A Study of H3B-6545 in Combination With Palbociclib in Women With Advanced or Metastatic Estrogen Receptor-Positive Human Epidermal Growth Factor Receptor-2 (HER2)-Negative Breast Cancer

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the safety and tolerability of H3B-6545 and palbociclib when administered in combination in order to determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of this combination in women with advanced or metastatic estrogen receptor-positive (ER+) HER2- breast cancer.

Official Title
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An Open-Label Multicenter Phase 1b Study of H3B-6545 in Combination With Palbociclib in Women With Advanced or Metastatic Estrogen Receptor-Positive HER2-Negative Breast Cancer

Conditions
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Receptors, Estrogen, Genes, Erbb-2, Breast Neoplasms

Intervention / Treatment
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* Drug: Palbociclib (75, 100, 125 milligram [mg])
* Drug: H3B-6545 (150, 300, 450 mg)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ER+ HER2- locally advanced, recurrent, or metastatic breast cancer, as per local laboratory Prior therapy in the advanced/metastatic setting Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Has adequate bone marrow and organ function Exclusion Criteria: Uncontrolled significant active infections Major surgery or other locoregional treatment within 4 weeks before the 1st dose of study drug Inability to take oral medication or presence of malabsorption Active cardiac disease or a history of cardiac dysfunction Evidence of ongoing Alcohol or Drug Abuse

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
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Palbociclib + H3B-6545 (Dose Escalation and Dose Expansion)<br>Participants will receive Palbociclib 75, 100, 125 milligram (mg) capsules or tablets, orally, once daily from Days 1 to 21 followed by 7 days off treatment in 28-day cycles along with H3B-6545 150, 300, 450 mg capsules or tablets, orally, once daily from Days 1 to 28 in 28-day cycles in dose escalation part. Based on MTD or RP2D determined for H3B-6545 in combination with palbociclib in dose escalation part, participants will continue to receive study treatment in dose expansion part until PD, development of unacceptable toxicity, or withdrawal of consent (up to 24 months). | Drug: Palbociclib (75, 100, 125 milligram [mg])<br>* Palbociclib orally, once daily (QD).<br>Drug: H3B-6545 (150, 300, 450 mg)<br>* H3B-6545 orally, QD.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation Part: MTD and/or RP2D of Palbociclib and H3B-6545 |  | From Cycle 1 Day 9 up to Cycle 2 Day 8 (Each cycle length is equal to [=] 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) |  | From first dose up to 28 days after the last dose of study drug (up to Month 24) | 
| AUC(0-t): Area Under the Plasma Concentration-time Curve from Time 0 to the Last Measurable Point for Palbociclib and H3B-6545 |  | Dose Escalation Part: Cycle 1 Days 8, 21 and 28: 0-24 hours postdose; Dose Expansion Part: Cycle 1 Day 21: 0-24 hours postdose (Each Cycle length=28 days) | 
| Cmax: Maximum Observed Plasma Concentration for Palbociclib and H3B-6545 |  | Dose Escalation Part: Cycle 1 Days 8, 21 and 28: 0-24 hours postdose; Dose Expansion Part: Cycle 1 Day 21: 0-24 hours postdose (Each Cycle length=28 days) | 
| Tmax: Time to Reach the Cmax for Palbociclib and H3B-6545 |  | Dose Escalation Part: Cycle 1 Days 8, 21 and 28: 0-24 hours postdose; Dose Expansion Part: Cycle 1 Day 21: 0-24 hours postdose (Each Cycle length=28 days) | 
| C24: Plasma Concentration at 24 hour Post-dose for Palbociclib and H3B-6545 |  | Dose Escalation Part: Cycle 1 Days 8, 21 and 28: 0-24 hours postdose; Dose Expansion Part: Cycle 1 Day 21: 0-24 hours postdose (Each Cycle length=28 days) | 
| Ratio of Pharmacokinetic (PK) Cmax Parameter Estimates Between Day 21 (Palbociclib) and Day 8 (Palbociclib) | Ratio of palbociclib Cmax Day 21/Day 8, is the ratio of palbociclib exposure on Day 21 and palbociclib exposure on Day 8. | Dose Escalation Part: Cycle 1 Days 8 and 21: 0-24 hours postdose; Dose Expansion Part: Cycle 1 Day 21: 0-24 hours postdose (Each Cycle length=28 days) | 
| Ratio of PK AUC24 Parameter Estimates Between Day 21 (Palbociclib) and Day 8 (Palbociclib) | Ratio of palbociclib AUC24 Day 21/Day 8, is the ratio of palbociclib exposure on Day 21 and palbociclib exposure on Day 8. | Dose Escalation Part: Cycle 1 Days 8 and 21: 0-24 hours postdose; Dose Expansion Part: Cycle 1 Day 21: 0-24 hours postdose (Each Cycle length=28 days) | 
| Ratio of PK C24 Parameter Estimates Between Day 21 (Palbociclib) and Day 8 (Palbociclib) | Ratio of palbociclib C24 Day 21/Day 8, is the ratio of palbociclib exposure on Day 21 and palbociclib exposure on Day 8. | Dose Escalation Part: Cycle 1 Days 8 and 21: 0-24 hours postdose; Dose Expansion Part: Cycle 1 Day 21: 0-24 hours postdose (Each Cycle length=28 days) | 
| Ratio of PK Cmax Parameter Estimates Between Day 21 (H3B-6545) and Day 28 (H3B-6545) | Ratio of palbociclib Cmax Day 21/Day 28, is the ratio of H3B-6545 exposure on Day 21 and H3B-6545 exposure on Day 28. | Dose Escalation Part: Cycle 1 Days 21 and 28: 0-24 hours postdose; Dose Expansion Part: Cycle 1 Day 21: 0-24 hours postdose (Each Cycle length=28 days) | 
| Ratio of PK AUC24 Parameter Estimates Between Day 21 (H3B-6545) and Day 28 (H3B-6545) | Ratio of H3B-6545 AUC24 Day 21/Day 28, is the ratio of H3B-6545 exposure on Day 21 and H3B-6545 exposure on Day 28. | Dose Escalation Part: Cycle 1 Days 21 and 28: 0-24 hours postdose; Dose Expansion Part: Cycle 1 Day 21: 0-24 hours postdose (Each Cycle length=28 days) | 
| Ratio of PK C24 Parameter Estimates Between Day 21 (H3B-6545) and Day 28 (H3B-6545) | Ratio of H3B-6545 C24 Day 21/Day 28, is the ratio of H3B-6545 exposure on Day 21 and H3B-6545 exposure on Day 28. | Dose Escalation Part: Cycle 1 Days 21 and 28: 0-24 hours postdose; Dose Expansion Part: Cycle 1 Day 21: 0-24 hours postdose (Each Cycle length=28 days) | 
| Objective Response Rate (ORR) | ORR is defined as the percentage of participants achieving a best overall response (BOR) of confirmed partial response (PR) or complete response (CR). The ORR will be assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. | From first dose of study drug up to Month 24 | 
| Duration of Response (DoR) | DoR is defined as the time from the date of the first documented CR/PR until the first documentation of disease progression (PD) or death, whichever comes first. The DoR will be assessed according to RECIST version 1.1. | From the date of first documented CR/PR until the PD or death, whichever occurs first (up to Month 24) | 
| Clinical Benefit Rate (CBR) | CBR is defined as the percentage of participants with BOR of PR, CR, or durable stable disease (SD) (duration of SD greater than or equal to 23 weeks). Duration of SD is defined as the time from the date of first dose to the date of the first documentation of disease progression or death, whichever occurs first. It will be calculated for participants whose BOR is SD. The CBR will be assessed according to RECIST version 1.1. | From the first dose of study drug until disease progression or death, whichever occurs first (up to Month 24) | 
| Progression-free Survival (PFS) | PFS is defined as the time from the first dose date to the date of the first documentation of PD or death (whichever occurs first). | From first dose of study drug until first documentation of PD or death, whichever occurs first (up to Month 24) | 
| Overall Survival (OS) | OS is defined as the time from first dose date to the date of death from any cause. | From the date of first dose to the date of death from any cause (up to Month 24) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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H3B-6545, Palbociclib, Metastatic Estrogen Receptor-Positive, HER2-Negative Breast Cancer