A Study of M701 (EpCAM and CD3) in Malignant Ascites

A Phase 1, Multicenter, Open-label, Dose-escalation Study to Evaluate the Safety, Tolerability and PK/PD of Recombinant Anti-EpCAM and Anti-CD3 Human-Mouse Chimeric Bispecific Antibody Via Intraperitoneal Infusion in Malignant Ascites

This study is to investigate the safety, tolerability, PK, PD and immunogenicity of multiple ascending doses of M701 administered intraperitoneally to patients with malignant ascites caused by advanced solid tumors.

Study Overview

• Status: Unknown
• Conditions: Cancer; Malignant Ascites
• Intervention / Treatment: Drug: Cohort 1 of M701; Drug: Cohort 2 of M701; Drug: Cohort 3 of M701; Drug: Cohort 4 of M701; Drug: Cohort 5 of M701; Drug: Cohort 6 of M701; Drug: Cohort 7 of M701

Detailed Description

To evaluate the safety and tolerability of multiple ascending doses of M701 administered intraperitoneally in patients with malignant ascites.

• Study Type: Interventional
• Enrollment (Anticipated): 42
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100000
      • Recruiting
      • The 307th Hospital of Chinese People's Liberation Army
      • Contact: Jianming Xu; Phone Number: 86-010-66947176; Email: jmxu2003@163.com
  • Hubei
    • Wuhan, Hubei, China, 430000
      • Recruiting
      • Tongji Hospital of Tongji Medical College,Huazhong University of Science and Technology
      • Contact: Shixuan Wang; Phone Number: 86-027-83663180

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Males or females, aged > 18 years;
2. Histologically- or cytologically-confirmed advanced solid tumors;
3. Patients who require therapeutic paracentesis, defined as at least 1 therapeutic paracentesis (e.g., to relieve abdominal pressure and discomfort) during 4 weeks prior to the baseline paracentesis;
4. Patients who have failed to standard treatment, or who have no standard treatment available that may confer clinical benefit;
5. EpCAM+ tumor cells in ascites fluid;
6. Patients who have received anti-tumor therapy including chemotherapy, hormone therapy, radiotherapy (except local radiotherapy for pain relief) ≥ 2 weeks or received immunotherapy, biological agents ≥ 3 weeks prior to the first dose of study drug;
7. Patients who have recovered from any toxic reaction to previous medications (Grade 0 or 1 based on NCI-CTCAE v5.0);
8. Patients with an ECOG Performance Status score (PS) 0-3;
9. Patients with a life expectancy > 8 weeks;

10. Organ function levels must meet the following requirements:

    Bone marrow: absolute neutrophil count (ANC) ≥ 1.5 ×10^9/L, platelet count ≥ 80 ×10^9/L, hemoglobin ≥ 9.0 g/dL (without blood transfusion within14 days of the first dose of study drug); Liver: bilirubin ≤ 1.5 x upper limit of normal (ULN), aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤ 3 x ULN ( ≤ 5 x ULN in case of liver metastases); Kidney: serum creatinine ≤1.5 x ULN and estimated glomerular filtration rate (eGFR) ≥ 50 ml/min;

11. Patients must understand and voluntarily sign the informed consent form.

Exclusion Criteria:

1. Known to have a history of allergy to the active ingredients of M701; or with a definite history of drug allergy or specific allergy (asthma, rubella, eczema dermatitis);
2. Known or suspected hypersensitivity to M701 or similar antibodies;
3. Extensive liver metastases (> 70% organ volume comprises malignancy);
4. Uncontrolled active infection (CTCAE ≥ Grade 2);
5. Serious diarrhea (CTCAE ≥ Grade 2);
6. Serious dyspnea requiring oxygen therapy;
7. History of auto-immune diseases (e.g. inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic anemia, scleroderma, serious psoriasis, rheumatoid arthritis);
8. History of acute or chronic pancreatitis;
9. Other serious diseases that may prevent patients participation in this trial (such as uncontrolled diabetes mellitus, severe gastrointestinal disorders);
10. Cardiac insufficiency, NYHA class III or IV;
11. Intestinal obstruction that occurred within 30 days prior to the first dose of study drug;
12. Non-drainable ascites;
13. Confirmed portal vein obstruction;
14. History of immunodeficiency, including positive HIV test;
15. Active hepatitis B virus infection or hepatitis C virus infection, positive syphilis antibody test and positive HIV antibody test;
16. Pregnant or breastfeeding woman;
17. Plan to conceive within six months;
18. Previous confirmed history of neurological or mental disorders, including epilepsy and dementia;
19. Have received a clinical study active drug treatment within 1 month prior to the first dose of study drug;
20. Those that are deemed ineligible for this clinical trial by study personnel.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: M701; Patients will undergo a 2-week screening period and a 4-week core treatment period, and eligible patients who complete the core treatment period will receive a cycle of extended treatment (once weekly for 4 weeks) until disease progression or toxicity intolerance.

Drug: Cohort 1 of M701; Patients in Cohort 1 will receive 4 escalating doses (2, 5, 10 and 25 μg) of M701 on Days 1, 8, 15 and 22. The maintenance dose during extended treatment period is 25 μg.; Drug: Cohort 2 of M701; Patients in Cohort 2 will receive a starting dose on Day 1 and three infusions at a higher maintenance dose level on Days 8, 15 and 22. The starting dose is 25 μg, and the maintenance dose during core treatment period and extended treatment period is 50 μg.; Drug: Cohort 3 of M701; Patients in Cohort 3 will receive a starting dose on Day 1 and three infusions at a higher maintenance dose level on Days 8, 15 and 22. The starting dose is 50 μg, and the maintenance dose during core treatment period and extended treatment period is 100 μg.; Drug: Cohort 4 of M701; Patients in Cohort 4 will receive a starting dose on Day 1 and three infusions at a higher maintenance dose level on Days 8, 15 and 22. The starting dose is 100 μg, and the maintenance dose during core treatment period and extended treatment period is 200 μg.; Drug: Cohort 5 of M701; Patients in Cohort 5 will receive a starting dose on Day 1 and three infusions at a higher maintenance dose level on Days 8, 15 and 22. The starting dose is 150 μg, and the maintenance dose during core treatment period and extended treatment period is 300 μg.; Drug: Cohort 6 of M701; Patients in Cohort 6 will receive a starting dose on Day 1 and three infusions at a higher maintenance dose level on Days 8, 15 and 22. The starting dose is 200 μg, and the maintenance dose during core treatment period and extended treatment period is 400 μg.; Drug: Cohort 7 of M701; Patients in Cohort 7 will receive a starting doseon Day 1 and three infusions at a higher maintenance dose level on Days 8, 15 and 22. The starting dose is 250 μg, and the maintenance dose during core treatment period and extended treatment period is 500 μg.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MTD	Number of DLTs (dose limiting toxicities) during the first 28 days after the first administrations of study drug in each cohort.	From the time of the first dose (Day 1) until the forth dosing (Day 28)
Incidence of AEs	Incidence and severity of AEs, including but not limited to vital signs, physical examination, laboratory tests. All AEs will be classified as Grades 1 through 5 as defined by NCI CTCAE v5.0.	From the start of administration to the end of the study or 28 days after the administration is stopped (up to 6 months and 28 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under the curve (AUC) of M701	The endpoints for assessment of PK of M701 include serum concentrations of M701 at different timepoints after M701 administration.	From the time of first dosing (Day 1) until disease progression or toxicity intolerance (up to 6 months).
Maximum observed concentration (Cmax) of M701	The endpoints for assessment of PK of M701 include serum concentrations of M701 at different timepoints after M701 administration.	From the time of first dosing (Day 1) until disease progression or toxicity intolerance (up to 6 months).
Minimum observed concentration (Cmin) of M701	The endpoints for assessment of PK of M701 include serum concentrations of M701 at different timepoints after M701 administration.	From the time of first dosing (Day 1) until disease progression or toxicity intolerance (up to 6 months).
The antibody titer of the neutralizing antibody	The immunogenicity of M701 will be collected by testing the antibody titer of the neutralizing antibody.	From the time of first dosing (Day 1) until disease progression or toxicity intolerance (up to 6 months).
Number of subjects who develop detectable anti-drug antibodies (ADAs)	The immunogenicity of M701 will be assessed by summarizing the number of subjects who develop detectable anti-drug antibodies (ADAs).	From the time of first dosing (Day 1) until disease progression or toxicity intolerance (up to 6 months).
Expression levels of CEA	As tumor marker, expression levels of CEA will be tested in each study site.	From the time of screening period until disease progression or toxicity intolerance (up to 6 months and 14 days).
Expression levels of CA125	As tumor marker, expression levels of CA125 will be tested in each study site.	From the time of screening period until disease progression or toxicity intolerance (up to 6 months and 14 days).
Expression levels of CA72-4	As tumor marker, expression levels of CA72-4 will be tested in each study site.	From the time of screening period until disease progression or toxicity intolerance (up to 6 months and 14 days).
Expression levels of CA19-9	As tumor marker, expression levels of CA19-9 will be tested in each study site.	From the time of screening period until disease progression or toxicity intolerance (up to 6 months and 14 days).
Expression levels of AFP	As tumor marker, expression levels of AFP will be tested in each study site.	From the time of screening period until disease progression or toxicity intolerance (up to 6 months and 14 days).
Cytokines	The levels of pharmacodynamic cytokines will be determined at the PD central laboratory.	From the time of first dosing (Day 1) until disease progression or toxicity intolerance (up to 6 months).
Counts of Lymphocyte subsets	Lymphocyte subsets will be determined at the PD central laboratory.	From the time of first dosing (Day 1) until disease progression or toxicity intolerance (up to 6 months).
Ascites volume	Ascites volume will be collected before each dose.	From the time of first dosing (Day 1) until disease progression or toxicity intolerance (up to 6 months).

Collaborators and Investigators

• Sponsor: Wuhan YZY Biopharma Co., Ltd.
• Investigators: Principal Investigator: Jianming Xu, 307 Hospital of PLA; Principal Investigator: Shixuan Wang, Tongji Hospital

Study record dates

Study Major Dates

• Study Start (Actual): October 30, 2018
• Primary Completion (Anticipated): January 31, 2021
• Study Completion (Anticipated): June 30, 2021

Study Registration Dates

• First Submitted: July 17, 2020
• First Submitted That Met QC Criteria: August 4, 2020
• First Posted (Actual): August 6, 2020

Study Record Updates

• Last Update Posted (Actual): August 6, 2020
• Last Update Submitted That Met QC Criteria: August 4, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Ascites
• Other Study ID Numbers: M70102

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No