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

IRB NFI 1114

CC 14-1481

Hospital Main Campus

Phase Phase 1, Phase 2

Disease Breast

Drug Neratinib, Trastuzumab Emtansine



Primary Objectives
  • Phase I: To determine the safety and tolerability of T-DM1 and neratinib in patients with metastatic HER2-positive breast cancer
  • Phase II: To determine the overall response rate (ORR) in patients with measurable metastatic breast cancer treated with T-DM1 and neratinib
Secondary Objectives
  • To determine the PFS in patients who present with measurable metastatic disease
  • To determine objective tumor decrease and stable disease (SD) at 24 weeks by RECIST 1.1 criteria
  • To evaluate the overall toxicity for the combination of T-DM1 and neratinib
  • To explore molecular and genetic correlatives for the degree of benefit from T-DM1 and neratinib.
  • To determine pharmacokinetic interaction of T-DM1 and neratinib combination
Inclusion Criteria

Inclusion Criteria

  1. The patient must have consented to participate and, prior to study entry, must have signed and dated an appropriate IRB-approved consent form that conforms to federal and institutional guidelines (see treatment consent form).
  2. Patients must be female.
  3. Patients must be ≥ 18 years old.
  4. The ECOG performance status must be ≤ 2 (see Appendix A).
  5. Patients must have the ability to swallow oral medication.
  6. Patients must have histologic or cytologic confirmation of the diagnosis of invasive adenocarcinoma of the breast.
  7. Patients must have had one (and only one) regimen of anti-HER2 based therapy for metastatic disease (dual anti-HER agents may have been given in combination e.g., docetaxel, trastuzumab and pertuzumab).
  8. There must be documentation that the patient has evidence of measurable metastatic breast cancer (see Section 13.0). Histologic confirmation of metastatic disease is not required.
  9. Patients must have ER analysis performed prior to study entry. If ER analysis is negative, then PgR analysis must also be performed. (Patients are eligible with either hormone receptor-positive or hormone receptor-negative tumors.)
  10. Breast cancer must be determined by local testing to be HER2-positive prior to study entry using ASCO-CAP HER2 test guidelines.
  11. At the time of study entry, blood counts performed within 4 weeks prior to study entry must meet the following criteria:
    • ANC must be ≥ 1000/mm3;
    • platelet count must be ≥ 100,000/mm3; and
    • hemoglobin must be ≥ 9 g/dL.

    (Note: Patient must have discontinued growth factors ≥ two weeks prior to entry labs.)

  12. The following criteria for evidence of adequate hepatic function performed within 4 weeks prior to study entry must be met:
    • Total bilirubin must be ≤ 1.5 x ULN, and
    • AST and ALT must be ≤ 1.5 x ULN for the lab or ≤ 5 x ULN if liver metastasis.
  13. Serum creatinine performed within 4 weeks prior to study entry must be ≤ 1.5 x ULN for the lab.
  14. The LVEF assessment by 2-D echocardiogram or MUGA scan performed within 90 days prior to study entry must be ≥ 50% regardless of the facility's LLN.
  15. 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

Exclusion Criteria

  1. Previous therapy with T-DM1 or any HER2 TKI including neratinib for any malignancy.
  2. Symptomatic brain metastases or brain metastases requiring chronic steroids to control symptoms.
  3. Active hepatitis B or hepatitis C with abnormal liver function tests; HIV positive patients receiving antivirals.
  4. Lung disease resulting in dyspnea at rest.
  5. Active infection or chronic infection requiring chronic suppressive antibiotics.
  6. Malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of the stomach or small bowel, or other disease or condition significantly affecting gastrointestinal function.
  7. Persistent ≥ grade 2 diarrhea regardless of etiology.
  8. Conditions that would prohibit intermittent administration of corticosteroids for T-DM1 premedication.
  9. Chronic daily treatment with corticosteroids with a dose of ≥ 10 mg/day methylprednisolone equivalent (excluding inhaled steroids).
  10. Uncontrolled hypertension defined as a systolic BP > 150 mmHg or diastolic BP > 90 mmHg, with or without anti-hypertensive medications. (Patients with hypertension that is well controlled on medication are eligible.)
  11. 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 LV function;
    • history of documented CHF; and
    • documented cardiomyopathy

  12. Other nonmalignant systemic disease that would preclude the patient from receiving study treatment or would prevent required follow up.
  13. 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.)
  14. 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.
  15. Use of any investigational agent within 4 weeks prior to study entry.