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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

NCT02236000

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: NSABP FB-10
  • NCT ID: NCT02236000

Trial Conditions

  • Breast Cancer

Trial Interventions

DrugSynonymsArms
NeratinibNeratinib and T-DM1
T-DM1Neratinib and T-DM1

Trial Purpose

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.

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.

Trial Arms

NameTypeDescriptionInterventions
Neratinib and T-DM1Experimental
  • Neratinib
  • T-DM1

Eligibility Criteria

Inclusion Criteria:

- The ECOG performance status must be greater 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 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. Histologic confirmation of metastatic disease is not required.

- 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.

Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure: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.
Safety Issue:Yes
Description: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.

Secondary Outcome Measures

Measure: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
Safety Issue:No
Description:
Measure: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.
Safety Issue:No
Description:
Measure: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.
Safety Issue:Yes
Description:
Measure: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
Safety Issue:No
Description:
Measure: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
Safety Issue:No
Description:Describe pharmacokinetic variations in absorption, metabolism and elimination that may affect total drug concentration.
Measure: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
Safety Issue:No
Description:TDM analysis measures the plasma concentrations of a therapeutic agent and metabolites in patients to individualize appropriate drug dosages and schedules.

Trial Keywords

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