Neoadjuvant Her2-targeted Therapy and Immunotherapy With Pembrolizumab

Study Overview
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Brief Summary
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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.

Detailed Description
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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. Patients will be randomized to either Arm A: THP (trastuzumab, pertuzumab and weekly paclitaxel), Arm B: THP-K (trastuzumab, pertuzumab, pembrolizumab and weekly paclitaxel) or Arm C: TH-K (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.

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

Conditions
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HER2-positive Breast Cancer, Breast Cancer

Intervention / Treatment
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* Drug: Paclitaxel
* Drug: Trastuzumab
* Drug: Pertuzumab
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male/female patients with histologically confirmed invasive HER2-positive (by American Society of Clinical Oncology (ASCO)/College of American Pathologists (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. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial. Provides adequate 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. Have adequate organ function as defined by the following parameters. Specimens must be collected within 7 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 aspartate aminotransferase (AST, SGOT) and alanine aminotransferase (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 (multigated radionuclide angiography) Baseline LVEF ≥ 55% Exclusion Criteria: A WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization. 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 (programmed death protein 1), anti-PD-L1 (Programmed death-ligand 1), or anti PD L2 (Programmed death-ligand 2) 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 systemic 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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 1:1:1 randomization
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A: THP<br>Arm A: Paclitaxel weekly x12 + Trastuzumab + Pertuzumab All subjects may receive standard of care systemic therapy after surgery per their treating physician's discretion. | Drug: Paclitaxel<br>* All subjects will receive Paclitaxel weekly for 12 weeks<br>* Other names: Taxol;Drug: Trastuzumab<br>* All subjects will receive Trastuzumab every 3 weeks<br>* Other names: Herceptin;Drug: Pertuzumab<br>* Arm A and Arm B subjects will receive Pertuzumab every 3 weeks<br>* Other names: Perjeta;|
| Experimental: Arm B: THP-K<br>Arm B: Paclitaxel weekly x12 + Trastuzumab + Pertuzumab + Pembrolizumab All subjects may receive standard of care systemic therapy after surgery per their treating physician's discretion. | Drug: Paclitaxel<br>* All subjects will receive Paclitaxel weekly for 12 weeks<br>* Other names: Taxol;Drug: Trastuzumab<br>* All subjects will receive Trastuzumab every 3 weeks<br>* Other names: Herceptin;Drug: Pertuzumab<br>* Arm A and Arm B subjects will receive Pertuzumab every 3 weeks<br>* Other names: Perjeta;Drug: Pembrolizumab<br>* Arm B and Arm C subjects will receive Pembrolizumab every 3 weeks<br>* Other names: Keytruda;|
| Experimental: Arm C: TH-K<br>Arm C: Paclitaxel weekly x12 + Trastuzumab + Pembrolizumab All subjects may receive standard of care systemic therapy after surgery per their treating physician's discretion. | Drug: Paclitaxel<br>* All subjects will receive Paclitaxel weekly for 12 weeks<br>* Other names: Taxol;Drug: Trastuzumab<br>* All subjects will receive Trastuzumab every 3 weeks<br>* Other names: Herceptin;Drug: Pembrolizumab<br>* Arm B and Arm C subjects will receive Pembrolizumab every 3 weeks<br>* Other names: Keytruda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological complete response (pCR) | 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 pathologist assessment. | 16 weeks from randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological complete invasive and in situ response rate (breast and axilla) | 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 pathological assessment. | 16 weeks from randomization | 
| Pathological complete response rate (pCR) in breast only | 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 pathological assessment. | 16 weeks from randomization | 
| Residual Cancer Burden (RCB) | 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. | 16 weeks from randomization | 
| Breast conserving surgery rate | 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). | 16 weeks from randomization | 
| Event free survival | 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. | 36 months from randomization | 
| Invasive disease-free survival (IDFS) | Mean difference in time (in months) from date of surgery (date of no disease) to the first documentation of invasive progressive disease or death. | 33 months from surgery | 
| Overall survival | Mean difference in time (in months) from randomization to death. | 36 months from randomization | 
| Symptomatic cardiac events and asymptomatic LVEF events | Incidence of symptomatic cardiac events and asymptomatic left ventricular ejection fraction (LVEF) events (LVEF < 50% or a decrease ≥ 10 ejection fraction points from baseline). | 36 months from randomization | 
| AEs and SAEs | 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 | 20 weeks from treatment initiation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Trastuzumab, her2-positive breast cancer, Breast Cancer, Pembrolizumab, Immunotherapy, Neoadjuvant her2 targeted therapy, Pertuzumab, Paclitaxel