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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT05797168




Registration number
NCT05797168
Ethics application status
Date submitted
21/02/2023
Date registered
4/04/2023

Titles & IDs
Public title
Phase I/IIa Study of AZD5335 as Monotherapy and Combination Therapy in Participants With Solid Tumors
Scientific title
A Modular Phase I/IIa, Open-label Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of Ascending Doses of AZD5335 Monotherapy and in Combination With Anti-cancer Agents in Participants With Solid Tumors
Secondary ID [1] 0 0
2022-502576-23-00
Secondary ID [2] 0 0
D8990C00001
Universal Trial Number (UTN)
Trial acronym
FONTANA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Ovarian Cancer 0 0
Lung Adenocarcinoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Ovarian and primary peritoneal
Cancer 0 0 0 0
Lung - Non small cell

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - AZD5335
Treatment: Drugs - Saruparib (AZD5305)
Treatment: Drugs - Bevacizumab
Treatment: Drugs - Carboplatin

Experimental: Module 1: AZD5335 Monotherapy - AZD5335 Monotherapy

Experimental: Module 2: AZD5335 + Saruparib - AZD5335 + Saruparib

Experimental: Module 3: AZD5335 + Bevacizumab - AZD5335 + Bevacizumab

Experimental: Module 4: AZD5335 + Carboplatin +/- Bevacizumab - AZD5335 + Carboplatin +/- Bevacizumab


Treatment: Drugs: AZD5335
IV Antibody-drug conjugate

Treatment: Drugs: Saruparib (AZD5305)
Oral PARP inhibitor

Treatment: Drugs: Bevacizumab
IV Monoclonal antibody

Treatment: Drugs: Carboplatin
IV Alkylating agent
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Number of participants with adverse events/serious adverse events
Timepoint [1] 0 0
From time of Informed Consent to 30 days post last dose.
Primary outcome [2] 0 0
The number of participants with dose limiting toxicity(DLT), as defined in the protocol
Timepoint [2] 0 0
From the first dose of AZD5335 on Cycle 1 Day 1 up to and including the planned end of Cycle 1 (At the end of 21 days)
Secondary outcome [1] 0 0
Objective Response Rate (ORR)
Timepoint [1] 0 0
From time of Informed Consent to progressive disease or withdrawal of consent.(approx 2 years)
Secondary outcome [2] 0 0
Duration of Response (DoR)
Timepoint [2] 0 0
From the first documented response to confirmed progression or death in the absence of disease progression.(approx 2 years)
Secondary outcome [3] 0 0
Disease Control Rate (DCR)
Timepoint [3] 0 0
From time of Informed Consent until progression.(approx 15 weeks)
Secondary outcome [4] 0 0
Progression free Survival (PFS)
Timepoint [4] 0 0
From time of first dose of AZD5335 or AZD5305 until the date of objective disease progression or death (by any cause in the absence of progression).(approx 2 years)
Secondary outcome [5] 0 0
Overall Survival (OS)
Timepoint [5] 0 0
From time of first dose of AZD5335 or AZD5305 until death due to any cause.(approx 2 years)
Secondary outcome [6] 0 0
Module 1: Pharmacokinetics of AZD5335: Area Under the concentration-time curve(AUC)
Timepoint [6] 0 0
From the first dose of study intervention, at predefined intervals throughout the administration of AZD5335(approximately 12 weeks)
Secondary outcome [7] 0 0
Module 1: Pharmacokinetics of AZD5335: Maximum plasma concentration of the study drug (Cmax)
Timepoint [7] 0 0
From the first dose of study intervention, at predefined intervals throughout the administration of AZD5335 (approximately 12 weeks)
Secondary outcome [8] 0 0
Module 1: Pharmacokinetics of AZD5335: Time to maximum plasma concentration of the study drug (T-max)
Timepoint [8] 0 0
From the first dose of study intervention, at predefined intervals throughout the administration of AZD5335 (approximately 12 weeks)
Secondary outcome [9] 0 0
Module 1: Pharmacokinetics of AZD5335: Clearance
Timepoint [9] 0 0
From the first dose of study intervention, at predefined intervals throughout the administration of AZD5335 (approximately 12 weeks)
Secondary outcome [10] 0 0
Module 1: Pharmacokinetics of AZD5335: Terminal elimination half-life (t 1/2)
Timepoint [10] 0 0
From the first dose of study intervention, at predefined intervals throughout the administration of AZD5335 (approximately 12 weeks)
Secondary outcome [11] 0 0
Immunogenicity of AZD5335
Timepoint [11] 0 0
From the first dose of study intervention, at predefined intervals throughout the administration of AZD5535.(approx 2 years)
Secondary outcome [12] 0 0
Module 1: To investigate baseline and on treatment changes in target expression.
Timepoint [12] 0 0
Baseline and predicted intervals throughout the administration of AZD5335(approx 2 years)
Secondary outcome [13] 0 0
Module 2: Pharmacokinetics of AZD5335 and AZD5305 when given in combination.
Timepoint [13] 0 0
From the first dose of study intervention, at predefined intervals throughout the administration of AZD5335 and AZD5305.(approx 12 weeks)
Secondary outcome [14] 0 0
Module 2, 3, and 4: Area Under the concentration-time curve (AUC)
Timepoint [14] 0 0
At predefined intervals throughout the treatment period (approximately 12 weeks)
Secondary outcome [15] 0 0
Module 2, 3, and 4: Maximum plasma concentration of the study drug (Cmax)
Timepoint [15] 0 0
At predefined intervals throughout the treatment period (approximately 12 weeks)
Secondary outcome [16] 0 0
Module 2, 3, and 4: Time to maximum plasma concentration of the study drug (T-max)
Timepoint [16] 0 0
At predefined intervals throughout the treatment period (approximately 12 weeks)
Secondary outcome [17] 0 0
Module 2, 3, and 4: Clearance
Timepoint [17] 0 0
At predefined intervals throughout the treatment period (approximately 12 weeks)
Secondary outcome [18] 0 0
Module 2, 3, and 4: Terminal elimination half-life (t 1/2)
Timepoint [18] 0 0
From the first dose of study intervention, at predefined intervals throughout the administration of AZD5335 (approximately 12 weeks)
Secondary outcome [19] 0 0
Module 3: Pharmacokinetics of AZD5335 and bevaczizumab when given in combination.
Timepoint [19] 0 0
From the first dose of study intervention, at predefined intervals throughout the administration of AZD5335 and bevacizumab.(approx 12 weeks)
Secondary outcome [20] 0 0
Module 4: Pharmacokinetics of AZD5335 and carboplatin (+/- bevacizumab) when given in combination.
Timepoint [20] 0 0
From the first dose of study intervention, at predefined intervals throughout the administration of AZD5335 and carboplatin (+/- bevacizumab).(approx 12 weeks)

Eligibility
Key inclusion criteria
Core

* Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
* Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports Genomic Initiative. Participants who do not provide informed consent for Optional Genetic Research may still be enrolled in the study.
* Consent to provide adequate baseline tumor sample, as applicable per module-specific criteria.
* Participant must be = 18 years at the time of signing the informed consent.
* Willing to provide archival or baseline tumor sample.
* For participants who have previously received targeted therapies such as ADCs, a fresh baseline biopsy will be required.
* Eastern Cooperative Oncology Group Performance Status of 0 or 1.
* Participants with advanced solid tumors must have received prior adequate therapy in accordance with local practice for their tumor type and stage of disease, or, in the opinion of the Investigator, a clinical trial is the best option for the next treatment based on response and/or tolerability to prior therapy. Participants with contraindications or who refuse therapy in accordance with local practice may also be considered provided that it is documented that he/she was informed about all therapeutic options.
* Participants must have measurable disease per RECIST v1.1,

1. A previously irradiated lesion can be considered a target lesion if the lesion is progressing and well defined.
2. For participants who undergo biopsies at screening and/or on treatment, it is preferred though not required, that the biopsied lesion, be distinct from any target lesion used in the RECIST v1.1 evaluation.
* Life expectancy = 12 weeks.
* Adequate organ and marrow function.
* Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

(a) Male participants: (i) Male participants who are sexually active with a female partner of childbearing potential must use a male condom (plus an additional contraceptive method) post-screening through 5 half-lives (45 days) plus 6 months (approximately 7.5 months) following the last dose of study intervention. It is strongly recommended for the female partner of a male participant to also use a highly effective method of contraception throughout this period. In addition, male participants must refrain from sperm donation while on study and for 5 half lives (45 days) plus 6 months (~7.5 months) following the last dose of study intervention.

(b) Female participants: (i) Females of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study intervention and a negative urine or serum pregnancy test prior to starting their next cycle of treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

(ii) (ii) Sex and Contraceptive/Barrier Requirements: Highly effective birth control methods include: Total sexual abstinence is an acceptable method provided it is the usual lifestyle of the participant (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments) [(periodic abstinence e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of exposure to study intervention, and withdrawal are not acceptable methods of contraception], a vasectomized partner, Implanon®, bilateral tubal occlusion, intrauterine device/levonorgestrel intrauterine system, Depo Provera™ injections, oral contraceptive associated with inhibition of ovulation, and Evra Patch™, Xulane™, or NuvaRing®.

Female participants of childbearing potential who are sexually active with a non-sterilized male partner must agree to use one highly effective method of birth control (defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly), from enrolment throughout the study and for 5 half-lives (45 days) plus 6 months (In total, 7.5 months) following the last dose of study intervention. It is strongly recommended for the male partner of a female participants to also use male condom (plus spermicide, if available) throughout this period. Cessation of contraception after this point should be discussed with a responsible physician. In addition, female participants must refrain from egg donation while on study and for 5 half-lives (45 days) plus 6 months (~7.5 months) following the last dose of study intervention.

Core
Minimum age
18 Years
Maximum age
130 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Patients with spinal cord compression or a history of leptomeningeal carcinomatosis.
* Patients with brain metastases unless, asymptomatic, stable, and not requiring continuous corticosteroids at a dose of > 10 mg prednisone/day or equivalent for at least 4 weeks prior to first dose of study intervention.
* Treatment with any of the protocol defined medications, without adequate washout periods or time before the first dose of study intervention.
* Unresolved toxicities of Grade = 2 (National Cancer Institute [NCI] CTCAE v5.0) from prior therapy (excluding vitiligo, alopecia, and endocrine disorders that are controlled with replacement hormone therapy). Participants with stable = Grade 2 neuropathy are eligible.
* Active infection, including tuberculosis and infections with hepatitis B virus (HBV; verified by known positive hepatitis B surface antigen [HBsAg] result), hepatitis C virus (HCV) or known HIV infection that is not well controlled. All of the following criteria are required to define an HIV infection that is well controlled: undetectable viral RNA, CD4+ count = 350/mm3, no history of acquired immune deficiency syndrome-defining opportunistic infection within the past 12 months, and stable for at least 4 weeks on the same anti-HIV medications (meaning there are no expected further changes in that time to the number or type of antiretroviral drugs in the regimen).

Patients with a past or resolved HBV/HCV infection are eligible if:

(a) Negative for HBsAg and positive for anti-hepatitis B virus core protein (HBc) or (b) Are HBsAg + with chronic HBV infection (lasting 6 months or longer) and meet conditions i-iii below: (i) HBV DNA viral load <100 IU/mL. (ii) Have normal transaminase values, or, if liver metastases are present, abnormal transaminases, with a result of AST/ALT <3 × ULN, which are not attributable to HBV infection.

(iii) Start or maintain antiviral treatment if clinically indicated as per the Investigator or as per local guideline.

Note for Japan: Japanese patients with positive anti-HBs/anti-HBc and negative HBsAg will be assessed following local guidelines.

(c) Participants testing positive for HCV antibody are eligible only if the polymerase chain reaction test result is negative for HCV RNA.

* Patient has ILD/pneumonitis or has a history of (non-infectious) ILD/pneumonitis that required oral or IV steroids or supplemental oxygen, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.

* Patients with a history of radiation pneumonitis which has clinically and radiologically resolved and not requiring treatment with steroids may be eligible.
* History of another primary malignancy except for:

* Malignancy treated with curative intent and with no known active disease for at least 2 years prior to screening of study intervention and with low potential risk for recurrence.
* Adequately treated nonmelanoma skin cancer or lentigo maligna without evidence of disease.
* Adequately treated carcinoma in situ without evidence of disease.
* Localized non-invasive primary disease under surveillance.
* Patients with any of the following cardiac criteria:

* History of arrhythmia (such as multifocal premature ventricular contractions, bigeminy, trigeminy, and ventricular tachycardia), which is symptomatic or requires treatment (NCI CTCAE v5.0 Grade 3); symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia.

* NOTE: significant abnormalities in serum electrolytes that can increase the risk of arrhythmic events (ie, sodium, potassium, calcium, and magnesium) should be corrected before starting the study intervention.
* Uncontrolled hypertension.
* Acute coronary syndrome/acute myocardial infarction, unstable angina pectoris, coronary intervention procedure with percutaneous coronary intervention, or coronary artery bypass grafting within 6 months of screening.
* History of brain perfusion problems (eg, carotid stenosis) or stroke, or transient ischemic attack in the last 6 months prior to screening.
* Symptomatic heart failure (as defined by New York Heart Association class = 2).
* Prior or current cardiomyopathy.
* Severe valvular heart disease.
* Mean resting QTcF > 470 msec obtained from triplicate electrocardiograms (ECGs) and averaged, recorded within 5 minutes.
* Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age.
* Uncontrolled intercurrent illness within 12 months prior to screening, including but not limited to serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirements and activities, substantially increase risk of incurring AEs or compromise the ability of the participant to give written informed consent.
* Substance abuse or any other medical conditions that would increase the safety risk to the participant or interfere with participation of the participant or evaluation of the clinical study in the opinion of the Investigator.
* Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention. Note: Participants, if enrolled, should not receive live vaccine whilst receiving study intervention and up to 3 months after the last dose of study intervention. Participants can receive Coronavirus (COVID)-19 vaccines, at the discretion of the Investigator, following a benefit/risk evaluation for the individual participant and in accordance with local rules and regulations and vaccination guidelines. Note: If a COVID-19 vaccine is administered it should be done > 72 hours prior to study intervention initiation or after completion of the DLT period.
* For women only - currently pregnant (confirmed with positive pregnancy test), lactating, breastfeeding, or intend to become pregnant during the study period.
* 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.
* Patients with a known hypersensitivity to study intervention or any of the excipients of the product.
* Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
* 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.
* Previous enrolment in the present study. **Other module specific criteria may apply

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
5/06/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
6/01/2028
Actual
Sample size
Target
396
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Research Site - Liverpool
Recruitment hospital [2] 0 0
Research Site - Melbourne
Recruitment postcode(s) [1] 0 0
2170 - Liverpool
Recruitment postcode(s) [2] 0 0
3000 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Colorado
Country [3] 0 0
United States of America
State/province [3] 0 0
Kentucky
Country [4] 0 0
United States of America
State/province [4] 0 0
Massachusetts
Country [5] 0 0
United States of America
State/province [5] 0 0
Ohio
Country [6] 0 0
United States of America
State/province [6] 0 0
Oregon
Country [7] 0 0
United States of America
State/province [7] 0 0
Rhode Island
Country [8] 0 0
United States of America
State/province [8] 0 0
Texas
Country [9] 0 0
Canada
State/province [9] 0 0
Alberta
Country [10] 0 0
Canada
State/province [10] 0 0
Ontario
Country [11] 0 0
Canada
State/province [11] 0 0
Quebec
Country [12] 0 0
China
State/province [12] 0 0
Chengdu
Country [13] 0 0
China
State/province [13] 0 0
Chongqing
Country [14] 0 0
China
State/province [14] 0 0
Guangzhou
Country [15] 0 0
China
State/province [15] 0 0
Jinan
Country [16] 0 0
China
State/province [16] 0 0
Xi'an
Country [17] 0 0
China
State/province [17] 0 0
Zhengzhou
Country [18] 0 0
Israel
State/province [18] 0 0
Haifa
Country [19] 0 0
Israel
State/province [19] 0 0
Ramat Gan
Country [20] 0 0
Japan
State/province [20] 0 0
Hidaka-shi
Country [21] 0 0
Japan
State/province [21] 0 0
Kashiwa
Country [22] 0 0
Japan
State/province [22] 0 0
Koto-ku
Country [23] 0 0
Japan
State/province [23] 0 0
Sunto-gun
Country [24] 0 0
Japan
State/province [24] 0 0
Tokyo
Country [25] 0 0
Spain
State/province [25] 0 0
Barcelona
Country [26] 0 0
Spain
State/province [26] 0 0
Madrid
Country [27] 0 0
Spain
State/province [27] 0 0
Málaga
Country [28] 0 0
Taiwan
State/province [28] 0 0
Taichung
Country [29] 0 0
Taiwan
State/province [29] 0 0
Tainan City
Country [30] 0 0
Taiwan
State/province [30] 0 0
Taipei
Country [31] 0 0
Turkey
State/province [31] 0 0
Ankara
Country [32] 0 0
Turkey
State/province [32] 0 0
Istanbul
Country [33] 0 0
United Kingdom
State/province [33] 0 0
Cambridge
Country [34] 0 0
United Kingdom
State/province [34] 0 0
Glasgow, Scotland
Country [35] 0 0
United Kingdom
State/province [35] 0 0
London
Country [36] 0 0
United Kingdom
State/province [36] 0 0
Sutton

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
AstraZeneca
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Funda Meric-Bernstam, MD
Address 0 0
UT MD Anderson Cancer Center
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
AstraZeneca Clinical Study Information Center
Address 0 0
Country 0 0
Phone 0 0
1-877-240-9479
Fax 0 0
Email 0 0
information.center@astrazeneca.com
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal.

All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

Supporting document/s available: Study protocol, Statistical analysis plan (SAP)
When will data be available (start and end dates)?
AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Available to whom?
When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Available for what types of analyses?
How or where can data be obtained?
IPD available at link: https://astrazenecagroup-dt.pharmacm.com/DT/Home


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT05797168