Neratinib and Paclitaxel With or Without Pertuzumab and Trastuzumab Before Combination Chemotherapy in Treating Patients With Metastatic or Locally Advanced Breast Cancer

A Phase 1b Study of Neratinib, Pertuzumab, and Trastuzumab With Taxol (3HT) in Metastatic and Locally Advanced Breast Cancer, and Phase II Study of 3HT Followed by AC in HER2 + Primary IBC, and Neratinib With Taxol (NT) Followed by AC in HR+ /HER2- Primary IBC

This phase I/II trial studies the side effect and best dose of neratinib and to see how well it works with paclitaxel and with or without pertuzumab and trastuzumab before combination chemotherapy in treating patients with breast cancer that has spread to other places in the body (metastatic). Neratinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with pertuzumab and trastuzumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as paclitaxel, doxorubicin, and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving neratinib, pertuzumab, trastuzumab, paclitaxel and combination chemotherapy may work better in treating patients with breast cancer.

Study Overview

• Status: Active, not recruiting
• Conditions: Stage IV Breast Cancer AJCC v6 and v7; Stage III Breast Cancer AJCC v7; Stage IIIA Breast Cancer AJCC v7; Stage IIIB Breast Cancer AJCC v7; Stage IIIC Breast Cancer AJCC v7; Metastatic Breast Carcinoma; Locally Advanced Breast Carcinoma; Breast Inflammatory Carcinoma
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Biological: Trastuzumab; Drug: Paclitaxel; Drug: Cyclophosphamide; Drug: Doxorubicin; Biological: Pertuzumab; Drug: Neratinib

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of neratinib in combination with paclitaxel, pertuzumab, and trastuzumab in HER2-positive (HER2+) metastatic or locally advanced (stage III) breast cancer within 2 cycles. (Cohort 1: Phase Ib) II. To determine the pathologic complete response (pCR) rate of neratinib in combination with paclitaxel, pertuzumab, and trastuzumab followed by doxorubicin and cyclophosphamide (AC) in HER2+ metastatic or locally advanced (stage III) inflammatory breast cancer (IBC) patients. (Cohort 1: Phase II) III. To determine the pCR rate of neratinib in combination with paclitaxel followed by AC in HER2-negative/hormone receptor (HR)-positive (HER2-/HR+) metastatic or locally advanced (stage III) IBC patients. (Cohort 2)

SECONDARY OBJECTIVES:

I. To estimate 2 years progression free survival (PFS) rate of HER2+ metastatic or locally advanced (stage III) IBC patients, and HER2-/HR+ IBC patients treated with neratinib plus anthracycline and taxane based chemotherapy. (Cohort I Phase II and Cohort II) II. To determine toxicity and safety of the combination therapy.

EXPLORATORY OBJECTIVES:

I. To determine the adaptive target and downstream changes in pan-HER family members induced by one-week window period of neratinib based on tissue and blood based biomarkers.

II. To determine the correlation between positive/negative changes in EGFR, HER2 and HER4 and the occurrence of pCR.

III. To determine the rate of HER2 mutation in HER2+ IBC and HER2-/HR+ IBC. IV. To determine the association between HER2 mutation and pCR achieved by study combination therapy.

V. To determine the correlation between tumor tissue based pharmacodynamic marker changes in association with circulating tumor cells (CTC) and circulating tumor deoxyribonucleic acid (ctDNA).

OUTLINE: This is a phase I, dose-escalation study of neratinib followed by a phase II study. Patients are assigned to 1 of 3 groups.

GROUP A (COHORT 1 PHASE IB): Patients receive neratinib orally (PO) once daily (QD) on days 1-21, paclitaxel intravenously (IV) over 1-3 hours on days 1, 8, and 15, pertuzumab IV over 1 hour on day 1, and trastuzumab IV over 1-2 hours on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients without progression or excessive toxicity with metastatic disease may receive up to 4 additional courses and with locally advanced disease may receive up to 2 additional courses.

GROUP B (COHORT 1 PHASE II): Patients receive neratinib, paclitaxel, pertuzumab, and trastuzumab as in Group A. Patients then receive doxorubicin IV and cyclophosphamide IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care surgery.

GROUP C (COHORT 2): Patients receive neratinib PO QD on days 1-21, paclitaxel IV over 1-3 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery/ Patients then receive doxorubicin and cyclophosphamide as in Group B. Patients then undergo standard of care surgery.

After completion of study treatment, patients are followed up at 1 month.

• Study Type: Interventional
• Enrollment (Actual): 43
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histological confirmation of breast cancer
• Able to provide written informed consent for the trial
• Performance status of =< 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
• Able to swallow oral medication
• Left ventricular ejection fraction (LVEF) assessment by 2-dimensional (D) echocardiogram or multi-gated acquisition (MUGA) scan performed within 90 days prior to registration must be >= 50%
• Absolute neutrophil count >= 1,500 /uL
• Platelets >= 100,000 /uL
• Hemoglobin >= 9 g/dL
• Creatinine clearance >= 50 ml/min
• Total bilirubin =< 1.5 X upper limit of normal (ULN), for patients with congenital unconjugated hyperbilirubinemia (Crigler-Najjar syndrome type 1 and 2, Gilbert syndrome) that transient hyperbilirubinemia can occur due to physiological condition, as long as there is clear documentation of diagnosis, allowed to be enrolled if direct (conjugated) bilirubin is =< 1.5 X ULN
• Alanine aminotransferase and aspartate aminotransferase =< 2.5 X ULN except in patients with aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation that is declared to be caused due to liver metastasis, they are allowed to be enrolled as long as < 5 x ULN
• Subject of childbearing potential should be willing to use effective methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study and through at least 4 months after the last dose of study drug; subject of childbearing potential is defined as has not been surgically sterilized or free from menses for > 1 year; effective methods of birth control include: 1) use of hormonal birth control methods: pills, shots/injections, implants (placed under the skin by a health care provider), or patches (placed on the skin); 2) intrauterine devices (IUDs); 3) using 2 barrier methods (each partner must use 1 barrier method) with a spermicide; males must use the male condom (latex or other synthetic material) with spermicide; females must choose either a diaphragm with spermicide, or cervical cap with spermicide, or a sponge (spermicide is already in the contraceptive sponge); female patients of childbearing potential must have a negative urine pregnancy test no more than 7 days prior to starting study drug; 4) for male participant, they must agree and commit to use a barrier method of contraception while on treatment and for 3 months after the last dose of investigational product
• Cohort 1: Phase 1b: patient must have HER2 + (regardless of hormonal receptor status) metastatic or locally advanced breast cancer (IBC or Non-IBC); HER2 positive status is defined as strongly positive (3+) staining score by immunohistochemistry (IHC), or gene amplification using fluorescence in situ hybridization (FISH), if performed; if IHC is equivocal (2+), please refer to current American Society of Clinical Oncology (ASCO) guidelines algorithm for evaluation of HER2; HER2 negative status, which is determined by assays using IHC require negative (0 or 1+) staining score; if IHC is equivocal (2+) staining score, please refer to current ASCO guidelines algorithm for evaluation of HER2; IBC is determined by using international consensus criteria: onset: rapid onset of breast erythema, edema and/or peau d'orange, and/or warm breast, with/without an underlying breast mass; duration: history of such findings no more than 6 months; extent erythema occupying at least 1/3 of whole breast; pathology: pathologic confirmation of invasive carcinoma
• Cohort 1: Phase II: patient must have HER2+ (regardless of hormonal receptor status) stage III IBC or Stage IV IBC if the metastatic sites are amenable for local therapy (i.e. radiation and/ or surgery) and will have breast surgery
• Cohort 2: Patient must have HER2-/HR+ stage III IBC or Stage IV IBC if the metastatic sites are amenable for local therapy (i.e. radiation and/ or surgery) and will have breast surgery

Exclusion Criteria:

• Excisional biopsy or lumpectomy for the current breast cancer
• Any other previous malignancies (except for cervical in situ cancers treated only by local excision, and basal and squamous cell carcinomas of the skin) within 5 years
• Any other previous antitumor therapies for the current cancer event; this exclusion does not apply to phase Ib part of cohort 1
• Breast-feeding at screening or planning to become pregnant during the course of therapy
• History of active or known autoimmune disease that can cause diarrhea like (but not limited to) Addison's disease, celiac disease/gluten intolerance/irritable bowel syndrome, scleroderma
• Active infection or chronic infection requiring chronic suppressive antibiotics
• Known hepatitis B or hepatitis C with abnormal liver function tests
• Malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of the stomach or small bowel, or other disease or condition significantly affecting gastrointestinal function
• Persistent >= grade 2 diarrhea regardless of etiology
• Sensory or motor neuropathy >= grade 2
• Conditions that would prohibit intermittent administration of corticosteroids for paclitaxel premedication; however, corticosteroid can be dropped after confirming of no asthma like reaction to paclitaxel after 3 doses
• Uncontrolled hypertension defined as a systolic blood pressure (BP) > 150 mmHg or diastolic BP > 90 mmHg, with or without anti-hypertensive medications

• Cardiac disease (history of and/or active disease) that would preclude the use of any of the drugs included in the treatment regimen; this includes but is not confined to:

  • Active cardiac diseases including:

    • Symptomatic angina pectoris within the past 180 days that required the initiation of or increase in anti-anginal medication or other intervention
    • Ventricular arrhythmias except for benign premature ventricular contractions
    • Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication
    • Conduction abnormality requiring a pacemaker
    • Valvular disease with documented compromise in cardiac function
    • Symptomatic pericarditis

  • History of cardiac disease:

    • Myocardial infarction documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of left ventricular (LV) function
    • History of documented congestive heart failure (CHF)
    • Documented cardiomyopathy
• If you are pregnant, you will not be enrolled on this study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A (Cohort 1 Phase Ib); Patients receive neratinib PO QD on days 1-21, paclitaxel IV over 1-3 hours on days 1, 8, and 15, pertuzumab IV over 1 hour on day 1, and trastuzumab IV over 1-2 hours on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients without progression or excessive toxicity with metastatic disease may receive up to 4 additional courses and with locally advanced disease may receive up to 2 additional courses.	Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Trastuzumab; Given IV; Other Names: Herceptin; ABP 980; ALT02; Anti-c-ERB-2; Anti-c-erbB2 Monoclonal Antibody; Anti-ERB-2; Anti-erbB-2; Anti-erbB2 Monoclonal Antibody; Anti-HER2/c-erbB2 Monoclonal Antibody; Anti-p185-HER2; c-erb-2 Monoclonal Antibody; HER2 Monoclonal Antibody; Herceptin Biosimilar PF-05280014; Herceptin Trastuzumab Biosimilar PF-05280014; Herzuma; MoAb HER2; Monoclonal Antibody c-erb-2; Monoclonal Antibody HER2; Ogivri; Ontruzant; PF-05280014; rhuMAb HER2; RO0452317; SB3; Trastuzumab Biosimilar ABP 980; Trastuzumab Biosimilar ALT02; trastuzumab biosimilar EG12014; Trastuzumab Biosimilar HLX02; Trastuzumab Biosimilar PF-05280014; Trastuzumab Biosimilar SB3; Trastuzumab-dkst; Trastuzumab-dttb; Trastuzumab-pkrb; Trazimera; Kanjinti; Trastuzumab Biosimilar SIBP-01; Trastuzumab-anns; Trastuzumab-qyyp; Drug: Paclitaxel; Given IV; Other Names: Taxol; Anzatax; Asotax; Bristaxol; Praxel; Taxol Konzentrat; Biological: Pertuzumab; Given IV; Other Names: Perjeta; 2C4; 2C4 Antibody; MoAb 2C4; Monoclonal Antibody 2C4; Omnitarg; rhuMAb2C4; RO4368451; Drug: Neratinib; Given PO; Other Names: HKI-272; (2E)-N-(4-((3-chloro-4-((pyridin-2-yl)methoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide; HKI 272; PB 272; PB-272
Experimental: Group B (Cohort 1 Phase II); Patients receive neratinib, paclitaxel, pertuzumab, and trastuzumab as in Group A. Patients then receive doxorubicin IV and cyclophosphamide IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care surgery.	Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Trastuzumab; Given IV; Other Names: Herceptin; ABP 980; ALT02; Anti-c-ERB-2; Anti-c-erbB2 Monoclonal Antibody; Anti-ERB-2; Anti-erbB-2; Anti-erbB2 Monoclonal Antibody; Anti-HER2/c-erbB2 Monoclonal Antibody; Anti-p185-HER2; c-erb-2 Monoclonal Antibody; HER2 Monoclonal Antibody; Herceptin Biosimilar PF-05280014; Herceptin Trastuzumab Biosimilar PF-05280014; Herzuma; MoAb HER2; Monoclonal Antibody c-erb-2; Monoclonal Antibody HER2; Ogivri; Ontruzant; PF-05280014; rhuMAb HER2; RO0452317; SB3; Trastuzumab Biosimilar ABP 980; Trastuzumab Biosimilar ALT02; trastuzumab biosimilar EG12014; Trastuzumab Biosimilar HLX02; Trastuzumab Biosimilar PF-05280014; Trastuzumab Biosimilar SB3; Trastuzumab-dkst; Trastuzumab-dttb; Trastuzumab-pkrb; Trazimera; Kanjinti; Trastuzumab Biosimilar SIBP-01; Trastuzumab-anns; Trastuzumab-qyyp; Drug: Paclitaxel; Given IV; Other Names: Taxol; Anzatax; Asotax; Bristaxol; Praxel; Taxol Konzentrat; Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamide Monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Drug: Doxorubicin; Given IV; Other Names: Adriablastin; Hydroxydaunomycin; Hydroxyl Daunorubicin; Hydroxyldaunorubicin; Biological: Pertuzumab; Given IV; Other Names: Perjeta; 2C4; 2C4 Antibody; MoAb 2C4; Monoclonal Antibody 2C4; Omnitarg; rhuMAb2C4; RO4368451; Drug: Neratinib; Given PO; Other Names: HKI-272; (2E)-N-(4-((3-chloro-4-((pyridin-2-yl)methoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide; HKI 272; PB 272; PB-272
Experimental: Group C (Cohort 2); Patients receive neratinib PO QD on days 1-21, paclitaxel IV over 1-3 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery/ Patients then receive doxorubicin and cyclophosphamide as in Group B. Patients then undergo standard of care surgery.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Paclitaxel; Given IV; Other Names: Taxol; Anzatax; Asotax; Bristaxol; Praxel; Taxol Konzentrat; Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamide Monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Drug: Doxorubicin; Given IV; Other Names: Adriablastin; Hydroxydaunomycin; Hydroxyl Daunorubicin; Hydroxyldaunorubicin; Drug: Neratinib; Given PO; Other Names: HKI-272; (2E)-N-(4-((3-chloro-4-((pyridin-2-yl)methoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide; HKI 272; PB 272; PB-272

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathologic complete response (pCR) rate determined by pCR in breast and axillary lymph nodes (pCR breast & nodes) in HER2+ and HER2-/hormone receptor (HR)+ inflammatory breast cancer treated with neratinib-based treatment	Evaluated at the end of neoadjuvant chemotherapy. In cohort 1, HER2-positive patients, will use Simon's optimum two-stage design to monitor the pathologic complete response rate. In cohort 2, HER2-negative/HR-positive patients, will also use Simon's minimax two-stage design to monitor the pathologic response rate.	Up to 84 days (course 4)
Maximum tolerated dose of neratinib, pertuzumab, trastuzumab and paclitaxel treatment defined as dose limiting toxicities of grade 3 or higher	Will use the Bayesian modified toxicity probability interval dose-escalation algorithm to determine the maximum tolerated dose of neratinib.	Up to 42 days (course 2)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival rate of HER2+, and HER2-/HR+ inflammatory breast cancer subgroups		Up to 2 years
Incidence of adverse events of combination therapy	Monitored separately by cohort by the method of Thall and Sung.	Up to 42 days (course 2)

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Rachel Layman, MD, M.D. Anderson Cancer Center

Publications and helpful links

Helpful Links

• M D Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): January 29, 2018
• Primary Completion (Estimated): January 1, 2026
• Study Completion (Estimated): January 1, 2026

Study Registration Dates

• First Submitted: March 30, 2017
• First Submitted That Met QC Criteria: March 30, 2017
• First Posted (Actual): April 5, 2017

Study Record Updates

• Last Update Posted (Estimated): December 7, 2023
• Last Update Submitted That Met QC Criteria: December 5, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Breast Diseases; Breast Neoplasms; Carcinoma; Inflammatory Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Cyclophosphamide; Paclitaxel; Trastuzumab; Antibodies; Immunoglobulins; Albumin-Bound Paclitaxel; Doxorubicin; Liposomal doxorubicin; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Daunorubicin; Trastuzumab biosimilar HLX02; Pertuzumab
• Other Study ID Numbers: 2016-0537 (Other Identifier: M D Anderson Cancer Center); NCI-2017-00813 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No