Clinical Trials /

Neoadjuvant Her2-targeted Therapy and Immunotherapy With Pembrolizumab

NCT03747120

Description:

A phase 2 open-label, randomized, multi-center trial to evaluate the efficacy and safety of neoadjuvant trastuzumab, pertuzumab and weekly paclitaxel (THP) as compared to neoadjuvant trastuzumab, pertuzumab, pembrolizumab and weekly paclitaxel (THP-K), or neoadjuvant trastuzumab, pembrolizumab and weekly paclitaxel (TH-K) in chemo naive patients with invasive human epidermal growth factor receptor 2 (HER2) positive breast cancer whose primary tumors are > 2 cm and/or clinically lymph node positive. Treatment will be followed by standard of care breast surgery and physician's choice adjuvant therapy per standard of care.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Neoadjuvant Her2-targeted Therapy and Immunotherapy With Pembrolizumab
  • Official Title: Neoadjuvant Her2-targeted Therapy and Immunotherapy With Pembrolizumab (neoHIP)

Clinical Trial IDs

  • ORG STUDY ID: IIT2018-04-MCARTHUR-NEOHP
  • NCT ID: NCT03747120

Conditions

  • HER2-positive Breast Cancer
  • Breast Cancer

Interventions

DrugSynonymsArms
PaclitaxelTaxolArm A
TrastuzumabHerceptinArm A
PertuzumabPerjetaArm A
PembrolizumabKeytrudaArm B

Purpose

A phase 2 open-label, randomized, multi-center trial to evaluate the efficacy and safety of neoadjuvant trastuzumab, pertuzumab and weekly paclitaxel as compared to neoadjuvant trastuzumab, pertuzumab, pembrolizumab and weekly paclitaxel, or neoadjuvant trastuzumab, pembrolizumab and weekly paclitaxel in chemo naive patients with invasive HER2 positive breast cancer whose primary tumors are > 2 cm or clinically lymph node positive. Treatment will be followed by standard of care breast surgery and physician's choice adjuvant therapy per standard of care.

Detailed Description

      A phase 2 open-label, randomized, multi-center trial to evaluate the efficacy and safety of
      neoadjuvant trastuzumab, pertuzumab and weekly paclitaxel as compared to neoadjuvant
      trastuzumab, pertuzumab, pembrolizumab and weekly paclitaxel, or neoadjuvant trastuzumab,
      pembrolizumab and weekly paclitaxel in chemo naive patients with invasive HER2 positive
      breast cancer whose primary tumors are > 2 cm and/or clinically lymph node positive.

      Patients will be randomized to either Arm A (trastuzumab, pertuzumab and weekly paclitaxel),
      Arm B (trastuzumab, pertuzumab, pembrolizumab and weekly paclitaxel) or Arm C (trastuzumab,
      pembrolizumab and weekly paclitaxel). Patients will be stratified according to hormone
      receptor status and lymph node status. All patients will be treated weekly every three weeks
      for four cycles (only paclitaxel will be administered weekly) and then undergo breast
      surgery. Arm A patients will be regarded as the reference group.
    

Trial Arms

NameTypeDescriptionInterventions
Arm AActive ComparatorPaclitaxel weekly x12 + Trastuzumab + Pertuzumab
  • Paclitaxel
  • Trastuzumab
  • Pertuzumab
Arm BExperimentalPaclitaxel weekly x12 + Trastuzumab + Pertuzumab + Pembrolizumab
  • Paclitaxel
  • Trastuzumab
  • Pertuzumab
  • Pembrolizumab
Arm CExperimentalPaclitaxel weekly x12 + Trastuzumab + Pembrolizumab
  • Paclitaxel
  • Trastuzumab
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Male/female patients with histologically confirmed invasive HER2-positive (by ASCO/CAP
             guidelines) unilateral breast cancer

          -  Have previously untreated non-metastaic (M0), cT2-4N0 or cT1-4N1-3 (biopsies of
             clinically suspicious lymph nodes to confirm nodal status is encouraged).

          -  Multifocal/centric disease is permitted if all suspicious foci have been biopsied and
             are consistent with HER2-positive (by ASCO/CAP guidelines) invasive breast cancer

          -  Be a male or female subject 18 years of age on the day of signing informed consent

        Male Participants:

          -  A male participant must agree to use a contraception as detailed in Appendix C of this
             protocol during the treatment period and for at least 6 months after the last dose of
             study treatment and refrain from donating sperm during this period.

        Female Participants:

          -  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: a.) Not a
             woman of childbearing potential (WOCBP) as defined in Appendix C OR b.) A WOCBP who
             agrees to follow the contraceptive guidance in Appendix C during the treatment period
             and for at least 6 months after the last dose of study treatment.

          -  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.

        Note: If submitting unstained cut slides, newly cut slides should be submitted to the
        testing laboratory within 14 days from the date slides are cut.

          -  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.

          -  Have adequate organ function as defined by the following parameters. Specimens must be
             collected within 10 days prior to the start of study treatment.

          -  Absolute neutrophil count (ANC) ≥1500/µL

          -  Platelets ≥100 000/µL

          -  Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La

          -  Renal Creatinine (≤1.5 × ULN OR) OR Measured or calculated(b) creatinine clearance
             (≥30 mL/min for participant with creatinine levels) (GFR can also be used in place of
             creatinine or CrCl) (>1.5 × institutional ULN)

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

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

          -  Cardiac Echocardiogram or MUGA Baseline LVEF ≥ 55%

        Exclusion Criteria:

          -  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 therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with
             an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g.,
             CTLA-4, OX 40, CD137).

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

        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.

          -  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 3 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 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).

          -  Has a known active Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]
             reactive) or Hepatitis C virus (i.d. HCV RNA [qualitative] is detected) infection.

          -  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 significant cardiovascular disease, such as:

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

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

               -  Angina pectoris requiring anti-anginal medication, uncontrolled arrhythmias, or
                  uncontrolled hypertension (systolic blood pressure > 180mmHg and/or diastolic
                  blood pressure > 100mmHg).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Pathological complete response (pCR)
Time Frame:16 weeks from randomization
Safety Issue:
Description:Proportion of subjects without residual invasive cancer in the breast and axilla from randomization to definitive surgery. - Residual invasive cancer defined based on hematoxylin and eosin evaluation of complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy by AJCC staging criteria (8th edition) per pathologist assessment.

Secondary Outcome Measures

Measure:Pathological complete invasive and in situ response rate (breast and axilla)
Time Frame:16 weeks from randomization
Safety Issue:
Description:Proportion of subjects without residual invasive and in situ cancer in the breast and axilla disease from randomization to definitive surgery. - Residual invasive cancer and in situ disease defined based on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy by AJCC staging criteria (8th edition) per pathological assessment.
Measure:Pathological complete response rate (pCR) in breast only
Time Frame:16 weeks from randomization
Safety Issue:
Description:Proportion of subjects without residual invasive cancer in the breast from randomization to definitive surgery. - Residual invasive breast cancer defined based on hematoxylin and eosin evaluation of the complete resected breast specimen following completion of neoadjuvant systemic therapy by AJCC staging criteria (8th edition) per pathological assessment.
Measure:Residual Cancer Burden (RCB)
Time Frame:16 weeks from randomization
Safety Issue:
Description:Proportion of subjects with RCB 0-I, II or III from randomization to definitive surgery. -Residual Cancer Burden defined based on the RCB index, a component of four pathological parameters: bi-dimensional diameter of primary tumor bed, percent of cellularity in the tumor bed, number of involved lymph nodes and size of the largest nodal metastasis. The RCB possible scores are: RCB 0 (pCR), RCB I, RCB II, RCB III.
Measure:Breast conserving surgery rate
Time Frame:16 weeks from randomization
Safety Issue:
Description:Proportion of subjects who achieved breast conserving surgery out of the intent-to-treat population without inflammatory breast cancer from randomization to definitive surgery (breast conserving surgery).
Measure:Event free survival
Time Frame:36 months from randomization
Safety Issue:
Description:Mean difference in time (in months) from randomization to any of the following events progression of disease that precludes surgery, local or distant recurrence, or death due to any cause.
Measure:Invasive disease-free survival (IDFS)
Time Frame:33 months from surgery
Safety Issue:
Description:Mean difference in time (in months) from date of surgery (date of no disease) to the first documentation of invasive progressive disease or death.
Measure:Overall survival
Time Frame:36 months from randomization
Safety Issue:
Description:Mean difference in time (in months) from randomization to death.
Measure:Symptomatic cardiac events and asymptomatic LVEF events
Time Frame:36 months from randomization
Safety Issue:
Description:Incidence of symptomatic cardiac events and asymptomatic LVEF events (LVEF < 50% or a decrease ≥ 10 ejection fraction points from baseline).
Measure:AEs and SAEs
Time Frame:20 weeks from treatment initiation
Safety Issue:
Description:Incidence and severity of adverse events (AE) and serious adverse events (SAE) from cycle 1 day 1 until 30 days post-surgery. -AEs and SAEs based on CTCAE 5.0

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Cedars-Sinai Medical Center

Trial Keywords

  • her2-positive breast cancer
  • Breast Cancer
  • Pembrolizumab
  • Immunotherapy
  • Neoadjuvant her2 targeted therapy

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