Clinical Trials /

Pembrolizumab in Combination With Olaparib in Advanced BRCA-mutated or HDR-defect Breast Cancer

NCT03025035

Description:

This trial will evaluate the use of immunotherapy and PARP inhibition in a population with incurable advanced breast cancer associated with a germline BRCA mutation or HDR-defect. The main objective is to examine overall response rate of pembrolizumab (immunotherapy) in combination with Olaparib (PARP inhibitor) in advanced BRCA-mutated or Homology-directed repair (HDR)-defect breast cancer.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab in Combination With Olaparib in Advanced BRCA-mutated or HDR-defect Breast Cancer
  • Official Title: Open Label, Phase II Pilot Study of Immune Checkpoint Inhibition With Pembrolizumab in Combination With PARP Inhibition With Olaparib in Advanced BRCA-mutated or HDR-defect Breast Cancers

Clinical Trial IDs

  • ORG STUDY ID: IIT2015-18-Mita-MK3475
  • NCT ID: NCT03025035

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
PembrolizumabKeytruda, MK-3475Pembrolizumab + Olaparib
OlaparibLynparzaPembrolizumab + Olaparib

Purpose

This trial will evaluate the use of immunotherapy and PARP inhibition in a population with incurable advanced breast cancer associated with a germline BRCA mutation or HDR-defect. The main objective is to examine overall response rate of pembrolizumab (immunotherapy) in combination with Olaparib (PARP inhibitor) in advanced BRCA-mutated or Homology-directed repair (HDR)-defect breast cancer.

Detailed Description

      There are two BRCA genes, BRCA1 and BRCA2, and they play a role in protecting cells from
      cancer. HDR-defect is another type of gene mutation that can contribute to development and
      progression of cancer. If one of these genes is mutated, cells may rapidly change and divide,
      which can lead to cancer. Pembrolizumab is a drug that works with the immune system to target
      the tumor (immunotherapy). The investigators want to know if combining pembrolizumab and
      Olaparib therapy will be able to reduce the size and amount of cancer cells with fewer side
      effects than standard treatment by targeting the tumor. This research study is designed to
      test the investigational use of pembrolizumab and Olaparib in breast cancer.
    

Trial Arms

NameTypeDescriptionInterventions
Pembrolizumab + OlaparibExperimentalThis is an open-label, single-arm pilot study of pembrolizumab (study drug) in combination with Olaparib in 20 subjects with advanced BRCA mutation or HDR-defect associated breast cancer having progressed through at least a standard first line therapy.
  • Pembrolizumab
  • Olaparib

Eligibility Criteria

        Inclusion Criteria:

          -  Be willing and able to provide written informed consent/assent for the trial

          -  Be ≥18 years of age on day of signing informed consent

          -  Advanced BRCA-mutated and/or HDR-defect breast cancer progressing on or after prior
             therapy for metastatic disease or locally advanced disease; Prior therapy is defined
             as follows: for triple negative breast cancer - progressing after at least 1 line of
             any prior chemotherapy; for HER2 positive disease must have progressed after at least
             two HER2 directed therapies in the metastatic setting including ado-trastuzumab
             emtansine (T-DM1); for hormone receptor positive disease (ER, PR, or both) must have
             progressed after palbociclib plus hormonal therapy

          -  Measurable disease by RECIST 1.1, with 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. Patients with non-measurable bone metastases in addition to measurable
             disease are eligible; however patients with non-measurable bone disease as the only
             site(s) of disease are not eligible.

          -  ECOG 0 or 1

          -  Documented BRCA deleterious germline or somatic mutation and/or HDR-defect.

          -  FFPE tumor tissue available for analysis

          -  Adequate organ function

          -  Female subjects: Postmenopausal or evidence of non-childbearing status for women of
             childbearing potential: negative urine or serum pregnancy test within 28 days of study
             treatment and confirmed prior to treatment on day 1. Postmenopausal is defined as:

               1. 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

               2. radiation-induced oophorectomy with last menses >1 year ago

               3. chemotherapy-induced menopause with >1 year interval since last menses

               4. surgical sterilization (bilateral oophorectomy or hysterectomy)

          -  Women of childbearing potential and their partners, who are sexually active, must
             agree to the use of TWO highly effective forms of contraception in combination. This
             should be started from the signing of the informed consent and continue throughout the
             period of taking study treatment and for at least 1 month after last dose of study
             drug(s), or they must totally/truly abstain from any form of sexual intercourse.

          -  Male patients must use a condom during treatment and for 3 months after the last dose
             of olaparib when having sexual intercourse with a pregnant woman or with a woman of
             childbearing potential. Female partners of male patients should also use a highly
             effective form of contraception if they are of childbearing potential

          -  Patients must have a life expectancy ≥ 16 weeks

        Exclusion Criteria:

          -  Is currently participating or has participated in a study of investigational agent or
             using an investigational device with 30 days of the first dose of pembrolizumab.

               1. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
                  within 3 weeks prior to study Day 1.

               2. Subjects must have recovered (i.e., ≤ Grade 1 or at baseline) from any adverse
                  events due to a previously administered agent. Subjects with ≤ Grade 2 neuropathy
                  are an exception to this criterion and may qualify for the study.

               3. If subject received major surgery, they must have recovered adequately from the
                  toxicity and/or complications from the intervention prior to starting therapy.

          -  Is receiving systemic steroid therapy within three days prior to the first dose of
             pembrolizumab or receiving any other form of immunosuppressive medication

          -  Is expected to require any other form of systemic or localized antineoplastic therapy
             while on trial.

               1. Subjects with ER+/PR+ disease may be given endocrine therapy.

               2. Subjects with HER2+ disease will be required to discontinue trastuzumab
                  (Herceptin).

          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or
             anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including
             ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation
             or checkpoint pathways). Has participated in another MK03475 trial.

             a. Note: Patients with or without prior PARP-inhibitor exposure may be included.

          -  Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin,
             clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
             saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg.
             ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout
             period prior to starting olaparib is 2 weeks.

          -  Concomitant use of known strong (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 any major surgery.

          -  Has known hypersensitivity to pembrolizumab or any of its excipients

          -  Has a known additional malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
             skin, or in situ cervical cancer that has undergone potentially curative therapy.

          -  Has known history of prior malignancy except if the patient has undergone potentially
             curative therapy with no evidence of that disease recurrence for 5 years since
             initiation of that therapy.

          -  Has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis. Subjects with previously treated brain metastases may participate provided
             they are stable (without evidence of progression by MRI for at least four weeks prior
             to the first dose of pembrolizumab and any neurologic symptoms have returned to
             baseline), have no evidence of new or enlarging brain metastases, and are using no
             steroids for at least three days prior to study medication.

          -  Has evidence of interstitial lung disease or active, non-infectious pneumonitis

          -  Has active tuberculosis

          -  Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as
             judged by the investigator (eg., unstable ischemia, uncontrolled symptomatic
             arrhythmia, congestive heart failure, QTcF prolongation >500 ms, electrolyte
             disturbances, etc.), or patients with congenital long QT syndrome.

          -  Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) grade 2)
             caused by previous cancer therapy, excluding alopecia.

          -  Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features
             suggestive of MDS/AML.

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

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

          -  Has received a live vaccine or live-attenuated vaccine within 30 days prior to the
             first dose of pembrolizumab. Administration of killed vaccines is allowed.

          -  Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

          -  Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
             [qualitative] is detected).

          -  Has an active autoimmune disease that has required systemic treatment in the past 2
             years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Subjects with vitiligo or resolved childhood asthma/atopy would be exception
             to this rule. Subjects that require inhaled steroid or local steroid injections will
             not be excluded from the study. Subjects with hypothyroidism not from autoimmune
             disease and stable on hormone replacement will not be excluded from the study. Note:
             Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment.

          -  Has had an allogenic tissue / solid organ transplant.

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

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the subject's
             participation for the full duration of the trial, or is not in the best interest of
             the subject to participate, in the opinion of the treating Investigator.

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the screening visit (Visit 1) through
             120 days after the last dose of study treatment.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR) per RECIST1.1
Time Frame:Up to 2 years
Safety Issue:
Description:Defined as complete or partial response per RECIST 1.1 criteria with assessment every 9 weeks during the first year and while on the study drug, and every 12 weeks thereafter.

Secondary Outcome Measures

Measure:Progression free survival (PFS), per RECIST 1.1
Time Frame:Up to 2 years
Safety Issue:
Description:As measured by RECIST 1.1, in patients progressing after 1st line therapy
Measure:Overall survival (OS)
Time Frame:Up to 2 years
Safety Issue:
Description:Calculated in months from the start of treatment to the date of death from any cause
Measure:Clinical Benefit Rate (CBR = CR+PR+SD) per RECIST 1.1
Time Frame:Up to 2 years
Safety Issue:
Description:As measured by RECIST 1.1, in patients progressing after 1st line therapy
Measure:Duration of Response (DOR) for Complete Response (CR) and Partial Response (PR) per RECIST 1.1
Time Frame:Up to 2 years
Safety Issue:
Description:As measured by RECIST 1.1, in patients progressing after 1st line therapy

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Monica Mita

Trial Keywords

  • BRCA-mutation
  • Immune checkpoint inhibition
  • Immunotherapy
  • Advanced BRCA-mutated breast cancer
  • HDR-defect
  • PARP inhibitor

Last Updated

September 1, 2021