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

• ClinicalTrials.gov Identifier: NCT05489211
• Recruitment Status: Recruiting
• First Posted: August 5, 2022
• Last Update Posted: April 25, 2024
• Sponsor: AstraZeneca
• Collaborator: Daiichi Sankyo
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: July 21, 2022
• First Posted Date: August 5, 2022
• Last Update Posted Date: April 25, 2024
• Actual Study Start Date: September 6, 2022
• Estimated Primary Completion Date: August 19, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 24, 2023)

• Objective response rate (ORR) [ Time Frame: From baseline to progressive disease or death (approximately 1 year) ]
  Proportion of participants who have a confirmed CR or confirmed PR, as determined by the investigator at local site per RECIST 1.1.
• The number of subjects with adverse events/serious adverse events [ Time Frame: 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) ]
  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.
• PSA50 response (Substudy 3 only) [ Time Frame: Time to PSA progression is defined as the time from randomization to PSA progression per PCWG3 criteria (up to 12 weeks) ]
  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.

Original Primary Outcome Measures (submitted: August 3, 2022)

• Objective response rate (ORR) [ Time Frame: From baseline to progressive disease or death (approximately 1 year) ]
  Best response until progression, as defined by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1.
• The number of subjects with adverse events/serious adverse events [ Time Frame: 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) ]
  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.

Current Secondary Outcome Measures (submitted: August 24, 2023)

• Progression free survival (PFS) [ Time Frame: From baseline to progressive disease or death (approximately 1 year) ]
  PFS is defined as time from start of treatment until progression per RECIST 1.1 as assessed by the investigator.
• Duration Of Response (DOR) [ Time Frame: From baseline to progressive disease or death (approximately 1 year) ]
  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.
• Disease Control Rate (DCR) [ Time Frame: at 12 and 24 weeks ]
  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.
• Best percentage change in tumour size [ Time Frame: From baseline to progressive disease or death (approximately 1 year) ]
  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.
• Anti Drug Antibody (ADA) for Dato-DXd (all substudies), Durvalumab (substudy 1), volrustomig and rilvegostomig (substudy 6) [ Time Frame: Throughout the treatment period at pre-defined intervals and including the safety follow-up period (approximately 1 year) ]
  Whole blood samples for determination of ADA in plasma will be collected; Percentage of patients who develop ADA
• 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) [ Time Frame: At predefined intervals throughout the treatment period (approximately 1 year) ]
  The concentration in plasma will be determined.
• 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) [ Time Frame: At predefined intervals throughout the treatment period (approximately 1 year) ]
  The concentration in plasma will be determined.
• 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) [ Time Frame: At predefined intervals throughout the treatment period (approximately 1 year) ]
  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.
• Plasma concentration of Total anti-TROP2 antibody [ Time Frame: Throughout the treatment period at pre-defined intervals (approximately 1 year) ]
  Expression of TROP2 will be measured in blood sample
• Plasma concentration of MAAA-1181a [ Time Frame: Throughout the treatment period at pre-defined intervals (approximately 1 year) ]
  The concentration in plasma will be determined (Cmax will be derived).
• Radiographic PFS (substudy 3) [ Time Frame: From baseline to radiographic progression or death (approximately 1 year) ]
  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.
• Overall survival (OS) (substudy 4) [ Time Frame: From baseline to death (approximately 1 year) ]
  OS is defined as time from start of treatment until death.
• CA-125 response (Substudy 4) [ Time Frame: From baseline to CA-125 response evaluated according to the GCIG criteria (up to 12 weeks) ]
  Proportion of participants achieving a > 50% reduction in CA-125 levels from a pre-treatment sample confirmed and maintained for at least 28 days.

Original Secondary Outcome Measures (submitted: August 3, 2022)

• Progression free survival (PFS) [ Time Frame: From baseline to progressive disease or death (approximately 1 year) ]
  PFS is defined as time from start of treatment until progression per RECIST 1.1 as assessed by the investigator.
• Duration Of Response (DOR) [ Time Frame: From baseline to progressive disease or death (approximately 1 year) ]
  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.
• Disease Control Rate (DCR) [ Time Frame: at 12 and 24 weeks ]
  DCR at 12 and 24 weeks is defined as the percentage of participants who have a confirmed 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.
• Best percentage change in tumour size [ Time Frame: From baseline to progressive disease or death (approximately 1 year) ]
  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.
• Anti Drug Antibody (ADA) [ Time Frame: Throughout the treatment period at pre-defined intervals and including the safety follow-up period (approximately 1 year) ]
  Whole blood samples for determination of ADA for Dato-DXd in plasma will be collected in patients receiving Dato-DXd;Percentage of patients who develop ADA for Dato-Dxd
• Pharmacokinetics of Dato-DXd, Maximum plasma concentration of the drug (Cmax) [ Time Frame: At predefined intervals throughout the treatment period (approximately 1 year) ]
  The concentration of Dato-Dxd in plasma will be determined (Cmax will be derived).
• Pharmacokinetics of Dato-DXd, The time taken to reach the maximum concentration (Tmax) [ Time Frame: At predefined intervals throughout the treatment period (approximately 1 year) ]
  The concentration of Dato-DXd in plasma will be determined (Tmax will be derived).
• Pharmacokinetic Parameter: Area under the plasma concentration- time curve (AUC) [ Time Frame: At predefined intervals throughout the treatment period (approximately 1 year) ]
  The concentration of Dato-Dxd 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.
• Plasma concentration of Total anti-TROP2 antibody [ Time Frame: Throughout the treatment period at pre-defined intervals (approximately 1 year) ]
  Expression of TROP2 will be measured in blood sample
• Plasma concentration of MAAA-1181a [ Time Frame: Throughout the treatment period at pre-defined intervals (approximately 1 year) ]
  The concentration in plasma will be determined (Cmax will be derived).

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention 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 + Saruparib, Dato-DXd + durvalumab +Saruparib

Substudy 2 (Gastric): Dato-DXd + capecitabine, Dato-DXd + 5-FU, Dato-DXd + capecitabine/ 5-FU + volrustomig

Substudy 3 (mCRPC): MONO; COMBO: Dato-DXd + AZD5305, Dato-DXd + prednisone/prednisolone

Substudy 4 (Ovarian): MONO; COMBO: Dato-DXd + carboplatin --> Dato-DXd + Saruparib

Substudy 5 (CRC): MONO; COMBO Dato-DXd + 5-FU + leucovorin + bevacizumab or Dato-DXd + capecitabine + bevacizumab

Substudy 6 (Urothelial): Dato-DXd + volrustomig, Dato-DXd + rilvegostomig

Substudy 7 (BTC): MONO

Masking: None (Open Label)
Masking Description:

The study is open label. Patients will be assigned treatment in all Substudies.

Primary Purpose: Treatment

Condition

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

Intervention

• Drug: Datopotamab deruxtecan (Dato-DXd)
  Intravenous (IV) Antibody drug conjugate
  Other Name: DS-1062a
• Drug: Saruparib
  Oral poly ADP ribose polymerase (PARP) inhibitor
  Other Name: AZD5305
• Drug: Durvalumab
  Administered as an IV
  Other Names:

  • MEDI4736
  • IMFINZI
• Drug: Capecitabine
  Administered orally
  Other Name: Xeloda
• Drug: 5-Fluorouracil
  Administered as an IV
  Other Name: Adrucil
• Drug: Volrustomig
  Administered as an IV
  Other Name: MEDI5752
• Drug: Carboplatin
  Administered as an IV
  Other Name: Paraplatin
• Drug: Leucovorin LV
  Administered as an IV
  Other Name: Folinic acid
• Drug: Bevacizumab
  Administered as an IV
  Other Name: Avastin
• Drug: Rilvegostomig
  Administered as an IV
  Other Name: AZD2936
• Drug: Prednisone/ prednisolone
  Administered orally
  Other Name: Prednisolone

Study Arms

• Experimental: Substudy-1A
  Dato-DXd will be evaluated as monotherapy
  Intervention: Drug: Datopotamab deruxtecan (Dato-DXd)
• Experimental: Substudy-1B
  Dato-Dxd in combination with Durvalumab will be evaluated
  Interventions:

  • Drug: Datopotamab deruxtecan (Dato-DXd)
  • Drug: Durvalumab
• Experimental: Substudy-1C
  Dato-Dxd in combination with Saruparib (AZD5305) will be evaluated
  Interventions:

  • Drug: Datopotamab deruxtecan (Dato-DXd)
  • Drug: Saruparib
• Experimental: Substudy-1D
  Dato-Dxd in combination with Durvalumab + Saruparib (AZD5305) will be evaluated
  Interventions:

  • Drug: Datopotamab deruxtecan (Dato-DXd)
  • Drug: Saruparib
  • Drug: Durvalumab
• Experimental: Substudy-2A
  Dato-DXd in combination with capecitabine will be evaluated
  Interventions:

  • Drug: Datopotamab deruxtecan (Dato-DXd)
  • Drug: Capecitabine
• Experimental: Substudy-2B
  Dato-DXd in combination with 5-FU will be evaluated
  Interventions:

  • Drug: Datopotamab deruxtecan (Dato-DXd)
  • Drug: 5-Fluorouracil
• Experimental: Substudy-2C
  Dato-DXd in combination with chemotherapy (capecitabine or 5-FU) + volrustomig (MEDI5752) will be evaluated
  Interventions:

  • Drug: Datopotamab deruxtecan (Dato-DXd)
  • Drug: Capecitabine
  • Drug: 5-Fluorouracil
  • Drug: Volrustomig
• Experimental: Substudy-3A
  Dato-DXd will be evaluated as monotherapy
  Intervention: Drug: Datopotamab deruxtecan (Dato-DXd)
• Experimental: Substudy-3B
  Dato-DXd in combination with Saruparib (AZD5305) will be evaluated
  Interventions:

  • Drug: Datopotamab deruxtecan (Dato-DXd)
  • Drug: Saruparib
• Experimental: Substudy-3C
  Dato-DXd will be evaluated in combination with prednisone/prednisolone
  Interventions:

  • Drug: Datopotamab deruxtecan (Dato-DXd)
  • Drug: Prednisone/ prednisolone
• Experimental: Substudy-4A
  Dato DXd will be evaluated as monotherapy
  Intervention: Drug: Datopotamab deruxtecan (Dato-DXd)
• Experimental: Substudy-4B
  Dato-DXd in combination with carboplatin followed by Dato-DXd + Saruparib (AZD5305) will be evaluated
  Interventions:

  • Drug: Datopotamab deruxtecan (Dato-DXd)
  • Drug: Saruparib
  • Drug: Carboplatin
• Experimental: Substudy-5A
  Dato-DXd will be evaluated as monotherapy
  Intervention: Drug: Datopotamab deruxtecan (Dato-DXd)
• Experimental: Substudy-5B
  Dato-DXd + 5-FU + LV + bevacizumab OR Dato-DXd + capecitabine + bevacizumab will be evaluated
  Interventions:

  • Drug: Datopotamab deruxtecan (Dato-DXd)
  • Drug: Capecitabine
  • Drug: 5-Fluorouracil
  • Drug: Leucovorin LV
  • Drug: Bevacizumab
• Experimental: Substudy- 6A
  Dato-DXd in combination with volrustomig (MEDI5752) will be evaluated
  Interventions:

  • Drug: Datopotamab deruxtecan (Dato-DXd)
  • Drug: Volrustomig
• Experimental: Substudy-6B
  Data-DXd in combination with rilvegostomig (AZD2936) will be evaluated
  Interventions:

  • Drug: Datopotamab deruxtecan (Dato-DXd)
  • Drug: Rilvegostomig
• Experimental: Substudy- 7A
  Dato-DXd will be evaluated as monotherapy
  Intervention: Drug: Datopotamab deruxtecan (Dato-DXd)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 24, 2024): 531
• Original Estimated Enrollment (submitted: August 3, 2022): 451
• Estimated Study Completion Date: August 19, 2026
• Estimated Primary Completion Date: August 19, 2026 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 130 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: AstraZeneca Clinical Study Information Center; 1-877-240-9479; information.center@astrazeneca.com

• Listed Location Countries: Canada, China, France, Germany, Italy, Japan, Korea, Republic of, Poland, Spain, Switzerland, Taiwan, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT05489211
• Other Study ID Numbers: D926UC00001; 2022-000776-19 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the European Federation of Pharmaceutical Industries and Associations (EFPIA) Pharma Data Sharing Principles. For details of our timelines, please refer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

• Current Responsible Party: AstraZeneca
• Original Responsible Party: Same as current
• Current Study Sponsor: AstraZeneca
• Original Study Sponsor: Same as current
• Collaborators: Daiichi Sankyo

Investigators

• Principal Investigator: Global Clinical Lead, MD; AstraZeneca

• PRS Account: AstraZeneca
• Verification Date: April 2024