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Trial registered on ANZCTR


Registration number
ACTRN12623000174684
Ethics application status
Approved
Date submitted
13/12/2022
Date registered
21/02/2023
Date last updated
17/03/2024
Date data sharing statement initially provided
21/02/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase Ib/II Study of APG-2449 in Combination with Doxorubicin Hydrochloride Liposome in Patients with Ovarian Cancer
Scientific title
A Phase Ib/II Study of APG-2449 in Combination with Doxorubicin Hydrochloride Liposome in Patients with Ovarian Cancer
Secondary ID [1] 308681 0
APG2449OG101
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Ovarian Cancer 328506 0
Condition category
Condition code
Cancer 325533 325533 0 0
Ovarian and primary peritoneal

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a multi-centre, open-label study of APG-2449 combined with Doxorubicin Hydrochloride Liposome (PLD) to evaluate the safety and efficacy in patients with ovarian cancer.

APG-2449 capsules will be administered orally on Day 1 of Cycle 1, and then once daily from Day 4 of Cycle 1 on a 28-day repeated cycles, 1200mg as the starting dose, following the principle of 3+3 study design to determine the safety of the combination/RP2D of the combination, and the dose escalation or de-escalation will be performed based on the safety of the starting dose. The escalated dose will be 1500 mg and the de-escalated dose will be 900 mg. PLD 40 mg/m2 is intravenously infused on Day 4 of Cycle 1 and then Day 1 of each subsequent 28-day cycles. Patient will be continuously treated until disease progression, unacceptable toxicity, or other criteria for treatment discontinuation are met, whichever comes first.

No intra-patient dose escalation will be allowed.

Once the RP2D is determined, expansion study cohort will be enrolled to assess the efficacy and safety of APG-2449/PLD combination in treating patients with platinum-resistant ovarian cancer. Specifically, APG-2449 will be administered at the RP2D orally daily for 28 days in each treatment cycle, in combination with PLD 40 mg/m2 intravenously infused on Day 1 of each 28-day cycle.

Patient will be continuously treated until disease progression, unacceptable toxicity, or other criteria for treatment discontinuation are met, whichever comes first.

Throughout the study, compliance and safety of the participants will be closedly monitored via regular medical review, safety lab assessments, drug administration diary and timely reconciliation of returned pills, etc.


Intervention code [1] 325062 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 333372 0
To characterize the safety and tolerability of APG-2449 in combination with PLD, including determination of the dose-limiting toxicities (DLT) and RP2D, when treating patients with ovarian cancer. Safety and Tolerabilty will be assessed by evaluating the below factors.

1. Vital signs include blood pressure (BP) measured using a sphygmomanometer, heart rate (HR) assessed using a pulse oximeter, respiratory rate (RR) counted by a qualified person, and temperature (temp) with a thermometer.
2. Electrocardiogram (ECG) parameters, ECOG performance status data,
3. Clinical laboratory tests, including haematological parameters, biochemistry, coagulation function heart muscle function and liver function tests assessed using blood samples
4. Adverse event (AE) will be assessed in accordance with the CTCAE5.0, using the above data, and also via medical review, physical examination, participant self-reported data in each treatment cycle. Known AEs for APG2449 include Gastrointestinal reaction, haematologic effects (e.g. neutropenia), liver function impairment, etc. Common AEs for PLD include fatigue, loss of appetite, dyspepsia, etc.
Timepoint [1] 333372 0
Patient will be monitored for safety during each 28 days treatment cycle. During Cycle 1, patient will visit study site 4 time including Days 1, 8, 15, and 21 of Cycle 1, and be closely monitored at each visit by taking blood samples, measuring vital signs, conducting a Physical Exam and ECG and assessing the ECOG performance status. From cycle 2 onwards these assessments will be done at Days 1 and 15 of each following cycle. At each visit -regardless of cycle - any adverse events and/or new concomitant medication will be discussed with the Patient. These procedures will last until disease progression, unacceptable toxicity, or other criteria for treatment discontinuation are met, whichever comes first.
Secondary outcome [1] 416826 0
To obtain a preliminary assessment of efficacy (RECIST 1.1 criteria) and PK characteristics of APG2449 in combination with PLD in patients with platinum resistant ovarian cancer. Specifically, objective assessment will consist of disease specific radiological, clinical and/or pathological studies, including, but not limited to: • Chest, abdominal, and/or pelvic CT scan or MRI. • CT scan or MRI of the head and spine only if clinically indicated. • Other imaging studies as clinically indicated (e.g., bone scan, positron emission tomography (PET) etc. • Physical exam, as indicated. • Appropriate hematological and biochemical lab tests.

In additon, blood sample will be collected for PK analysis.
Timepoint [1] 416826 0
Tumor response will be evaluated at screening, every 2 cycles and End of Treatment visit (if >28 days since last assessment).

Blood will be collected for PK analysis at pre-dose and various time points post dose on Cycle 1 Day 1 and Cycle 1 Day 21.

Eligibility
Key inclusion criteria
Patients must meet all the following inclusion criteria to be eligible for participation in this
study:
1. greater than or equal to 18 years of age
2. Histologically confirmed ovarian cancer, including fallopian tube cancer, or primary peritoneal cancer, especially the subtype high-grade serous ovarian cancer (HGSOC).
3. Prior treatment with a platinum-based regimen and disease progression or relapse during platinum-based regimen therapy (at least 4 cycles) or within 6 months (184 calendar days) of the last platinum therapy. Note: Progression or recurrence of disease requires evidence of radiographic or clinical progression (e.g. cytological reports of new ascites or pleural effusion). Primary platinum-refractory (defined as progression during or within 4 weeks post to the first platinum-containing regimen) subjects could not be enrolled, but secondary platinum-refractory subjects could be enrolled in the study without the requirement for at least 4 cycles of platinum containing therapy.
4. Up to 5 lines of prior systemic therapies are permitted; up to 2 lines of prior systemic therapy are permitted following diagnosis of platinum-resistant relapse. Note: Hormone therapy (eg, tamoxifen), maintenance therapy with PARP inhibitors and bevacizumab are not counted as treatment lines. Other special maintenance options may not be counted as treatment lines.
5. Presence of at least one measurable tumor lesion (as assessed by the investigator) according to RECIST 1.1 criteria.
6. Eastern Cooperative Oncology Group (ECOG) score 0 to 1.
7. Life expectancy at least 3 months.
8. Adequate bone marrow, liver, kidney, and coagulation function reserve as confirmed by
laboratory tests within 3 days prior to the first dose.
a) Hemoglobin (Hb) greater than or equal to 90 g/L independent of transfusion red blood cell transfusion and erythropoietin (EPO) use.
b) Platelet count greater than or equal to 100 x 10^9/L and independent of platelet transfusion.
c) Absolute neutrophil count (ANC) greater than or equal to 10^9/L and independent of the use of colony-stimulating factor (CSF).
d) Total bilirubin less than or equal to 1.5×upper limit of normal (ULN).
e) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 2.5×ULN (less than or equal to 5× ULN for subjects with confirmed liver metastases).
f) Albumin greater than or equal to 30 g/L.
g) Serum creatinine less than or equal to 1.5×ULN, and if serum creatinine greater than 1.5×ULN, creatinine clearance greater than or equal to 50 mL/min calculated using the Cockcroft-Gault formula.
h) Negative or weakly positive urine protein (±); or urine protein 1 + but 24-hour urine protein
quantification less than 1.0g/24 h.
i) International normalized ratio (INR) less than or equal to 1.5 and activated partial thromboplastin time (aPTT) less than or equal to 1.5×ULN. Subjects on stable anticoagulant therapy may be enrolled at the discretion of the investigator.
9. AEs caused by previous treatment must be recovered to Grade 1 (CTCAEv5.0) or stable state as assessed by the investigator. Note: Mild toxicities without safety concerns, such as alopecia and grade 2 neuralgia, may be included at the investigator 's discretion.
10. Female subjects must be non-pregnant and non-lactating and meet either of the following: a) Does not meet the definition of women of childbearing potential (WOCBP). Or b) WOCBP agrees to comply with the contraception guidelines during the treatment period and for 3 months following the last dose.
11. Willing to sign an informed consent form. Voluntary written informed consent must be obtained from the subject before any study-specific procedures are performed, unless the procedures are performed according to clinical criteria and fall within the protocol-required time window and meet study-specific requirements, such as tumor imaging.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients who meet any of the following exclusion criteria are not to be enrolled in this study:
1. Major surgery or major trauma within 28 days prior to the first dose or diagnostic biopsy within 14 days prior to the first dose. Note: Patients who are expected to require major surgery during study treatment will also be excluded. Subjects who had a diagnostic biopsy within 14 days prior to the first dose could also be enrolled if the investigator judged that the diagnostic biopsy did not affect the efficacy assessments during the study.
2. Have received systemic antineoplastic agents including investigational agents within a specified period, including targeted therapy within 14 days or 5 half-lives (whichever is shorter) before the first dose, or immunotherapy within 28 days before the first dose.
3. Radiotherapy within 14 days prior to first dose.
4. Previous FAK inhibitors
5. Previous cumulative anthracycline dose greater than or equal to 550 mg/m2.
6. Other sites or other histological types of tumors other than existing ovarian cancer within 3 years before the first dose, except curable tumors such as cervical carcinoma in situ.
7. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Note: Subjects may be considered for enrollment if they have previously treated brain metastases that are clinically stable or radiologically stable within 14 days prior to the first dose (confirmed by repeat imaging at least 4 weeks apart and performed at screening).
8. Major cardiovascular or cerebrovascular disease (such as congestive heart failure, acute myocardial infarction, unstable angina pectoris, stroke, transient ischemic attack, deep venous thrombosis) within 6 months before the first dose, or any of the following abnormalities:
a) QTc interval greater than 480 milliseconds.
b) Left ventricular ejection fraction (LVEF) less than 50%.
c) New York Heart Association (NYHA) cardiac function classification greater than or equal to grade 2.
d) Severe arrhythmia.
e) Poorly controlled hypertension or diabetes.
f) Other serious heart disease.
9. Clinical symptoms of pleural effusion, pericardial effusion, or ascites should need puncture, drainage or drainage within 1 month before the first dose, except for a small amount of effusion on imaging but not accompanied by clinical symptoms.
10. Presence of malabsorption syndrome, or inability to take oral medication, or bowel obstruction.
11. Presence of serious gastrointestinal disease such as poorly controlled gastrointestinal inflammatory disease (active Crohn 's disease or ulcerative colitis) or poorly controlled gastrointestinal bleeding. Presence of clinical or radiographic evidence of ileus, or etiology of previous recurrent ileus will not be excluded.
12. Uncontrolled or active infectious diseases such as HIV, hepatitis B and hepatitis C.
13. Systemic administration of moderate or strong inhibitors/inducers of CYP3A4, CYP2C9 or CYP2C19 within 7 days prior to the first dose. Systemic administration of CYP3A4 sensitive substrates with narrow therapeutic index within 7 days prior to the first dose.
14. Other factors may cause the subject to be forced to terminate the study halfway as judged by the investigator, such as having other serious diseases (including mental illness) requiring concomitant treatment, severely abnormal laboratory tests, family, or social factors, which may affect the safety of the subject or the collection of trial data, etc.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised 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
3+3 dose escalation
expansion at RP2D
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
31/03/2023
Actual
8/08/2023
Date of last participant enrolment
Anticipated
31/01/2025
Actual
Date of last data collection
Anticipated
30/01/2026
Actual
Sample size
Target
40
Accrual to date
6
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 23718 0
Blacktown Hospital - Blacktown
Recruitment hospital [2] 26282 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment hospital [3] 26283 0
Icon Cancer Care South Brisbane - South Brisbane
Recruitment postcode(s) [1] 39156 0
2148 - Blacktown
Recruitment postcode(s) [2] 42253 0
2050 - Camperdown
Recruitment postcode(s) [3] 42254 0
4101 - South Brisbane

Funding & Sponsors
Funding source category [1] 312856 0
Commercial sector/Industry
Name [1] 312856 0
Ascentage Pharma Pty Ltd
Country [1] 312856 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Ascentage Pharma Pty Ltd
Address
Suite 30.03, Level 30, 133 Castlereagh Street, Sydney, NSW 2000, Australia
Country
Australia
Secondary sponsor category [1] 314509 0
None
Name [1] 314509 0
Not applicable
Address [1] 314509 0
Not applicable
Country [1] 314509 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312134 0
Bellberry
Ethics committee address [1] 312134 0
Ethics committee country [1] 312134 0
Australia
Date submitted for ethics approval [1] 312134 0
30/01/2023
Approval date [1] 312134 0
21/03/2023
Ethics approval number [1] 312134 0
2023/ETH00043

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

Contacts
Principal investigator
Name 123598 0
Dr Bo Gao
Address 123598 0
Blacktown Hospital, 18 Blacktown Rd, Blacktown NSW 2148, Australia
Country 123598 0
Australia
Phone 123598 0
+61 0402348016
Fax 123598 0
Email 123598 0
[email protected]
Contact person for public queries
Name 123599 0
Zhicong He
Address 123599 0
Ascentage Pharma, Suite 30.03, Level 30, 133 Castlereagh Street, Sydney, NSW 2000, Australia
Country 123599 0
Australia
Phone 123599 0
+61 414668863
Fax 123599 0
Email 123599 0
[email protected]
Contact person for scientific queries
Name 123600 0
Zhicong He
Address 123600 0
Ascentage Pharma, Suite 30.03, Level 30, 133 Castlereagh Street, Sydney, NSW 2000, Australia
Country 123600 0
Australia
Phone 123600 0
+61 414668863
Fax 123600 0
Email 123600 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.