Estrogen Receptor-Positive, HER2-Negative, Locally Advanced Breast Cancer, Metastatic Breast Cancer
Conditions
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.
Interventions
DRUGZB716
Pharmaceutical form: capsule Route of administration: oral
DRUGPalbociclib
Pharmaceutical form: capsule Route of administration: oral
Sponsors
Zenopharm
EnhancedBio USA Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: To determine the RD(Recommended Dose) of ZB716 | 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 | 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 C: To determine the RD of ZB716 in combination with palbociclib | At the end of Cycle 1 (each cycle is 28 days) | Incidence of study treatment-related DLTs at Cycle 1 |
| Part D: To assess antitumor activities in the combination therapy of ZB716 and Palbociclib | 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
| Measure | Time frame | Description |
|---|---|---|
| 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) | Cmax is maximum concentration observed. |
| 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 is time to reach Cmax. |
| 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) | AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) |
| 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) | Cmax is maximum concentration observed. |
| 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) | Tmax is time to reach Cmax. |
| 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) | AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) |
| Adverse Events (Part A, B, C and D) | Up to 30 days after last dose of ZB716 or ZB716 with Palbociclib | Number of patients with adverse events according to the National Cancer Institute - Common Toxicity Criteria (NCI-CTC) version 5.0 grade scaling. Incidence of adverse events, including laboratory test results and electrocardiogram (ECG) findings that were adverse events |
| Tmax of Palbociclib after single dose (Part C and D) | Cycle 1, Day 1 (Part C and D) (each cycle is 28 days) | Tmax is time to reach Cmax. |
| AUC0-24 of Palbociclib after single dose (Part C and D) | Cycle 1, Day 1 (Part C and D) (each cycle is 28 days) | AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) |
| Cmax of Palbociclib after repeated dose (Part C and D) | Cycle 1, Day 15 (Part C and D) (each cycle is 28 days) | Cmax is maximum concentration observed. |
| Tmax of Palbociclib after repeated dose (Part C and D) | Cycle 1, Day 15 (Part C and D) (each cycle is 28 days) | Tmax is time to reach Cmax. |
| AUC0-24 of Palbociclib after repeated dose (Part C and D) | Cycle 1, Day 15 (Part C and D) (each cycle is 28 days) | AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) |
| Cmax of Palbociclib after single dose (Part C and D) | Cycle 1, Day 1 (Part C and D) (each cycle is 28 days) | Cmax is maximum concentration observed. |
| 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 | Proportion of patients with CR(Complete Response) or PR(Partial Response) according to RECIST 1.1 assessed by investigator/local radiologist |
| 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 | Proportion of patients with CR(Complete Response) or PR(Partial Response) or SD(Stable Disease) ≥16 weeks according to RECIST v.1.1 relative to the total number of treated patients by investigators/local radiologists |
| 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 | Time from initial response to the first documented tumor progression |
Countries
South Korea, United States
Contacts
Primary ContactEnhancedBio Inc.
Backup ContactZenopharm LLC
Outcome results
None listed