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PETRA - A Modular Phase I/IIa, Open-label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of Ascending Doses of AZD5305 as Monotherapy and in Combination With Anti-cancer Agents in Patients With Advanced Solid Malignancies - D9720C00001

Studio Clinico

Patologia: Carcinoma del pancreas esocrino, Carcinoma della prostata, Carcinoma della vescica, Neoplasie della mammella, Neoplasie del polmone, Tumori del colon retto, Tumori delle vie biliari, Tumori dell’utero, Tumori dell’ovaio

Osservazionale-Sperimentale: Sperimentale

Monocentrico-Multicentrico: Multicentrico

Randomizzato: No

Fase di studio: 1, II

Richiesta mandatoria di tessuto: 

Linee di trattamento: Non applicabile

Criteri di inclusione: 

- Age ≥ 18 at the time of screening
- Histological or cytological confirmation of advanced malignancy considered to be suitable for study treatment and meeting module specific eligibility criteria..
- Eastern Cooperative Oncology Group Performance status (ECOG PS: 0-2)
- Life expectancy ≥ 12 weeks
- Progressive cancer at the time of study entry
- Patients must have evaluable disease as defined in module-specific criteria for Part A and Part B
- Adequate organ and marrow function as defined by the protocol.
- For Part B expansion cohorts: Provision of formalin-fixed and paraffin embedded (FFPE) tumour specimen is mandatory, where available, except if stated that it is optional in a specific Module.

For Part A:
- Patients may have received up to one prior line of therapy with a PARPi-based regimen (either as a treatment or as maintenance)

For Part B:
- Patients must not have received prior therapy with a PARPi-based regimen (either as a treatment or as maintenance)

Criteri di esclusione: 

- Treatment with any of the following:
    - Nitrosourea or mitomycin C within 6 weeks of the first dose of study treatment
    - 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
    - Any other chemotherapy, immunotherapy or anticancer agents within 3 weeks of the first dose of study treatment
    - Any live virus or bacterial vaccine within 28 days of the first dose of study treatment
- Concomitant use of medications or herbal supplements known to be cytochrome P450 3A4 (CYP3A4) strong and moderate inhibitors or inducers.
- Concomitant use of drugs that are known to prolong or shorten QT and have a known risk of Torsades de Pointes.
- Receiving continuous corticosteroids at a dose of >10 mg prednisone/day or equivalent for any reason.
- Major surgery within 4 weeks of the first dose of study treatment.
- 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.
- Any history of persisting (> 2 weeks) severe pancytopenia due to any cause
- 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.
- Cardiac conditions as defined by the clinical study protocol
- Other cardiovascular diseases as defined by any of the following:
    - Symptomatic heart failure,
    - uncontrolled hypertension,
    - hypertensive heart disease with significant left ventricular hypertrophy
    - 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.
    - cardiomyopathy of any etiology
    - presence of clinically significant valvular heart disease
    - history of atrial or ventricular arrhythmia requiring treatment.
    - subjects with atrial fibrillation and optimally controlled ventricular rate are permitted
    - transient ischaemic attack, or stroke within 6 months prior to screening
    - patients with symptomatic hypotension at screening
- Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML).
- 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
- Known allergy or hypersensitivity to investigational product(s) or any of the excipients of the investigational product(s).
other module-specific criteria may apply.

Trattamento sperimentale: 

Module 1 (AZD5305 monotherapy)
Module 2 (AZD5305 in combination with paclitaxel)
Module 3 (AZD5305 in combination with carboplatin, with or without paclitaxel)
Module 4 (AZD5305 in combination with T DXd)
Module 5 (AZD5305 in combination with Dato-DXd).
Each Module has 2 study parts: Part A consisting of dose-escalation cohorts and Part B, consisting of expansion cohorts. Module 4 and Module 5 have only PART A

Trattamento di controllo: 

NA

Obiettivi primari dello studio: 

- The number of subjects with adverse events/serious adverse events [ Time Frame: From time of Informed Consent to 28 days post last dose (approximately 1 year). 40 days post last dose for Module 4 ]
Number of patients with adverse events and with serious adverse events including abnormal clinical observations, abnormal ECG parameters, abnormal laboratory assessments and abnormal vital signs that changed from baseline
- The number of subjects with dose-limiting toxicity (DLT), as defined in the protocol. [ Time Frame: From first dose of study treatment until the end of Cycle 1. ]
A DLT is defined as any toxicity that occurs from the first dose of study treatment (either AZD5305 or combination anti-cancer agent) up to and including the planned end of Cycle 1 (the DLT assessment period) that is assessed as unrelated to the disease or disease-related processes under investigation and .and which includes pre-defined toxicities criteria defined in the CSP.

Obiettivi secondari dello studio: 

- Best percentage change in target lesion [ Time Frame: From Screening to confirmed progressive disease (approximately 1 year)]
Change in target lesion size from baseline, as defined by RECIST 1.1.
- Objective Response Rate [ Time Frame: From Screening to confirmed progressive disease (approximately 1 year) ]
Best response until progression, as defined by RECIST 1.1.
- Duration of Response [ Time Frame: From Screening to confirmed progressive disease (approximately 1 year) ]
Time from response to progression, as defined by RECIST 1.1.
- Progression Free Survival [ Time Frame: From Screening to confirmed progressive disease (approximately 1 year) ]
Time from C1D1 to progression or death, as defined by RECIST 1.1.
- Time To Response [ Time Frame: From Screening to confirmed progressive disease (approximately 1 year) ]
Time from C1D1 to complete or partial response, as defined by RECIST 1.1.
- Effects of AZD5305 on Ph2AX (Ser139) PD biomarker [ Time Frame: From Cycle 0 Day 1 to Cycle 1 Day 15 (approximately 21 days) ]
Measure change from baseline in pH2AX
- CA125 response (ovarian cancer) [ Time Frame: From Screening to confirmed progressive disease (approximately 1 year) ]
at least a 50% reduction in CA125 levels from a pre-treatment sample as defined by GCIG criteria.
- Module 1: Area Under Curve (AUC) [ Time Frame: At predefined intervals throughout the treatment period (approximately 12 weeks) ]
The concentration of AZD5305 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.
- Module 1: Maximum plasma concentration of the drug (Cmax) [ Time Frame: At predefined intervals throughout the treatment period (approximately 12 weeks) ]
The concentration of AZD5305 in plasma will be determined (Cmax will be derived).
- Module 1: The time taken to reach the maximum concentration (Tmax) [ Time Frame: At predefined intervals throughout the treatment period (approximately 12 weeks) ]
The concentration of AZD5305 in plasma will be determined (Tmax will be derived).
- Module 1 and Module 5: Objective Response Rate (prostate cancer) [ Time Frame: From Screening to confirmed progressive disease (approximately 1 year) ]
Best response until progression, as defined by RECIST 1.1 or PCWG3 (bone)
- Module 1: Radiographic progression free survival (prostate cancer) [ Time Frame: From Screening to confirmed progressive disease (approximately 1 year) ]
Time from C1D1 to progression or death, as defined by RECIST 1.1 and PCWG3(bone).
- Module 1: Proportion of subjects with ≥ 50% PSA decrease (prostate cancer) [ Time Frame: From Screening to confirmed progressive disease (approximately 1 year) ]
PSA from baseline to the lowest post-baseline PSA result, confirmed by a second consecutive PSA assessment
- Module 2: Area Under Curve (AUC) [ Time Frame: At predefined intervals throughout the treatment period (approximately 12 weeks) ]
The concentration of AZD5305 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.
- Module 2: Maximum plasma concentration of the drug (Cmax) [ Time Frame: At predefined intervals throughout the treatment period (approximately 12 weeks) ]
The concentration of AZD5305 in plasma will be determined (Cmax will be derived).
- Module 2: The time taken to reach the maximum concentration (Tmax) [ Time Frame: At predefined intervals throughout the treatment period (approximately 12 weeks) ]
The concentration of AZD5305 in plasma will be determined (Tmax will be derived).
- Module 3: Area Under Curve (AUC) [ Time Frame: At predefined intervals throughout the treatment period (approximately 12 weeks) ]
The concentration of AZD5305 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.
- Module 3: Maximum plasma concentration of the drug (Cmax) [ Time Frame: At predefined intervals throughout the treatment period (approximately 12 weeks) ]
The concentration of AZD5305 in plasma will be determined (Cmax will be derived).
- Module 3: The time taken to reach the maximum concentration (Tmax) [ Time Frame: At predefined intervals throughout the treatment period (approximately 12 weeks) ]
The concentration of AZD5305 in plasma will be determined (Tmax will be derived).
- Module 4 : Area Under Curve [ Time Frame: At predefined intervals throughout the treatment period (approximately 12 weeks)]
The concentration of AZD5305 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.
- Module 4: Maximum plasma concentration of the drug (Cmax) [ Time Frame: At predefined intervals throughout the treatment period (approximately 12 weeks) ]
The concentration of AZD5305 in plasma will be determined (Cmax will be derived).
- Module 4: The time taken to reach the maximum concentration (Tmax) [ Time Frame: At predefined intervals throughout the treatment period (approximately 12 weeks) ]
The concentration of AZD5305 in plasma will be determined (Tmax will be derived).
- Module 4: Anti-Drug Antibody (ADA) [ Time Frame: Samples will be collected within 1 hour before dose administration on Day 1 of Cycle 1, 2, and 4, then every 4 Cycles (each cycle is 21 days), EoT, and at safety follow-up (40 days after last dose) as per Schedule of Assessments ]
To investigate the presence of ADAs for T-DXd
- Module 5: Area Under Curve [ Time Frame: At predefined intervals throughout the treatment period (approximately 12 weeks) ]
The concentration of AZD5305 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.
- Module 5: Maximum plasma concentration of the drug (Cmax) [ Time Frame: At predefined intervals throughout the treatment period (approximately 12 weeks) ]
The concentration of AZD5305 in plasma will be determined (Cmax will be derived).
- Module 5: The time taken to reach the maximum concentration (Tmax) [ Time Frame: At predefined intervals throughout the treatment period (approximately 12 weeks) ]
The concentration of AZD5305 in plasma will be determined (Tmax will be derived).
- Module 5: Anti-Drug Antibody (ADA) [ Time Frame: Whole blood samples for determination of ADA for Dato-DXd in plasma will be collected in patients receiving Dato-DXd per the schedule specified in the SoA : Day 1 of Cycle 1, 2, 4, and 8 (each cycle is 21 days) , EoT, and then 28 day follow up visit. ]
Presence of ADAs for Dato-DXd
- Module 1 : To investigate the effect of a high-fat meal on the PK of AZD5305 [ Time Frame: Cycle 0, Day 1 (C0D1), in either the 'fasted' or 'fed' state, followed by a single oral dose of AZD5305 in the other state for Cycle 1, Day 1 (C1D1) at least 72 hours later; 1 cycle is 28 days. ]
Effect on High fat meal on PK parameters of AZD5305.PK parameters, including but not limited to AUC and/or AUC(0-t), Cmax, Tmax, AUC(0-t) and Cmax ratio, with and without food.

Data di inizio dell'arruolamento: 12.11.2020

Data di fine dell'arruolamento: 29.07.2025

Centri partecipanti

Nord Italia

Istituto Europeo di Oncologia
Via Ripamonti 435 - 20141 Milano - MI

 

A.O.U. Policlinico di Modena
Via del Pozzo 71 - 41100 Modena - MO
NB: Arruolamento pazienti non ancora attivo

 

Istituto Oncologico Veneto IRCCS
Via Gattamelata 64 - 35128 Padova - PD
NB: Arruolamento pazienti non ancora attivo

 

Centro Italia

Fondazione Policlinico A. Gemelli
Largo Agostino Gemelli 8 - 00168 Roma - RM
NB: Arruolamento pazienti non ancora attivo

 

Sud Italia e isole

Istituto Nazionale Tumori IRCCS Fondazione Pascale
Via Mariano Semmola - 80131 Napoli - NA

Riferimento: Dr. Adriano Gravina
Telefono: 0815903448
Email: a.gravina@istitutotumori.na.it

Informazioni Generali

Protocollo

Numero di iscrizione a registro: 2020-002688-77

Data di inserimento: 24.02.2022

Promotore

AstraZeneca

Principal Investigator ITALIA

Istituto Nazionale Tumori IRCCS - Fondazione Pascale, Napoli

Riferimento: Dr. Adriano Gravina

Telefono: 0815903448

Email: a.gravina@istitutotumori.na.it

Localita: Napoli

 

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