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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Breast Cancer, Non Small Cell Lung Cancer, GastroEsophageal Cancer, Bladder Cancer

Intervention / Treatment
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* Drug: ADCT-502


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ADCT-502<br>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<br>* Intravenous Infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced Dose-Limiting Toxicities |  | Day 1 to 3 Weeks (one cycle) | 
| 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. | Day 1 to 3 Weeks (one cycle) | 
| 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. | Day 1 to end of trial, a maximum of 168 days (+ 30 days) | 
| Number of Participants Who Experience At Least One Treatment Emergent Serious Adverse Event (SAE) |  | Day 1 to end of trial, a maximum of 168 days (+ 30 days) | 
| Number of Participants With Clinically Significant Clinical Laboratory Tests | Clinical significance was determined by the investigator. | Day 1 to end of trial, a maximum of 168 days (+ 30 days) | 
| Number of Participants With Clinically Significant Physical Examination Results | Clinical significance was determined by the investigator. | Day 1 to end of trial, a maximum of 168 days (+ 30 days) | 
| 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. | Day 1 to end of trial, a maximum of 168 days (+ 30 days) | 
| 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. | Day 1 to end of trial, a maximum of 168 days (+ 30 days) | 
| 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. | Day 1 to end of trial, a maximum of 168 days (+ 30 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Screening, day 1 of cycle 3 and cycle 5, then every 4 cycles, approximately every 12 weeks | 
| 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. | Screening, day 1 of cycle 3 and cycle 5, then every 4 cycles, approximately every 12 weeks | 
| 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. | Screening, day 1 of cycle 3 and cycle 5, then every 4 cycles, approximately every 12 weeks | 
| 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. | Screening, day 1 of cycle 3 and cycle 5, then every 4 cycles, approximately every 12 weeks | 
| Overall Survival (OS) | Median OS was defined as the time from the beginning of study drug treatment until death due to any cause. | Screening, day 1 of cycle 3 and cycle 5, then every 4 cycles, approximately every 12 weeks | 
| Area Under the Plasma Concentration Versus Time Curve (AUC) of ADCT-502 (Total Antibody) |  | 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 | 
| Area Under the Plasma Concentration Time Curve (AUC) of Drug To-antibody Ratio [DAR] ≥0 |  | 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 | 
| Area Under the Plasma Concentration Versus Time Curve (AUC) of PBD-conjugated Antibody (DAR ≥1) |  | 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 | 
| Area Under the Plasma Concentration Versus Time Curve (AUC) of Free Warhead SG3199 |  | 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 | 
| Maximum Observed Plasma Concentration (Cmax) for ADCT-502 (Total Antibody) |  | 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 | 
| Maximum Observed Plasma Concentration (Cmax) for Drug To-antibody Ratio [DAR] ≥0 |  | 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 | 
| Maximum Observed Plasma Concentration (Cmax) for PBD-conjugated Antibody (DAR ≥1) |  | 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 | 
| Maximum Observed Plasma Concentration (Cmax) for Free Warhead SG3199 |  | 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 | 
| Time to Reach the Maximum Plasma Concentration (Tmax) for ADCT-502 (Total Antibody) |  | 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 | 
| Time to Reach the Maximum Plasma Concentration (Tmax) for Drug To-antibody Ratio [DAR] ≥0) |  | 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 | 
| Time to Reach the Maximum Plasma Concentration (Tmax) for PBD-conjugated Antibody (DAR ≥1) |  | 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 | 
| Time to Reach the Maximum Plasma Concentration (Tmax) for Free Warhead SG3199 |  | 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 | 
| Anti-drug Antibody (ADA) Titers to ADCT-502 |  | 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 |