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

NCT02236000 | Completed Phase 1 Results

• 1 other identifier: NSABP FB-10
• Study Type: interventional
• Target: 49
• Locations: 1 country
• Sites: 15

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.

Conditions

Breast Cancer

Keywords

NSABP; Trastuzumab Emtansine; T DM1; Neratinib; Metastatic Breast Cancer; HER2 positive; Dose Escalation

Outcome Measures

Primary Outcomes (2)

• 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.

  Day 1, 8, and 15 of cycle 1.

• 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.

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

Secondary Outcomes (3)

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

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

• Adverse Events Experienced by Participants as a Measure of Toxicity

  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.

• Clinical Benefit Rate (Phase II)

  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.

Study Arms (1)

Neratinib and T-DM1

EXPERIMENTAL

Drug: Neratinib; Drug: T-DM1

Interventions

Neratinib DRUG

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

Neratinib and T-DM1

T-DM1 DRUG

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.

Neratinib and T-DM1

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.)

Sponsors & Collaborators

• NSABP Foundation Inc: lead
• Puma Biotechnology, Inc.: collaborator

Study Sites (15)

Cleveland Clinic Weston

Weston, Florida, 33331, United States

Location

Cancer Care Specialists of Central Illinois

Decatur, Illinois, 62526, United States

Location

Crossroads Cancer Center

Effingham, Illinois, 62401, United States

Location

Cancer Care Specialists of Central Illinois-Swansea

Swansea, Illinois, 62226, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

Stephenson Cancer Center at the University of Oklahoma Health Services Center

Oklahoma City, Oklahoma, 73104, United States

Location

UPMC- Hillman Cancer Center-Monroeville

Monroeville, Pennsylvania, 15146, United States

Location

Alleheny General Hospital

Pittsburgh, Pennsylvania, 15212, United States

Location

Hillman Cancer Center

Pittsburgh, Pennsylvania, 15213, United States

Location

Magee Womens Hospital of UPMC

Pittsburgh, Pennsylvania, 15213, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

UPMC- St. Margaret

Pittsburgh, Pennsylvania, 15215, United States

Location

UPMC Hillman Cancer Center North Hills at Passavant

Pittsburgh, Pennsylvania, 15237, United States

Location

Women & Infants Hospital of Rhode Island

Providence, Rhode Island, 02905, United States

Location

West Virginia University

Morgantown, West Virginia, 26501, United States

Location

Related Publications (2)

• 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.

  PMID: 38650031 DERIVED

• 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.

  PMID: 31442103 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

neratinib

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Results Point of Contact

• Title: Judy Langer, Director of Regulatory Affairs
• Organization: NSABP Foundation, Inc.

judy.langer@nsabp.org

412-339-5300

Study Officials

• Norman Wolmark, MD

  NSABP Foundation Inc

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 2, 2014
• First Posted: September 10, 2014
• Study Start: August 1, 2014
• Primary Completion: December 1, 2020
• Study Completion: August 1, 2021
• Last Updated: January 26, 2023
• Results First Posted: January 26, 2023

Record last verified: 2023-01

Locations

US (15)