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

Sponsor

AstraZeneca (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04644068

Collaborator

(none)

715

Enrollment

Locations

Arms

56.5

Anticipated Duration (Months)

14.6

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

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

Study Type:

Interventional

Anticipated Enrollment :

715 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). 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.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). 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.

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 :

Nov 12, 2020

Anticipated Primary Completion Date :

Jul 29, 2025

Anticipated Study Completion Date :

Jul 29, 2025

Arms and Interventions

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

Primary Outcome Measures

The number of subjects with adverse events/serious adverse events [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. [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

Best percentage change in target lesion [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 [From Screening to confirmed progressive disease (approximately 1 year)]
Best response until progression, as defined by RECIST 1.1.
Duration of Response [From Screening to confirmed progressive disease (approximately 1 year)]
Time from response to progression, as defined by RECIST 1.1.
Progression Free Survival [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 [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 [From Cycle 0 Day 1 to Cycle 1 Day 15 (approximately 21 days)]
Measure change from baseline in pH2AX
CA125 response (ovarian cancer) [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) [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) [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) [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) [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) [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) [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) [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) [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) [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) [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) [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) [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 [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) [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) [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) [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 [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) [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) [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) [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 [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

Criteria

Ages Eligible for Study:

18 Years to 130 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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:

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 (< 100 beats per minute) are permitted.
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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	San Francisco	California	United States	94143
2	Research Site	New York	New York	United States	10021
3	Research Site	Oklahoma City	Oklahoma	United States	73104
4	Research Site	Houston	Texas	United States	77030
5	Research Site	Melbourne		Australia	3000
6	Research Site	Kelowna	British Columbia	Canada	V1Y 5L3
7	Research Site	Vancouver	British Columbia	Canada	V5Z 1K1
8	Research Site	London	Ontario	Canada	N6A 4L6
9	Research Site	Toronto	Ontario	Canada	M5G 2M9
10	Research Site	Montreal	Quebec	Canada	H2X 0A9
11	Research Site	Montreal	Quebec	Canada	H3T 1E2
12	Research Site	Quebec		Canada	G1R 2J6
13	Research Site	Changsha		China	410013
14	Research Site	Chengdu		China	610041
15	Research Site	Chongqing		China	400030
16	Research Site	Shanghai		China	200032
17	Research Site	Brno		Czechia	656 53
18	Research Site	Budapest		Hungary	1062
19	Research Site	Budapest		Hungary	1083
20	Research Site	Budapest		Hungary	1122
21	Research Site	Milano		Italy	20132
22	Research Site	Milan		Italy	20141
23	Research Site	Modena		Italy	41125
24	Research Site	Napoli		Italy	80131
25	Research Site	Padova		Italy	35128
26	Research Site	Roma		Italy	00168
27	Research Site	Chuo-ku		Japan	104-0045
28	Research Site	Koto-ku		Japan	135-8550
29	Research Site	Seoul		Korea, Republic of	03080
30	Research Site	Seoul		Korea, Republic of	03722
31	Research Site	Seoul		Korea, Republic of	05505
32	Research Site	Seoul		Korea, Republic of	06351
33	Research Site	Bydgoszcz		Poland	85-796
34	Research Site	Gdynia		Poland	81-519
35	Research Site	Grzepnica		Poland	72-003
36	Research Site	Warszawa		Poland	02-781
37	Research Site	Moscow		Russian Federation	111123
38	Research Site	Moscow		Russian Federation	115478
39	Research Site	Moscow		Russian Federation	117997
40	Research Site	Moscow		Russian Federation	143442
41	Research Site	Barcelona		Spain	08035
42	Research Site	Madrid		Spain	28041
43	Research Site	Madrid		Spain	28050
44	Research Site	Málaga		Spain	29010
45	Research Site	Sevilla		Spain	41013
46	Research Site	Cambridge		United Kingdom	CB2 0QQ
47	Research Site	Manchester		United Kingdom	M20 4BX
48	Research Site	Oxford		United Kingdom	OX3 7LE
49	Research Site	Sutton		United Kingdom	SM2 5PT