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A Phase 1b Study of Neratinib, Pertuzumab and Trastuzumab With Taxol (3HT) in Primary 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

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ClinicalTrials.gov Identifier: NCT03101748
Recruitment Status : Recruiting
First Posted : April 5, 2017
Last Update Posted : August 3, 2018
Sponsor:
Collaborator:
Puma Biotechnology, Inc.
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:

The goal of this clinical research study is to learn if adding neratinib to either taxol (paclitaxel) or to the combination of pertuzumab, trastuzumab, and paclitaxel can help to control metastatic or locally advanced breast cancer when given before other standard chemotherapy (doxorubicin and/or cyclophosphamide) and surgery. Researchers also want to find the highest tolerable dose of neratinib that can be used in these study drug combinations. The safety of these drug combinations will also be studied.

This is an investigational study. Pertuzumab and trastuzumab are FDA approved and commercially available for the treatment of HER2-positive breast cancer. Paclitaxel, doxorubicin, and cyclophosphamide are FDA approved and commercially available for the treatment of breast cancer. Neratinib is FDA approved and commercially available. The drug combinations are investigational and are currently being used for research purposes only.

The study doctor can describe how the study drugs are designed to work.

Up to 99 participants will be enrolled in this study. All will take part at MD Anderson.


Condition or disease Intervention/treatment Phase
Malignant Neoplasm of Breast Drug: Neratinib Drug: Paclitaxel Drug: Pertuzumab Drug: Trastuzumab Drug: Doxorubicin Drug: Cyclophosphamide Phase 1 Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 99 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b Study of Neratinib, Pertuzumab and Trastuzumab With Taxol (3HT) in Primary 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
Actual Study Start Date : January 29, 2018
Estimated Primary Completion Date : January 2026
Estimated Study Completion Date : January 2027


Arm Intervention/treatment
Experimental: Group A: HER2-Positive Breast Cancer

Group A consists of HER2-positive metastatic or locally advanced breast cancer patients.

All participants take Neratinib 1 time a day by mouth for the first week as a 1-week "pre-cycle". After that, all study cycles are 21 days long. Participants take Neratinib tablets 1 time a day by mouth with food at the same time each day (in the morning, if possible) during Cycles 1 - 4.

Participants receive Paclitaxel by vein over about 1-3 hours on Days 1, 8, and 15 of Cycles 1 - 4.

Participants receive Pertuzumab by vein over about 1 hour on Day 1 of Cycles 1 - 4.

Participants receive Trastuzumab by vein over about 1-2 hours on Day 1 of Cycles 1 - 4.

All participants take Neratinib 1 time a day by mouth for the first week as a 1-week "pre-cycle". After that, all study cycles will be 21 days long.

Drug: Neratinib

Group A - Phase 1b: Participants take starting dose of Neratinib 80 mg, 1 time a day by mouth for the first week as a 1-week "pre-cycle". After that, all study cycles are 21 days long. Participants take neratinib tablets 1 time a day by mouth with food at the same time each day (in the morning, if possible) during Cycles 1 - 4.

Group A - Phase II: Participants take Neratinib at the maximum tolerated dose from Phase 1b.

Group B: Participants receive Neratinib at the recommended phase II dose for 4, 21 day cycles.

Group C: Participants receive Neratinib 200 mg by mouth daily in a 21 day cycle for 12 cycles.


Drug: Paclitaxel

Group A: Participants receive Paclitaxel 80 mg by vein over about 1-3 hours on Days 1, 8, and 15 of Cycles 1 - 4.

Group B: Participants receive Paclitaxel 80 mg by vein over about 1-3 hours on Days 1, 8, and 15 of Cycles 1-4.

Group C: Participants receive Paclitaxel 80 mg by vein over about 1 - 3 hours on Days 1, 8, and 15 of Cycles 1 - 4.

Other Name: Taxol

Drug: Pertuzumab

Group A: Participants receive Pertuzumab by vein over about 1 hour on Day 1 of Cycles 1 - 4. Loading dose 840 mg, followed by 420 mg by vein on Day 1 of Cycles 1 - 4.

Group B: Participants receive Pertuzumab by vein over about 1 hour on Day 1 of Cycles 1 - 4. Loading dose 840 mg, followed by 420 mg by vein on Day 1 of Cycles 1 - 4.

Other Name: Perjeta

Drug: Trastuzumab

Group A: Participants receive Trastuzumab by vein over about 1-2 hours on Day 1 of Cycles 1 - 4. Loading dose 8 mg/kg, followed by 6 mg/kg by vein on Day 1 of Cycles 1 - 4.

Group B: Participants receive Trastuzumab by vein over about 1-2 hours on Day 1 of Cycles 1 - 4. Loading dose 8 mg/kg, followed by 6 mg/kg by vein on Day 1 of Cycles 1 - 4.

Other Name: Herceptin

Experimental: Group B: HER2+ Locally Advanced Inflammatory Breast Cancer

Group B consists of HER2+ locally advanced inflammatory breast cancer (IBC) patients.

All participants take Neratinib 1 time a day by mouth for the first week as a 1-week "pre-cycle". After that, all study cycles are 21 days long. Participants take Neratinib tablets 1 time a day by mouth with food at the same time each day (in the morning, if possible) during Cycles 1 - 4.

Participants receive Paclitaxel by vein over about 1-3 hours on Days 1, 8, and 15 of Cycles 1-4.

Participants receive Pertuzumab by vein over about 1 hour on Day 1 of Cycles 1 - 4.

Participants receive Trastuzumab by vein over about 1 - 2 hours on Day 1 of Cycles 1 - 4.

Participants receive standard-of-care Doxorubicin and Cyclophosphamide by vein over about 90 minutes on Day 1 of Cycles 5 - 8.

Drug: Neratinib

Group A - Phase 1b: Participants take starting dose of Neratinib 80 mg, 1 time a day by mouth for the first week as a 1-week "pre-cycle". After that, all study cycles are 21 days long. Participants take neratinib tablets 1 time a day by mouth with food at the same time each day (in the morning, if possible) during Cycles 1 - 4.

Group A - Phase II: Participants take Neratinib at the maximum tolerated dose from Phase 1b.

Group B: Participants receive Neratinib at the recommended phase II dose for 4, 21 day cycles.

Group C: Participants receive Neratinib 200 mg by mouth daily in a 21 day cycle for 12 cycles.


Drug: Paclitaxel

Group A: Participants receive Paclitaxel 80 mg by vein over about 1-3 hours on Days 1, 8, and 15 of Cycles 1 - 4.

Group B: Participants receive Paclitaxel 80 mg by vein over about 1-3 hours on Days 1, 8, and 15 of Cycles 1-4.

Group C: Participants receive Paclitaxel 80 mg by vein over about 1 - 3 hours on Days 1, 8, and 15 of Cycles 1 - 4.

Other Name: Taxol

Drug: Pertuzumab

Group A: Participants receive Pertuzumab by vein over about 1 hour on Day 1 of Cycles 1 - 4. Loading dose 840 mg, followed by 420 mg by vein on Day 1 of Cycles 1 - 4.

Group B: Participants receive Pertuzumab by vein over about 1 hour on Day 1 of Cycles 1 - 4. Loading dose 840 mg, followed by 420 mg by vein on Day 1 of Cycles 1 - 4.

Other Name: Perjeta

Drug: Trastuzumab

Group A: Participants receive Trastuzumab by vein over about 1-2 hours on Day 1 of Cycles 1 - 4. Loading dose 8 mg/kg, followed by 6 mg/kg by vein on Day 1 of Cycles 1 - 4.

Group B: Participants receive Trastuzumab by vein over about 1-2 hours on Day 1 of Cycles 1 - 4. Loading dose 8 mg/kg, followed by 6 mg/kg by vein on Day 1 of Cycles 1 - 4.

Other Name: Herceptin

Drug: Doxorubicin

Group B: Participants received Doxorubicin 60 mg/m2 by vein over about 90 minutes on Day 1 of Cycles 5 - 8.

Group C: Participants received Doxorubicin 60 mg/m2 by vein over about 90 minutes on Day 1 of Cycles 5 - 8.

Other Names:
  • Doxorubicin Hydrochloride
  • Adriamycin PFS
  • Adriamycin RDF
  • Adriamycin
  • Rubex

Drug: Cyclophosphamide

Group B: Participants receive Cyclophosphamide 600 mg/m2 by vein over about 90 minutes on Day 1 of Cycles 5 - 8.

Group C: Participants receive Cyclophosphamide 600 mg/m2 by vein over about 90 minutes on Day 1 of Cycles 5 - 8.

Other Names:
  • Cytoxan
  • Neosar

Experimental: Group C: HER2-/ER+ Locally Advanced IBC Patients

Group C consists of HER2-negative/ER-positive (HER2-/ER+) locally advanced IBC patients.

All participants take Neratinib 1 time a day by mouth for the first week as a 1-week "pre-cycle". After that, all study cycles are 21 days long. Participants take Neratinib tablets 1 time a day by mouth with food at the same time each day (in the morning, if possible) during Cycles 1 - 4. Participants take Neratinib tablets 1 time a day by mouth with food at the same time each day (in the morning, if possible) during Cycles 1 - 4.

Participants receive Paclitaxel by vein over about 1 - 3 hours on Days 1, 8, and 15 of Cycles 1 - 4.

Participants receive standard-of-care Doxorubicin and Cyclophosphamide by vein over about 90 minutes on Day 1 of Cycles 5 - 8.

Drug: Neratinib

Group A - Phase 1b: Participants take starting dose of Neratinib 80 mg, 1 time a day by mouth for the first week as a 1-week "pre-cycle". After that, all study cycles are 21 days long. Participants take neratinib tablets 1 time a day by mouth with food at the same time each day (in the morning, if possible) during Cycles 1 - 4.

Group A - Phase II: Participants take Neratinib at the maximum tolerated dose from Phase 1b.

Group B: Participants receive Neratinib at the recommended phase II dose for 4, 21 day cycles.

Group C: Participants receive Neratinib 200 mg by mouth daily in a 21 day cycle for 12 cycles.


Drug: Paclitaxel

Group A: Participants receive Paclitaxel 80 mg by vein over about 1-3 hours on Days 1, 8, and 15 of Cycles 1 - 4.

Group B: Participants receive Paclitaxel 80 mg by vein over about 1-3 hours on Days 1, 8, and 15 of Cycles 1-4.

Group C: Participants receive Paclitaxel 80 mg by vein over about 1 - 3 hours on Days 1, 8, and 15 of Cycles 1 - 4.

Other Name: Taxol

Drug: Doxorubicin

Group B: Participants received Doxorubicin 60 mg/m2 by vein over about 90 minutes on Day 1 of Cycles 5 - 8.

Group C: Participants received Doxorubicin 60 mg/m2 by vein over about 90 minutes on Day 1 of Cycles 5 - 8.

Other Names:
  • Doxorubicin Hydrochloride
  • Adriamycin PFS
  • Adriamycin RDF
  • Adriamycin
  • Rubex

Drug: Cyclophosphamide

Group B: Participants receive Cyclophosphamide 600 mg/m2 by vein over about 90 minutes on Day 1 of Cycles 5 - 8.

Group C: Participants receive Cyclophosphamide 600 mg/m2 by vein over about 90 minutes on Day 1 of Cycles 5 - 8.

Other Names:
  • Cytoxan
  • Neosar




Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) of Neratinib in Combination with Paclitaxel, Pertuzumab, and Trastuzumab in HER2-positive (HER2+) Primary Metastatic or Locally Advanced Breast Cancer [ Time Frame: 42 days ]

    MTD is defined as the highest dose for which the posterior probability of toxicity is closest to 20%.

    The phase Ib portion of the trial uses the Bayesian modified Toxicity Probability Interal (mTPI)[34] dose-escalation algorithm to determine the MTD of Neratinib from among four doses.


  2. Pathologic Complete Response (pCR) Rate of Neratinib in Combination with Paclitaxel, Pertuzumab, and Trastuzumab Followed by Doxorubicin and Cyclophosphamide (AC) in HER2+ Locally Advanced Inflammatory Breast Cancer (IBC) Patients [ Time Frame: 84 days ]
    Simon's optimum two-stage design used to monitor the pCR rate.

  3. Pathologic Complete Response (pCR) Rate of Neratinib in Combination with Paclitaxel Followed by Doxorubicin and Cyclophosphamide in HER2-Negative/ER-Positive (HER2-/ER+) Locally Advanced Inflammatory Breast Cancer (IBC) Patients [ Time Frame: 84 days ]
    Simon's minimax two-stage design to monitor the pCR rate.


Secondary Outcome Measures :
  1. Progression Free Survival (PFS) Rate of HER2+ Primary de novo Metastatic and Locally Advanced Inflammatory Breast Cancer (IBC) Patients, and HER2-/ER+ IBC Patients Treated with Neratinib Plus Anthracycline and Taxane Based Chemotherapy [ Time Frame: 2 years ]
    Progression-free survival (PFS) estimated by the Kaplan-Meier method, and distributions compared using the log-rank test.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Histological confirmation of breast cancer
  2. 18 years of age or older
  3. Able to provide written informed consent for the trial
  4. Performance status of </= 1 on the ECOG performance scale
  5. Able to swallow oral medication
  6. LVEF assessment by 2-D echocardiogram or MUGA scan performed within 90 days prior to registration must be >/= 50%
  7. 7. Adequate organ function as determined by the following laboratory values: Absolute neutrophil count >/= 1,500 /uL, Platelets >/= 100,000 / uL, Hemoglobin >/=9 g/dL, Creatinine clearance >/= 50 ml/min, Total bilirubin </= 1.5 X 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 AST/ALT elevation that is declared to be caused due to liver metastasis, they are allowed to be enrolled as long as <5 x ULN.
  8. Subject of Childbearing potential should is willing to use effective methods of birth control or be surgically sterile, or abstain from heterosexual activity during study and 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.
  9. Subject of childbearing potential is willing to use 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.
  10. Cohort 1: Phase 1b: Subject must have HER2 + (regardless of hormonal receptor status) primary metastatic or locally advanced breast cancer (IBC or Non-IBC). HER2 positive status is defined as strongly positive (3+) staining score by IHC, or gene amplification using FISH, if performed. If IHC is equivocal (2+), assays using FISH require gene amplification based on recent ASCO-CAP guideline: dual-probe HER2/CEP17 ratio is >/=2.0 and/or an average HER2 copy number >/= 6.0 signals/cell. 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
  11. Cohort 1: Phase II: Patient must have HER2+ (regardless of hormonal receptor status) stage III IBC.
  12. Cohort 2 Patient must have HER2-/HR+ stage III IBC. HER2 negative status, which determined by assays using IHC require negative (0 or 1+) staining score. If IHC is equivocal (2+) staining score, assays using FISH require the absence of gene amplification: dual-probe HER2/CEP17 ratio is < 2.0 and an average HER2 copy number <4.0 signals/cell. If HER2 testing result is confirmed at MDACC, it does not require centralized repeat testing. Hormone receptor (HR) positivity is determined by ER >/=10% and /or PR >/=10% by IHC staining.

Exclusion Criteria:

  1. Excisional biopsy or lumpectomy for the current breast cancer.
  2. 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.
  3. Any other previous antitumor therapies for the current cancer event. This exclusion does not apply to phase Ib part of cohort 1.
  4. Breast-feeding at screening or planning to become pregnant during the course of therapy.
  5. 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.
  6. Active infection or chronic infection requiring chronic suppressive antibiotics.
  7. Known hepatitis B or hepatitis C with abnormal liver function tests.
  8. Malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of the stomach or small bowel, or other disease or condition significantly affecting gastrointestinal function.
  9. Persistent >/= grade 2 diarrhea regardless of etiology.
  10. Sensory or motor neuropathy >/= grade 2
  11. 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.
  12. Uncontrolled hypertension defined as a systolic BP > 150 mmHg or diastolic BP > 90 mmHg, with or without anti-hypertensive medications.
  13. 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: (A)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; and • symptomatic pericarditis. (B) History of cardiac disease: • myocardial infarction documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LV function; • history of documented CHF; and • documented cardiomyopathy.
  14. If you are pregnant, you will not be enrolled on this study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03101748


Contacts
Contact: Bora Lim, MD 713-792-2817 blim@mdanderson.org

Locations
United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact       blim@mdanderson.org   
Sponsors and Collaborators
M.D. Anderson Cancer Center
Puma Biotechnology, Inc.
Investigators
Principal Investigator: Bora Lim, MD M.D. Anderson Cancer Center

Additional Information:
Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT03101748     History of Changes
Other Study ID Numbers: 2016-0537
NCI-2017-00813 ( Registry Identifier: NCI CTRP )
First Posted: April 5, 2017    Key Record Dates
Last Update Posted: August 3, 2018
Last Verified: August 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by M.D. Anderson Cancer Center:
Malignant neoplasm of breast
Metastatic breast cancer
Locally advanced breast cancer
HER2-positive
HER2+
HER2-negative/ER-positive
HER2-/ER+
Locally advanced inflammatory breast cancer
IBC
Neratinib
Paclitaxel
Taxol
Doxorubicin
Doxorubicin Hydrochloride
Adriamycin PFS
Adriamycin RDF
Adriamycin
Rubex
Pertuzumab
Perjeta
Trastuzumab
Herceptin
Cyclophosphamide
Cytoxan
Neosar

Additional relevant MeSH terms:
Breast Diseases
Breast Neoplasms
Neoplasms
Neoplasms by Site
Skin Diseases
Paclitaxel
Liposomal doxorubicin
Pertuzumab
Albumin-Bound Paclitaxel
Cyclophosphamide
Doxorubicin
Trastuzumab
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors