Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618000977279
Ethics application status
Approved
Date submitted
13/03/2018
Date registered
12/06/2018
Date last updated
12/06/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Open-label, dose escalation, first-in-human study of HLX20, an anti PD-L1 monoclonal antibody, in patients with metastatic or recurrent solid tumors who have failed standard therapy
Scientific title
A Phase 1 Study on the safety and maximum tolerated dose of HLX20, a Human Monoclonal Antibody Targeting Programmed Death Ligand 1 (PD-L1) Protein, in Patients with Advanced Solid Tumors
Secondary ID [1] 294250 0
HLX20-001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metastatic Solid Tumour for patients who have failed/not tolerated/not available standard treatment 306932 0
Condition category
Condition code
Cancer 306031 306031 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
HLX20 is a recombinant human IgG4 monoclonal antibody directed against human PD-L1.
The treatment is divided into cycles. Each cycle of treatment is 4 weeks with no break between cycles. HLX20 will be administered as a single infusion every fortnight on Days 1 and 15 of a 28 day (4 week) cycle. The IV infusion will be delivered over 60 ± 10 minutes and will be followed by a 30 minute observation period.
The 4 planned dose levels (cohorts) to be tested are 1, 3, 10, and 20 mg/kg. The dose level for a cohort may be adjusted, although the dose cannot be more than 20 mg/kg HLX20. The Safety Monitoring Committee, will conduct the safety data review of each cohort and will approve the subsequent dose escalation or de-escalation in the study. Enrolment of the next higher dose cohort will be initiated only after the verified safety data for the 4-week dose-limiting toxicity (DLT) period has been reviewed by the Safety Monitoring Committee. Each participant will continue on the same dose level through the study unless the safety monitoring committee deems the dose to be reduced.
The total study duration per patient is variable. Screening will be up to 28 days before the first infusion. The maximum duration of HLX20 administration to an individual patient in this study is 1 year. All patients will be followed up from the last dose of HLX20 for up to 90 days until relapse, initiation of a new therapy, or until prior toxicities less than or equal to Grade 1 or stabilized.
Intervention code [1] 300548 0
Treatment: Drugs
Comparator / control treatment
No Control Group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 305060 0
Safety of HLX20 assessed by
-Blood and Urine tests and resulting laboratory data,
-Physical examinations analysing vital signs, ECG, ECOG performance status
-Incidence of treatment-emergent Adverse Events.
Timepoint [1] 305060 0
Safety measures will be assessed at all visits - Screening, Day 1 and Day 15 of all cycles and follow up visit.
Primary outcome [2] 305834 0
Maximum Tolerated Dose (MTD) of HLX20 assessed by dose limiting toxicity (DLT) assessment
Timepoint [2] 305834 0
Timepoint: DLT observation period- 4 weeks after the start of infusion
Secondary outcome [1] 344029 0
The pharmacokinetics (PK) of HLX20 at different doses will be determined where possible from the serum concentrations of HLX20 using non-compartmental analysis:
-Cmax, time to maximum serum concentration
-(Tmax), Cmin, elimination rate constant ,
-T1/2, AUC0-tau, area under the serum concentration versus-time curve until infinity (AUC0-inf) if possible, Vss, CL, and mean residence time (MRT).
Timepoint [1] 344029 0
Blood samples for PK analysis will be collected at
-Cycle 1 and 3 -pre-dose,
-Cycle 1 and 3-within 30 minutes of the end-of-infusion,
-Cycle 1 and 3- at 2 and 6 hours (± 15-minute window), after first infusion
-Cycle 1 and 3- at 24, 48, 96, and 168 hours (± 6-hour window) after first infusion
-Cycle 1 and 3- Additional time points include pre-dose and at the end of second infusions (with 30 minutes allowable)
- Cycle 2 and 4 to Cycle 6 or up to 24 weeks,-Pre-dose and after the first infusion of whichever comes first;
-28-day Follow-up Visit
Secondary outcome [2] 344034 0
The pharmacodynamics of HLX20 at different doses in patients.
Blood samples will be collected for PD assessments, Ex vivo assays will be used to measure the induction of interleukin-2 (IL-2) to assess functional modulation of target activity in circulating T-cells by HLX20. PD-L1 receptor occupancy on circulating T-cells will be measured as an indication of target engagement.
Timepoint [2] 344034 0
Blood samples for pharmacodynamic assessments will be collected at
-Cycle 1- pre-dose
-Cycle 1- 24 hours after first infusion
-Cycle 1- 168 hours after first infusion
-Cycle 1- before second infusion
-Cycle 2 to 6- before first infusion
-28-day Follow-up period.
Secondary outcome [3] 344036 0
The immunogenicity of HLX20 in patients. The blood samples will be evaluated for the timing and titer of anti-HLX20 antibody response.
Timepoint [3] 344036 0
Blood samples for immunogenicity analysis will be collected at
-pre-dose
-Cycle 1-before first and second infusion
-Cycles 2 to 6- pre-dose before first infusion
- 28-day Follow-up period
Secondary outcome [4] 344037 0
The anti-tumor effects of HLX20 will be assessed by newly biopsied or archival tissues within 6 months before the first infusion of HLX20. These will be subjected to PDL1 immunohistochemistry (IHC) staining. Expression of PD-L1 on tumor cells will be evaluated to correlate with the anti-tumor activity of HLX20
Timepoint [4] 344037 0
Timepoint: fresh biopsy or archival tissue collected 6 month prior to infusion
Secondary outcome [5] 344038 0
The potential predictive and prognostic biomarkers of HLX20 for advanced solid tumors.
Newly biopsied or archival tissue collected 6 months prior to infusion will be used for biomarker study.
This is an exploratory outcome. Several exploratory biomarker studies may be integrated into this study.
-PD-L1 Immunohistochemistry Staining
Expression of PD-L1 on tumor cells will be evaluated to correlate with the anti-tumor activity of HLX20 using immunohistochemistry (IHC).
-Immunohistochemistry Staining for DNA Mismatch Repair Proteins
DNA mismatch repair deficiency will be evaluated by IHC staining pattern of MLH1, MSH2,
MSH6, and PMS2
- Microsatellite Instability
The MSI status of the tumor cells will be assessed by MSI Analysis System.
-Total Mutation Burden (Optional)
Total tumor mutation burden will be assessed using next generation sequencing technology of suitable platform. This assessment will be performed to correlate with the response to HLX20.
Timepoint [5] 344038 0
Timepoint: fresh biopsy or archival tissue collected 6 month prior to infusion
Secondary outcome [6] 347777 0
Duration of response (DOR) in patients will be assessed by newly biopsied or archival tissues within 6 months before the first infusion of HLX20.
Timepoint [6] 347777 0
Timepoint: fresh biopsy or archival tissue collected 6 month prior to infusion

Eligibility
Key inclusion criteria
1. Males or females of 18 years of age or older
2. Have histologically-proven measurable, or evaluable advanced (systemically or locally progressive), or metastatic solid tumours or the locally advanced disease is not amenable to local therapy, who have failed, or are intolerant to standard therapy or for whom no standard therapy is available. (For patients with hepatocellular carcinoma, the diagnosis needs to be supported by dynamic computed tomography [CT]/magnetic resonance imaging, if pathological confirmation is not attainable).
3. Eastern Cooperative Oncology Group (ECOG) performance status of <= 2 at the time of study entry.
4. Able to comprehend and provide informed consent.
5. A life expectancy longer than 3 months in the opinion of the Investigator.
6. Adequate hematologic functions, as defined by: absolute neutrophil counts
>= 1500/mm3; a hemoglobin level >= 10 g/dL; a platelet count >= 100,000/mm3.
7. Adequate hepatic function defined by: a total bilirubin level <=1.5 × of upper limit of
normal (ULN); aspartate transaminase and alanine transaminase levels<= 2.5 × ULN or
<= 5 × ULN in known hepatic metastases or with primary hepatocellular carcinoma.
8. Adequate renal function, as defined by the creatinine clearance >= 50 mL/minute (as
calculated by the Cockcroft-Gault formula).
9. Adequate cardiac function defined as left ventricular ejection fraction >= 50% by
cardiac ultrasound or multigated acquisition (MUGA) scan. A recent MUGA scan is
acceptable if performed within 8 weeks of the first infusion of IP.
10. Females of child-bearing potential must have a negative pregnancy test upon entry into this study and must be willing to use highly effective birth control upon enrollment, during the Treatment Phase and for 180 days following the last dose of study drug. A female is considered of child-bearing potential following menarche and until becoming postmenopausal (no menstrual period for a minimum of 12 months) unless permanently sterile (undergone a hysterectomy, bilateral salpingectomy, or bilateral oophorectomy).
11. If male, must be surgically sterile or willing to use highly effective birth control upon enrollment, during the Treatment Phase, and for 180 days following the last dose of study drug.
12. History of prior major surgery, prior cytotoxic chemotherapy, or prior therapy with investigational agents, medical device, or local radiotherapy should be at least > =28 days prior to Screening and at least >= 42 days from the last infusion of immune check point inhibitors (including anti-programmed cell death receptor-1 [PD-1] or anti-PD-L1) before the first infusion of IP.
13. Child-Pugh score of A (patients with hepatocellular carcinoma only).
14. Able to be followed up as required by the study protocol.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
The following are the main exclusion criteria:
1. Persistent >= Grade 2 toxicities from prior therapies, with the exception of alopecia of any grade, Grade <= 2 peripheral neuropathy, and laboratory values listed per the inclusion criteria.
2. Concurrent unstable or uncontrolled medical conditions, including:
• Active systemic infections;
• Poorly controlled hypertension (systolic blood pressure >= 160 mmHg or
diastolic blood pressure >= 100 mmHg), or poor compliance with antihypertensive
agents;
• Clinically significant arrhythmia, unstable angina pectoris, congestive heart failure (Class III or IV of New York Heart Association) or acute myocardial infarction within 6 months;
• Uncontrolled diabetes or poor compliance with hypoglycemic agents;
• The presence of chronically unhealed wound or ulcers;
• Other chronic diseases, which, in the opinion of the Investigator, could compromise safety of the patient or the integrity of the study.
3. Newly-diagnosed or symptomatic brain metastases (patients with a history of brain metastases must have received definitive surgery or radiotherapy, be clinically stable, and not be taking steroids for brain edema). Anticonvulsants are allowed. Patients with history of leptomeningeal disease will be excluded.
Any concurrent malignancy other than basal cell carcinoma or carcinoma in situ of the
cervix. (Patients with a previous malignancy but without evidence of disease for
>= 3 years are allowed to participate).
5. Females who are pregnant, lactating, or intend to become pregnant during their participation in this study.
6. Known history of human immunodeficiency virus infection.
7. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease, diverticulitis with the exception of diverticulosis, celiac disease, irritable bowel disease, Wegner syndrome) within the past 2 years. Patients with well controlled vitiligo, alopecia, and Grave’s disease, hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement, or psoriasis not requiring systemic treatment (within the past 3 years), or patients with controlled Type 1 diabetes mellitus who are on a stable insulin regimen are not excluded.
8. Current or prior use of immunosuppressive medication within 14 days before the first dose. The following are exceptions to this criterion:
• Intranasal, inhaled, topical steroids or local steroid injections (eg, intra-articular injection), OR
• systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent, OR
• steroids as premedication for hypersensitivity reactions (eg, CT scan premedication).
9. History of primary immunodeficiency or allogeneic transplantation.
10. Active hepatitis B (HBsAg reactive). Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test followed by a positive HCV RNA test at Screening.
11. History of interstitial lung disease.
12. Receipt of live attenuated vaccines within 30 days prior to the first dose of IP. Patients, if enrolled, should not receive live or live attenuated vaccines during the study and for 30 days after the last dose of IP.
13. The patient is the Investigator, sub-investigator or anyone directly involved in the conduct of the study.
14. History or current evidence of any condition or disease that could confound the results of the study or, in the opinion of Investigator, is not in the best interest of the patient to participate.

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)
The study site will contact the Sponsor or its designee for dose assignment once a patient is determined to be eligible for enrollment. Patients who meet all the eligibility criteria will be assigned a number and to the dose level for first infusion as determined by the Sponsor or its designee. Once assigned, numbers for any Screening failures, non-treated, non-evaluable, or discontinued patients will not be re-used.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Sponsor or its designee to determine the assignment of patients to each treatment cohort
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
This study uses a novel adaptive trial design termed Bayesian optimal interval (BOIN) design to investigate the safety and determine the MTD of HLX20.
BOIN design is a hybrid of rule-based and model-based design, which has the flexibility of dose escalation and de-escalation, and allows more patients enrolled into the doses closest to the target toxicity rate.
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Descriptive statistics and table/graphic representations will be performed and presented by dose level (cohort). Statistics may include counts, percentages, rates, means, medians, ranges and variabilities, and any statistical analysis will be exploratory.
The primary efficacy parameters are the DCR (the number of patients with complete response [CR], partial response [PR], or stable disease, divided by the total number of treated patients) and ORR (number of patients with confirmed responses of CR or PR, divided by the total number of treated patients with measurable disease at baseline). Tumour response status will be defined according to Response Evaluation Criteria in Solid Tumors (RECIST) and immune-related Response Evaluation Criteria in Solid Tumors (iRECIST). To perform an evaluation of anti-tumor activity, BOR outcomes, ORR and DCR will be tabulated by overall frequency distribution. Median TTR and DOR will be summarised for those patients with confirmed responses, using Kaplan-Meier methods; PFS will be similarly summarised. Listings of individual tumour measurements, tumour burden and %changes in tumour burden will be provided. Changes in tumour burden will be presented graphically for each disease type, eg, by waterfall or spider plots.
Safety variables (including incidence of treatment-emergent AEs, laboratory data, vital signs, 12-lead electrocardiogram results, ECOG performance status) will be summarised with descriptive statistics and will be presented in tabular format with the appropriate summary statistics. The number of DLTs will be listed for each dose cohort.
The following PK parameters will be determined where possible from the serum concentrations of HLX20 using non-compartmental analysis: Cmax, Tmax, Cmin, elimination rate constant, T1/2, AUC0-tau, area under the serum concentration-versus-time curve until infinity (AUC0-inf) if possible, Vss, CL, and mean residence time (MRT).
Pharmacokinetic results will be presented only descriptively. No statistical tests will be performed with PK parameters.
The PK parameters will be calculated and listed for each patient and treatment cycle, along with summary statistics including arithmetic and geometric means; standard deviation; minimum, maximum, and median values; and coefficients of variations. The PK data will also be displayed graphically, as appropriate. Exploratory analyses on the PK data and their relationship to pharmacodynamic, safety, and immunogenicity evaluation may be investigated. Pharmacokinetic concentrations from limited samples will be listed, and may be used in combination with other studies for exposure-response or population PK modeling.
Pharmacodynamic parameters and biomarker data will be listed and summarized using descriptive statistics, as appropriate.
The frequency of patients with at least one positive human anti-human antibody (HAHA) assessment, frequency of patients who develop HAHA after a negative baseline assessment will be provided by dose. To examine the potential relationship between immunogenicity and safety, the frequency and type of AEs of special interest may be examined by overall immunogenicity status.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
2/07/2018
Actual
Date of last participant enrolment
Anticipated
31/12/2019
Actual
Date of last data collection
Anticipated
31/12/2020
Actual
Sample size
Target
30
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC
Recruitment hospital [1] 10301 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment hospital [2] 10302 0
Gold Coast Hospital - Southport
Recruitment hospital [3] 10310 0
Sunshine Coast University Hospital - Birtinya
Recruitment hospital [4] 11094 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [5] 11095 0
Cabrini Hospital - Malvern - Malvern
Recruitment hospital [6] 11096 0
Macquarie University Hospital - Macquarie Park
Recruitment postcode(s) [1] 21970 0
5000 - Adelaide
Recruitment postcode(s) [2] 21971 0
4215 - Southport
Recruitment postcode(s) [3] 21978 0
4575 - Birtinya
Recruitment postcode(s) [4] 22906 0
2010 - Darlinghurst
Recruitment postcode(s) [5] 22907 0
3144 - Malvern
Recruitment postcode(s) [6] 22908 0
2109 - Macquarie Park

Funding & Sponsors
Funding source category [1] 298889 0
Commercial sector/Industry
Name [1] 298889 0
Shanghai Henlius Biotech, Inc.
Country [1] 298889 0
China
Primary sponsor type
Commercial sector/Industry
Name
Shanghai Henlius Biotech, Inc.
Address
No. 1289 Yishan Road
Shanghai 200233
China
Country
China
Secondary sponsor category [1] 298103 0
Commercial sector/Industry
Name [1] 298103 0
Covance Pty Ltd
Address [1] 298103 0
Suite 3.02, Level 3, 97 Waterloo Rd,
Macquarie Park, NSW 2113
Country [1] 298103 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299833 0
Bellberry HREC (Committee A)
Ethics committee address [1] 299833 0
Ethics committee country [1] 299833 0
Australia
Date submitted for ethics approval [1] 299833 0
21/03/2018
Approval date [1] 299833 0
28/05/2018
Ethics approval number [1] 299833 0
Ethics committee name [2] 299870 0
Gold Coast Hospital and Health Service Human Research Ethics Committee
Ethics committee address [2] 299870 0
Ethics committee country [2] 299870 0
Australia
Date submitted for ethics approval [2] 299870 0
27/04/2018
Approval date [2] 299870 0
Ethics approval number [2] 299870 0

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

Contacts
Principal investigator
Name 81702 0
Dr Ganessan Kichendasse
Address 81702 0
CMAX Clinical Research, Level 5, 18a North Terrace, Adelaide, SA 5000
Country 81702 0
Australia
Phone 81702 0
+61 8 7088 7900
Fax 81702 0
Email 81702 0
[email protected]
Contact person for public queries
Name 81703 0
Xin Zhang
Address 81703 0
Shanghai Henlius Biotech, Inc.
NO.1289 Yishan Road, Shanghai 200233,P.R.China
Country 81703 0
China
Phone 81703 0
+86 021 33395788
Fax 81703 0
Email 81703 0
[email protected]
Contact person for scientific queries
Name 81704 0
Xin Zhang
Address 81704 0
Shanghai Henlius Biotech, Inc.
NO.1289 Yishan Road, Shanghai 200233,P.R.China
Country 81704 0
China
Phone 81704 0
+86 021 33395788
Fax 81704 0
Email 81704 0
[email protected]

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No Supporting Document Provided



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