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Trial registered on ANZCTR


Registration number
ACTRN12621000811808
Ethics application status
Approved
Date submitted
21/05/2021
Date registered
28/06/2021
Date last updated
28/06/2021
Date data sharing statement initially provided
28/06/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Cancer Molecular Screening and Therapeutics (MoST) Program Addendum 17 - substudies 38-39: Tepotinib
Scientific title
A single arm, open label, signal-seeking, phase II trial of tepotinib in patients with advanced non-small cell lung cancer harbouring MET exon 14 skipping mutations detected by comprehensive genomic profiling
Secondary ID [1] 303330 0
CTC0141- addendum 17
Universal Trial Number (UTN)
U1111-1182-6652
Trial acronym
MoST Addendum 17
Linked study record
This record is an addendum to the MoST framework (ACTRN12616000908437). The MoST framework protocol consists of 1/molecular screening (genomic analysis to determine whether participants are suitable for a sub-study) and 2/ sub-study design structure (study treatment for specific genomic expression/participant population). Additionally, the sub-study shares the same study objectives and outcomes as the framework. Hence, this is a substudy that linked to ACTRN12616000908437.

Health condition
Health condition(s) or problem(s) studied:
Advanced non-small cell lung cancer harbouring MET exon 14 skipping mutations 320572 0
Condition category
Condition code
Cancer 318425 318425 0 0
Lung - Non small cell

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will receive continuous tepotinib. Tepotinib will be administered as tablets, to be taken orally by participants, at a dose of 500mg daily (days 1 to 21 in a 21-day treatment cycle). Tepotinib is to be taken continuously with no interruption between cycles.

If participants experience any severe (grade 3-4) adverse events, treatment will be withheld until the adverse event is resolved (grade 0-1). If participants experience intolerable toxicity, tepotinib dose may be reduced to 250mg once daily. If a second dose reduction is required, the patient should discontinue study treatment.

Participants will receive tepotinib until disease progression is documented, intolerable toxicity or withdrawal for another reason. Participants will be asked to return unused drug and empty drug containers at each return visit. The Pharmacy Department at participating institutions will maintain a record of drugs dispensed for each participant.
Intervention code [1] 319638 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 326402 0
The primary objective is to assess the clinical activity of tepotinib using objective tumour response rate (OTRR), based on complete or partial response using cancer specific response criteria such as RECIST v1.1, RANO or disease-specific guidelines.
Timepoint [1] 326402 0
Imaging (eg. CT scans) for disease evaluation will take place every 6 weeks from first dose of study treatment until 18 weeks, then every 12 weeks until disease progression.
Secondary outcome [1] 391344 0
Overall survival (OS) (death from any cause)
Timepoint [1] 391344 0
For the duration of the study. From the date of registration to date of death from any cause, or the date of last known follow-up alive.
Secondary outcome [2] 391345 0
Progression free survival (PFS). PFS is defined as the interval from date of registration to the date of first evidence of disease progression or death from any cause, whichever occurs first. Participants who did not progress or die will be censored on the date of their last clinical assessment or tumour assessment. Disease progression is defined according to RECIST v1.1, RANO guidelines, or disease specific guidelines.
Timepoint [2] 391345 0
Imaging (eg. CT scans) for disease evaluation will take place every 6 weeks from first dose of study treatment until 18 weeks, then every 12 weeks until disease progression.
Secondary outcome [3] 391346 0
Time to treatment failure. This is defined as the interval from the date of registration to date of permanently ceasing study treatment for any reason. Participants who are still on study treatment at time of analysis will be censored on the date of their last reported study treatment. Patients who receive subsequent systemic cancer therapy before progression will be considered to be censored at the time of commencement of subsequent therapy.
Timepoint [3] 391346 0
Time to treatment failure analysis is performed at 12 months from last patient registration.
Secondary outcome [4] 391347 0
Depth of response, defined as the percentage of tumour shrinkage based on the sum of the longest diameters of all target lesions observed at the lowest point (nadir), compared with the sum of their diameters at baseline.
Timepoint [4] 391347 0
Imaging (eg. CT scans) for disease evaluation will take place every 6 weeks from first dose of study treatment until 18 weeks, then every 12 weeks until disease progression.
Secondary outcome [5] 391349 0
Duration of response according to RECIST 1.1

Timepoint [5] 391349 0
Imaging (eg. CT scans) for disease evaluation will take place every 6 weeks from first dose of study treatment until 18 weeks, then every 12 weeks until disease progression.
Secondary outcome [6] 391350 0
Progression Free Survival (PFS) at 6 months. PFS is defined as the interval from date of registration to the date of first evidence of disease progression or death from any cause, whichever occurs first and is the proportion of participants on study who are alive and progression free at 6 months. The disease progression is defined according to RECIST v1.1, RANO guidelines, or disease specific guidelines.
Timepoint [6] 391350 0
At 6 months post participant registration via imaging (e.g. CT) scans of disease evaluation
Secondary outcome [7] 391351 0
Safety and tolerability of treatment (rates of adverse events). All adverse events (AEs), including event grading as per NCI CTCAE criteria, will be captured from the first dose of study treatment until 30 days after cessation of study treatment. Reported AEs by participants will be documented by study site staff and subsequently transcribed into the study electronic data capture (EDC) system. In order to evaluate the safety and tolerability of the study treatment, the entered AE types, frequency and severity in the EDC will be analysed.
Timepoint [7] 391351 0
Adverse events will be recorded from the first dose of study treatment until 30 days after cessation of study treatment.
Secondary outcome [8] 391385 0
Health related quality of life during treatment assessed using the EORTC QLQ-C30 Form.
Timepoint [8] 391385 0
Every 3 weeks from first dose of study treatment until end of treatment. Subsequently, every 9 weeks for 12 months and then every 12 weeks until disease progression.
Secondary outcome [9] 396867 0
Health related quality of life during treatment assessed using The Brief Pain Inventory Form.
Timepoint [9] 396867 0
Every 3 weeks from first dose of study treatment until end of treatment. Subsequently, every 9 weeks for 12 months and then every 12 weeks until disease progression.

Eligibility
Key inclusion criteria
1. Adults, aged 18 years and older, with newly diagnosed metastatic non-squamous NSCLC;
2. METex14 skipping mutation identified using CGP;
3. Confirmation of molecular eligibility by the molecular tumour board;
4. Measurable disease as assessed by RECIST 1.1;
5. ECOG 0 to 2;
6. Adequate organ system function as assessed by the following minimal laboratory requirements (within 7 days prior to first administration of study drug):
a. bone marrow function; platelets greater than or equal to 100 x 10^9/L, ANC greater than or equal to 1.5 x 10^9/L, and haemoglobin greater than or equal to 90g/L (5.6mmol/L);
b. liver function; ALT/AST less than or equal to 3xULN (in the absence of liver metastases, less than or equal to 5xULN for patients with liver involvement) and total bilirubin less than or equal to 1.5xULN;
c. renal function; serum creatinine less than or equal to 1.5xULN;
7. Life expectancy greater than or equal to 12 weeks;
8. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments;
9. Signed, written informed consent to participation in the specific treatment substudy.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Prior systemic therapy for advanced disease. Up to two cycles of systemic therapy (excluding prior MET inhibitor treatment) while awaiting the results of CGP testing are permitted.
2. Prior MET/HGF pathway inhibitor treatment;
3. Known history of hypersensitivity or contraindication to tepotinib;
4. Specific comorbidities or conditions (e.g. psychiatric) or concomitant medications which may interact with tepotinib, including:
a. Known history of interstitial lung disease or drug-induced pneumonitis requiring steroid treatment
b. Congenital QT syndrome or baseline QTc >500ms
5. Active CNS involvement. Patients with stable neurological function, on stable anticonvulsants and/or steroids less than or equal to 10 mg prednisone equivalent over 4 weeks are eligible;
6. Co-morbidities or conditions that may compromise assessment of key outcomes or in the opinion of the clinician, limit the ability of the patient to comply with the protocol;
7. Treatment with any of the following anti-cancer therapies prior to the first dose of tepotinib:
a. Radiation therapy, major surgery, or tumour embolization within 14 days prior to the first dose of study treatment. Palliative radiotherapy (for analgesia) is acceptable only if the irradiated field does not include target lesions;
b. Any systemic therapy within 28 days prior to the first dose of tepotinib;
8. Administration of any investigational treatment within 28 days prior to receiving the first dose of tepotinib;
9. Prior or concurrent malignancy. History of another primary malignancy except for:
a. Malignancy treated with curative intent and with no known active disease within 2 years before consent to molecular screening and of low potential risk for recurrence;
b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease;
c. Adequately treated carcinoma-in-situ without evidence of disease;
10. Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal, infertile, or use a reliable means of contraception. Women of childbearing potential must have a negative pregnancy test done within 7 days prior to registration. Men must have been surgically sterilised or use a (double if required) barrier method of contraception.

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
Single group
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
A group of 32 patients will be recruited for 2 substudies containing 16 subjects each. As described in the framework protocol (ACTRN12616000908437), substudies with greater than or equal to 3 out of 16 responding patients, will in general be sufficiently interesting to investigate further. As a general rule, substudies with less than 3 out of 16 responses will be considered to not support the molecular hypothesis behind the substudy.

If some activity is recognised in a 16 patient substudy cohort but further information is needed to inform development of phase II testing, iterative substudies may be opened to enrich for patients that harbour a specific common biomarker or histologic cancer subtype. Each such iteration would constitute a new substudy for the purposes of this framework.

The sample size and guiding definitions of what constitutes an interesting signal are determined empirically as the investigators considered these numbers of patients as sufficient for signal-seeking purpose.

Recruitment
Recruitment status
Not yet 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)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 18567 0
The Canberra Hospital - Garran
Recruitment hospital [2] 18568 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [3] 18569 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [4] 18570 0
Royal Darwin Hospital - Tiwi
Recruitment hospital [5] 18571 0
Royal Hobart Hospital - Hobart
Recruitment hospital [6] 18572 0
Linear Clinical Research - Nedlands
Recruitment hospital [7] 18573 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [8] 18574 0
The Prince Charles Hospital - Chermside
Recruitment hospital [9] 19225 0
Westmead Hospital - Westmead
Recruitment hospital [10] 19226 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [11] 19227 0
St George Hospital - Kogarah
Recruitment hospital [12] 19228 0
Royal North Shore Hospital - St Leonards
Recruitment postcode(s) [1] 32940 0
2605 - Garran
Recruitment postcode(s) [2] 32941 0
3000 - Melbourne
Recruitment postcode(s) [3] 32942 0
5000 - Adelaide
Recruitment postcode(s) [4] 32943 0
0810 - Tiwi
Recruitment postcode(s) [5] 32944 0
7000 - Hobart
Recruitment postcode(s) [6] 32945 0
6009 - Nedlands
Recruitment postcode(s) [7] 32946 0
4102 - Woolloongabba
Recruitment postcode(s) [8] 32947 0
4032 - Chermside
Recruitment postcode(s) [9] 33799 0
2145 - Westmead
Recruitment postcode(s) [10] 33800 0
3065 - Fitzroy
Recruitment postcode(s) [11] 33801 0
2217 - Kogarah
Recruitment postcode(s) [12] 33802 0
2065 - St Leonards

Funding & Sponsors
Funding source category [1] 307749 0
Government body
Name [1] 307749 0
Office for Health and Medical Research
Address [1] 307749 0
Locked Bag 961
North Sydney NSW 2059
Country [1] 307749 0
Australia
Funding source category [2] 307751 0
Other Collaborative groups
Name [2] 307751 0
Australian Genomic Cancer Medicine Centre (AGCMC)
Address [2] 307751 0
Kinghorn Cancer Centre,
370 Victoria Street
Darlinghurst NSW 2010
Country [2] 307751 0
Australia
Funding source category [3] 307823 0
Commercial sector/Industry
Name [3] 307823 0
Merck Healthcare KGaA
Address [3] 307823 0
Frankfurter Str. 250
64293 Darmstadt
Country [3] 307823 0
Germany
Funding source category [4] 308591 0
Commercial sector/Industry
Name [4] 308591 0
Roche Products Pty Limited
Address [4] 308591 0
Level 8, 30-34 Hickson Road
Sydney NSW 2000
Country [4] 308591 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country
Australia
Secondary sponsor category [1] 308449 0
None
Name [1] 308449 0
Address [1] 308449 0
Country [1] 308449 0
Other collaborator category [1] 281633 0
Other Collaborative groups
Name [1] 281633 0
Australian Genomic Cancer Medicine Centre (AGCMC)
Address [1] 281633 0
Kinghorn Cancer Centre,
370 Victoria Street
Darlinghurst NSW 2010
Country [1] 281633 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307771 0
St Vincent's Hospital Human Research Ethics Committee
Ethics committee address [1] 307771 0
Translational Research Centre,
97-105 Boundary Street
Darlinghurst NSW 2010
Ethics committee country [1] 307771 0
Australia
Date submitted for ethics approval [1] 307771 0
Approval date [1] 307771 0
02/03/2021
Ethics approval number [1] 307771 0

Summary
Brief summary
This is a substudy of the Cancer Molecular Screening and Therapeutics (MoST) Program, which is registered on ANZCTR with ID ACTRN12616000908437. This substudy will evaluate the activity of tepotinib in a population of participants with metastatic non-small cell lung cancers (NSCLC) harbouring METex14 skipping mutations identified using comprehensive genomic profiling (CGP).

Who is it for?
You may be eligible to join the study if you are aged 18 years and older, with pathologically confirmed metastatic NSCLC. Your tumour will need to harbour METex14 skipping mutations identified using CGP.

Study details:
Participants will receive tepotinib treatment. The tepotinib is to be taken orally, at 500mg once daily (days 1 to 21 in a 21-day treatment cycle).
Tepotinib will be given to participants continuously as long as they and their doctor agree there is a benefit from treatment. Participants will undergo imaging assessments at 6 weekly intervals from first treatment until 18 weeks, and then 12 weekly intervals until progression. Safety and tolerability of treatment will be assessed at 3 weekly intervals. Health related quality of life during treatment will be assessed at 3 weekly intervals and then every 9 weeks after end of treatment for 12 months, and then every 12 weeks until progression.

We cannot guarantee that participants will receive any benefits from this study. This study is being carried out to improve the way we treat cancer patients who may have limited treatment options available to them. It is hoped that tepotinib will be well tolerated and will improve outcomes for future patients, however, there may be no clear benefit from participation in this study.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 108438 0
A/Prof Chee Khoon Lee
Address 108438 0
St George Hospital,
Grey St,
Kogarah NSW 2217
Country 108438 0
Australia
Phone 108438 0
+61 2 9562 5365
Fax 108438 0
Email 108438 0
chee.lee@sydney.edu.au
Contact person for public queries
Name 108439 0
Dr Lucille Sebastian
Address 108439 0
NHMRC Clinical Trials Centre
Medical Foundation Building
Levels 4-6, 92-94 Parramatta Road
Camperdown NSW 2050
Country 108439 0
Australia
Phone 108439 0
+61 295625000
Fax 108439 0
Email 108439 0
most.study@sydney.edu.au
Contact person for scientific queries
Name 108440 0
A/Prof Chee Khoon Lee
Address 108440 0
St George Hospital,
Grey St,
Kogarah NSW 2217
Country 108440 0
Australia
Phone 108440 0
+61 2 9562 5000
Fax 108440 0
Email 108440 0
chee.lee@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
There are no plans for this to occur at this time and participant consent is required for data sharing.
What supporting documents are/will be available?
No other documents available
Summary results
No Results