Prospective Evaluation of the Ddr Genes Alteration to Predict Response to Platinum-Based Chemotherapy in Advanced Urothelial Cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

31 Dec 2024 → ongoing

Decision date (initial)

2024-11-20

Transition trial

No

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

No

Funding sources

Merck KGaA

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Therapy

To assess if patients with metastatic or locally advanced urothelial cancer harboring DDR genes alterations have increased response to platinum-based chemotherapy compared to those who did not

Secondary objectives 7

1. To evaluate the efficacy of first line therapy in patients with or without DDR genes alterations.
2. To evaluate the survival in patients with or without DDR gene alterations
3. To evaluate the response in patients with or without DDR genes alterations between those treated with carboplatin o cisplatin
4. To evaluate the disease control in patients with or without DD genes alterations between those treated with carboplatin or cisplatin
5. To evaluate the safety profile of chemotherapy in patients with or without DDR genes alterations
6. Translational objectives: To describe the incidence of DDR alteration in mUC
7. Translational objectives: To describe the expression of Nectin4, PDL1, Trop2 and Her2 proteins in tumor tissue

Conditions and MedDRA coding

metastatic or locally advanced urothelial cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Informed consent obtained before any study-specific procedures. Patients must be able to understand and be willing to sign a written informed consent
2. Male or female patient ≥18 years of age
3. Histological or cytological documentation of urothelial cancer
4. Available tumor tissue for analysis
5. Measurable disease according to Response Evaluation Criteria in Solid Tumors criteria, version 1.1
6. 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)
7. Life expectancy of at least 6 months
8. Eligible to standard chemotherapy with cisplatin or carboplatin + gemcitabine as per clinical practice
9. Women of childbearing potential and men must agree to use adequate contraception since signing of the informed consent form until at least 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
10. 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); Synopsis_SELECTIO-UC_Version 1.0 of 29 May 2024 5 / 12 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)

Exclusion criteria 19

1. Previous treatment for metastatic or locally advanced disease
2. Previous adjuvant therapy within 1 year from the diagnosis of metastatic disease
3. Prior treatment with immunotherapy
4. 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 pT2 prostate cancer with PSA<0.01
5. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study medication
6. 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
7. Any cardiological condition among: a Congestive heart failure of New York Heart Association class 3 or worse. b 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. c Cardiac arrhythmias requiring anti-arrhythmic therapy (betablockers or digoxin are permitted). Synopsis_SELECTIO-UC_Version 1.0 of 29 May 2024 6 / 12 d Uncontrolled hypertension (systolic blood pressure >150 mmHg or diastolic pressure >90 mmHg despite optimal medical management). e 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
8. Ongoing infection higher than National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 grade 2
9. Known history of human immunodeficiency (HIV) virus infection or known history of chronic hepatitis B or C
10. Any autoimmune disease that contraindicates the use of maintenance immunotherapy in case of stable or responsive disease to chemotherapy
11. Seizure disorder requiring medication
12. Symptomatic metastatic brain or meningeal tumors unless the patient is >2 months from definitive therapy, has a negative imaging study within 4 weeks of study entry and is clinically stable with respect to the tumor at the time of study entry. Also, the patient must not be undergoing acute steroid therapy or tapering (chronic steroid therapy is acceptable provided that the dose is stable for 1 month before and after screening radiographic studies)
13. History of organ allograft
14. Evidence or history of bleeding diathesis. Any hemorrhage or bleeding event of CTCAE grade 3 or higher within 4 weeks of start of study medication
15. Non-healing wound, ulcer, or bone fracture
16. Renal failure requiring hemodialysis or peritoneal dialysis
17. Any illness or medical conditions that are unstable or could jeopardize the safety of the patient and his or her compliance in the study
18. Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed
19. Participation to another clinical trial at the time of the enrollment

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. To assess 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. Radiological confirmation of the response is not required

Secondary endpoints 7

1. To evaluate the PFS defined as the time elapsed from start of investigational treatment to the documentation of investigatorassessed disease progression, according to RECIST 1.1, or death due to any cause, whichever occurs first in patients with or without DDR genes alterations
2. To evaluate the OS defined as time elapsed from start of investigational treatment to the date of death due to any cause in patients with or without DDR genes alterations
3. To evaluate the ORR defined as the percentage of patients who achieve PR or CR as measured by RECIST 1.1 criteria in patients with or without DDR genes alterations between those treated with carboplatin o cisplatin
4. To evaluate the disease control rate (DCR) defined as the percentage of patients who achieve stable disease (SD) or PR or CR as measured by RECIST 1.1 criteria in patients with or without DDR genes alterations between those treated with carboplatin o cisplatin
5. To evaluate the incidence of chemo-related adverse events in patients with or without DDR genes alterations graded according to NCI CTCAE version 5.0
6. Translational endpoint: to describe the incidence of DDR alteration found in NGS analysis performed among the eligible patients
7. Traslational endpoint: To describe the expression of Nectin4, PDL1, Trop2 and Her2 proteins in tumor tissue

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 9

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Sponsor organisation

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Address

Largo Francesco Vito 1

City

Rome

Postcode

00168

Country

Italy

Scientific contact point

Organisation

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Contact name

Roberto Iacovelli

Public contact point

Organisation

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Contact name

Roberto Iacovelli

Locations

1 EU/EEA country · 23 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 26 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications