Clinical Trials /

Bortezomib Followed by Pembrolizumab and Cisplatin in metTNBC

NCT04265872

Description:

The hypothesis of this pilot trial is that administration of bortezomib will inhibit NHEJ in metastatic TNBC leading at the time of disease progression to metastases that are HR-deficient and sensitive to pembrolizumab and cisplatin therapy. The trial will include in depth analysis of the patients' TNBC genome and phosphoproteome to evaluate HR-proficiency and deficiency, and nuclear proteins that drive NHEJ, before and upon progression with bortezomib therapy.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Bortezomib Followed by Pembrolizumab and Cisplatin in metTNBC
  • Official Title: Pilot Clinical Trial of Treatment With Bortezomib to Inhibit Homologous Recombination (HR) Followed by Pembrolizumab and Cisplatin in Patients With Chemotherapy-Pretreated Metastatic Triple Negative Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: 020-008
  • NCT ID: NCT04265872

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
Bortezomib; pembrolizumab and cisplatin injections--bortezomib followed by pembro/cisKeytruda, Velcade, PlatinolBortezomib followed by pembro/cis

Purpose

The hypothesis of this pilot trial is that administration of bortezomib will inhibit NHEJ in metastatic TNBC leading at the time of disease progression to metastases that are HR-deficient and sensitive to pembrolizumab and cisplatin therapy. The trial will include in depth analysis of the patients' TNBC genome and phosphoproteome to evaluate HR-proficiency and deficiency, and nuclear proteins that drive NHEJ, before and upon progression with bortezomib therapy.

Detailed Description

      Seventy to 80% of breast cancers have a basal gene expression profile which is characterized
      by homologous recombination deficiency (HRD) and high proliferation. HRD leads to
      upregulation of the activity of the non-homologous end joining (NHEJ) error-prone pathway
      that repairs DNA double strand breaks, a process required for TNBC survival. The hypothesis
      of this pilot trial is that administration of bortezomib will inhibit NHEJ in metastatic TNBC
      leading at the time of disease progression to metastases that are HR-deficient and sensitive
      to pembrolizumab and cisplatin therapy. A patient with an exceptional complete and durable
      response of her primary-refractory metastatic TNBC with PI3K pathway inhibition followed at
      disease progression by nab paclitaxel/cisplatin provides the clinical rationale for the
      present trial which will utilize bortezomib to inhibit HR proficiency prior to administration
      of pembrolizumab and cisplatin in pretreated metastatic TNBC patients.

      Patients will receive bortezomib until PD, followed by pembrolizumab and cisplatin until PD
      or a maximum of 6 cycles on study. If patients are responding, they may continue
      pembrolizumab at the physician's discretion off study. Metastatic TNBC patients will undergo
      core needle biopsies of a metastatic lesion at study entry and at disease progression from
      bortezomib for NGS, RPPA, and other molecular analyses.

      Patients whose disease does not respond to pembrolizumab and cisplatin may be treated with
      standard of care breast cancer therapies off study, at the recommendation of the treating
      physician.
    

Trial Arms

NameTypeDescriptionInterventions
Bortezomib followed by pembro/cisExperimentalThere is only one arm.
  • Bortezomib; pembrolizumab and cisplatin injections--bortezomib followed by pembro/cis

Eligibility Criteria

        Inclusion Criteria:

          -  A patient will be eligible for inclusion in this study if she meets all of the
             following criteria:

               1. Female patients ≥18 years of age

               2. Have a diagnosis of metastatic TNBC previously treated with standard
                  anthracycline, cyclophosphamide, and taxane chemotherapy, unless there was a
                  contraindication to doxorubicin, in which case prior treatment with this agent is
                  not required.

               3. Have not received more than 3 prior chemotherapy regimens for metastatic disease.
                  Prior platinum and/or taxane therapy in the adjuvant or metastatic setting is
                  permitted.

               4. Have locoregional (eg, breast, chest wall, regional lymphatic) or pulmonary or
                  hepatic metastatic disease that is amenable to core needle biopsy. If a research
                  biopsy from a patient's metastatic disease cannot be safely obtained, a skin
                  biopsy is permitted. If a skin biopsy cannot be safely obtained, patients may
                  still be eligible, per physician discretion.

               5. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 (See
                  Appendix I)

               6. Have adequate hematologic function, defined by:

                    1. Absolute neutrophil count (ANC) >1500/μL

                    2. Platelet count ≥100,000/μL

                    3. Hemoglobin ≥9 g/dL or ≥5.6 mmol/L

               7. Have adequate liver function, defined by:

                    1. AST and ALT ≤2.5 x the upper limit of normal (ULN) or ≤5 x ULN in presence
                       of liver metastases

                    2. Total bilirubin ≤1.5 x ULN OR direct bilirubin ≤ULN for patients with total
                       bilirubin levels >1.5 × ULN

               8. Have adequate renal function, defined by:

                  a. Serum creatinine ≤1.5 x ULN or calculated creatinine clearance of ≥30 mL/min

               9. Have adequate coagulation function, defined by:

                    1. International Normalized Ratio (INR) OR prothrombin time (PT) and activated
                       partial thromboplastin time (aPTT) ≤1.5 × ULN.

                    2. If patient is receiving anticoagulant therapy, PT or aPTT must be within
                       therapeutic range of intended use of anticoagulants.

              10. Patients who have a history of brain metastasis are eligible for the study
                  provided that all the following criteria are met:

                    1. Brain metastases which have been treated

                    2. Off-treatment with steroids for 2 weeks before administration of the first
                       dose of bortezomib

                    3. No ongoing requirement for dexamethasone or anti-epileptic drugs

                    4. No clinical or radiological evidence of progression of brain metastases

              11. Patient must be accessible for treatment and follow-up.

              12. All patients must be able to understand the investigational nature of the study
                  and give written informed consent prior to study entry.

        Exclusion Criteria:

          -  EXCLUSION CRITERIA

        A patient will be ineligible for inclusion in this study if she meets any of the following
        criteria:

          1. Has received a live vaccine within 30 days of the first dose of study treatment. NOTE:
             seasonal influenza vaccines for injection are generally inactivated flu vaccines and
             are allowed; however, intranasal influenza vaccines (ie, FluMist ®) are live
             attenuated vaccines, and are not allowed.

          2. Has an active autoimmune disease that has required systemic treatment in the past 2
             years (ie, 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) is not considered a form
             of systemic therapy.

          3. 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.

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

          5. Has known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]
             reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is
             detected) infection

          6. Has a history of non-infectious pneumonitis that required steroids or current
             pneumonitis

          7. Has peripheral neuropathy ≥grade 2

          8. Has completed previous radiotherapy for metastatic disease <2 weeks prior to study
             treatment initiation

          9. Has an active infection requiring systemic therapy

         10. Has significant cardiovascular disease, such as:

               1. History of myocardial infarction, acute coronary syndrome, or coronary
                  angioplasty/stenting/bypass grafting within the last 6 months

               2. Congestive heart failure (CHF) New York Heart Association (NYHA) Class II-IV, or
                  history of CHF NYHA class III or IV.

         11. Has a known history of active tuberculosis

         12. Women who are pregnant or lactating. All patients with reproductive potential must
             agree to use effective contraception from time of study entry until at least 3 months
             after the last administration of study drug.

         13. Patients who have any severe and/or uncontrolled medical conditions or other
             conditions that could affect their participation such as:

               1. severe impaired lung functions as defined as spirometry and DLCO that is 50% of
                  the normal predicted value and/or O2 saturation that is 88% or less at rest on
                  room air

               2. liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class
                  C).

         14. Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the study, interfere with the patient's
             participation for the full duration of the study, or is not in the best interest of
             the patient to participate, in the opinion of the Treating Physician.

         15. Has received prior systemic anti-cancer therapy including investigational agents
             within 4 weeks prior to study treatment (this would not include bortezomib while on
             study). Monoclonal antibody agents should have a 4-week (28 day) washout period.

         16. Any other investigational or anti-cancer treatments while participating in this study

         17. Any other active malignancy
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Calculate objective response rate (CR+PR) associated with bortezomib followed at disease progression with pembrolizumab and cisplatin in metastatic TNBC
Time Frame:18 months
Safety Issue:
Description:objective response rate will be calculated by defining the proportion of patients who have a complete or partial response to the study therapy, as determined by the treating physician

Secondary Outcome Measures

Measure:Calculate response
Time Frame:18 months
Safety Issue:
Description:duration of response will be calculated from the time of tumor response to disease progression in patients responding to study therapy;

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Baylor Research Institute

Last Updated

February 10, 2020