C5731001 - An Open-label, Randomized, Controlled Phase 3 Study of Disitamab Vedotin in Combination with Pembrolizumab Versus Chemotherapy in Subjects with Previously Untreated Locally Advanced or Metastatic Urothelial Carcinoma that Expresses HER2 (IHC 1+ and Greater)
- Trial ID
- 2022-501105-12-00
- Protocol
- SGNDV-001/KN-D74
- Sponsor
- Seagen Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the **efficacy** of disitamab vedotin in combination with pembrolizumab to chemotherapy as a first-line treatment in participants with advanced **urothelial carcinoma** that expresses HER2. This comparison is clinically relevant as it may offer insights into more effective treatment options for patients with this specific type of cancer, potentially improving outcomes and providing a new standard of care.
Secondary objectives include:
- Comparing the objective response rate (ORR) between treatment with disitamab vedotin in combination with pembrolizumab versus chemotherapy.
- Comparing the duration of response (DOR) between the two treatment regimens.
- Comparing the disease control rate (DCR) between the treatment groups.
- Comparing progression-free survival (PFS) as assessed by the investigator between the treatment groups.
- Evaluating the safety profile of each treatment regimen.
- Comparing the impact of treatment on quality of life (QoL) and symptoms, including pain, from the participant's perspective.
Participants
The clinical trial involves a total of **302 participants** diagnosed with **urothelial carcinoma**. The study population includes both male and female subjects aged **18 years and older**, with no upper age limit specified. Participants are required to have a confirmed diagnosis of locally advanced or metastatic urothelial carcinoma, with histopathological confirmation of the disease. The trial population was selected based on specific inclusion criteria, including adequate baseline laboratory values and the ability to comply with trial procedures. Participants must have measurable disease according to RECIST v1.1 and must not have received prior systemic therapy for locally advanced or metastatic urothelial carcinoma, except under certain conditions. The study considers lifestyle factors such as the ability to provide tumor tissue for biomarker analysis and the requirement for HER2 expression of 1+ or greater. Both male and female subjects of childbearing potential must adhere to strict contraceptive measures throughout the study duration. The trial includes a vulnerable population, ensuring that all participants provide documented informed consent and are willing to comply with the follow-up schedule.
Plans and Procedures
The clinical trial is designed as an open-label, randomized, controlled Phase 3 study to evaluate the efficacy of **disitamab vedotin** in combination with **pembrolizumab** compared to chemotherapy in subjects with previously untreated locally advanced or metastatic **urothelial carcinoma** expressing HER2. The trial will involve a comparison between the investigational combination therapy and standard chemotherapy regimens, including **cisplatin**, **carboplatin**, and **gemcitabine**. The study is expected to commence recruitment on July 1, 2024, and is estimated to conclude by January 31, 2031.
Participants will be randomly assigned to receive either the investigational combination therapy or the control chemotherapy. The trial will be conducted over an estimated duration of 108 weeks for the investigational arm, with a maximum treatment period of 18 weeks for the chemotherapy arm. The study will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess overall outcomes.
The inclusion visit will involve comprehensive screening procedures to ensure participants meet the eligibility criteria, including age, laboratory values, and disease characteristics. Follow-up visits will be scheduled at regular intervals to evaluate the primary endpoints of progression-free survival and overall survival, as well as secondary endpoints such as objective response rate and duration of response. The end-of-study visit will provide a final assessment of the participant's health status and treatment efficacy.
Participant involvement is expected to last for the duration of the treatment period, with additional follow-up as required by the study protocol. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with study procedures. The trial aims to provide valuable insights into the potential benefits of the investigational therapy in this patient population.
Treatment
The clinical trial involves the administration of several treatments, including both experimental and comparator medications. **Disitamab Vedotin** is an experimental medication used in this study. It is provided as a **powder for solution for infusion** and is administered via **intravenous infusion**. The dosing regimen for Disitamab Vedotin is set at a maximum daily dose of 1.5 mg/kg, with a total maximum dose of 150 mg. The treatment period for Disitamab Vedotin is extensive, allowing for administration over an indefinite period, as indicated by the maximum treatment period code.
**Pembrolizumab**, marketed as **KEYTRUDA 25 mg/mL concentrate for solution for infusion**, is another experimental treatment in this trial. It is administered as a **solution for infusion** through **intravenous infusion**. The maximum daily dose is 400 mg, with a total maximum dose of 7200 mg. The treatment period for Pembrolizumab extends up to 108 weeks. Pembrolizumab is a **PD-1 inhibitor** and is used in combination with Disitamab Vedotin to potentially achieve synergistic effects in the treatment of locally advanced or metastatic urothelial carcinoma.
The comparator treatments in this study include **Cisplatin**, **Carboplatin**, and **Gemcitabine**. **Cisplatin** is provided as a **concentrate for solution for infusion** and is administered via **IV infusion**. The dosing schedule allows for a maximum daily dose of 70 mg/m², with a total maximum dose of 420 mg/m² over a treatment period of 18 weeks. Cisplatin is classified as a **cytostatic drug**.
**Carboplatin** is also a **concentrate for solution for infusion** administered through **IV infusion**. The maximum daily dose is 400 mg/m², with a total maximum dose of 400 mg/m² over 18 weeks. Carboplatin is indicated for various malignant tumors and is part of the standard care for certain patients with metastatic urothelial carcinoma.
**Gemcitabine** is provided as a **powder for solution for infusion** and administered via **IV infusion**. The dosing regimen includes a maximum daily dose of 1000 mg/m², with a total maximum dose of 36000 mg/m² over 18 weeks. Gemcitabine is classified as a **nucleoside analog**.
Participant compliance with the dosing schedules and administration routes is monitored throughout the trial to ensure adherence to the protocol. The trial aims to compare the efficacy of the experimental combination of Disitamab Vedotin and Pembrolizumab against the standard chemotherapy regimens in participants with HER2-expressing advanced urothelial carcinoma.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include **Progression-Free Survival (PFS)** as per the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, evaluated by a blinded independent central review (BICR), and **Overall Survival (OS)**. Secondary endpoints encompass a range of measures, including **Objective Response Rate (ORR)** and **Duration of Response (DOR)**, both assessed by RECIST v1.1 through BICR and investigator assessment. Additionally, **Disease Control Rate (DCR)**, PFS by investigator, and various safety and quality of life metrics will be evaluated.
Safety and quality of life assessments will include the type, incidence, relatedness, severity, and seriousness of adverse events (AEs), laboratory abnormalities, treatment discontinuation rates due to AEs, electrocardiogram abnormalities, and effects on left ventricular ejection fraction. Quality of life will be measured by changes from baseline to Week 16 in the European Organisation for Research and Treatment of Cancer core Quality of Life questionnaire (EORTC QLQ C30) Global Health Status/Quality of Life Score, and time to deterioration in this score, as well as time to pain progression.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age 18 years and older at the time of consent or considered an adult by local regulations
- Subjects must have LA/mUC with histopathological confirmation (Stage IIIB-IV per American Joint Committee on Cancer, Cancer Staging Atlas 8th ed.), including UC originating from the renal pelvis, ureters, bladder, or urethra. Mixed-cell type tumors are eligible as long as urothelial (transitional cell histology) carcinoma is the predominant cell type.
- Subjects must have measurable disease by investigator assessment according to RECIST v1.1. Note: Subjects with prior definitive radiation therapy must have measurable disease per RECIST v1.1 that is outside the radiation field or has demonstrated unequivocal progression since completion of radiation therapy.
- Subjects must not have received prior systemic therapy for locally advanced or metastatic UC with the following exceptions: a. Neoadjuvant or adjuvant therapy, including PD-(L)1 inhibitors, is acceptable, if disease recurrence/progression occurred more than 12 months after the last dose of therapy
- Subjects must be considered eligible to receive cisplatin- or carboplatin-containing chemotherapy, per the investigator’s evaluation. Subjects meeting any of the following criteria should be considered cisplatin ineligible, and will receive carboplatin: a. CrCl <60 mL/min but ≥30 mL/min within 7 days of randomization (measured by the Cockcroft-Gault formula). Note: Subjects with a CrCl ≥50 mL/min and no other cisplatin ineligibility criteria may be considered cisplatin-eligible based on the investigator’s clinical judgment. b. ECOG performance status of 2 within 7 days of randomization (refer to Inclusion Criterion 8 for additional criteria for ECOG 2 subjects). c. NCI CTCAE Grade 2 or higher hearing loss. Note: If a subject is determined to be cisplatin eligible, gemcitabine and cisplatin are to be administered without exception.
- Subjects must be willing and able to provide archived formalin-fixed paraffin-embedded tumor tissue blocks (or, alternatively, freshly sectioned slides; see laboratory manual for details) from a muscle-invasive or metastatic UC lesion or a biopsy sample of metastatic UC. This must be obtained prior to study treatment initiation and will be sent to a sponsor designated central laboratory for biomarker analysis. If archival tissue is not available, then a newly obtained baseline biopsy of an accessible tumor lesion is required within 28 days prior to Cycle 1 Day 1. Biopsy must provide adequate tissue for HER2 testing. a. Tumor tissue recommended to be collected within 12 months prior to enrollment, and after completion of the most recent (neo) adjuvant systemic therapy
- HER2 expression of 1+ or greater on IHC determined by central laboratory
- An ECOG performance status score of 0, 1, or 2 within 7 days prior to randomization. a. Subjects with ECOG 2 must meet additional criteria: Hb ≥10 g/dL, CrCl ≥50 mL/min, and heart failure severity less than New York Heart Association (NYHA) Class III.
- Adequate baseline cardiac parameters: a. LVEF ≥50% b. Fridericia’s corrected QT interval (QTcF) <470 ms
- The following baseline laboratory data, laboratory values collected within 7 days prior to randomization are acceptable: a. Hb ≥9 g/dL without transfusion b. ANC ≥1.5 × 109/L c. Platelet count ≥100 × 109/L d. ALT and AST ≤2.5 × upper limit of normal (ULN) without liver metastases or ≤5 × ULN with liver metastases e. Serum total bilirubin ≤1.5 × ULN or direct bilirubin ≤ ULN for subjects with total bilirubin >1.5 × ULN; serum total bilirubin ≤3 × ULN for subjects with Gilbert's syndrome f. CrCl ≥30 mL/min, as calculated using the Cockcroft-Gault formula g. International normalized ratio (INR) or prothrombin time (PT) ≤1.5 × ULN and activated partial thromboplastin time (aPTT) ≤1.5 × ULN. Subjects receiving anticoagulant therapy are eligible and are required to have INR/PT and aPTT within therapeutic range. Note: In subjects transfused before the study, the transfusion (such as red blood cell, whole blood, or plasma transfusion) must be ≥14 days prior to start of therapy to establish adequate laboratory parameters independent from transfusion support
- Subjects of childbearing potential (as defined in Section 10.4) under the following conditions: a. Must have a negative serum pregnancy test (minimum sensitivity 25 mIU/mL or equivalent units of beta human chorionic gonadotropin [β-hCG]) result within 72 hours prior to the first dose of study intervention. Subjects with false positive results and documented verification that the subject is not pregnant are eligible for participation. b. Must agree not to try to become pregnant during the study and for at least 2 months after the final dose of disitamab vedotin and 4 months after the final dose of pembrolizumab, and 6 months after the final dose of cisplatin, carboplatin, and gemcitabine. c. Must agree not to breastfeed or donate ova, from the time of informed consent and continuing through 2 months after the final dose of disitamab vedotin and 4 months after the final dose of pembrolizumab, and 6 months after the final dose of cisplatin, carboplatin, and gemcitabine. d. If sexually active in a way that could lead to pregnancy, must consistently use at least 2 acceptable methods of birth control (contraception), at least one of which must be highly effective (as defined in Section 10.4) starting at time of informed consent and continuing through at least 2 months after the final dose of disitamab vedotin and 4 months after the final dose of pembrolizumab, and 6 months after the final dose of cisplatin, carboplatin, and gemcitabine.
- Subjects who can get someone pregnant (as defined in Section 10.4) under the following conditions: a. Must agree not to donate sperm from the time of informed consent and continuing through at least 4 months after the final dose of disitamab vedotin and 6 months after the final dose of cisplatin, carboplatin, and gemcitabine. b. If sexually active with a person of childbearing potential in a way that could lead to pregnancy, must consistently use at least 2 acceptable methods of birth control (contraception), at least 1 of which must be highly effective (as defined in Section 10.4) from the time of informed consent and continuing through at least 4 months after the final dose of disitamab vedotin and 6 months after the final dose of cisplatin, carboplatin, and gemcitabine. c. If sexually active with a person who is pregnant or breastfeeding, must consistently use a condom (as defined in Section 10.4) from the time of informed consent and continuing through at least 4 months after the final dose of disitamab vedotin and 6 months after the final dose of cisplatin, carboplatin, and gemcitabine.
- The subject must provide documented informed consent.
- Subject must be willing and able to comply with the trial procedures and the follow-up schedule.
Exclusion Criteria
- Known hypersensitivity to any excipient contained in the drug formulation of disitamab vedotin, cisplatin, carboplatin, gemcitabine, or pembrolizumab
- History of severe/life threatening irAE with PD-(L)1 inhibitors are excluded. Please consult with medical monitor. a. Grade ≥3 pneumonitis IMAEs, cardiomyopathy, etc. b. Grade 4 diarrhea/colitis IMAEs, hepatitis IMAEs, rash IMAEs c. Grade 3/4 adrenal insufficiency, hypophysitis, uveitis, hypothyroidism
- CNS and/or leptomeningeal metastasis. a. Subjects with treated CNS metastases (by whole brain radiation therapy, surgery or radiosurgery, etc.) are permitted on study if all of the following are met: b. CNS metastases have been clinically stable for at least 4 weeks and baseline scans show no evidence of new or worsening CNS metastasis. c. Subject is on a stable dose of ≤10 mg/day of prednisone or equivalent for at least 2 weeks
- History of or active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). a. Replacement therapy (eg, thyroxine, insulin, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic disease-modifying treatment and is allowed. b. Subjects with vitiligo, psoriasis, type 1 diabetes mellitus, hypothyroidism, or resolved childhood asthma/atopy are allowed. c. Subjects requiring intermittent use of bronchodilators, inhaled steroids, or local steroid injections are allowed. d. Subjects with hypothyroidism that is stable with hormone replacement or Sjögren's syndrome are allowed.
- Subjects who have previously received any prior treatment with an agent directed to another stimulatory or co-inhibitory T cell receptor (including but not limited to CD137 agonists, CAR-T cell therapy, CTLA-4 inhibitors, or OX-40 agonists) are excluded
- Subjects with prior solid organ or bone marrow transplantation
- Pleural effusion or ascites with symptoms or requiring symptomatic treatment
- Subjects with an estimated life expectancy <12 weeks
- Subjects with ongoing clinically significant toxicity associated with prior treatment that has not resolved to ≤ Grade 1 or returned to baseline, except for Grade 2 alopecia
- Subject has received prior radiotherapy to a metastatic site without the use of chemotherapy radiosensitization within 3 weeks of the first dose of study intervention, with the exception of palliative radiotherapy to bone lesions, which is allowed if completed 2 weeks before the start of study intervention. Subjects must have recovered from all radiation-related toxicities and must not require corticosteroids. Note: Ongoing hormonal/antihormonal treatment (eg, for breast cancer) is allowed, provided that the subject is eligible per exclusion criteria of prior malignancy
- Subjects who previously received treatment with an MMAE agent or anti-HER2 therapy
- Ongoing sensory or motor neuropathy Grade 2 or higher
- Subjects with acute, chronic, or symptomatic infections, including: a. Ongoing symptomatic severe acute respiratory syndrome-associated coronavirus 2 (SARS-CoV-2) infection except for subjects who have recovered clinically but continue to have a detectable presence of SARS-CoV-2. b. History of human immunodeficiency virus (HIV) infection. Testing is not required unless mandated by local regulations. c. History of hepatitis B virus (HBV) infection (defined as positive for HBV surface antigen) or known active hepatitis C virus (HCV) infection (defined as HCV RNA [qualitative] is detected). Subjects who have been curatively treated for hepatitis C infection are permitted if they have documented sustained virologic response of ≥12 weeks. HBV negative DNA of ≥12 weeks is also allowed. No HBV or HCV testing is required, unless mandated by local regulations or institutional standard
- Has a diagnosis of immunodeficiency condition/disorder (ie, immunoglobulin A [IgA] deficiency, etc.) or is receiving chronic systemic steroid therapy (dose >10 mg daily of prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
- Subjects with history of idiopathic pulmonary fibrosis, organizing pneumonia, drug induced pneumonitis, noninfectious pneumonitis, interstitial lung disease, or idiopathic pneumonitis are excluded. Subjects with current pneumonitis or interstitial lung disease are also excluded
- Subjects with a history of another invasive malignancy within 3 years before the first dose of study intervention, or any evidence of residual disease from a previously diagnosed malignancy. a. Subjects with adequately resected early-stage non-melanoma skin cancer or carcinoma in situ are allowed. b. Subjects with a history of prostate cancer (T2NXMX or lower with Gleason score ≤7) treated with definitive intent (surgically or with radiation therapy), provided that the subject is considered prostate cancer free and the following criteria are met: Subjects who have undergone an adequate surgical resection must have undetectable prostate specific antigen (PSA) for ≥1 year and at screening. Subjects who have had radiation must have a PSA doubling time >1 year (based on at least 3 values determined >1 month apart) and a total PSA value that does not meet Phoenix criteria for biochemical recurrence (ie, <2.0 ng/mL above nadir). Subjects with untreated low-risk prostate cancer (Gleason score ≤6) on active surveillance with PSA doubling time >1 month (based on at least 3 values determined <1 month apart) are also eligible. c. Malignancies that can be cured after treatment (including but not limited to adequately treated thyroid cancer, cervical carcinoma in situ, basal or squamous cell skin cancer, or radical treatment of ductal carcinoma in situ to the breast).
- Uncontrolled cardiac disease including: a. Cardiac failure – NYHA Class III or IV heart failure (see Section 10.5) b. Cardiac arrhythmia – Grade 2 or higher arrhythmia or heart block c. Cardiac ischemia – unstable angina within the past 12 months, myocardial infarction or cerebral infarction within the past 6 months, etc. Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, any other structural heart disease interventions. d. Hypertension: Subjects with CTCAE Grade 3, defined as systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg despite adequate medical intervention will be excluded. Subjects with hypertension adequately controlled at baseline may be enrolled into the study. e. Unexplained syncope, symptomatic hypotension, or asymptomatic hypotension with systolic blood pressure <90 mmHg
- Subjects who have received radiotherapy within 2 weeks prior to randomization
- Subjects who have received major surgery within 4 weeks prior to randomization. Subject must have recovered adequately from complications from the study intervention prior to randomization
- Subjects requiring chronic oxygen therapy or have Grade ≥3 pulmonary disease unrelated to underlying malignancy
- Subjects who have received a live or live-attenuated vaccine within 30 days prior to randomization
- Subjects who are pregnant or breastfeeding women
- Other serious underlying medical condition, psychiatric or substance abuse disorder that, in the opinion of the investigator, would impair the subject’s ability to receive or tolerate the planned treatment, or comply with the requirements of the study and follow-up
- Other serious, uncontrolled concomitant diseases that may affect protocol compliance or interpretation of outcomes, including active opportunistic infections or advanced (severe) infections, or uncontrolled diabetes
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 01 Jul 2024 | 5 |
 Belgium | Not Recruiting | 01 Jul 2024 | 5 |
 Czechia | Not Recruiting | 01 Jul 2024 | 2 |
 France | Not Recruiting | 01 Jul 2024 | 14 |
 Greece | Not Recruiting | 01 Jul 2024 | 4 |
 Hungary | Not Recruiting | 01 Jul 2024 | 3 |
 Ireland | Not Recruiting | 01 Jul 2024 | 2 |
 Italy | Not Recruiting | 01 Jul 2024 | 11 |
 The Netherlands | Not Recruiting | 01 Jul 2024 | — |
 Norway | Not Recruiting | 01 Jul 2024 | 2 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
CISPLATIN | Comparator | — | IV INFUSION | 70 | 18 | SUB07483MIG |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 400 | 108 | PRD4323105 |
GEMCITABINE | Comparator | — | IV INFUSION | 1000 | 18 | SUB07892MIG |
CARBOPLATIN | Comparator | — | IV INFUSION | 400 | 18 | SUB06614MIG |
Disitamab Vedotin | Test | POWDER FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 1.5 | 9999999 | PRD9442609 |