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

Study Overview
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Brief Summary
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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.

Official Title
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Genetically-informed Therapy for ER+ Breast Cancer in a Post-CDK4/6 Inhibitor Setting: a Phase II Umbrella Study (GERTRUDE)

Conditions
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Advanced Breast Cancer

Intervention / Treatment
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* Drug: Fulvestrant
* Drug: Neratinib
* Drug: Alpelisib
* Drug: Everolimus
* Drug: Abemaciclib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A- neratinib and fulvestrant<br>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<br>* Fulvestrant will be administered intramuscularly into the buttocks in combination with one of the other interventions as outlined above.<br>Drug: Neratinib<br>* Neratinib will be administered orally in tablet form once daily with food in combination with fulvestrant administration as outlined above.<br>|
| Experimental: Arm B- alpelisib and fulvestrant<br>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<br>* Fulvestrant will be administered intramuscularly into the buttocks in combination with one of the other interventions as outlined above.<br>Drug: Alpelisib<br>* Alpelisib will be administered orally in tablet form once daily with food in combination with fulvestrant administration as outlined above.<br>|
| Experimental: Arm C- everolimus and fulvestrant<br>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<br>* Fulvestrant will be administered intramuscularly into the buttocks in combination with one of the other interventions as outlined above.<br>Drug: Everolimus<br>* Everolimus will be administered orally in tablet form once daily in combination with fulvestrant administration as outlined above.<br>|
| Experimental: Arm D- abemaciclib and fulvestrant<br>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<br>* Fulvestrant will be administered intramuscularly into the buttocks in combination with one of the other interventions as outlined above.<br>Drug: Abemaciclib<br>* Abemaciclib will be administered orally in tablet form twice daily in combination with fulvestrant administration as outlined above.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence rate of adverse events within each treatment arm. | Number of participants with treatment-related adverse events as assessed by CTCAE within each treatment arm. | 12 months | 
| Progression-free survival within each treatment arm. | Progression-free survival will be measured by the time between the initiation of study treatment to the time of progression per RECIST 1.1. | 12 months | 
| Rate of objective response within each treatment arm. | The proportion of participants within each arm who experience objective response defined as complete or partial response per RECIST 1.1 while on study treatment will be measured. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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locally recurrent, metastatic, ER+, ER+/HER2-