A Phase 1/2, Open-label, Multicenter Study to Evaluate the Safety, Tolerability, Preliminary Antitumor Activity, Pharmacokinetics, and Pharmacodynamics of ZB716 as Monotherapy and in Combination With Palbociclib in Patients With Estrogen Receptor-Positive, HER2-Negative Locally Advanced or Metastatic Breast Cancer
Overview
- Phase
- Phase 1
- Intervention
- ZB716
- Conditions
- Estrogen Receptor-Positive
- Sponsor
- EnhancedBio USA Inc.
- Enrollment
- 106
- Locations
- 8
- Primary Endpoint
- Part C: To determine the RD of ZB716 in combination with palbociclib
- Last Updated
- 4 years ago
Overview
Brief Summary
For patients with ER-positive, HER2-negative breast cancer, blockage of the ER pathway has been proven to be an effective anticancer approach. These patients showed good response to endocrine therapy.
Fulvestrant, the approved SERD as monotherapy or in combination with CDK4/6 inhibitors, showed superior clinical benefit compared to other endocrine therapies. Fulvestrant exhibits differential mechanism of action from other endocrine therapy, such as tamoxifen, aromatase inhibitors, which indicates that direct blockage of ER might derive better clinical activity.
However, due to its route of administration by intramuscular injection, the clinical application is limited, especially with long term use. In addition, a higher dose of fulvestrant at 500 mg showed better overall survival than the lower dose at 250 mg, suggesting that more profound ER pathway modulation could derive better clinical benefit. Therefore, a SERD with improved oral bioavailability and good safety profile which enables its overdose is anticipated to achieve a more satisfactory clinical outcome with better compliance of clinical use.
Preclinical data indicates that ZB716 is a novel orally bioavailable, selective ERα degrader with full ER antagonism that demonstrates superior properties than Fulvestrant. Thus, it has a potential to be effective therapy for patients with ER-positive breast cancer.
This is the first time ZB716 will be administered to humans. The principal aim of this study is to obtain safety and tolerability data when ZB716 is administered orally as monotherapy and in combination with palbociclib to subjects with ER-positive, HER2 negative advanced breast cancer. This information, together with the PK data, will help establish the doses and dosing regimen suitable for future studies in patients. The PD effect of ZB716 on the select biomarkers for cytochrome P450 (CYP)3A4 induction (4β hydroxycholesterol) and expression of ER, PgR, and Ki67 will also be investigated. The effect of ZB716 on antitumor activity as measured by objective response rate (ORR), clinical benefit rate (CBR), duration of response (DOR), and PFS rate will also be investigated. The study will also investigate the effects of food on the PK of ZB716 monotherapy.
Investigators
Eligibility Criteria
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
Part A: Dose Escalation of ZB716 monotherapy (with Food Effect Cohort)
Cohorts will follow a 3+3 study design. Approx. 3 to 6 subjects will be enrolled in each dose cohort (6 subjects in Cohort A6; food-effect evaluation). (Dose levels: 50, 100, 200, 300, 400 mg, orally QD in a 28 day cycle) The overall DLT observation period of ZB716 monotherapy will be 4 weeks following the initial dose of study drug on Cycle 1 Day 1. There will be 2 \~ 6 days between dose escalations to allow sufficient time for an adequate safety review. The max. dose may be lower than 400 mg. In the first dosing group of Part A (Cohort A1), subject dosing will be staggered such that administration of the first dose is separated by at least 7 days between the first 2 subjects. In each of Cohorts A1 to A5, 3 to 6 subjects will receive ZB716 doses according to the assigned dose level in the fasted state. For Cohort A6, Period 1, doses will be administered in the fasted state in Treatment Period 1 and 2, doses will be given 30 min. after starting a standard high fat breakfast.
Intervention: ZB716
Part B: Dose Expansion of ZB716 monotherapy
Potential subjects will be screened to assess their eligibility to enter the study within 28 days prior to the first dose administration. Subjects will come to the clinical site before the first dose of study drug to confirm eligibility. Cohorts will be enrolled sequentially based on an optional Simon 2-stage study design. Approx. 29 subjects may be enrolled in the dose expansion cohorts of Part B. For Part B, doses will be administered (self-administered by subjects at home or administered by subjects under observation of clinical staff during clinic visits) at the determined monotherapy RD of ZB716 (based on Part A) QD in a 28-day cycle. Doses will be administered in the dietary status for dosing as determined from Part A fed/fasted comparison.
Intervention: ZB716
Part C: Dose Escalation of ZB716 in combination with palbociclib
Cohorts will follow a 3+3 study design. Approx. 6 to 12 subjects will be enrolled in the dose escalation phase of ZB716 in combination with Palbociclib. For Part C, doses will be administered at escalating doses starting with 1 dose level below the monotherapy RD (determined in Part A) and Palbociclib will be dosed at the fixed standard dose of 125 mg QD. ZB716 will be administered on a 28 day cycle and Palbociclib will be administered for 21 days in the cycle with 7 days off treatment. Administration of the higher dose level (at monotherapy RD) of ZB716 (with the standard dose of Palbociclib) to subsequent subjects will be based on the occurrence of DLTs during the DLT observation period (Cycle 1), until MAD of ZB716 with combination of Palbociclib is reached. Doses will be administered in the dietary status for dosing as determined from Part A fed/fasted comparison.
Intervention: ZB716
Part C: Dose Escalation of ZB716 in combination with palbociclib
Cohorts will follow a 3+3 study design. Approx. 6 to 12 subjects will be enrolled in the dose escalation phase of ZB716 in combination with Palbociclib. For Part C, doses will be administered at escalating doses starting with 1 dose level below the monotherapy RD (determined in Part A) and Palbociclib will be dosed at the fixed standard dose of 125 mg QD. ZB716 will be administered on a 28 day cycle and Palbociclib will be administered for 21 days in the cycle with 7 days off treatment. Administration of the higher dose level (at monotherapy RD) of ZB716 (with the standard dose of Palbociclib) to subsequent subjects will be based on the occurrence of DLTs during the DLT observation period (Cycle 1), until MAD of ZB716 with combination of Palbociclib is reached. Doses will be administered in the dietary status for dosing as determined from Part A fed/fasted comparison.
Intervention: Palbociclib
Part D: Dose Expansion of ZB716 in combination with palbociclib
Potential subjects will be screened to assess their eligibility to enter the study within 28 days prior to the first dose administration. Subjects will come to the clinical site before the first dose of study drug to confirm eligibility. Cohorts will be enrolled sequentially based on an optional Simon 2-stage study design. Approx. 29 subjects may be enrolled in the dose expansion cohorts of Part D. For Part D, doses will be administered (self-administered by subjects at home or administered by subjects under observation of clinical staff during clinic visits) at the determined RD of ZB716 QD for 28 days from Part C in combination with the standard dose of Palbociclib (125 mg QD for 21 days with 7 days off treatment). Doses will be administered in the dietary status for dosing as determined from Part A fed/fasted comparison.
Intervention: ZB716
Part D: Dose Expansion of ZB716 in combination with palbociclib
Potential subjects will be screened to assess their eligibility to enter the study within 28 days prior to the first dose administration. Subjects will come to the clinical site before the first dose of study drug to confirm eligibility. Cohorts will be enrolled sequentially based on an optional Simon 2-stage study design. Approx. 29 subjects may be enrolled in the dose expansion cohorts of Part D. For Part D, doses will be administered (self-administered by subjects at home or administered by subjects under observation of clinical staff during clinic visits) at the determined RD of ZB716 QD for 28 days from Part C in combination with the standard dose of Palbociclib (125 mg QD for 21 days with 7 days off treatment). Doses will be administered in the dietary status for dosing as determined from Part A fed/fasted comparison.
Intervention: Palbociclib
Outcomes
Primary Outcomes
Part C: To determine the RD of ZB716 in combination with palbociclib
Time Frame: At the end of Cycle 1 (each cycle is 28 days)
Incidence of study treatment-related DLTs at Cycle 1
Part A: To determine the RD(Recommended Dose) of ZB716
Time Frame: At the end of Cycle 1 (each cycle is 28 days)
Incidence of study treatment-related DLTs at Cycle 1
Part B: To assess antitumor activities at the ZB716 RD in monotherapy
Time Frame: Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered patient
Proportion of patients with CR(Complete Response), PR(Partial Response) or SD(Stable Disease) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessed by independent central reviewer relative to the total number of treated patients
Part D: To assess antitumor activities in the combination therapy of ZB716 and Palbociclib
Time Frame: Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered patient
Proportion of patients with CR(Complete Response), PR(Partial Response) or SD(Stable Disease) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessed by independent central reviewer relative to the total number of treated patients
Secondary Outcomes
- ORR(Object Response Rate) (Part A, B, C and D)(Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered patient)
- AUC0-24 of ZB716 after single dose (Part A, B, C and D)(Cycle 0, Day -7 (Part A), Cycle 1, Day 1 (Part B, C and D) (each cycle is 28 days))
- Cmax of ZB716 after repeated dose (Part A, B, C and D)(Cycle 2, Day 1 (Part A), Cycle 1, Day 15 (Part B, C and D) (each cycle is 28 days))
- AUC0-24 of Palbociclib after single dose (Part C and D)(Cycle 1, Day 1 (Part C and D) (each cycle is 28 days))
- Adverse Events (Part A, B, C and D)(Up to 30 days after last dose of ZB716 or ZB716 with Palbociclib)
- Tmax of ZB716 after repeated dose (Part A, B, C and D)(Cycle 2, Day 1 (Part A), Cycle 1, Day 15 (Part B, C and D) (each cycle is 28 days))
- AUC0-24 of Palbociclib after repeated dose (Part C and D)(Cycle 1, Day 15 (Part C and D) (each cycle is 28 days))
- CBR(Clinical Benefit Rate) (Part A and C)(Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered patient)
- Duration of response (Part A, B, C and D)(Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered patient)
- Cmax of ZB716 after single dose (Part A, B, C and D)(Cycle 0, Day -7 (Part A), Cycle 1, Day 1 (Part B, C and D) (each cycle is 28 days))
- Tmax of ZB716 after single dose (Part A, B, C and D)(Cycle 0, Day -7 (Part A), Cycle 1, Day 1 (Part B, C and D) (each cycle is 28 days))
- Tmax of Palbociclib after single dose (Part C and D)(Cycle 1, Day 1 (Part C and D) (each cycle is 28 days))
- AUC0-24 of ZB716 after repeated dose (Part A, B, C and D)(Cycle 2, Day 1 (Part A), Cycle 1, Day 15 (Part B, C and D) (each cycle is 28 days))
- Cmax of Palbociclib after single dose (Part C and D)(Cycle 1, Day 1 (Part C and D) (each cycle is 28 days))
- Cmax of Palbociclib after repeated dose (Part C and D)(Cycle 1, Day 15 (Part C and D) (each cycle is 28 days))
- Tmax of Palbociclib after repeated dose (Part C and D)(Cycle 1, Day 15 (Part C and D) (each cycle is 28 days))