Genetically-informed Therapy for ER+ Breast Cancer Post-CDK4/6 Inhibitor

NCT05933395 | Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: STUDY02001800NCI-2024-09317
• Study Type: interventional
• Target: 135
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to learn if certain drug combinations are effective treatments for patients with advanced ER+/HER2- who have previously been treated with palbociclib, ribociclib, or abemaciclib.

Conditions

Advanced Breast Cancer

Keywords

locally recurrent; metastatic; ER+; ER+/HER2-

Outcome Measures

Primary Outcomes (1)

• Rate of clinical benefit within each arm in patients previously treated with a CDK4/6 inhibitor.

  Clinical benefit rate will be measured as the proportion of participants who experience stable disease (SD) at 24 weeks, complete response, and partial response per RECIST 1.1.

  6 - 12 months

Secondary Outcomes (3)

• Incidence rate of adverse events within each treatment arm.

  12 months

• Progression-free survival within each treatment arm.

  12 months

• Rate of objective response within each treatment arm.

  12 months

Study Arms (4)

Arm A- neratinib and fulvestrant

EXPERIMENTAL

Participants with a qualifying ERBB2 (HER2) mutation will be assigned to Treatment Arm A and given the combination of neratinib and fulvestrant until the end of the primary treatment phase. Fulvestrant (500 mg) will be administered by intramuscular injection into the buttocks on Cycle 1 Day 1 and Day 15, and on Day 1 of subsequent Cycles. Neratinib will initially be administered orally in 3 tablets (total dose of 120 mg) taken 1 time per day with food on Cycle 1 Days 1-7, in combination with fulvestrant starting on Cycle 1 Day 1 as described above. The dose of neratinib will be increased to 4 tablets (total dose of 160 mg) taken 1 time per day with food on Cycle 1 Days 8-14, and then increased further to 6 tablets (240 mg) taken once daily with food thereafter.

Drug: Fulvestrant; Drug: Neratinib

Arm B- alpelisib and fulvestrant

EXPERIMENTAL

If a participant does not have a qualifying ERBB2 (HER2) mutation, but they have a qualifying PIK3CA mutation, the subject will be assigned to Treatment Arm B and given the combination of alpelisib and fulvestrant until the end of the primary treatment phase. Fulvestrant (500 mg) will be administered by intramuscular injection into the buttocks on Cycle 1 Day 1 and Day 15, and on Day 1 of subsequent Cycles. Alpelisib will be administered orally in 2 tablets (total dose of 300 mg) taken 1 time per day with food, in combination with fulvestrant as described above.

Drug: Fulvestrant; Drug: Alpelisib

Arm C- everolimus and fulvestrant

EXPERIMENTAL

If a subject does not have a qualifying ERBB2 or PIK3CA mutation, but they have a qualifying mutation/alteration in AKT1, MTOR, or PTEN, the subject will be assigned to Treatment Arm C and given the combination of everolimus and fulvestrant until the end of the primary treatment phase. Fulvestrant (500 mg) will be administered by intramuscular injection into the buttocks on Cycle 1 Day 1 and Day 15, and on Day 1 of subsequent Cycles. Everolimus will be administered orally in 1 tablet (10 mg per tablet) taken 1 time per day, in combination with fulvestrant as described above.

Drug: Fulvestrant; Drug: Everolimus

Arm D- abemaciclib and fulvestrant

EXPERIMENTAL

If a participant does not have a qualifying mutation/alteration for Arms A/B/C, and the participant does not have mutation or loss of RB1, the subject will be assigned to Treatment Arm D and given the combination of abemaciclib and fulvestrant until the end of the primary treatment phase. Fulvestrant (500 mg) will be administered by intramuscular injection into the buttocks on Cycle 1 Day 1 and Day 15, and on Day 1 of subsequent Cycles. Abemaciclib will be administered orally in 1 tablet (150 mg) taken 2 times per day, in combination with fulvestrant as described above.

Drug: Fulvestrant; Drug: Abemaciclib

Interventions

Fulvestrant DRUG

Fulvestrant will be administered intramuscularly into the buttocks in combination with one of the other interventions as outlined above.

Arm A- neratinib and fulvestrant; Arm B- alpelisib and fulvestrant; Arm C- everolimus and fulvestrant; Arm D- abemaciclib and fulvestrant

Neratinib DRUG

Neratinib will be administered orally in tablet form once daily with food in combination with fulvestrant administration as outlined above.

Arm A- neratinib and fulvestrant

Alpelisib DRUG

Alpelisib will be administered orally in tablet form once daily with food in combination with fulvestrant administration as outlined above.

Arm B- alpelisib and fulvestrant

Everolimus DRUG

Everolimus will be administered orally in tablet form once daily in combination with fulvestrant administration as outlined above.

Arm C- everolimus and fulvestrant

Abemaciclib DRUG

Abemaciclib will be administered orally in tablet form twice daily in combination with fulvestrant administration as outlined above.

Arm D- abemaciclib and fulvestrant

Eligibility Criteria

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

You may qualify if:

• Post-menopausal women ≥18 years of age with metastatic ER+ breast cancer, or with locally recurrent ER+ disease not amenable to therapy for curative intent.
• Patient must be post-menopausal per NCCN guidelines.
• Patient must have been treated with a CDK4/6i (either palbobclib, ribociclib, or abemaciclib) alone or in combination with an endocrine agent in the advanced disease setting.
• Up to 3 lines of therapy following CDK4/6i are permissible.
• Any number of prior lines of endocrine-containing therapy is permissible.
• Up to 1 prior line of chemotherapy is permissible.
• Histologic documentation of ER+ breast cancer by core needle biopsy, fine needle aspiration, incisional biopsy, or surgical biopsy of ≥1 site(s) of metastatic or locally recurrent disease performed as standard of care.
• Exceptions: patients with bone-dominant metastatic disease, or non-bone metastatic disease in whom a safe and accurate biopsy of recurrent/metastatic disease cannot be readily obtained, with a history of ER+ breast cancer are eligible, and biopsy is not required, providing their primary cancer is consistent with the ER criteria described below.
• ER+ status defined as ER staining by immunohistochemistry in ≥1% of malignant cell nuclei.
• Tumor must be HER2-non-amplified as defined by an immunohistochemistry score of 0-1+, or with a FISH ratio \<2 if IHC is 2+ or if IHC has not been done (as per ASCO/CAP definitions). In cases of borderline or equivocal HER2 status, eligibility will be determined by the PI.
• Genetic profiling of a tumor or plasma specimen acquired after disease progression on a CDK4/6i must have been performed in a CAP-accredited, CLIA-certified laboratory using clinically validated methods. Profiling must minimally include analysis of study-relevant alterations in ERBB2, PIK3CA, AKT1, MTOR, PTEN, and RB1.
• If not done: Profiling of a tumor (preferable) or plasma specimen will be performed as part of the study in the DHMC Pathology Laboratory. A plasma specimen may be obtained for study-specific genetic profiling to direct treatment assignment. Tumor specimens must be obtained outside of this study (e.g., by biopsy).
• If available, archived tumor tissue must be accessible for research purposes, sufficient to make ≥10 five-micron sections; more tumor tissue is preferred.
• Radiographic staging performed as standard of care, including specifically either PET/CT, or contrast CT (CAP) and bone scan.
• Patient must be capable and willing to provide informed written consent for study participation.

You may not qualify if:

• Treatment with abemaciclib in the most recent or current line of therapy.
• During the study Treatment Phases, no concurrent anti-cancer therapies are allowed with the following exception: anti-resorptive bone therapies (e.g., bisphosphonates, denosumab) are permitted.
• Any investigational cancer therapy in the last 3 weeks.
• Known untreated CNS disease, unless clinically stable for ≥ 3 months.

Sponsors & Collaborators

• Dartmouth-Hitchcock Medical Center: lead

Study Sites (1)

Dartmouth Hitchcock Medical Center

Lebanon, New Hampshire, 03756, United States

RECRUITING

MeSH Terms

Conditions

Neoplasm Metastasis

Interventions

Fulvestrant; neratinib; Alpelisib; Everolimus; abemaciclib

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Sirolimus; Macrolides; Lactones; Organic Chemicals

Study Officials

• Mary Chamberlin, MD

  Dartmouth-Hitchcock Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Research Nurse

CONTACT

603-650-5021; hem-onc.research.nurses@hitchcock.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: This study has a non-randomized umbrella design. Participants will be assigned to a treatment arm based on tumor/plasma genetic profiling and treatment history using the primary treatment phase algorithm.

Study Record Dates

• First Submitted: May 25, 2023
• First Posted: July 6, 2023
• Study Start: September 23, 2024
• Primary Completion (Estimated): October 1, 2030
• Study Completion (Estimated): October 1, 2031
• Last Updated: January 20, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)