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A Dose-Escalation Study Evaluating the Combination of Trastuzumab Emtansine (T-DM1) With Neratinib in Women With Metastatic HER2-Positive Breast Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02236000
Recruitment Status : Unknown
Verified March 2020 by NSABP Foundation Inc.
Recruitment status was:  Active, not recruiting
First Posted : September 10, 2014
Last Update Posted : September 10, 2020
Puma Biotechnology, Inc.
Information provided by (Responsible Party):
NSABP Foundation Inc

Brief Summary:

This study is being done for the following reasons:

  • The study has two parts. The purpose of the first part (Phase I) of the study is to find out the highest dose of neratinib that can be given safely with T-DM1.
  • The purpose of the second part of the study (Phase II) is to find out whether the dose of neratinib with T-DM1 determined in Phase I will keep breast cancer from getting worse for a period of time.
  • In order to learn more about study therapy levels in blood and discover genetic and protein changes associated with cancer, the study includes special research tests using samples from blood and from breast tumor. Blood samples will be collected before study treatment, once during treatment, and after study treatment stops.
  • In the optional part of this study, three biopsies will be performed to obtain fresh tumor samples from an area where your cancer has spread.

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: Neratinib Drug: T-DM1 Phase 1 Phase 2

Detailed Description:

The FB-10 study is designed as an open label, single arm, Phase Ib/II study with a dose-escalation phase and an expanded cohort (phase II) to evaluate the combination of trastuzumab emtansine (T-DM1) with neratinib in women with metastatic, HER2-positive breast cancer. The primary aim of the phase Ib portion of this study is to determine the safety and tolerability of the two-drug combination. The primary aim of the phase II portion is to demonstrate efficacy.

Patients will receive concurrent therapy with T-DM1 (3.6 mg/kg IV) on Day 1 of a 3-week (21 day) cycle and neratinib as a continuous daily oral dose. The neratinib dose-escalation will include 4 dose levels (120 mg, 160 mg, 200 mg, and 240 mg). At the recommended phase II dose (RP2D) of the T-DM1 and neratinib combination, up to 39 additional patients will be treated.

The sample size of the phase I portion of the study will be between 2 and 24 patients. The sample size of the Phase II portion will be 42 patients. Approximately 6 patients at the Phase I RP2D level will be included in the Phase II portion. The total study enrollment will be a maximum of 63 patients. Accrual is expected to occur over 16 months.

Submission of diagnostic tumor samples and blood samples for FB-10 correlative science studies will be a study requirement for all patients. Blood samples will be collected at baseline, at Cycle 2, Day 1, and at progression. Blood samples for pharmacokinetic (PK) determination will be collected at Phase 1 sites from consenting patients at various time points during the first 24 hours of study therapy (Cycle 1, Days 1 and 2).

An optional tumor biopsy will be procured from consenting patients from an accessible site of metastasis before study dose level assignment (after the patient has signed the consent form and has been screened for eligibility), after Cycle 1 of treatment, and at the time of disease progression.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 63 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase Ib/II Dose-Escalation Study Evaluating the Combination of Trastuzumab Emtansine (T-DM1) With Neratinib in Women With Metastatic HER2-Positive Breast Cancer
Study Start Date : August 2014
Estimated Primary Completion Date : November 2020
Estimated Study Completion Date : November 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Neratinib and T-DM1 Drug: Neratinib

Dose-Escalation Phase (Part 1) - Neratinib Dose-escalation will proceed on the basis of DLT during Cycle 1 starting at 120 mg/day.

Dose level 1: 120 mg/day; Dose level 2: 160 mg/day; Dose level 3: 200 mg/day; Dose level 4: 240 mg/day

Dose-evaluation Phase (Part 2) - Patients will receive the highest dose of neratinib with T-DM1 found in Phase I as study therapy

Drug: T-DM1

Dose-Escalation Phase (Part 1) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.

Dose-evaluation Phase (Part 2) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.

Primary Outcome Measures :
  1. Safety and tolerability of T-DM1 and neratinib to determine the recommended Phase II dose (RP2D) [ Time Frame: Day 1, 8, and 15 of cycle 1. ]
    If 1 of 3 patients in this cohort experiences a dose limiting toxicity (DLT), 3 more patients will be added at the same dose level. If 0 of 3 initial patients or 1 of 6 patients in an expanded cohort experiences a DLT, the dose for the next cohort will be escalated to dose level 2; otherwise, the combination will be considered too toxic.

  2. Overall response rate (ORR) by measurement of target lesions [ Time Frame: Every 42 days after the start of protocol therapy through disease progression, approximately 2 years ]

Secondary Outcome Measures :
  1. Progression-free survival (PFS) time from start of study therapy to disease progression [ Time Frame: From the start of study therapy through 30 days after study therapy stops, approximately 2 years ]
  2. Objective tumor decrease and stable disease (SD) measurement of target lesions [ Time Frame: Measurement of target lesions prior to study therapy and every 42 days through the end of study therapy, approximately 2 years. ]
  3. Adverse events experienced by participants as a measure of toxicity [ Time Frame: Day 1 of every cycle; at the end of protocol therapy; and 30 days following the end of protocol therapy in addition day 8 and 15 of cycle one. ]
  4. Molecular and genetic profiles of tumor samples collected. [ Time Frame: Baseline (prior to study entry), within 72 hours prior to day 1 of cycle 2, and at the time of disease progression, approximately 2 years ]
  5. Pharmacokinetic interactions [ Time Frame: Before therapy begins, within 72 hours prior to day 1 of cycle 2, and at the time of disease progression, approximately 2 years ]
    Describe pharmacokinetic variations in absorption, metabolism and elimination that may affect total drug concentration.

  6. Therapeutic drug monitoring (TDM) [ Time Frame: Before therapy begins, within 72 hours prior to day 1 of cycle 2, and at the time of disease progression, approximately 2 years ]
    TDM analysis measures the plasma concentrations of a therapeutic agent and metabolites in patients to individualize appropriate drug dosages and schedules.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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

Inclusion Criteria:

  • The ECOG performance status must be less than or equal to 2.
  • Patients must have the ability to swallow oral medication.
  • Patients must have histologic or cytologic confirmation of the diagnosis of invasive adenocarcinoma of the breast.
  • Patients must have had anti-HER2 based therapy with pertuzumab and trastuzumab for neoadjuvant therapy, adjuvant therapy or with first line therapy for metastatic disease (which may include trastuzumab and pertuzumab either sequentially or in combination).
  • There must be documentation that the patient has evidence of measurable metastatic breast cancer that is accessible to biopsy at study entry.
  • Patients must have estrogen receptor (ER) analysis performed prior to study entry. If ER analysis is negative, then progesterone receptor (PgR) analysis must also be performed. (Patients are eligible with either hormone receptor-positive or hormone receptor-negative tumors.)
  • Breast cancer must be determined by local testing to be human epidermal growth factor receptor 2 (HER2)-positive prior to study entry using American Society of Clinical Oncology (ASCO) - College of American Pathologists (CAP) HER2 test guidelines.
  • At the time of study entry, blood counts performed within 4 weeks prior to study entry must meet the following criteria:

    • absolute neutrophil count (ANC) must be greater than or equal to 1000/mm3;
    • platelet count must be greater than or equal to 100,000/mm3; and
    • hemoglobin must be greater than or equal to 9 g/dL. (Note: Patient must have discontinued growth factors greater than or equal to two weeks prior to entry labs.)
  • The following criteria for evidence of adequate hepatic function performed within 4 weeks prior to study entry must be met:

    • Total bilirubin must be less than or equal to 1.5 x upper limit of normal (ULN), and
    • aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be less than or equal to 1.5 x ULN for the lab or less than or equal to 5 x ULN if liver metastasis.
  • Serum creatinine performed within 4 weeks prior to study entry must be less than or equal to 1.5 x ULN for the lab.
  • The left ventricular ejection fraction (LVEF) assessment by 2-D echocardiogram or multi-gated acquisition (MUGA) scan performed within 90 days prior to study entry must be greater than or equal to 50% regardless of the facility's lower limit of normal (LLN).
  • Patients with reproductive potential must agree to use an effective non-hormonal method of contraception during therapy, and for at least 7 months after the last dose of study therapy.

Exclusion Criteria

  • Previous therapy with T-DM1 or any HER2 tyrosine kinase inhibitor (TKI) including neratinib for any malignancy.
  • Symptomatic brain metastases or brain metastases requiring chronic steroids to control symptoms.
  • Active hepatitis B or hepatitis C with abnormal liver function tests; HIV positive patients receiving antivirals.
  • Lung disease resulting in dyspnea at rest.
  • Active infection or chronic infection requiring chronic suppressive antibiotics.
  • Malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of the stomach or small bowel, or other disease or condition significantly affecting gastrointestinal function.
  • Persistent greater than or equal to grade 2 diarrhea regardless of etiology.
  • Conditions that would prohibit intermittent administration of corticosteroids for T-DM1 premedication.
  • Chronic daily treatment with corticosteroids with a dose of greater than or equal to 10 mg/day methylprednisolone equivalent (excluding inhaled steroids).
  • Uncontrolled hypertension defined as a systolic BP greater than 150 mmHg or diastolic BP greater than 90 mmHg, with or without anti-hypertensive medications. (Patients with hypertension that is well controlled on medication are eligible.)
  • 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 disease: symptomatic angina pectoris within the past 90 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
    • 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); and documented cardiomyopathy
  • Other nonmalignant systemic disease that would preclude the patient from receiving study treatment or would prevent required follow up.
  • Pregnancy or lactation at the time of study entry. (Note: Pregnancy testing should be performed within 14 days prior to study entry according to institutional standards for women of childbearing potential.)
  • The investigator should assess the patient to determine if she has any psychiatric or addictive disorder or other condition that, in the opinion of the investigator, would preclude her from meeting the study requirements.
  • Use of any investigational agent within 4 weeks prior to study entry.

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 identifier (NCT number): NCT02236000

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United States, Florida
Cleveland Clinic Weston
Weston, Florida, United States, 33331
United States, Illinois
Cancer Care Specialists of Central Illinois
Decatur, Illinois, United States, 62526
Crossroads Cancer Center
Effingham, Illinois, United States, 62401
Cancer Care Specialists of Central Illinois-Swansea
Swansea, Illinois, United States, 62226
United States, Ohio
Cleveland Clinic
Cleveland, Ohio, United States, 44195
United States, Oklahoma
Stephenson Cancer Center at the University of Oklahoma Health Services Center
Oklahoma City, Oklahoma, United States, 73104
United States, Pennsylvania
UPMC- Hillman Cancer Center-Monroeville
Monroeville, Pennsylvania, United States, 15146
Alleheny General Hospital
Pittsburgh, Pennsylvania, United States, 15212
Hillman Cancer Center
Pittsburgh, Pennsylvania, United States, 15213
Magee Womens Hospital of UPMC
Pittsburgh, Pennsylvania, United States, 15213
University of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15213
UPMC- St. Margaret
Pittsburgh, Pennsylvania, United States, 15215
UPMC Hillman Cancer Center North Hills at Passavant
Pittsburgh, Pennsylvania, United States, 15237
United States, Rhode Island
Women & Infants Hospital of Rhode Island
Providence, Rhode Island, United States, 02905
United States, West Virginia
West Virginia University
Morgantown, West Virginia, United States, 26501
Sponsors and Collaborators
NSABP Foundation Inc
Puma Biotechnology, Inc.
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Principal Investigator: Norman Wolmark, MD NSABP Foundation Inc
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: NSABP Foundation Inc Identifier: NCT02236000    
Other Study ID Numbers: NSABP FB-10
First Posted: September 10, 2014    Key Record Dates
Last Update Posted: September 10, 2020
Last Verified: March 2020
Keywords provided by NSABP Foundation Inc:
Trastuzumab Emtansine
Metastatic Breast Cancer
HER2 positive
Dose Escalation
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases