First-in-Human Study of RGT-419B Alone and With Endocrine Therapy in Subjects With HR-Positive, HER2-Negative Advanced/Metastatic Breast Cancer

Study Overview
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Brief Summary
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This is a phase I, First-in-Human (FIH), open-label study to evaluate the safety, tolerability, pharmacokinetic (PK) profile, and preliminary efficacy of RGT-419B administered orally as monotherapy OR in combination with Hormonal Therapy in subjects with HR+, HER2- locally advanced and unresectable (Stage III) or metastatic (Stage IV) breast cancer whose disease has progressed during prior therapy with an approved CDK4/6i plus hormonal therapy.

Official Title
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First-in-Human, Escalating Oral Dose Study of RGT-419B Given Alone and With Endocrine Therapy in Subjects With Hormone Receptor Positive, Human Epidermal Growth Factor Receptor 2 Negative Advanced/Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: RGT-419B
* Drug: RGT-419B in combination with hormonal therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female >/= 18 years old ECOG Performance Status 0 to 1 HR+, HER2- tumor by most recent biopsy with measurable disease Have had no more than 1 prior line of cytotoxic chemotherapy in the ABC setting AND no serious/severe toxicity to a prior CKD4/6i AND no known contraindication to receiving RT-419B AND have had all acute/residual toxic effects of any prior therapy In the ABC setting, eligible subjects must have failed to respond to or progressed after <3 lines of prior CDK4/6i therapy and unlimited lines of prior HT and have had no more than 1 prior line of chemotherapy. Eligible subjects must have received and progressed on any combination of HTs including any approved AI, SERD, or SERM, and/or any approved CDK4/6i in any order. (5a) For subjects in Arm B, at least one line of prior therapy must have included a locally approved HT which was well tolerated and which the subject is willing to receive again (5b) Subjects with tumors harboring a PIK3CA mutation will be allowed to enroll, and treatment with a PI3Ki in combination with HT will be allowed as a prior line of therapy. Surgical excision of tumor tissue accompanied by chemotherapy or targeted therapy is also counted as 1 line of prior treatment. Exclusion Criteria: Presence of visceral metastases with severe organ dysfunction as evidence by signs and symptoms, laboratory studies, lymphangitic spread and/or rapid progression of disease Pregnant or planning to become pregnant Prior irradiation to >25% of the bone marrow and/or inadequate bone marrow function or evidence of clinically significant end-organ damage Major surgery, chemotherapy, targeted therapy, experimental agents, or radiation within 14 days prior to Cycle 1, Day 1 Active, serious medical condition that is not well controlled with locally approved medications allowed by the protocol History of allergic reactions attributed to compounds of similar chemical or biologic composition to the drugs used in the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Sequential Assignment
Interventional Model Description: There will be two study arms opened sequentially to the same patient population. Arm A is RGT-419B alone (singlet). Arm B is RGT-419B + Hormonal Therapy (doublet) and will follow completion of Arm A.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>RGT-419B given alone as monotherapy | Drug: RGT-419B<br>* oral capsules<br>|
| Experimental: Arm B<br>RGT-419B in combination with Hormonal Therapy | Drug: RGT-419B in combination with hormonal therapy<br>* RGT-419B in combination with hormonal therapy (Selective Estrogen Receptor Degrader, Selective Estrogen Receptor Modulator, or Aromatase Inhibitor)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety & Tolerability - Number of subjects with Dose-Limiting Toxicities (DLTs) at each cohort dose level in singlet and doublet therapy | Number of subjects who have a confirmed DLT at each cohort dose level in singlet and doublet study arms during the first 28-day cycle of RGT-419B treatment. | 4 weeks (1 cycle) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety & Tolerability - Incidence, Severity, and Causality of all Treatment Emergent Adverse Events (TEAEs) | Incidence, severity, and causality of all TEAEs will be assessed for all patient participating from Day 1 dosing through end of study. | through study completion, an average of 1 year | 
| Day 1 and steady-state PK assessment of RGT-419B and major metabolites - Cmax | Plasma and urine samples that are being collected for PK assessment may also be used for exploratory metabolite identification | through study completion, an average of 1 year | 
| Day 1 and steady-state PK assessment of RGT-419B and major metabolites - Area Under Concentration-Time Curve (AUC0-t) | Plasma and urine samples that are being collected for PK assessment may also be used for exploratory metabolite identification | through study completion, an average of 1 year | 
| Day 1 and steady-state PK assessment of RGT-419B and major metabolites - Area Under Concentration-Time Curve to Infinity (AUC0-inf) | Plasma and urine samples that are being collected for PK assessment may also be used for exploratory metabolite identification | through study completion, an average of 1 year | 
| Day 1 and steady-state PK assessment of RGT-419B and major metabolites - Plasma Decay Half-Life (t 1/2) | Plasma and urine samples that are being collected for PK assessment may also be used for exploratory metabolite identification | through study completion, an average of 1 year | 
| Day 1 and steady-state PK assessment of RGT-419B and major metabolites - Time to Reach Maximum Observed Plasma Concentration (Tmax) | Plasma and urine samples that are being collected for PK assessment may also be used for exploratory metabolite identification | through study completion, an average of 1 year | 
| Day 1 and steady-state PK assessment of RGT-419B and major metabolites - Accumulation rate after multiple doses | Plasma and urine samples that are being collected for PK assessment may also be used for exploratory metabolite identification | through study completion, an average of 1 year | 
| Day 1 and steady-state PK assessment of RGT-419B and major metabolites - Cumulative urinary excretion | Plasma and urine samples that are being collected for PK assessment may also be used for exploratory metabolite identification | through study completion, an average of 1 year | 
| Tumor Response assessed by Investigator according to RECIST v1.1 | Tumor response measured by radiologic imaging techniques at baseline and throughout the study | through study completion, an average of 1 year | 
| QTc Interval - Changes in corrected QT interval | Number of subjects with a clinically significant increase from baseline in corrected QT (QTc) interval on repeated ECGs during RGT-419B monotherapy. | through study completion, an average of 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer