be based on logrank tests stratified by the stratification factors as recorded at randomization. All enrolled patients will be included, regardless of compliance with their assigned study regimen. Patients will be grouped by their randomized treatment for intention-to-treat analyses (ITT). Treatment hazard ratios and 90% confidence intervals will be estimated using proportional hazards models specified with a main-effect for the randomized treatment assignment (experimental versus [vs] reference), and stratified using the stratification factors recorded at randomization. Treatment group differences will be graphed using Kaplan-Meier methods.
Secondary Outcome Measures
- Incidence of adverse events (AE) [Up to 5 years]
The safety population will support these analyses. The nature, frequency, and degree of toxicity will be tabulated at the System Organ Class and AE-specific term levels using Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Each patient will be represented according to the maximum grade observed for each term. Tabulations will show the number and percentage of patients by maximum grade, within the treatment group received, regardless of the randomized treatment assignment.
- Objective response rate (ORR) between two arms [Within 6 months of the date of last enrollment]
ORR is defined as the binomial proportion of evaluable patients with a best overall response of complete response (CR) or partial response (PR) (by RECIST 1.1) within 6 months of the date of the last enrollment. Responses reported by the treating physician will be used for these analyses. The ORR estimates by treatment arm will be supported by their 2-sided, 95% Wilson-Score confidence intervals. The relative odds of response in the experimental arm (vs the reference arm) will be estimated using a multivariable logistic regression model specified with main effects for the randomized treatment assignment and covariate adjustments for the stratification factors reported at baseline.
- ORR in crossover patients [Up to 5 years]
Determined by RECIST 1.1. The crossover population will support these analyses. The same evaluation criteria for ORR in the measurable disease population will be applied to the crossover population. These analyses will be done separately for each cohort.
- Duration of response of both arms [The time from documentation of either PR or CR until disease progression or death, whichever is observed first, assessed up to 5 years]
These analyses will be supported by patients in the measurable disease population who have a best overall response of PR or CR. Treatment group differences in response duration will be graphed using Kaplan-Meier methods and compared using logrank tests, stratified by the stratification factors defined at randomization. The relative hazards of progression or death in the experimental group (vs the reference group) will be estimated using a multivariable proportional hazards regression model specified with main effects for the treatment indicators and covariate adjustments for the stratification factors reported at baseline. These analyses will be done separately for each cohort.
Other Outcome Measures
- ORR [Up to 5 years]
Defined as the binomial proportion of patients with a best overall response of CR or PR. Defined using RECIST 1.1 criteria. Roughly 10 genomic and transcriptomic measures are expected to present as dichotomous factors. When 3 or more levels are presented, the relatively small sample sizes will likely require collapsing down to 2 levels. If presented as continuous variables, the median of the observed values will classify evaluable patients as having wild-type (WT) or mutated expression.
- Resistance to therapy [Up to 5 years]
defined as the proportion of patients with best overall response of disease progression. Defined using RECIST 1.1 criteria. Roughly 10 genomic and transcriptomic measures are expected to present as dichotomous factors. When 3 or more levels are presented, the relatively small sample sizes will likely require collapsing down to 2 levels. If presented as continuous variables, the median of the observed values will classify evaluable patients as having WT or mutated expression.
- Concordance between the diagnostic tumor mutation profile, biopsy mutations, and pre-treatment circulating tumor deoxyribonucleic acid (ctDNA) mutations [Up to 5 years]
assess the concordance of the diagnostic tumor mutation profile generated by the designated laboratory, the pre-treatment biopsy mutation profile, and the pre-treatment ctDNA mutation profile.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Patients must be enrolled on the ComboMATCH Master Registration Trial EAY191
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Patients must have RAS pathway mutations as determined by the ComboMATCH screening assessment
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Cohort 1: Patients with histologically confirmed RAS pathway mutant ovarian cancer (activating mutations in KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, or inactivating mutations in NF1)
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Cohort 2: Patients with histologically confirmed RAS pathway mutant endometrial cancer (activating mutations in KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, or inactivating mutations in NF1).
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Patients must have disease that can be safely biopsied and agree to a pre-treatment biopsy or have archival tissue available from within 12 months prior to registration
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Patients must have progressed after first-line treatment for recurrent or persistent disease
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Patients with ovarian cancer should not be eligible for further platinum-based therapy
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Patients with endometrial cancer must have received or been offered an immune oncology agent (alone or in combination with lenvatinib) unless there are existing contraindications for immune oncology agents or lenvatinib
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Patients may have received unlimited prior therapy
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Patients must have measurable and biopsiable disease. Measurable disease is defined by RECIST 1.1 as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded). Each lesion must be > 10 mm when measured by CT, magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or > 20 mm when measured by chest x-ray. Lymph nodes must be > 15 mm in short axis when measured by CT or MRI
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Patients must have at least one "target lesion" separate from the lesion to be biopsied to be used to assess response on this protocol as defined by RECIST version 1.1. Tumors within a previously irradiated field will be designated as "non-target" lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy
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Prior therapy must have been completed at least four weeks prior to registration
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Age >= 18
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Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or 2
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Hemoglobin (Hgb) >= 9.5 g/dL with no blood transfusion in the past 28 days (within 14 days prior to registration)
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Platelets >= 100,000/mcl (within 14 days prior to registration)
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Absolute neutrophil count (ANC) >= 1,500/mcl (within 14 days prior to registration)
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Patients must have creatinine clearance estimated of >= 50 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test (within 14 days prior to registration)
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Total serum bilirubin level =< 1.5 x institutional upper limit of normal (ULN) or =< 3 x ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) (within 14 days prior to registration)
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Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (within 14 days prior to registration)
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Patients must be able to swallow and retain oral medications and be without gastrointestinal illnesses that would preclude absorption of selumetinib or olaparib
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Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
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Women of childbearing potential (WOCBP) must agree to use two forms of birth control (hormonal or barrier method of birth control; abstinence) during the study and for 12 weeks after completing treatment
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Non-sterilized male participants or male partners of WOCBP (including males sterilized by a method other than bilateral orchidectomy e.g., vasectomy) who intend to be sexually active with a female partner must be using an acceptable method of contraception such as male condom plus spermicide (condom alone in countries where spermicides are not approved) from the time of screening throughout the total duration of the study and the drug washout period (at least 16 weeks after the last dose of study intervention) to prevent pregnancy in a partner. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Vasectomized (i.e., sterile) males are considered fertile and should still use a male condom plus spermicide as indicated above during the clinical study. Even if the female partner is pregnant, male participants should still use a condom plus spermicide (where approved), as indicated above during the clinical study. Male participants must not donate or bank sperm during this same period. Female partners (of childbearing potential) of male participants must also use a highly effective method of contraception throughout this period
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Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
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Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial
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Patients with evidence of chronic hepatitis B virus (HBV) infection must have an undetectable HBV viral load on suppressive therapy, if indicated
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Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
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Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate central nervous system (CNS) specific treatment is not required and is unlikely to be required during the first cycle of therapy
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Patients with treated brain metastases are eligible if follow-up brain imaging after CNS-directed therapy shows no evidence of progression
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Extra caution should be taken with olaparib, as it crosses the blood brain barrier and can cause edema in brain metastases
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The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information
Exclusion Criteria:
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Patients who have received any MEK inhibitors
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Patients who have progressed while receiving a PARP inhibitor
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Patients who have received chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to registration
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Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia
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Patients with uncontrolled intercurrent illness
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Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to olaparib and selumetinib or any excipients thereof
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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
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Supplementation with vitamin E greater than 100% of the daily recommended dose. Any multivitamin containing vitamin E must be stopped prior to study enrollment even if less than 100% of the daily recommended dosing for vitamin E
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Vitamin E must not be taken in the 7 days prior to initiation of treatment with selumetinib
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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 known moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, Fluconazole, verapamil). The required washout period prior to starting olaparib is at least 14 days or 5 half-lives (whichever is longer) before the first dose of study medication
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Concomitant use of strong CYP2C19 inhibitors (e.g., ticlopidine) or moderate CYP2C19 inhibitors (e.g., omeprazole). The required washout period prior to starting selumetinib is at least 14 days or 5 half-lives (whichever is longer) before the first dose of study medication
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Have received or are receiving an investigational medicinal product (IMP) or other systemic anti-cancer treatment (including chemotherapy, immunotherapy, targeted therapy, biologic therapy, tumor embolization, or monoclonal antibodies) within 4 weeks prior to registration, or within a period during which the IMP or systemic target treatment has not been cleared from the body (e.g., a period of 5 'half-lives'), whichever is longer
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Known myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
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Patients who have had previous organ transplant, allogenic bone marrow transplant or double umbilical cord blood transplantation
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Patients who have had whole blood transfusion within 28 days prior to registration
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Patients with ophthalmological conditions as follows:
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Current or past history of retinal pigment epithelial detachment/central serous retinopathy or retinal vein occlusion.
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Intraocular pressure >21 mmHg (or ULN adjusted by age) or uncontrolled glaucoma (irrespective of intraocular pressure [IOP]). Subjects with known glaucoma and increased IOP who do not have meaningful vision (light perception only or no light perception) and are not experiencing pain related to the glaucoma, may be eligible after discussion with the study chair
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Patients with any other significant abnormality on ophthalmic examination should be discussed with the study chair for potential eligibility
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Ophthalmological findings secondary to long-standing optic pathway glioma (such as visual loss, optic nerve pallor or strabismus) or longstanding orbito-temporal plexiform neurofibroma (PN) (such as visual loss, strabismus) will NOT be considered a significant abnormality for the purposes of the study
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Patients with severe, active co-morbidity defined as any of the following:
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History and/or confirmed pneumonitis
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Uncontrolled hypertension (blood pressure [BP] >= 150/90 mmHg despite medical therapy)
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Acute coronary syndrome within 6 months prior to registration
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Uncontrolled atrial fibrillation on electrocardiogram (ECG) at rest
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Corrected QT interval by Fredericia (QTcF) > 470ms on two or more time points or other factors that increase the risk of QT prolongation such as family history of long QT syndrome
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Women who are pregnant or unwilling to discontinue nursing
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Shannon N Westin, NRG Oncology
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- NCI-2022-06841
- NCI-2022-06841
- EAY191-N4
- EAY191-N4
- U10CA180868