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

NCT ID: NCT04669587

Last Updated: 2022-03-22

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 106 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-07-26
• Study Completion Date: 2024-01-31

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

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

ZB716

Intervention Type: DRUG

Pharmaceutical form: capsule Route of administration: oral

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.

Group Type: EXPERIMENTAL

ZB716

Intervention Type: DRUG

Pharmaceutical form: capsule Route of administration: oral

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.

Group Type: EXPERIMENTAL

ZB716

Intervention Type: DRUG

Pharmaceutical form: capsule Route of administration: oral

Palbociclib

Intervention Type: DRUG

Pharmaceutical form: capsule Route of administration: oral

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.

Group Type: EXPERIMENTAL

ZB716

Intervention Type: DRUG

Pharmaceutical form: capsule Route of administration: oral

Palbociclib

Intervention Type: DRUG

Pharmaceutical form: capsule Route of administration: oral

Interventions

ZB716

Pharmaceutical form: capsule Route of administration: oral

Intervention Type: DRUG

Palbociclib

Pharmaceutical form: capsule Route of administration: oral

Intervention Type: DRUG

Other Intervention Names

Borestrant; Ibrance®

Eligibility Criteria

Inclusion Criteria

Subjects must satisfy all of the following criteria for study entry:

1. 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.

2. Subjects aged ≥18 years old at time of signing ICF (or country's legal age of majority if the legal age is >18 years).

3. Histologically or cytologically confirmed diagnosis of adenocarcinoma of the breast.

4. Subjects with evidence of either locally advanced disease not amenable to radiation therapy or surgery in a curative intent, or metastatic disease.

5. ER-positive tumor (≥1% positive stained cells) based on most recent tumor cell staining by immunohistochemistry (IHC) assay consistent with local standards.

Note: If primary tumor is ER-positive and any further metastatic lesions are ER negative, the subject cannot be selected for inclusion.

Exclusion Criteria

Subjects who meet any of the following criteria will be excluded from study entry:

1. 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.

2. Concurrent treatment with warfarin or phenytoin.

3. 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.

4. 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.

5. 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Zenopharm

UNKNOWN

Sponsor Role: collaborator

EnhancedBio USA Inc.

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Swedish Cancer Institute

Seattle, Washington, United States

Site Status: RECRUITING

National Cancer Center

Goyang-si, Gyeonggi-do, South Korea

Site Status: RECRUITING

CHA Bundang Medical Center, CHA University

Seongnam-si, , South Korea

Site Status: RECRUITING

Korea University Anam Hospital

Seoul, , South Korea

Site Status: RECRUITING

Kangbuk Samsung Hospital

Seoul, , South Korea

Site Status: RECRUITING

Severance Hospital, Yonsei University Health System

Seoul, , South Korea

Site Status: RECRUITING

Asan Medical Center

Seoul, , South Korea

Site Status: RECRUITING

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

Seoul, , South Korea

Site Status: RECRUITING

Countries

United States; South Korea

Central Contacts

EnhancedBio Inc.

Role: CONTACT

sophia@enhancedbio.com

1-504-236-5452

Zenopharm LLC

Role: CONTACT

guangdi.wang@zenopharm.com

1-609-433-2039

Facility Contacts

Fengting Yan

Role: primary

Keun Seok Lee

Role: primary

Yong Wha Moon

Role: primary

Kyong Hwa Park

Role: primary

Yun-Gyoo Lee

Role: primary

Joohyuk Sohn

Role: primary

Sung-Bae Kim

Role: primary

Jieun Lee

Role: primary

Other Identifiers

ENZENO-C-101

Identifier Type: -

Identifier Source: org_study_id