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Breast CancerPhase 1/2NCT02236000

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

A Phase 1/2 study testing Neratinib and T-DM1 in people with Breast Cancer, run by NSABP Foundation Inc at 15 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older, women only
Conditions the study is for
Breast Cancer
What is being tested?
Neratinib and T-DM1
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
49 participants
Where
15 sitesUnited States
Study dates
Aug 2014to Aug 2021
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.)
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  • 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.

Who cannot join

  • 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.
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  • 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.

Trial locations and contacts

15 sites in 1 country.

15 sites in 1 country

United States15 sites

  • Cleveland Clinic

    Cleveland, Ohio, 44195

  • Cancer Care Specialists of Central Illinois

    Decatur, Illinois, 62526

  • Crossroads Cancer Center

    Effingham, Illinois, 62401

  • UPMC- Hillman Cancer Center-Monroeville

    Monroeville, Pennsylvania, 15146

  • West Virginia University

    Morgantown, West Virginia, 26501

  • Stephenson Cancer Center at the University of Oklahoma Health Services Center

    Oklahoma City, Oklahoma, 73104

  • Alleheny General Hospital

    Pittsburgh, Pennsylvania, 15212

  • Hillman Cancer Center

    Pittsburgh, Pennsylvania, 15213

  • Magee Womens Hospital of UPMC

    Pittsburgh, Pennsylvania, 15213

  • University of Pittsburgh

    Pittsburgh, Pennsylvania, 15213

  • UPMC- St. Margaret

    Pittsburgh, Pennsylvania, 15215

  • UPMC Hillman Cancer Center North Hills at Passavant

    Pittsburgh, Pennsylvania, 15237

  • Women & Infants Hospital of Rhode Island

    Providence, Rhode Island, 02905

  • Cancer Care Specialists of Central Illinois-Swansea

    Swansea, Illinois, 62226

  • Cleveland Clinic Weston

    Weston, Florida, 33331

Other trials in United States

About this study

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

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.
Read the 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 was 27 patients. The sample size of the Phase II portion will be 22 evaluable patients (and 4 replacement patients). The total study enrollment, phase Ib and II, will be a maximum of 50 patients.

Submission of diagnostic tumor samples and blood samples for FB-10 correlative science studies will be a study requirement for all patients. Blood samples for pharmacokinetics (PKs) and for future study will be collected prior to administration of study therapy on Cycle 1/Day 1, Cycle 1/Day 8, and Cycle 2/Day1.

A tumor biopsy will be procured from an accessible site of metastasis before study therapy is initiated (after the patient has signed the consent and has been screened for eligibility).

Conditions
Breast Cancer
Being tested
Neratinib, T-DM1
Keywords
NSABP, Trastuzumab Emtansine, T DM1, Neratinib, Metastatic Breast Cancer, HER2 positive, Dose Escalation
Medical subject headings
Breast Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • NeratinibDrug

    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

  • T-DM1Drug

    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.

Study groups in NCT02236000
Study groupRoleWhat they receive
Neratinib and T-DM1ExperimentalNot described
Receives: Drug: Neratinib; Drug: T-DM1

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of Evaluable Patients With Dose Limiting Toxicity Events in Phase 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.

    Measured: Day 1, 8, and 15 of cycle 1.

  2. Overall Response Rate (ORR) by Measurement of Target Lesions in Phase II

    Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

    Measured: Every 42 days after the start of protocol therapy through disease progression, approximately 2 years

Secondary outcomes (3)

  1. Progression-free Survival (PFS) Time From Start of Study Therapy to Disease Progression or Death From Any Cause

    Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

    Measured: Every 42 days after the start of protocol therapy through disease progression, approximately 2 years

  2. Adverse Events Experienced by Participants as a Measure of Toxicity

    Summary of frequency and severity of serious adverse events,

    Measured: Day 1, 8, 15 of cycle one, day 1 of each subsequent cycle, at the end of protocol therapy and 30 days following the end of protocol therapy. Duration of therapy varied across patients from a few days to a couple of years.

  3. Clinical Benefit Rate (Phase II)

    Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0) for target lesions assessed by MRI or CT; Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of new lesions; Stable Disease (SD) otherwise; Clinical Benefit (CB) = CR+PR+SD (confirmation of response not required).

    Measured: Every 63 days after the start of study therapy until disease progression or until 30 days following the end of protocol therapy if due to another cause. Duration of therapy varied across patients from a few days to a couple of years.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted10 Sep 2014 (estimated)
  2. Study startAug 2014
  3. Primary completionDec 2020
  4. Study completionAug 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
49 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02236000
Sponsor's protocol ID
NSABP FB-10
Status last verified
Jan 2023
First submitted
2 Sep 2014
Last updated
26 Jan 2023
Data monitoring committee
No

Publications

  • Jacobs SA, Wang Y, Abraham J, Feng H, Montero AJ, Lipchik C, Finnigan M, Jankowitz RC, Salkeni MA, Maley SK, Puhalla SL, Piette F, Quinn K, Chang K, Nagy RJ, Allegra CJ, Vehec K, Wolmark N, Lucas PC, Srinivasan A, Pogue-Geile KL. NSABP FB-10: a phase Ib/II trial evaluating ado-trastuzumab emtansine (T-DM1) with neratinib in women with metastatic HER2-positive breast cancer. Breast Cancer Res. 2024 Apr 22;26(1):69. doi: 10.1186/s13058-024-01823-8.

    PubMed 38650031

  • Abraham J, Montero AJ, Jankowitz RC, Salkeni MA, Beumer JH, Kiesel BF, Piette F, Adamson LM, Nagy RJ, Lanman RB, Sperinde J, Huang W, Allegra CJ, Srinivasan A, Wang Y, Pogue-Geile KL, Lucas PC, Jacobs SA. Safety and Efficacy of T-DM1 Plus Neratinib in Patients With Metastatic HER2-Positive Breast Cancer: NSABP Foundation Trial FB-10. J Clin Oncol. 2019 Oct 10;37(29):2601-2609. doi: 10.1200/JCO.19.00858. Epub 2019 Aug 23.

    PubMed 31442103

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Neratinib and T-DM1 in people with Breast Cancer, run by NSABP Foundation Inc at 15 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 17 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 26 Jan 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 15 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 26 Jan 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Evaluable Patients With Dose Limiting Toxicity Events in Phase 1 (time frame: Day 1, 8, and 15 of cycle 1.). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02236000, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Jan 2023.

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