Clinical Trials /

Olaparib and Cediranib Maleate in Treating Patients With Recurrent, Refractory, or Metastatic Endometrial Cancer

NCT03660826

Description:

This phase II trial studies how well olaparib and cediranib maleate work in treating patients with endometrial cancer that has come back (recurrent), does not respond to treatment (refractory), or has spread to other places in the body (metastatic). Olaparib and cediranib maleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Endometrial Carcinoma
Recruiting Status:

Suspended

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Olaparib and Cediranib Maleate in Treating Patients With Recurrent, Refractory, or Metastatic Endometrial Cancer
  • Official Title: A Randomized Phase II Study Comparing Single-Agent Olaparib, Single Agent Cediranib, and the Combination of Cediranib/Olaparib in Women With Recurrent, Persistent or Metastatic Endometrial Cancer

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-01672
  • SECONDARY ID: NCI-2017-01672
  • SECONDARY ID: NRG-GY012
  • SECONDARY ID: NRG-GY012
  • SECONDARY ID: U10CA180868
  • NCT ID: NCT03660826

Conditions

  • Endometrial Undifferentiated Carcinoma
  • Endometrioid Adenocarcinoma
  • Recurrent Endometrial Serous Adenocarcinoma
  • Recurrent Uterine Corpus Carcinoma
  • Stage IV Uterine Corpus Cancer AJCC v7
  • Stage IVA Uterine Corpus Cancer AJCC v7
  • Stage IVB Uterine Corpus Cancer AJCC v7

Interventions

DrugSynonymsArms
CediranibAZD2171Arm I (cediranib maleate)
Cediranib MaleateAZD2171, AZD2171 Maleate, RecentinArm I (cediranib maleate)
OlaparibAZD 2281, AZD-2281, AZD2281, KU-0059436, Lynparza, PARP inhibitor AZD2281Arm II (olaparib)

Purpose

This phase II trial studies how well olaparib and cediranib maleate work in treating patients with endometrial cancer that has come back (recurrent), does not respond to treatment (refractory), or has spread to other places in the body (metastatic). Olaparib and cediranib maleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To compare the efficacy of single-agent olaparib and the combination of olaparib and
      cediranib (and potentially other combination arms that may be added by subsequent amendment)
      versus single agent cediranib as measured by progression free survival (PFS), in patients
      with recurrent, persistent or metastatic endometrial cancer.

      SECONDARY OBJECTIVES:

      I. To compare the efficacy of single-agent olaparib and the combination of olaparib and
      cediranib (and potentially other combination arms that may be added by subsequent amendment)
      versus single-agent cediranib as measured by overall survival (OS) in patients with
      recurrent, persistent or metastatic endometrial cancer.

      II. To compare the efficacy of single-agent olaparib and the combination of olaparib and
      cediranib (and potentially other combination arms may be added by subsequent amendment versus
      single-agent cediranib as measured by response rate in patients with recurrent, persistent or
      metastatic endometrial cancer.

      III. To assess the safety and tolerability of single-agent cediranib, single-agent olaparib,
      and the combination of olaparib and cediranib (and potentially other combination arms may be
      added by subsequent amendment).

      IV. To assess if mutations in deoxyribonucleic acid (DNA) homologous repair genes (assayed
      prior to all treatment and prior to the study treatment) are predictive of response to
      olaparib alone or in combination with cediranib. (Integrated Biomarker) V. To assess if
      markers of angiogenesis in serial plasma samples are associated with response to cediranib
      alone or in combination with olaparib. (Integrated Biomarker)

      EXPLORTORY OBJECTIVES:

      I. To compare the efficacy of the combination of olaparib and cediranib (and potentially
      other combination arms may be added by subsequent amendment) versus single agent olaparib as
      measured by PFS, response rate and OS, if and only if the combination is superior to the
      single-agent cediranib arm.

      II. To assess if phosphatase and tensin homolog (PTEN) loss as assessed by
      immunohistochemistry (IHC) is predictive of response to olaparib alone or in combination with
      cediranib. (Exploratory Biomarker) III. To assess if loss of function of ARID1A assessed by
      immunohistochemistry (IHC) and mutational profile is predictive of response to olaparib alone
      or in combination with cediranib. (Exploratory Biomarker) IV. To assess if TP53 mutation
      status and p53 expression as assessed by IHC is associated with response to olaparib or in
      combination with cediranib. (Exploratory Biomarker) V. To assess if markers of angiogenesis
      in tissue are associated with response to cediranib alone or in combination with olaparib.
      (Exploratory Biomarker) VI. To assess if microsatellite instability (MSI) as assessed by loss
      of DNA mismatch repair (MMR) proteins is associated with response to olaparib alone or in
      combination with cediranib. (Exploratory Biomarker) VII. To assess if surrogate markers for
      the TCGA molecular subgroups p53 IHC, MSI, and mutational status of the exonuclease domain of
      polymerase-epsilon (POLE) are associated with response to treatment in all arms. (Exploratory
      Biomarker) VIII. To examine the association of the change in mutant allele frequency with
      response to treatment and to identify resistance mutations at the time of recurrence using
      circulating tumor (ct)DNA. (Exploratory Biomarker)

      OUTLINE: Patients are randomized to 1 of 3 arms.

      ARM I: Patients receive cediranib maleate orally (PO) once daily (QD). Cycles repeat every 28
      days in the absence of disease progression or unaccepted toxicity.

      ARM II: Patients receive olaparib PO twice daily (BID). Cycles repeat every 28 days in the
      absence of disease progression or unaccepted toxicity.

      ARM III: Patients receive olaparib PO BID and cediranib maleate PO QD. Cycles repeat every 28
      days in the absence of disease progression or unaccepted toxicity.

      After completion of study treatment, patients are followed up every 3 months for 2 years and
      then every 6 months for 3 years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (cediranib maleate)ExperimentalPatients receive cediranib maleate PO QD. Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity.
  • Cediranib
  • Cediranib Maleate
Arm II (olaparib)ExperimentalPatients receive olaparib PO BID. Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity.
  • Olaparib
Arm III (cediranib maleate, olaparib)ExperimentalPatients receive olaparib PO BID and cediranib maleate PO QD. Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity.
  • Cediranib
  • Cediranib Maleate
  • Olaparib

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have recurrent or persistent endometrial carcinoma, which is refractory
             to curative therapy or established treatments; histologic confirmation of the original
             primary tumor is required; patients with the following histologic epithelial cell
             types are eligible: endometrioid adenocarcinoma, serous adenocarcinoma,
             undifferentiated carcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise
             specified (N.O.S.); NOTE: clear cell histology is excluded

          -  Patients must have evaluable disease as defined by Response Evaluation Criteria in
             Solid Tumors (RECIST) 1.1 or non-measurable (detectable) disease

               -  Measurable disease is defined 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 computed tomography (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 with measurable disease must have at least one "target lesion" 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

               -  Non-measurable (detectable) disease in a patient is defined in this protocol as
                  one who does not have measurable disease but has at least one of the following
                  conditions:

                    -  Ascites and/or pleural effusion attributed to tumor;

                    -  Solid and/or cystic abnormalities on radiographic imaging that do not meet
                       RECIST 1.1 definitions for target lesions

          -  Patients must have signed an approved informed consent and authorization permitting
             release of personal health information

          -  Patients must have had one prior chemotherapeutic regimen for management of
             endometrial carcinoma; initial treatment may include chemotherapy, chemotherapy and
             radiation therapy, and/or consolidation/maintenance therapy; chemotherapy administered
             in conjunction with primary radiation as a radio-sensitizer WILL be counted as a
             systemic chemotherapy regimen

          -  Patients are allowed to receive, but are not required to receive, one additional
             cytotoxic regimen for management of recurrent or persistent disease according to the
             following definition: cytotoxic regimens include any agent that targets the genetic
             and/or mitotic apparatus of dividing cells, resulting in dose-limiting toxicity to the
             bone marrow and/or gastrointestinal mucosa; Note: patients on this non-cytotoxic study
             are allowed to receive one additional cytotoxic chemotherapy regimen for management of
             recurrent or persistent disease, as defined above; however, patients are encouraged to
             enroll on second-line non-cytotoxic studies prior to receiving additional cytotoxic
             therapy

          -  Patients may have received non cytotoxic therapy including immunotherapy but excluding
             cediranib and olaparib for management of recurrent or persistent disease; prior
             hormonal therapy is allowed; hormonal therapy for grade 1 endometrial cancers with low
             volume or indolent disease is encouraged

          -  The trial is open to females only (including women with an intact uterus with uterine
             cancer); fertile females of childbearing potential need to agree to use adequate
             contraceptive measures from 2 weeks prior to the study and until 1 month after study
             treatment discontinuation, and have a negative serum or urine pregnancy test within 3
             days prior to the start of study treatment

          -  Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of
             0,1 or 2 (Karnofsky >= 60%) within 7 days prior to registration

          -  Hemoglobin >= 10 mg/dL with no blood transfusion in the past 28 days (within 28 days
             prior to administration of study drug)

          -  Platelet count >= 100 x 10^9/L (within 28 days prior to administration of study drug)

          -  Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (within 28 days prior to
             administration of study drug)

          -  Creatinine clearance >= 51 mL/min (within 28 days prior to administration of study
             drug)

          -  Serum bilirubin =< 1.5 X upper limit of normal (ULN) (within 28 days prior to
             administration of study drug)

          -  Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x ULN (within 28
             days prior to administration of study drug)

          -  Urine protein: creatinine (UPC) < 1 or < 2+ proteinuria on two consecutive dipsticks
             taken no less than 1 week apart. Patients with 2+ proteinuria on dipstick must also
             have UPC < 0.5 on 2 consecutive samples (within 28 days prior to administration of
             study drug)

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

          -  Patients must have adequately controlled blood pressure (BP), with a BP no greater
             than 140 mmHg (systolic) and 90 mmHg (diastolic) for eligibility; patients must have a
             BP of =< 140/90 mmHg taken in the clinic setting by a medical professional within 2
             weeks prior to starting study; patients with hypertension may be managed with up to a
             maximum of three antihypertensive medications; it is strongly recommended that
             patients who are on three antihypertensive medications be followed by a cardiologist
             or blood pressure specialist for management of blood pressure while on protocol

               -  Patients must be willing and able to check and record daily blood pressure
                  readings

          -  The patient or a legally authorized representative must provide study-specific
             informed consent prior to study entry

          -  Adequately controlled thyroid function, with no symptoms of thyroid dysfunction

          -  Postmenopausal or evidence of non-childbearing status for women of childbearing
             potential as confirmed by a negative urine or serum pregnancy test within 7 days prior
             to start of investigational products (IPs); postmenopausal is defined as:

               -  Age >= 60 years, or

               -  Age < 60 with any one or more of the conditions below:

                    -  Amenorrheic for >= 1 year in the absence of chemotherapy and/or hormonal
                       treatments,

                    -  Luteinizing hormone and/or follicle stimulating hormone and/or estradiol
                       levels in the post-menopausal range

                    -  Radiation-induced oophorectomy with last menses > 1 year ago,

                    -  Chemotherapy-induced menopause with > 1 year interval since last menses,

                    -  Surgical sterilization (bilateral oophorectomy or hysterectomy)

          -  Patients must have a life expectancy of greater than 16 weeks

        Exclusion Criteria:

          -  Prior enrollment into a clinical trial including cediranib or olaparib; Note: prior
             bevacizumab is not an exclusion criterion

          -  Prior chemotherapy, endocrine therapy, radiotherapy, or investigational agents within
             4 weeks

          -  Current signs/symptoms of bowel obstruction and/or signs/symptoms of bowel obstruction
             within the preceding 3 months

          -  History of gastrointestinal perforation; patients with a history of abdominal fistula
             will be considered eligible if the fistula was surgically repaired or has healed,
             there has been no evidence of fistula for at least 6 months, and patient is deemed to
             be at low risk of recurrent fistula

          -  Uncontrolled intercurrent illness including, but not limited to known ongoing or
             active infection, symptomatic congestive heart failure, unstable angina pectoris,
             cardiac arrhythmia, extensive interstitial bilateral lung disease on high resolution
             computed tomography (HRCT) scan or psychiatric illness/social situations that would
             limit compliance with study requirements

          -  Concomitant use of known strong cytochrome (CYP) 3A 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 study treatments is 2 weeks
             for strong inhibitors, and at least 1 week for moderate inhibitors

          -  Concomitant use of known strong CYP3A inducers (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 study treatments is 5 weeks for enzalutamide or
             phenobarbital and 4 weeks for other agents

          -  Pregnant women are excluded from this study because cediranib and olaparib are agents
             with the potential for teratogenic or abortifacient effects; because there is an
             unknown but potential risk of adverse events in nursing infants secondary to treatment
             of the mother with cediranib and olaparib, breastfeeding should be discontinued if the
             mother is treated with cediranib or olaparib; these potential risks may also apply to
             other agents used in this study; for women of child bearing capacity a negative
             pregnancy test is required

          -  Known human immunodeficiency virus (HIV)-positive individuals are ineligible because
             of the potential for pharmacokinetic interactions with cediranib or olaparib; in
             addition, these individuals are at increased risk of lethal infections when treated
             with marrow-suppressive therapy

          -  Known active hepatitis B or hepatitis C infection on antiviral treatment

          -  Prior history of stroke or transient ischemic attack within the last 6 months

          -  Left ventricular ejection fraction (LVEF) < lower limit of normal (LLN) per
             institutional guidelines, or < 55%, if threshold for normal not otherwise specified by
             institutional guidelines, for patients with the following risk factors:

               -  Prior treatment with anthracyclines

               -  Prior treatment with trastuzumab

               -  Prior central thoracic radiation therapy (RT), including exposure of heart to
                  therapeutic doses of ionizing RT

               -  History of myocardial infarction within 6-12 months prior to start of IPs

               -  Prior history of other significant impaired cardiac function

          -  Patients with any of the following:

               -  History of myocardial infarction within 6 months prior to starting treatment

               -  Unstable angina

               -  Resting electrocardiogram (ECG) with clinically significant abnormal findings or
                  with corrected QT interval (QTc) > 470 msec on 2 or more time points within a 24
                  hour period or family history of long QT syndrome

               -  New York Heart Association functional classification of III or IV

          -  Prior history of hypertensive crisis or hypertensive encephalopathy

          -  Major surgical procedure within 2 weeks prior to starting treatment; patients must
             have recovered from any effects of any major surgery and surgical wound should have
             healed prior to starting treatment

          -  History of intra-abdominal abscess within 3 months prior to starting treatment

          -  Patients may not use any complementary or alternative medicines including natural
             herbal products or folk remedies as they may interfere with the effectiveness of the
             study treatments

          -  No prior allogeneic bone marrow transplant or double umbilical cord blood
             transplantation (dUBCT)

          -  Whole blood transfusions in the last 120 days prior to entry to the study (packed red
             blood cells and platelet transfusions are acceptable)

          -  Patients with myelodysplastic syndrome (MDS)/treatment-related acute myeloid leukemia
             (t-AML) or with features suggestive of MDS/AML

          -  Central nervous system metastases:

               -  Symptomatic uncontrolled brain metastases requiring corticosteroid treatment;
                  history of spinal cord compression unless after definitive treatment the patient
                  has clinically stable disease (SD) for at least 28 days prior to starting IPs; in
                  the absence of these features and in an asymptomatic patient a scan to confirm
                  the absence of brain metastases is not required

          -  Other malignancy within the last 5 years except for:

               -  Curatively treated basal cell or squamous cell carcinoma of skin; in situ cancer
                  of the cervix, ductal carcinoma in situ of the breast or stage 1, grade 1
                  endometrial carcinoma

               -  Curatively treated other solid tumors including lymphomas (without bone marrow
                  involvement) with no evidence of disease for >= 5 years prior to start of IPs

          -  Persisting >= grade 2 Common Terminology Criteria for Adverse Events (CTCAE) toxicity
             (except alopecia and grade 2 peripheral neuropathy) from previous anti-cancer
             treatment(s)

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to cediranib or olaparib
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival
Time Frame:From the date of study enrollment to the investigator-determined date of progression, or death due to any cause, whichever occurs first, assessed up to 5 years
Safety Issue:
Description:Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Will be tested using pairwise log-rank tests stratified by the factors.

Secondary Outcome Measures

Measure:Overall survival
Time Frame:From the date of study enrollment to the date of death regardless of the cause, assessed up to 5 years
Safety Issue:
Description:Will be tested using pairwise log-rank tests stratified by the factors.
Measure:Objective tumor response
Time Frame:Up to 5 years
Safety Issue:
Description:Will be assessed by RECIST version 1.1. Will be tested using pairwise Cochran-Mantel-Haenszel tests stratified by the factors.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

December 25, 2019