An Open-label Study to Investigate the Efficacy and Safety of Dato-DXd + Rilvegostomig vs SoC in Adult Participants With High-risk MIUC

Phase 3RecruitingNCT07720284

AstraZeneca915 enrolled

Overview

Purpose: to assess efficacy and safety of Dato-DXd + rilvegostomig as adjuvant therapy versus SoC in MIUC participants with high-risk residual disease after radical resection. Study details: Duration: \~78 months (6.5 years) from FSI to last subject visit Treatment length: up to \~12 months, depending on randomized arm Visit frequency: every 3 weeks in Arms 1 and 2; every 2-4 weeks per SoC in Arm 3

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

SINGLE

Enrollment

915

Conditions

High-risk Muscle Invasive Urothelial Carcinoma

Interventions

Dato-DXdDRUG

Dato-DXd is an ADC comprised of a recombinant humanised anti-TROP2 IgG1 mAb, MAAP-9001a, which is covalently conjugated via a cleavable drug-linker, MAAA1162a (the complex of MAAA-1181a and a maleimide tetrapeptide linker), using thioether bonds to the topoisomerase I inhibitor DXd.

RilvegostomigDRUG

Rilvegostomig is a monovalent, bispecific, humanised, IgG1 mAb engineered with an Fc domain that carries a triple mutation (L234F/L235E/P331S) designed to reduce Fc-mediated effector functions. Rilvegostomig contains 2 distinct paratopes that bind to human TIGIT and PD-1 and inhibit binding to their respective immuno-suppressive ligands.

NivolumabDRUG

A fully human monoclonal antibody against PD-1, promoting anti-tumor immunity. Approved across many malignancies such as melanoma, NSCLC, renal cell carcinoma, Hodgkin lymphoma, hepatocellular carcinoma, and colorectal cancer (dMMR/MSI-H), often alone or with ipilimumab. It's used in several cancers, notably unresectable stage III non-small cell lung cancer after chemoradiation and extensive-stage small cell lung cancer in combination regimens, among others, and is also approved for patients with muscle-invasive urothelial carcinoma (MIUC) at high risk of recurrence in the adjuvant setting.

PembrolizumabDRUG

A humanized monoclonal antibody targeting PD-1, enhancing T-cell-mediated immune responses against tumors. Indications span multiple cancers including melanoma, NSCLC, head and neck squamous cell carcinoma, urothelial carcinoma, MSI-H/dMMR tumors, and more.

Enfortumab vedotinDRUG

An antibody-drug conjugate (ADC) comprised of a fully human anti-Nectin-4 IgG1 monoclonal antibody, linked via a protease-cleavable maleimide-based linker to the microtubule-disrupting agent monomethyl auristatin E (MMAE), which is conjugated through thioether bonds. Upon binding to Nectin-4-expressing cells, the ADC is internalized and releases MMAE, leading to disruption of microtubule dynamics and subsequent tumor cell death. Enfortumab vedotin is approved in urothelial cancers.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion criteria: 1. Participant must be \> 18 years of age at the time of signing the ICF. 2. Histologically confirmed MIUC of the bladder or upper tract. 3. Completed R0 radical resection 28 to 120 days before randomisation, with negative margins and no residual or metastatic disease. 4. Pathologic evidence of urothelial carcinoma at high-risk of recurrence and 1. not received neoadjuvant therapy and has pT3-pT4aN0, or any pT with pN+ stage 2. completed neoadjuvant treatment and has ypT2-ypT4a, or any ypT with ypN+ stage 5. No evidence of disease at screening, 6. ECOG performance status of 0 or 1 with no deterioration over the previous 2 weeks prior to randomisation. 7. Minimum life expectancy of \> 12 weeks at time of screening. 8. An archival surgical tumour sample must be available pre-randomisation for central testing. 9. Adequate organ and bone marrow function within 28 days before randomisation. Exclusion criteria: 1. Any tumour with predominant or pure high grade neuroendocrine carcinoma component. 2. Partial cystectomy in the setting of bladder cancer primary tumour or partial nephrectomy. 3. Any adjuvant systemic or radiation therapy post-surgery for urothelial carcinoma. 4. Severe or uncontrolled systemic diseases, history of organ transplant or allogeneic stem cell transplant, or psychological disorders/social situations, and/or substance abuse. 5. History of clinically significant corneal disease. 6. History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 2 years before the first dose of study intervention and of low potential risk for recurrence. 7. Ongoing toxicities except alopecia from prior cancer treatment must be Grade ≤ 1 or at baseline. Stable Grade 2 toxicities are allowed if unchanged for ≥3 months and managed by standard care. 8. Active or uncontrolled hepatitis B or C virus infection. 9. Known HIV infection that is not well controlled. 10. Any other active or uncontrolled infection including tuberculosis requiring systemic treatment that has not resolved by the time of randomisation. 11. History of non-infectious ILD/pneumonitis including radiation, pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening. 12. Has clinically severe pulmonary function compromise. 13. Mean resting corrected QTcF \> 470 ms regardless of gender, obtained from triplicate 12-lead ECGs performed at screening 14. Uncontrolled or significant cardiac conditions. 15. Active or prior documented autoimmune or inflammatory disorders requiring systemic treatment in the past 5 years. 16. Prior exposure to TROP2-directed therapies, other ADCs with deruxtecan, therapeutic anti-cancer vaccines, anti-TIGIT therapy or any other anti-cancer therapy targeting immune-regulatory receptors or mechanisms. 17. Current or prior use of immunosuppressive medication within 14 days prior to treatment assignment/randomisation. 18. Known history of severe hypersensitivity reactions to any study drug 19. Not eligible to receive at least one of SoC according to local regulations/approvals. 20. Currently pregnant (confirmed with positive pregnancy test), breastfeeding or planning to become pregnant.

Locations (160)

Research Site

Hot Springs, Arkansas, United States

NOT_YET_RECRUITING

Research Site

Little Rock, Arkansas, United States

NOT_YET_RECRUITING

Research Site

Little Rock, Arkansas, United States

NOT_YET_RECRUITING

Research Site

San Francisco, California, United States

NOT_YET_RECRUITING

Outcomes

Primary Outcomes

To demonstrate the superiority of Dato-DXd + rilvegostomig (Arm 1) relative to SoC (Arm 3) by assessment of disease-free survival (DFS) (based on Investigator assessments).

DFS is defined as the time from randomisation until disease recurrence (local urothelial tract, local non urothelial tract or distant) per RECIST 1.1 as assessed by Investigator, or death due to any cause. The analysis will include all randomised participants as randomised. All events will be included, regardless of whether the participant discontinues study treatment or receives another anti-cancer therapy. The measure of interest is the HR of DFS.

Time frame: From randomisation until disease recurrence as assessed by investigator or death due to any cause (anticipated to be up to 49 months after the first subject in).

Secondary Outcomes

To demonstrate the superiority of Dato-DXd + rilvegostomig (Arm 1) relative to SoC (Arm 3) by assessment of OS (Overall survival).

OS defined as the time from randomisation until the date of death due to any cause. The analysis will include all randomised participants as randomised. All deaths will be included regardless of whether the participant withdraws from therapy or receives another anti-cancer therapy. The measure of interest is the HR of OS.

Time frame: OS is defined as the time from randomisation until the date of death due to any cause, up to 78 months from first subject in.

To demonstrate the superiority of Dato-DXd + rilvegostomig (Arm 1) relative to SoC (Arm 3) by assessment of DFS (based on Blinded Independent Central Review [BICR] assessments).

DFS is defined as the time from randomisation until disease recurrence (local urothelial tract, local non urothelial tract or distant) per RECIST 1.1 as assessed by BICR, or death due to any cause. The analysis will include all randomised participants as randomised. All events will be included, regardless of whether the participant discontinues study treatment or receives another anti-cancer therapy. The measure of interest is the HR of DFS.

Time frame: From randomisation until disease recurrence as assessed by BICR or death due to any cause (anticipated to be up to 49 months after the first subject in).

To estimate the effectiveness of Dato-DXd monotherapy (Arm 2) versus SoC (Arm 3) and effectiveness of Dato-DXd in combination with rilvegostomig (Arm 1) versus Dato-DXd monotherapy (Arm 2) by assessment of OS.

Time frame: OS is defined as the time from randomisation until the date of death due to any cause, up to 78 months from first subject in.

Time frame: From randomisation until disease recurrence as assessed by investigator or death due to any cause (anticipated to be up to 49 months after the first subject in).

Time frame: From randomisation until disease recurrence as assessed by BICR or death due to any cause (anticipated to be up to 49 months after the first subject in).

To demonstrate effectiveness of Dato-DXd + rilvegostomig (Arm 1) vs SoC (Arm 3) by evaluating DSS (Disease specific survival), NUTRFS (Non-urothelial tract recurrence-free survival), DMFS (Distant metastasis free survival).

DSS is defined as time from randomisation until death due to disease (urothelial cancer). The analysis will include all randomised participants as randomised. The measure of interest is the HR of DSS. NUTRFS is defined as time from randomisation until first local non-urothelial tract or distant recurrence or death due to any cause. The analysis will include all randomised participants as randomised. The measure of interest is the HR of NUTRFS. DMFS is defined as time from randomisation until first distant recurrence (non-local) or death due to any cause The analysis will include all randomised participants as randomised. The measure of interest is the HR of DMFS.

Time frame: From randomisation up to 49 months after the first subject in.

An Open-label Study to Investigate the Efficacy and Safety of Dato-DXd + Rilvegostomig vs SoC in Adult Participants With High-risk MIUC

Overview

Conditions

Interventions

Eligibility

Locations (160)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts