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Trial registered on ANZCTR


Registration number
ACTRN12620000849998
Ethics application status
Approved
Date submitted
13/05/2020
Date registered
27/08/2020
Date last updated
27/08/2020
Date data sharing statement initially provided
27/08/2020
Type of registration
Retrospectively registered

Titles & IDs
Public title
A clinical trial to assess the safety, tolerability and efficacy of MG010 in combination with sorafenib-(Nexavar), in people with solid tumours who have failed existing treatments.
Scientific title
A phase I/II, open label, multi-centre study to assess the safety, tolerability, and efficacy of MG010 in combination with sorafenib in subjects with solid tumours who have failed existing treatments.
Secondary ID [1] 300570 0
Nil
Universal Trial Number (UTN)
U1111-1248-4265
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metastatic solid tumours having failed existing treatments. 316302 0
Condition category
Condition code
Cancer 314570 314570 0 0
Bowel - Back passage (rectum) or large bowel (colon)
Cancer 314728 314728 0 0
Liver
Cancer 314729 314729 0 0
Lung - Non small cell
Cancer 315526 315526 0 0
Kidney

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Stage 1 of the trial - dose escalation
Cohort 1: 200mg tablet Sorafenib once daily and 200 mg capsule MG010 once daily for up to one cycle (28 days)
Cohort 2: 200mg tablet Sorafenib once daily and 400 mg capsules MG010 once daily for one cycle (28 days)
Cohort -1: 200mg tablet Sorafenib once daily and 100 mg capsule MG010 once daily for one cycle (28 days)
Cohort and Phase Timing:
Cohort 1 concludes when all subjects complete their cycles, then safety assessments are undertaken within 7 days of the last patients.

If Dose Limiting Toxicity (DLT) is observed in >1 out of 6 subjects in cohort 1, 3 subjects will be recruited for dose cohort -1 (dose de-escalation);

Cohort 2 commences with 3 new patients and after all subjects complete their cycles, then within 7 days safety assessments are performed. After approximately 2 weeks, if all goes well, the report of the safety committee will be finalised, after which stage 2 will commence if the report provides a favourable recommendation.

Stage 1 participants are eligible for stage 2, subject to signing a new informed consent and compliance with the inclusion exclusion criteria.
Stage 2 of the trial - dose expansion stage
The dose will be decided at the completion of stage 1.
Sorafenib once daily and MG010 once or twice daily for up to six cycles (168 days)
Adherence will be monitored by returned medication counts.
Intervention code [1] 316875 0
Treatment: Drugs
Comparator / control treatment
No Control Group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 322898 0
Phase I: PK Composite Outcome Measures
Individual plasma concentrations of MG010 and sorafenib collected at specified time points will be used to calculate pharmacokinetic parameters using a non-compartmental approach. Data will be listed for all subjects with available MG010 concentrations.
Pharmacokinetic parameters to be determined may include:
• Peak plasma concentration at steady state (Cmax,ss)
• Time to reach peak concentration at steady state (Tmax,ss)
• Trough plasma concentration (Ctrough)
• Minimum plasma concentration at steady state (Cmin,ss)
• AUC in 1 dosing interval at steady state (AUC0>t,ss)
• Average concentration at steady state (Cave): AUC0>t,ss/t?
• Fluctuation: (Cmax,ss Cmin,ss)/Cave

Timepoint [1] 322898 0
Day 1 at -0.5 hr pre-dose, 0.5 hr post-dose, subsequently at 1,2,3,4,5,6,8,23 and 24 hr post dose
Primary outcome [2] 322899 0
Phase I and II: Safety Outcome Measures
The safety assessments selected for this study will include the assessment of vital signs,
12-lead electrocardiograms, clinical safety, laboratory examinations, physical
examinations, and adverse events.
Safety endpoints include:
• SAEs and/or TEAEs, regardless of causality or relationship
• Vital Signs - Systolic and diastolic blood pressure, pulse rate, body temperature, and body
weight
• 12-lead electrocardiograms
• Clinically relevant changes in laboratory measurements
Timepoint [2] 322899 0
At each visit (Screening, Day 1, Day 7, Day 14, Day 21, Day 28 and Day 56) safety outcome measures are assessed. In addition:

Phase I: After 7 days of the first dose, the safety review committee will assess the safety of the participant. Then there will be data safety committee who will conduct assessments on a regular basis for each cohort.

Phase II: An independent Data Safety Monitoring Board will be formed. They will review the safety of the study on a quarterly basis.
Primary outcome [3] 322900 0
Phase II: Efficacy Outcome Measures
• Disease control rate (DCR): subjects achieving any one of the following responses:
confirmed complete response (CR), confirmed partial response (PR) or stable disease (SD) during the study (up to and including visit 9) as per Response Evaluation Criteria in Solid
Tumours (RECIST) v1.1 criteria.
Timepoint [3] 322900 0
For the phase I study, the assessment will be performed on day 56. For the phase II study, the tumour response assessments will occur on days 56, 112, 168 and day 210.

Secondary outcome [1] 380182 0
Clinical Benefit Outome Measures
Progression Free Survival (PFS)
Progression free survival (PFS) after initiation of treatment to progressive
disease (PD) or death from any cause. Subjects who did not experience
disease progression or are lost to follow-up will be censored.


Timepoint [1] 380182 0
PFS will be assessed on Days 180, 210.

Secondary outcome [2] 383299 0
Quality of life (QoL)
Outcome Measures will use the EORTC QLQ-C30.
Timepoint [2] 383299 0
Every 28 day cycle up to day 210.
Secondary outcome [3] 383300 0
Exploratory outcome measures.
The presence of pDAPKS308 will be confirmed by analysis of the biopsy taken at the time of diagnosis of the cancer. Then the result will be considered with the outcome data from the study.
Timepoint [3] 383300 0
On completion of the study at day 210.
Secondary outcome [4] 384115 0
Clinical Benefit Outome Measures
Objective Response Rate (ORR)
For the ORR; subjects who achieved confirmed CR or PR during the study up until and including Visit 9 will be evaluated.


Timepoint [4] 384115 0
Days, 56, 112, 168 and 210.
Secondary outcome [5] 384116 0
Clinical Benefit Outcome Measures
Overall Survival (OS) time is defined as the time from first treatment to time of death. Subjects alive at the analysis time points will be censored.
Timepoint [5] 384116 0
Day 240.
Secondary outcome [6] 384117 0
Tumour response duration
Tumour response duration is defined as the time from day 1 of the documented CR/PR to the first day of documented progressive disease (PD) or death. Subjects who did not experience PD will be censored.
The criteria and method for the determination of CR/PR/SD/PD will be based on RECIST 1.1.

Timepoint [6] 384117 0
Up to day 140.

Eligibility
Key inclusion criteria
1.Age over 18 years
2.For subject to be enrolled in cohort 1 of dose-escalation stage:
Histologically confirmed diagnosis of advanced or metastatic solid tumors for which standard treatment is unavailable/ineffective/intolerable.
3. For subject to be enrolled in additional cohorts of dose-
escalation stage and dose expansion cohort: Histologically confirmed diagnosis of one of the following advanced or metastatic solid tumours for which standard treatment is unavailable/ineffective/intolerable:
a.Non-small cell lung carcinoma
b.Renal cell carcinoma
c.Colorectal cancer, or
d. Hepatocellular carcinoma with liver function of Child-Pugh Class A or B (score 7 only), who are resistant to sorafenib
4.Disease progression within 6 months after most recent standard therapy
5.ECOG performance status of less than or equal to 2
6.Have at least one tumour lesion measurable in a unidimensional way with either spiral CT/PET or CT or MRI (in case of brain lesions) only according to Response Evaluation Criteria In Solid Tumours (RECIST 1.1)
7.Adequate organ function within 14 days prior to enrolment, as defined below:
a.Bilirubin less than or equal to x Upper Normal Limit (UNL)
b.AST/ALT/ALP < 5 x UNL
c.Polynuclear neutrophils greater than or equal to 1 500/mm^3
d.Haemoglobin > 90g/L
e.Platelets greater than or equal to 100 000/mm^3
f.Serum Creatinine < 2 x UNL
g.GFR > 30 mL/min
8. .Adequate oral intake without the need for enteral or parenteral feeding
9.Life expectancy > 3 months
10.Ability to understand and willing to sign a written informed consent document and to comply with the study protocol
11.Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry, during the last study period and for the following 6 months after the last study drug intake. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
12.No known or suspected allergy or hypersensitivity to sorafenib or any component of the excipients of MG010
13.For subjects with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
14. Subjects with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For subjects with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1.Surgery (except biopsy) within 4 weeks before enrolment
2.Received any chemotherapy, radiotherapy, targeted therapy or immunotherapy within 4 weeks prior to the enrolment
3.Archived tumour tissue, biopsy tissue or blood sample not available/not suitable for analysis of pDAPKS308 expression
4.History of additional malignancies, except non-melanoma skin cancer, in situ cancer of the cervix, or other solid tumours thathave been considered cured for > 3 years
5.Participated in any other investigational trial, unless treatment in that trial has been discontinued at least 30 days prior to the enrolment
6.Known or suspected allergy or hypersensitivity to any of the therapeutic agents to be administered during the study
7.Uncontrolled concurrent illness including, but not limited to active infection, symptomatic congestive heart failure or cardiac arrhythmia
8.Known to have hypertension (systolic BP>180mmHg or diastolic BP>110mmHg)
9.Receiving inducers of CYP3A4 activity (for example, St. John’s wort, phenytoin, carbamazepine, phenobarbital, and dexamethasone) or sensitive substrates of CYP1A2, 1B1, 2C8, and 2C19 (e.g. theophylline, duloxetine, alosetron or tizanidine) within 2 weeks prior to the enrolment
10.Uncontrolled mental disease or psychotic manifestation that would prohibit compliance with the protocol, the understanding of the informed consent form or the ability to withdraw from the study
11.Malabsorption problem that may affect absorption of sorafenib or MG010
12.ActiveHIV, HBV or HCV infections
13.Pregnancy or breast feeding

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
Enrolment will be monitored to determine when one cancer type reaches 20 after which enrolment in that cancer type will stop.
Phase
Phase 1 / Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
For Phase I, the standard 3+3 design is used, 6 to 12 patients will be enrolled for evaluation.
For Phase II, based on the aggregated data from the literature(Lu et al. 2017; Grothey et al. 2013; Escudier et al. 2008; Kudoet al., 2018; Kudoet al., 2016; Xu et al. 2017;Cohen et al. 2010; Yoshino et al. 2014; Hanet al. 2017)involving similar types of drugs used to treat lung, liver, colorectal, and kidney cancers, the overall DCR attainable is estimated to be 65% for the treated population and 30% for placebo. Using one-sided binomial test (testing whether the true proportion exceeds 30%, assuming 65% can be attained for the treated population), a sample size of 32 subjects will achieve more than 98% of power and control the overall type I error (false positive rate) to be under 5%. Assuming a loss of follow-up of 20%, the total sample size needed will be 40.Subjects with non-small cell lung carcinoma, hepatocellular carcinoma, renal cell carcinoma, and colorectal cancer will be randomly assigned into each treatment arm. Recruitment of a particular cancer type will be stopped when a total of 20 subjects with the same cancer type have been enrolled.

Recruitment
Recruitment status
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
Recruitment hospital [1] 15921 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment hospital [2] 15922 0
Scientia Clinical Research - Randwick
Recruitment hospital [3] 15923 0
Concord Repatriation Hospital - Concord
Recruitment hospital [4] 15924 0
Icon Cancer Care South Brisbane - South Brisbane
Recruitment postcode(s) [1] 29387 0
2031 - Randwick
Recruitment postcode(s) [2] 29386 0
2050 - Camperdown
Recruitment postcode(s) [3] 29388 0
2139 - Concord
Recruitment postcode(s) [4] 29389 0
4101 - South Brisbane

Funding & Sponsors
Funding source category [1] 304986 0
Commercial sector/Industry
Name [1] 304986 0
Metagone Biotech Australia Pty Ltd
Address [1] 304986 0
Metagone Biotech Australia Pty Ltd
Suite 201, 134 William St
Woolloomooloo NSW 2011
Country [1] 304986 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Metagone Biotech Australia Pty Ltd
Address
Metagone Biotech Australia Pty Ltd
Suite 201, 134 William St
Woolloomooloo NSW 2011
Country
Australia
Secondary sponsor category [1] 305374 0
None
Name [1] 305374 0
Address [1] 305374 0
Country [1] 305374 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305389 0
Bellberry HREC
Ethics committee address [1] 305389 0
123 Glen Osmond Road Eastwood Adelaide
South Australia 5063
Ethics committee country [1] 305389 0
Australia
Date submitted for ethics approval [1] 305389 0
10/07/2019
Approval date [1] 305389 0
29/01/2020
Ethics approval number [1] 305389 0
2019-07-586-A-3

Summary
Brief summary
This purpose of this study is to determine the safety, tolerability and efficacy of MG010 in combination with sorafenib in patients with solid tumors who have failed existing treatments

Who is it for?
You may be eligible to join this study if you are aged between 18 years and above, and have histologically confirmed diagnosis of advanced or metastatic solid tumors for which standard treatment is unavailable/ineffective/intolerable

Study details
All participants in this study will receive MG010 and sorafenib. This study will have 2 stages: the dose escalation stage and the dose expansion stage.

In the dose escalation stage, there will be 3 groups of participants who each receive different doses of each drug. The drug will be given orally once every day of a 28-day cycle.

In the dose expansion stage, participants will receive once/twice a day MG010 and once daily sorafenib (at a dose determined from the dose escalation stage) for up to 6 28-day cycles.

Participants will be monitored for reactions and treatment effectiveness, and provide blood and urine for analysis. Medical imaging, e.g. PET and/or CAT scans for stage I will be performed at the beginning and the end. For stage II 5 images will be taken throughout the study; at screening, days, 56, 112, 168 and 210.

It is hoped this trial will provide information on the treatment of solid tumours by demonstrating a benefit in the proposed combination treatment, by improving the tolerability and expand the usage of sorafenib in cancer treatment.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 100214 0
A/Prof Jim Coward
Address 100214 0
ICON CANCER CENTRE
PO BOX 3787
SOUTH BRISBANE QLD 4141
Country 100214 0
Australia
Phone 100214 0
+61 7 3737 4730
Fax 100214 0
Email 100214 0
drjcoward@icon.team
Contact person for public queries
Name 100215 0
A/Prof Jim Coward
Address 100215 0
ICON CANCER CENTRE
PO BOX 3787
SOUTH BRISBANE QLD 4141
Country 100215 0
Australia
Phone 100215 0
+61 7 3737 4730
Fax 100215 0
Email 100215 0
drjcoward@icon.team
Contact person for scientific queries
Name 100216 0
A/Prof Jim Coward
Address 100216 0
ICON CANCER CENTRE
PO BOX 3787
SOUTH BRISBANE QLD 4141
Country 100216 0
Australia
Phone 100216 0
+61 7 3737 4730
Fax 100216 0
Email 100216 0
drjcoward@icon.team

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
At this time there is no plan to submit IPD, however, should this change, this record will be updated accordingly.
What supporting documents are/will be available?
No other documents available
Summary results
No Results