Trial registered on ANZCTR


Trial ID
ACTRN12614001176651
Ethics application status
Approved
Date submitted
17/10/2014
Date registered
10/11/2014
Date last updated
27/10/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Phase 1A/1B, Open-Label, Multiple-Dose, Dose Escalation and Expansion Study to Investigate the Safety, Pharmacokinetics and Preliminary Antitumor Activities of the B RAF Inhibitor BGB 283 in Subjects with Solid Tumors
Scientific title
A Phase 1A/1B, Open-Label, Multiple-Dose, Dose Escalation and Expansion Study to Investigate the Safety, Pharmacokinetics and Preliminary Antitumor Activities of the B RAF Inhibitor BGB 283 in Subjects with Solid Tumors
Secondary ID [1] 285501 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
solid tumors 293295 0
Condition category
Condition code
Cancer 293565 293565 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a multicenter, Phase I, open label, multiple dose, dose escalation, first in human study of the B-RAF inhibitor BGB-283.

The dose levels will be escalated throughout the study up to the MTD or the predicted efficacy level. Dose escalation will follow a standard 3+3 dose escalation design (detail is described as below).

Cohort 1: 5 mg oral capsule once daily
Cohort 2: 10 mg oral capsule once daily
Cohort 3: 20 mg oral capsule once daily
Cohort 4: 30 mg oral capsule once daily
Cohort 5: 40 mg oral capsule once daily
Cohort 6: 60 mg oral capsule once daily

The starting dose will be 5 mg/day (5 mg once daily). The 24 day initial treatment cycle (Cycle 1) of each dose will consist of a single administration of BGB-283 (Day 1), followed by a 2 day treatment free period (Days 2 and 3) and a 21 day period of repeated drug administration (Days 4 to 24).

Evaluation of a cohort of at least three (3) subjects completing one cycle of treatment at that dose level is required prior to determining the next dose level and dose regimen for the next cohort.

If a subject wishes to continue study treatment on completion of Cycle 1, the subject can continue study treatment in 21 day Cycle 2 (with no treatment free or rest period) and subsequent cycles (same as Cycle 2, all of 21 days' duration), at the discretion of the investigator.

The continuous safety evaluation will be performed by the sponsor, the coordinating investigator, and investigators. A Safety Monitoring Committee (SMC) will be established for the determination of dose levels to be administered and dose regimen during dose escalation, and will depend on the data available from the previous dose levels.

The investigator is responsible for investigational product accountability, reconciliation, and record maintenance. In accordance with all applicable regulatory requirements, the investigator or designated study center personnel must maintain investigational product accountability records throughout the course of the study. This person(s) will document the amount of investigational product received from the sponsor, the amount supplied and/or administered to and returned by subjects, if applicable. After completion of the study, all unused BGB-283 will be inventoried and packaged for return shipment by the hospital unit pharmacist. The inventoried supplies will be returned to the sponsor or destroyed on site, after receiving written sponsor approval.
Intervention code [1] 290441 0
Treatment: Drugs
Comparator / control treatment
not applicable
Control group
Uncontrolled

Outcomes
Primary outcome [1] 293379 0
The safety of BGB 283 will be assessed throughout the study by monitoring Adverse Events (AEs) per the National Cancer Institute Common Toxicity Criteria for AEs (NCI-CTCAE), serious adverse events (SAEs), physical examination, and laboratory measurements.
Timepoint [1] 293379 0
Monitored from day 1 to end of treatment (about 1 year) in each participant.
Primary outcome [2] 293429 0
Dose-Limiting Toxicity (DLT) will be done by monitoring each participant for study drug treatment-related toxicities at each dose level
Timepoint [2] 293429 0
Monitored after first cycle (24 days).
Primary outcome [3] 293497 0
Determination of the maximum tolerated dose (MTD) will be assessed by occurrence of DLT
Timepoint [3] 293497 0
Determined after first cycle (24 days)
Secondary outcome [1] 310906 0
To characterize the pharmacokinetics (PK) of BGB 283 after single dose and multiple dose administration.
For a single dose profile: area under the plasma concentration time curve from zero to the last measureable concentration (AUClast), area under the plasma concentration time curve from zero to infinity (AUC), maximum observed plasma concentration (Cmax), time to maximum observed plasma concentration (tmax), terminal half life (t1/2), apparent clearance (CL/F), and apparent volume of distribution (Vd/F).
After steady state: AUClast,ss, Cmax,ss, and tmax,ss.
Blood plasma samples will be assayed using LC/MS method.
Timepoint [1] 310906 0
Baseline, and day 1, 2, 3, 4, 18 of Cycle 1. Day 1 of Cycle 2 onwards
Secondary outcome [2] 310907 0
The number and proportion of subjects who achieve objective tumor response (complete response [CR], partial response [PR], and CR+PR) or stable disease (SD) using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (defined as CR, PR or SD, according to local radiological assessments from the first administration of the investigational product to the end of the study treatment).
Timepoint [2] 310907 0
Baseline, and every 6 weeks after intervention commencement
Secondary outcome [3] 310908 0
Progression free survival (defined as the interval between the day of the first administration of the investigational product and the first documentation of progressive disease (PD) or death, whichever occurs earlier. Subjects, who are withdrawn from the study without documented progression, will be censored at the date of the last tumor assessment when the subject was known to be progression free. Subjects without post baseline tumor assessments, but known to be alive will be censored at the time of the first administration of the investigational product).
Disease assessments will be performed by multiple events, such as laboratory evaluation, physical examination, vital signs, electrocardiogram, and CT scan.
Timepoint [3] 310908 0
End of study (about 1 year)
Secondary outcome [4] 310909 0
Duration of response for responders (CR or PR) and duration of SD (defined only for subjects whose confirmed best response is CR or PR, as the time interval between the date of the earliest qualifying response and the date of PD or death for any cause, whichever occurs earlier. For subjects who are alive without progression following the qualifying response, duration of response will be censored on the date of last evaluable tumor assessment or last follow up for progression of disease).
Timepoint [4] 310909 0
End of study (about 1 year)

Eligibility
Key inclusion criteria
1. Provided written informed consent prior to enrollment.
2. Male or female and at least 18 years of age.
3. A life expectancy of at least 12 weeks.
4. Histologically or cytologically confirmed advanced or metastatic solid tumor for which no effective standard therapy is available.
5. One of B-RAF, N-RAS, or K-RAS mutation positive solid tumor.
6. Eastern Cooperative Oncology Group (ECOG) performance status of <=1.
7. Able to swallow and retain oral medication.
8. Adequate bone marrow, liver, and renal function:
i) Absolute neutrophil count >=1000/mm3
ii) Platelets >=100,000/mm3
iii) Total bilirubin <=1.5 times the upper limit of normal (ULN)
iv) Aspartate aminotransferase and alanine aminotransferase <=2.5 x ULN (<=5 x ULN for subjects with known liver metastasis)
v) Creatinine clearance >=45 mL/min (calculated by the Cockcroft Gault formula).
9. Female subjects are eligible to enter and participate in the study if they are of:
a) Non childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who
i) Has had a hysterectomy,
ii) Has had a bilateral oophorectomy (ovariectomy),
iii) Has had a bilateral tubal ligation, or
iv) Is post menopausal (total cessation of menses for >=1 year).
b) Childbearing potential, has a negative serum pregnancy test at screening (within 7 days of the first investigational product administration), and uses adequate contraception before study entry and throughout the study until 28 days after the last investigational product administration. Adequate contraception, when used consistently and in accordance with both the product label and the instructions of the physician, are defined as follows:
i) Vasectomized partner who is sterile prior to the female subject’s entry and is the sole sexual partner for that female.
ii) Any intrauterine device with a documented failure rate of less than 1% per year.
iii) Double barrier contraception defined as condom with spermicidal jelly, foam, suppository, or film; OR diaphragm with spermicide; OR male condom and diaphragm.
10. Subjects with treated brain metastasis are eligible to enter and paticipate in the study if they are neurologically stable.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Female subjects who are pregnant or lactating.
2. Subjects receiving cancer therapy (chemotherapy or other systemic anti cancer therapies, immunotherapy, radiation therapy, or surgery) at the time of enrollment.
3. Have received prior systemic anti cancer treatment within the following time frames:
i) Cyclical chemotherapy within a period of time that is shorter than the cycle length used for that treatment (e.g,. 6 weeks for nitrosourea, mitomycin C) prior to starting study treatment
ii) Biologic therapy (e.g,. antibodies), continuous or intermittent small molecule therapies, or any other investigational agents within a period of five times the half life of the agent or <=4 weeks (whichever is shorter) prior to starting study treatment
4. Any major surgery within 28 days prior to enrollment.
5. Any radiotherapy within 14 days prior to enrollment, providing the subject has recovered from all toxicities to NCI-CTCAE <=Grade 1.
6. Use of any investigational anti cancer drug within 28 days before the first investigational product administration.
7. Unresolved toxicity >Grade 1 (according to NCI-CTCAE, Version 4.03) from previous anti cancer therapy, unless agreed by the sponsor.
8. History or presence of gastrointestinal disease or other condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs.
9. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drug or to any component of BGB-283. (To date there are no known Food and Drug Administration [FDA] approved drugs chemically related to BGB-283).
10. Untreated leptomeningeal or brain metastasis. Subjects with previously treated brain metastasis that are asymptomatic, off steroids and anti seizure medications for longer than 28 days are permitted.
11. Any unstable, pre-existing major medical condition that in the opinion of the Investigator contra indicates the use of an investigational product, including active infection, known human immunodeficiency virus (HIV) positive subjects, or known Hepatitis B or C.
12. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
13. As a result of the medical interview, physical examination or screening investigations, the investigator considers the subject unfit for study.
14. Is on medication listed in the protocol or requires any of these medications during treatment with BGB-283.
15. Candidates for curative therapy.
16. Unable or unwilling to comply with the required treatment.

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
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
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
Current
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment outside Australia
Country [1] 7348 0
New Zealand
State/province [1] 7348 0
Willington, Waikato, Otago, Canterbury

Funding & Sponsors
Funding source category [1] 290106 0
Commercial sector/Industry
Name [1] 290106 0
BeiGene Aus Pty Ltd
Address [1] 290106 0
c/o Becis Pty Ltd, 1C/528 Compton Road, Stretton Qld Australia 4116
Country [1] 290106 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
BeiGene Aus Pty Ltd
Address
c/o Becis Pty Ltd, 1C/528 Compton Road, Stretton Qld Australia 4116
Country
Australia
Secondary sponsor category [1] 288814 0
None
Name [1] 288814 0
None
Address [1] 288814 0
None
Country [1] 288814 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291815 0
Peter MacCallum Cancer Centre Ethics Committee
Ethics committee address [1] 291815 0
Peter MacCallum Cancer Centre
Level 4, #10 St Andrews Place
East Melbourne Victoria
Locked Bag 1 A'Beckett Street
Victoria 8006 Australia
Ethics committee country [1] 291815 0
Australia
Date submitted for ethics approval [1] 291815 0
Approval date [1] 291815 0
22/10/2013
Ethics approval number [1] 291815 0
HREC/13/PMCC/34

Summary
Brief summary
This study will evaluate the safety, tolerability, pharmacokinetic profile and treatment effect of a new drug known as BGB-283 in patients with solid tumours.

Who is it for?
You may be eligible to join this study if you are aged 18 years or above, and have a confirmed diagnosis of advanced or metastatic solid tumour for which no effective standard therapy is available.

Study details
All participants in this study will receive treatment with a new drug known as BGB-283. Treatment will be administered by oral capsule [once daily for 24 days (Cycle 1 only) and 21 days (Cycle 2 onwards) each cycle]. Initially a low dose will be administered to participants. If this dose is tolerated, then it will be increased in the next group of patients and so on until the maximum tolerated dose is determined.

All participants will be regularly monitored for safety and tolerability of the medication for about 1 year. They will also be required to give blood samples (on days when frequent pharmacokinetic sampling is required), FDG-PET scan (screening and the first day of Cycle 2) and CT scans (screening and subsequent every 6 weeks) during the study. This will provide us with supportive data for further development of this medication.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 52114 0
Dr Jayesh Desai
Address 52114 0
Department of Medical Oncology,
Royal Melbourne Hospital,
Grattan Street,
Parkville,
VIC 3050
Country 52114 0
Australia
Phone 52114 0
+61 3 9342 7000
Fax 52114 0
Email 52114 0
Jayesh.Desai@mh.org.au
Contact person for public queries
Name 52115 0
Dr Jason Yang
Address 52115 0
BeiGene (Beijing) Co., Ltd,
No. 30 Science Park Road,
Zhong Guan Cun Life Science Park,
Changping District,
Beijing, 102206
Country 52115 0
China
Phone 52115 0
+861058958057
Fax 52115 0
Email 52115 0
Clinicaltrials@beigene.com
Contact person for scientific queries
Name 52116 0
Dr Jason Yang
Address 52116 0
BeiGene (Beijing) Co., Ltd,
No. 30 Science Park Road,
Zhong Guan Cun Life Science Park,
Changping District,
Beijing, 102206
Country 52116 0
China
Phone 52116 0
+861058958057
Fax 52116 0
Email 52116 0
Clinicaltrials@beigene.com