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

Official title

A Phase III, Open-Label, Randomised, Multicentre, Global Study of Adjuvant Datopotamab Deruxtecan in Combination With Rilvegostomig in Participants With High-risk Muscle Invasive Urothelial Carcinoma

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

Interventions

• Drug Dato-DXd
  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.
• Drug Rilvegostomig
  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.
• Drug Durvalumab
  A fully human monoclonal antibody that blocks the PD-L1 checkpoint to restore anti-tumor T-cell activity. Durvalumab is approved for Muscle invasive bladder cancer (MIBC) as perioperative regime.
• Drug Nivolumab
  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 wit
• Drug Pembrolizumab
  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.
• Drug Enfortumab vedotin
  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.

Primary outcome measures

• 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). [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 outcome measures (6)

• To demonstrate the superiority of Dato-DXd + rilvegostomig (Arm 1) relative to SoC (Arm 3) by assessment of OS (Overall survival). [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). [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.]
• 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 DFS based on Investigator assessments. [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).]
• 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 DFS by BICR. [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). [Time frame: From randomisation up to 49 months after the first subject in.]

Eligibility criteria

Inclusion criteria

• Participant must be > 18 years of age at the time of signing the ICF.
• Histologically confirmed MIUC of the bladder or upper tract.
• Completed R0 radical resection 28 to 120 days before randomisation, with negative margins and no residual or metastatic disease.
• Pathologic evidence of urothelial carcinoma at high-risk of recurrence and

• not received neoadjuvant therapy and has pT3-pT4aN0, or any pT with pN+ stage
• completed neoadjuvant treatment and has ypT2-ypT4a, or any ypT with ypN+ stage
• No evidence of disease at screening,
• ECOG performance status of 0 or 1 with no deterioration over the previous 2 weeks prior to randomisation.
• Minimum life expectancy of > 12 weeks at time of screening.
• An archival surgical tumour sample must be available pre-randomisation for central testing.
• Adequate organ and bone marrow function within 28 days before randomisation.

Exclusion criteria

• Any tumour with predominant or pure high grade neuroendocrine carcinoma component.
• Partial cystectomy in the setting of bladder cancer primary tumour or partial nephrectomy.
• Any adjuvant systemic or radiation therapy post-surgery for urothelial carcinoma.
• Severe or uncontrolled systemic diseases, history of organ transplant or allogeneic stem cell transplant, or psychological disorders/social situations, and/or substance abuse.
• History of clinically significant corneal disease.
• 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.
• 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.
• Active or uncontrolled hepatitis B or C virus infection.
• Known HIV infection that is not well controlled.
• Any other active or uncontrolled infection including tuberculosis requiring systemic treatment that has not resolved by the time of randomisation.
• 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.
• Has clinically severe pulmonary function compromise.
• Mean resting corrected QTcF > 470 ms regardless of gender, obtained from triplicate 12-lead ECGs performed at screening
• Uncontrolled or significant cardiac conditions.
• Active or prior documented autoimmune or inflammatory disorders requiring systemic treatment in the past 5 years.
• 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.
• Current or prior use of immunosuppressive medication within 14 days prior to treatment assignment/randomisation.
• Known history of severe hypersensitivity reactions to any study drug
• Not eligible to receive at least one of SoC according to local regulations/approvals.
• Currently pregnant (confirmed with positive pregnancy test), breastfeeding or planning to become pregnant.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

China · 35 centers

• Research Site — Beijing
• Research Site — Beijing
• Research Site — Beijing
• Research Site — Changsha
• Research Site — Chengdu
• Research Site — Chengdu
• Research Site — Chongqing
• Research Site — Chongqing
• … and 27 more centers

Germany · 20 centers

Center list to be confirmed — check the primary protocol.

United States · 19 centers

• Research Site — Hot Springs
• Research Site — Little Rock
• Research Site — Little Rock
• Research Site — San Francisco
• Research Site — Chicago
• Research Site — Boston
• Research Site — Kansas City
• Research Site — Lincoln
• … and 11 more centers

Japan · 17 centers

Center list to be confirmed — check the primary protocol.

Canada · 9 centers

• Research Site — Calgary
• Research Site — Abbotsford British Columbia
• Research Site — Barrie
• Research Site — Hamilton
• Research Site — Kingston
• Research Site — London
• Research Site — Mississauga
• Research Site — Montreal
• … and 1 more center

Australia · 7 centers

• Research Site — Auchenflower
• Research Site — Ballarat
• Research Site — Clayton
• Research Site — Darlinghurst
• Research Site — Elizabeth Vale
• Research Site — South Brisbane
• Research Site — St Albans

India · 7 centers

Center list to be confirmed — check the primary protocol.

Poland · 7 centers

Center list to be confirmed — check the primary protocol.

France · 6 centers

• Research Site — Bordeaux
• Research Site — Montpellier
• Research Site — Paris
• Research Site — Pierre-Bénite
• Research Site — Poitiers
• … and 1 more center

Italy · 6 centers

Center list to be confirmed — check the primary protocol.

Taiwan · 6 centers

Center list to be confirmed — check the primary protocol.

Brazil · 5 centers

• Research Site — Barretos
• Research Site — Curitiba
• Research Site — Salvador
• Research Site — São Paulo
• Research Site — São Paulo

South Korea · 5 centers

Center list to be confirmed — check the primary protocol.

Spain · 5 centers

Center list to be confirmed — check the primary protocol.

United Kingdom · 4 centers

Center list to be confirmed — check the primary protocol.

Thailand · 2 centers

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07720284 · D763TC00001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗