A Phase 2 Multi-Cohort, Open-Label, Multi-Center Clinical Study Evaluating the Efficacy and Safety of Disitamab Vedotin (RC48-ADC)

This research study is studying disitamab vedotin for injection (RC48-ADC) alone and in combination with pembrolizumab in patients with HER2-expressing urothelial carcinoma as a possible treatment for locally advanced or metastatic urothelial carcinoma. The purpose of this research study is to see if disitamab vedotin alone or with pembrolizumab has any benefits at dose levels thought to be acceptable in earlier studies.

The researchers want to find out what effects (good and bad) disitamab vedotin alone or with pembrolizumab has on urothelial cancer.

Inova Schar Cancer Institute
8081 Innovation Park Dr.
Fairfax, VA 22031

A department of Inova Fairfax Hospital

• Adults 18 years of age or older
• Locally-advanced unresectable or metastatic UC with histopathological confirmation, including UC originating from the renal pelvis, ureters, bladder, or urethra. Mixed-cell type tumors are eligible as long as urothelial (transitional cell) carcinoma is the predominant cell type.
• Prior therapy, Cohorts A and B: Subjects must have received only 1 or 2 lines of prior systemic therapy for LA/mUC, including 1 line of platinum-containing chemotherapy.
  • Neoadjuvant or adjuvant systemic therapy, with progression within 12 months of completing last dose of therapy, is considered a line of prior therapy.
  • Maintenance avelumab therapy delivered following first-line platinum therapy is not considered a separate line of therapy.
  • Prior therapy with PD-(L)1 inhibitors as (neo)adjuvant therapy, first-line maintenance therapy or as second-line treatment is allowed.
• Prior therapy, Cohort C: No prior systemic therapy for LA/mUC
  • Neoadjuvant or adjuvant therapy, including PD-(L1) inhibitors, is acceptable, if disease recurrence/progression occurred more than 12 months after the last dose of systemic therapy.
• Cohorts A and B only: Radiographically documented disease progression during or after the most recent line of therapy for LA/mUC
• Cohort C only: Subjects must be considered eligible to receive cisplatin- or carboplatin-containing chemotherapy, per the investigator’s evaluation.
• HER2-expression status determined by the central laboratory to be IHC 1+, 2+ or 3+, on the provided tumor tissue sample of muscle-invasive or metastatic UC.
• Adequate baseline cardiac, bone marrow, hepatic, renal, and coagulation functions
• Additional eligibility in protocol

• Known hypersensitivity to disitamab vedotin, pembrolizumab (in Cohort C), or any of their components
• Received antitumor treatment (including chemotherapy, radiotherapy, targeted therapy, immunotherapy, etc.) or participated in another clinical study within 2 weeks prior to the start of the study
• Toxicity from a previous treatment has not returned to Grades 0 or 1 (except for Grade 2 alopecia)
• Prior MMAE-based ADCs (eg, enfortumab vedotin) or HER2-directed therapy
• Major surgery that has not fully recovered within 4 weeks prior to dose administration
• Peripheral sensory or motor neuropathy ≥ Grade 2 at baseline
• Received live or live-attenuated vaccines within 4 weeks prior to study treatment initiation or plan on receiving such vaccines during the course of study treatment
• Subjects with acute, chronic or symptomatic infections, including:
  • Ongoing symptoms of SARS-CoV-2 infection. Investigators should exercise clinical judgment and individualized decision-making on enrollment of subjects who have recovered clinically but continue to have a detectable presence of SARS-CoV-2.
  • History of human immunodeficiency virus infection. Testing is not required unless mandated by the local regulations.
  • 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. No HBV or HCV testing is required, unless mandated by local regulations.
• 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
• Uncontrolled cardiac disease including:
  • Cardiac failure-New York Heart Association Class III–IV heart failure
  • Cardiac arrhythmia – Grade 2 or higher arrhythmia or heart block
  • Cardiac ischemia – unstable angina within the past 12 months, myocardial infarction or cerebral infarction within the past 6 months, etc.
• Hypertension: uncontrolled hypertension (systolic blood pressure >180 mmHg and/or diastolic blood pressure >100 mmHg)
• History of other malignant tumors within 3 years prior to dose administration, except for:
  • A history of prostate cancer (T2NXMX or lower, with Gleason score ≤7) treated with definitive intent (surgically or with radiation therapy) at least 1 year prior to treatment initiation is acceptable, provided that the subject is considered prostate cancer-free and the following criteria are met:
    − Subjects who have undergone radical prostatectomy 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 year (based on at least 3 values determined >1 month apart) are also eligible.
  • 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 of the breast)
• Subjects with active CNS metastases. Subjects with treated CNS metastases are permitted on study if all of the following conditions are met:
  • CNS metastases have been clinically stable for at least 4 weeks prior to treatment initiation and baseline scans show no evidence of new or enlarged lesions
  • If the subject requires corticosteroids, the dose is stable at ≤10 mg/day of prednisone or equivalent for at least 2 weeks prior to treatment initiation
  • Subject does not have leptomeningeal disease.
• History of or active autoimmune disease that has required systemic therapy (such as the use of disease-modifying drugs [eg, methotrexate, sulfasalazine, leflunomide, hydroxychloroquine], corticosteroids, or immunosuppressive drugs) in the past 2 years.
  • Replacement therapies (eg, thyroxine, insulin, physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency) are not considered to be a form of systemic treatment and are allowed.
  • Subjects with vitiligo, psoriasis, type 1 diabetes mellitus, hypothyroidism, or resolved childhood asthma/atopy are allowed.
  • Subjects requiring intermittent use of bronchodilators, inhaled steroids, or local steroid injections are allowed.
  • Subjects with hypothyroidism that is stable with hormone replacement or Sjögren's syndrome are allowed.
• Received hematopoietic stem cell transplantation or solid organ transplantation
• Pleural effusion or ascites with symptoms or requiring symptomatic treatment
• Pregnant or breastfeeding women
• Cohort C Only:
  • Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug.
  • History of idiopathic pulmonary fibrosis, organizing pneumonia, or any (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
  • History of severe/life threatening immune-related AE (irAE) with PD-(L)1 inhibitors are excluded.
  • Currently on high dose steroid (>10 mg prednisone or equivalent per day) or other immune suppressant or has a condition requiring chronic high dose steroid or immune suppressant.
  • Requiring chronic oxygen therapy or have Grade ≥3 pulmonary disease unrelated to underlying malignancy
• Additional ineligibility in protocol.

For more information, go to: https://clinicaltrials.gov/ct2/show/NCT04879329