Endometrial Cancer, Gastric Cancer, Metastatic Castration-resistant Prostate Cancer, Ovarian Cancer, Colorectal Cancer, Urothelial Cancer, Biliary Tract Cancer
Conditions
Keywords
TROPION-PanTumor03, Datopotamab Deruxtecan (Dato-DXd), Solid Tumours, Antibody-drug conjugate (ADC), Trophoblast cell surface protein 2 (TROP2)
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) and in combination with approved or novel anticancer agents that may be active in the tumour type being evaluated (for all substudies except Substudy 1 and Substudy 7).
Interventions
Intravenous (IV) Antibody drug conjugate
DRUGCapecitabine
Administered orally
DRUG5-Fluorouracil
Administered as an IV
DRUGVolrustomig
Administered as an IV
DRUGCarboplatin
Administered as an IV
DRUGBevacizumab
Administered as an IV
DRUGRilvegostomig
Administered as an IV
DRUGPrednisone/ prednisolone
Administered orally
DRUGCisplatin
Administered as an IV
Sponsors
AstraZeneca
Daiichi Sankyo
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
The study is open label. Patients will be assigned treatment in all Substudies.
Intervention model description
Within each substudy, Dato-DXd will be evaluated as monotherapy (all except #2 Gastric Cancer) and in combination with approved or novel anticancer agents that may be active in the tumour type being evaluated (all except #1 Endometrial Cancer and #7 Biliary Tract Cancer). All substudies will be treatment assigned. Substudy 1 (Endometrial): MONO: Dato-DXd Substudy 2 (Gastric): COMBO: Dato-DXd + capecitabine, Dato-DXd + 5-fluorouracil (5-FU) Substudy 3 (mCRPC): MONO: Dato-DXd; COMBO: Dato-DXd + prednisone/prednisolone Substudy 4 (Ovarian): MONO: Dato-DXd; COMBO: Dato-DXd + carboplatin + bevacizumab --\> Dato-DXd + bevacizumab Substudy 5 (CRC): MONO: Dato-DXd; COMBO: Dato-DXd + 5-FU + leucovorin + bevacizumab or Dato-DXd + capecitabine + bevacizumab Substudy 6 (Urothelial): MONO: Dato-DXd; COMBO: Dato-DXd + volrustomig, Dato-DXd + rilvegostomig, Dato-DXd + carboplatin or cisplatin Substudy 7 (BTC): MONO: Dato-DXd
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: There are additional substudy requirements not reflected here. This list is based solely on the master CSP * 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 * Irreversible toxicity that is not reasonably expected to be exacerbated by study intervention in the opinion of the investigator, for example hearing loss * 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 * Known active tuberculosis infection * Mean resting corrected QTcF \> 470 ms * In the judgement of the investigator, history of QT prolongation associated with other medications that required discontinuation of that medication, or any current concomitant medication known to prolong the QT interval and cause TdP * In the judgement of the investigator, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives * Uncontrolled or significant cardiac diseases * History of non-infectious Interstitial lung disease (ILD)/pneumonitis, including radiation 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 * Palliative radiotherapy with a limited field of radiation within ≤ 2 weeks or to more than 30% of the bone marrow within ≤ 4 weeks before the first dose of study intervention * 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 therapies or other antibody-drug conjugate (ADCs) with deruxtecan payload * Herbal or natural products intended as treatment or prophylaxis for any type of cancer that may interfere with the activity of the study intervention * Previous treatment in the present study * Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 4 weeks prior to first dose of study intervention or concurrent enrolment in another clinical study * Severe hypersensitivity to Dato-DXd or any of the excipients, including but not limited to polysorbate 80 or other monoclonal antibodies * Involvement in the planning and/or conduct of the study * Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements * Females that are pregnant, breastfeeding, or planning to become pregnant * Female participants should refrain from breastfeeding from enrolment throughout the study and for at least 7 months after last dose of Dato-DXd
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective response rate (ORR) | 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 | 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 (approximately 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) | From baseline to PSA response evaluated according to the PCWG3 criteria (approximately 1 year) | 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. |
| Progression free survival (PFS) response (Substudy 4C only) | 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 or death due to any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) | At approximately 1 year | DCR at 12 and 24 weeks is defined as the percentage of participants who prior to Progression of Disease (PD) and starting anticancer therapy have either at least one visit response of Complete response (CR)/Partial response (PR) or 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 | 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. |
| Pharmacokinetic Parameter of Dato-DXd (all substudies) and volrustomig and rilvegostomig (substudy 6): Area under the plasma concentration- time curve (AUC) | 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 | 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 | Throughout the treatment period at pre-defined intervals (approximately 1 year) | The concentration in plasma will be determined (Cmax will be derived). |
| Anti Drug Antibody (ADA) for Dato-DXd (all substudies) and volrustomig and rilvegostomig (substudy 6) | 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 |
| Radiographic PFS (Substudy 3) | 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 due to any cause. |
| PSA progression (Substudy 3) | From baseline to PSA response evaluated according to the PCWG3 criteria (approximately 1 year) | PSA progression is defined as an increase in PSA (after Week 12) of ≥25% greater than the nadir and an absolute increase of at least 2 ng/mL above nadir. |
| CA-125 response (Substudy 4) | From baseline to CA-125 response evaluated according to the GCIG criteria (approximately 1 year) | Proportion of participants achieving a \> 50% reduction in CA-125 levels from a pre-treatment sample confirmed and maintained for at least 28 days. |
| Pharmacokinetics of Dato-DXd (all substudies) and volrustomig and rilvegostomig (substudy 6): Maximum plasma concentration of the drug (Cmax) | At predefined intervals throughout the treatment period (approximately 1 year) | The concentration in plasma will be determined. |
| Overall survival (OS) (Substudy 4) | From baseline to death (approximately 1 year) | OS is defined as time from start of treatment until death due to any cause. |
| Pharmacokinetics of Dato-DXd (all substudies) and volrustomig and rilvegostomig (substudy 6): The time taken to reach the maximum concentration (Tmax) | At predefined intervals throughout the treatment period (approximately 1 year) | The concentration in plasma will be determined. |
| Progression free survival (PFS) | 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 or death due to any cause. |
| Duration Of Response (DoR) | 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 due to any cause. |
Countries
Canada, China, France, Germany, Italy, Japan, Poland, South Korea, Spain, Switzerland, Taiwan, Turkey (Türkiye), United Kingdom, United States
Contacts
CONTACTAstraZeneca Clinical Study Information Center
PRINCIPAL_INVESTIGATORGlobal Clinical Lead, MD
AstraZeneca
Outcome results
None listed