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Study of ADCT-502 in Patients With Advanced Solid Tumors Withhuman Epidermal Growth Factor Receptor-2 (HER2) Expression

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ClinicalTrials.gov Identifier: NCT03125200
Recruitment Status : Terminated (Safety)
First Posted : April 24, 2017
Results First Posted : August 28, 2019
Last Update Posted : August 28, 2019
Sponsor:
Information provided by (Responsible Party):
ADC Therapeutics S.A.

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.

Condition or disease Intervention/treatment Phase
Breast Cancer Non Small Cell Lung Cancer GastroEsophageal Cancer Bladder Cancer Drug: ADCT-502 Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 21 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : May 18, 2017
Actual Primary Completion Date : April 5, 2018
Actual Study Completion Date : April 5, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: ADCT-502

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.

Drug: ADCT-502
Intravenous Infusion




Primary Outcome Measures :
  1. Number of Participants Who Experienced Dose-Limiting Toxicities [ Time Frame: Day 1 to 3 Weeks (one cycle) ]
  2. Number of Participants Who Experienced a Dose-Limiting Toxicity With a CTCAE Grade of 3 or Above [ Time Frame: Day 1 to 3 Weeks (one cycle) ]
    The Common Terminology Criteria For Adverse Events (CTCAE) Version 4 will be used.

  3. Number of Participants Who Experience At Least One Treatment Emergent Adverse Event (TEAE) [ Time Frame: Day 1 to end of trial, a maximum of 168 days (+ 30 days) ]
    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.

  4. 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) ]
  5. Number of Participants With Clinically Significant Clinical Laboratory Tests [ Time Frame: Day 1 to end of trial, a maximum of 168 days (+ 30 days) ]
    Clinical significance was determined by the investigator.

  6. Number of Participants With Clinically Significant Physical Examination Results [ Time Frame: Day 1 to end of trial, a maximum of 168 days (+ 30 days) ]
    Clinical significance was determined by the investigator.

  7. Number of Participants Who Experience a Clinically Significant Change in Eastern Cooperative Oncology Group (ECOG) Performance Status [ Time Frame: Day 1 to end of trial, a maximum of 168 days (+ 30 days) ]
    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.

  8. Number of Participants With Clinically Significant Vital Signs [ Time Frame: Day 1 to end of trial, a maximum of 168 days (+ 30 days) ]
    Vital sign measurements include arterial blood pressure, heart rate, respiratory rate, and body temperature. Clinical significance was determined by the investigator.

  9. Number of Participants Who Experience Clinically Significant Electrocardiogram (ECG) Results [ Time Frame: Day 1 to end of trial, a maximum of 168 days (+ 30 days) ]
    Standard 12-lead ECG's will be used. Clinical significance was determined by the investigator.


Secondary Outcome Measures :
  1. Overall Response Rate (ORR) [ Time Frame: Screening, day 1 of cycle 3 and cycle 5, then every 4 cycles, approximately every 12 weeks ]
    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.

  2. Disease Control Rate (DCR) [ Time Frame: Screening, day 1 of cycle 3 and cycle 5, then every 4 cycles, approximately every 12 weeks ]
    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.

  3. Duration of Response (DOR) [ Time Frame: Screening, day 1 of cycle 3 and cycle 5, then every 4 cycles, approximately every 12 weeks ]
    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.

  4. Progression-Free Survival (PFS) [ Time Frame: Screening, day 1 of cycle 3 and cycle 5, then every 4 cycles, approximately every 12 weeks ]
    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.

  5. Overall Survival (OS) [ Time Frame: Screening, day 1 of cycle 3 and cycle 5, then every 4 cycles, approximately every 12 weeks ]
    Median OS was defined as the time from the beginning of study drug treatment until death due to any cause.

  6. 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 ]
  7. 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 ]
  8. 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 ]
  9. 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 ]
  10. 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 ]
  11. 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 ]
  12. 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 ]
  13. 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 ]
  14. 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 ]
  15. 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 ]
  16. 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 ]
  17. 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 ]
  18. 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 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03125200


Locations
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United States, California
Stanford Cancer Center
Palo Alto, California, United States, 94304
United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
Memorial Sloan Kettering Memorial Hospital
New York, New York, United States, 10065
United States, Texas
South Texas Accelerated Research Therapeutics, LLC
San Antonio, Texas, United States, 78229
Belgium
Medical Oncology Clinic - Institut Jules Bordet
Brussels, Belgium, 1000
Sponsors and Collaborators
ADC Therapeutics S.A.
  Study Documents (Full-Text)

Documents provided by ADC Therapeutics S.A.:
Study Protocol  [PDF] August 17, 2017
Statistical Analysis Plan  [PDF] July 5, 2018


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Responsible Party: ADC Therapeutics S.A.
ClinicalTrials.gov Identifier: NCT03125200     History of Changes
Other Study ID Numbers: ADCT-502-101
First Posted: April 24, 2017    Key Record Dates
Results First Posted: August 28, 2019
Last Update Posted: August 28, 2019
Last Verified: July 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma, Non-Small-Cell Lung
Urinary Bladder Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Urologic Neoplasms
Urogenital Neoplasms
Urinary Bladder Diseases
Urologic Diseases