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Trial registered on ANZCTR


Registration number
ACTRN12616001597482
Ethics application status
Approved
Date submitted
2/11/2016
Date registered
18/11/2016
Date last updated
13/01/2023
Date data sharing statement initially provided
8/01/2019
Date results provided
27/09/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A study of the safety, pharmacokinetic and pharmacodynamic properties of a novel anticancer drug APG-1252 in patients with small cell lung cancer or other solid tumors
Scientific title
A phase I study of the safety, pharmacokinetic and pharmacodynamic properties of intravenously administered APG-1252 in patients with small cell lung cancer (SCLC) or other solid tumors
Secondary ID [1] 290412 0
None
Universal Trial Number (UTN)
Trial acronym
APG-1252-AU-001
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Solid tumour 300752 0
Small cell lung cancer 300828 0
Condition category
Condition code
Cancer 300586 300586 0 0
Lung - Small cell
Cancer 300653 300653 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Investigational product will be administered via intravenous infusion for 30 minutes. No investigational or commercial agents or therapies may be administered with the intent to treat the patient's malignancy other than APG-1252. Supportive care measures including those directed at controlling symptoms resulting from the patient’s malignancy are allowed. Patients will be treated in 28-day cycles. Treatment will begin in the first cycle at 10 mg of APG-1252 administered via intravenous infusion for 30 minutes, twice weekly (on Days 1, 4, 8, 11, 15, 18 and 22 of each cycle), then will be one week off treatment before commencing the next treatment cycle. Doses can be modified depending on toxicity and PK results based on discussions with the Investigators and Sponsor. If no DLTs or less than two drug related Grade 2 toxicities are observed by the end of Cycle 1, the dose of APG-1252 will be increased in subsequent cohorts, to 80 mg, 120 mg, 240 mg, 320 mg and 400 mg accordingly. If a DLT or two drug related Grade 2 toxicities occur in Cycle 1 at any dose level escalation will convert to the standard 3+3 design and will occur at increments of 1.4 x the preceding dose. If greater than or equal to 2/6 patients develop DLT at any dose level dose escalation will cease and the dose level immediately below will be expanded to 6 patients. If less than or equal to 1/6 patients develop a DLT at the highest dose reached this will be declared the MTD.
Intervention code [1] 296247 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 300026 0
To characterize the safety of APG-1252, when intravenously administered to patients with small cell lung cancer (SCLC) or other solid tumors. All the patients will be monitored by performing and assessing the vital signs, ECG, serum chemistry, full blood examination, coagulation and urinalysis at screening, day1, day2, day 8, day 15 and day 22 of cycle 1, and day 1, day 22 for the subsequent cycles, end of study, and 30 days after last dose.
Timepoint [1] 300026 0
Baseline screening, cycle 1: day1, day2, day 8, day 15 and day 22; subsequent cycle(s): day 1 and day 22, end of the study, and 30 days after the last dose.
Primary outcome [2] 300163 0
To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT), when intravenously administered to patients with small cell lung cancer (SCLC) or other solid tutors. DLTs are assessed and determined as per NCI CTCAE v4.0.
Timepoint [2] 300163 0
End of each treatment cycle.
Secondary outcome [1] 328831 0
To determine the pharmacokinetic (PK) profile (AUC, Cmax) of APG-1252 and its metabolite APG-1252M1. Plasma and urine PK data will be analyzed using compartmental or non-compartmental methods, as appropriate, with appropriate standard non-linear analytic software. Dose proportionality will be explored by regression model for log transformed area under the curve (AUC) and maximum APG-1252 and APG-1252 M1 concentration (Cmax) data if data warranted.
Timepoint [1] 328831 0
Blood samples will be taken at Day 1, Day 2, Day 22 and Day 23. Urine samples will be collected at Day 1 and Day 22.
Secondary outcome [2] 328832 0
To evaluate the pharmacodynamics (PD) effects of APG-1252 in study participants, Blood samples for isolation of peripheral blood mononuclear cells (PBMCs) will be obtained in Cycle 1 from all patients for the analysis of Bcl-2/Bcl-xL inhibition and activation of apoptosis. Serum will also be sampled for the detection of cytokeratin 18 (CK18) using two enzyme-linked immunosorbent assays. Tumor tissue biopsies and surrogate tissue biopsies, if easily accessible and the patient is agreeable, will be obtained in Cycle 1 for immunohistochemical (IHC) analysis of target-related proteins.
Timepoint [2] 328832 0
Blood samples (10 mL per time point) for pharmacodynamic analysis will be collected in Cycle 1 on Day 1, pre-dose (within 1 hour prior to the APG-1252 administration), 6 and 24 hours post APG-1252 administration; and on Day 22 at 6 and 24 hours post APG-1252 administration. Patients who volunteer to have paired tumor biopsies will have tumor tissue samples collected via a fresh punch or core biopsy (approximately > 3 mm) at Baseline and post-treatment (at any time post dose on Day 8 until post dose on Day 22 of treatment).
Secondary outcome [3] 328833 0
To obtain a preliminary assessment of efficacy in patients with SCLC and other solid tumors Patients with solid tumors will be evaluated for response every 2 cycles (i.e.., 8 weeks), according to the new response evaluation criteria in solid tumors: revised RECIST Guideline, Version 1.1 . The lesions will be assessed by CT, MRI, Chest X-ray, Ultrasound, Endoscopy, Laparoscopy, Tumor Markers, Cytology and Histology and etc. depending on tumour types.
Timepoint [3] 328833 0
Once every two cycles

Eligibility
Key inclusion criteria
Patients must meet all of the following inclusion criteria to be eligible for participation in this study:
1. Histologically or cytologically confirmed small cell lung cancer (SCLC) or other solid tumors;
2. Male or non-pregnant, non-lactating female patients age of 18 years or above;
3. Locally advanced or metastatic disease for which no standard therapy is judged appropriate by the investigator;
4. Eastern Cooperative Oncology Group (ECOG) Performance Status equal to or less than 2;
5. Adequate hematologic function as indicated by:
a. Platelet count greater than or equal to 100,000/mm3,
Note: Use of transfusions or thrombopoietic agents to achieve baseline platelet count criterion is prohibited.
b. Absolute neutrophil count (ANC) greater than or equal to 1000/micro litre
Note: Use of growth-factors to maintain ANC criterion is not permitted.
c. Hemoglobin greater than or equal to 9.0g/dL
6. Adequate renal and liver function as indicated by:
a. Serum creatinine less than or equal to 2.0mg/dL or calculated creatinine clearance greater than or equal to 50mL/min;
b. Total bilirubin less than or equal to 1.5 x ULN; If Gilbert's Syndrome may have Bilirubin greater than or equal to 1.5 x ULN
c. Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) less than or equal to 3 x ULN of institution's normal range; AST and ALT may be less than or equal to 5 x ULN for patients with known liver metastases.
d. Coagulation: aPTT and PT less than or equal to 1.2 x the upper limit of normal
7. Brain metastases with clinically controlled neurologic symptoms, defined as surgical excision
and/or radiation therapy followed by 21 days of stable neurologic function & no evidence of CNS disease progression as determined by CT or MRI within 21 days prior to the first dose of study drug.
8. Willingness to use contraception by a method that is deemed effective by the investigator by both males and female patients of child bearing potential (postmenopausal women must have been amenorrheal for at least 12 months to be considered of non-childbearing potential) and their partners throughout the treatment period and for at least three months following the last dose of study drug;
9. Ability to understand and willingness to sign a written informed consent form (the consent form must be signed by the patient prior to any study-specific procedures);
10. Willingness and ability to comply with study procedures and follow-up examination.
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. Receiving concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, hormonal therapy, targeted therapy, biologic therapy, with the exception of hormones for hypothyroidism or estrogen replacement therapy (ERT), anti-estrogen analogs, agonists required to suppress serum testosterone levels); or any investigational therapy, or has had tumor embolization or tumor lysis syndrome (TLS) within 14 days prior to the first dose of study drug.
2. Steroid therapy for anti-neoplastic intent within 7 days prior to the first dose of study drug.
3. Continuance of toxicities due to prior radiotherapy or chemotherapy agents that do not recover to < Grade 2;
4. Known bleeding diathesis/disorder;
5. Recent history of non-chemotherapy induced thrombocytopenia associated bleeding within 1 year prior to first dose of study drug.
6. Have active immune thrombocytopenic purpura (ITP), active autoimmune hemolytic anemia
(AIHA), or a history of being refractory to platelet transfusions (within 1 year prior to the first dose of study drug).
7. Serious gastrointestinal bleeding within 3 months.
8. Use of therapeutic doses of anti-coagulants is excluded, along with anti-platelet agents; lowdose
anticoagulation medications that are used to maintain the patency of a central intravenous catheter are permitted.
9. Received a biologic (G-CSF, GM-CSF or erythropoietin) within 28 days prior to the first dose
of study drug.
10. Failure to recover adequately, as judged by the investigator, from prior surgical procedures. Patients who have had major surgery within 28 days from study entry, and patients who have had minor surgery within 14 days of study entry;
11. Unstable angina, myocardial infarction, or a coronary revascularization procedure within 180
days of study entry.
12. Neurologic instability per clinical evaluation due to tumor involvement of the central nervous system (CNS). Patients with CNS tumors that have been treated, are asymptomatic and who have discontinued steroids (for the treatment of CNS tumors) for >28 days may be enrolled;
13. Active symptomatic fungal, bacterial and/or viral infection including, but not limited to, active human immunodeficiency virus (HIV) or viral hepatitis (B or C); testing for hepatitis B and C is not required for study enrollment.
14. Diagnosis of fever and neutropenia within 1 week prior to study drug administration.
15. Uncontrolled concurrent illness including, but not limited to: serious uncontrolled infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric llness/social situations that would limit compliance with the study requirements.
16. Prior treatment with Bcl-2/Bcl-xL inhibitors.
17. Any other condition or circumstance of that would, in the opinion of the investigator, make the patient unsuitable for participation in the study.

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
This is a multi-center, single-agent, open-label, Phase I dose escalation study of APG-1252. Initially, single patient cohorts will be evaluated and doses of APG-1252 will increase to next dose level untilone DLT or two Grade 2 drug related toxicities are observed, at which point dose escalation and cohort rules will follow a standard 3+3 escalation design. Allowances for intra-patient dose escalations are provided.
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Data will be summarized and tabulated using the latest available version of SAS analytic software. Descriptive statistics (i.e., mean, standard deviation, range, etc.) will be derived where appropriate. Safety and tumor response data will be compared over time to assess change from baseline during treatment and follow-up. Dose level differences will be assessed using appropriate parametric or nonparametric significance tests, as applicable. Pharmacokinetic data will be analyzed with appropriate, standard non-linear analytic software. If data warrant, the relationship between PK and pharmacodynamic parameters will be explored. Exploratory data analysis may be conducted to investigate the relationship between biomarkers, for example Bcl-2 in PBMCs, and APG-1252 PK parameters. Data analysis may include fitting standard pharmacodynamic model relationships to the biomarker data.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
22/01/2018
Actual
21/03/2018
Date of last participant enrolment
Anticipated
31/12/2020
Actual
26/11/2020
Date of last data collection
Anticipated
29/01/2021
Actual
3/12/2020
Sample size
Target
30
Accrual to date
Final
24
Recruitment in Australia
Recruitment state(s)
NSW,QLD
Recruitment hospital [1] 20613 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [2] 22943 0
Blacktown Hospital - Blacktown
Recruitment hospital [3] 22944 0
Chris O’Brien Lifehouse - Camperdown
Recruitment postcode(s) [1] 35404 0
4102 - Woolloongabba
Recruitment postcode(s) [2] 38249 0
2148 - Blacktown
Recruitment postcode(s) [3] 38250 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 294836 0
Commercial sector/Industry
Name [1] 294836 0
ASCENTAGE PHARMA PTY LTD
Country [1] 294836 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Ascentage Pharma Pty Ltd
Address
Level 26, 44 Market Street, Sydney, NSW 2000
Country
Australia
Secondary sponsor category [1] 293678 0
Commercial sector/Industry
Name [1] 293678 0
Jiangsu Ascentage Pharma Inc
Address [1] 293678 0
QB3 Building, China Medical City Avenue
Taizhou, Jiangsu, 215300, China
Country [1] 293678 0
China

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296222 0
Sydney Local Health District Human Research Ethics Committee
Ethics committee address [1] 296222 0
Ethics committee country [1] 296222 0
Australia
Date submitted for ethics approval [1] 296222 0
10/06/2016
Approval date [1] 296222 0
23/10/2017
Ethics approval number [1] 296222 0
X16-0254 & HREC/16/RPAH/305

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

Contacts
Principal investigator
Name 70006 0
Prof Michael Boyer
Address 70006 0
Chris O'brien Lifehouse
119-143 Missenden Road
Camperdown NSW 2050
Country 70006 0
Australia
Phone 70006 0
+61 2 8514 0140
Fax 70006 0
Email 70006 0
michael.boyer@sydney.edu.au
Contact person for public queries
Name 70007 0
Chong Ho
Address 70007 0
Ascentage Pharma Pty Ltd
L26, 44 Market Street, Sydney, NSW, 2000
Country 70007 0
Australia
Phone 70007 0
+61 414 668 863
Fax 70007 0
Email 70007 0
Zhicong.he@ascentage.com
Contact person for scientific queries
Name 70008 0
Yifan Zhai
Address 70008 0
Jiangsu Ascentage Pharma Inc.
QB3 Building, China Medical City Avenue
Taizhou, Jiangsu, 225300, China
Country 70008 0
China
Phone 70008 0
+86 189 9833 4688
Fax 70008 0
Email 70008 0
Yzhai@ascentage.com

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


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.