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Trial registered on ANZCTR


Registration number
ACTRN12618000382279p
Ethics application status
Submitted, not yet approved
Date submitted
27/02/2018
Date registered
14/03/2018
Date last updated
14/03/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A Study of CS1003 in People with Advanced Solid Tumours
Scientific title
A Phase Ia/Ib, Open-Label, Multiple-Dose, Dose-Escalation and Expansion Study of the Anti-PD-1 Monoclonal Antibody CS1003 in Subjects with Advanced Solid Tumors
Secondary ID [1] 294108 0
None
Universal Trial Number (UTN)
Trial acronym
CS1003-101
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Participants with Advanced Solid Tumors 306701 0
Condition category
Condition code
Cancer 305802 305802 0 0
Head and neck
Cancer 305846 305846 0 0
Stomach
Cancer 305844 305844 0 0
Sarcoma (also see 'Bone') - soft tissue
Cancer 305847 305847 0 0
Oesophageal (gullet)
Cancer 305848 305848 0 0
Lung - Non small cell
Cancer 305845 305845 0 0
Bladder
Cancer 305849 305849 0 0
Lung - Small cell
Cancer 305850 305850 0 0
Lung - Mesothelioma
Cancer 305851 305851 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All participants will receive treatment with CS1003. Participants enrolled in Phase Ia may receive one of the following doses dependent upon time of enrolment into the study:

Cohort 1: 1 mg/kg
Cohort 2:: 3 mg/kg
Cohort 3: 200 mg
Cohort 4: 10 mg/kg

Participants enrolled in Phase Ib will receive treatment at the MTD or Recommended Phase 2 dose (if less than the MTD) decided upon completion of Phase Ia of the study. The Phase 1b dose will be decided by the Safety Monitoring Committee after review of the Phase Ia data.

CS1003 will be given as an intravenous infusion (through a drip inserted into a vein) over 90 minutes on Day 1 of each 21 day treatment cycle. Participants may receive treatment for up to 34 cycles (or 2 years) or disease progression or intolerance (whichever occurs first).

Participants who enrol in Phase Ia of the study are not eligible to enrol in Phase Ib of the study.
Intervention code [1] 300388 0
Treatment: Drugs
Comparator / control treatment
No control group - all participants will receive treatment with CS1003
Control group
Uncontrolled

Outcomes
Primary outcome [1] 304866 0
The primary outcome of the study is to determine the maximum tolerated dose (MTD) and schedule of CS1003.

The outcome is assessed predefined dose escalation rules and Dose Limiting Toxicity (DLT) events. Toxicity will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

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)

And grade toxicity that requires termination of the study drug
Timepoint [1] 304866 0
The incidence of AEs will be measured by clinical examination and recorded at Screening and on Day 1 of every treatment cycle and if clinically indicated. All participants will be followed for at least 30 days after their last dose of study drug or until initiation of a new anti-cancer treatment, whichever occurs first.

Any DLT occurring in the first 21 days of treatment will be used to determine MTD.
Primary outcome [2] 304898 0
Obtain preliminary evidence of clinical efficacy (response rate, progression free survival, overall survival) for CS1003 using CT and/or MRI imaging (according to RECIST 1.1 criteria)
Timepoint [2] 304898 0
CT and/or MRI scan performed at screening and every 9 weeks for the first year and then every 12 weeks thereafter
Primary outcome [3] 305005 0
Safety of CS1003 including: Laboratory tests; including blood and urine samples, 12-lead electrocardiogram (ECG) and Adverse events (and Serious Adverse Events)

Clinical experience with existing drugs of the same therapeutic class (anti-PD-1 monoclonal antibodies) suggests the most common AEs were grade 1/2, including arthralgia, cough, diarrhoea, fatigue, fever, nausea, pruritus, and rash. However, grade 3/4 treatment-related AEs occurred in 15% of patients in the nivolumab study. Grade 3/4 AEs were also reported in the pembrolizumab studies with one subject died of myocardial infarction while being treated for pneumonitis/pneumonia.

Drug-related AEs of special interest (AEs with potentially immune-related etiology) included vitiligo, pneumonitis, hepatitis, colitis, thyroiditis, and hypophysitis may be observed during multiple dose escalation in participants with cancer.
Timepoint [3] 305005 0
Physical examination: Screening, at the beginning of each cycle and the end of treatment
ECGs: Screening, at the beginning of each cycle and end of treatment
Vital signs: Screening, C1/Days 1, 8 and 15, at the beginning of each cycle thereafter and the end of treatment
Clinical laboratory tests: Screening, C1/Days 1, 8 and 15, at the beginning of each cycle thereafter and the end of treatment
AEs: at the time of reporting

For dose escalation, safety will be evaluated up to Day 8 to allow for dose escalation,
Secondary outcome [1] 343558 0
Assess the immunogenicity of CS1003 by measuring the development of antidrug antibodies (ADA)
Timepoint [1] 343558 0
Blood samples will be taken to measure ADA on Cycle 1 on Days 1 and 15 and on Day 1 of Cycles 2, 3, 5, 7, 10, 13, 16 and every 8 cycles thereafter
Secondary outcome [2] 343417 0
Determine the pharmacokinetics (PK) in plasma of CS1003 when administered intravenously on Day 1 of a 21 day cycle, Parameters measured (using enzyme-linked immunosorbent assay (ELISA) methods) : AUC0-21d, AUC0-8, Cmax, Tmax, t½, CL and Vss.
Timepoint [2] 343417 0
Blood samples will be taken to measure PK parameters on Cycles 1 and 4/Day 1 at pre-dose, 30 mins, 90 mins and 6 hours post-dose and Days 2, 4, 8 and 15 and on Day 1 of Cycles 2, 3, 5, 7, 10, 13, 16 and every 8 cycles thereafter.

Eligibility
Key inclusion criteria
1. Willing and able to provide written informed consent for the trial.
2. Male or female and > = 18 years of age on day of signing informed consent.
3. With histologically or cytologically confirmed advanced-stage or metastatic tumour (unresectable) and experienced progression since last anti-tumour treatment with standard therapy; or for which treatment is not available, not tolerated or refused:
Phase Ia: Subjects with advanced, relapsed or refractory solid tumours, which should refer to but not limited to the following description for Phase Ib;
Phase Ib: Subjects with tumour of specific types:
a) Subjects with soft tissue sarcoma (UPS (undifferentiated pleomorphic sarcoma), LPS (dedifferentiated or other high grade liposarcoma)).
b) Subjects with malignant pleural mesothelioma (MPM). Subjects with bladder cancer, Merkel-cell carcinoma, gastrointestinal stromal tumour (GIST), gastric cancer, oesophageal carcinoma, small-cell lung cancer (SCLC), large-cell lung cancer (LCLC), head and neck squamous cell carcinoma (HNSCC) or cutaneous squamous cell carcinoma (cuSCC). Any solid tumours with microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR). Or other tumour types after discussion with the medical monitor and in consultation with the Sponsor.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
5. For Phase Ia, participants with evaluable but non-measurable lesion are allowed. For Phase Ib, participants must have at least one measurable lesion per RECIST Version 1.1.
6. Tumor tissue samples need to be collected from the participants for biological marker analysis. The samples can be tumour samples fixed with formalin and embedded in paraffin wax (paraffin wax block or approximately at least 10 unstained slices); for tumour tissue samples that are not archived, the participant has to be willing to undergo biopsy of the tumour focus within 8 weeks before the start of the treatment in order to collect corresponding tumour samples (in quantities determined in accordance with the biopsy results). Subjects may be permitted to enrol on a case-by-case basis after discussion with the medical monitor and in consultation with the Sponsor if tissue or biopsy is not available.
7. Patients with life expectancy > = 3 months.
8. Subject must have adequate organ function (had not received blood transfusion, EPO, G-CSF or other medical support within 14 days before the administration of the study drug):
9. Fertile men and women of childbearing potential must agree to use an effective method of birth control from providing signed consent and for 180 days after last study drug administration. Women of childbearing potential include pre-menopausal women and women within the first 2 years of the onset of menopause. Women of childbearing potential must have a negative pregnancy test < = 7 days prior to the first dose of study drug.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Known brain metastasis or other CNS metastasis that is either symptomatic or untreated. Central nervous system metastases that have been treated by complete resection and/or radiotherapy demonstrating stability or improvement are not an exclusion criterion provided they are stable as shown by imaging for at least 4 weeks before screening without evidence of cerebral oedema and no requirements for corticosteroids or anticonvulsants.
2. Subjects with active autoimmune diseases or history of autoimmune diseases should be excluded; these include but are not limited to participants with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis, systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease including Crohn’s disease and ulcerative colitis, hepatitis, toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or antiphospholipid syndrome.
3. Patients who had to receive glucocorticoids (prednisone at > 10 mg/day or other similar drugs at equivalent dose) or other immunosuppressive medication within 14 days prior to the first dose of the study drug. 4. Phase Ib participants who had other malignant tumour(s) in the past 2 years, except for participants with basal cell carcinoma, in situ breast cancer and cervical carcinoma in situ who had undergone radical treatment.
5. Patients who have received any targeted T-Cell co-regulated proteins (immune checkpoint proteins) antibody/medicine (including PD-1, PD-L1, etc) for treatment.
6. Has had prior chemotherapy, targeted therapy, or any other agents used as systemic treatment for cancer, within 2 weeks prior to the first dose of study drug.
7. Patients who had undergone a major surgical procedure (as defined by the Investigator), or wide field of radiation, within 28 days prior to the first dose of study drug, or received local radiotherapy within 14 days prior to the first dose of study drug, or taken radioactive agents (strontium, samarium, etc.) within 56 days before the first dose of study drug.
8. Patients who had received treatment with Chinese herbal medicine or Chinese prepared medicine within 7 days prior to the first dose of the study drug.
9. Has received a live vaccine within 28 days prior to the first dose of study drug.
10. Has history of interstitial lung disease or non-infectious pneumonitis except for those induced by radiation therapies.
11. Known history of HIV infection.
12. Subjects who are Hepatitis B surface antigen (HBsAg) and Hepatitis B core antibody (HBcAb) positive or Hepatitis C virus (HCV) antibody positive at screening must not be enrolled until further definite testing with Hepatitis B virus (HBV) DNA titres and HCV RNA tests can conclusively rule out presence of active infection (HBV DNA > = 1000 cps/mL or 200 IU/mL) requiring therapy with Hepatitis B and C, respectively.
13. Active infection of tuberculosis.
14. Have signs or symptoms of any active infection requiring systemic therapy.
15. Patients who have received organ transplantation.
16. Any unresolved CTCAE Grade > = 2 toxicities from prior anti-cancer therapy with the exception of vitiligo, alopecia, and the laboratory values defined in the inclusion criteria.
17. History of any irAE of Grade > = 3.
18. Patients who have serious hypersensitive reaction to monoclonal antibodies, and have history of uncontrolled allergic asthma.
19. Patients with known history of alcoholism or drug abuse.
20. Patients with major cardiovascular diseases (e.g.: congestive heart failure, unstable angina pectoris, atrial fibrillation, arrhythmia, etc.): participants who had experienced such diseases as acute myocardial infarction, unstable angina pectoris, apoplexia, or transient ischemic attack within 6 months prior to the first dose of study drug; participants with congestive heart failure of NYHA Grade > = 2;
21. Has known psychiatric disorders that would interfere with cooperation with the requirements of the trial.
22. Concurrent condition that in the investigator's opinion would jeopardize compliance with the protocol.

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)
Not applicable as open-label study
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable as open-label study
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
Safety
Statistical methods / analysis
A formal sample size calculation has not been performed and the number of dose levels and schedules examined and the emerging toxicities will determine the sample size. It is anticipated that in Part Ia of the study approximately 12-24 participants will be required to establish the MTD and RP2D(s) of CS1003 when administered as a single agent.

In Part Ib of the study, it is anticipated that approximately 60 participants will be required to evaluate the preliminary efficacy of CS1003 when administered as a single agent.

The number of subjects in each part is considered sufficient to achieve the study objectives.

Safety assessments will include adverse events, vital signs, physical examinations, ophthalmologic examination, electrocardiograms (ECG), and clinical laboratory tests. Incidence of DLTs will be evaluated for each dose escalation cohort. All treatment-emergent adverse events (TEAEs) will be summarized by system organ class and preferred term for each dose cohort. All TEAEs will be summarized by incidence, severity, and relationship to study drug(s). Clinical laboratory tests and vital signs will be summarized descriptively for each dose cohort. All abnormal findings in clinical laboratory test results, vital signs, physical examinations, ophthalmologic examination, ECGs, echocardiogram will be listed.

Efficacy assessments, including ORR, DCR, DOR and PFS will be based on RECIST 1.1. The ORR based on the Investigator’s assessment will be the efficacy endpoint and will be summarized for each dose cohort and for all treated patients. OS and PFS will be presented by using Kaplan-Meier method for all treated patients.

Pharmacokinetic data will be presented in graphical and/or tabular form and will be summarized descriptively. Summary statistics (AUC0-21d, AUC0-8, Cmax, Tmax, t½, CL, Vss, etc) will be tabulated for PK parameters by CS1003 dose level.

Immunogenicity Analyses:
Immunogenicity results will be reported descriptively by summarizing the number and percentage of patients who develop detectable anti-CS1003 antibodies.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/04/2018
Actual
Date of last participant enrolment
Anticipated
1/04/2019
Actual
Date of last data collection
Anticipated
1/04/2021
Actual
Sample size
Target
90
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC
Recruitment hospital [1] 10105 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [2] 10109 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [3] 10107 0
Macquarie University Hospital - Macquarie Park
Recruitment hospital [4] 10108 0
Scientia Clinical Research - Randwick
Recruitment hospital [5] 10106 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment postcode(s) [1] 21640 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 21643 0
2031 - Randwick
Recruitment postcode(s) [3] 21641 0
3168 - Clayton
Recruitment postcode(s) [4] 21642 0
2109 - Macquarie Park
Recruitment postcode(s) [5] 21644 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 298744 0
Commercial sector/Industry
Name [1] 298744 0
CStone Pharmaceuticals Australia Pty Ltd
Country [1] 298744 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
CStone Pharmaceuticals Australia Pty Ltd
Address
Level 9, 31 Market Street, Sydney NSW 2000
Country
Australia
Secondary sponsor category [1] 297916 0
Commercial sector/Industry
Name [1] 297916 0
Covance Pty Ltd
Address [1] 297916 0
Suite 3.02, Level 3, Building A, Macquarie Corporate Centre, 97 Waterloo Road, Macquarie Park NSW 2113
Country [1] 297916 0
Australia

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 299719 0
Bellberry HREC
Ethics committee address [1] 299719 0
Ethics committee country [1] 299719 0
Australia
Date submitted for ethics approval [1] 299719 0
19/12/2017
Approval date [1] 299719 0
Ethics approval number [1] 299719 0
Ethics committee name [2] 299683 0
Monash Health Human Research Ethics Committee
Ethics committee address [2] 299683 0
Ethics committee country [2] 299683 0
Australia
Date submitted for ethics approval [2] 299683 0
17/01/2018
Approval date [2] 299683 0
Ethics approval number [2] 299683 0
Ethics committee name [3] 299720 0
Central Adelaide Local Health Network (CALHN) Human Research Ethics Committee
Ethics committee address [3] 299720 0
Ethics committee country [3] 299720 0
Australia
Date submitted for ethics approval [3] 299720 0
12/03/2018
Approval date [3] 299720 0
Ethics approval number [3] 299720 0
Ethics committee name [4] 299721 0
Macquarie University Human Research Ethics Committee
Ethics committee address [4] 299721 0
Ethics committee country [4] 299721 0
Australia
Date submitted for ethics approval [4] 299721 0
07/02/2018
Approval date [4] 299721 0
Ethics approval number [4] 299721 0

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

Contacts
Principal investigator
Name 81282 0
Dr Ben Markman
Address 81282 0
Monash Medical Centre, 246 Clayton Road, Clayton VIC 3168
Country 81282 0
Australia
Phone 81282 0
+61 3 9594 6666
Fax 81282 0
Email 81282 0
ben.markman@monash.edu
Contact person for public queries
Name 81283 0
Queenie Yu
Address 81283 0
Building 25 , 1000 Zhangheng Road, Pudong New District, Shanghai 201203, China
Country 81283 0
China
Phone 81283 0
+86 21 6109 7678
Fax 81283 0
Email 81283 0
yuxiaokun@cstonepharma.com
Contact person for scientific queries
Name 81284 0
Queenie Yu
Address 81284 0
Building 25 , 1000 Zhangheng Road, Pudong New District, Shanghai 201203, China
Country 81284 0
China
Phone 81284 0
+86 21 6109 7678
Fax 81284 0
Email 81284 0
yuxiaokun@cstonepharma.com

No information has been provided regarding IPD availability


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No Supporting Document Provided


Results publications and other study-related documents

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