Clinical Trials /

A Study of Radiation Therapy With Pembrolizumab and Olaparib in Women Who Have Triple-Negative Breast Cancer

NCT04683679

Description:

The purpose of this study is to find out whether adding pembrolizumab, with or without olaparib, to standard radiation therapy is a safe and effective treatment for triple-negative breast cancer/TNBC.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of Radiation Therapy With Pembrolizumab and Olaparib in Women Who Have Triple-Negative Breast Cancer
  • Official Title: A Phase II Study of Pembrolizumab and Ablative Radiotherapy With or Without Olaparib in Metastatic Triple-Negative Breast Cancers : Initial Test Cohorts of a Platform Trial to Sequentially Investigate Combinations of DNA-Damage Response Inhibitors and Immunotherapy for the Augmentation of Immune Responses

Clinical Trial IDs

  • ORG STUDY ID: 20-505
  • NCT ID: NCT04683679

Conditions

  • Triple Negative Breast Cancer
  • TNBC - Triple-Negative Breast Cancer
  • Breast Cancer

Interventions

DrugSynonymsArms
PembrolizumabpembroArm A
OlaparibArm A

Purpose

The purpose of this study is to find out whether adding pembrolizumab, with or without olaparib, to standard radiation therapy is a safe and effective treatment for triple-negative breast cancer/TNBC.

Trial Arms

NameTypeDescriptionInterventions
Arm AExperimentalParticipants will have triple negative breast cancer diagnosis Treatment will be pembro + RT + olaparib
  • Pembrolizumab
  • Olaparib
Arm BExperimentalParticipants will have triple negative breast cancer diagnosis Treatment will be pembro + RT only
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Female participants who are at least 18 years of age on the day of signing informed
             consent with histologically confirmed diagnosis of triple negative breast cancer will
             be enrolled in this study.

          -  Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
             Evaluation of ECOG is to be performed within 7 days prior to the date of
             allocation/randomization

          -  Histologically or cytologically-confirmed TNBC (defined as ER <5%, PR <5%, HER- 2-neu
             0-1+ by IHC or FISH-negative or as per MD discretion).

          -  Metastatic or recurrent TNBC.

          -  Prior receipt of ICI with progression and/or PDL1-negative.

          -  Note: PDL1-status may be determined on tissues from either primary or mTNBC.
             Determination of PD-L1 status by any prototype assays is acceptable. PD-L1 status is
             required or archival tissue must be readily available for testing during screening if
             status was not previously determined.

          -  The participant (or legally acceptable representative if applicable) provides written
             informed consent for the trial.

          -  Have measurable disease based on RECIST 1.1. There should be at least one
             radiographically-confirmed non-bone metastatic lesion that will not undergo RT and is
             measurable based on RECIST and suitable for repeated measurements.

          -  Lesions situated in a previously irradiated area are considered measurable if
             progression has been demonstrated in such lesions.

          -  No more than 2 prior lines of systemic therapy for inoperable/recurrent or metastatic
             disease.

          -  At least one tumor site for which palliative RT is considered clinically appropriate.

        The site under consideration can be a metastatic site, or uncontrolled primary/locally
        recurrent disease in the breast/chest wall or in the nodes, that has not received prior RT.

          -  Have provided archival tumor tissue sample or newly obtained core or excisional biopsy
             of a tumor lesion not previously irradiated. Formalin- fixed, paraffin embedded (FFPE)
             tissue blocks are preferred to slides. Newly obtained biopsies are preferred to
             archived tissue. Newly-obtained is defined as a specimen obtained up to 28 days prior
             to initiation of treatment on Day 1 of RT. (Note: PI can waive this requirement at his
             discretion if specimen collection is deemed unfeasible).

          -  A female participant is eligible to participate if she is not pregnant (see Appendix
             C), not breastfeeding, and at least one of the following conditions applies:

               1. Not a woman of childbearing potential (WOCBP) as defined in Appendix C

                  OR

               2. A WOCBP who agrees to follow the contraceptive guidance in Appendix C during the
                  treatment period and for at least one month after the last dose of study
                  treatment.

          -  Have adequate organ function as defined in the following table (Table 2). Specimens
             must be collected within 30 days prior to the start of study treatment.

        Table 2 Adequate Organ Function Laboratory Values

        System: Laboratory Value

        Hematological Absolute neutrophil count (ANC): ≥ 1500/µL Platelets: ≥ 100 000/µL
        Hemoglobin: ≥ 10.0 g/dL with no blood transfusion in the past 28 days

        Renal Creatinine: 1.5 x ULN OR Measured or calculatedb creatinine clearance (GFR can also
        be used in place of creatinine or CrCl): ≥ 51 mL/min

        Hepatic Total bilirubin: ≤ 1.5 x ULN OR direct bilirubin ≤ ULN for participants with total
        bilirubin levels >1.5 x ULN AST (SGOT) and ALT (SGPT): ≤ 2.5 x ULN (≤ 5 x ULN for
        participants with liver metastases)

        Coagulation International normalized ratio (INR) OR prothrombin time (PT); Activated
        partial thromboplastin time (aPTT): ≤ 1.5 x ULN unless participant is receiving
        anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of
        anticoagulants

        ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST
        (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular
        filtration rate; ULN=upper limit of normal.

        a - Criteria must be met without erythropoietin dependency and without packed red blood
        cell (pRBC) transfusion within last 2 weeks.

        b - Creatinine clearance (CrCl) should be calculated per institutional standard.

        Note: This table includes eligibility-defining laboratory value requirements for treatment;
        laboratory value requirements should be adapted according to local regulations and
        guidelines for the administration of specific chemotherapies.

          -  Participant must agree not to breastfeed during the study or for 180 days after the
             last dose of study treatment.

          -  Participant receiving corticosteroids may continue as long as their dose is stable for
             at least 4 weeks prior to initiating protocol therapy.

          -  Ability to swallow (whole) and retain oral medications.

        Exclusion Criteria:

          -  Germline or somatic BRCA mutation-positive status

          -  Prior treatment with a PARP inhibitor

          -  Receipt of > 2 lines of chemo in the metastatic setting

          -  A WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization
             (see Appendix C). If the urine test is positive or cannot be confirmed as negative, a
             serum pregnancy test will be required.

               -  Note: in the event that 72 hours have elapsed between the screening pregnancy
                  test and the first dose of study treatment, another pregnancy test (urine or
                  serum) must be performed and must be negative in order for subject to start
                  receiving study medication.

          -  Has received prior systemic anti-cancer therapy including investigational agents
             within 4 weeks prior to randomization.

               -  Note: Participants must have recovered from all AEs due to previous therapies to
                  ≤ Grade 1 or baseline. Participants with ≤ Grade 2 neuropathy may be eligible.

               -  Note: If participant received major surgery, they must have recovered adequately
                  from the toxicity and/or complications from the intervention prior to starting
                  study treatment.

          -  Has received prior radiotherapy within 2 weeks of start of study treatment.
             Participants must have recovered from all radiation-related toxicities, not require
             corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
             for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease.

          -  Has received prior radiotherapy to the site of palliation under consideration (ie
             re-irradiation is disallowed).

          -  Has previously experienced grade 3 or higher immune-mediated adverse events from prior
             courses of immunotherapy.

          -  Has received a live vaccine within 30 days prior to the first dose of study drug.
             Examples of live vaccines include, but are not limited to, the following: measles,
             mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
             Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
             are generally killed virus vaccines and are allowed; however, intranasal influenza
             vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.

          -  Is currently participating in or has participated in a study of an investigational
             agent or has used an investigational device within 4 weeks prior to the first dose of
             study treatment.

               -  Note: Participants who have entered the follow-up phase of an investigational
                  study may participate as long as it has been 4 weeks after the last dose of the
                  previous investigational agent.

          -  Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
             (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
             immunosuppressive therapy within 7 days prior to the first dose of study drug.

          -  Has a known additional malignancy that is progressing or has required active treatment
             within the past 2 years. Note: Participants with basal cell carcinoma of the skin,
             squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma,
             cervical cancer in situ) that have undergone potentially curative therapy are not
             excluded.

          -  Has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or olaparib and/or any of
             their excipients.

          -  Has 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). 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 a history of (non-infectious) pneumonitis that required steroids or has current
             pneumonitis.

          -  Has an active infection requiring systemic therapy.

          -  Has a known history of Human Immunodeficiency Virus (HIV).

               -  Note: No HIV testing is required.

          -  Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]
             reactive) or known active Hepatitis C virus (defined as HCV RNA is detected)
             infection. Note: no testing for Hepatitis B and Hepatitis C is required unless
             mandated by local health authority.

          -  Has a known history of active TB (Bacillus Tuberculosis).

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the study, interfere with the subject's
             participation for the full duration of the study, 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 study, starting with the screening visit through 120 days
             after the last dose of trial treatment

          -  Has had an allogenic tissue/solid organ transplant

             ° Note: Seasonal influenza vaccines for injection are generally inactivated flu
             vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are
             live attenuated vaccines, and are not allowed.

          -  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 5.0)
             grade 2) caused by previous cancer therapy, excluding alopecia.

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

          -  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 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, nonmalignant 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.

          -  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.

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

          -  Judgment by the investigator that the patient should not participate in the study if
             the patient is unlikely to comply with study procedures, restrictions and
             requirements.

          -  Previous enrollment in the present study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate
Time Frame:8 weeks from baseline
Safety Issue:
Description:To assess overall response rate (ORR) to pembrolizumab, RT +/- olaparib, in non-targeted unirradiated lesions at 8 weeks using RECIST v1.1 in patients with mTNBC who have progressed on ICI or are PD-L1 negative.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Memorial Sloan Kettering Cancer Center

Trial Keywords

  • triple-negative breast cancer
  • TNBC
  • Breast Cancer
  • PDL-1 negative
  • pembrolizumab
  • olaparib
  • 20-505
  • Memorial Sloan Kettering Cancer Center

Last Updated

December 24, 2020