Study of Dato-Dxd as Monotherapy and in Combination With Anti-cancer Agents in Patients With Advanced Solid Tumours (TROPION-PanTumor03)

Study Overview
=================
Brief Summary
-----------------
TROPION-PanTumor03 will investigate the safety, tolerability, and anti-tumour activity of Datopotamab Deruxtecan (Dato-DXd) as Monotherapy and in Combination with Anticancer Agents in Patients with Advanced/Metastatic Solid Tumours.

Detailed 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).

Official 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

Conditions
-----------------
Endometrial Cancer, Gastric Cancer, Metastatic Castration-resistant Prostate Cancer, Ovarian Cancer, Colorectal Cancer, Urothelial Cancer, Biliary Tract Cancer

Intervention / Treatment
-----------------
* Drug: Datopotamab deruxtecan (Dato-DXd)
* Drug: AZD5305
* Drug: Durvalumab
* Drug: Capecitabine
* Drug: 5-Fluorouracil
* Drug: Volrustomig
* Drug: Carboplatin
* Drug: Leucovorin LV
* Drug: Bevacizumab
* Drug: Rilvegostomig
* Drug: Prednisone/ prednisolone


Participation Criteria
=================
Eligibility Criteria
-----------------
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 Key Exclusion Criteria: Any evidence of diseases which, in the investigator's opinion, makes it undesirable for the participant to participate in the study or that would jeopardize compliance with the protocol History of another primary malignancy except for adequately resected basal cell carcinoma or in situ squamous cell carcinoma of the skin, or other solid malignancy treated with curative intent Persistent toxicities caused by previous anticancer therapy, excluding alopecia, not yet improved Spinal cord compression or brain metastases unless treated Leptomeningeal carcinomatosis Clinically significant corneal disease Active hepatitis or uncontrolled hepatitis B or C virus infection Uncontrolled infection requiring IV antibiotics, antivirals or antifungals, for example prodromal symptoms Known HIV infection that is not well controlled Active TB infection Significant cardiac diseases History of non-infectious Interstitial lung disease (ILD)/pneumonitis that required steroids Has severe pulmonary function compromise Prior exposure to chloroquine/hydroxychloroquine without an adequate treatment washout period Receipt of live, attenuated vaccine within 30 days prior to the first dose of study intervention Prior exposure to anticancer therapies without an adequate treatment washout period prior to enrolment or any concurrent anticancer treatment Major surgical procedure or significant traumatic injury within ≤ 3 weeks of the first dose of study intervention or an anticipated need for major surgery during the study Prior treatment with TROP2-directed Anti-drug antibody, ADC Antibody-drug conjugate (ADCs), other ADCs with deruxtecan payload Severe hypersensitivity to monoclonal antibodies Pregnant, breastfeeding, planning to become pregnant

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Within each substudy, Dato-DXd will be evaluated as monotherapy (all except #2 Gastric Cancer and #6 Urothelial Cancer) and in combination with approved or novel anticancer agents that may be active in the tumour type being evaluated (all except #7 Biliary Tract Cancer). All substudies will be treatment assigned. Substudy 1 (Endometrial): MONO: Dato-DXd monotherapy; COMBO; Dato-DXd + durvalumab, Dato-DXd + AZD5305, Dato-DXd + durvalumab +AZD5305 Substudy 2 (Gastric): Dato-DXd + capecitabine, Dato-DXd + 5-FU, Dato-DXd + capecitabine/ 5-FU + volrustomig (MEDI5752) Substudy 3 (mCRPC): MONO; COMBO: Dato-DXd + AZD5305, Dato-DXd + prednisone/prednisolone Substudy 4 (Ovarian): MONO; COMBO: Dato-DXd + carboplatin --> Dato-DXd + AZD5305 Substudy 5 (CRC): MONO; COMBO Dato-DXd + 5-FU + leucovorin + bevacizumab or Dato-DXd + capecitabine + bevacizumab Substudy 6 (Urothelial): Dato-DXd + volrustomig (MEDI5752), Dato-DXd + rilvegostomig (AZD2936) Substudy 7 (BTC): MONO
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Substudy-1A<br>Dato-DXd will be evaluated as monotherapy | Drug: Datopotamab deruxtecan (Dato-DXd)<br>* Intravenous (IV) Antibody drug conjugate<br>* Other names: DS-1062a;|
| Experimental: Substudy-1B<br>Dato-Dxd in combination with Durvalumab will be evaluated | Drug: Datopotamab deruxtecan (Dato-DXd)<br>* Intravenous (IV) Antibody drug conjugate<br>* Other names: DS-1062a;Drug: Durvalumab<br>* Administered as an IV<br>* Other names: IMFINZI;|
| Experimental: Substudy-1C<br>Dato-Dxd in combination with AZD5305 will be evaluated | Drug: Datopotamab deruxtecan (Dato-DXd)<br>* Intravenous (IV) Antibody drug conjugate<br>* Other names: DS-1062a;Drug: AZD5305<br>* Oral poly ADP ribose polymerase (PARP) inhibitor<br>|
| Experimental: Substudy-1D<br>Dato-Dxd in combination with Durvalumab + AZD5305 will be evaluated | Drug: Datopotamab deruxtecan (Dato-DXd)<br>* Intravenous (IV) Antibody drug conjugate<br>* Other names: DS-1062a;Drug: AZD5305<br>* Oral poly ADP ribose polymerase (PARP) inhibitor<br>Drug: Durvalumab<br>* Administered as an IV<br>* Other names: IMFINZI;|
| Experimental: Substudy-2A<br>Dato-DXd in combination with capecitabine will be evaluated | Drug: Datopotamab deruxtecan (Dato-DXd)<br>* Intravenous (IV) Antibody drug conjugate<br>* Other names: DS-1062a;Drug: Capecitabine<br>* Administered orally<br>* Other names: Xeloda;|
| Experimental: Substudy-2B<br>Dato-DXd in combination with 5-FU will be evaluated | Drug: Datopotamab deruxtecan (Dato-DXd)<br>* Intravenous (IV) Antibody drug conjugate<br>* Other names: DS-1062a;Drug: 5-Fluorouracil<br>* Administered as an IV<br>* Other names: Adrucil;|
| Experimental: Substudy-2C<br>Dato-DXd in combination with chemotherapy (capecitabine or 5-FU) + volrustomig (MEDI5752) will be evaluated | Drug: Datopotamab deruxtecan (Dato-DXd)<br>* Intravenous (IV) Antibody drug conjugate<br>* Other names: DS-1062a;Drug: Capecitabine<br>* Administered orally<br>* Other names: Xeloda;Drug: 5-Fluorouracil<br>* Administered as an IV<br>* Other names: Adrucil;Drug: Volrustomig<br>* Administered as an IV<br>* Other names: MEDI5752;|
| Experimental: Substudy-3A<br>Dato-DXd will be evaluated as monotherapy | Drug: Datopotamab deruxtecan (Dato-DXd)<br>* Intravenous (IV) Antibody drug conjugate<br>* Other names: DS-1062a;|
| Experimental: Substudy-3B<br>Dato-DXd in combination with AZD5305 will be evaluated | Drug: Datopotamab deruxtecan (Dato-DXd)<br>* Intravenous (IV) Antibody drug conjugate<br>* Other names: DS-1062a;Drug: AZD5305<br>* Oral poly ADP ribose polymerase (PARP) inhibitor<br>|
| Experimental: Substudy-3C<br>Dato-DXd will be evaluated in combination with prednisone/prednisolone | Drug: Datopotamab deruxtecan (Dato-DXd)<br>* Intravenous (IV) Antibody drug conjugate<br>* Other names: DS-1062a;Drug: Prednisone/ prednisolone<br>* Administered orally<br>* Other names: Prednisolone;|
| Experimental: Substudy-4A<br>Dato DXd will be evaluated as monotherapy | Drug: Datopotamab deruxtecan (Dato-DXd)<br>* Intravenous (IV) Antibody drug conjugate<br>* Other names: DS-1062a;|
| Experimental: Substudy-4B<br>Dato-DXd in combination with carboplatin followed by Dato-DXd + AZD5305 will be evaluated | Drug: Datopotamab deruxtecan (Dato-DXd)<br>* Intravenous (IV) Antibody drug conjugate<br>* Other names: DS-1062a;Drug: AZD5305<br>* Oral poly ADP ribose polymerase (PARP) inhibitor<br>Drug: Carboplatin<br>* Administered as an IV<br>* Other names: Paraplatin;|
| Experimental: Substudy-5A<br>Dato-DXd will be evaluated as monotherapy | Drug: Datopotamab deruxtecan (Dato-DXd)<br>* Intravenous (IV) Antibody drug conjugate<br>* Other names: DS-1062a;|
| Experimental: Substudy-5B<br>Dato-DXd + 5-FU + LV + bevacizumab OR Dato-DXd + capecitabine + bevacizumab will be evaluated | Drug: Datopotamab deruxtecan (Dato-DXd)<br>* Intravenous (IV) Antibody drug conjugate<br>* Other names: DS-1062a;Drug: Capecitabine<br>* Administered orally<br>* Other names: Xeloda;Drug: 5-Fluorouracil<br>* Administered as an IV<br>* Other names: Adrucil;Drug: Leucovorin LV<br>* Administered as an IV<br>* Other names: Folinic acid;Drug: Bevacizumab<br>* Administered as an IV<br>* Other names: Avastin;|
| Experimental: Substudy- 6A<br>Dato-DXd in combination with volrustomig (MEDI5752) will be evaluated | Drug: Datopotamab deruxtecan (Dato-DXd)<br>* Intravenous (IV) Antibody drug conjugate<br>* Other names: DS-1062a;Drug: Volrustomig<br>* Administered as an IV<br>* Other names: MEDI5752;|
| Experimental: Substudy-6B<br>Data-DXd in combination with rilvegostomig (AZD2936) will be evaluated | Drug: Datopotamab deruxtecan (Dato-DXd)<br>* Intravenous (IV) Antibody drug conjugate<br>* Other names: DS-1062a;Drug: Rilvegostomig<br>* Administered as an IV<br>* Other names: AZD2936;|
| Experimental: Substudy- 7A<br>Dato-DXd will be evaluated as monotherapy | Drug: Datopotamab deruxtecan (Dato-DXd)<br>* Intravenous (IV) Antibody drug conjugate<br>* Other names: DS-1062a;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | Proportion of participants who have a confirmed CR or confirmed PR, as determined by the investigator at local site per RECIST 1.1. | From baseline to progressive disease or death (approximately 1 year) | 
| The number of subjects with adverse events/serious adverse events | Number of patients with adverse events and with serious adverse events including abnormal clinical observations, abnormal Electrocardiogram (ECG) parameters, abnormal laboratory assessments and abnormal vital signs that changed from baseline. | Throughout the treatment and the safety follow-up period 28 [+ 7] days after the discontinuation of all study interventions, except durvalumab, nivolumab, and bevacizumab for which it will be 90 [+ 7] days (approximatelt 1 year) | 
| PSA50 response (Substudy 3 only) | Proportion of participants achieving a ≥ 50% decrease in PSA from baseline to the lowest post-baseline PSA result, confirmed by a second consecutive PSA assessment at least 3 weeks later. | Time to PSA progression is defined as the time from randomization to PSA progression per PCWG3 criteria (up to 12 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) | PFS is defined as time from start of treatment until progression per RECIST 1.1 as assessed by the investigator. | From baseline to progressive disease or death (approximately 1 year) | 
| Duration Of Response (DOR) | DoR is defined as the time from the date of first documented confirmed response until date of documented progression per RECIST 1.1 as assessed by the investigator or death. | From baseline to progressive disease or death (approximately 1 year) | 
| Disease Control Rate (DCR) | DCR at 12 and 24 weeks is defined as the percentage of participants who have a Complete response (CR) or Partial response (PR) in the first 13 and 25 weeks or who have Stable disease (SD) for at least 11 and 23 weeks after the date of first dose respectively, per RECIST 1.1 as assessed by the investigator at local site and derived from the raw tumour data. | at 12 and 24 weeks | 
| Best percentage change in tumour size | The best percentage change from baseline in tumour size will be derived as the maximum reduction from baseline or (in the absence of reduction) the minimum increase from baseline. | From baseline to progressive disease or death (approximately 1 year) | 
| Anti Drug Antibody (ADA) for Dato-DXd (all substudies), Durvalumab (substudy 1), volrustomig and rilvegostomig (substudy 6) | Whole blood samples for determination of ADA in plasma will be collected; Percentage of patients who develop ADA | Throughout the treatment period at pre-defined intervals and including the safety follow-up period (approximately 1 year) | 
| Pharmacokinetics of Dato-DXd (all substudies), durvalumab (substudy 1) and AZD5305 (substudy 1, substudy 3, substudy 4), volrustomig and rilvegostomig (substudy 6): Maximum plasma concentration of the drug (Cmax) | The concentration in plasma will be determined. | At predefined intervals throughout the treatment period (approximately 1 year) | 
| Pharmacokinetics of Dato-DXd (all substudies), durvalumab (substudy 1) and AZD5305 (substudy 1, substudy 3, substudy 4), volrustomig and rilvegostomig (substudy 6): The time taken to reach the maximum concentration (Tmax) | The concentration in plasma will be determined. | At predefined intervals throughout the treatment period (approximately 1 year) | 
| Pharmacokinetic Parameter of Dato-DXd (all substudies), durvalumab (substudy 1) and AZD5305 (substudy 1, substudy 3, substudy 4), volrustomig and rilvegostomig (substudy 6): Area under the plasma concentration- time curve (AUC) | The concentration in plasma will be determined. Area under the curve is the integral of the concentration-time curve. The AUC reflects the actual body exposure to drug after administration. The AUC is dependent on the rate of elimination of the drug from the body and the dose administered. | At predefined intervals throughout the treatment period (approximately 1 year) | 
| Plasma concentration of Total anti-TROP2 antibody | Expression of TROP2 will be measured in blood sample | Throughout the treatment period at pre-defined intervals (approximately 1 year) | 
| Plasma concentration of MAAA-1181a | The concentration in plasma will be determined (Cmax will be derived). | Throughout the treatment period at pre-defined intervals (approximately 1 year) | 
| Radiographic PFS (substudy 3) | PFS is defined as time from start of treatment until radiographic progression per RECIST 1.1 (soft tissue) and/or PCWG3 criteria (bone) as assessed by the investigator or death. | From baseline to radiographic progression or death (approximately 1 year) | 
| Overall survival (OS) (substudy 4) | OS is defined as time from start of treatment until death. | From baseline to death (approximately 1 year) | 
| CA-125 response (Substudy 4) | Proportion of participants achieving a > 50% reduction in CA-125 levels from a pre-treatment sample confirmed and maintained for at least 28 days. | From baseline to CA-125 response evaluated according to the GCIG criteria (up to 12 weeks) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
TROPION-PanTumor03, Datopotamab Deruxtecan (Dato-DXd), Solid Tumours, Antibody-drug conjugate (ADC), Trophoblast cell surface protein 2 (TROP2)