Advanced Solid Tumors, Hematological Malignancies
Conditions
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 .
Detailed description
This is a Phase I, multi-center, open-label study of ATG-018 administered orally as monotherapy in patients with advanced solid tumors and hematological malignancies. The study design includes a Dose Escalation Phase and a Dose Expansion Phase.
Interventions
DRUGATG-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.
Sponsors
Antengene Discovery Limited
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Exclusion criteria
* Subjects meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| MTD | 12 months after the last subject enrolled | Maximum Tolerated Dose |
| AE/SAE | 12 months after the last subject enrolled | Adverse Event/Serious Adverse Event |
| RP2D | 12 months after the last subject enrolled | RP2D= Recommended Phase 2 Dose |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| DOR | 12 months after the last subject enrolled | Duration of Response |
| ORR | 12 months after the last subject enrolled | Overall Response Rate |
Other
| Measure | Time frame | Description |
|---|---|---|
| PFS | 12 months after the last subject enrolled | Progression Free Survival |
| OS | 12 months after the last subject enrolled | Overall Survival |
Countries
Australia
Outcome results
None listed