| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
various Advanced/Metastatic solid tumour types
- Endometrial Cancer
- Gastric Cancer
- Ovarian Cancer
- Metastatic castration-resistant prostate cancer
- Colorectal cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic Cancer, Multiple cancers |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.0 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10007129 |
| E.1.2 | Term | Cancer-related morbidities |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
-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 |
|
| E.2.2 | Secondary objectives of the trial |
- To further assess the efficacy of Dato-DXd as monotherapy and in combination with anticancer
agents by assessment of PFS, DoR, DCR at 12 and 24 weeks, Best percentage change in tumour size (where applicable)
- To assess the PK of Dato-DXd, total anti-TROP2 antibody, and MAAA-1181a in plasma
- To investigate the immunogenic potential of Dato-DXd |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Objectives and endpoints specific to each Substudies are listed below. Refer to Section E.2.1 and E.2.2 of the form for objectives that are common to all substudies.
*Substudy 1: Endometrial Cancer, 23 Jun 2022, v2.0
Secondry Objectives:
-To assess the PK of durvalumab and AZD5305
-To investigate the immunogenic potential of durvalumab
*Substudy 2: Gastric Cancer, 23 Jun 2022, v2.0
*Substudy 3: Castration-resistant Prostate Cancer, 04 April 2022, v1.0
Primary Objectives:
-To assess the efficacy of Dato-DXd as monotherapy and in combination with anticancer agents by assessment of PSA50 response.
Secondary objectives:
-To assess the efficacy of Dato-DXd as monotherapy and in combination with anticancer agents by assessment of rPFS and Time to PSA progression.
-To assess the PK of AZD5305
*Substudy 4: Ovarian Cancer, 04 April 2022, v1.0
Primary objectives:
-To assess the efficacy of Dato-DXd in combination with anticancer agents assessed by PFS
Secondary objectives:
-To assess the efficacy of Dato-DXd as monotherapy and in combination with anticancer agents by assessment of CA-125 and OS
-To assess the PK of AZD5305
*Substudy 5: Colorectal Cancer, 23 Jun 2022, v2.0 |
|
| E.3 | Principal inclusion criteria |
1- Male and female, ≥ 18 years at the time of screening
2-Histologically or cytologically documented advanced or metastatic malignancy.
3- 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. Archival FFPE tumour samples must be < 12 months old from the time of collection to the time of start of protocol screening. The exception is for gastric Substudy Cohorts 2A and 2B, where prospective PD-L1 central testing is required for enrolment, archival FFPE tumour samples must be < 6 months old from the time of collection to the time of start of protocol.
4- 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.
5- Adequate bone marrow reserve and organ function within 7 days before randomization/treatment assignment defined as:
-Haemoglobin ≥ 9.0 g/dL
-Absolute neutrophil count ≥ 1.5 × 109/L
-Platelet count ≥100 × 109/L (platelet transfusion 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 if no liver metastases or < 3 × ULN in the presence of documented Gilbert’s syndrome or liver metastases at baseline.
-ALT and AST ≤ 3 × ULN (< 5 × ULN in participants with liver metastases).
-Calculated CrCL ≥ 30 mL/min
6 Minimum life expectancy of 12 weeks.
7- 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.
8- Negative pregnancy test (serum) for women of childbearing potential who are sexually active with a non-sterilised male partner.
9- Female participants must be 1 year post-menopausal, surgically sterile, or using 1 highly effective form of birth control. Women of childbearing potential who are sexually active with a non-sterilised male partner must agree to use 1 highly effective method of birth control. 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.
10- Male participants who intend to be sexually active with a female partner of childbearing potential must be surgically sterile or using a highly effective method of contraception from the time of screening throughout the total duration of the study and for drugs that are potentially genotoxic the drug washout period (at least 4 months after the last dose of study intervention) to prevent pregnancy in a partner. Male participants must not donate or bank sperm during this same time period.
11-Capable of giving signed informed consent
12 Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of sample for optional genetic research that supports Genomic Initiative. |
|
| E.4 | Principal exclusion criteria |
1-Any evidence of diseases such as QT prolongation and persistent toxicities associated with prior or current medication or previous anti-cancer therapy
2-History of another primary malignancy except that treated with curative intent with no known active disease within 3 years before the first dose of study intervention and of low potential risk for recurrence
3-Persistent toxicities caused by previous anticancer therapy, excluding alopecia, not yet improved to Grade ≤ 1 or baseline
4-Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention may be included (eg, hearing loss) after consultation with the AstraZeneca study clinical lead
5-Spinal cord compression or brain metastases unless treated, asymptomatic, stable, and not requiring steroids for at least 4 weeks prior to randomisation/start of study intervention. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy/stereotactic radiation and study enrolment
6-Leptomeningeal carcinomatosis
7-Clinically significant corneal disease
8-Active hepatitis or uncontrolled hepatitis B or C virus infection
9-Uncontrolled infection requiring IV antibiotics, antivirals or antifungals eg, prodromal symptoms
10- Known HIV infection that is not well controlled
11-Known to have active tuberculosis infection
12- Mean resting corrected QTcF > 470 ms, regardless of gender, obtained from triplicate 12-lead ECGs performed at screening.
13- 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 under 40 years of age in first-degree relatives.
14-Significant cardiac diseases including:
- Myocardial infarction or uncontrolled/unstable angina within 6 months before enrolment.
- Congestive heart failure (New York Heart Association Class II to IV).
- Cardiac arrhythmia, multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia, which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted upon discussion with the study clinical lead.
- Uncontrolled hypertension (resting systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg)
15-History of non-infectious ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening
16-Clinically severe pulmonary function (ie, pulmonary emboli within 3 months prior to study enrolment, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion etc); or any autoimmune, connective tissue or inflammatory disorders (ie, rheumatoid arthritis, Sjögren’s syndrome, sarcoidosis, etc)
17-Prior exposure to chloroquine/hydroxychloroquine without an adequate treatment washout period of > 14 days prior to first dose
18-Receipt of live, attenuated vaccine within 30 days prior to the first dose of the study intervention
19-Prior exposure to the following anticancer therapies without an adequate treatment washout period prior to enrolment:
Immunotherapy non-antibody-based therapy, retinoid therapy: ≥ 2 weeks or 5 times the terminal elimination t1/2 of the chemotherapeutic agent, whichever is longer;≥ 6 weeks for nitrosoureas or mitomycin C. Antibody-based anticancer therapy: ≥ 4 weeks
20-Any concurrent anticancer treatment
21-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
22-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
23-Prior treatment with TROP2-directed ADCs, other ADCs with deruxtecan payload and Previous treatment in the present study
24-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, unless it is non-interventional clinical study or during the follow-up period of an interventional study
25-Severe hypersensitivity to Dato-DXd or any of the excipients, including but not limited to polysorbate 80 or other monoclonal antibodies
26-Involvement in the planning, conducting of the study (AstraZeneca staff and/or staff at the study site)
27-The participant is unlikely to comply with study procedures, restrictions and requirements.
28-Pregnant, breastfeeding, planning to become pregnant. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Objective response rate (ORR)
- AEs/SAEs, ECOG performance status, changes from baseline in laboratory findings,ECGs, vital signs, physical examinations, and ophthalmologic assessments
- PSA50 response
- Progression-free survival (PFS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- ORR, PSA50, PFS: data obtained from first dose up until progression per RECIST 1.1 as assessed by the investigator or death, or the last evaluable assessment in the absence of an event (regardless of whether the participant withdraws from therapy)
- Safety: during the study treatment or the safety follow-up period (defined as 28 days after last dose of study intervention, or if durvalumab, nivolumab, or bevacizumab is given, 90 days after the last dose will be reported) but prior to subsequent cancer therapy |
|
| E.5.2 | Secondary end point(s) |
- Progression-free survival (PFS)
- Duration of response (DoR)
- Disease control rate (DCR)
- Best percentage change in tumour size
- Overall survival (OS)
- Radiographic Progression-free survival (rPFS)
- CA-125 response
- Plasma concentrations and PK parameters, total anti-TROP2 antibody, and MAAA-1181a
- Presence of ADAs for Dato-DXd |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- PFS, DoR, DCR, Best percentage change in tumour size, rPFS, CA-125 response: data obtained from first dose up until progression per RECIST 1.1 as assessed by the investigator or death, or the last evaluable assessment in the absence of an event (regardless of whether the participant withdraws from therapy)
- OS: data obtained from first dose up until death, or the last evaluable assessment in the absence of an event
- PK and Immunogenicity: blood samples will be taken for specific drugs at limited time points |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 13 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| China |
| Japan |
| Korea, Republic of |
| Taiwan |
| United States |
| France |
| Poland |
| Spain |
| Switzerland |
| Germany |
| Italy |
| Turkey |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of study is defined as the date of the last visit of the last participant.
The end of cohort is defined as the last scheduled visit or contact of the last participant in the cohort |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
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