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Trial registered on ANZCTR


Trial ID
ACTRN12614000268640
Ethics application status
Approved
Date submitted
6/12/2013
Date registered
13/03/2014
Date last updated
17/05/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
Intravenous APG-1387 administered to patients with advanced solid tumors and lymphomas to test for safety, tolerability and effect of APG-1387 on the body and how APG-1387 is processed by the human body
Scientific title
A phase 1, open label, multi-center, dose escalation study of the safety, tolerability, pharmacokinetic and pharmacodynamic properties of intravenously administered APG-1387 in patients with advanced solid tumors and lymphomas
Secondary ID [1] 283583 0
NIL
Universal Trial Number (UTN)
NIL
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
advanced solid tumor 290487 0
lymphoma 291007 0
Condition category
Condition code
Cancer 290879 290879 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Cancer 291352 291352 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
Cancer 291713 291713 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a multi-center, single-agent, open-label, Phase I accelerated dose escalation study of APG-1387. Initially, single patient cohorts will be evaluated and doses of APG-1387will increase by 50% until = Grade 2 drug related toxicity is observed, at which point dose escalation and cohort rules will follow a modified Fibonacci 3/6 Phase I design. Allowances for intra-patient dose escalations are provided. Treatment cycles will begin at 0.3 mg of APG-1387 administered via intravenous infusion for 30 minutes on Days 1, 8 and 15, then take one–week treatment off; each dosing cycle is 28 days. Doses could be modified depending on toxicity and PK results based on discussions with the Investigators and Sponsor. If no DLTs are observed by the end of Cycle 1, the dose of APG-1387 will be increased in subsequent cohorts, at 0.6 mg, 1 mg, 1.5 mg, 2.5 mg, 4.0 mg, 7.0 mg, 12 mg, 20 mg and 30 mg accordingly. Patients will be treated with APG-1387 until disease progression, unacceptable toxicity occurs or the patient withdraws consent.
Intervention code [1] 288303 0
Treatment: Drugs
Comparator / control treatment
not applicable
Control group
Uncontrolled

Outcomes
Primary outcome [1] 290916 0
To characterize the safety and tolerability of APG-1387, including determination of the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT), when intravenously administered to patients with advanced solid tumors or lymphomas. The Response to treatment will be evaluated by using RECIST (Response evaluation Criteria in Solid Tumors) after every 8 weeks of treatment by using the appropriate imaging technique (CT,MRI,X-Ray). The assessment of the size of lesions over time will give an indication of the status of the disease. Safety and Tolerabilty will be assessed throughout the study by close monitoring of blood results and the condition the patient is in. Regular visits to the study site are planned to ensure close monitoring of patient health.
Timepoint [1] 290916 0
The patient will attend the study site 4 times during each treatment cycle. During Cycle 1 the patients health will 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 Day 1 of each following cycle. At each visit -regardless of cycle - any adverse events and/or new concomitant medication will be discussed with the Patient.
Secondary outcome [1] 305592 0
To determine the pharmacokinetic (PK) profile of APG-1387 - this will be done by taking blood samples at specified timepoints. Plasma will be stored for analysis.
Timepoint [1] 305592 0
PK samples will be taken during Cycle 1 at Day 1 (9 samples) and 24 hours post-dosing (Day 2), Cycle 1 Day 15 (9 samples) and 24 hours post dosing (Day 16)
Secondary outcome [2] 306565 0
To evaluate the pharmacodynamic (PDy) effects of APG-1387 in study subjects - assessment by collection of Blood and Tissue samples
Timepoint [2] 306565 0
Blood samples (5 mL per sample) for PDy analysis will be collected into heparanized glass collection tubes at pre dose Day 1, 24 hours post dosing (Day 2), Day 8 and Day 15.
Tumor tissue samples will be obtained by collecting a fresh punch biopsy (approximately> 3 mm) from the patient before and post treatment between Day 8 and Day 15.
Secondary outcome [3] 306566 0
To obtain a preliminary assessment of efficacy in patients with advanced solid tumors and lymphomas - by using Response Evaluation Criteria in Solid tumors (RECIST)
Timepoint [3] 306566 0
RECIST will be assessed every 8 weeks until the patient is withdrawn from the study
Secondary outcome [4] 306567 0
To support selection of suitable tumor type(s) for the next stage of clinical development, based on PDy and preliminary efficacy data
Timepoint [4] 306567 0
Summary of all assessments above

Eligibility
Key inclusion criteria
-Histologically or cytologically confirmed solid tumor or lymphoma;
-Male or non-pregnant, non-lactating female patients age greater than or equal to 18 years;
-Locally advanced or metastatic disease for which no standard therapy is judged appropriate by the investigator;
-Life expectancy greater than or equal to 3 months;
-Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to 1;
-Adequate hematologic function as indicated by:
ANC greater than or equal to 1,500/mm3; Hemoglobin greater than or equal to 9.0 g/dL; platelet count greater than or equal to 100,000/mm3
-QTc interval less than or equal to 450ms
-Adequate renal and liver function as indicated by:
-Serum creatinine less than or equal to 1. x ULN or if serum creatinine is >1.5 X ULN, creatinine clearance of greater than or equal to 50 cc/min; total bilirubin less than or equal to 1.5 x ULN
AST and ALT less than or equal to 2.5 x ULN ; Alkaline phosphatase less than or equal to 2.5 x ULN
-Negative Hepatitis B and Hepatitis C screening:
-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 one month following the last dose of study drug;
-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;
-Willingness and ability to comply with study procedures and follow-up examination.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
-Received chemotherapy within 21 days (42 days for nitrosoureas or mitomycin C) prior to entering the study;
Received hormonal, biologic therapies (e.g. interferons), or therapeutic antibodies (e.g. trastuzumab, cetuximab, rituximab, etc) within 21 days or <4 half-lives (whichever is greater) of study entry;
Note: Leuteinizing hormone-releasing hormone (LHRH) agonists or antagonists to maintain castrate levels of testosterone in patients with hormone-refractory prostate cancer is allowed. Oral contraceptives and estrogen/progestogen HRT are acceptable
-Receiving concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, hormonal therapy, targeted therapy, biologic therapy); or has had tumor embolization within 14 days of study entry.
-Radiation within 14 days of study entry, thoracic radiation within 28 days of study entry. Patients who have received prior radiotherapy must have discontinued steroids for 14 days prior to study entry and be clinically stable;
-Failure to recover to less than or equal to Grade 1 from adverse events due to radiotherapy or chemotherapy agents;
-Requirement for corticosteroid treatment, with the exception of megestrol, topical corticosteroids and inhaled corticosteroids for reactive airway disease. Patients who received prior therapy with corticosteroids must have discontinued use of corticosteroid therapy 14 days prior to the first dose of APG-1387 ; The patients who require replacement dose corticosteroids are allowed (eg if they have had endocrinopathy from ipilimumab)
-Use of therapeutic doses of anti-coagulants is excluded. Therapeutic is defined as a target International Normalized Ratio (INR) of 1.5 or above. However, the prophylactic dose anticoagulation is allowed.
-Concurrent treatment with an investigational agent or device within 28 days prior to the first dose of therapy;
-Failure to recover adequately, as judged by the investigator, from prior surgical procedures. Patients with active wound healing, 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;
-Elevated (above institutional normal limits) serum troponin T or I.
-Unstable angina, myocardial infarction, or a coronary revascularization procedure within 180 days of study entry.
-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;
-History of Bell’s palsy
-Active rheumatoid arthritis (RA), active inflammatory bowel disease, chronic infections, or any other disease or condition associated with chronic inflammation;
-Active symptomatic fungal, bacterial and/or viral infection including, but not limited to, active HIV or viral hepatitis (A, B or C);
-Known or suspected Wilson's Disease, or other conditions that affect copper accumulation or regulation.
-Uncontrolled concurrent illness including, but not limited to: serious uncontrolled infection, symptomatic congestive heart failure (CHF), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with the study requirements.
-Prior treatment with IAP inhibitors.
-Any other condition or circumstance 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)
Allocation is not concealed
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
Accelerated Dose Escalation
Phase
Phase 1
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Data analysis is complete
Reason for early stopping/withdrawal
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA,VIC

Funding & Sponsors
Funding source category [1] 288293 0
Commercial sector/Industry
Name [1] 288293 0
Jiangsu Ascentage Pharma Inc
Address [1] 288293 0
QB3 Building, China Medical City Avenue, Taizhou, Jiangsu, P.R. China, 225300
Country [1] 288293 0
China
Primary sponsor type
Commercial sector/Industry
Name
Jiangsu Ascentage Pharma Inc
Address
QB3 Building, China Medical City Avenue, Taizhou, Jiangsu, P.R. China, 225300
Country
China
Secondary sponsor category [1] 287014 0
Commercial sector/Industry
Name [1] 287014 0
INCResearch Australia Pty Ltd
Address [1] 287014 0
159 Port Road, Hindmarsh SA 5007
Country [1] 287014 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290190 0
Bellberry
Ethics committee address [1] 290190 0
129 Glen Osmond Road Eastwood South Australia 5063
Ethics committee country [1] 290190 0
Australia
Date submitted for ethics approval [1] 290190 0
13/11/2013
Approval date [1] 290190 0
19/12/2013
Ethics approval number [1] 290190 0
2013-11-609

Summary
Brief summary
This study aims to establish the safety and best tolerated dose of a new investigational drug called APG-1387 in participants with advanced cancer.
Who is it for?
You may be eligible to join this study if you are aged 18 years or more and have been diagnosed with an advanced solid tumour or lymphoma.
Study details
All participants in this study will be treated with a new investigational drug called APG-1387. This drug blocks tumour growth by promoting cell death (a process called apoptosis) in cancer cells and attempts to stop the cancer cells from spreading further throughout the body. This drug has not previously been tested in humans. APG-1387 has undergone extensive testing in various animal models (including rats and monkeys) and human cancer cell models in the laboratory. APG-1387 will be administered via intravenous (IV) infusion (i.e. directly into the vein) on Days 1, 8 and 15 of study participation. The first group of participants will receive a dose of 0.3 mg of APG-1387, and if tolerated the dose will be increased for subsequent patient groups. Participants will be regularly monitored until they reach their endpoint (disease progression, intolerable toxicity or withdrawal of consent) in order to determine safety, tolerability and preliminary efficacy of treatment. The results from this study will be analysed to see if it is worthwhile for this new drug to be tested in future studies involving larger numbers of cancer participants.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 44274 0
Prof Michael Millward
Address 44274 0
Linear Clinical Research Ltd
1st Floor, B Block, Hospital Avenue, Nedlands WA 6009
Country 44274 0
Australia
Phone 44274 0
+61 8 6382 5100
Fax 44274 0
Email 44274 0
contactus@linear.org.au
Contact person for public queries
Name 44275 0
Dr Yifan Zhai
Address 44275 0
Jiangsu Ascentage Pharma Inc.
QB3 Building, China Medical City Avenue
Taizhou, Jiangsu, P. R. China, 225300
Country 44275 0
China
Phone 44275 0
+86 18998334688
Fax 44275 0
Email 44275 0
yzhai@ascentagepharma.com
Contact person for scientific queries
Name 44276 0
Dr Yifan Zhai
Address 44276 0
Jiangsu Ascentage Pharma Inc.
QB3 Building, China Medical City Avenue
Taizhou, Jiangsu, P. R. China, 225300
Country 44276 0
China
Phone 44276 0
+86 18998334688
Fax 44276 0
Email 44276 0
yzhai@ascentagepharma.com