Neratinib +/- Fulvestrant in HER2+, ER+ Metastatic Breast Cancer

• ClinicalTrials.gov Identifier: NCT03289039
• Recruitment Status: Terminated
• First Posted: September 20, 2017
• Results First Posted: March 21, 2023
• Last Update Posted: February 13, 2024
• Sponsor: Dana-Farber Cancer Institute
• Collaborator: Puma Biotechnology, Inc.
• Information provided by (Responsible Party): Jose Pablo Leone, Dana-Farber Cancer Institute

Tracking Information

• First Submitted Date: September 18, 2017
• First Posted Date: September 20, 2017
• Results First Submitted Date: November 15, 2022
• Results First Posted Date: March 21, 2023
• Last Update Posted Date: February 13, 2024
• Actual Study Start Date: October 25, 2017
• Actual Primary Completion Date: July 20, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 17, 2023)

Progression Free Survival [ Time Frame: Participants were followed for PFS up to 20.3 months from registration. ]

Progression-Free Survival (PFS) is defined as the time from randomization (or registration) to the earlier of progression or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation. 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. Disease assessment were conducted at baseline and every two cycles after the first cycle.

Original Primary Outcome Measures (submitted: September 18, 2017)

Progression Free Survival [ Time Frame: 5 years ]

Estimate the efficacy, as measured by progression free survival (PFS), of neratinib combined with fulvestrant compared with neratinib alone in patients with inoperable locally advanced or metastatic HER2 positive, ER positive breast cancer

Current Secondary Outcome Measures (submitted: March 17, 2023)

• Overall Survival [ Time Frame: Participants were followed for up to 38.4 months (3 years and 2 months) from registration to removal from protocol therapy or death. ]
  Overall Survival (OS) is defined as the time from randomization (or registration) to death due to any cause, or censored at date last known alive. Participants will be evaluated every 6 months for survival until death. Participants removed from protocol therapy for unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse event.
• Overall Response Rate [ Time Frame: 2 years ]
  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; Overall Response Rate(ORR) = (CR + PR)/sample size.
• Duration Of Responses [ Time Frame: 2 years ]
  The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started, or death due to any cause. Participants without events reported are censored at the last disease evaluation).

Original Secondary Outcome Measures (submitted: September 18, 2017)

• Overall Survival [ Time Frame: 5 years ]
  Estimate the efficacy, as measured by overall survival (OS) of neratinib combined with fulvestrant compared with neratinib alone in patients with inoperable locally advanced or metastatic HER2-positive, ER-positive breast cancer.
• Overall Response Rate [ Time Frame: 2 years ]
  Estimate the clinical activity, as measured by overall response rate (ORR) of neratinib combined with fulvestrant compared with neratinib alone in patients with inoperable locally advanced or metastatic HER2-positive, ER-positive breast cancer.
• Duration Of Response [ Time Frame: 2 years ]
  Estimate the clinical activity, as measured by duration of response, of neratinib combined with fulvestrant compared with neratinib alone in patients with inoperable locally advanced or metastatic HER2-positive, ER-positive breast cancer.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Neratinib +/- Fulvestrant in HER2+, ER+ Metastatic Breast Cancer
• Official Title: A Phase 2 Study of Neratinib With or Without Fulvestrant in HER2-Positive, ER-Positive Metastatic Breast Cancer

Brief Summary

This research study is studying a drug called Neratinib with and without Fulvestrant as possible treatments for HER2-positive breast cancer .

The interventions involved in this study are:

• Neratinib and Fulvestrant
• Neratinib alone

Detailed Description

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied.

The FDA (the U.S. Food and Drug Administration) has approved Neratinib as a treatment for breast cancer. Fulvestrant has been FDA approved for treatment of metastatic hormone receptor positive breast cancer.

The purpose of this research study is to determine how well neratinib, by itself or together with Fulvestrant, works in treating breast cancer that has spread to other parts of the body. Neratinib is a recently discovered oral drug that may stop breast cancer cells from growing abnormally by inhibiting (or blocking) members of a family of proteins that include Human Epidermal Growth Factor Receptor 2 (HER2).

Neratinib has been used in other research studies and information from those other research studies suggests that neratinib may help to shrink or stabilize HER2-positive breast cancer in this research study.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer

Intervention

• Drug: Neratinib
  Neratinib is a recently discovered oral drug that may stop breast cancer cells from growing abnormally by inhibiting (or blocking) members of a family of proteins that include Human Epidermal Growth Factor Receptor 2 (HER2)
  Other Name: Nerlynx
• Drug: Fulvestrant
  Fulvestrant, works in treating breast cancer that has spread to other parts of the body
  Other Name: Faslodex

Study Arms

• Experimental: Neratinib
  • Neratinib will be administered orally once daily
  • Neratinib is dosed at 240mg (six 40mg tablets)
  Intervention: Drug: Neratinib
• Experimental: Neratinib + Fulvestrant
  • Neratinib will be administered orally once daily
  • Neratinib is dosed at 240mg (six 40mg tablets)
  • Fulvestrant will be administered intramuscular as an injection (shot) on day 1 and 15 of cycle 1, day 1 of cycle 2, and then on day 1 of each subsequent cycle.
  • Fulvestrant is dosed as 250 mg/5mL (x2) for a total of 500 mg via intramuscular injection (two injections).
  Interventions:

  • Drug: Neratinib
  • Drug: Fulvestrant

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: January 11, 2023): 21
• Original Estimated Enrollment (submitted: September 18, 2017): 152
• Actual Study Completion Date: July 20, 2021
• Actual Primary Completion Date: July 20, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Participants must have histologically or cytologically confirmed inoperable locally advanced or metastatic ER+ breast cancer. To fulfill the requirement for ER+ disease, a breast cancer must express, by immunohistochemistry (IHC), ER in ≥10% of cells, on the most recent biopsy. If ER quantification is not available, a determination of ER+ by IHC will suffice. Central confirmation of ER status is not required.
• Participants must have documented HER2+ disease by overexpression and/or gene amplification on the most recent biopsy, per current ASCO-CAP (American Society of Clinical Oncology - College of American Pathologists) guidelines. Central confirmation of HER2 status is not required.

• Participants must have received prior therapy with the following agents in any combination, and in setting (i.e., neoadjuvant, adjuvant, metastatic, etc.). These therapies do not need to be the most recent line of therapy.

  • Trastuzumab
  • Pertuzumab
  • Ado-trastuzumab emtansine (T-DM1)
• Participants must agree to undergo a research biopsy of a reasonably accessible metastatic lesion (chest wall, skin, subcutaneous tissue, lymph nodes, skin, breast, bones, lung, and liver metastases). If a reasonably accessible metastatic lesion is not available, the patient may go on study provided that archived tissue is available. However, if a reasonably accessible site is available for biopsy, the patient must agree to biopsy. Any patients not undergoing biopsy must be approved for study enrollment by the Overall Principal Investigator at DFCI. Biopsies may be done with local anesthesia or intravenous conscious sedation, according to institutional guidelines. If a biopsy requires general anesthesia, then it is only allowed if acquisition of tissue is clinically indicated, and excess tissue may be collected for research purposes. Patients without sites available for biopsy must have available tissue [archived formalin-fixed paraffin embedded blocks (FFPB), blocks from which slides can be created, or fresh frozen tissue from original diagnosis or metastatic setting] for correlative studies. Tissue needs to be located and available at the time of registration See Section 9.3 for more details.
• Women ≥ 18 years of age. Men are not eligible.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (see Appendix A).

• Participants must have normal organ and marrow function as described below:

  • Absolute neutrophil count ≥1,000/uL
  • Platelets ≥75,000/uL
  • Hemoglobin ≥8g/dL
  • Total bilirubin ≤ 1.5 X institutional upper limit of normal (ULN); in case of known Gilbert's syndrome, <2 x ULN is allowed
  • AST(SGOT)/ALT(SGPT) ≤3X institutional ULN without liver metastases, or ≤5X institutional ULN with liver metastases
  • Creatinine clearance ≥ 50 mL/min
  • Left ventricular ejection fraction ≥50%, as determined by RVG (MUGA) or echocardiogram (ECHO) within 60 days prior to initiation of protocol therapy
• Participants may have received any number of prior therapies as long as they have adequate performance status and meet all other eligibility criteria.
• Women of childbearing potential (including premenopausal women and women less than 12 months after menopause) must have a negative β-human chorionic gonadotropin (hCG) urine pregnancy test within 4 weeks of registration.
• The effects of neratinib and fulvestrant on the developing human fetus are unknown. For this reason and because SERD agents are known to be teratogenic, women of child-bearing potential must agree to be abstinent, or to use a highly effective double barrier method of contraception (e.g, a combination of male condom with an intravaginal device such as the cervical cap, diaphragm, or vaginal sponge with spermicide) or a non-hormonal method, while enrolled in the study, until at least 28 days after the last dose of neratinib or 1 year after the last dose of fulvestrant. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately. If a woman is of childbearing potential, she must agree to use adequate contraception prior to the study, for the duration of study participation, and for one year after completion of the study drug.
• Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

• Participants who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to neratinib or fulvestrant.
• Participants who have known hypersensitivity to any component of loperamide or colestipol.
• Participants who have received previous therapy with neratinib.
• Participants who have received anti-cancer therapy (including chemotherapy, biological therapy, investigational agents, hormonal therapy, or other anti-cancer therapy) or radiotherapy within ≤14 days prior to the planned initiation of investigational products, or those who have not recovered to grade ≤1from adverse events due to their most recent therapy (excepting alopecia).
• Participants who have had any major surgery ≤28 days prior to the planned initiation of study therapy, or those who have not recovered from adverse events due to agents/surgery administered more than 4 weeks earlier.
• Participants who are receiving any other investigational agents.
• Participants with known brain metastases that are untreated, symptomatic, or require therapy to control symptoms. Participants with a history of treated central nervous system (CNS) metastases are eligible. Treated brain metastases are defined as those without ongoing requirement for corticosteroids, as ascertained by clinical examination and/or brain imaging (magnetic resonance imaging or CT scan) completed during screening. Any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for ≥ 7 days prior to registration. Treatment for brain metastases may include whole brain radiotherapy, radiosurgery, surgery or a combination as deemed appropriate by the treating physician. Radiation therapy must be completed at least 14 days prior to registration.
• Participant has active, uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of ≥2), unstable angina, myocardial infarction within 12 months of enrollment, or ventricular arrhythmia.
• Participant has a QTc interval >470 ms or known history of QTc prolongation or Torsade de Pointes.
• Participant has an active infection or unexplained fever >38.5°C (101.3°F).
• Participant has had another malignancy within the past 5 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the breast, cervix or vulva; or c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas.
• Participant has significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn's disease, malabsorption, or Grade ≥2 (NCI CTCAE v.4.0) diarrhea of any etiology at screening).
• Participant has known active infection with hepatitis B or hepatitis C virus. Hepatitis B and C serology testing is not required, unless active infection is suspected.
• Participant is unable or unwilling to swallow tablets.
• Participant has evidence of significant medical illness, abnormal laboratory finding, or psychiatric illness/social situations that would, in the Investigator's judgment, limit compliance with study requirements.
• Pregnant women are excluded from this study because fulvestrant is a SERD agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with neratinib and/or fulvestrant, breastfeeding should be discontinued if the mother is treated with neratinib and/or fulvestrant.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03289039
• Other Study ID Numbers: 17-318
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Jose Pablo Leone, Dana-Farber Cancer Institute
• Original Responsible Party: Heather A. Parsons, Dana-Farber Cancer Institute, Parsons, Heather A.
• Current Study Sponsor: Dana-Farber Cancer Institute
• Original Study Sponsor: Same as current
• Collaborators: Puma Biotechnology, Inc.

Investigators

• Principal Investigator: Jose Leone, MD; Dana-Farber Cancer Institute

• PRS Account: Dana-Farber Cancer Institute
• Verification Date: February 2024