Clinical trial NCT04644068: Study of AZD5305 as Monotherapy and in Combination With Anti-cancer Agents in Patients With Advanced Solid Malignancies
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Ovarian Cancer
Breast Cancer
Pancreatic Cancer
Prostate Cancer
Additional Indications Below for Module 4 and 5
Non-small Cell Lung Cancer
Colorectal Cancer
Bladder Cancer
Gastric Cancer
Biliary Cancer
Cervical Cancer
Endometrial Cancer
Small Cell Lung Cancer Only in Module 5
Keywords: PARP inhibitor
Breast Cancer
Pancreatic Cancer
Prostate Cancer
Ovarian Cancer
AZD5305, T-DXd, Enhertu, Trastuzumab Deruxtecan, Dato-DXd, Datopotamab Deruxtecan, Camizestrant
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2020-11-25
Enrollment: 804
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
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).
* Module 6 (AZD5305 in combination with Camizestrant)

Modules 1 and 4 has 2 study parts: Part A consisting of dose-escalation cohorts and Part B, consisting of expansion cohorts. Modules 2, 3, 5 and 6 have only PART A.
Primary purpose: TREATMENT

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.

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.

Eligibility 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 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.
* patient with known predisposition to bleeding (e.g., active peptic ulceration, recent \[within 6 months\] haemorrhagic stroke, proliferative diabetic retinopathy).
* 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).

Prior malignancy whose natural history, in the Investigator's opinion, has the potential to interfere with safety and efficacy assessments of the investigational regimen.

other module-specific criteria may apply

Primary outcomes:
measure: The number of subjects with adverse events/serious adverse events
timeFrame: From time of Informed Consent to 28 + 7 days post last dose ( modules 1,2,3,5 and 6). 40+7 days post last dose for Module 4.
measure: The number of subjects with dose-limiting toxicity (DLT), as defined in the protocol.
timeFrame: From first dose of study treatment until the end of Cycle 1.
Secondary outcomes:
measure: Best percentage change in target lesion
timeFrame: From Screening to confirmed progressive disease (approximately 1 year)
measure: Objective Response Rate
timeFrame: From Screening to confirmed progressive disease (approximately 1 year)
measure: Duration of Response
timeFrame: From Screening to confirmed progressive disease (approximately 1 year)
measure: Progression Free Survival
timeFrame: From Screening to confirmed progressive disease (approximately 1 year)
measure: Time To Response
timeFrame: From Screening to confirmed progressive disease (approximately 1 year)
measure: Effects of AZD5305 on pH2AX (Ser139) PD biomarker
timeFrame: From Cycle 0 Day 1 to Cycle 1 Day 15 (approximately 21 days)
measure: CA125 response (ovarian cancer)
timeFrame: From Screening to confirmed progressive disease (approximately 1 year)
measure: Module 1: Area Under Curve (AUC)
timeFrame: At predefined intervals throughout the treatment period (approximately 12 weeks)
measure: Module 1: Maximum plasma concentration of the drug (Cmax)
timeFrame: At predefined intervals throughout the treatment period (approximately 12 weeks)
measure: Module 1: The time taken to reach the maximum concentration (Tmax)
timeFrame: At predefined intervals throughout the treatment period (approximately 12 weeks)
measure: Module 1 and Module 5: Objective Response Rate (prostate cancer)
timeFrame: From Screening to confirmed progressive disease (approximately 1 year)
measure: Module 1: Radiographic progression free survival (prostate cancer)
timeFrame: From Screening to confirmed progressive disease (approximately 1 year)
measure: Module 1: Proportion of subjects with ≥ 50% PSA decrease (prostate cancer)
timeFrame: From Screening to confirmed progressive disease (approximately 1 year)
measure: Module 1 : To investigate the effect of a high-fat meal on the PK of AZD5305
timeFrame: 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.
measure: Module 2: Area Under Curve (AUC)
timeFrame: At predefined intervals throughout the treatment period (approximately 12 weeks)
measure: Module 2: Maximum plasma concentration of the drug (Cmax)
timeFrame: At predefined intervals throughout the treatment period (approximately 12 weeks)
measure: Module 2: The time taken to reach the maximum concentration (Tmax)
timeFrame: At predefined intervals throughout the treatment period (approximately 12 weeks)
measure: Module 3: Area Under Curve (AUC)
timeFrame: At predefined intervals throughout the treatment period (approximately 12 weeks)
measure: Module 3: Maximum plasma concentration of the drug (Cmax)
timeFrame: At predefined intervals throughout the treatment period (approximately 12 weeks)
measure: Module 3: The time taken to reach the maximum concentration (Tmax)
timeFrame: At predefined intervals throughout the treatment period (approximately 12 weeks)
measure: Module 4 : Area Under Curve
timeFrame: At predefined intervals throughout the treatment period (approximately 12 weeks)
measure: Module 4: Maximum plasma concentration of the drug (Cmax)
timeFrame: At predefined intervals throughout the treatment period (approximately 12 weeks)
measure: Module 4: The time taken to reach the maximum concentration (Tmax)
timeFrame: At predefined intervals throughout the treatment period (approximately 12 weeks)
measure: Module 4: Anti-Drug Antibody (ADA)
timeFrame: 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
measure: Module 4: To assess the preliminary anti-tumour activity of AZD5305 as monotherapy and in combination with T-DXd.
timeFrame: From screening to approximately 6 months
measure: Module 5: Area Under Curve
timeFrame: At predefined intervals throughout the treatment period (approximately 12 weeks)
measure: Module 5: Maximum plasma concentration of the drug (Cmax)
timeFrame: At predefined intervals throughout the treatment period (approximately 12 weeks)
measure: Module 5: The time taken to reach the maximum concentration (Tmax)
timeFrame: At predefined intervals throughout the treatment period (approximately 12 weeks)
measure: Module 5: Anti-Drug Antibody (ADA)
timeFrame: 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.
measure: Module 5: Premilinary anti tumour activity AZD5305 in combination with Dato-DXd
timeFrame: From screening to confirmed progresive disease ( approximately 12 weeks)
measure: Module 6: To characterise the PK of AZD5305 and camizestrant following a single dose and at steady state after multiple dosing, when given in combination.
timeFrame: At predefined interval throughout the treatment (approximately 12 weeks)
measure: Module 6: To evaluate the effect of camizestrant on the PK of AZD5305.
timeFrame: At predefined intervals throughout the treatment period (approximately 12 weeks)
measure: Module 6: To evaluate the effect of AZD5305 on the PK of Camizestrant.
timeFrame: At predefined intervals throughout the treatment period (approximately 12 weeks)
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: Research Site
state: California
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: New York
country: United States
facility: Research Site
state: New York
city: Oklahoma City
country: United States
facility: Research Site
state: Oklahoma
city: Houston
country: United States
facility: Research Site
state: Texas
city: Heidelberg
country: Australia
facility: Research Site
city: Melbourne
country: Australia
facility: Research Site
city: Kelowna
country: Canada
facility: Research Site
state: British Columbia
city: Vancouver
country: Canada
facility: Research Site
state: British Columbia
city: London
country: Canada
facility: Research Site
state: Ontario
city: Ottawa
country: Canada
facility: Research Site
state: Ontario
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Montreal
country: Canada
facility: Research Site
state: Quebec
city: Montreal
country: Canada
facility: Research Site
state: Quebec
city: Quebec
country: Canada
facility: Research Site
city: Beijing
country: China
facility: Research Site
city: Changchun
country: China
facility: Research Site
city: Changsha
country: China
facility: Research Site
city: Changsha
country: China
facility: Research Site
city: Chengdu
country: China
facility: Research Site
city: Chongqing
country: China
facility: Research Site
city: Guangzhou
country: China
facility: Research Site
city: Harbin
country: China
facility: Research Site
city: Jining
country: China
facility: Research Site
city: Shandong
country: China
facility: Research Site
city: Shanghai
country: China
facility: Research Site
city: Shanghai
country: China
facility: Research Site
city: Taiyuan
country: China
facility: Research Site
city: Wuhan
country: China
facility: Research Site
city: Xi'an
country: China
facility: Research Site
city: Brno
country: Czechia
facility: Research Site
city: Olomouc
country: Czechia
facility: Research Site
city: Praha
country: Czechia
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Milan
country: Italy
facility: Research Site
city: Modena
country: Italy
facility: Research Site
city: Napoli
country: Italy
facility: Research Site
city: Padova
country: Italy
facility: Research Site
city: Roma
country: Italy
facility: Research Site
city: Chuo-ku
country: Japan
facility: Research Site
city: Koto-ku
country: Japan
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Bydgoszcz
country: Poland
facility: Research Site
city: Gdańsk
country: Poland
facility: Research Site
city: Gdynia
country: Poland
facility: Research Site
city: Gliwice
country: Poland
facility: Research Site
city: Grzepnica
country: Poland
facility: Research Site
city: Kraków
country: Poland
facility: Research Site
city: Lublin
country: Poland
facility: Research Site
city: Toruń
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Łódź
country: Poland
facility: Research Site
city: Moscow
country: Russian Federation
facility: Research Site
city: Moscow
country: Russian Federation
facility: Research Site
city: Moscow
country: Russian Federation
facility: Research Site
city: Moscow
country: Russian Federation
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Málaga
country: Spain
facility: Research Site
city: Pozuelo de Alarcon
country: Spain
facility: Research Site
city: Sevilla
country: Spain
facility: Research Site
city: Chernivtsі
country: Ukraine
facility: Research Site
city: Ivano-Frankivsk
country: Ukraine
facility: Research Site
city: Kyiv
country: Ukraine
facility: Research Site
city: Uzhgorod
country: Ukraine
facility: Research Site
city: Cambridge
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Oxford
country: United Kingdom
facility: Research Site
city: Sutton
country: United Kingdom
facility: Research Site
Study officials:
affiliation: M.D. Anderson Cancer Center
name: Timothy Yap
role: PRINCIPAL_INVESTIGATOR
References:
citation: Illuzzi G, Staniszewska AD, Gill SJ, Pike A, McWilliams L, Critchlow SE, Cronin A, Fawell S, Hawthorne G, Jamal K, Johannes J, Leonard E, Macdonald R, Maglennon G, Nikkila J, O'Connor MJ, Smith A, Southgate H, Wilson J, Yates J, Cosulich S, Leo E. Preclinical Characterization of AZD5305, A Next-Generation, Highly Selective PARP1 Inhibitor and Trapper. Clin Cancer Res. 2022 Nov 1;28(21):4724-4736. doi: 10.1158/1078-0432.CCR-22-0301.