A Study of the Safety and Efficacy of Various Combinations of Avelumab as Therapy in Locally Advanced or Metastatic Urothelial Carcinoma

Phase 1

• Conditions: Advanced or metastatic urothelial carcinoma whose disease did not progress with 1L platinum-containing chemotherapy.; MedDRA version: 20.0Level: PTClassification code 10005003Term: Bladder cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2021-003669-36-DK
• Lead Sponsor: Merck Healthcare KGaA

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2022-05-04
• Last Update Posted: 21 May 2024

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 252

Inclusion Criteria

1.Are = 18 years of age at the time of signing the informed consent.
2.Has
a.Histologically confirmed, unresectable locally advanced or metastatic urothelial carcinoma. Both transitional cell and mixed transitional/non- transitional cell histologies are allowed, but transitional cell carcinoma must be the predominant histology.
b.Documented Stage IIIA/IIIB with N1-N3, or Stage IV disease (per American Joint Committee on Cancer/International Union for Cancer Control Tumor Node Metastasis system, 8th edition) at the start of first line chemotherapy.
3. Prior 1L chemotherapy must have consisted of at least 4 cycles and no more than 6 cycles of gemcitabine + cisplatin and/or gemcitabine + carboplatin. No other chemotherapy regimens are allowed in this study. (Note: Switch between platinum agents due for toxicity to complete a total of - 4 to 6 cycles first line platinum-based chemotherapy is acceptable).
4.The last dose of first line chemotherapy must have been received no less than 4 weeks, and no more than 10 weeks, prior to randomization in the present study.
5.Participants without progressive disease as per RECIST v1.1 guidelines (i.e., with an ongoing CR, PR, or SD) following completion of 4 to 6 cycles of 1L chemotherapy.
Eligibility based on this criterion will be determined by Investigator review of prechemotherapy and post chemotherapy radiological assessments (CT/MRI scans).
6.All participants must provide archival formalin-fixed paraffin embedded (FFPE) tumor tissues (ideally < 6 months old prior to participant enrollment) from most recent primary or metastatic tumor biopsy or resection obtained prior to treatment with first line chemotherapy but within 24 months prior to randomization, with no intervening systemic anticancer therapy between the time the tissue was obtained and initiation of first line chemotherapy. If an archival FFPE tissue block cannot be provided, 10 or more unstained slides (15 slides minimum) will be acceptable. In addition, fresh baseline tumor samples (collected within 28 days before first dose) may be collected at Screening if archival tissue biopsy is not available. Provision of a tumor biospecimen is required for randomization into the study. The sample must be submitted to the Central Laboratory prior to randomization and deemed acceptable to allow the patient to randomize. Refer to the Central Laboratory Manual for additional specifications.
7.Participants who are willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
8.Estimated life expectancy of at least 3 months.
9.Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
10.Adequate bone marrow function, including:
a.Absolute neutrophil count (ANC) = 1,500/mm3 or = 1.5 × 109/L;
b.Platelets = 100,000/mm3 or = 100 × 109/L;
c.Hemoglobin = 9 g/dL (may have been transfused) during the screening period in order to meet inclusionary criteria provided there is no active bleeding).
11.Adequate renal function, defined as estimated creatinine clearance = 30 mL/min as calculated using the Cockcroft-Gault equation or by 24-hour urine collection for creatinine clearance or according to the local institutional standard method.
12.Adequate liver function, including:
a.Total serum bilirubin = 1.5 × upper limit of normal (ULN);
b.Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 2.5 × ULN, or, for participants with documented metastatic disease to the liver, AST and ALT

Exclusion Criteria

1.Participants with symptomatic central nervous system (CNS) metastases requiring steroids. Participants with diagnosed CNS metastases are eligible if they have completed treatment, recovered from the acute effects of radiation therapy or surgery prior to randomization and off steroid treatment 7 days before randomization, have discontinued corticosteroid treatment for these metastases for at least 4 weeks, and are neurologically stable.
2.Persisting toxicity related to prior therapy NCI-CTCAE v5.0 Grade > 1; however, alopecia, sensory neuropathy Grade = 2 is acceptable, or other Grade = 2 adverse events not constituting a safety risk based on the Investigator’s judgment are acceptable.
3.Diagnosis of any other malignancy unless a complete remission without further recurrence was achieved and the participant was deemed to have been cured with no additional therapy required or anticipated to be required. The exceptions to this criterion may include carcinoma in situ of cervical, colorectal, breast, or all localized prostate cancer that is not being treated. Other malignancies should be discussed with the Sponsor.
4.Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Participants with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
5.Current significant cardiac conduction abnormalities, including corrected QT interval (QTcF, corrected with Fridericia formula) prolongation of > 450 for male and > 470 for female participants on triplicate 12-lead ECG or impaired cardiovascular function.
6.Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication (except for atrial fibrillation that is well controlled with antiarrhythmic medication).
7.Active infection 48 hours before randomization requiring systemic therapy.
8.Known severe hypersensitivity reactions to monoclonal antibodies (Grade = 3), any history of anaphylaxis, or uncontrolled asthma (i.e., 3 or more features of asthma symptom control per the Global Initiative for Asthma 2015).
9.Known prior or suspected hypersensitivity to study drugs or any component in their formulations.
10.Diagnosis of prior immunodeficiency or organ transplant requiring immunosuppressive therapy.
11.Pregnant female participants; breastfeeding female participants; and female participants of childbearing potential who are unwilling or unable to use a highly effective method of contraception as outlined in the protocol for the duration of the study and for at least 6 months after the last dose of investigational product. Male participants who are unwilling or unable to follow the Contraception and Barrier Requirements (refer to Appendix 3) for the duration of the study and for at least 3 months after the last dose of study intervention.
12.Other severe acute or chronic medical conditions including but not limited to inflammatory bowel disease (colitis, Crohn's disease) or gastrointestinal (GI) perforation within 6 months of enrollment, pneumonitis, and pulmonary fibrosis; psychiatric condition including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormality that may increase the risk asso

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified