DDR Genes Alteration and Response to Platinum-based Chemotherapy in Advanced Urothelial Cancer.

NCT06820255 | Recruiting Phase 4

• 2 other identifiers: 70042024-516450-21
• Study Type: interventional
• Target: 135
• Locations: 1 country
• Sites: 1

Brief Summary

This study aims to prospectively observe whether certain alterations in some genes related to the DNA repair mechanism are related to better response to platinum-based chemotherapy used to treat metastatic bladder or urothelial cancers.

Conditions

Bladder (Urothelial, Transitional Cell) Cancer Metastatic or Unresectable; Upper Tract Urothelial Cancer

Keywords

DNA damage response genes; cisplatin; carboplatin

Outcome Measures

Primary Outcomes (1)

• Overall Response Rate (ORR) by DDR group.

  The difference in ORR defined as the percentage of patients who achieve PR or CR as measured by RECIST 1.1, to the platinum-based chemotherapy between patients with metastatic or locally advanced urothelial cancer with or without DDR genes alterations.

  Six months

Secondary Outcomes (6)

• Progression Free Survival (PFS) by DDR group.

  12 months

• Overall Survival (OS) by DDR group.

  12 months

• Overall Response Rate (ORR) by treatment group.

  six months

• Disease Control Rate (DCR) by treatment group.

  six months

• Disease Control Rate (DCR) by DDR group.

  six months

Other Outcomes (4)

• Expression of PDL1

  six months

• Expression of Nectin-4

  six months

• Expression of Trop-2

  six months

Study Arms (2)

DDR alterations positive

ACTIVE COMPARATOR

This arm included all patients with DDR alteration in urothelial cancer

Drug: Platinum + Gemcitabine; Drug: Avelumab first-line maintenance; Diagnostic Test: NGS test for DDR alterations

DDR alterations negative

ACTIVE COMPARATOR

This arm included all patients without DDR alteration in urothelial cancer

Drug: Platinum + Gemcitabine; Drug: Avelumab first-line maintenance; Diagnostic Test: NGS test for DDR alterations

Interventions

Platinum + Gemcitabine DRUG

Eligible patients will be treated with platinum-based chemotherapy (i.e. cisplatin + gemcitabine or carboplatin + gemcitabine).

DDR alterations negative; DDR alterations positive

Avelumab first-line maintenance DRUG

Patients with stable disease or tumor response after treatment with platinum-based chemotherapy will start treatment with avelumab 800 mg fat dose Q2 weeks until progression of disease or unacceptable toxicity

DDR alterations negative; DDR alterations positive

NGS test for DDR alterations DIAGNOSTIC_TEST

All patients will be tested for DDR alterations on tumor tissue.

DDR alterations negative; DDR alterations positive

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Informed consent obtained before any study-specific procedures. Patients must be able to understand and be willing to sign a written informed consent.
• Male or female patient ≥18 years of age.
• Histological or cytological documentation of urothelial cancer.
• Available tumor tissue for analysis
• Measurable disease according to Response Evaluation Criteria in Solid Tumors criteria, version 1.1.
• Eastern Cooperative Oncology Group performance status of ≤2. (Patients with ECOG PS of 2 were required to also meet the additional criteria: hemoglobin ≥10 g/dL, GFR ≥50mL/min, may not have NYHA class III heart failure).
• Life expectancy of at least 6 months.
• Eligible to standard chemotherapy with cisplatin or carboplatin + gemcitabine as per clinical practice.
• Women of childbearing potential and men must agree to use adequate contraception since signing of the informed consent form until 180 days after the last dose of chemotherapy and 30 days after the last dose of avelumab. The investigator or a designated associate is requested to advise the subject how to achieve an adequate birth control. Adequate contraception is defined in the study as any medically recommend method (or combination of methods) as per standard of care.
• Adequate bone-marrow, liver, and renal function as assessed by the following laboratory requirements conducted within 7 days of starting to study treatment:
• a Creatinine value \<2.5 mg/dl and creatinine clearance \> 30 ml/min evaluated by the Cockcroft-Gault Formula.
• b Total bilirubin ≤1∙5 × the upper limit of normal (ULN); c Alanine aminotransferase and aspartate aminotransferase ≤2 × ULN (≤5 × ULN for patients with liver involvement of their cancer); d International normalized ratio (INR) and partial thromboplastin time (PTT) ≤1∙5 × ULN. Subjects who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate if no prior evidence of an underlying abnormality in coagulation parameters exists. Close monitoring of at least weekly evaluations will be performed until INR and PTT are stable based on a pre-dose measurement as defined by the local standard of care; e Platelet count ≥100 000/mm3, hemoglobin \>9 g/dl, absolute neutrophil count \>1,500/mm3; f Alkaline phosphatase limit ≤2∙5 × ULN (≤5 × ULN for patients with liver involvement of their cancer).

You may not qualify if:

• Previous treatment for metastatic or locally advanced disease.
• Previous adjuvant therapy within 1 year from the diagnosis of metastatic disease.
• Prior treatment with immunotherapy.
• Previous or concurrent cancer that is distinct in primary site or histology from urothelial cancer within 3 years before enrollment EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors (Ta \[non-invasive tumor\], Tis \[carcinoma in situ\], and T1 \[tumor invades lamina propria\]), pT2 prostate cancer with PSA\<0.01.
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study medication
• Pregnancy or breast-feeding. Women of childbearing potential must have a pregnancy test performed a maximum of 7 days before start of treatment, and a negative result must be documented before start of treatment.
• Any cardiological condition among:
• Congestive heart failure of New York Heart Association class 3 or worse.
• Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months). Myocardial infarction less than 6 months before start of study drug.
• Cardiac arrhythmias requiring anti-arrhythmic therapy (beta-blockers or digoxin are permitted).
• Uncontrolled hypertension (systolic blood pressure \>150 mmHg or diastolic pressure \>90 mmHg despite optimal medical management).
• Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), pulmonary embolism within the 4 months before start of study medication.
• Ongoing infection higher than National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 grade 2.
• Known history of human immunodeficiency (HIV) virus infection or known history of chronic hepatitis B or C.
• Any autoimmune disease that contraindicates the use of maintenance immunotherapy in case of stable or responsive disease to chemotherapy.

Sponsors & Collaborators

• Fondazione Policlinico Universitario Agostino Gemelli IRCCS: lead

Study Sites (1)

Fondazione Policlinico Universitario A. Gemelli IRCCS

Rome, 00168, Italy

RECRUITING

MeSH Terms

Conditions

Neoplasm Metastasis

Interventions

Platinum; Gemcitabine

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Metals, Heavy; Elements; Inorganic Chemicals; Transition Elements; Metals; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring

Study Officials

• Roberto Iacovelli, Prof

  Fondazione Policlinico Universitario A. Gemelli, IRCCS

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Roberto Iacovelli, Prof

CONTACT

+390630157373; roberto.iacovelli@policlinicogemelli.it

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Both patients and clinicians are blinded for results of DDR test during platinum-based chemotherapy.
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Patients will be screened for DDR alteration on tumor tissue and treated with platinum-based chemotherapy followed by avelumab maintenance. Outcome to therapy will be evaluated based on presence or not of DDR alterations.

Study Record Dates

• First Submitted: February 6, 2025
• First Posted: February 11, 2025
• Study Start: January 7, 2025
• Primary Completion: January 7, 2026
• Study Completion (Estimated): January 7, 2027
• Last Updated: February 11, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)