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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT05338346




Registration number
NCT05338346
Ethics application status
Date submitted
14/04/2022
Date registered
21/04/2022
Date last updated
22/04/2024

Titles & IDs
Public title
A Study of ATG-018 (ATR Inhibitor) Treatment in Patients With Advanced Solid Tumors and Hematological Malignancies
Scientific title
A Phase I, Open-Label, Multi-Center, Dose Finding Study to Investigate the Safety, Pharmacokinetics, and Preliminary Efficacy of ATG-018 (ATR Inhibitor) Treatment in Patients With Advanced Solid Tumors and Hematological Malignancies
Secondary ID [1] 0 0
ATG-018-001
Universal Trial Number (UTN)
Trial acronym
ATRIUM
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced Solid Tumors 0 0
Hematological Malignancies 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - ATG-018

Experimental: ATG-018 - Dose Escalation Phase:
For Solid Tumors Group: A maximum of 44 subjects with solid tumors will be enrolled during the Dose Escalation Phase.
For Hematological Malignancies Group: Subjects with hematological malignancy will be enrolled.
Dose Expansion Phase:
The tumor types in Dose Expansion Phase may involve other tumor types based on the signals from the Dose Escalation Phase. Each tumor type is planned to enroll at least 12 subjects, and a further expansion (up to 40 subjects in each tumor type) may be triggered if 2 or more confirmed responses are observed in this cohort.


Treatment: Drugs: ATG-018
Dose Escalation Phase:
For both dose escalation groups, subjects will receive a single dose of ATG-018 monotherapy on Cycle 1 Day 1 (C1D1) for single dose PK samples' collection. From the morning dose on Cycle 1 Day 2, twice daily dosing (except Dose Level 1: 5 mg QD) will be initiated. Subject(s) will receive intermittent dosing in a 3 days on/4 days off schedule in 21-day cycles until disease progression or unacceptable toxicity.
Dose Expansion Phase :
Dose Expansion Phase will begin at the defined MTD/RP2D for solid tumors and hematological malignancies groups, to further evaluate the safety, tolerability, and PDx profile of ATG-018. Subjects with solid tumors and hematological malignancies will be enrolled.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
AE/SAE
Timepoint [1] 0 0
12 months after the last subject enrolled
Primary outcome [2] 0 0
MTD
Timepoint [2] 0 0
12 months after the last subject enrolled
Primary outcome [3] 0 0
RP2D
Timepoint [3] 0 0
12 months after the last subject enrolled
Secondary outcome [1] 0 0
ORR
Timepoint [1] 0 0
12 months after the last subject enrolled
Secondary outcome [2] 0 0
DOR
Timepoint [2] 0 0
12 months after the last subject enrolled

Eligibility
Key inclusion criteria
- Subjects must meet all the following inclusion criteria to be eligible to enroll in
this study:

1. Provision of signed and dated, written informed consent prior to any study
specific procedures, sampling, and analyses.

2. Aged at least 18 years.

3. After completion of Dose level 3, subjects will need to demonstrate a defect in
one or more DDR genes such as: ATM (including ATM protein loss by IHC), ATRX,
ARID1A, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, FANCC, FANCD2, FANCE,
FANCF, FANCM, MRE11A, MSH2, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, or other
related genes at the discretion of the investigator in consultation with sponsor
Medical Monitor; Or mutations in p53 pathway/MYC pathway.

4. Subjects with solid tumor must meet the following criteria: histological or
cytological confirmation of a solid tumor, and have progressed despite standard
therapy(ies), or are intolerant to standard therapy(ies), or have a tumor for
which no standard therapy(ies) exists. Locally recurrent disease must not be
amenable to surgical resection or radiotherapy with curative intent (subjects who
are considered suitable for surgical or ablative techniques following
down-staging with study treatment are not eligible).

5. Subjects with hematological malignancies must meet the following criteria: have
pathologically confirmed de novo DLBCL or DLBCL transformed from previously
diagnosed indolent lymphoma (eg, follicular lymphoma) or B-cell indolent
Non-Hodgkin's Lymphoma (iNHL) with histological subtype limited to FL Grade 1,
Grade 2, or Grade 3a, or Grade 3b, or splenic marginal zone lymphoma (MZL), or
nodal MZL, or extranodal MZL based on criteria established by the World Health
Organization (WHO) 2016 classification.

6. Subjects with DLBCL must have received at least 2 previous systemic regimens for
the treatment of their de novo or transformed DLBCL including at least 1 course
of anthracycline-based chemotherapy (unless absolutely contraindicated due to
cardiac dysfunction, in which case other active agents such as etoposide,
bendamustine, or gemcitabine must have been given) combined with at least 1
course of anti-CD20 immunotherapy (eg, rituximab), unless contraindicated due to
severe toxicity. Prior stem cell transplantation was allowed; induction,
consolidation, stem cell collection, preparative regimen, and transplantation ±
maintenance were considered a single line of therapy.

7. Subjects with B-cell iNHL must have received at least one previous line of
therapy including a CD20-targeted monoclonal antibody, and systemic therapy does
not include local involved field radiotherapy for limited stage disease and/or H.
Pylori eradication.

Please note that all hematological malignancies must have documented clinical or
radiographic evidence of progressive prior to dosing.

8. Subjects must have measurable lesion defined as below:

1. Subject with solid tumors must have at least 1 lesion, not previously
irradiated, that can be accurately measured at pre dose as =10 mm in the
longest diameter (except lymph nodes which must have short axis =15 mm) with
CT or MRI and which is suitable for accurate repeated measurements.

2. Subject with B-NHL must have measurable disease as defined by at least one
bi-dimensionally measurable lesion that node >1.5 cm in longest diameter
(LDi) or extranodal lesion >1 cm in LDi (per the Lugano 2014 Criteria).

9. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 with no
deterioration over the previous 2 weeks, or prior to the first dose of study
treatment (C1D1).

10. Except for hearing loss, alopecia, and pigmentation, all toxicity caused by
previous antitumor therapy has recovered to Grade 1 or less (according to the
NCI-CTCAE version 5.0).

11. Life expectancy >3 months.

12. Men and women of childbearing potential must agree to use effective
contraceptives from they sign the informed consent to 180 days after the last
dose of study drug. Women of childbearing potential include premenopausal women
and women within 2 years after menopause. Women of childbearing age must have a
negative serum pregnancy test at screening.

13. Male subjects (including those who have undergone vasectomy) must consent to the
use of condoms during sex with women of childbearing potential and have no plans
to impregnate the woman during the use of the study drug and within 180 days
after the last dose of the study drug from the date of signing the ICF.

14. Subjects should have the ability and willingness to comply with the study and
follow up.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Subjects meeting any of the following exclusion criteria are not eligible to enroll in
this study:

1. Central nervous system (CNS) metastatic disease, leptomeningeal disease, or
metastatic cord compression.

2. Prior treatment with ATR inhibitor.

3. Subjects with B-NHL in the condition as below:

1. DLBCL with MALT lymphoma.

2. Composite lymphoma (Hodgkin's lymphoma + NHL).

3. Primary mediastinal (thymic) large B-cell lymphoma.

4. Prior therapy with any other investigational product or anticancer systemic
therapy including chemotherapy, immunotherapy, or other anticancer agents within
21 days (or within a period during which the investigational product or systemic
anticancer treatment has not been cleared from the body, eg, a period of 5
'half-lives') of the first dose of study treatment, whichever is the most
appropriate as judged by the investigator.

5. Radiotherapy with a wide field of radiation within 28 days, or radiotherapy with
a limited field of radiation for palliation within 14 days of the first dose of
study treatment. Subject must have recovered from all radiation related toxicity,
not requiring corticosteroids.

6. Prior major surgery (excluding placement of vascular access) within 28 days of
the first dose of study treatment or minor surgical procedures =7 days. No
waiting is required following implantable port and catheter placement.

7. Subjects receiving unstable or increasing doses of corticosteroids. For patients
receiving corticosteroids for endocrine deficiencies or symptoms associated to
their disease (excluding central nervous system disease), the dose must have been
stabilized (or reducing) for at least 14 days before the first dose of study
treatment.

8. As judged by the investigator, any evidence of severe or uncontrolled systemic
diseases, including uncontrolled hypertension defined as a blood pressure (BP)
=150/95 mmHg despite medical therapy, unstable or uncompensated respiratory and
renal disease, active bleeding diseases, allogeneic stem cell transplantation, or
any solid organ transplant.

9. Have active or previous autoimmune diseases that are likely to recur (such as
systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease,
autoimmune thyroid disease, vasculitis, and psoriasis), or are at risk of such
diseases.

10. Poorly controlled of pleural effusion or pericardial effusion (with clinical
symptoms, fluctuation of effusion or need for repeated drainage, oral diuretics,
etc) at screening. Ascites that can be detected on physical examination, or
clinical symptoms caused by ascites, or that require special treatment, such as
repeated drainage, intraperitoneal drug infusion, etc, at screening (Subjects
with a small amount of ascites that can only be detected by imaging examination
can be considered for inclusion).

11. Active infection including hepatitis B, and/or hepatitis C (HBV-DNA or HCV-RNA
detected above lower limit of normal [LLN] by local laboratory, respectively).

12. Known history of human immunodeficiency virus (HIV) infection.

13. Active infection requiring parenteral antibiotics, antivirals, or antifungals
within 14 days prior to C1D1; however, prophylactic use of these agents is
acceptable (including parenteral).

14. Autologous stem cell transplant < 6 months or CAR-T cell infusion < 6 months
prior to C1D1.

15. History of allogeneic stem cell transplant.

16. Impaired cardiac function or clinically significant cardiac diseases, including
any of the following:

1. Unstable angina or acute myocardial infarction =3 months prior to C1D1.

2. Clinically significant heart disease (eg, symptomatic congestive heart
failure with New York Heart Association Grade 3 or above).

3. Uncontrolled arrhythmia, or hypertension; history of labile hypertension or
poor compliance with an antihypertensive regimen.

4. Baseline left ventricular ejection fraction (LVEF) below institution's LLN
or <50% if assessed by echocardiogram (ECHO), or baseline LVEF below
institution's LLN if assessed by multiple gated acquisition scan (MUGA).

17. Inadequate bone marrow reserve (within 14 days) or organ function as demonstrated
by any of the following laboratory values:

1. Absolute neutrophil count <1.5 × 109/L

2. Platelet count <100 × 109/L

3. Hemoglobin <90 g/L Please note that platelet transfusions within 7 days, red
blood cell transfusions within 14 days, hematopoietic growth factors within
7 days (G-CSF or erythropoietin) are not permitted prior to obtaining these
laboratory values.

1. Alanine aminotransferase (ALT) >2.5 times the upper limit of normal (ULN)

2. Aspartate aminotransferase (AST) >2.5 times ULN

3. Total bilirubin >1.5 times ULN

4. Creatinine >1.5 times ULN concurrent with creatinine clearance <50 mL/min
(measured or calculated by Cockcroft and Gault equation); confirmation of
creatinine clearance is only required when creatinine is >1.5 times ULN

1. Serum albumin <30 g/L

2. Coagulation: international normalized ratio (INR) >2.0, prothrombin time
(PT) >1.5×ULN

18. Subject inability or unwillingness to comply with requirement for oral drug
administration or presence of a gastro-intestinal condition, eg, refractory
nausea and vomiting, any acute or chronic gastrointestinal disease, inability to
swallow the formulated product or previous significant bowel resection that would
preclude adequate absorption of ATG-018.

19. History of hypersensitivity to any excipient of ATG-018 or these medicinal
products or history of allergic reactions attributed to drugs with a similar
chemical structure or class to ATG-018.

20. Any chronic or uncontrolled dermatological condition that will be adversely
impacted by the potential skin toxicity of the study treatment(s).

21. Judgment by the investigator that the subject should not participate in the study
if the subject is unlikely to comply with study procedures, restrictions, and
requirements.

22. Other primary malignancies developed within 2 years prior to the first
administration of the study drug, except locally curable malignancies after
radical treatment (such as basal or squamous cell skin cancer, superficial
bladder cancer, or carcinoma in situ of the prostate, cervix, or breast, etc).

23. Psychological, familial, sociological, or geographical conditions that do not
permit compliance with the protocol.

24. Subjects was in receipt of any live attenuated vaccination within 30 days prior
to the first dose of study treatment.

25. History or current evidence of any condition or disease that could confound the
results of the study or, in the opinion of investigator, is not in the best
interest of the subject to participate.

Study design
Purpose of the study
Treatment
Allocation to intervention
N/A
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
Single group
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
8/07/2022
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
30/06/2024
Actual
Sample size
Target
88
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Icon Cancer Centre South Brisbane - Brisbane
Recruitment hospital [2] 0 0
Chris O'Brien Lifehouse - Camperdown
Recruitment hospital [3] 0 0
Austin Health - Heidelberg
Recruitment hospital [4] 0 0
Alfred Health - Melbourne
Recruitment hospital [5] 0 0
Liverpool Hospital - Sydney
Recruitment postcode(s) [1] 0 0
- Brisbane
Recruitment postcode(s) [2] 0 0
- Camperdown
Recruitment postcode(s) [3] 0 0
- Heidelberg
Recruitment postcode(s) [4] 0 0
- Melbourne
Recruitment postcode(s) [5] 0 0
- Sydney

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Antengene Discovery Limited
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
This is a Phase I, Open-Label, Multi-Center, Dose Finding Study to Investigate the Safety,
Pharmacokinetics, and Preliminary Efficacy of ATG-018 (ATR inhibitor) Treatment in Patients
with Advanced Solid Tumors and Hematological Malignancies .
Trial website
https://clinicaltrials.gov/ct2/show/NCT05338346
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Edwin Hoe
Address 0 0
Country 0 0
Phone 0 0
+61 497 390477
Fax 0 0
Email 0 0
edwin.hoe@antengene.com
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT05338346