ER+/HER2- Locally Advanced or Metastatic Breast Cancer (ENZENO Study)

NCT04669587 | Unknown Phase 1 DMC FDA Drug

• 1 other identifier: ENZENO-C-101
• Study Type: interventional
• Target: 106
• Locations: 2 countries
• Sites: 8

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.

Conditions

Estrogen Receptor-Positive; HER2-Negative; Locally Advanced Breast Cancer; Metastatic Breast Cancer

Outcome Measures

Primary Outcomes (4)

• Part A: To determine the RD(Recommended Dose) of ZB716

  Incidence of study treatment-related DLTs at Cycle 1

  At the end of Cycle 1 (each cycle is 28 days)

• Part B: To assess antitumor activities at the ZB716 RD in monotherapy

  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

  Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered patient

• Part C: To determine the RD of ZB716 in combination with palbociclib

  Incidence of study treatment-related DLTs at Cycle 1

  At the end of Cycle 1 (each cycle is 28 days)

• Part D: To assess antitumor activities in the combination therapy of ZB716 and Palbociclib

  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

  Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered patient

Secondary Outcomes (16)

• Adverse Events (Part A, B, C and D)

  Up to 30 days after last dose of ZB716 or ZB716 with Palbociclib

• 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

• 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)

Study Arms (4)

Part A: Dose Escalation of ZB716 monotherapy (with Food Effect Cohort)

EXPERIMENTAL

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.

Drug: ZB716

Part B: Dose Expansion of ZB716 monotherapy

EXPERIMENTAL

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.

Drug: ZB716

Part C: Dose Escalation of ZB716 in combination with palbociclib

EXPERIMENTAL

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.

Drug: ZB716; Drug: Palbociclib

Part D: Dose Expansion of ZB716 in combination with palbociclib

EXPERIMENTAL

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.

Drug: ZB716; Drug: Palbociclib

Interventions

ZB716 DRUG

Pharmaceutical form: capsule Route of administration: oral

Also known as: Borestrant

Part A: Dose Escalation of ZB716 monotherapy (with Food Effect Cohort); Part B: Dose Expansion of ZB716 monotherapy; Part C: Dose Escalation of ZB716 in combination with palbociclib; Part D: Dose Expansion of ZB716 in combination with palbociclib

Palbociclib DRUG

Pharmaceutical form: capsule Route of administration: oral

Also known as: Ibrance®

Part C: Dose Escalation of ZB716 in combination with palbociclib; Part D: Dose Expansion of ZB716 in combination with palbociclib

Eligibility Criteria

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

You may qualify if:

• Subjects must satisfy all of the following criteria for study entry:
• Subjects must be able to understand the nature of the trial and provide a signed and dated, written informed consent form (ICF) prior to any study-specific procedures, sampling, and analyses.
• Subjects aged ≥18 years old at time of signing ICF (or country's legal age of majority if the legal age is \>18 years).
• Histologically or cytologically confirmed diagnosis of adenocarcinoma of the breast.
• Subjects with evidence of either locally advanced disease not amenable to radiation therapy or surgery in a curative intent, or metastatic disease.
• ER-positive tumor (≥1% positive stained cells) based on most recent tumor cell staining by immunohistochemistry (IHC) assay consistent with local standards.

You may not qualify if:

• Subjects who meet any of the following criteria will be excluded from study entry:
• Treatment with any systemic anticancer therapies for locally advanced or metastatic breast cancer within 4 weeks or 5 half-lives of prior anticancer therapy, whichever is shorter, prior to initiation of study treatment.
• Concurrent treatment with warfarin or phenytoin.
• Diagnosis of any secondary malignancy within 3 years prior to enrollment, except for all intraepithelial neoplasia, appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer.
• Active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, major upper gastrointestinal (GI) surgery including gastric resection, or any other condition that may affect absorption of oral study drug.
• Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, including active viral or other hepatitis (eg, hepatitis B or hepatitis C virus), current alcohol abuse, or cirrhosis. Active viral or positive test for viral hepatitis as defined below:
• Note: If reports of serology test for HBV and HCV containing normal ranges issued by formal medical institutions within 28 days prior to C1D1 (and prior to informed consent) are available, these tests are exempt while screening. Unless required by local regulations, patients are not required to have HIV assessments at screening.
• Active infection is defined as requiring treatment with antiviral therapy or presence of positive test results for hepatitis B (hepatitis B surface antigen \[HBsAg\] and/or total hepatitis B core antibody \[HBcAb\]) or HCV antibody.
• Patients who test positive for HBcAb are eligible only if test results are also positive for hepatitis B surface antibody and polymerase chain reaction is negative for HBV DNA.
• Patients who are positive for HCV serology are only eligible if testing for HCV RNA is negative.

Sponsors & Collaborators

• EnhancedBio USA Inc.: lead
• Zenopharm: collaborator

Study Sites (8)

Swedish Cancer Institute

Seattle, Washington, 98104, United States

RECRUITING

National Cancer Center

Goyang-si, Gyeonggi-do, 10408, South Korea

RECRUITING

CHA Bundang Medical Center, CHA University

Seongnam-si, 13496, South Korea

RECRUITING

Korea University Anam Hospital

Seoul, 02841, South Korea

RECRUITING

Kangbuk Samsung Hospital

Seoul, 03181, South Korea

RECRUITING

Severance Hospital, Yonsei University Health System

Seoul, 03722, South Korea

RECRUITING

Asan Medical Center

Seoul, 05505, South Korea

RECRUITING

The Catholic University of Korea, Seoul St. Mary's Hospital

Seoul, 06591, South Korea

RECRUITING

MeSH Terms

Conditions

Breast Neoplasms

Interventions

palbociclib

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Central Study Contacts

EnhancedBio Inc.

CONTACT

1-504-236-5452; sophia@enhancedbio.com

Zenopharm LLC

CONTACT

1-609-433-2039; guangdi.wang@zenopharm.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 15, 2020
• First Posted: December 17, 2020
• Study Start: July 26, 2021
• Primary Completion: January 31, 2023
• Study Completion: January 31, 2024
• Last Updated: March 22, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will not share

Locations

KR (7); US (1)