Clinical Trials /

Olaparib and Temozolomide in Treating Patients With Advanced, Metastatic, or Unresectable Uterine Leiomyosarcoma

NCT03880019

Description:

This phase II trial studies olaparib and temozolomide in treating patients with uterine leiomyosarcoma (LMS) that has spread to other places in the body (advanced or metastatic) or cannot be removed by surgery (unreserctable). Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving olaparib and temozolomide may work better than giving either drug alone in treating patients with LMS.

Related Conditions:
  • Uterine Corpus Leiomyosarcoma
Recruiting Status:

Suspended

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Olaparib and Temozolomide in Treating Patients With Advanced, Metastatic, or Unresectable Uterine Leiomyosarcoma
  • Official Title: A Phase II Study of the PARP Inhibitor Olaparib in Combination With the DNA Damaging Agent Temozolomide for the Treatment of Advanced Uterine Leiomyosarcoma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-01500
  • SECONDARY ID: NCI-2019-01500
  • SECONDARY ID: 10250
  • SECONDARY ID: 10250
  • SECONDARY ID: UM1CA186686
  • NCT ID: NCT03880019

Conditions

  • Stage III Uterine Corpus Leiomyosarcoma AJCC v8
  • Stage IIIA Uterine Corpus Leiomyosarcoma AJCC v8
  • Stage IIIB Uterine Corpus Leiomyosarcoma AJCC v8
  • Stage IIIC Uterine Corpus Leiomyosarcoma AJCC v8
  • Stage IV Uterine Corpus Leiomyosarcoma AJCC v8
  • Stage IVA Uterine Corpus Leiomyosarcoma AJCC v8
  • Stage IVB Uterine Corpus Leiomyosarcoma AJCC v8

Interventions

DrugSynonymsArms
OlaparibAZD 2281, AZD-2281, AZD2281, KU-0059436, Lynparza, PARP Inhibitor AZD2281Treatment (olaparib, temozolomide)
TemozolomideCCRG-81045, Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-, M & B 39831, M and B 39831, Methazolastone, RP-46161, SCH 52365, Temcad, Temodal, Temodar, Temomedac, TMZTreatment (olaparib, temozolomide)

Purpose

This phase II trial studies olaparib and temozolomide in treating patients with uterine leiomyosarcoma (LMS) that has spread to other places in the body (advanced or metastatic) or cannot be removed by surgery (unreserctable). Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving olaparib and temozolomide may work better than giving either drug alone in treating patients with LMS.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To evaluate whether combination treatment with temozolomide (TMZ) + olaparib shows
      preliminary evidence of clinical activity among patients with advanced uterine leiomyosarcoma
      (LMS) as measured by the confirmed objective response rate (ORR).

      SECONDARY OBJECTIVES:

      I. To evaluate the toxicity profile associated with the combination treatment. II. To
      evaluate the progression free survival (PFS) associated with the combination treatment.

      III. To evaluate what proportion of uterine LMS tumors exhibit homologous recombination (HR)
      deficiency as measured by (1) genomic alterations in HR components at baseline and (2)
      deoxyribonucleic acid (DNA) repair protein RAD51 homolog (RAD51) foci formation at baseline
      and while on study treatment.

      IV. To evaluate the feasibility of these assays in human tissue, and to preliminarily
      evaluate for any association between presence of HR deficiency as measured by each assay and
      increased clinical benefit from the study treatment.

      EXPLORATORY OBJECTIVES:

      I. To evaluate what proportion of uterine LMS tumors exhibit HR deficiency as measured by
      Schlafen family member number 11(SLFN11) protein expression at baseline.

      II. To evaluate the feasibility of these assays in human tissue, and to preliminarily
      evaluate for any association between presence of HR deficiency as measured by this assay and
      increased clinical benefit from the study treatment.

      III. To evaluate MGMT protein expression in uterine LMS tumors, and to preliminarily evaluate
      for any association between MGMT expression and increased clinical benefit from the study
      treatment.

      IV. To perform an optional third tissue biopsy in patients who initially benefit from study
      treatment but later show early evidence of disease progression to evaluate for changes in the
      status of the RAD51 foci, MGMT, and SLFN11 assays at that time.

      OUTLINE:

      Patients receive olaparib orally (PO) twice per day (BID) and temozolomide PO once daily (QD)
      on days 1-7. Cycles repeat every 21 days in the absence of disease progression or
      unacceptable toxicity.

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

Trial Arms

NameTypeDescriptionInterventions
Treatment (olaparib, temozolomide)ExperimentalPatients receive olaparib PO BID and temozolomide PO QD on days 1-7. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Olaparib
  • Temozolomide

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically documented LMS of uterine origin. Pathology review
             and confirmation of diagnosis will occur at the site enrolling the patient on this
             study.

          -  Patients must have locally advanced and unresectable or metastatic disease.

          -  Patients must have disease which is measurable at study entry according to Response
             Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria. Additionally,
             patients must have a site of disease deemed accessible for biopsy at no or minimal
             risk to the patient (including through the use of image-guidance). If there are
             questions regarding the feasibility of biopsy, the case should be reviewed with
             interventional radiology or the appropriate department at the study site prior to
             registration.

          -  Patients must have had prior progression on, or intolerance to, at least one line of
             systemic therapy for advanced LMS. Adjuvant therapy administered after curative
             resection will not qualify as prior treatment. There is no upper limit on the number
             of prior therapies received.

          -  Patients must demonstrate an Eastern Cooperative Oncology Group (ECOG) performance
             status (PS) of =< 2 (Karnofsky >= 50%)

          -  Absolute neutrophil count >= 1,500/mcL (measured within 28 days prior to
             administration of study treatment)

          -  Hemoglobin >= 9 g/dL (without transfusion of packed red blood cells within the past 28
             days) (measured within 28 days prior to administration of study treatment)

          -  Platelets >= 100,000/mcL (measured within 28 days prior to administration of study
             treatment)

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (measured within 28
             days prior to administration of study treatment)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x institutional ULN (measured within 28 days prior to administration of study
             treatment)

          -  Glomerular filtration rate (GFR) >= 51 mL/min, based on a 24-hour urine test for
             creatinine clearance or estimated using the Cockcroft-Gault equation (measured within
             28 days prior to administration of study treatment)

          -  If patients have evidence of chronic hepatitis B virus (HBV) infection, HBV viral load
             must be undetectable on suppressive therapy if indicated. Patients with a past or
             resolved HBV infection (defined as the presence of hepatitis B core antibody and
             absence of hepatitis B surface antigen [HBsAg]) are eligible.

          -  If patients have a history of hepatitis C virus (HCV) infection, they must be treated
             with undetectable HCV viral load (polymerase chain reaction is negative for HCV
             ribonucleic acid [RNA]).

          -  Patients must be postmenopausal or have evidence of non-childbearing status, OR, for
             women of childbearing potential, must have a negative urine or serum pregnancy test
             within 28 days of study treatment and confirmed again on day 1 prior to study
             treatment.

               -  Postmenopausal is defined as:

                    -  Amenorrheic for >= 1 year 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

                    -  Surgical sterilization (bilateral oophorectomy or hysterectomy)

          -  Patients and their partners, if sexually active and of childbearing potential, must
             agree to the use of two highly effective forms of contraception in combination
             throughout the period of taking study treatment and for 3 months after the last dose
             of study drug(s) to prevent pregnancy in the study patient or partner.

          -  Patients must be able to swallow orally administered medication.

          -  Patients must have a life expectancy >= 16 weeks.

          -  Patients must be able to understand and be willing to sign a written informed consent
             document. Patients with impaired decision-making capacity (IDMC) will be eligible if
             they have a close caregiver or legally authorized representative (LAR) available to
             assist them.

          -  Patients must be willing and able to comply with the protocol for the duration of the
             study, including undergoing treatment and attending scheduled visits and examinations.

          -  Patients with human immunodeficiency virus (HIV) infection may be enrolled on this
             study provided: (a) they are on a stable regimen of highly active anti-retroviral
             therapy (HAART) with no medications otherwise prohibited by this protocol (e.g.
             drug-drug interactions) and (b) require no concurrent antibiotics or antifungals for
             the prevention of opportunistic infections and (c) have a CD4 count above 250 cell/mcL
             and an undetectable viral load on standard polymerase chain reaction (PCR)-based tests
             within 1 month of initiation of study treatment. Other patients with clinically
             significant immunosuppression, e.g. organ transplant patients, are not eligible. If
             clarification is needed, this may be discussed with the medical monitor.

          -  Patients must be able to have temozolomide provided as a standard of care medication.

        Exclusion Criteria:

          -  Patients must not have had any previous treatment with any poly(adenosine
             diphosphate[ADP]-ribose) polymerase (PARP) inhibitors, including olaparib, or prior
             treatment with dacarbazine and/or temozolomide.

          -  Patients must have recovered from adverse events due to prior anti-cancer therapy
             (i.e., may not have residual toxicities > grade 1 or above baseline), excluding
             alopecia. Patients who have endocrinopathies associated with prior immunotherapy
             treatment but which are controlled with replacement therapy are eligible.

          -  Prior to initiating study treatment, at least 28 days must have elapsed from the last
             dose of systemic anti-cancer treatment (cytotoxic, biologic or immunotherapeutic) or
             radiation therapy (except for palliative radiation, in which case a 14-day washout
             applies).

          -  Patients must not have had major surgery within 2 weeks of starting study treatment
             and must have recovered from any effects of any major surgery that occurred > 2 weeks
             before starting study treatment.

          -  Patients must not be receiving any other investigational agent.

          -  Patients must not have been diagnosed with another malignancy unless curatively
             treated with no evidence of disease for >= 5 years except: adequately treated
             non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal
             carcinoma in situ (DCIS), any other malignant condition considered indolent and
             unlikely to require active therapy.

          -  Patients must not have myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or
             bone marrow biopsy findings consistent with MDS and/or AML.

          -  Patients must not have active central nervous system (CNS) or leptomeningeal disease
             at the time of enrollment. Patients with a history of such disease previously treated
             with curative intent (such as with surgery or radiation) that have not progressed on
             subsequent imaging, have been clinically asymptomatic, and have not received systemic
             corticosteroids for at least 28 days, are eligible.

          -  Patients must not have a history of allergic reactions attributed to compounds of
             similar chemical or biologic composition to olaparib or TMZ or any of the excipients
             of any study product.

          -  Patients must refrain from 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 for strong or moderate CYP3A inhibitors prior
             to starting olaparib is 2 weeks. Because the lists of these agents are constantly
             changing, it is important to regularly consult a frequently-updated medical reference.
             As part of the enrollment/informed consent procedures, the patient will be counseled
             on the risk of interactions with other agents, and what to do if new medications need
             to be prescribed or if the patient is considering a new over-the-counter medicine or
             herbal product.

          -  Patients must refrain from 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 for strong or moderate
             CYP3A inducers prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital
             and 3 weeks for other agents.

          -  Patients must not have an uncontrolled intercurrent illness including, but not limited
             to, ongoing or active infection, uncontrolled ventricular arrhythmia, recent (within 3
             months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal
             cord compression, superior vena cava syndrome, extensive interstitial bilateral lung
             disease on high resolution computed tomography (HRCT) scan, or psychiatric illness
             that would limit compliance with study requirements.

          -  Pregnant women are excluded from this study because olaparib is a PARP inhibitor with
             the potential for teratogenic or abortifacient effects. Because there is an unknown
             but potential risk for adverse events in nursing infants secondary to treatment of the
             mother with olaparib, breastfeeding should be discontinued if the mother is treated
             with olaparib. These potential risks may also apply to other agents used in this
             study.

          -  Patients must not have gastrointestinal disorders likely to interfere with absorption
             of the study medication.

          -  Patients must not have had involvement in the planning and/or conduct of the study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Confirmed objective response rate (ORR) (complete response + partial response)
Time Frame:Within first 6 months of study treatment
Safety Issue:
Description:Will be measured by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria. A response rate of 10% is considered inactive and unworthy of further study. A response rate of 35% would be promising for further study among patients with advanced uterine leiomyosarcoma (LMS) treated with at least one prior systemic regimen. A response rate of 35% for the temozolomide (TMZ) + poly(adenosine diphosphate[ADP]-ribose) polymerase inhibitor (PARPi) combination would also be suggestive of superior efficacy over TMZ monotherapy in sarcoma. Will be reported with a 95% confidence interval.

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 2 years after study treatment
Safety Issue:
Description:Recorded at each clinical visit and will be categorized according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Adverse event rates will be reported as counts and percentages per adverse event by grade.
Measure:Progression-free survival (PFS)
Time Frame:Time from first treatment with the study drug to the earliest of either disease progression or death from any cause, assessed up to 2 years
Safety Issue:
Description:The Kaplan-Meier method will be used to evaluate time to event endpoints. Median PFS will be reported with a 95% confidence interval.
Measure:Proportion of uterine LMS tumors exhibit homologous recombination (HR) deficiency
Time Frame:Up to 2 years
Safety Issue:
Description:Will be measured by genomic alterations in HR components at baseline and deoxyribonucleic acid (DNA) repair protein RAD51 homolog (RAD51) foci formation. The two integrated assays are genomics for alterations in HR genes and RAD51 foci formation. Both of these assays report binary results. The rate of response will be compared between binary variables using the Fisher's exact test. The log-rank test will be used to compare PFS between binary variables. Additional results from whole exome sequencing and ribonucleic acid sequencing (RNAseq) analysis on study samples will be reported in a descriptive fashion.
Measure:Schlafen family member number 11(SLFN11) protein expression
Time Frame:Up to 2 years
Safety Issue:
Description:Will be assessed by immunohistochemistry (ICH). Macro ribonucleic acid (mRNA) expression may also be performed. Expression are reported as a continuous variable. Logistic regression will be used to estimate the odds of response for every unit increase in protein expression. Cox-regression will be used to evaluate the association between PFS and protein expression. Graphical displays such as box plots and Kaplan-Meier plots will be used to visualize the data. Evaluate for any association between presence of HR deficiency and increased clinical benefit from study treatment.
Measure:Proportion of MGMT protein expression in uterine LMS tumors
Time Frame:Up to 2 years
Safety Issue:
Description:Will be assessed by ICH. mRNA expression may also be performed. Expression are reported as a continuous variable. Logistic regression will be used to estimate the odds of response for every unit increase in protein expression. Cox-regression will be used to evaluate the association between PFS and protein expression. Graphical displays such as box plots and Kaplan-Meier plots will be used to visualize the data. Evaluate for any association between MGMT expression and increased clinical benefit from the study treatment.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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