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Study of AZD5305 as Monotherapy and in Combination With Anti-cancer Agents in Patients With Advanced Solid Malignancies (PETRA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04644068
Recruitment Status : Recruiting
First Posted : November 25, 2020
Last Update Posted : May 22, 2023
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Study Description
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Brief Summary:
This research is designed to determine if experimental treatment with PARP inhibitor, AZD5305, alone, or in combination with anti-cancer agents is safe, tolerable, and has anti-cancer activity in patients with advanced solid tumors.

Condition or disease Intervention/treatment Phase
Ovarian Cancer Breast Cancer Pancreatic Cancer Prostate Cancer Additional Indications Below for Module 4 and 5 Non-small Cell Lung Cancer Small Cell Lung Cancer Colorectal Cancer Bladder Cancer Gastric Cancer Biliary Cancer Cervical Cancer Endometrial Cancer Drug: AZD5305 Drug: Paclitaxel Drug: Carboplatin Drug: T- Dxd Drug: Dato-DXd Phase 1 Phase 2

Detailed Description:
This study is a Phase I/IIa modular, open-label, multi-center study of AZD5305 administered orally, either as monotherapy or in combination with other anti-cancer agents in patients with advanced solid malignancies.
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 559 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

The study consists of individual modules each evaluating the safety and tolerability of AZD5305 dosed as monotherapy, or with a specific combination partner:

  • 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).

Modules 1 and 2 has 2 study parts: Part A consisting of dose-escalation cohorts and Part B, consisting of expansion cohorts. Module 3, Module 4 and Module 5 have only PART A.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : November 12, 2020
Estimated Primary Completion Date : January 15, 2026
Estimated Study Completion Date : January 15, 2026

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Module 1: AZD5305 Monotherapy
AZD5305 Monotherapy
 Drug: AZD5305
Oral PARP inhibitor
Experimental: Module 2: AZD5305 + Paclitaxel
AZD5305 + Paclitaxel
 Drug: AZD5305
Oral PARP inhibitor

Drug: Paclitaxel
IV Anti-microtubule agent
Experimental: Module 3: AZD5305 + Carboplatin with or without Paclitaxel
AZD5305 + Carboplatin with or without Paclitaxel
 Drug: AZD5305
Oral PARP inhibitor

Drug: Paclitaxel
IV Anti-microtubule agent

Drug: Carboplatin
IV Platinum chemotherapeutic
Experimental: Module 4: AZD5305 + Trastuzumab Deruxtecan
AZD5305 + T- Dxd
 Drug: AZD5305
Oral PARP inhibitor

Drug: T- Dxd
IV Antibody-drug conjugate
Experimental: Module 5 AZD5305 + Datopotamab Deruxtecan
AZD5305 + Dato-DXd
 Drug: AZD5305
Oral PARP inhibitor

Drug: Dato-DXd
IV Antibody-drug conjugate


Outcome Measures
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Primary Outcome Measures :
  1. 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

  2. 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. DLTs occurring outside the DLT window (ie, late onset toxicities) may be defined as a DLT after consultation with the sponsor and investigators, based on the emerging safety profile.


Secondary Outcome Measures :
  1. 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.

  2. Objective Response Rate [ Time Frame: From Screening to confirmed progressive disease (approximately 1 year) ]
    Best response until progression, as defined by RECIST 1.1.

  3. 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.

  4. 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.

  5. 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.

  6. 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

  7. 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.

  8. 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.

  9. 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).

  10. 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).

  11. 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)

  12. 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).

  13. 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

  14. 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.

  15. 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).

  16. 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).

  17. 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.

  18. 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).

  19. 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).

  20. 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.

  21. 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).

  22. 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).

  23. 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

  24. 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.

  25. 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).

  26. 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).

  27. 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

  28. 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


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  • 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).

Key Exclusion Criteria:

  • Treatment with any of the following:

    1. Nitrosourea or mitomycin C within 6 weeks of the first dose of study treatment
    2. 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
    3. Any other chemotherapy, immunotherapy or anticancer agents within 3 weeks of the first dose of study treatment
    4. 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:

    1. Symptomatic heart failure,
    2. uncontrolled hypertension,
    3. hypertensive heart disease with significant left ventricular hypertrophy
    4. 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.
    5. cardiomyopathy of any etiology
    6. presence of clinically significant valvular heart disease
    7. history of atrial or ventricular arrhythmia requiring treatment; subjects with atrial fibrillation and optimally controlled ventricular rate (< 100 beats per minute) are permitted.
    8. subjects with atrial fibrillation and optimally controlled ventricular rate are permitted
    9. transient ischaemic attack, or stroke within 6 months prior to screening
    10. 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

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04644068


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com
Contact: AZ Breast Cancer Study Navigators +1-877-400-4656 AstraZeneca@CareboxHealth.com

Locations
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Sponsors and Collaborators
AstraZeneca
Investigators
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Principal Investigator: Timothy Yap M.D. Anderson Cancer Center
More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT04644068    
Other Study ID Numbers: D9720C00001
2020-002688-77 ( EudraCT Number )
First Posted: November 25, 2020    Key Record Dates
Last Update Posted: May 22, 2023
Last Verified: May 2023

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
PARP inhibitor
Breast Cancer
Pancreatic Cancer
 Prostate Cancer
Ovarian Cancer
AZD5305, T-DXd, Enhertu, Trastuzumab Deruxtecan, Dato-DXd, Datopotamab Deruxtecan
Additional relevant MeSH terms:
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Lung Neoplasms
Prostatic Neoplasms
Pancreatic Neoplasms
Ovarian Neoplasms
Small Cell Lung Carcinoma
Endometrial Neoplasms
Neoplasms by Site
Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Lung Diseases
Respiratory Tract Diseases
Genital Neoplasms, Male
Urogenital Neoplasms
Genital Diseases, Male
 Genital Diseases
Urogenital Diseases
Prostatic Diseases
Male Urogenital Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Endocrine Gland Neoplasms
Pancreatic Diseases
Endocrine System Diseases
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Female Urogenital Diseases