A Study of FDA018-ADC in Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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This is a Phase 1, open-label, dose escalation and dose expansion study to evaluate the safety, tolerability, pharmacokinetics and efficacy of FDA018-ADC in patients with advanced/metastatic solid tumors.

Detailed Description
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This is a first-in-human (FIH), Phase 1, open-label, dose escalation and dose expansion study to evaluate the safety, tolerability, pharmacokinetics and preliminary efficacy of FDA018-ADC in patients with advanced/metastatic solid tumors. FDA018-ADC is administered via intravenous infusion using an accelerated titration method followed by a conventional 3 + 3 study design to identify the maximum tolerated dose (MTD) and dose-limiting toxicities（DLT）during 35-day cycle with 3 doses. In addition, the maximum-tolerated dose and recommended Phase II dose for FDA018-ADC will be determined.

Official Title
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A PhaseⅠStudy to Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of FDA018-ADC in Patients With Advanced Solid Tumors

Conditions
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Advanced/ Metastatic Solid Tumors

Intervention / Treatment
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* Drug: FDA018-ADC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients able to give written informed consent; Age ≥ 18 and ≤ 75 years old, male or female; Patients have histological or cytological diagnosis with advanced solid tumors, cann't benefit from existing standard treatment options, and are not suitable for surgical resection or radiation therapy for the purpose of cure; tumor types in the study include: triple-negative breast cancer (TNBC), urothelial cancer (UC), non-small-cell lung cancer (NSCLC), small-cell lung cancer (SCLC), endometrial, gastric adenocarcinoma, esophageal, ovarian, colorectal and so on. Have measurable lesions defined in RECIST v. 1.1; Expected survival ≥ 12 weeks; Eastern Cancer Cooperative Group (ECOG) performance status 0-1; Adequate bone marrow, hepatic, and renal function; All acute toxicity of previous anti-tumor treatment or surgery is relieved to baseline severity or NCI CTCAE version 5.0 ≤ 1; Tumor tissue sections available； Patients of child bearing potential must agree to take contraception during the study and for 6 months after the last day of treatment. Exclusion Criteria: Previous treatments for anti-Trop-2 antibody or other treatments against Trop-2, such as IMMU-132; Have history of an anaphylactic reaction to irinotecan or ≥ Grade 3 GI toxicity to prior irinotecan, or previously allergic to macromolecular protein preparations; Have had other malignant tumors in the past 5 years; Received other anti-tumor treatments (including chemotherapy, radiotherapy, Targeted therapy, immunotherapy, experimental treatment and so on) within 4 weeks; Infection requiring intravenous antibiotic use within 1 week or Fever of unknown cause occurred before the first administration> 38.5℃； Have CNS (central nervous system) metastasis with clinical symptoms; Any of the following cardiac criteria: Known history of severe heart disease, such as CHF≥ level 2, NYHA≥ level 2 and angina requiring medication; Clinically significant cardiac arrhythmia requiring anti-arrhythmia therapy; Hypertension not controlled by medication; Have history of clinical significant active COPD, or other moderate-to-severe chronic respiratory illness present within 6 months; Patients with poorly controlled diabetes; Suffering from active chronic inflammatory bowel disease (ulcerative colitis, Crohn disease), and history of intestinal obstruction, or GI perforation; Patients who had undergone major surgery or severe trauma within 4 weeks prior to the first dose; Patients who had undergone autologous within 3 months of initiation of study treatment or allogeneic organ or stem cell transplantation within 6 months of initiation of study treatment; Clinically active bacterial, fungal or viral infections (eg active hepatitis B (HBV), hepatitis C (HCV), human immunodeficiency virus (HIV), syphilis positive and so on); Patients who had undergone systemic high-dose steroids within 2 weeks of initiation of study treatment; Occurrence of serious venous/venous thrombosis within 1 year prior to the first dose, such as cerebrovascular accidents (including transient ischemic attack), deep vein thrombosis and pulmonary embolism; Patients have history of psychotropic drug abuse, alcohol or drug abuse； Women who are pregnant or lactating； Any condition that is unstable or may jeopardize patient safety and its compliance with the study; Other circumstances that is deemed not appropriate for the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

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: FDA018-ADC A mg/kg<br>Subjects will receive FDA018-ADC A mg/kg of body weight via intravenous (IV) infusion on Day 1, 15 and 22 of a 35-Day cycle (Cycle 1) and on Day 1 and 8 of a 21-day cycle (Cycle 2   Cycle 5) in dose escalation phase, and on Day 1 and 8 of a 21-day cycle(Cycle 1   Cycle 6) in dose expansion phase, and Day 1 and 8 of a 21-day cycle in follow-up period until disease progression, unacceptable toxicity or death. | Drug: FDA018-ADC<br>* FDA018-ADC will be administered via IV infusion on Day 1, 15 and 22 of a 35-Day cycle (Cycle 1) and on Day 1, 15 and 22 of a 35-Day cycle (Cycle 1) and on Day 1 and 8 of a 21-day cycle (Cycle 2   Cycle 5) in dose escalation phase, and on Day 1 and 8 of a 21-day cycle(Cycle 1   Cycle 6) in dose expansion phase, and Day 1 and 8 of a 21-day cycle in follow-up period until disease progression, unacceptable toxicity or death.<br>* Other names: FDA018-Antibody-drug Conjugate;|
| Experimental: FDA018-ADC B mg/kg<br>Subjects will receive FDA018-ADC B mg/kg of body weight via intravenous (IV) infusion on Day 1, 15 and 22 of a 35-Day cycle (Cycle 1) and on Day 1 and 8 of a 21-day cycle (Cycle 2   Cycle 5) in dose escalation phase, and on Day 1 and 8 of a 21-day cycle(Cycle 1   Cycle 6) in dose expansion phase, and Day 1 and 8 of a 21-day cycle in follow-up period until disease progression, unacceptable toxicity or death. | Drug: FDA018-ADC<br>* FDA018-ADC will be administered via IV infusion on Day 1, 15 and 22 of a 35-Day cycle (Cycle 1) and on Day 1, 15 and 22 of a 35-Day cycle (Cycle 1) and on Day 1 and 8 of a 21-day cycle (Cycle 2   Cycle 5) in dose escalation phase, and on Day 1 and 8 of a 21-day cycle(Cycle 1   Cycle 6) in dose expansion phase, and Day 1 and 8 of a 21-day cycle in follow-up period until disease progression, unacceptable toxicity or death.<br>* Other names: FDA018-Antibody-drug Conjugate;|
| Experimental: FDA018-ADC C mg/kg<br>Subjects will receive FDA018-ADC C mg/kg of body weight via intravenous (IV) infusion on Day 1, 15 and 22 of a 35-Day cycle (Cycle 1) and on Day 1 and 8 of a 21-day cycle (Cycle 2   Cycle 5) in dose escalation phase, and on Day 1 and 8 of a 21-day cycle(Cycle 1   Cycle 6) in dose expansion phase, and Day 1 and 8 of a 21-day cycle in follow-up period until disease progression, unacceptable toxicity or death. | Drug: FDA018-ADC<br>* FDA018-ADC will be administered via IV infusion on Day 1, 15 and 22 of a 35-Day cycle (Cycle 1) and on Day 1, 15 and 22 of a 35-Day cycle (Cycle 1) and on Day 1 and 8 of a 21-day cycle (Cycle 2   Cycle 5) in dose escalation phase, and on Day 1 and 8 of a 21-day cycle(Cycle 1   Cycle 6) in dose expansion phase, and Day 1 and 8 of a 21-day cycle in follow-up period until disease progression, unacceptable toxicity or death.<br>* Other names: FDA018-Antibody-drug Conjugate;|
| Experimental: FDA018-ADC D mg/kg<br>Subjects will receive FDA018-ADC D mg/kg of body weight via intravenous (IV) infusion on Day 1, 15 and 22 of a 35-Day cycle (Cycle 1) and on Day 1 and 8 of a 21-day cycle (Cycle 2   Cycle 5) in dose escalation phase, and on Day 1 and 8 of a 21-day cycle(Cycle 1   Cycle 6) in dose expansion phase, and Day 1 and 8 of a 21-day cycle in follow-up period until disease progression, unacceptable toxicity or death. | Drug: FDA018-ADC<br>* FDA018-ADC will be administered via IV infusion on Day 1, 15 and 22 of a 35-Day cycle (Cycle 1) and on Day 1, 15 and 22 of a 35-Day cycle (Cycle 1) and on Day 1 and 8 of a 21-day cycle (Cycle 2   Cycle 5) in dose escalation phase, and on Day 1 and 8 of a 21-day cycle(Cycle 1   Cycle 6) in dose expansion phase, and Day 1 and 8 of a 21-day cycle in follow-up period until disease progression, unacceptable toxicity or death.<br>* Other names: FDA018-Antibody-drug Conjugate;|
| Experimental: FDA018-ADC E mg/kg<br>Subjects will receive FDA018-ADC E mg/kg of body weight via intravenous (IV) infusion on Day 1, 15 and 22 of a 35-Day cycle (Cycle 1) and on Day 1 and 8 of a 21-day cycle (Cycle 2   Cycle 5) in dose escalation phase, and on Day 1 and 8 of a 21-day cycle(Cycle 1   Cycle 6) in dose expansion phase, and Day 1 and 8 of a 21-day cycle in follow-up period until disease progression, unacceptable toxicity or death. | Drug: FDA018-ADC<br>* FDA018-ADC will be administered via IV infusion on Day 1, 15 and 22 of a 35-Day cycle (Cycle 1) and on Day 1, 15 and 22 of a 35-Day cycle (Cycle 1) and on Day 1 and 8 of a 21-day cycle (Cycle 2   Cycle 5) in dose escalation phase, and on Day 1 and 8 of a 21-day cycle(Cycle 1   Cycle 6) in dose expansion phase, and Day 1 and 8 of a 21-day cycle in follow-up period until disease progression, unacceptable toxicity or death.<br>* Other names: FDA018-Antibody-drug Conjugate;|
| Experimental: FDA018-ADC F mg/kg<br>Subjects will receive FDA018-ADC F mg/kg of body weight via intravenous (IV) infusion on Day 1, 15 and 22 of a 35-Day cycle (Cycle 1) and on Day 1 and 8 of a 21-day cycle (Cycle 2   Cycle 5) in dose escalation phase, and on Day 1 and 8 of a 21-day cycle (Cycle 1   Cycle 6) in dose expansion phase, and Day 1 and 8 of a 21-day cycle in follow-up period until disease progression, unacceptable toxicity or death. | Drug: FDA018-ADC<br>* FDA018-ADC will be administered via IV infusion on Day 1, 15 and 22 of a 35-Day cycle (Cycle 1) and on Day 1, 15 and 22 of a 35-Day cycle (Cycle 1) and on Day 1 and 8 of a 21-day cycle (Cycle 2   Cycle 5) in dose escalation phase, and on Day 1 and 8 of a 21-day cycle(Cycle 1   Cycle 6) in dose expansion phase, and Day 1 and 8 of a 21-day cycle in follow-up period until disease progression, unacceptable toxicity or death.<br>* Other names: FDA018-Antibody-drug Conjugate;|
| Experimental: FDA018-ADC G mg/kg<br>Subjects will receive FDA018-ADC G mg/kg of body weight via intravenous (IV) infusion on Day 1, 15 and 22 of a 35-Day cycle (Cycle 1) and on Day 1 and 8 of a 21-day cycle (Cycle 2   Cycle 5) in dose escalation phase, and on Day 1 and 8 of a 21-day cycle (Cycle 1   Cycle 6) in dose expansion phase, and Day 1 and 8 of a 21-day cycle in follow-up period until disease progression, unacceptable toxicity or death. | Drug: FDA018-ADC<br>* FDA018-ADC will be administered via IV infusion on Day 1, 15 and 22 of a 35-Day cycle (Cycle 1) and on Day 1, 15 and 22 of a 35-Day cycle (Cycle 1) and on Day 1 and 8 of a 21-day cycle (Cycle 2   Cycle 5) in dose escalation phase, and on Day 1 and 8 of a 21-day cycle(Cycle 1   Cycle 6) in dose expansion phase, and Day 1 and 8 of a 21-day cycle in follow-up period until disease progression, unacceptable toxicity or death.<br>* Other names: FDA018-Antibody-drug Conjugate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The dose limiting toxicity ( DLT) | Evaluated according to NCI CTCAE V5.0 | From first dose to the end of Cycle 1, up to 35 days. | 
| The maximum tolerated dose (MTD) | Maximum tolerated dose (MTD) is defined as the dose level immediately below the dose level at which 2 or more in a cohort of either 3 or 6 patients experiences a dose limiting toxicity (DLT) attributed to FDA018. | From first dose to the end of Cycle 1, up to 35 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to peak (Tmax) | Tmax of Total Antibody, Total SN-38, Free SN-38, SN-38 Glucuronide and FDA018-ADC will be measured. | Up to 17 weeks. | 
| Half-life time (t1/2) | t1/2 of Total Antibody, Total SN-38, Free SN-38, SN-38 Glucuronide and FDA018-ADC will be measured. | Up to 17 weeks. | 
| Peak Plasma Concentration (Cmax) | Cmax of Total Antibody, Total SN-38, Free SN-38, SN-38 Glucuronide and FDA018-ADC will be measured. | Up to 17 weeks. | 
| Area under the plasma concentration versus time curve (AUC) | AUC of Total Antibody, Total SN-38, Free SN-38, SN-38 Glucuronide and FDA018-ADC will be measured. | Up to 17 weeks. | 
| Number of subjects who develop detectable anti-drug antibodies (ADAs) | The subject's ADA positive rate will be assessed By ELISA. | From subject randomization up to 60 months. | 
| Objective Response Rate (ORR) according to RECIST 1.1 | ORR was defined as the rate an overall best response of either complete response (CR) or partial response (PR) according to RECIST1.1. CR was defined as the disappearance of all target lesions and reduction in short axis of any pathologic lymphnode to <10 mm. PR was defined as ≥ 30% decrease in the sum of diameters of target lesions, taking the baseline sum diameters. | From subject randomization up to 60 months. | 
| Progression free survival(PFS) according to RECIST 1.1 | Progression-free survival (PFS) was defined as the interval from the first dose start date to the date of disease progression defined as documented progressive disease (PD) or death from any cause, whichever occurs first. | From subject randomization up to 60 months. | 
| Duration of Response(DOR) according to RECIST 1.1 | Duration of Response was defined as the duration of overall response measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). | From subject randomization up to 60 months. | 
| Overall Survival (OS) according to RECIST 1.1 | Overall survival was defined as the time from the date of the first dose start date to the date of death due to any cause. | From subject randomization up to 60 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid tumor, Trop-2, TNBC, Antibody-drug conjugate, ADC