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Trial registered on ANZCTR


Registration number
ACTRN12618000848202
Ethics application status
Approved
Date submitted
7/05/2018
Date registered
21/05/2018
Date last updated
21/10/2019
Date data sharing statement initially provided
21/10/2019
Date results information initially provided
21/10/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Participants with advanced solid tumor will be treated with KN046 to evaluate the safety, tolerability, pharmacokinetics, immunogenicity and antitumor activity of KN046.
Scientific title
An Open-Label, Multicenter, Dose-Escalation Phase I Study to Evaluate Safety, Tolerability, Pharmacokinetics and Immunogenicity of KN046 in Subjects with Advanced Solid Tumors.
Secondary ID [1] 294817 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
advanced solid tumors 307748 0
Condition category
Condition code
Cancer 306803 306803 0 0
Any cancer
Cancer 306896 306896 0 0
Kidney
Cancer 306897 306897 0 0
Lung - Non small cell
Cancer 306898 306898 0 0
Myeloma
Cancer 306899 306899 0 0
Lung - Small cell

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is single-arm dose-escalation trial, All participants will receive treatment with KN046. Participants enrolled in this trial may receive one of the following doses dependent upon time of enrolment into the study.

Cohort 1: 0.3 mg/kg
Cohort 2: 1 mg/kg
Cohort 3: 3 mg/kg
Cohort 4: 5 mg/kg
Cohort 5: 10 mg/kg

KN046 will be given as an intravenous infusion over 60 minutes every 2 weeks. Participants may receive treatment for 6 months or until excessive toxicity, disease progression, patient consent withdral, physician's judgment (whichever occurs first). 
Intervention code [1] 301130 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 305791 0
Number and proportio of participants with dose limiting toxicity (DLT) -  
An DLT is defined as greater or equal to Grade 3 drug-related adverse event occurring within the first cycle (28 days) of dosing, which include adverse events, vital signs, physical examinations, ophthalmologic examination, electrocardiograms (ECG), and clinical laboratory tests, excluding tumor flare causing local pain at sites of known or suspected tumor, localized rash, or a transient less or equal to Grade 3 infusion reaction using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE Version 4.03 ). Incidence of DLTs will be evaluated for each dose escalation cohort.

Any of the following events judged by the investigator to be related to study drug during
Cycle 1, will be considered a DLT:

Non-hematologic toxicity:
1. Grade 4 (life-threatening consequences or urgent indication indicated) or 5 (resulting in death) AEs
2. Grade 3 immune-related adverse events (irAEs)
3. Grade 3 toxicities irrespective of duration, except for the following situations:
laboratory abnormalities, diarrhoea, nausea, and vomiting that improve to < = Grade 2 within 3 days of institution of supportive care
4. Any Grade 3 tumour flare reaction for continuous 7 days or above (local pain, irritation or rash at known or suspected tumour focus);

Hematologic toxicity:
1. Grade 4 neutropenia lasting > 7 days
2. Febrile neutropenia (ANC < 1000/mm3, with a single temperature of 38.3°C or a sustained temperature of > = 38°C for more than one hour)
3. Grade 3 neutropenia with infection
4. Grade 3 thrombocytopenia with bleeding
5. Grade 4 thrombocytopenia.
6. Grade 4 anaemia (life-threatening)
Timepoint [1] 305791 0
Baseline and Day 1, 2, 3, 4, 8, 15, 29 post-treatment,
Secondary outcome [1] 346556 0
Number of participants with adverse events (AEs) - An AE is defined as any untoward medical occurrence in a participant administered KN046, whether or not considered related to the study treatment. AEs will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Examples of adverse events that may occur including diarrhea, fatigue, pruritus, rash, nausea, decreased appetite, etc.
Timepoint [1] 346556 0
From the time of informed consent signed through end of trial visit, Assessed time points are Day 1, 2, 3, 4, 8, 15, 29 on first cycle, every two weeks in cycle 2,3, 4, 5,6. Then every month maxium up to 2 years.
Secondary outcome [2] 346561 0
Duration of response (DoR) - Duration of response is defined as the time period from the first documentation of objective response to the first documented disease progression or death due to any cause, whichever occurs first. This data will collected from hospital recordsand be assessed by the Investigator based on RECIST 1.1.

Timepoint [2] 346561 0
Data collected every 8 weeks, maxium up to 2 years.
Secondary outcome [3] 346562 0
Objective response rate (ORR) - The ORR is defined as the proportion of subjects with confirmed CR or confirmed PR based on RECIST V 1.1. by tumor imaging (either CT or MRI). The same imaging technique should be used in a subject throughout the study.
Timepoint [3] 346562 0
Tumor imaging (either CT or MRI) will be performed within 21 days prior to enrollment and while on study approximately every 8 weeks, maxium up to 2 years.
Secondary outcome [4] 346563 0
Progression-free survival (PFS) - Progression-free survival is defined as the time from commencement of treatment with KN046 until the first documentation of disease progression or death due to any cause, whichever occurs first. Disease progression will be assessed by the Investigator based on RECIST 1.1.
Timepoint [4] 346563 0
Tumor imaging (either CT or MRI) will be performed within 21 days prior to enrollment and while on study approximately every 8 weeks, maxium up to 2 years.
Secondary outcome [5] 346564 0
Clinical benefit rate (CBR) - Clinical benefit rate is defined as the percentage of patients who have achieved complete response (CR), partial response (PR) and stable disease (SD) to KN046 intervention. Efficacy will be assessed by the Investigator based on RECIST 1.1.
Timepoint [5] 346564 0
Tumor imaging (either CT or MRI) will be performed within 21 days prior to enrollment and while on study approximately every 8 weeks, maxium up to 2 years.
Secondary outcome [6] 346565 0
Area under the curve (AUC) of KN046 - The endpoints for assessment of PK of KN046 include serum concentrations of KN046 at different timepoints after KN046 administration.
Timepoint [6] 346565 0
Assessed time points are baseline, on day 1, 2, 3, 4, 8, 15, 29 of first cycle, every two weeks from cycle 1, 2, 3, 4, 5, 6 and 28 days± 2 days after last dose, up to 9 months.
Secondary outcome [7] 346566 0
Maximum observed concentration (Cmax) of KN046 - The endpoints for assessment of PK of KN046 include serum concentrations of KN046 at different timepoints after KN046 administration.
Timepoint [7] 346566 0
Assessed time points are baseline, on day 1, 2, 3, 4, 8, 15, 29 of first cycle, every two weeks from cycle 1, 2, 3, 4, 5, 6 and 28 days± 2 days after last dose, up to 9 months.
Secondary outcome [8] 346567 0
Minimum observed plasma concentration (Ctrough) of KN046 at steady state - The endpoints for assessment of PK of KN046 include serum concentrations of KN046 at different timepoints after KN046 administration.
Timepoint [8] 346567 0
Assessed time points are baseline, on day 1, 2, 3, 4, 8, 15, 29 of first cycle, every two weeks from cycle 1, 2, 3, 4, 5, 6 and 28 days± 2 days after last dose, up to 9 months.
Secondary outcome [9] 346568 0
Number of subjects who develop detectable anti-drug antibodies (ADAs) - The immunogenicity of KN046 will be assessed by summarizing the number of subjects who develop detectable anti-drug antibodies (ADAs). This outcome will be assessed by serum assay,
Timepoint [9] 346568 0
Assessed before KN046 infusion in Cycle 1, 2, 3, 4, 5, 6 and at the mandatory Safety Follow-up Visit, maxium up to 2 years.
Secondary outcome [10] 346569 0
Number of subjects who develop detectable neutralizing ADA (NADA) - The neutralizing ADA will be assessed by summarizing the number of subjects who develop detectable neutralizing ADA .This outcome will be assessed by serum assay,
Timepoint [10] 346569 0
Assessed before KN046 infusion in Cycle 1, 2, 3, 4, 5, 6 and at the mandatory Safety Follow-up Visit, maxium up to 2 years.

Eligibility
Key inclusion criteria
-Signed written informed consent.
-Confirmed Advanced solid tumors.
-Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
-Adequate organ function within 3 weeks prior to commence of treatment.
-Able to comply comply with study requirements.
-Female participants and male participants with partners of childbearing potential must use highly effective contraceptive measures (with a failure rate of less than 1% per year). 
-All participants must agree to use contraception for a period of 24 weeks after dosing has been completed.
-Negative serum or urine pregnancy test required for female participants and they must not be breastfeeding.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
-Subjects with brain metastases or leptomeningeal.
-Receipt of any immunotherapy, any conventional or investigational systemic anticancer therapy within 4 weeks prior to the first dose of KN046.
-Prior treatment or with sequential monotherapy with anti-CTLA-4 and anti-PD-1/PD-L agents.
-Patients who have received monotherapy with PD-L1 / PD-1, CTLA4 or other antibodies and had intolerable toxicity or required steroids to manage toxicity.
-History of, or currently active, or suspected, autoimmune or inflammatory disorders.
-A current or prior use of immunosuppressive medication within 14 days of the 1st dose of study treatment.
-Any unresolved toxicity greater than or equal to NCI CTCAE Grade 2 from previous anticancer therapy.
-Confirmed heart diseases, such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age, Acute coronary syndrome within 6 months prior to starting treatment, Baseline LVEF (Left ventricular ejection fraction) less than or equal to 55% measured by echocardiography or MUGA, et, al.
-Uncontrolled hypertension.
-Positive blood screen for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV Ab), or human immunodeficiency virus 1/2 antibody (HIV 1/2 Ab).
-History of severe allergic reactions to any unknown allergens or known allergy or reaction to any component of the KN046 formulation.

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
Single group
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
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)
NSW,QLD,VIC

Funding & Sponsors
Funding source category [1] 299415 0
Commercial sector/Industry
Name [1] 299415 0
Alphamab (Australia) Co Pty Ltd
Address [1] 299415 0
58 Gipps Street, Melbourne Collingwood VIC 3066 Australia
Country [1] 299415 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Alphamab (Australia) Co Pty Ltd
Address
58 Gipps Street, Melbourne Collingwood VIC 3066 Australia
Country
Australia
Secondary sponsor category [1] 298701 0
None
Name [1] 298701 0
None
Address [1] 298701 0
None
Country [1] 298701 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300315 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 300315 0
129 Glen Osmond Rd,Eastwood SA 5063,
Ethics committee country [1] 300315 0
Australia
Date submitted for ethics approval [1] 300315 0
Approval date [1] 300315 0
16/03/2018
Ethics approval number [1] 300315 0

Summary
Brief summary
This is an open-label, multi-center, dose-escalation phase I study. The primary purpose of this trial is to evaluate the safety and tolerability as well as the preliminary efficacy of KN046 in participants with advanced solid tumors.

Who is it for?
You may be eligible to enroll in this trial if you are aged 18 or over and have been diagnosed with advanced malignant solid tumor with no standard therapy is available.

Study details
All participants enrolled in this trial will receive KN046 intravenously every two weeks for 6 months or until excessive toxicity, disease progression, patient consent withdral, physician's judgment (whichever occurs first), up to 2 years. The dose received by each participant depends on the time of their enrolment. KN046 is a biological drug for treatment of advanced solid tumor.
As a part of the clinical research study patients will have regular blood tests, physical examinations, Tumor imaging examinations by either CT or MRI.

It is hoped this study will contribute important safety and efficacy information as well as to determined the optimal dose of KN046 to administer for treatment.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 83266 0
A/Prof Jermaine Coward
Address 83266 0
Icon Cancer Care, PO Box 3787, SOUTH BRISBANE QLD 4101
Country 83266 0
Australia
Phone 83266 0
+61 07 3737 4500
Fax 83266 0
Email 83266 0
jim.coward@gmail.com
Contact person for public queries
Name 83267 0
Dr Hardy Van
Address 83267 0
Alphamab Co. Ltd
218 Xinhu St. Building #C23, Suzhou, Jiangsu, China
Country 83267 0
China
Phone 83267 0
+86 512 6595 1826
Fax 83267 0
Email 83267 0
jiazhufang@alphamabonc.com
Contact person for scientific queries
Name 83268 0
A/Prof Jermaine Coward
Address 83268 0
Icon Cancer Care, PO Box 3787, SOUTH BRISBANE QLD 4101
Country 83268 0
Australia
Phone 83268 0
+61 07 3737 4500
Fax 83268 0
Email 83268 0
jim.coward@gmail.com

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 other documents available
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
Yes
Other publication details
Citation type [1] 5410 0
Conference abstract
Citation/DOI/link/details [1] 5410 0
https://meetinglibrary.asco.org/record/172559/abstract
Attachments [1] 5410 0
Results – basic reporting
Results – plain English summary