| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10048683 |
| E.1.2 | Term | Advanced cancer |
| 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 safety and tolerability of AZD5305 as monotherapy and in combination with anti-cancer agents in patients with advanced malignancies |
|
| E.2.2 | Secondary objectives of the trial |
-To characterize the PK of AZD5305 in plasma following a single dose and at steady state after multiple dosing, when given orally as monotherapy and in combination with anti-cancer agents
- To assess the preliminary anti-tumour activity of AZD5305 as monotherapy and in combination with anti-cancer agents
- To evaluate PD of AZD5305 in tumour tissue when given orally as monotherapy
-Module 1: To characterize the PK of AZD5305 in plasma and urine, following a single dose and at steady state after multiple dosing, when given orally as monotherapy
-Module 2: To characterise the PK of AZD5305 and paclitaxel, following a single dose and at steady state after multiple dosing in plasma, when given in combination.
-Module 4: PK of AZD5305 and T-DXd
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1 Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses
2 Age ≥ 18 at the time of screening
3 Patients must have histological or cytological confirmation of advanced malignancy considered to be suitable for study treatment and meeting module specific eligibility criteria.
4 Eastern Cooperative Oncology Group Performance status (ECOG) PS: 0-2 with no deterioration in the previous 2 weeks
5 Life expectancy ≥ 12 weeks
6 Progressive cancer at the time of study entry
7 Patients must have evaluable disease as per RECIST v1.1
8 Female subjects of childbearing potential: Must have negative
pregnancy test result at screening and prior to each cycle administration of study treatment and must use at least one highly effective method of birth control plus a barrier method.
9 Female subjects must not breastfeed and must not donate or retrieve ova for their own use, from screening to approximately 6 months after the last dose of study treatment with IMP.
10 Male patients must use a condom with spermicide with all sexual
partners from screening to approximately 6 months after the last dose of AZD5305 IMP.
11. Adequate organ and marrow function as defined by the protocol.
12. For part B expansion cohorts: Provision of formalin-fixed and paraffin embedded (FFPE) tumour specimen is mandatory except if stated that it is optional in a specific Module.
Other module specific criteria may apply. |
|
| E.4 | Principal exclusion criteria |
1 Treatment with any of the following:
a Nitrosourea or mitomycin C within 6 weeks of the first dose of study treatment
b Any investigational agents or study drugs from a previous clinical
study within 5 half-lives or 3 weeks (whichever is shorter) of the first dose of study treatment
c Any other anticancer treatment within the time periods to the first dose of study treatment as indicated in the protocol
d Any live virus or bacterial vaccine within 28 days of the first dose of study treatment
2 Concomitant use of medications or herbal supplements known to be cytochrome P450 3A4 (CYP3A4) strong and moderate inhibitors or inducers.
3 Concomitant use of drugs that are known to prolong or shorten QT and have a known risk of Torsades de Pointes.
4 During the 4 weeks prior to the first dose, receiving continuous
corticosteroids at a dose of > 10 mg prednisone/day or equivalent for any reason.
5 Major surgery within 4 weeks of the first dose of study treatment.
6 Radiotherapy with a wide field of radiation within 4 weeks or
radiotherapy with a limited field of radiation for palliation within 2
weeks of the first dose of study treatment.
7 With the exception of alopecia, any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 at the time of starting study treatment.
8 Any history of persisting (> 2 weeks) severe pancytopenia due to any cause
9 Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring continuous corticosteroids at a dose of >10mg prednisone/day or equivalent for at least 4 weeks prior to start of study treatment. Patients with leptomeningeal carcinomatosis are excluded. Any evidence of severe or uncontrolled systemic diseases, including, active bleeding diatheses, or active infection including hepatitis B, hepatitis C and HIV. Screening for chronic conditions is not required.
10 Patients with any known predisposition to bleeding
11 Any of the following cardiac criteria
Mean resting corrected QT interval (QTcF) > 450 milliseconds or
QTcF<340 milliseconds
Any factors that increase the risk of QT prolongation, shortening or risk of arrhythmic events, congenital long or short QT syndrome, family history of long QT syndrome, familial short QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong or shorten the QT interval
Any clinically important abnormalities in rhythm, conduction or
morphology of resting ECG and clinically significant sinus node
dysfunction not treated with pacemaker.
12 Other cardiovascular diseases as defined by any of the following
(a) Symptomatic heart failure,
(b) uncontrolled hypertension,
(c) hypertensive heart disease with significant left ventricular
hypertrophy
(d) acute coronary syndrome (ACS)/acute myocardial infarction (AMI), unstable angina pectoris, coronary intervention procedure with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) within 6 months.
(e) cardiomyopathy of any etiology
(f) presence of clinically significant valvular heart disease
(g) history of atrial or ventricular arrhythmia requiring treatment;
subjects with atrial fibrillation/flutter and optimally controlled
ventricular rate (<100 beats per minute) are permitted
(h) transient ischaemic attack, or stroke within 6 months prior to
screening
(i) patients with symptomatic hypotension at screening
13 Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML).
14 Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD5305
15 Known allergy or hypersensitivity to investigational product(s) or any of the excipients of the investigational product(s)
16 Any concurrent therapy anti-cancer therapy or concurrent use of
prohibited medications
17 Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements
18 Any condition that, in the investigator's opinion, would interfere with evaluation of the study treatment or interpretation of subject safety or study results
19 Concurrent enrolment in another clinical study, unless it is an
observational (non interventional) clinical study or during the follow-up period of an interventional study
20 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site
21 Previous study treatment assignment in the present study
22 Uncontrolled intercurrent illness within the last 12 months
23 Prior malignancy whose natural history has the potential to interfere with safety and efficacy assessments of the investigational regimen
Other module specific criteria may apply |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety and tolerability will be assessed by the presence of AEs, SAEs, DLTs, MTD, physical examination changes from baseline, ECOG changes
from baseline, and changed from baseline in laboratory findings, vital
signs, and ECG results |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From time of Informed Consent to 90 days post last dose |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints are:
- Plasma concentrations of AZD5305 and plasma PK parameters, including but not limited to AUC, Cmax and Tmax as data allow, of AZD5305 after single dose and multiple doses administration but not limited to AUC, Cmax, Tmax, as data allow
- Radiological response evaluated according to response evaluation criteria in solid tumours (RECIST v1.1)
- Best percentage change in target lesion
- ORR, DoR, PFS, TTR
- For ovarian cancer patients, CA125 response evaluated according to the GCIG criteria
- For prostate cancer patients, PSA50 response and ORR and rPFS using RECIST 1.1 and PCWG3 criteria
- Includes, but is not limited to assessment pH2AX (Ser139) PD biomarker modulations at baseline visit 1 and during treatment and other module specific biomarker
-Plasma and urine concentrations and PK parameters of AZD5305 and paclitaxel after single dose and multiple doses administration, including, but not limited to AUC, Cmax and Tmax, as data allow.
-Total plasma concentration and PK parameters, as data allow, of
carboplatin during and after infusion.
- Plasma concentrations and PK parameters of T-DXd (T-DXd, total anti- HER2 antibody and MAAA-1181a) after single dose and multiple dose administration, including, but not limited to AUC, Cmax and Tmax, as data allow.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| All endpoints will be assessed from Day 1 of treatment through the end of treatment, with the exception of efficacy which will be assessed from screening through objective disease progression. |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Dose escalation and dose expansion |
|
| 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 | No |
| E.8.1.2 | Open | No |
| 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| 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 |
| Korea, Democratic People's Republic of |
| Australia |
| Canada |
| China |
| Russian Federation |
| United Kingdom |
| United States |
| Czechia |
| Hungary |
| Italy |
| Poland |
| Spain |
|
| 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 the study is defined as completing the last expected visit/contact of the last patient
undergoing the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 3 |
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