Phase II Study of REPotrectinib With or Without Fulvestrant in Patients With Hormone Receptor-positive Human Epidermal Growth Factor 2-negative Metastatic Invasive LObular Carcinoma Who Received a Prior Endocrine Therapy in Combination With Cyclin-dependent Kinase 4 and 6 Inhibitor (REPLOT Trial)

NCT06408168 | Terminated Phase 2 DMC FDA Drug

• 2 other identifiers: 2024-0099NCI-2024-03805
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

To find out if the combination of repotrectinib and fulvestrant can control the disease in participants with metastatic invasive lobular carcinoma.

Conditions

Hormone Receptor-positive Human Epidermal Growth Factor 2-negative; Metastatic Invasive LObular Carcinoma

Outcome Measures

Primary Outcomes (1)

• Safety and adverse events (AEs)

  Incidence of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0

  Through study completion; an average of 1 year

Study Arms (2)

Cohort 1

EXPERIMENTAL

Cohort 1 will include participants who have never received fulvestrant before. The first 15 participants enrolled in Cohort 1 will receive the study drug combination starting on Day 1 of their first treatment cycle. The next 14 participants enrolled in Cohort 1 will begin with fulvestrant alone for at least 12 days and then start repotrectinib sometime between Days 13 and 20 (depending on when their Cycle 1 biopsy is performed). This is done in order to use the biopsy results to study the effects of fulvestrant alone in these patients.

Drug: Fulvestrant; Drug: Repotrectinib

Cohort 2

EXPERIMENTAL

About 6 months after the first 15 participants are enrolled, based on their study data, Cohort 2 will begin enrolling up to 29 participants who have received fulvestrant in earlier treatments. Participants in Cohort 2 will receive repotrectinib alone.

Drug: Repotrectinib

Interventions

Fulvestrant DRUG

Given by PO

Also known as: Faslodex®

Cohort 1

Repotrectinib DRUG

Given by IV

Cohort 1; Cohort 2

Eligibility Criteria

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

You may qualify if:

• years of age or older.
• Confirmed ILC with negative E-cadherin immunohistochemistry (IHC) staining on pre-treatment biopsy or archival biopsy.
• o Participants with ILC who have a germline CDH1 mutation will be included if the E-cadherin IHC staining is negative.
• Estrogen receptor positive (\>1%), progesterone receptor positive or negative, and HER2-negative according to HER2 testing guidelines from the American Society of Clinical Oncology/College of American Pathologists.
• Patients must be willing to undergo biopsy as required by the study, if the tumor is safely accessible.
• Participant must have been exposed to a CDK4/6i prior to enrollment.
• Participants who received prior chemotherapy, ADCs, mTOR inhibitor and/or PI3K are eligible.
• o Participants with ESR1 mutation who received prior elacestrant can still enroll on the study. If they did not receive prior fulvestrant they will be enrolled on Cohort 1. If they received prior fulvestrant they will be enrolled on Cohort 2.
• Participants should not have received more than 2 chemotherapeutic agents and/or ADCs in the metastatic setting.
• o The enrollment of patients who received 2 or more prior line of therapy (including endocrine therapy) in the metastatic setting will be limited to 50% of the total accrual in both cohorts.
• Eastern Cooperative Oncology Group (ECOG) Performance status ≤2
• Participant has either measurable disease per response evaluation criteria in solid tumors (RECIST) v1.1 criteria OR at least one predominantly lytic bone lesion must be present.
• Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 2 weeks prior to study treatment initiation.
• WOCBP must agree to use adequate contraception for the duration of study treatment and 7 months after the last dose of study treatment.
• Participants must have adequate organ and marrow function as defined below:

You may not qualify if:

• Participants with symptomatic visceral disease or any disease burden that makes the participant ineligible for endocrine therapy per the investigator's best judgment.
• Participants who have had chemotherapy, hormonal therapy, biotherapy, immunotherapy or radiotherapy within 4 weeks prior to entering the study.
• Systemic small molecule-targeted therapies (eg, tyrosine kinase inhibitors) within 5 half-lives or 4 weeks (whichever is shorter) prior to the first dose of study drug.
• Participants who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> Grade 1) with the exception of alopecia.
• Participants who are receiving any other investigational agents.
• Participants with prior history of pneumonitis/ILD
• Participants with Grade ≥2 ataxia, muscle weakness, dysgeusia, dizziness, paresthesia and/or peripheral neuropathy.
• Participants with untreated or progressing brain metastases.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to repotrectinib, fulvestrant or other agents used in study.
• Participants with psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant women are excluded from this study because repotrectinib and fulvestrant have 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 repotrectinib, breastfeeding should be discontinued if the mother is treated with repotrectinib. These potential risks may also apply to other agents used in this study.

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead

Study Sites (1)

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Links

• MD Anderson Cancer Center

MeSH Terms

Conditions

Carcinoma, Lobular

Interventions

Fulvestrant; repotrectinib

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Ductal, Lobular, and Medullary; Breast Neoplasms; Neoplasms by Site; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

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

Study Officials

• Jason Mouabbi, MD

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 30, 2024
• First Posted: May 10, 2024
• Study Start: August 8, 2024
• Primary Completion: December 8, 2025
• Study Completion: December 8, 2025
• Last Updated: January 5, 2026

Record last verified: 2025-12

Locations

US (1)