Back to resultsStudy of ADCT-502 in Patients With Advanced Solid Tumors Withhuman Epidermal Growth Factor Receptor-2 (HER2) Expression
Primary Purpose
Breast Cancer, Non Small Cell Lung Cancer, GastroEsophageal Cancer
Status
Terminated
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
ADCT-502
Sponsored by
About this trial
This is an interventional treatment trial for Breast Cancer
Eligibility Criteria
Main Inclusion Criteria:
- Male or female age 18 years or older
- Refractory to or intolerant of existing therapy(ies) known to provide clinical benefit for their condition.
- Eastern Cooperative Oncology Group (ECOG) performance status: Part 1: 0-2, Part 2: 0-1
- Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block or unstained slides to demonstrate HER2 expression.
- Pathologic diagnosis of solid tumor malignancy that is locally advanced or metastatic at time of Screening with documented HER2 expression.
- Part 2/Dose Expansion Only: Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
- Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥1.5× 109/L).
- Platelet count ≥100,000 //mm3 (≥100 × 109/L).
- Hemoglobin ≥ 9 g/L (≥5.6 mmol/L).
- Aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN); or ≤ 5.0 × ULN if liver metastases are present.
- Total bilirubin ≤ 1.5× ULN (or ≤ 3× ULN, with direct bilirubin ≤1.5 × ULN, in participants with known Gilbert syndrome).
- Creatinine ≤ 1.5× ULN; or, if serum creatinine > 1.5 × ULN, a measured creatinine clearance must be >60mL/min/1.73m2 as calculated by the Cockcroft and Gault equation for participants to be eligible.
- Women of childbearing potential must agree to use a highly effective method of contraception from the time of giving informed consent until at least 16 weeks after the last dose of ADCT-502. Men with female partners who are of childbearing potential must agree that they or their partners will use a highly effective method of contraception from the time of giving informed consent until at least 16 weeks after the participant receives his last dose of ADCT-502.
Main Exclusion Criteria:
- Known history of ≥ Grade 3 hypersensitivity to a therapeutic antibody.
- Known history of positive serum human anti-drug antibody (ADA) to trastuzumab.
- Major surgical procedure or significant traumatic injury, radiotherapy, chemotherapy, targeted therapy, hormone therapy, or other anticancer therapy.
- Failure to recover to Grade 0 or Grade 1 from acute non-hematologic toxicity due to previous therapy, prior to screening (with the exception of alopecia).
- Central Nervous System (CNS) disease only.
- Symptomatic CNS metastases or evidence of leptomeningeal disease.
- Active cardiovascular disease or significant history thereof.
- Other active disease including but not limited to ulceration of the upper gastrointestinal tract, autoimmune disease, HIV infection, active Hepatitis B virus (HBV) and hepatitis C virus (HCV) infection.
- Breastfeeding or pregnant.
- Other concurrent severe and/or uncontrolled medical conditions.
Sites / Locations
- Stanford Cancer Center
- Roswell Park Cancer Institute
- Memorial Sloan Kettering Memorial Hospital
- South Texas Accelerated Research Therapeutics, LLC
- Medical Oncology Clinic - Institut Jules Bordet
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
ADCT-502
Arm Description
Part 1 (dose escalation): Participants received an infusion of ADCT-502, at escalating doses. Part 1 continued until the maximum tolerated dose or the recommended dose(s) and schedule(s) for expansion were determined. Part 2 (expansion): Participants were due to be assigned to the recommended dose level of ADCT-502 as identified in Part 1 by the Dose Escalation Steering Committee.
Outcomes
Primary Outcome Measures
Number of Participants Who Experienced Dose-Limiting Toxicities
Number of Participants Who Experienced a Dose-Limiting Toxicity With a CTCAE Grade of 3 or Above
The Common Terminology Criteria For Adverse Events (CTCAE) Version 4 will be used.
Number of Participants Who Experience At Least One Treatment Emergent Adverse Event (TEAE)
An adverse event is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.
Number of Participants Who Experience At Least One Treatment Emergent Serious Adverse Event (SAE)
Number of Participants With Clinically Significant Clinical Laboratory Tests
Clinical significance was determined by the investigator.
Number of Participants With Clinically Significant Physical Examination Results
Clinical significance was determined by the investigator.
Number of Participants Who Experience a Clinically Significant Change in Eastern Cooperative Oncology Group (ECOG) Performance Status
Performance status was assessed using the ECOG performance status grades. These range between Grade 0 (fully active) and Grade 5 (dead). Clinical significance was determined by the investigator.
Number of Participants With Clinically Significant Vital Signs
Vital sign measurements include arterial blood pressure, heart rate, respiratory rate, and body temperature. Clinical significance was determined by the investigator.
Number of Participants Who Experience Clinically Significant Electrocardiogram (ECG) Results
Standard 12-lead ECG's will be used. Clinical significance was determined by the investigator.
Secondary Outcome Measures
Overall Response Rate (ORR)
ORR was defined as the number of participants with a best overall response of Complete Response (CR) or Partial Response (PR) at the time each participant discontinues ADCT-502. Analysis will be determined by the investigator per Response Evaluation In Solid Criteria (RECIST) version 1.1 criteria: partial response is when there is a decrease in sum of target disease ≥ 30%, and complete response is when all lesions have disappeared or all lesions have disappeared and all nodal disease is < 10 mm each.
Disease Control Rate (DCR)
DCR was defined as the number of participants with a best overall response of Complete Response (CR) or Partial Response (PR), or Stable Disease (SD). Analysis will be determined by the investigator per Response Evaluation In Solid Criteria (RECIST) version 1.1 criteria: stable disease is when the change is > -30% and ≤ 20%, partial response is when there is a decrease in sum of target disease ≥ 30%, and complete response is when all lesions have disappeared or all lesions have disappeared and all nodal disease is < 10 mm each.
Duration of Response (DOR)
DOR was defined among responders (CR or PR) as the time from the earliest date of first response until the first date of either disease progression or death due to any cause.
Progression-Free Survival (PFS)
PFS was defined among the efficacy population as the time from first dose of study drug until the first date of either disease progression or death due to any cause.
Overall Survival (OS)
Median OS was defined as the time from the beginning of study drug treatment until death due to any cause.
Area Under the Plasma Concentration Versus Time Curve (AUC) of ADCT-502 (Total Antibody)
Area Under the Plasma Concentration Time Curve (AUC) of Drug To-antibody Ratio [DAR] ≥0
Area Under the Plasma Concentration Versus Time Curve (AUC) of PBD-conjugated Antibody (DAR ≥1)
Area Under the Plasma Concentration Versus Time Curve (AUC) of Free Warhead SG3199
Maximum Observed Plasma Concentration (Cmax) for ADCT-502 (Total Antibody)
Maximum Observed Plasma Concentration (Cmax) for Drug To-antibody Ratio [DAR] ≥0
Maximum Observed Plasma Concentration (Cmax) for PBD-conjugated Antibody (DAR ≥1)
Maximum Observed Plasma Concentration (Cmax) for Free Warhead SG3199
Time to Reach the Maximum Plasma Concentration (Tmax) for ADCT-502 (Total Antibody)
Time to Reach the Maximum Plasma Concentration (Tmax) for Drug To-antibody Ratio [DAR] ≥0)
Time to Reach the Maximum Plasma Concentration (Tmax) for PBD-conjugated Antibody (DAR ≥1)
Time to Reach the Maximum Plasma Concentration (Tmax) for Free Warhead SG3199
Anti-drug Antibody (ADA) Titers to ADCT-502
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03125200
Brief Title
Study of ADCT-502 in Patients With Advanced Solid Tumors Withhuman Epidermal Growth Factor Receptor-2 (HER2) Expression
Official Title
A Phase 1, Open-Label, Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antitumor Activity of ADCT-502 in Patients With Advanced Solid Tumors With HER2 Expression
Study Type
Interventional
2. Study Status
Record Verification Date
January 2021
Overall Recruitment Status
Terminated
Why Stopped
Safety
Study Start Date
May 18, 2017 (Actual)
Primary Completion Date
April 5, 2018 (Actual)
Study Completion Date
April 5, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
ADC Therapeutics S.A.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
This study evaluated ADCT-502 in participants with Advanced Solid Tumors with HER2 Expression. Participants participated in a dose-escalation phase (Part 1) and were due to participate in the dose expansion phase (Part 2). In Part 2, patients were due to receive the dose level identified in Part 1, but the study was terminated prior to the beginning of Part 2.
Detailed Description
Study ADCT-502-101 was the first clinical study with ADCT-502 in participants with Advanced Solid Tumors with HER2 Expression.
ADCT-502 is an antibody drug conjugate (ADC) composed of an engineered version of the humanized monoclonal antibody trastuzumab, directed against the human HER2 receptor, conjugated to a pyrrolobenzodiazepine (PBD) dimer cytotoxin. ADCT-502 specifically binds to HER2, and once internalized, releases the PBD dimer to allow cross-linking of DNA and eventually trigger cell death.
The study had 2 parts. In Part 1 (dose escalation) participants received an infusion of ADCT-502, at escalating doses. Part 1 continued until the maximum tolerated dose or the recommended dose(s) and schedule(s) for expansion were determined. In Part 2 (expansion), participants were due to be assigned to the recommended dose level of ADCT-502 identified in Part 1 by the Dose Escalation Steering Committee, but the study was terminated prior to the beginning of Part 2.
For each participant, the study included a screening period (up to 28 days), a treatment period, and a follow-up period to assess disease progression and survival for up to 12 weeks after the last dose of study drug. The total study duration was dependent on overall participant tolerability to the study drug and response to treatment as participants were able to continue treatment until disease progression or unacceptable toxicity.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Breast Cancer, Non Small Cell Lung Cancer, GastroEsophageal Cancer, Bladder Cancer
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
21 (Actual)
8. Arms, Groups, and Interventions
Arm Title
ADCT-502
Arm Type
Experimental
Arm Description
Part 1 (dose escalation): Participants received an infusion of ADCT-502, at escalating doses. Part 1 continued until the maximum tolerated dose or the recommended dose(s) and schedule(s) for expansion were determined.
Part 2 (expansion): Participants were due to be assigned to the recommended dose level of ADCT-502 as identified in Part 1 by the Dose Escalation Steering Committee.
Intervention Type
Drug
Intervention Name(s)
ADCT-502
Intervention Description
Intravenous Infusion
Primary Outcome Measure Information:
Title
Number of Participants Who Experienced Dose-Limiting Toxicities
Time Frame
Day 1 to 3 Weeks (one cycle)
Title
Number of Participants Who Experienced a Dose-Limiting Toxicity With a CTCAE Grade of 3 or Above
Description
The Common Terminology Criteria For Adverse Events (CTCAE) Version 4 will be used.
Time Frame
Day 1 to 3 Weeks (one cycle)
Title
Number of Participants Who Experience At Least One Treatment Emergent Adverse Event (TEAE)
Description
An adverse event is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.
Time Frame
Day 1 to end of trial, a maximum of 168 days (+ 30 days)
Title
Number of Participants Who Experience At Least One Treatment Emergent Serious Adverse Event (SAE)
Time Frame
Day 1 to end of trial, a maximum of 168 days (+ 30 days)
Title
Number of Participants With Clinically Significant Clinical Laboratory Tests
Description
Clinical significance was determined by the investigator.
Time Frame
Day 1 to end of trial, a maximum of 168 days (+ 30 days)
Title
Number of Participants With Clinically Significant Physical Examination Results
Description
Clinical significance was determined by the investigator.
Time Frame
Day 1 to end of trial, a maximum of 168 days (+ 30 days)
Title
Number of Participants Who Experience a Clinically Significant Change in Eastern Cooperative Oncology Group (ECOG) Performance Status
Description
Performance status was assessed using the ECOG performance status grades. These range between Grade 0 (fully active) and Grade 5 (dead). Clinical significance was determined by the investigator.
Time Frame
Day 1 to end of trial, a maximum of 168 days (+ 30 days)
Title
Number of Participants With Clinically Significant Vital Signs
Description
Vital sign measurements include arterial blood pressure, heart rate, respiratory rate, and body temperature. Clinical significance was determined by the investigator.
Time Frame
Day 1 to end of trial, a maximum of 168 days (+ 30 days)
Title
Number of Participants Who Experience Clinically Significant Electrocardiogram (ECG) Results
Description
Standard 12-lead ECG's will be used. Clinical significance was determined by the investigator.
Time Frame
Day 1 to end of trial, a maximum of 168 days (+ 30 days)
Secondary Outcome Measure Information:
Title
Overall Response Rate (ORR)
Description
ORR was defined as the number of participants with a best overall response of Complete Response (CR) or Partial Response (PR) at the time each participant discontinues ADCT-502. Analysis will be determined by the investigator per Response Evaluation In Solid Criteria (RECIST) version 1.1 criteria: partial response is when there is a decrease in sum of target disease ≥ 30%, and complete response is when all lesions have disappeared or all lesions have disappeared and all nodal disease is < 10 mm each.
Time Frame
Screening, day 1 of cycle 3 and cycle 5, then every 4 cycles, approximately every 12 weeks
Title
Disease Control Rate (DCR)
Description
DCR was defined as the number of participants with a best overall response of Complete Response (CR) or Partial Response (PR), or Stable Disease (SD). Analysis will be determined by the investigator per Response Evaluation In Solid Criteria (RECIST) version 1.1 criteria: stable disease is when the change is > -30% and ≤ 20%, partial response is when there is a decrease in sum of target disease ≥ 30%, and complete response is when all lesions have disappeared or all lesions have disappeared and all nodal disease is < 10 mm each.
Time Frame
Screening, day 1 of cycle 3 and cycle 5, then every 4 cycles, approximately every 12 weeks
Title
Duration of Response (DOR)
Description
DOR was defined among responders (CR or PR) as the time from the earliest date of first response until the first date of either disease progression or death due to any cause.
Time Frame
Screening, day 1 of cycle 3 and cycle 5, then every 4 cycles, approximately every 12 weeks
Title
Progression-Free Survival (PFS)
Description
PFS was defined among the efficacy population as the time from first dose of study drug until the first date of either disease progression or death due to any cause.
Time Frame
Screening, day 1 of cycle 3 and cycle 5, then every 4 cycles, approximately every 12 weeks
Title
Overall Survival (OS)
Description
Median OS was defined as the time from the beginning of study drug treatment until death due to any cause.
Time Frame
Screening, day 1 of cycle 3 and cycle 5, then every 4 cycles, approximately every 12 weeks
Title
Area Under the Plasma Concentration Versus Time Curve (AUC) of ADCT-502 (Total Antibody)
Time Frame
Before infusion, End of Infusion, and 1, 3, 6, 24, 48, 96, 168 and 336 hours post infusion for Cycle 1 & 2. Before infusion and end of infusion of Cycle 3 to disease progression, and 30 days and 12 weeks after last dose
Title
Area Under the Plasma Concentration Time Curve (AUC) of Drug To-antibody Ratio [DAR] ≥0
Time Frame
Before infusion, End of Infusion, and 1, 3, 6, 24, 48, 96, 168 and 336 hours post infusion for Cycle 1 & 2. Before infusion and end of infusion of Cycle 3 to disease progression, and 30 days and 12 weeks after last dose
Title
Area Under the Plasma Concentration Versus Time Curve (AUC) of PBD-conjugated Antibody (DAR ≥1)
Time Frame
Before infusion, End of Infusion, and 1, 3, 6, 24, 48, 96, 168 and 336 hours post infusion for Cycle 1 & 2. Before infusion and end of infusion of Cycle 3 to disease progression, and 30 days and 12 weeks after last dose
Title
Area Under the Plasma Concentration Versus Time Curve (AUC) of Free Warhead SG3199
Time Frame
Before infusion, End of Infusion, and 1, 3, 6, 24, 48, 96, 168 and 336 hours post infusion for Cycle 1 & 2. Before infusion and end of infusion of Cycle 3 to disease progression, and 30 days and 12 weeks after last dose
Title
Maximum Observed Plasma Concentration (Cmax) for ADCT-502 (Total Antibody)
Time Frame
Before infusion, End of Infusion, and 1, 3, 6, 24, 48, 96, 168 and 336 hours post infusion for Cycle 1 & 2. Before infusion and end of infusion of Cycle 3 to disease progression, and 30 days and 12 weeks after last dose
Title
Maximum Observed Plasma Concentration (Cmax) for Drug To-antibody Ratio [DAR] ≥0
Time Frame
Before infusion, End of Infusion, and 1, 3, 6, 24, 48, 96, 168 and 336 hours post infusion for Cycle 1 & 2. Before infusion and end of infusion of Cycle 3 to disease progression, and 30 days and 12 weeks after last dose
Title
Maximum Observed Plasma Concentration (Cmax) for PBD-conjugated Antibody (DAR ≥1)
Time Frame
Before infusion, End of Infusion, and 1, 3, 6, 24, 48, 96, 168 and 336 hours post infusion for Cycle 1 & 2. Before infusion and end of infusion of Cycle 3 to disease progression, and 30 days and 12 weeks after last dose
Title
Maximum Observed Plasma Concentration (Cmax) for Free Warhead SG3199
Time Frame
Before infusion, End of Infusion, and 1, 3, 6, 24, 48, 96, 168 and 336 hours post infusion for Cycle 1 & 2. Before infusion and end of infusion of Cycle 3 to disease progression, and 30 days and 12 weeks after last dose
Title
Time to Reach the Maximum Plasma Concentration (Tmax) for ADCT-502 (Total Antibody)
Time Frame
Before infusion, End of Infusion, and 1, 3, 6, 24, 48, 96, 168 and 336 hours post infusion for Cycle 1 & 2. Before infusion and end of infusion of Cycle 3 to disease progression, and 30 days and 12 weeks after last dose
Title
Time to Reach the Maximum Plasma Concentration (Tmax) for Drug To-antibody Ratio [DAR] ≥0)
Time Frame
Before infusion, End of Infusion, and 1, 3, 6, 24, 48, 96, 168 and 336 hours post infusion for Cycle 1 & 2. Before infusion and end of infusion of Cycle 3 to disease progression, and 30 days and 12 weeks after last dose
Title
Time to Reach the Maximum Plasma Concentration (Tmax) for PBD-conjugated Antibody (DAR ≥1)
Time Frame
Before infusion, End of Infusion, and 1, 3, 6, 24, 48, 96, 168 and 336 hours post infusion for Cycle 1 & 2. Before infusion and end of infusion of Cycle 3 to disease progression, and 30 days and 12 weeks after last dose
Title
Time to Reach the Maximum Plasma Concentration (Tmax) for Free Warhead SG3199
Time Frame
Before infusion, End of Infusion, and 1, 3, 6, 24, 48, 96, 168 and 336 hours post infusion for Cycle 1 & 2. Before infusion and end of infusion of Cycle 3 to disease progression, and 30 days and 12 weeks after last dose
Title
Anti-drug Antibody (ADA) Titers to ADCT-502
Time Frame
Blood sample collection before start of infusion in Cycles 1 and 2, and on Day 1 starting with Cycle 3 until disease progression, 30 days and 12 weeks after last dose
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Main Inclusion Criteria:
Male or female age 18 years or older
Refractory to or intolerant of existing therapy(ies) known to provide clinical benefit for their condition.
Eastern Cooperative Oncology Group (ECOG) performance status: Part 1: 0-2, Part 2: 0-1
Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block or unstained slides to demonstrate HER2 expression.
Pathologic diagnosis of solid tumor malignancy that is locally advanced or metastatic at time of Screening with documented HER2 expression.
Part 2/Dose Expansion Only: Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥1.5× 109/L).
Platelet count ≥100,000 //mm3 (≥100 × 109/L).
Hemoglobin ≥ 9 g/L (≥5.6 mmol/L).
Aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN); or ≤ 5.0 × ULN if liver metastases are present.
Total bilirubin ≤ 1.5× ULN (or ≤ 3× ULN, with direct bilirubin ≤1.5 × ULN, in participants with known Gilbert syndrome).
Creatinine ≤ 1.5× ULN; or, if serum creatinine > 1.5 × ULN, a measured creatinine clearance must be >60mL/min/1.73m2 as calculated by the Cockcroft and Gault equation for participants to be eligible.
Women of childbearing potential must agree to use a highly effective method of contraception from the time of giving informed consent until at least 16 weeks after the last dose of ADCT-502. Men with female partners who are of childbearing potential must agree that they or their partners will use a highly effective method of contraception from the time of giving informed consent until at least 16 weeks after the participant receives his last dose of ADCT-502.
Main Exclusion Criteria:
Known history of ≥ Grade 3 hypersensitivity to a therapeutic antibody.
Known history of positive serum human anti-drug antibody (ADA) to trastuzumab.
Major surgical procedure or significant traumatic injury, radiotherapy, chemotherapy, targeted therapy, hormone therapy, or other anticancer therapy.
Failure to recover to Grade 0 or Grade 1 from acute non-hematologic toxicity due to previous therapy, prior to screening (with the exception of alopecia).
Central Nervous System (CNS) disease only.
Symptomatic CNS metastases or evidence of leptomeningeal disease.
Active cardiovascular disease or significant history thereof.
Other active disease including but not limited to ulceration of the upper gastrointestinal tract, autoimmune disease, HIV infection, active Hepatitis B virus (HBV) and hepatitis C virus (HCV) infection.
Breastfeeding or pregnant.
Other concurrent severe and/or uncontrolled medical conditions.
Facility Information:
Facility Name
Stanford Cancer Center
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304
Country
United States
Facility Name
Roswell Park Cancer Institute
City
Buffalo
State/Province
New York
ZIP/Postal Code
14263
Country
United States
Facility Name
Memorial Sloan Kettering Memorial Hospital
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
South Texas Accelerated Research Therapeutics, LLC
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States
Facility Name
Medical Oncology Clinic - Institut Jules Bordet
City
Brussels
ZIP/Postal Code
1000
Country
Belgium
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Study of ADCT-502 in Patients With Advanced Solid Tumors Withhuman Epidermal Growth Factor Receptor-2 (HER2) Expression
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