Title
A Phase II, Multicentre, Open-label, Master Protocol to Evaluate the Efficacy and Safety of Datopotamab Deruxtecan (Dato-DXd) as Monotherapy and in Combination with Anticancer Agents in Patients with Advanced/Metastatic Solid Tumours (TROPION-PanTumor03)

Description
This Phase II, open-label, uncontrolled, multicentre study evaluating the efficacy and safety of Dato-DXd as monotherapy (MONO) and in combination with anticancer agents (COMBO) in various advanced solid tumour types.

This study has a modular design, as such a master protocol with independent substudies enables simultaneous evaluation of the safety profile, recommended Phase II dose (RP2D), and efficacy of Dato-DXd in multiple disease populations and treatment combinations. This study will evaluate various solid tumour types, including endometrial cancer (Substudy 1), gastric cancer (Substudy 2), metastatic castration-resistant prostate cancer (mCRPC) (Substudy 3), ovarian cancer (Substudy 4), colorectal cancer (CRC) (Substudy 5), urothelial cancer (Substudy 6) and biliary tract cancer (Substudy 7) in the advanced or metastatic setting. Within each substudy, Dato-DXd will be evaluated as monotherapy (for all substudies except Substudy 2 (Gastric Cancer) and Substudy 6 (Urothelial Cancer) and in combination with approved or novel anticancer agents that may be active in the tumour type being evaluated (for all substudies except Substudy 7).

Objective
Primary Objectives:
- To assess the efficacy of Dato-DXd as monotherapy and in combination with anticancer agents by assessment of ORR
- To assess the safety and tolerability of Dato-DXd as monotherapy and in combination with anticancer agents

Secondary Objectives:
- To further assess the efficacy of Dato-DXd as monotherapy and in combination with anticancer agents by assessment of PFS
- To further assess the efficacy of Dato-DXd as monotherapy and in combination with anticancer agents by assessment of DoR
- To further assess the efficacy of Dato-DXd as monotherapy and in combination with anticancer agents of DCR at 12 and 24 weeks
- To further assess the efficacy of Dato-DXd as monotherapy and in combination with anticancer agents by assessment of Best percentage change in tumour size (where applicable)
- To assess the PK and Dato-DXd, total anti-TROP2 antibody, and MAAA-1181a in plasma
- To investigate the immunogenic potential of Dato-DXd

Treatment Substudy 7 will evaluate the efficacy and safety of Dato-DXd as monotherapy in participants with advanced or metastatic BTC who have positive TROP2 tumour expression (positive membrane staining of any intensity in ≥ 10% of tumour cells by IHC).
This substudy will include the following treatment cohorts:
-Cohort 7A: Dato-DXd monotherapy (6.0 mg/kg every 3 weeks)

Key Eligibility Key Inclusion Criteria:

Male and female, >/= 18 years

Documented advanced or metastatic malignancy

Eastern Cooperative Oncology Group performance status of 0 or 1 with no deterioration over the 2 weeks prior to baseline or day of first dosing

All participants must provide a tumour sample for tissue-based analysis

At least 1 measurable lesion not previously irradiated, except Substudy 3 (Prostate Cancer) which allows participants with non measurable bone metastatic disease

Adequate bone marrow reserve and organ function

Minimum life expectancy of 12 weeks

At the time of screening, contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies

All women of childbearing potential must have a negative serum pregnancy test documented during screening

Female participants must be 1 year post-menopausal, surgically sterile, or using 1 highly effective form of birth control. Female participants must not donate, or retrieve for their own use, ova at any time during this study

Male participants who intend to be sexually active with a female partner of childbearing potential must be surgically sterile, avoid intercourse, or use a highly effective method of contraception. Male participants must not freeze or donate sperm at any time during this study.

Capable of giving signed informed consent

Provision of signed and dated written optional genetic research informed consent prior to collection of samples for optional genetic research that supports the Genomic Initiative

Applicable Disease Sites
Colon and Rectum; Esophagus; Gastrointestinal cancers, other; Genitourinary cancers, other; Ovary; Prostate; Stomach; Uterus

Participating Institutions
UW Health University Hospital