A Phase Ib/II Clinical Trial of M701 in the Treatment of Malignant Pleural Effusions Caused by NSCLC
Primary Purpose
Malignant Pleural Effusions, NSCLC Stage IV
Status
Not yet recruiting
Phase
Phase 1
Locations
China
Study Type
Interventional
Intervention
M701 pleural infusion
Pleural drainage
Cisplatin pleural infusion
Sponsored by
About this trial
This is an interventional treatment trial for Malignant Pleural Effusions focused on measuring Malignant Pleural Effusions, NSCLC
Eligibility Criteria
Inclusion Criteria:
- Males or females, aged > 18 years.
- Histologically- or cytologically-confirmed non-small cell lung cancer that has progressed after first line systemic therapy.
- Malignant pleural effusion diagnosed histologically or cytologically, with moderate or above moderate pleural fluid (sitting pleural fluid depth ≥ 4 cm via ultrasound, expected pleural fluid volume ≥ 500 mL) . Require clinical intervention and not treated yet.
- Patients who have an washout period of ≥ 4 weeks or 5 half-life of the drug (including radiotherapy, chemotherapy, immunotherapy, biologic, targeted, hormonal therapy, and 14 days for local radiotherapy) between the last systemic therapy and the first dose; however, no washout period is required if the subject has new pleural fluid or poor control of current pleural fluid after at least 2 cycle systemic therapy.
- Patients who had recovered to grade 0-1 of any toxic reaction to prior antineoplastic therapy as determined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) V5.0, with the exception of alopecia, hyperpigmentation and ≤ grade 2 neuropathy, hormone replacement hypothyroidism or other adverse events confirmed to have turned chronic.
- Patients with physical status ECOG score (PS) of 0-2.
- Patients with life expectancy ≥ 12 weeks.
- Bone marrow: absolute neutrophil count (ANC) ≥ 1.5 ×10^9/L, platelet count ≥ 100 ×10^9/L, hemoglobin ≥ 8.5 g/dL (without blood transfusion within14 days of the first dose of study drug); Liver: bilirubin (TBIL)≤ 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.
- Patients must understand and voluntarily sign the written informed consent.
Exclusion Criteria:
- Patients with asymptomatic pleural fluid and not requiring clinical intervention, or bilateral malignant pleural fluid, or proposed perfusion of the chest cavity presenting with pleural fluid separation.
- Patients with central nervous system (CNS) metastases resulting in clinical symptoms or requiring therapeutic intervention; patients previously treated for brain metastases may be enrolled if they have been asymptomatic for ≥ 4 weeks prior to the first dose and have imaging indicating stable disease and do not require corticosteroid or anticonvulsant therapy.
- Patients with a known history of severe allergy to M701 drug components or antibody-like macromolecular drugs.
- Patients with contraindications to thoracentesis.
- Patients who have undergone major surgical procedures within 4 weeks prior to the first dose.
- Patients with extensive liver metastases (>70%).
- Patients with uncontrollable active infection (NCI-CTCAE V5.0 ≥ grade 2).
- Patients required long-term hormonal or immunosuppressive therapy, e.g. active autoimmune disease, maintenance therapy after organ transplantation, except that the following are allowed to enter screening: type I diabetes mellitus, hypothyroidism that can be controlled by replacement therapy only, skin diseases that do not require systemic therapy (e.g. vitiligo, psoriasis or alopecia).
- Patients with severe respiratory disease which, in the judgment of the investigator, makes them unsuitable for entry; or combined interstitial pneumonia.
- Patients with history of severe cardiovascular disease, including previous coronary artery bypass grafting or coronary stenting, myocardial infarction within 6 months, congestive heart failure (New York Classification of Cardiac Function Class III-IV) or unstable angina, or uncontrolled hypertension.
- Patients with QTc interval > 480 ms,family or personal history of long or short QT syndrome, clinically significant history of ventricular arrhythmias or implantation of a defibrillation device for ventricular arrhythmias.
- Patients with a history of (non-study tumour) malignancy (except squamous and basal cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or other, non-invasive lesions that the investigator and sponsor agree have been cured and have a minimal risk of recurrence within 3 years) within 3 years prior to the date of first study drug administration.
- Patients who have active hepatitis B (HBV-DNA quantification ≥ 1 x 10^4 copies/mL or 2000 IU/mL), active hepatitis C (positive for hepatitis C antibodies and HCV-RNA above the lower limit of detection of the assay), active syphilis with positive HIV antibodies.
- Pregnant or breastfeeding woman,Plan to conceive within six months;
- Patients with a confirmed history of neurological or mental disorders, including epilepsy and dementia.
- Those that are deemed ineligible for this clinical trial by investigator.
Sites / Locations
- Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital)
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Sham Comparator
Arm Label
Experimental group
Control group
Arm Description
Pleural drainage and M701 infusion
Pleural drainage only or plus chemotherapy as investigator's choice.
Outcomes
Primary Outcome Measures
Dose Limiting Toxicities (DLTs)
Dose limiting toxicities during the first 28 days after the first administrations of study drug in each cohort.
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.
Objective Response Rate(4 weeks/8 weeks) of pleural effusion
the rate of patients with pleural effusion CR and PR at 4 weeks / 8 weeks, based on CT evaluation .
Secondary Outcome Measures
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.
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.
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.
Half-time (t1/2) of M701
Half-time (t1/2) of M701
Anti-drug antibodies(ADAs) titer
The immunogenicity of M701 will be assessed by summarizing the number of subjects who develop detectable anti-drug antibodies (ADAs).
Neutralizing antibody titer
The immunogenicity of M701 will be collected by testing the antibody titer of the neutralizing antibody.
Concentrations of tumor biomarker in pleural effusions
As tumor biomarkers, concentrations of CEA, CyFra21-1, SCC and NSE in malignant pleural effusions will be examined at Day 1 and Day10.
Expression level of EpCAM-positive cells in pleural effusions
The number and expression levels of EpCAM-positive cells in pleural effusions will be measured by pathological methods (including cytospin, immunohistochemical techniques, etc.)
Ratio of EpCAM-positive tumour cell/leucocyte
Ratio of EpCAM positive tumour cell/leucocyte in pleural effusions will be measured by FACS method.
Rate of with successful pleurodesis (4/8 weeks)
the rate of patients with successful pleurodesis at 4 weeks / 8 weeks
Puncture-free survival rate at 4/8 weeks
the rate of patients without extra puncture at 4/8 weeks after the initial drainage.
Pleural signs and symptoms
Using the Lister Quadruple Scale to record pleural effusions at 4 weeks/ 8 weeks.
Full Information
NCT ID
NCT05543330
First Posted
September 14, 2022
Last Updated
September 14, 2022
Sponsor
Wuhan YZY Biopharma Co., Ltd.
1. Study Identification
Unique Protocol Identification Number
NCT05543330
Brief Title
A Phase Ib/II Clinical Trial of M701 in the Treatment of Malignant Pleural Effusions Caused by NSCLC
Official Title
A Phase 1, Multicenter, Open-label, Dose-increasing Study to Evaluate the Safety, Tolerability, PK/PD and Preliminary Efficacy of M701, a Recombinant Epcam and CD3 Bispecific Antibody , in Patients With Malignant Pleural Effusions Caused by NSCLC
Study Type
Interventional
2. Study Status
Record Verification Date
September 2022
Overall Recruitment Status
Not yet recruiting
Study Start Date
September 30, 2022 (Anticipated)
Primary Completion Date
June 1, 2024 (Anticipated)
Study Completion Date
December 1, 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Wuhan YZY Biopharma Co., Ltd.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
5. Study Description
Brief Summary
This is a phase 1/phase 2, multicenter, open-label study to evaluate the safety, tolerability, PK, PD, immunogenicity and preliminary efficacy of M701 in patients with treatment of malignant pleural effusions caused by NSCLC.
Detailed Description
This study is consisted of two phase, Phase Ib and II:
Phase 1b includes dose escalation phase and cohort expansion phase. In dose escalation phase, up to 4 dose-escalation cohorts will be sequentially enrolled with regular "3+3" design. DLTs will be evaluated during the first treatment cycle, which is 28 days. In cohort expansion phase, after the RP2D was identified, participants were enrolled in an open-ended manner. Participants were assigned to groups A(3 injections), B (4 injections)and C(6 injections) on a 1:1:1 basis to evaluate the dose frequency.
Phase II:The dose and dosing frequency of M701 drug for the Phase II clinical trial were determined based on a combination of the tolerance1 and efficacy of M701 in the Phase Ib trial. Then the participants were randomly divided into two groups: the test group(M701) and the control group(cisplatin or pleural effusions suctions). The pleural effusions response (ORR) and Puncture Free Survival (PuFS)will be evaluated.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malignant Pleural Effusions, NSCLC Stage IV
Keywords
Malignant Pleural Effusions, NSCLC
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Model Description
For Phase 2 study, the patients are enrolled into 2 arm parallelly.
Masking
None (Open Label)
Allocation
Randomized
Enrollment
96 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Experimental group
Arm Type
Experimental
Arm Description
Pleural drainage and M701 infusion
Arm Title
Control group
Arm Type
Sham Comparator
Arm Description
Pleural drainage only or plus chemotherapy as investigator's choice.
Intervention Type
Drug
Intervention Name(s)
M701 pleural infusion
Intervention Description
M701 pleural infusion on Days 1,4,7 and 10.
Intervention Type
Procedure
Intervention Name(s)
Pleural drainage
Intervention Description
Pleural effusion drainage via Ultra-sound guidance on Day 1.
Intervention Type
Drug
Intervention Name(s)
Cisplatin pleural infusion
Intervention Description
Cisplatin pleural infusion (30-50mg/m2) on Day 1.
Primary Outcome Measure Information:
Title
Dose Limiting Toxicities (DLTs)
Description
Dose limiting toxicities during the first 28 days after the first administrations of study drug in each cohort.
Time Frame
From the time of the first dose (Day 1) until the forth dosing (Day 28)
Title
Incidence of AEs
Description
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.
Time Frame
From the start of administration to the end of the study or 28 days after the administration is stopped
Title
Objective Response Rate(4 weeks/8 weeks) of pleural effusion
Description
the rate of patients with pleural effusion CR and PR at 4 weeks / 8 weeks, based on CT evaluation .
Time Frame
From the time of first dosing (Day 1) until disease progression(up to 56 days)
Secondary Outcome Measure Information:
Title
Area under the curve (AUC) of M701
Description
The endpoints for assessment of PK of M701 include serum concentrations of M701 at different timepoints after M701 administration.
Time Frame
From the time of first dosing (Day 1) until disease progression or toxicity intolerance(up to 16 days)
Title
Maximum observed concentration (Cmax) of M701
Description
The endpoints for assessment of PK of M701 include serum concentrations of M701 at different timepoints after M701 administration.
Time Frame
From the time of first dosing (Day 1) until disease progression or toxicity intolerance(up to 16 days)
Title
Minimum observed concentration (Cmin) of M701
Description
The endpoints for assessment of PK of M701 include serum concentrations of M701 at different timepoints after M701 administration.
Time Frame
From the time of first dosing (Day 1) until disease progression or toxicity intolerance(up to 16 days)
Title
Half-time (t1/2) of M701
Description
Half-time (t1/2) of M701
Time Frame
From the time of first dosing (Day 1) until disease progression or toxicity intolerance(up to 16 days)
Title
Anti-drug antibodies(ADAs) titer
Description
The immunogenicity of M701 will be assessed by summarizing the number of subjects who develop detectable anti-drug antibodies (ADAs).
Time Frame
From the time of first dosing (Day 1) until disease progression or toxicity intolerance(up to 16 days)
Title
Neutralizing antibody titer
Description
The immunogenicity of M701 will be collected by testing the antibody titer of the neutralizing antibody.
Time Frame
From the time of first dosing (Day 1) until disease progression or toxicity intolerance(up to 16 days)
Title
Concentrations of tumor biomarker in pleural effusions
Description
As tumor biomarkers, concentrations of CEA, CyFra21-1, SCC and NSE in malignant pleural effusions will be examined at Day 1 and Day10.
Time Frame
From the time of first dosing (Day 1) until disease progression or toxicity intolerance(up to 56 days)
Title
Expression level of EpCAM-positive cells in pleural effusions
Description
The number and expression levels of EpCAM-positive cells in pleural effusions will be measured by pathological methods (including cytospin, immunohistochemical techniques, etc.)
Time Frame
From the time of first dosing (Day 1) until disease progression (up to 56 days)
Title
Ratio of EpCAM-positive tumour cell/leucocyte
Description
Ratio of EpCAM positive tumour cell/leucocyte in pleural effusions will be measured by FACS method.
Time Frame
From the time of first dosing (Day 1) until disease progression (up to 56 days)
Title
Rate of with successful pleurodesis (4/8 weeks)
Description
the rate of patients with successful pleurodesis at 4 weeks / 8 weeks
Time Frame
From the time of first dosing (Day 1) until disease progression (up to 56 days)
Title
Puncture-free survival rate at 4/8 weeks
Description
the rate of patients without extra puncture at 4/8 weeks after the initial drainage.
Time Frame
From the time of first dosing (Day 1) until disease progression (up to 56 days)
Title
Pleural signs and symptoms
Description
Using the Lister Quadruple Scale to record pleural effusions at 4 weeks/ 8 weeks.
Time Frame
From the time of first dosing (Day 1) until disease progression (up to 56 days)
Other Pre-specified Outcome Measures:
Title
Objective Response Rate of Tumor
Description
ORR is defined as percentage of participants who achieved complete response (CR), partial response (PR), based on RESIST 1.1 .
Time Frame
From the time of first dosing (Day 1) until disease progression (up to 56 days)
Title
Disease Control Rate of tumor
Description
ORR is defined as percentage of participants who achieved complete response (CR), partial response (PR), and stable disease (SD), based on RESIST 1.1 .
Time Frame
From the time of first dosing (Day 1) until disease progression (up to 56 days)
Title
Duration of disease control(DDC)
Description
Duration of disease control(DDC) was calculated from the date of initial documentation of a response (PR or better) to the date of first documented evidence of progressive disease, based on RESIST 1.1 .
Time Frame
12 months (anticipated)
Title
Progression-free disease survival (PFS)
Description
PFS was defined as the time between the date of first dose of M701 and either disease progression or death, whichever occurs first.
Time Frame
12 months (anticipated)
Title
Half-year / One-year Survival Rates
Description
Survival Rates at 6 months and 12 months
Time Frame
12 months (anticipated)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Males or females, aged > 18 years.
Histologically- or cytologically-confirmed non-small cell lung cancer that has progressed after first line systemic therapy.
Malignant pleural effusion diagnosed histologically or cytologically, with moderate or above moderate pleural fluid (sitting pleural fluid depth ≥ 4 cm via ultrasound, expected pleural fluid volume ≥ 500 mL) . Require clinical intervention and not treated yet.
Patients who have an washout period of ≥ 4 weeks or 5 half-life of the drug (including radiotherapy, chemotherapy, immunotherapy, biologic, targeted, hormonal therapy, and 14 days for local radiotherapy) between the last systemic therapy and the first dose; however, no washout period is required if the subject has new pleural fluid or poor control of current pleural fluid after at least 2 cycle systemic therapy.
Patients who had recovered to grade 0-1 of any toxic reaction to prior antineoplastic therapy as determined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) V5.0, with the exception of alopecia, hyperpigmentation and ≤ grade 2 neuropathy, hormone replacement hypothyroidism or other adverse events confirmed to have turned chronic.
Patients with physical status ECOG score (PS) of 0-2.
Patients with life expectancy ≥ 12 weeks.
Bone marrow: absolute neutrophil count (ANC) ≥ 1.5 ×10^9/L, platelet count ≥ 100 ×10^9/L, hemoglobin ≥ 8.5 g/dL (without blood transfusion within14 days of the first dose of study drug); Liver: bilirubin (TBIL)≤ 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.
Patients must understand and voluntarily sign the written informed consent.
Exclusion Criteria:
Patients with asymptomatic pleural fluid and not requiring clinical intervention, or bilateral malignant pleural fluid, or proposed perfusion of the chest cavity presenting with pleural fluid separation.
Patients with central nervous system (CNS) metastases resulting in clinical symptoms or requiring therapeutic intervention; patients previously treated for brain metastases may be enrolled if they have been asymptomatic for ≥ 4 weeks prior to the first dose and have imaging indicating stable disease and do not require corticosteroid or anticonvulsant therapy.
Patients with a known history of severe allergy to M701 drug components or antibody-like macromolecular drugs.
Patients with contraindications to thoracentesis.
Patients who have undergone major surgical procedures within 4 weeks prior to the first dose.
Patients with extensive liver metastases (>70%).
Patients with uncontrollable active infection (NCI-CTCAE V5.0 ≥ grade 2).
Patients required long-term hormonal or immunosuppressive therapy, e.g. active autoimmune disease, maintenance therapy after organ transplantation, except that the following are allowed to enter screening: type I diabetes mellitus, hypothyroidism that can be controlled by replacement therapy only, skin diseases that do not require systemic therapy (e.g. vitiligo, psoriasis or alopecia).
Patients with severe respiratory disease which, in the judgment of the investigator, makes them unsuitable for entry; or combined interstitial pneumonia.
Patients with history of severe cardiovascular disease, including previous coronary artery bypass grafting or coronary stenting, myocardial infarction within 6 months, congestive heart failure (New York Classification of Cardiac Function Class III-IV) or unstable angina, or uncontrolled hypertension.
Patients with QTc interval > 480 ms,family or personal history of long or short QT syndrome, clinically significant history of ventricular arrhythmias or implantation of a defibrillation device for ventricular arrhythmias.
Patients with a history of (non-study tumour) malignancy (except squamous and basal cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or other, non-invasive lesions that the investigator and sponsor agree have been cured and have a minimal risk of recurrence within 3 years) within 3 years prior to the date of first study drug administration.
Patients who have active hepatitis B (HBV-DNA quantification ≥ 1 x 10^4 copies/mL or 2000 IU/mL), active hepatitis C (positive for hepatitis C antibodies and HCV-RNA above the lower limit of detection of the assay), active syphilis with positive HIV antibodies.
Pregnant or breastfeeding woman,Plan to conceive within six months;
Patients with a confirmed history of neurological or mental disorders, including epilepsy and dementia.
Those that are deemed ineligible for this clinical trial by investigator.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
ShaoYi Huang
Phone
86-027-82668440
Email
huangshaoyi@yzybio.com
First Name & Middle Initial & Last Name or Official Title & Degree
Yong Xu
Phone
18607183926
Email
xuyong@yzybio.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Yiping Zhang
Organizational Affiliation
Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital)
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Zhengbo Song
Organizational Affiliation
Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital)
Official's Role
Principal Investigator
Facility Information:
Facility Name
Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital)
City
Hangzhou
State/Province
Zhejiang
ZIP/Postal Code
310022
Country
China
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
A Phase Ib/II Clinical Trial of M701 in the Treatment of Malignant Pleural Effusions Caused by NSCLC
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