Clinical Trials /

Hyperthermia and Olaparib in Treating Breast Cancer Patients With Chest Wall Recurrences

NCT03955640

Description:

This phase I trial studies the side effects and best dose of olaparib when given with hyperthermia in treating patients with breast cancer that has come back in the chest wall. Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Hyperthermia treatment may kill or damage tumor cells by heating them to several degrees above normal body temperature. Giving olaparib and hyperthermia treatment may work better in treating patients with breast cancer that has come back in the chest well compared to standard of care.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Hyperthermia and Olaparib in Treating Breast Cancer Patients With Chest Wall Recurrences
  • Official Title: A Pilot Trial of Hyperthermia in Combination With Olaparib in Breast Cancer Patients With Chest Wall Recurrences

Clinical Trial IDs

  • ORG STUDY ID: 19P.117
  • NCT ID: NCT03955640

Conditions

  • Metastatic Melanoma
  • Metastatic Malignant Neoplasm in the Chest Wall
  • Recurrent Breast Carcinoma

Interventions

DrugSynonymsArms
Olaparib763113-22-0, AZD2281, KU-0059436, Lynparza, PARP Inhibitor AZD2281Treatment (olaparib, hyperthermia)

Purpose

This phase I trial studies the side effects and best dose of olaparib when given with hyperthermia in treating patients with breast cancer that has come back in the chest wall. Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Hyperthermia treatment may kill or damage tumor cells by heating them to several degrees above normal body temperature. Giving olaparib and hyperthermia treatment may work better in treating patients with breast cancer that has come back in the chest well compared to standard of care.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the dose limiting toxicities and maximum tolerated dose of olaparib given in
      combination with chest wall hyperthermia in patients with locally advanced or metastatic
      breast cancer with chest wall recurrences who have wild-type BRCA status (patients with
      germline BRCA mutations are excluded from this study).

      SECONDARY OBJECTIVES:

      I. To determine the local progression free survival (in months) for patients with chest wall
      recurrences defined as time to progression of disease on chest wall with olaparib with
      hyperthermia.

      II. To determine the 1-year progression free survival (in months) for patients with chest
      wall recurrences treated with olaparib with hyperthermia.

      III. To determine the best local overall response rate of chest wall after the combination of
      hyperthermia and olaparib.

      IV. To determine the quality of life and pain scores before, during and after treatment as
      measured by the Edmonton Symptom Assessment System which includes a pain score and 8 other
      subjective measures of wellness for cancer patients (0 to 10).

      EXPLORATORY OBJECTIVES:

      I. To evaluate BRCA1/2 levels by immunohistochemistry and explore if hyperthermia induced
      BRCA1/2 expression.

      II. To evaluate HR (homologous recombination) competency by RAD51 foci and explore if
      hyperthermia induces homologous recombination in breast tissue.

      III. To explore deoxyribonucleic acid (DNA) damage as measured by gammaH2AX and comet assay
      in cells dissociated from biopsy tissues.

      OUTLINE: This is a dose-escalation study of olaparib.

      Patients receive olaparib orally (PO) twice daily (BID). Treatment continues for 4 weeks in
      the absence of disease progression and unacceptable toxicity. Beginning week 2, patients also
      undergo hyperthermia treatment over 1 hour twice weekly for 3 weeks in the absence of disease
      progression and unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for 12 months.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (olaparib, hyperthermia)ExperimentalPatients receive olaparib PO BID. Treatment continues for 4 weeks in the absence of disease progression and unacceptable toxicity. Beginning week 2, patients also undergo hyperthermia treatment over 1 hour twice weekly for 3 weeks in the absence of disease progression and unacceptable toxicity.
  • Olaparib

Eligibility Criteria

        Inclusion Criteria:

          -  Patients regardless of estrogen receptor (ER)/progesterone receptor (PR)/HER2 status
             and have breast cancer recurrence on the chest wall

          -  Capable of giving signed informed consent which includes compliance with the
             requirements and restrictions listed in the informed consent form (ICF) and in this
             protocol

          -  Provision of signed and dated, written informed consent form prior to any mandatory
             study specific procedures, sampling, and analyses

          -  Hemoglobin >= 10.0 g/dL with no blood transfusion in the past 28 days (within 28 days
             prior to administration of study treatment)

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

          -  Platelet count >= 100 x 10^9/L (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 glutamic pyruvate transaminase [SGPT]) =< 2.5 x
             institutional upper limit of normal unless liver metastases are present in which case
             they must be =< 5x ULN (measured within 28 days prior to administration of study
             treatment)

          -  Patients must have creatinine clearance estimated of >= 51 mL/min using the
             Cockcroft-Gault equation or based on a 24 hour urine test (measured within 28 days
             prior to administration of study treatment)

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

          -  Patients must have a life expectancy >= 16 weeks

          -  Breast cancer with chest wall disease that is at least 2 cm in size at the greatest
             dimension

          -  Patients will be eligible for this trial regardless of number of lines of therapy and
             after adjuvant chemotherapy with recurrence on the chest wall

          -  Patients with hormone receptor positive disease who discontinue endocrine therapy two
             weeks prior to initiating study treatment are eligible

          -  Body mass index (BMI): 15 to 50 at the time of consent

          -  Postmenopausal or evidence of non-childbearing status for women of childbearing
             potential: negative urine or serum pregnancy test within 28 days of initiating study
             treatment and confirmed prior to treatment on day 1 and willingness to use effective
             contraception during study treatment and for at least 30 days after last dose of study
             drug. Postmenopausal is defined as:

               -  Amenorrhea 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

               -  Surgical sterilization (bilateral oophorectomy or hysterectomy)

        Exclusion Criteria:

          -  As judged by the investigator, any evidence of non-compliance which in the
             investigator's opinion makes it undesirable for the patient to participate in the
             trial

          -  Patients with rapidly progressing disease

          -  Metastatic disease should not be progressing so as to require systemic treatment
             within 4 weeks of enrollment based on clinical assessment by the investigator

          -  Metastatic disease should not be progressing so as to require palliative treatment
             within 4 weeks of enrollment based on clinical assessment by the investigator

          -  Other 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), stage 1, grade 1 endometrial carcinoma

          -  Resting electrocardiogram (EKG) indicating uncontrolled, potentially reversible
             cardiac conditions, as judged by the investigator (e.g. unstable ischemia,
             uncontrolled symptomatic arrhythmia, congestive heart failure, corrected QT interval
             by Fridericia [QTcF] prolongation > 500 ms, electrolyte disturbances, etc.), or
             patients with congenital long QT syndrome

          -  Persistent toxicities caused by previous cancer therapy >= grade 2, excluding alopecia
             and neuropathy

          -  Patients with current or previous diagnosis of myelodysplastic syndrome/acute myeloid
             leukemia or with features suggestive of myelodysplastic syndrome (MDS)/acute myeloid
             leukemia (AML)

          -  Patients with symptomatic uncontrolled brain metastases or spinal cord 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 4 weeks prior to treatment. Patients with spinal cord
             compression unless considered to have received definitive treatment for this and
             evidence of clinically stable disease for 28 days

          -  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, 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 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

          -  Immunocompromised patients, e.g., patients who are known to be serologically positive
             for human immunodeficiency virus (HIV)

          -  Any previous treatment with PARP inhibitor, including olaparib

          -  Subjects with a known hypersensitivity to olaparib or any of the excipients of the
             product

          -  Patients with a known hypersensitivity to hyperthermia

          -  Patients receiving any systemic chemotherapy or radiotherapy (except for palliative
             reasons) within 3 weeks prior to study treatment

          -  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 prior to starting olaparib is 2 weeks

          -  Concomitant use of known strong CYP3A inducers (eg. phenobarbital, enzalutamide,
             phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's
             wort) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required
             washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital
             and 3 weeks for other agents

          -  Major surgery within 2 weeks of starting study treatment and patients must have
             recovered from any effects of surgery

          -  Patients with known active hepatitis B or C

          -  Whole blood transfusions in the last 120 days prior to entry to the study (packed red
             blood cells and platelet transfusions are acceptable outside of 28 days prior to
             enrollment)

          -  Previous allogenic bone marrow transplant or double umbilical cord blood
             transplantation (dUCBT)

          -  Any patient with a known germline BRCA1 or 2 mutation

          -  Participation in another clinical study with an investigational product administered
             in the last 2 months

          -  Previous enrollment in the present study

          -  Breast feeding women

          -  Involvement in the planning and/or conduct of the study

          -  No radiotherapy, treatment with cytotoxic agents, biologic agents or endocrine therapy
             within 3 weeks prior to beginning treatment on this study. Patients must have
             recovered from the acute toxicities of any prior treatment with cytotoxic drugs to =<
             grade 1 (allowance for grade 2 alopecia and neuropathy) in order to be eligible.
             Patients who underwent post-mastectomy radiation will not be excluded from this study
      
Maximum Eligible Age:80 Years
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 1 year post treatment
Safety Issue:
Description:Will be continually assessed according to the National Cancer Institute Common Toxicity Criteria for Adverse Advents (CTCAE version [v]5.0).

Secondary Outcome Measures

Measure:Local progression free-survival (PFS)
Time Frame:From first dose of olaparib to the date of the first documented disease progression or recurrence on the chest wall, assessed up to 1 year
Safety Issue:
Description:Will be reported as Kaplan-Meier survival curves with the median survival time with 95% confidence interval. Will be analyzed using log-rank test as well as Cox proportional hazard models.
Measure:PFS
Time Frame:From first dose of olaparib to the date of the first documented disease progression or recurrence, or death due to any cause, whichever occurs first, assessed up to 1 year
Safety Issue:
Description:Will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Will be reported as Kaplan-Meier survival curves with the median survival time with 95% confidence interval. Will be analyzed using log-rank test as well as Cox proportional hazard models.
Measure:Best local overall response rate (ORR)
Time Frame:Up to 1 year post treatment
Safety Issue:
Description:Defined as the number of subjects with a best overall response (BOR) defined as a complete response (CR) or partial response (PR) divided by the number of enrolled subjects. The proportion of patients will be summarized together with the appropriate 95% confidence interval. The binary endpoint of ORR will be compared by test on proportions.
Measure:Quality of life (QOL)
Time Frame:Up to 1 year post treatment
Safety Issue:
Description:Defined by the Edmonton Symptom Assessment System (ESAS) using nine subjective patient measures of well-being including pain, tiredness, nausea, depression, anxiety, drowsiness, appetite, well-being, shortness of breath. These will be rated by the patients during each visit (visits 1-6) and the change in values will correlate to an improvement in quality of life (a positive change will correlate to an improvement and a negative change will correlate to a worsening of pain). The multinominal/ordinal endpoints in QOLs will be summarized in frequencies ad proportions and compared using trend test.
Measure:Pain scores
Time Frame:Up to 1 year post treatment
Safety Issue:
Description:Defined by the Edmonton Symptom Assessment System (ESAS) using nine subjective patient measures of well-being including pain, tiredness, nausea, depression, anxiety, drowsiness, appetite, well-being, shortness of breath. These will be rated by the patients during each visit (visits 1-6) and the change in values will correlate to an improvement in quality of life (a positive change will correlate to an improvement and a negative change will correlate to a worsening of pain).

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Thomas Jefferson University

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