A Phase I Clinical Trial of FWD1802 in Patients With ER+/HER2- BC.

Study Overview
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Brief Summary
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This is a phase I open-label dose escalation trial of FWD1802 as monotherapy and in combination with palbociclib in patients with ER+/HER2- unresectable locally advanced or metastatic breast cancer The goal of this clinical trial] is to learn about in ER+/HER2- BC participant population. The main questions it aims to answer are: Establish the recommended phase II dose (RP2D) and/or the maximum tolerated dose (MTD) of FWD1802 as monotherapy and in combination with palbociclib in patients with ER+/HER2- unresectable locally advanced or metastatic breast cancer. Explore the safety and tolerability of FWD1802 as monotherapy and in combination with Palbociclib. Characterise Pharmacokinetics of FWD1802 as monotherapy and in combination with palbociclib. Explore preliminary efficacy signals.

Detailed Description
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This is a multiple cohort study, an initial dose escalation phase is designed to confirm the safe dose of FWD1802 as monotherapy and in combination with Palbociclib. A Safety Monitoring Committee (SMC) will monitor the safety, tolerability, and PK data during this phase. Once ascertained, an expansion cohort will be opened to explore the efficacy of FWD1802 as monotherapy and in combination with Palbociclib. Part A is an open-label, dose escalation of FWD 1802 as monotherapy . Dose escalation steps will be determined by the Safety Monitoring Committee (SMC), based on 3+3 rule except for the accelerated escalation on the 1st dose level. With pharmacokinetic (PK), pharmacodynamics (PD), efficacy and safety data, SMC will evaluate to guide determination of potentially effective dose for part B and C. Part B is an open-label, dose escalation of FWD 1802 in combination with palbociclib fixed dose. Dose escalation steps will be determined by SMC, based on 3+3 rule. With PK, PD, efficacy and safety data, SMC will evaluate to guide determination of potentially effective combination dose. Part C is an open label , dose expansion of FWD 1802 monotherapy on patients with ER+/HER2-/ESR1 mutation, no more than 2 dose levels will be evaluated, with 30 patients at the most in either dose level cohort.

Official Title
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A Phase I Open-label Dose Escalation Trial of FWD1802 as Monotherapy and in Combination With Palbociclib in Patients With ER+/HER2- Unresectable Locally Advanced or Metastatic Breast Cancer

Conditions
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Metastatic Breast Cancer, Locally Advanced Breast Cancer, Breast Cancer Stage I, ER+ Breast Cancer

Intervention / Treatment
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* Drug: FWD1802
* Drug: palbocilib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must understand and voluntarily sign the Informed Consent Form (ICF). Patients ≥ 18 years, female. Provision of blood sample to test ESR1 mutation status and for other biomarker assessment. In part A/B, the ESR1 mutation status will be tested retrospectively; In part C, only the patients with ESR1 mutation positive is eligible. Documented positive oestrogen receptor status of primary or metastatic tumour tissue, according to the local laboratory parameters. HER-2 negative. These laboratory parameters are consistent with accepted diagnostic guidelines such as the American Society of Clinical Oncology (ASCO) / College of American Pathologists (CAP) Clinical Practice Guideline for Pathologists estrogen (ER) and progesterone receptor (PgR) testing in breast cancer (Allison et al., 2020). HER2- defined as an Immunohistochemistry (IHC) status of 0, 1+ or negative by in situ hybridization test. Menopausal women according to one of the following criteria: Prior bilateral ovariectomy; Patients ≥ 60 years of age; Patients < 60 years of age presenting an amenorrhea of more than 12 months and follicle stimulating hormone (FSH) and plasma estradiol levels within the postmenopausal range as assessed by the local laboratory in the absence of chemotherapy, tamoxifen, tolimifene, or ovarian castration in the past 1 year, and no oral contraceptives, hormone replacement therapy, or gonadotropin-releasing hormone agonist or antagonist; Patients < 60 years of age who are taking either tamoxifen or tolomifene with two consecutive FSH and estradiol levels in the postmenopausal range. Or premenopausal or perimenopausal female subjects but must be willing to receive and maintain an approved luteinizing hormone-releasing hormone(LHRH) agonist during the study treatment period (LHRH agonist treatment initiated 28 days prior to the first study drug treatment); Previous therapy failed or intolerable, or standard therapy not available: Part A：Previous therapy failed or intolerable, or standard therapy not available； Prat B/C：Patients should have received at least 1 line endocrinotherapy, or received no more than 1-line systematic chemotherapy for advanced/metastatic disease, no more than 1 target therapy. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. At least one measurable lesion according to RECISTv1.1 criteria. Life expectancy ≥ 12 weeks. Adequate organ and bone marrow function (no use of hematopoietic stimulating factor, no blood transfusion or human albumin within 7 days prior to screening): Blood routine: Absolute neutrophil count (ANC) ≥ 1.5×109/L; Platelet count (PLT) ≥100×109/L; Hemoglobin (HGB) ≥ 90 g/L; Liver function: Serum Total bilirubin (TBIL) ≤ 1.5 Upper limit of normal value (ULN); Alanine aminotransferase (ALT) and Aspartate transferase (AST) ≤ 3×ULN in subjects without liver metastasis; ALT or AST≤ 5×ULN with liver metastasis; Renal function: Serum creatinine ≤ 1.5×ULN or estimated creatinine clearance (CLcr) ≥ 60 mL/min as calculated using Cockcroft-Gault formula; Coagulation function: Activated Partial thromboplastin Time (APTT) and international normalized ratio (INR) ≤ 1.5×ULN (or within target range if on anticoagulation therapy); Cardiac function: Echocardiography (ECHO) shows left ventricular ejection fraction (LVEF) > 50%. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first dose. Female patients of childbearing potential must agree to use effective methods of contraception from the time of signature of informed consent, throughout the study and for 6 months after the last dose of the investigational product, like double barrier methods, condoms, oral or injectable contraceptives, intrauterine devices, etc. All female subjects will be considered to be of childbearing potential unless they are postmenopausal, postmenopausal, or sterilized (hysterectomy, tubal resection). Exclusion Criteria: 1. Documented medical history or ongoing gastrointestinal disease (Including difficulty in swallowing capsules, Crohn's disease, ulcerative colitis, or short bowel syndrome) or other malabsorption that may affect the absorption of oral study drug. 2. Participated in other clinical trials of investigational drugs or investigational devices within 4 weeks before the first medication; or received chemotherapy, targeted therapy, immunotherapy and clinical trial medication and other anti-tumor treatment within 4 weeks, or received radiotherapy, endocrine drugs or Chinese traditional medicines with anti-tumor indications 2 weeks prior to the first dose. 3. The toxicity of previous anti-tumor treatment has not recovered to grade 0 or 1 (except for alopecia, chemotherapy-induced peripheral neurotoxicity ≤ grade 2). 4. Major surgical surgery (except biopsy) or incomplete healing of the surgical incision within 4 weeks prior to the first study drug treatment. 5. Known other malignant tumors within 2 years before enrollment (except for cervical carcinoma insitu, superficial noninvasive bladder tumors, breast ductal carcinoma in situ, prostatic intraepithelial neoplasia without evidence of prostate cancer, or curatively treated Stage I nonmelanoma skin cancer); 6. unstable or syptomlor progressal Central nervous system brain metastasis ; 7. Previous history of interstitial lung disease, drug-induced interstitial lung disease, symptomatic interstitial lung disease or any evidence of active pneumonia on chest CT scan within 4 weeks prior to the first study drug treatment; 8. Known to interfere with the test requirements of mental illness or drug abuse disease; 9. History of human immunodeficiency virus HIV infection； 10. Active bacterial or fungal infection requiring systemic treatment within 14 days prior to the first study drug treatment. 11. Subjects with known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection with abnormal liver function (Absence of infection was defined as HBsAg negative, HBV DNA negative and HCV antibody negative), except to: Subjects who test positive for HBsAg or HBsAb during the screening period may be enrolled if the PCR test result for HCV-RNA is < 500 IU/ml (2000 copies/mL), but receive antiviral treatment according to the investigator's assessment and undergo PCR for HBV-DNA during the study treatment period; Subject has a positive test for HCV antibody at screening and can be enrolled if the PCR test result for HCV-RNA is negative. 12. History of clinically significant cardiovascular disease, such as: Symptomatic congestive heart failure according to New York Heart Association Grades (NYHA > Grade 2); Severe/unstable angina, new angina within last 3 months; Myocardial ischemia and long-term use of drugs for control; according to NYHA, grade Ⅲ-Ⅳ cardiac insufficiency; Any event of acute myocardial infarction within 6 months before screening; Any grade ≥ 2 supraventricular arrhythmia or ventricular arrhythmia requiring treatment or intervention; Any grade atrial fibrillation, coronary/peripheral artery bypass graft, or cerebrovascular symptoms including transient ischemic attack; QTcF (Fridericia's correction formula used) > 470 ms; ECG < 50 bpm. 13. History of serious allergic reactions to the study drugs or excipients used in the protocol. 14. Women who are pregnant or lactating. 15. Prior use of an oral selective estrogen receptor degrader (SERD). 16. Subjects who use drugs or herbal supplements known to be moderate/strong inhibitors or inducers of CYP3A within 2 weeks or 5 drug half-lives (whichever is longer) prior to the first study drug treatment. 17. Received medications which inhibits the production of stomoch acid within 2 weeks or 5 drug half-lives (whichever is longer) prior to the first dose of study drugs. 18. Received medications which inhibits P-gp within 2 weeks or 5 drug half-lives (whichever is longer) prior to the first dose of study drugs. 19. Patients with active or chronic corneal disease, other active eye disease requiring ongoing treatment, or any clinically significant corneal disease for which drug-induced keratopathy cannot be adequately monitored. 20. Other conditions that the investigator considers inappropriately for this study.

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Dose Escalation of FWD1802 as a Monotherapy<br>Part A study will be conducted in subjects diagnosed with ER+/HER2- unresectable locally advanced or metastatic breast cancer. A maximum of 27 subjects will be enrolled. They will be sequentially allocated to 5 planned dose cohorts: 25 mg, 75 mg, 150 mg, 300 mg and 450 mg. Subjects enrolled will be orally administered a single dose of FWD1802 Tablet on C0D1, followed by a 3-day observation period. Starting on C1D1, FWD1802 Tablet will be orally administered continuously QD for 28 consecutive days of each cycle. The DLT observation period is set as 32 days(C0D1-C1D28). The second cycle and subsequent cycles will last for 28 days per cycle. The patients will continue to receive the study treatment until PD, death, unacceptable toxicity, withdrawal of informed consent, or other reasons to discontinue study treatment occurs, whichever comes first. | Drug: FWD1802<br>* Subjects will receive FWD1802 tablets orally according to the overall study design; the administration scheme is shown above. Subjects will continue to receive FWD1802 until any of the criteria are met. Study drugs will be orally administered at the investigational site by site staff at 8 AM on the morning of the dosing days.<br>|
| Experimental: Part B- Dose Escalation of FWD1802 in combination with palbocilib<br>The dose expansion study will be conducted in approximately 12 eligible subjects diagnosed with ER+/HER2- unresectable locally advanced or metastatic breast cancer, to evaluate the safety, tolerability, PK, PD, and preliminary efficacy of FWD1802 in combination with palbocilib. The starting dose level for Part B study will be determined by SMC based on safety data (including the AE rate of non-DLT) , PK, PD and preliminary efficacy in Part A. Every treatment cycle consists of 28 days. In brief, based on the available data obtained from Part A, 1 to 2 dose levels may be selected as the recommended dose levels (RDs) to evaluate FWD1802 in combination with palbocilib in these patients. | Drug: FWD1802<br>* Subjects will receive FWD1802 tablets orally according to the overall study design; the administration scheme is shown above. Subjects will continue to receive FWD1802 until any of the criteria are met. Study drugs will be orally administered at the investigational site by site staff at 8 AM on the morning of the dosing days.<br>Drug: palbocilib<br>* The palbociclib dose is the fixed approved dose: 125 mg intake daily, for consecutive 21 days then off for 7 days, which composes 28-day treatment cycle, which is consistent with the 28-day treatment cycle of FWD1802. Every treatment cycle consists of 28 days.<br>|
| Experimental: Part C - Dose Expansion Study<br>Part C (Dose Expansion of FWD1802 as a Monotherapy) can be conducted in parallel with Part A provided that the following two conditions are met: The starting dose of Part C study should be lower than the dose of monotherapy RP2D or the dose that has been explored and confirmed as safe for monotherapy. The SMC will review all available PK, PD, safety, tolerability and efficacy data for Part A study and decide whether the study may proceed to Part C portions. The dose expansion study will be conducted in approximately 60 eligible subjects diagnosed with ER+/HER2-/ESR1 mutation unresectable locally advanced or metastatic BC, to evaluate the safety, tolerability, PK, PD, and preliminary efficacy of FWD1802 Tablet at the recommended 1 2 dose level(s) for expansion. | Drug: FWD1802<br>* Subjects will receive FWD1802 tablets orally according to the overall study design; the administration scheme is shown above. Subjects will continue to receive FWD1802 until any of the criteria are met. Study drugs will be orally administered at the investigational site by site staff at 8 AM on the morning of the dosing days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability | Incidence of DLT in the MTD evaluation period, adverse events, treatment emergent adverse event (TEAE), serious adverse event (SAE), their relationship with the investigational product and respective severity. Changes in vital signs, ECOG score, ECG, physical examination, and laboratory tests before and after treatment, and the use of concomitant medication. | Part A: FWD1802 single dose run-in period Day1, then off until Day4 and 1st 28-day treatment cycle (Cycle1Day1-Day28), total of 34 days; Part B: the 1st treatment cycle of FWD1802 in combination with palbociclib(Cycle1Day1-Day28). | 
| PK Assessment-Cmax | Maximum plasma concentration (Cmax) | Part A: Cycle0Day1\Cycle0Day2\Cycle0Day3\Cycle0Day4\Cycle1Day1\Cycle1Day8\ Cycle1Day 15, Cycle2Day 1\ Cycle3Day 1 Part B：Cycle1Day 1\ Cycle1Day 8\ Cycle1Day 15,Cycle2Day 1\ Cycle3Day 1 Part C: Cycle1Day 1\ Cycle2Day 1\ Cycle3Day 1 (each cycle is 28 days) | 
| PK Assessment-Tmax | Time to Cmax (Tmax) | Part A: Cycle0Day1\Cycle0Day2\Cycle0Day3\Cycle0Day4\Cycle1Day1\Cycle1Day8\ Cycle1Day 15, Cycle2Day 1\ Cycle3Day 1 Part B：Cycle1Day 1\ Cycle1Day 8\ Cycle1Day 15,Cycle2Day 1\ Cycle3Day 1 Part C: Cycle1Day 1\ Cycle2Day 1\ Cycle3Day 1 (each cycle is 28 days) | 
| PK Assessment-AUC0-t | Area under the concentration versus time curve from time 0 to the last measurable concentration (AUC0-t) | Part A: Cycle0Day1\Cycle0Day2\Cycle0Day3\Cycle0Day4\Cycle1Day1\Cycle1Day8\ Cycle1Day 15, Cycle2Day 1\ Cycle3Day 1 Part B：Cycle1Day 1\ Cycle1Day 8\ Cycle1Day 15,Cycle2Day 1\ Cycle3Day 1 Part C: Cycle1Day 1\ Cycle2Day 1\ Cycle3Day 1 (each cycle is 28 days) | 
| PK Assessment-AUC0-inf | The area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC0-inf) | Part A: Cycle0Day1\Cycle0Day2\Cycle0Day3\Cycle0Day4\Cycle1Day1\Cycle1Day8\ Cycle1Day 15, Cycle2Day 1\ Cycle3Day 1 Part B：Cycle1Day 1\ Cycle1Day 8\ Cycle1Day 15,Cycle2Day 1\ Cycle3Day 1 Part C: Cycle1Day 1\ Cycle2Day 1\ Cycle3Day 1 (each cycle is 28 days) | 
| PK Assessment-t1/2 | elimination half-life time (t1/2) | Part A: Cycle0Day1\Cycle0Day2\Cycle0Day3\Cycle0Day4\Cycle1Day1\Cycle1Day8\ Cycle1Day 15, Cycle2Day 1\ Cycle3Day 1 Part B：Cycle1Day 1\ Cycle1Day 8\ Cycle1Day 15,Cycle2Day 1\ Cycle3Day 1 Part C: Cycle1Day 1\ Cycle2Day 1\ Cycle3Day 1 (each cycle is 28 days) | 
| PK Assessment-CL/F | apparent clearance (CL/F) | Part A: Cycle0Day1\Cycle0Day2\Cycle0Day3\Cycle0Day4\Cycle1Day1\Cycle1Day8\ Cycle1Day 15, Cycle2Day 1\ Cycle3Day 1 Part B：Cycle1Day 1\ Cycle1Day 8\ Cycle1Day 15,Cycle2Day 1\ Cycle3Day 1 Part C: Cycle1Day 1\ Cycle2Day 1\ Cycle3Day 1 (each cycle is 28 days) | 
| PK Assessment-Vz/F | apparent volume of distribution (Vz/F) | Part A: Cycle0Day1\Cycle0Day2\Cycle0Day3\Cycle0Day4\Cycle1Day1\Cycle1Day8\ Cycle1Day 15, Cycle2Day 1\ Cycle3Day 1 Part B：Cycle1Day 1\ Cycle1Day 8\ Cycle1Day 15,Cycle2Day 1\ Cycle3Day 1 Part C: Cycle1Day 1\ Cycle2Day 1\ Cycle3Day 1 (each cycle is 28 days) | 
| PK Assessment-λz | elimination rate constant(λz) | Part A: Cycle0Day1\Cycle0Day2\Cycle0Day3\Cycle0Day4\Cycle1Day1\Cycle1Day8\ Cycle1Day 15, Cycle2Day 1\ Cycle3Day 1 Part B：Cycle1Day 1\ Cycle1Day 8\ Cycle1Day 15,Cycle2Day 1\ Cycle3Day 1 Part C: Cycle1Day 1\ Cycle2Day 1\ Cycle3Day 1 (each cycle is 28 days) | 
| PK Assessment-Cmin_ss | Minimum concentration at steady state (Cmin_ss) | Part A: Cycle0Day1\Cycle0Day2\Cycle0Day3\Cycle0Day4\Cycle1Day1\Cycle1Day8\ Cycle1Day 15, Cycle2Day 1\ Cycle3Day 1 Part B：Cycle1Day 1\ Cycle1Day 8\ Cycle1Day 15,Cycle2Day 1\ Cycle3Day 1 Part C: Cycle1Day 1\ Cycle2Day 1\ Cycle3Day 1 (each cycle is 28 days) | 
| PK Assessment-Cmax_ss | Maximum concentration at steady state (Cmax_ss) | Part A: Cycle0Day1\Cycle0Day2\Cycle0Day3\Cycle0Day4\Cycle1Day1\Cycle1Day8\ Cycle1Day 15, Cycle2Day 1\ Cycle3Day 1 Part B：Cycle1Day 1\ Cycle1Day 8\ Cycle1Day 15,Cycle2Day 1\ Cycle3Day 1 Part C: Cycle1Day 1\ Cycle2Day 1\ Cycle3Day 1 (each cycle is 28 days) | 
| PK Assessment-Cave_ss | Average concentration at steady state (Cave_ss) | Part A: Cycle0Day1\Cycle0Day2\Cycle0Day3\Cycle0Day4\Cycle1Day1\Cycle1Day8\ Cycle1Day 15, Cycle2Day 1\ Cycle3Day 1 Part B：Cycle1Day 1\ Cycle1Day 8\ Cycle1Day 15,Cycle2Day 1\ Cycle3Day 1 Part C: Cycle1Day 1\ Cycle2Day 1\ Cycle3Day 1 (each cycle is 28 days) | 
| PK Assessment-AUCtau_ss | AUCtau_ss | Part A: Cycle0Day1\Cycle0Day2\Cycle0Day3\Cycle0Day4\Cycle1Day1\Cycle1Day8\ Cycle1Day 15, Cycle2Day 1\ Cycle3Day 1 Part B：Cycle1Day 1\ Cycle1Day 8\ Cycle1Day 15,Cycle2Day 1\ Cycle3Day 1 Part C: Cycle1Day 1\ Cycle2Day 1\ Cycle3Day 1 (each cycle is 28 days) | 
| PK Assessment-Vss | Volume at steady state (Vss) | Part A: Cycle0Day1\Cycle0Day2\Cycle0Day3\Cycle0Day4\Cycle1Day1\Cycle1Day8\ Cycle1Day 15, Cycle2Day 1\ Cycle3Day 1 Part B：Cycle1Day 1\ Cycle1Day 8\ Cycle1Day 15,Cycle2Day 1\ Cycle3Day 1 Part C: Cycle1Day 1\ Cycle2Day 1\ Cycle3Day 1 (each cycle is 28 days) | 
| PK Assessment-AR | accumulation ratio (AR) based on Cmax and AUCtau_ss | Part A: Cycle0Day1\Cycle0Day2\Cycle0Day3\Cycle0Day4\Cycle1Day1\Cycle1Day8\ Cycle1Day 15, Cycle2Day 1\ Cycle3Day 1 Part B：Cycle1Day 1\ Cycle1Day 8\ Cycle1Day 15,Cycle2Day 1\ Cycle3Day 1 Part C: Cycle1Day 1\ Cycle2Day 1\ Cycle3Day 1 (each cycle is 28 days) | 
| Efficacy Assessment-ORR | Tumor response assessments by the corresponding criteria by RECIST v1.1 to assess Objective response rate (ORR) | During the treatment period, imagological examination and efficacy assessment should be repeated every 8 weeks (± 7 days) from Cycle1Day1 for the first 12 months, then every 12 weeks (± 7 days) thereafter until disease progression (each cycle is 28 days) | 
| Efficacy Assessment-CBR | Clinical benefit rate (CBR) | During the treatment period, imagological examination and efficacy assessment should be repeated every 8 weeks (± 7 days) from Cycle1Day1 for the first 12 months, then every 12 weeks (± 7 days) thereafter until disease progression (each cycle is 28 days) | 
| Efficacy Assessment-DOR | Duration of response (DoR） | During the treatment period, imagological examination and efficacy assessment should be repeated every 8 weeks (± 7 days) from Cycle1Day1 for the first 12 months, then every 12 weeks (± 7 days) thereafter until disease progression (each cycle is 28 days) | 
| Efficacy Assessment-DCR | Disease control rate (DCR) | During the treatment period, imagological examination and efficacy assessment should be repeated every 8 weeks (± 7 days) from Cycle1Day1 for the first 12 months, then every 12 weeks (± 7 days) thereafter until disease progression (each cycle is 28 days) |