Education and Training

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

This phase II ComboMATCH treatment trial compares selumetinib plus olaparib to selumetinib alone in women with endometrial or ovarian (fallopian tube and primary peritoneal) 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.

Stanford is currently not accepting patients for this trial.

Stanford Investigator(s):

Intervention(s):

  • procedure: Biopsy
  • procedure: Biospecimen Collection
  • procedure: Bone Marrow Aspiration and Biopsy
  • procedure: Computed Tomography
  • procedure: Echocardiography
  • procedure: Multigated Acquisition Scan
  • drug: Olaparib
  • drug: Selumetinib Sulfate

Eligibility


Inclusion Criteria:

   - Patient must have enrolled onto EAY191 and must have been given a treatment assignment
   to ComboMATCH to EAY191-N4 based on the presence of an actionable mutation as defined
   in EAY191

   - Patients must be enrolled on the ComboMATCH Master Registration Trial EAY191

   - Patients must have RAS pathway mutations as determined by the ComboMATCH screening
   assessment

      - Cohort 1: Patients with histologically confirmed RAS pathway mutant ovarian,
      primary peritoneal, or fallopian tube ("ovarian") cancer (activating mutations in
      KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, or inactivating mutations in NF1)

      - 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).

   - Patients must have disease that can be safely biopsied and agree to a pre-treatment
   biopsy, if disease cannot be safely biopsied, or have archival tissue available from
   within 12 months prior to registration on the ComboMATCH Registration Trial (EAY191)

   - Patients must have progressed after first-line treatment for recurrent or persistent
   disease

   - Patients with ovarian cancer should not be eligible for further platinum-based therapy

   - 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

   - Patients may have received unlimited prior therapy

   - 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

      - 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

   - Prior therapy must have been completed at least four weeks prior to registration

   - Age >= 18

   - Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or 2

   - Hemoglobin (Hgb) >= 9.5 g/dL with no blood transfusion in the past 28 days (within 14
   days prior to registration)

   - Platelets >= 100,000/mcl (within 14 days prior to registration)

   - Absolute neutrophil count (ANC) >= 1,500/mcl (within 14 days prior to registration)

   - 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)

   - Total 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)

   - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (within
   14 days prior to registration)

   - Patients must be able to swallow and retain oral medications and be without
   gastrointestinal illnesses that would preclude absorption of selumetinib or olaparib

   - 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

   - 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

      - Non-sterilized 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

   - 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

   - 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

   - Patients with evidence of chronic hepatitis B virus (HBV) infection must have an
   undetectable HBV viral load on suppressive therapy, if indicated

      - 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

   - 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

      - Patients with treated brain metastases are eligible if follow-up brain imaging
      after CNS-directed therapy shows no evidence of progression

      - Extra caution should be taken with olaparib, as it crosses the blood brain
      barrier and can cause edema in brain metastases

   - 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:

   - Patients who have received any MEK inhibitors

   - Patients who have progressed while receiving a PARP inhibitor

   - Patients who have received chemotherapy or radiotherapy within 4 weeks (6 weeks for
   nitrosoureas or mitomycin C) prior to registration

   - 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

   - Patients with uncontrolled intercurrent illness

   - Patients with >= grade 2 neuropathy within 14 days of registration

   - Patients with severe (Child-Pugh C) liver dysfunction

   - Patients with a history of allergic reactions attributed to compounds of similar
   chemical or biologic composition to olaparib and selumetinib or any excipients thereof

   - 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

      - 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

      - Vitamin E must not be taken in the 7 days prior to initiation of treatment with
      selumetinib

   - 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

   - 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

   - 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

   - Known myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of
   myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)

   - Patients who have had previous organ transplant, allogenic bone marrow transplant or
   double umbilical cord blood transplantation

   - Patients who have had whole blood transfusion within 28 days prior to registration

   - Patients with ophthalmological conditions as follows:

      - Current or past history of retinal pigment epithelial detachment/central serous
      retinopathy or retinal vein occlusion.

      - 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

      - Patients with any other significant abnormality on ophthalmic examination should
      be discussed with the study chair for potential eligibility

      - 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

   - Patients with severe, active co-morbidity defined as any of the following:

      - History and/or confirmed pneumonitis

      - Uncontrolled hypertension (blood pressure [BP] >= 150/90 mmHg despite medical
      therapy)

      - Acute coronary syndrome within 6 months prior to registration

      - Uncontrolled atrial fibrillation

      - Known family history of long QT syndrome

   - Women who are pregnant or unwilling to discontinue nursing

Ages Eligible for Study

18 Years - N/A

Genders Eligible for Study

Female

Not currently accepting new patients for this trial

Contact Information

Stanford University
School of Medicine
300 Pasteur Drive
Stanford, CA 94305
Sanjana Karamcheti
skaram@stanford.edu
Not Recruiting