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Trial registered on ANZCTR


Registration number
ACTRN12617001181392
Ethics application status
Approved
Date submitted
20/07/2017
Date registered
11/08/2017
Date last updated
19/03/2020
Date data sharing statement initially provided
19/03/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase I, Open-label, Dose-escalation Study of the Safety and Pharmacokinetics of A-337 in Patients with Advanced Solid Tumors
Scientific title
A Phase I, Open-label, Dose-escalation Study of the Safety and Pharmacokinetics of A-337 in Patients with Advanced Solid Tumors
Secondary ID [1] 292446 0
SP51616
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cancer 304057 0
Condition category
Condition code
Cancer 303381 303381 0 0
Lung - Non small cell
Cancer 303382 303382 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The conventional 3+3 design (3 patients per dose cohort, with the potential to add 3
additional patients to the same cohort to further evaluate toxicity) will be applied
for dose escalation and MTD determination.
A DLT is defined as a toxicity according to Section 7.1.1 (d) that occurs during the DLT
assessment window (Cycle 1, 4-week treatment period plus 2-week rest period) and
determined by the investigator or by the Sponsor to have a reasonable possibility of
being related to A-337.
Maximum tolerated dose (MTD) is defined as the maximum dose at which no more
than one of six evaluable patients in a single cohort experiences a DLT in the first cycle
(Cycle 1, 4-week treatment period plus 2-week rest period).
This trial will evaluate six adaptive dose levels: 0.15, 0.3, 0.6, 1.2, 2.4 and 3.6 µg/kg. For Cohort 1, patients will receive a dose of 0.15 µg/kg of A-337 twice (on day 1 and day 4) via IV infusion at 6-hour constant rate during the first week, followed by 3 weeks’ treatment with A-337 at 0.15 µg/kg with 6-hour IV infusions twice weekly. For all subsequent cohorts, patients will receive a conditioning dose of 0.3 µg/kg of A-337 twice (on day 1 and day 4) via IV infusion at 6-hour constant rate during the first week, followed by 3 weeks’
treatment with A-337 at one of the following dose levels (0.3, 0.6, 1.2, 2.4 and 3.6
µg/kg) with 6-hour IV infusions twice weekly. Dexamethasone at a dose of 20 mg
will be given 1 hour prior to the first conditioning dose of A-337 and the first rampup
dose (0.15 µg/kg to 3.6 µg/kg). Administration of Dexamethasone on subsequent
doses is given at either 20 mg or 10 mg based on clinical judgement regarding the potential toxicity of A-337. After completion of the dose escalation, up to 12 patients
may be enrolled in cohorts at dose levels up to the MTD to obtain additional
information on the safety, PK, and PD of monotherapy A-337. Dexamethasone can be administered as either oral or intravenous infusion at the discretion of the investigator.
3+3 Rules for Dose Escalation:
A minimum of 3 patients will be enrolled and observed for toxicity in each dose
cohort. If the 3 patients initially enrolled in a dose cohort complete the DLT
assessment window (Cycle 1, 4-week treatment period plus 2-week rest) without
experiencing a DLT, 3 patients will be enrolled at the next higher dose level.
There will be a minimum for 72 hours between patients being dosed in each cohort.
If 1 of the initial 3 patients enrolled at any dose level experiences a DLT during the
DLT assessment window, additional patients will be enrolled at that dose level for a
minimum of 6 evaluable for DLT. If a DLT is observed in 1 of the 6 evaluable patients
at this dose level, dose escalation will proceed to the next pre-defined dose level. If DLTs are observed in 2 or more of the 6 evaluable patients at a given dose level, the
dose escalation will be halted. If this dose level is > or equal to 50% higher than the previous dose level, an intermediate dose level may be evaluated for toxicity in the same manner as described above. If the dose level is < 50% higher than the previous dose level,
additional patients will be enrolled at the previous dose level, if necessary, to provide a
minimum of 6 evaluable patients.
Dose escalation beyond 3.6 µg/kg will be determined jointly by investigators and
sponsor based on the clinical safety, pharmacokinetic, and preliminary efficacy data.
There will be a minimum for 72 hours between patients being dosed in each cohort.
Each treatment cycle will be composed of a 4-week treatment period (the first week
with the conditioning doses of 0.15 µg/kg (Cohort 1) 0.3 µg/kg (Cohorts 2-6) on Day
1 and Day 4, 3 weeks with the ramp-up doses from 0.15 to 3.6 µg/kg on Day 1 and
Day 4), and followed by 2-week rest. Dose escalation and entry of the next cohort
will occur only after acceptable tolerance has been demonstrated throughout the
entire Cycle1.
Intervention code [1] 298624 0
Treatment: Drugs
Comparator / control treatment
None
Control group
Uncontrolled

Outcomes
Primary outcome [1] 302770 0
To evaluate the safety and tolerability of A-337 administered to patients with locally advanced or metastatic solid tumors. - blood tests and scans
Timepoint [1] 302770 0
Vital signs; ECG; adverse events and concomitant medications; and local laboratory assessments (haematology and clinical chemistry) - Week 1, 2, 3, 4 and week 6 prior to commencement of next cycle.
Primary outcome [2] 302990 0
Composite outcome - To determine the Maximum Tolerated Dose (MTD) and evaluate the Dose-Limiting Toxicities (DLTs) of A-337. - assessed by PK, PD, clinical chemistry and haematological testing along with physical examination by the Investigator
Timepoint [2] 302990 0
Vital signs; ECG; adverse events and concomitant medications; and local laboratory assessments (haematology and clinical chemistry) - Week 1, 2, 3, 4 and week 6 prior to commencement of next cycle.
Tumour assessment - every 6 weeks
PK sampling:
Cohort 1 and 2: Cycle 1,Week 2, Day 8- Pre-dose and 6 hours post-start of dose
Cohorts 3 to 5:
- Cycle 1, Week 2, Day 8 - Pre-dose; and 3, 6, 8, 24, 48, 72 hours post-start of dose
Week 3, Day 15 - Pre-dose; and 6 hours post- start of dose
Week 4, Day 25 - Pre-dose; and 3, 6, 8, 24, 48 and 72 hours post- start of dose
PD Sampling:
Cohort 1: Cycle 1, Week 1, Day 1 Pre-dose, 6 hours and 24 hours post dose; Cycle 1, Week 1, Day4: Pre-dose and 6 hours post dose; Cycle 1, Week 4 Day 25; pre-dose and 6 hours post dose.
Cohort 2: Cycle 1, Week 1, Day 1 Pre-dose, 6 hours and 24 hours post dose; Cycle 1, Week 2: Pre-dose and 6 hours post dose; Cycle 1, Week 4 Day 25; pre-dose and 6 hours post dose.
Cohort 3 – 5: Cycle 1, Week 1, Day 1 Pre-dose, 6 hours and 24 hours post dose; Cycle 1, Week 2: Pre-dose, 6, 8, 24 and 48 hours post dose; Cycle 1, Week3: Pre-dose and 6 hours post dose; Cycle 1 Week 4: pre-dose, 6, 8, 24, 48 and 72 hours post dose.
Secondary outcome [1] 336979 0
PK parameters of A-337 following administration: Area Under Curve (AUC),
Maximum serum concentration (Cmax), Clearance (CL), Volume of distribution (Vd), Mean Residence Time (MRT) and elimination half-life. assessed using serum assay
Timepoint [1] 336979 0
Cohort 1 and 2: Cycle 1,Week 2, Day 8- Pre-dose and 6 hours post-start of dose
Cohorts 3 to 5:
- Cycle 1, Week 2, Day 8 - Pre-dose; and 3, 6, 8, 24, 48, 72 hours post-start of dose
Week 3, Day 15 - Pre-dose; and 6 hours post- start of dose
Week 4, Day 25 - Pre-dose; and 3, 6, 8, 24, 48 and 72 hours post- start of dose

Eligibility
Key inclusion criteria
1. Histologically or cytologically confirmed advanced malignant solid tumor
that is refractory to, intolerant of, or for which no standard of therapy is available.
2. Advanced solid tumors that are known to widely express EpCAM, including
but not limited to colorectal cancer, gastric cancer, lung cancer, ovarian cancer and
prostate cancer.
3. At least one measurable tumor lesion as per RECIST criteria v1.1 defined as
having at least one dimension with a minimum size of 10 mm in the longest
diameter by CT or MRI scan for non-nodal lesions or > or equal to 15 mm in short axis for nodal lesions. Radiographic disease assessment at baseline can be performed up to 28
days prior to the first dose.
4. Adequate archival tumor tissue available or willingness to have a fresh
biopsy. A fresh pre-treatment biopsy is compulsory for the first six patients
enrolled at the expansion stage.
5. Age > or equal to 18 years
6. ECOG performance status < or equal to 2
7. Life expectancy of at least 3 months
8. Ability to understand the patient information and informed consent form.
9. Signed and dated written informed consent
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Inadequate hematologic function, defined by: Neutrophil count < 1,500/mm3
(= 1.5 x 10^9/L), Platelet count < 100,000/mm3 (= 100 x 10^9/L), White blood
cells (WBC) < 1,500/mm3 (3 x10^9/L), Hemoglobin < 9.0 g/dL at Screening.
2. Abnormal renal or hepatic function as defined by:
• ALT and AST > 2 x ULN, in case of liver metastases 3 x ULN
• Total bilirubin > 1.5 x ULN
• Creatinine clearance < 50 ml/min calculated by the Cockroft-Gault formula
or modification of diet in renal disease (MDRD)
• Coagulation: International Normalized Ratio (INR) < or equal to 1.6 (unless receiving
anticoagulation therapy). Subjects on full-dose oral anticoagulation must be on a
stable dose (minimum duration 14 days). If receiving warfarin, the subject must
have an INR < or equal to 3.0 and no active bleeding (ie, no bleeding within 14 days prior to
first dose of study drug). Subjects on low molecular weight heparin will be allowed.
3. Decompensated liver cirrhosis.
4. Subject with known central nervous system (CNS) metastases, unless
metastases are treated and stable for at least 4 weeks and the subject has not been
taking systemic steroids < or equal to 10mg prednisone/day or equivalent. Patients with
leptomeningeal disease or cord compression are excluded.
5. Any concurrent disease, medical or social condition that could affect
compliance with the protocol or interpretation of results as judged by the
investigator. In particular, patients with the following conditions are not allowed to
enter the study:
• Active infection or known bacteremia
• Known infection with human immunodeficiency virus (HIV) or chronic
infection with hepatitis B virus or hepatitis C virus
• Severe dyspnea or pulmonary dysfunction or need for continuous supportive
oxygen inhalation
• Insufficient cardiac function defined as NYHA (New York Heart Association)
Grade 3 or 4.
• History of myocardial infarction or unstable angina within 6 months prior to
Day 1.
• History of stroke or transient ischemic attack within 6 months prior to Day 1
• Clinically significant cardiac arrhythmias, uncontrolled hypertension
SBP>180 mmHg and DBP>100 mmHg
• History of autoimmune disease including, not limited to celiac
disease, diabetes mellitus type 1, inflammatory bowel disease, multiple sclerosis,
psoriasis, rheumatoid arthritis, and systemic lupus erythematosus.
6. Treatment with immune modulators including, but not limited to,
cyclosporine and tacrolimus within 2 weeks prior to enrollment; systemic steroids
< or equal to 10 mg prednisone or equivalent per day are allowed as well as ophthalmic,
inhaled or nasal steroids..
7. Pregnant, nursing women or women of childbearing potential who are not
willing to use effective forms of contraception during participation in the study and
at least three months thereafter. Positive pregnancy test (HCG) within 3 days prior
to Day 1.
8. Male patients with partners of child-bearing potential who are not willing to
use effective contraception during the trial and for at least three months thereafter,
unless surgically sterile.
9. Any anti-cancer therapy, including chemotherapy, hormonal therapy,
biologic therapy, or radiotherapy within 4 weeks prior to initiation of study
treatment with the following exceptions:
• Hormonal therapy with gonadotropin-releasing hormone (GnRH) agonists
for prostate cancer
• Hormone-replacement therapy or oral contraceptives
• Palliative radiation to bone metastases > 2 weeks prior to Day 1
10. Patients with previous immunotherapy that has same mechanism of action of
A-337 (CD3 activating bi-specific antibody). Patients treated with previous immune
checkpoint inhibitors are allowed.
11. Adverse events from prior anti-cancer therapy that have not resolved to
Grade < or equal to 1, except for alopecia.
12. Inability to comply with study and follow-up procedures
13. Any other diseases, metabolic dysfunction, physical examination finding or
clinical laboratory finding that, in the investigator’s opinion, gives reasonable
suspicion of a disease or condition that contraindicates the use of an investigational
drug or that may affect the interpretation of the results or renders the patient at
high risk from treatment complications

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
There are two stages to this study: a dose-escalation stage and a dose-expansion stage.
Approximately 15 to 42 patients will be enrolled in this two-stage study, 15 (3
patients per cohort) to 30 (6 patients per cohort) patients in the dose-escalation
stage and up to 12 additional patients per cohort in the dose-expansion stage. The
sample size may vary, depending on the number of dose levels evaluated and the
number of Dose-Limiting Toxicities (DLTs) observed in each cohort. Once the MTD
has been determined, up to 12 additional patients will be enrolled in the doseexpansion
stage at doses up to the MTD to better characterize the safety, tolerability
and PK property and explore efficacy of the specific A-337 dose. For Cohorts 1 and 2, patients will receive conditioning doses of 0.015 µg/kg of A-
337 twice (on Day 1 and Day 4) via intravenous (IV) infusion during the first week,
followed by 3 weeks of treatment with A-337 twice weekly as described in the
Cohort Dose Escalation Table (Table 1). For Cohorts 3-5, patients will receive
conditioning doses of 0.03 µg/kg of A-337 twice (on Day 1 and Day 4) via IV infusion
during the first week, followed by 3 weeks of treatment with A-337 twice weekly as
described in the Cohort Dose Escalation Table
Phase
Phase 1
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Primary analysis:
The final analysis will be based on patient data collected through study
discontinuation or termination. All analyses will be based on the safety-evaluable
population, which is defined as all patients who receive any amount of A-337. All
summaries will be presented by assigned dose level.
Safety will be assessed through summaries of adverse events, changes in laboratory test results, and changes in vital signs. All patients who receive any amount of A-337
will be included in the safety analysis (i.e., the safety-evaluable population).
All adverse event data will be listed by individual patient and cohort. All adverse
events occurring on or after treatment on Day 1 will be graded using the NCI CTCAE
v4.03 toxicity grades. In addition, all serious adverse events, including deaths, will be
listed separately and summarized.
Patients who withdraw from the study prior to completing the DLT assessment
window (Cycle 1, 4-week treatment period plus 2-week rest) for reasons other than a
DLT will be considered non-evaluable for DLT and MTD assessments and will be
replaced. Patients who experience a DLT during the first cycle will be listed.
Changes in laboratory data will be summarized by grade using the NCI CTCAE, v4.03.
Selected vital signs and selected laboratory data will be plotted over time for each
patient.

Recruitment
Recruitment status
Stopped early
Data analysis
No data analysis planned
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)
NSW
Recruitment hospital [1] 8544 0
Scientia Clinical Research - Randwick
Recruitment hospital [2] 8545 0
Blacktown Hospital - Blacktown
Recruitment hospital [3] 8546 0
Liverpool Hospital - Liverpool
Recruitment postcode(s) [1] 16641 0
2031 - Randwick
Recruitment postcode(s) [2] 16642 0
2148 - Blacktown
Recruitment postcode(s) [3] 16643 0
2170 - Liverpool

Funding & Sponsors
Funding source category [1] 297016 0
Commercial sector/Industry
Name [1] 297016 0
Generon (Shanghai) Corporation
Address [1] 297016 0
787 Kangqiao Road, Building 9, Shanghai, 201315
P.R.China.
Country [1] 297016 0
China
Primary sponsor type
Commercial sector/Industry
Name
INC Research Pty Ltd
Address
Suite 1, Level 2, 924 Pacific Highway, Gordon NSW 2072 Australia
Country
Australia
Secondary sponsor category [1] 296013 0
None
Name [1] 296013 0
Address [1] 296013 0
Country [1] 296013 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298201 0
The Alfred Hospital Ethics Committee
Ethics committee address [1] 298201 0
55 Commercial Rd, Melbourne VIC 3004
Ethics committee country [1] 298201 0
Australia
Date submitted for ethics approval [1] 298201 0
29/03/2017
Approval date [1] 298201 0
09/06/2017
Ethics approval number [1] 298201 0
HREC/17/Alfred/52 (Local Reference: Project 147/17)

Summary
Brief summary
The primary purpose of this trial is to evaluate the safety and tolerability of A-337, the rate that the drug is processed by the body, and the best dose for treatment in patients with solid tumours.

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 known to express EpCAM, that does not respond to standard therapy or for which no standard therapy is available.

Study details
All participants enrolled in this trial will receive eight doses of A-337, delivered twice per week over four weeks. The dose received by each participant depends on the time of their enrolment and the safety of previous doses. A-337 is an antibody designed to target a specific cancer marker, found in some cancers. Researchers will assess patients for side effects of the medication, and take blood samples until 6 weeks after the first dose.

It is hoped that the findings from this trial will determined the optimal dose of A-337 to administer for treatment, and to determine whether A-337 is safe and well tolerated by cancer patients.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 76314 0
Dr Charlotte Lemech
Address 76314 0
Scientia Clinical Research Ltd
Bright Building, Level 5, Corner High & Avoca Street, Randwick NSW 2031, Australia
Country 76314 0
Australia
Phone 76314 0
+61 (2) 9382 5807
Fax 76314 0
+61 (2) 9382 5836
Email 76314 0
charlotte.lemech@scientiaclinicalresearch.com.au
Contact person for public queries
Name 76315 0
Ms Tracy Liaw
Address 76315 0
Scientia Clinical Research Ltd
Bright Building, Level 5, Corner High & Avoca Street, Randwick NSW 2031, Australia
Country 76315 0
Australia
Phone 76315 0
+61-2-9382 5820
Fax 76315 0
+61 (2) 9382 5836
Email 76315 0
tracy.liaw@scientiaclinicalresearch.com.au
Contact person for scientific queries
Name 76316 0
Dr David Fuller
Address 76316 0
INC Research/inVentive Health, Suite 1, Level 2, 924 Pacific Highway, Gordon NSW 2072 Australia
Country 76316 0
Australia
Phone 76316 0
+61284379238
Fax 76316 0
+61284379299
Email 76316 0
david.fuller@incresearch.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?
Study protocol
Informed consent form
Ethical approval
How or where can supporting documents be obtained?
Type [1] 7398 0
Study protocol
Citation [1] 7398 0
Link [1] 7398 0
Email [1] 7398 0
Other [1] 7398 0
Type [2] 7399 0
Informed consent form
Citation [2] 7399 0
Link [2] 7399 0
Email [2] 7399 0
Other [2] 7399 0
Type [3] 7400 0
Ethical approval
Citation [3] 7400 0
Link [3] 7400 0
Email [3] 7400 0
Other [3] 7400 0
Summary results
No Results