Evaluation of Datopotamab Deruxtecan Monotherapy and Combination Therapy in Advanced/Metastatic Solid Tumors: A Phase II Multicenter Study
- Trial ID
- 2023-509436-26-00
- Protocol
- D926UC00001
- Sponsor
- AstraZeneca AB
Trial statistics
Objectives
The primary objective of this study is to evaluate the **efficacy** of Datopotamab Deruxtecan (Dato-DXd) as monotherapy and in combination with anticancer agents by assessing the Objective Response Rate (ORR). Additionally, the study aims to assess the safety and tolerability of Dato-DXd in these treatment settings. This is clinically relevant as it seeks to determine the potential of Dato-DXd in treating patients with advanced or metastatic solid tumors, which include endometrial cancer, gastric cancer, metastatic castration-resistant prostate cancer, ovarian cancer, colorectal cancer, urothelial cancer, and biliary tract cancer.
The secondary objectives include:
- Further assessment of the efficacy of Dato-DXd as monotherapy and in combination with anticancer agents by evaluating Progression-Free Survival (PFS), Duration of Response (DoR), Disease Control Rate (DCR) at 12 and 24 weeks, and the best percentage change in tumor size where applicable.
- Assessment of the pharmacokinetics (PK) of Dato-DXd, total anti-TROP2 antibody, and MAAA-1181a in plasma.
- Investigation of the immunogenic potential of Dato-DXd.
Participants
The clinical trial involves a total of **582 participants** diagnosed with various advanced or metastatic malignancies, including **endometrial cancer**, gastric cancer, metastatic castration-resistant prostate cancer, ovarian cancer, colorectal cancer, urothelial cancer, and biliary tract cancer. The study population comprises both male and female subjects aged 18 years and older. Participants were selected based on their ability to provide informed consent and their histologically or cytologically documented advanced or metastatic malignancy. The trial includes individuals with an Eastern Cooperative Oncology Group performance status of 0 or 1, indicating a relatively stable health status. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to specific contraceptive guidelines to prevent pregnancy during the study. The trial population includes a vulnerable population, and all participants must have adequate bone marrow reserve and organ function. Key inclusion criteria include the provision of a tumor sample for tissue-based analysis and a minimum life expectancy of 12 weeks. The sponsor has not provided additional information regarding specific lifestyle factors or other demographic details.
Plans and Procedures
The clinical trial is designed as a **Phase II**, multicenter, open-label study to evaluate the efficacy and safety of **Datopotamab Deruxtecan** (Dato-DXd) as monotherapy and in combination with anticancer agents in patients with advanced or metastatic solid tumors. The trial will include patients with conditions such as endometrial cancer, gastric cancer, metastatic castration-resistant prostate cancer, ovarian cancer, colorectal cancer, urothelial cancer, and biliary tract cancer. The study will assess the objective response rate (ORR) as the primary endpoint, alongside safety and tolerability measures, including adverse events (AEs), serious adverse events (SAEs), and changes in laboratory findings.
The trial will follow a structured sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and adequate organ function. Participants will then undergo randomization and treatment assignment. Follow-up visits will be scheduled to monitor treatment response and safety, with assessments including physical examinations, laboratory tests, and imaging studies. The end-of-study visit will conclude the participant's involvement, with final evaluations to document outcomes and any long-term effects.
Participants are expected to be involved in the trial from the estimated recruitment start date of May 1, 2024, until the estimated end date of August 19, 2026. The duration of individual participation will vary based on treatment response and tolerability. Conditions that may lead to early termination from the study include significant adverse reactions, disease progression, or withdrawal of consent. The trial will adhere to ethical standards, ensuring informed consent and compliance with local regulations regarding contraception and reproductive health for participants of childbearing potential.
Treatment
The clinical trial involves the administration of several experimental and non-experimental medications. **Datopotamab deruxtecan** is an experimental medication used in this study. It is an **antibody drug conjugate** formulated as a solution for infusion. The active substance, **DATOPOTAMAB DERUXTECAN**, is administered intravenously. The dosage is measured in milligrams per kilogram (mg/kg), with a maximum treatment period specified as 999999 time units. This medication is provided by DAIICHI SANKYO, INC.
**Rilvegostomig**, also known by its sponsor product code AZD2936, is another experimental medication in the trial. It is a **biologic** formulated as a solution for infusion, containing the active substance **RILVEGOSTOMIG**. This medication is administered intravenously, with dosing in milligrams (mg) and a maximum treatment period of 999999 time units. It is supplied by ASTRAZENECA AB.
**Volrustomig**, with the sponsor product code MEDI5752, is included as an experimental treatment. It is a **biologic** solution for infusion, containing the active substance **VOLRUSTOMIG**. The administration route is intravenous, with dosing in milligrams (mg) and a maximum treatment period of 999999 time units. This product is also provided by ASTRAZENECA AB.
**Calcium folinate** is used as a non-experimental treatment in the study. It is a **detoxifying agent** available as a solution for injection. The active substance, **CALCIUM FOLINATE**, is administered intravenously. The dosage is measured in milligrams per square meter (mg/m²), with a maximum treatment period of 999999 time units.
**Infliximab** is another non-experimental treatment, classified as an **immunosuppressant**. It is formulated as a solution for infusion, with the active substance **INFLIXIMAB** administered intravenously. The dosage is in milligrams per kilogram (mg/kg), with a maximum treatment period of 999999 time units.
**Fluorouracil** is included as a non-experimental treatment, categorized under **pyrimidine analogues**. It is available as a solution for injection/infusion, with the active substance **FLUOROURACIL** administered intravenously. The dosage is in milligrams per square meter (mg/m²), with a maximum treatment period of 999999 time units.
**Carboplatin** is used as a non-experimental treatment, classified as an **antineoplastic agent**. It is formulated as a solution for infusion, with the active substance **CARBOPLATIN** administered intravenously. The dosage is in milligrams (mg), with a maximum treatment period of 999999 time units.
**Capecitabine** is another non-experimental treatment, also classified as an **antineoplastic agent**. It is available as a film-coated tablet, with the active substance **CAPECITABINE** administered orally. The dosage is in milligrams per square meter (mg/m²), with a maximum treatment period of 999999 time units.
**Bevacizumab** is included as a non-experimental treatment, categorized as a **biologic**. It is a concentrate for solution for infusion, with the active substance **BEVACIZUMAB** administered intravenously. The dosage is in milligrams per kilogram (mg/kg), with a maximum treatment period of 999999 time units.
**Cisplatin** is used as a non-experimental treatment, classified as an **antineoplastic agent**. It is a concentrate for solution for infusion, with the active substance **CISPLATIN** administered intravenously. The dosage is in milligrams per square meter (mg/m²), with a maximum treatment period of 999999 time units.
**Prednisolone** is included as a non-experimental treatment, categorized as a **corticosteroid**. It is available in tablet form, with the active substance **PREDNISOLONE** administered orally. The dosage is in milligrams (mg), with a maximum treatment period of 999999 time units.
**Mycophenolate mofetil** is used as a non-experimental treatment, classified under **immunosuppressive agents**. It is available as a hard capsule, with the active substance **MYCOPHENOLATE MOFETIL** administered orally. The dosage is in milligrams per square meter (mg/m²), with a maximum treatment period of 999999 time units.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen. All medications are sourced locally or supplied centrally by AZ AB or Fisher DE, as applicable.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the **Objective Response Rate (ORR)**, which measures the proportion of patients with a predefined reduction in tumor size, and the assessment of adverse events (AEs) and serious adverse events (SAEs), along with changes in laboratory findings, ECGs, vital signs, physical examinations, and ophthalmologic assessments. For specific substudies, additional primary endpoints such as PSA50 response in castration-resistant prostate cancer and progression-free survival (PFS) in ovarian cancer will be evaluated.
Secondary endpoints will further assess efficacy through measures such as progression-free survival (PFS), duration of response (DoR), disease control rate (DCR), and the best percentage change in tumor size. Pharmacokinetic parameters, including plasma concentrations of the investigational drugs and the presence of anti-drug antibodies (ADAs), will also be analyzed. Specific substudies will evaluate additional endpoints like radiographic progression-free survival (rPFS), time to PSA progression, CA-125 response, and overall survival (OS) in ovarian cancer.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male and female, = 18 years at the time of screening
- Histologically or cytologically documented advanced or metastatic malignancy.
- Eastern Cooperative Oncology Group performance status of 0 or 1 with no deterioration over the previous 2 weeks prior to baseline or day of first dosing.
- All participants must provide an archival FFPE tumour sample or newly acquired FFPE tumour sample for tissue-based analysis.
- At least 1 lesion not previously irradiated that qualifies as a RECIST 1.1 target lesion at baseline and can be accurately measured at baseline as = 10 mm in the longest diameter (except lymph nodes, which must have short axis = 15 mm) with CT or MRI and is suitable for accurate repeated measurements. Substudy 3 (mCRPC) allows enrolment of participants with nonmeasurable (by RECIST 1.1) bone metastatic disease.
- Adequate bone marrow reserve and organ function within 7 days before randomization/treatment assignment defined as: -Haemoglobin = 9.0 g/dL (red blood cell/plasma transfusion or red blood cell stimulating factor, such as erythropoietin, is not allowed within 1 week prior to screening assessment) -Absolute neutrophil count = 1.5 × 109/L (granulocyte colony stimulating factor administration is not allowed within 1 week prior to screening assessment).; pegylated granulocyte colony stimulating factor is not allowed within 2 weeks prior to screening assessment). -Platelet count =100 × 109/L (platelet transfusion or platelet stimulating factor, such as thrombopoietin, is not allowed within 1 week prior to screening assessment). -Serum albumin = 2.5 g/dL, -International normalised ratio/prothrombin time and either partial thromboplastin time or activated partial thromboplastin time = 1.5 × ULN. -Total bilirubin = 1.5 × ULN or < 3 × ULN in the presence of documented Gilbert's syndrome. -Except in the setting of HBV, ALT and AST = 3 × ULN (< 5 × ULN in participants with liver metastases). See Exclusion Criterion 8 for requirements in the setting of HBV. -Calculated CrCL = 30 mL/min
- 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 pregnancy test (serum) documented during screening.
- Female participants must be 1 year post-menopausal, surgically sterile, or using 1 highly effective form of birth control. Women of childbearing potential must agree to use 1 highly effective method of birth control or avoid intercourse. They should have been stable on their chosen method of birth control for a minimum of 3 months before entering the study and continue for at least 7 months after the last dose of Dato-DXd. Starting at the time of first dose of Dato-DXd, female participants must not donate, or retrieve for their own use, ova at any time during this study and for at least 7 months after the last dose of Dato-DXd. Preservation of ova should be considered prior to enrolment in this study.
- Male participants who intend to be sexually active with a female partner of childbearing potential must be surgically sterile, avoid intercourse, or using a highly effective method of contraception from the time of screening throughout the total duration of the study and for at least 4 months after the last dose of Dato-DXd (6 months for France), in addition to the female partner using a highly effective contraception method, to prevent pregnancy in a partner. Starting at the time of first dose of Dato-DXd, male participants must not freeze or donate sperm at any time during this study and for at least 4 months after the last dose of Dato-DXd (6 months for France). Preservation of sperm should be considered prior to enrolment in this study. For substudy cohorts involving 5-FU or capecitabine, at least 6 months after the last dose of these study interventions will be required.
- Capable of giving signed informed consent
- Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports the Genomic Initiative.
- ***However, where specific substudy criteria differ from the master criteria below, the substudy criteria should be applied.
Exclusion Criteria
- Any evidence of diseases such as QT prolongation and persistent toxicities associated with prior or current medication or previous anticancer therapy
- History of another primary malignancy within 3 years prior to the first dose, except for those treated with curative intent and with no known active disease and low risk of recurrence (e.g., adequately treated basal cell carcinoma, squamous cell carcinoma, or carcinoma in situ).
- Persistent toxicities (excluding alopecia) from previous anticancer therapy that have not improved to Grade ≤1 or baseline, according to CTCAE v5.0
- Participants with irreversible toxicities (e.g., hearing loss) not reasonably expected to be exacerbated by study intervention may be eligible at the investigator’s discretion.
- Spinal cord compression or brain metastases unless treated, asymptomatic, stable, and not requiring steroids for at least 4 wks prior to randomisation/start of study intervention. A min 2 wks must have elapsed between the end of whole brain radiotherapy/stereotactic radiation and study enrolment
- Leptomeningeal carcinomatosis
- Clinically significant corneal disease
- Active hepatitis B or C infection (unless controlled as per protocol requirements), or any other uncontrolled chronic hepatitis.
- Uncontrolled infection requiring IV antibiotics, antivirals or antifungals eg, prodromal symptoms
- Known HIV infection unless well controlled (according to protocol-specific definitions, e.g., stable on antiretroviral therapy, undetectable viral load).
- Known to have active tuberculosis infection
- Mean resting corrected QTcF > 470 ms, regardless of gender, obtained from triplicate 12-lead ECGs performed at screening
- History of QT prolongation associated with other medications that required discontinuation of that medication, any current concomitant medication known to prolong the QT interval and cause TdP. Congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death <40 years of age in first-degree relatives.
- History of drug-induced QT prolongation requiring discontinuation, current use of medications known to prolong QT and cause torsades de pointes, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death in a first-degree relative aged <40.
- History of non-infectious ILD/pneumonitis that required steroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening
- Has severe pulmonary function compromised
- Prior exposure to chloroquine/hydroxychloroquine without an adequate treatment washout period of > 14d prior to first dose
- Receipt of live, attenuated vaccine within 30d prior to the 1st dose of the study intervention
- Prior exposure to the following anticancer therapies without an adequate treatment washout period prior to enrolment: Immunotherapy non-antibody-based therapy, retinoid therapy: = 2 wks or 5 times the terminal elimination t1/2 of the chemotherapeutic agent, whichever is longer;= 6 wks for nitrosoureas or mitomycin C. Antibodybased anticancer therapy: = 4 wks
- Any concurrent anticancer treatment
- Palliative radiotherapy with a limited field of radiation within = 2 wks or to more than 30% of the bone marrow within = 4 wks before the first dose of study intervention
- Major surgical procedure or significant traumatic injury within = 3 wks of the first dose of study intervention or an anticipated need for major surgery during the study
- Prior treatment with TROP2-directed therapies
- Prior treatment with other ADCs with deruxtecan payload
- Previous treatment in the present study
- Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 4 wks prior to first dose of study intervention or concurrent enrolment in another clinical study, unless it is non-interventional clinical study or during the follow-up period of an interventional 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, conducting of the study (AZ staff and/or staff at the study site)
- The participant is unlikely to comply with study procedures, restrictions and requirements.
- Pregnant, breastfeeding, planning to become pregnant
- Herbal or natural products intended as treatment or prophylaxis for any type of cancer that may interfere with the activity of the study intervention are excluded, see AI2
- Female participants should refrain from breastfeeding from enrolment throughout the study and for at least 7 months after last dose of Dato-DXd
- Participants legally protected cannot be included
- *However, where specific substudy criteria differ from the master criteria below, the substudy criteria should be applied
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 01 May 2024 | 29 |
 Italy | Recruiting | 01 May 2024 | 13 |
 Poland | Recruiting | 01 May 2024 | 25 |
 Spain | Recruiting | 01 May 2024 | 52 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
CALCIUM FOLINATE | Test | — | INTRAVENOUS USE | 00 | 999999 | SUB06052MIG |
INFLIXIMAB | Other | — | INTRAVENOUS USE | 00 | 999999 | SUB02681MIG |
CAPECITABINE | Test | — | ORAL USE | 00 | 999999 | SUB12474MIG |
Datopotamab deruxtecan | Test | SOLUTION FOR INFUSION | INTRAVENOUS USE | 00 | 999999 | PRD9684738 |
Rilvegostomig | Test | SOLUTION FOR INFUSION | INTRAVENOUS USE | 00 | 999999 | PRD10448215 |
CISPLATIN | Test | — | INTRAVENOUS USE | 00 | 999999 | SUB07483MIG |
BEVACIZUMAB | Test | — | INTRAVENOUS USE | 00 | 999999 | SUB16402MIG |
CAPECITABINE | Test | — | ORAL USE | 00 | 999999 | SUB12474MIG |
FLUOROURACIL | Test | — | INTRAVENOUS USE | 00 | 999999 | SUB07721MIG |
PREDNISOLONE | Test | — | ORAL USE | 00 | 999999 | SUB10018MIG |