Clinical Trials /

Talazoparib and Radiation Therapy in Treating Patients With Locally Recurrent Gynecologic Cancers

NCT03968406

Description:

This phase I trial studies the side effects and best dose of talazoparib in combination with radiation therapy and to see how well they work in treating patients with gynecologic cancers that have come back after previous treatment. Talazoparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving talazoparib in combination with radiation therapy may work better in treating patients with gynecologic cancers.

Related Conditions:
  • Cervical Carcinoma
  • Endometrial Carcinoma
  • Fallopian Tube Carcinoma
  • Malignant Ovarian Neoplasm
  • Primary Peritoneal Carcinoma
  • Vaginal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Talazoparib and Radiation Therapy in Treating Patients With Locally Recurrent Gynecologic Cancers
  • Official Title: Phase I Study of Talazoparib in Combination With Radiation Therapy for Locally Recurrent Gynecologic Cancers

Clinical Trial IDs

  • ORG STUDY ID: 2018-0899
  • SECONDARY ID: NCI-2019-00101
  • SECONDARY ID: 2018-0899
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03968406

Conditions

  • Recurrent Cervical Carcinoma
  • Recurrent Endometrial Carcinoma
  • Recurrent Fallopian Tube Carcinoma
  • Recurrent Ovarian Carcinoma
  • Recurrent Primary Peritoneal Carcinoma
  • Recurrent Vaginal Carcinoma
  • Stage IV Cervical Cancer AJCC v8
  • Stage IV Fallopian Tube Cancer AJCC v8
  • Stage IV Ovarian Cancer AJCC v8
  • Stage IV Primary Peritoneal Cancer AJCC v8
  • Stage IV Uterine Corpus Cancer AJCC v8
  • Stage IV Vaginal Cancer AJCC v8
  • Stage IVA Cervical Cancer AJCC v8
  • Stage IVA Fallopian Tube Cancer AJCC v8
  • Stage IVA Ovarian Cancer AJCC v8
  • Stage IVA Primary Peritoneal Cancer AJCC v8
  • Stage IVA Uterine Corpus Cancer AJCC v8
  • Stage IVA Vaginal Cancer AJCC v8
  • Stage IVB Cervical Cancer AJCC v8
  • Stage IVB Fallopian Tube Cancer AJCC v8
  • Stage IVB Ovarian Cancer AJCC v8
  • Stage IVB Primary Peritoneal Cancer AJCC v8
  • Stage IVB Uterine Corpus Cancer AJCC v8
  • Stage IVB Vaginal Cancer AJCC v8

Interventions

DrugSynonymsArms
TalazoparibBMN 673, BMN-673Treatment (talazoparib, radiation therapy)

Purpose

This phase I trial studies the side effects and best dose of talazoparib in combination with radiation therapy and to see how well they work in treating patients with gynecologic cancers that have come back after previous treatment. Talazoparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving talazoparib in combination with radiation therapy may work better in treating patients with gynecologic cancers.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the safety, tolerability, and maximally tolerated dose (MTD) of talazoparib
      combining talazoparib and fractionated radiotherapy in patients with refractory or recurrent
      ovarian, fallopian tube, primary peritoneal, cervical, or vaginal or endometrial carcinoma.

      SECONDARY OBJECTIVES:

      I. To determine the safety profile of talazoparib in combination with fractionated
      radiotherapy for recurrent gynecologic cancers.

      II. To determine a preliminary anti-cancer activity of this combination at the MTD.

      EXPLORATORY OBJECTIVES:

      I. To explore the potential feasibility of using biomarkers in tumor tissue, whole blood or
      serum as predictive markers of treatment response.

      II. To explore the impact of talazoparib when combined with radiotherapy for recurrent
      gynecologic cancers on 1) patient reported acute gastrointestinal (GI) toxicity and 2)
      overall longitudinal quality of life at week 5 of therapy.

      OUTLINE: This is a dose escalation study of talazoparib.

      Patients receive talazoparib orally (PO) once daily (QD) beginning on days -10 to -7 and
      continuing for up to 8 weeks in the absence of disease progression or unacceptable toxicity.
      Patients also undergo radiation therapy 5 days a week (Monday-Friday) for up to 7 weeks.

      After completion of study treatment, patients are followed up at 1, 3, 6, 9, and 12 months,
      and then every 6 months for up to 1 year.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (talazoparib, radiation therapy)ExperimentalPatients receive talazoparib PO QD beginning on days -10 to -7 and continuing for up to 8 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy 5 days a week (Monday-Friday) for up to 7 weeks.
  • Talazoparib

Eligibility Criteria

        Inclusion Criteria:

          -  Provision of informed consent prior to any study specific procedures

          -  Histologically-confirmed recurrent ovarian, fallopian tube, primary peritoneal cancer,
             endometrial, vaginal, or cervical cancer in the abdomen and pelvis

          -  Subjects with stage IV disease are eligible as long as disease elsewhere (other than
             the site(s) to receive radiation therapy [RT]) is undetectable or stable (>/+3 months)
             and immediate chemotherapy is not required. Willingness to discontinue any cytotoxic
             chemotherapeutic agents, immunotherapy, biologic therapy, and targeted therapies at
             least three weeks prior to start of investigational therapy

          -  Hemoglobin >= 10.0 g/dL and no blood transfusions in the 28 days prior to
             entry/randomization (choose whichever is most applicable to the study) (within 28 days
             prior to administration of study treatment)

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

          -  No features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
             on peripheral blood smear (within 28 days prior to administration of study treatment)

          -  White blood cells (WBC) > 3 x 10^9/L (within 28 days prior to administration of study
             treatment)

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

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (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 upper limit of normal unless liver metastases are present in
             which case it must be =< 5 x ULN (within 28 days prior to administration of study
             treatment)

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

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1

               -  Note: If cannot fulfill ECOG 0-1, must fulfill inclusion criteria below*

          -  Patients must have a life expectancy >= 16 weeks

          -  Evidence of non-childbearing status for women of childbearing potential: negative
             urine or serum pregnancy test within 28 days of study treatment, confirmed prior to
             treatment on day 1. 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 post menopausal 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)

          -  *Patient of child-bearing potential is willing to adhere to using two forms of highly
             effective birth control. Condoms with spermicide and one of the following are
             acceptable: oral contraceptive or hormonal therapy or placement of an intrauterine
             device (IUD). Acceptable non-hormonal birth control methods include: total sexual
             abstinence, vasectomized sexual partner plus male condom, tubal occlusion plus male
             condom with spermicide, IUD plus male condom+spermicide. Acceptable hormonal methods
             include: etonogestrel implants (i.e. Implanon, Norplan), normal and low dose combined
             oral pills, norelgestromin/ethinyl estradiol (EE) transdermal system, intravaginal
             device (i.e. EE and etonogestrel) or cerazette (desogestrel). All of these would need
             to be combined with male condom with spermicide

          -  Patient 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

          -  At least one lesion, not previously irradiated, that can be accurately measured at
             baseline as >= 10 mm in the longest diameter (except lymph nodes which must have short
             axis >= 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and
             which is suitable for accurate repeated measurements

          -  For inclusion in biomarker endpoint, patients must fulfill the following criterion:

               -  Provision of informed consent for tumor biopsies * If a patient declines to
                  participate in tumor biopsies, there will be no penalty or loss of benefit to the
                  patient. The patient will not be excluded from other aspects of the study
                  described in this Clinical Study Protocol, so long as they consent to that part

        Exclusion Criteria:

          -  Ascites, peritoneal carcinomatosis, hepatic metastases

          -  Prior radiotherapy in the region of planned radiotherapy

          -  Chemotherapy, radiotherapy, endocrine therapy, immunotherapy or use of other
             investigational agents within the 3 weeks prior to start of therapy

          -  Previous enrollment in the present study

          -  Participation in another clinical study with an investigational product during the
             last 4 weeks

          -  Patients with second primary cancer, except: adequately treated non-melanoma skin
             cancer, curatively treated in-situ cancer of the cervix, or other solid tumors
             curatively treated with no evidence of disease for >= 5 years (will require discussion
             with study physician)

          -  Patients receiving any systemic chemotherapy, radiotherapy

          -  Concomitant use of known CYP3A4 inhibitors such as ketoconazole, itraconazole,
             ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir

          -  Concomitant use of known P-gp inhibitors (i.e. dronedarone, quinidine, ranolazine,
             verapamil, ketoconazole, itraconazole), P-glycoprotein (P-gp) inducers (i.e. rifampin,
             tipranavir, ritonavir), or breast cancer resistance protein (BCRP) inhibitors (i.e.
             elacridar [GF120918]) should be avoided. If patients are taking any P-gp inhibitors,
             P-gp inducers, or BRCP inhibitors, they will need to stop them prior to enrolment on
             the study

          -  Persistent toxicities (>= Common Terminology Criteria for Adverse Events [CTCAE] grade
             2) with the exception of alopecia, caused by previous cancer therapy

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

          -  Patients with myelodysplastic syndrome/acute myeloid leukemia

          -  Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence
             of brain metastases is not required. The patient can receive a stable dose of
             corticosteroids before and during the study as long as these were started at least 28
             days prior to treatment

          -  Major surgery within 14 days of starting study treatment and patients must have
             recovered from any effects of any major surgery

          -  Patients considered a poor medical risk due to a serious, uncontrolled medical
             disorder, non-malignant systemic disease or active, uncontrolled infection. Examples
             include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3
             months) myocardial infarction, unstable spinal cord compression (untreated and
             unstable for at least 28 days prior to study entry), superior vena cava syndrome,
             extensive bilateral lung disease on high resolution computed tomography (CT) scan or
             any psychiatric disorder that prohibits obtaining informed consent

          -  Patients unable to swallow orally administered medication and patients with
             gastrointestinal disorders likely to interfere with absorption of the study medication

          -  Breast feeding women

          -  Patients with a known hypersensitivity to talazoparib or any of the excipients of the
             product

          -  Patients with uncontrolled seizures

          -  Patients requiring pelvic and para-aortic radiotherapy (defined as levels L1/T12)

          -  Patients with isolated vaginal relapse (i.e. no disease in lymph nodes or else where
             in pelvis/abdomen)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD)
Time Frame:Up to 30 days
Safety Issue:
Description:MTD is determined by dose limiting toxicity (DLT). The MTD will be determine using the time-to-event Bayesian optimal interval (TITE-BOIN) model, and it is defined as the dose for which the isotonic estimate of the DLT rate is closest to the target DLT rate.

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 2 years
Safety Issue:
Description:Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE).
Measure:Response rate
Time Frame:From the start of study treatment until documentation of local or regional recurrence, progression, time to next therapy, and death, assessed up to 2 years
Safety Issue:
Description:Anti-cancer activity will be measured by response rate by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Each endpoint will be analyzed using the cumulative incidence method when competing events exist or the product-limit method of Kaplan and Meier when competing events are absent. Additionally, competing risk regression or proportional hazards modeling, whichever is appropriate, will be used to examine each endpoint while adjusting for disease. Estimates and 95% intervals will be reported.
Measure:Local control rate
Time Frame:From the start of study treatment until documentation of local or regional recurrence, progression, time to next therapy, and death, assessed up to 2 years
Safety Issue:
Description:Will be analyzed using the cumulative incidence method when competing events exist or the product-limit method of Kaplan and Meier when competing events are absent. Additionally, competing risk regression or proportional hazards modeling, whichever is appropriate, will be used to examine each endpoint while adjusting for disease. Local control will be summarized as freedom from local failure calculated as 1 minus the cumulative incidence of local or regional recurrence. Estimates and 95% intervals will be reported.
Measure:Time to progression
Time Frame:From the start of study treatment until documentation of local or regional recurrence, progression, time to next therapy, and death, assessed up to 2 years
Safety Issue:
Description:Will be analyzed using the cumulative incidence method when competing events exist or the product-limit method of Kaplan and Meier when competing events are absent. Additionally, competing risk regression or proportional hazards modeling, whichever is appropriate, will be used to examine each endpoint while adjusting for disease. Estimates and 95% intervals will be reported.
Measure:Progression-free survival
Time Frame:From the start of study treatment until documentation of local or regional recurrence, progression, time to next therapy, and death, assessed up to 2 years
Safety Issue:
Description:Will be analyzed using the cumulative incidence method when competing events exist or the product-limit method of Kaplan and Meier when competing events are absent. Additionally, competing risk regression or proportional hazards modeling, whichever is appropriate, will be used to examine each endpoint while adjusting for disease. Estimates and 95% intervals will be reported.
Measure:Overall survival
Time Frame:From the start of study treatment until documentation of local or regional recurrence, progression, time to next therapy, and death, assessed up to 2 years
Safety Issue:
Description:Will be analyzed using the cumulative incidence method when competing events exist or the product-limit method of Kaplan and Meier when competing events are absent. Additionally, competing risk regression or proportional hazards modeling, whichever is appropriate, will be used to examine each endpoint while adjusting for disease. Estimates and 95% intervals will be reported.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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