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Trial registered on ANZCTR


Registration number
ACTRN12619001147178
Ethics application status
Approved
Date submitted
29/07/2019
Date registered
16/08/2019
Date last updated
8/01/2024
Date data sharing statement initially provided
16/08/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Cancer Molecular Screening and Therapeutics (MoST) Program Substudy Addendum 6 substudy 14-15: Larotrectinib
Scientific title
Single arm, open label, signal seeking, phase IIa trial of the activity of Larotrectinib in patients with advanced NTRK1-3 positive tumours.
Secondary ID [1] 297752 0
CTC0141-Addendum 6
Universal Trial Number (UTN)
U1111-1182-6652
Trial acronym
MoST Addendum 6
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:
Cancer 312089 0
Condition category
Condition code
Cancer 310648 310648 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Larotrectinib will be taken orally by the participant at home, at a dose of 100 mg twice daily. The Larotrectinib dosage may be reduced to 75 mg or 50 mg twice daily if participant experiences intolerance toxicity. Larotrectinib is to be taken continuously until disease progression is documented or when the participant experiences intolerable toxicity or withdraws 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] 313991 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 319495 0
The primary end point is disease control defined as: 1. Objective tumour response, based on complete and partial responses using cancer specific response criteria or 2. Time to progressive (TTP) disease exceeds the documented time to progressive disease on the last treatment prior to substudy entry by at least 1.3 times (TTP2/TTP1 > 1.3). Or exceeds 6 months if TTP1 is not evaluable. Where disease evaluation is not based on CT scans alternative validated guidelines, such as Gynecologic Cancer Intergroup (GCIG) and Prostate Cancer Working Group 2 (PCWG2) criteria will be employed. Where radiological progression cannot be assessed, evidence for clinical progression will be documented. These data will be collected from participant questionnaires, such as quality of life per the QLQ-C30 version 3 or The Brief Pain Inventory, or clinical reports to supplement the primary outcome.
Timepoint [1] 319495 0
CT or MRI scans for disease evaluation will take place every 8 weeks until disease progression.
Secondary outcome [1] 368427 0
Overall survival (OS) (death from any cause).
Timepoint [1] 368427 0
For the duration of the study.
Secondary outcome [2] 368429 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 (eg. diarrhoea, gastrointestinal disorder) by participants will be documented by study site staff and subsequently transcript onto study electronic data capturing (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 [2] 368429 0
Adverse events will be recorded from the first dose of study treatment until 30 days after cessation of study treatment.
Secondary outcome [3] 368430 0
Health related quality of life during treatment will be assessed using the EORTC QLQ-C30 and The Brief Pain Inventory Forms
Timepoint [3] 368430 0
Every 4 weeks during treatment and every 8 weeks during follow-up until disease progression

Eligibility
Key inclusion criteria
1. Adults, aged 18 years and older, with pathologically confirmed advanced and/or metastatic solid cancer of any histologic type or an earlier diagnosis of a poor prognosis cancer.
2. Confirmation of molecular eligibility by the molecular tumour board, patients with tumours harbouring somatic NTRK1-3 rearrangements/ fusions OR extreme overexpression of NTRK1,2 or 3
3. For non primary CNS cancers, at least one site of measurable disease according to RECIST version 1.1.
4. For primary CNS tumours, the following additional inclusion criteria must be met:
a. Radiation as first line therapy, if given, completed more than 12 weeks prior to C1D1 of study treatment
b. At least one site of bi-dimensionally measurable disease (confirmed by magnetic resonance imaging [MRI] and evaluable by RANO criteria), with the size of at least one of the measurable lesions greater or equal to 1 cm in each dimension and noted on more than one imaging slice
c. Baseline imaging done while on a stable dose of steroid medication for at least 5 days immediately before the MRI
5. ECOG performance status 0, 1 or 2
6. Received and failed all standard anticancer therapy or have documented unsuitability for any further standard therapy, if standard therapy exists
7. Clinical or radiological progression on or following last anticancer therapy unless such anticancer therapy stopped due to toxicity / treatment intolerance
8. 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 9g/dL (5.6mmol/L);
b. liver function; ALT/AST less than or equal to 3 x ULN (in the absence of liver metastases, less than or equal to 5 x ULN 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
9. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments
10. Signed, written informed consent to participation in the specific treatment substudy
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Amongst patients eligible on the basis of extreme overexpression of NTRK1-3, patients whose tumours also harbor gain-of-function mutations in KRAS, NRAS, BRAF, MAP2K1, EGFR, ALK, RET, ROS1, KIT, PDGFRA will not be eligible.
2. Contraindications to investigational product;
3. Known history of hypersensitivity to active or inactive components of investigational product;
4. Previous treatment with a NTRK inhibitor
5. Patients unable or unwilling to swallow capsules or oral solution
6. Treatment with strong inhibitors or inducers of CYP3A4 within 7 days of registration
7. Patients who require treatment with an enzyme-inducing anti-epileptic drug
8. Specific comorbidities or conditions (e.g. psychiatric) or concomitant medications which may interact with the investigational product(s);
9. 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;
10. Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment:
a. Radiation therapy, 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. Immunotherapy within 28 days prior to the first dose of study treatment;
c. Chemotherapy, biologic therapy, or hormonal therapy within 14 days or 5 half-lives of a drug prior to the first dose of study treatment or until recovery from previous therapy (whichever is longer);
11. Any unresolved toxicity (greater than CTCAE grade 2) from previous anti-cancer therapy. Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, peripheral neuropathy);
12. Administration of any investigational treatment within 30 days or 5 half-lives (whichever is longer) prior to receiving the first dose of study treatment;
13. For non central nervous system (CNS) cancers, patients with symptomatic CNS involvement of his/her cancer are excluded. Subjects with stable neurological function, on stable doses of steroids/anti-epileptics over 4 weeks, and with no evidence of CNS progression within 12 weeks prior to screening are eligible;
14. History of another malignancy within 2 years prior to molecular screening registration are excluded unless adequately treated and determined free of progressive and metastatic disease for at least 6 months. Patients with a past history of adequately treated carcinoma-in-situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or superficial transitional cell carcinoma of the bladder can be included;
15. 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
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
Active, not recruiting
Date of first participant enrolment
Anticipated
2/11/2020
Actual
2/11/2020
Date of last participant enrolment
Anticipated
30/09/2023
Actual
24/10/2023
Date of last data collection
Anticipated
29/09/2024
Actual
Sample size
Target
32
Accrual to date
Final
17
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 13440 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [2] 13443 0
The Canberra Hospital - Garran
Recruitment hospital [3] 13444 0
Linear Clinical Research - Nedlands
Recruitment hospital [4] 13445 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [5] 13446 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [6] 13447 0
Royal Hobart Hospital - Hobart
Recruitment hospital [7] 13448 0
Royal Darwin Hospital - Tiwi
Recruitment hospital [8] 13449 0
Princess Alexandra Hospital - Woolloongabba
Recruitment postcode(s) [1] 26053 0
0810 - Tiwi
Recruitment postcode(s) [2] 26045 0
2010 - Darlinghurst
Recruitment postcode(s) [3] 26048 0
2605 - Garran
Recruitment postcode(s) [4] 26050 0
3000 - Melbourne
Recruitment postcode(s) [5] 26054 0
4102 - Woolloongabba
Recruitment postcode(s) [6] 26051 0
5000 - Adelaide
Recruitment postcode(s) [7] 26049 0
6009 - Nedlands
Recruitment postcode(s) [8] 26052 0
7000 - Hobart

Funding & Sponsors
Funding source category [1] 302276 0
Government body
Name [1] 302276 0
Office for Health and Medical Research
Country [1] 302276 0
Australia
Funding source category [2] 303410 0
Other Collaborative groups
Name [2] 303410 0
Australian Genomic Cancer Medicine Centre (AGCMC)
Country [2] 303410 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] 302150 0
None
Name [1] 302150 0
Address [1] 302150 0
Country [1] 302150 0
Other collaborator category [1] 280883 0
Other Collaborative groups
Name [1] 280883 0
Australian Genomic Cancer Medicine Centre
Address [1] 280883 0
Kinghorn Cancer Centre,
370 Victoria Street,
Darlinghurst NSW 2010
Country [1] 280883 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302952 0
St Vincent's Hospital Ethics Committee
Ethics committee address [1] 302952 0
Ethics committee country [1] 302952 0
Australia
Date submitted for ethics approval [1] 302952 0
29/06/2019
Approval date [1] 302952 0
21/08/2019
Ethics approval number [1] 302952 0

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

Contacts
Principal investigator
Name 91958 0
Dr Subotheni Thavaneswaran
Address 91958 0
Garvan Institute of Medical Research,
The Kinghorn Cancer Centre,
370 Victoria Street,
Darlinghurst NSW 2010
Country 91958 0
Australia
Phone 91958 0
+61 2 9355 5655
Fax 91958 0
+61 (0)2 9355 5872
Email 91958 0
s.thavaneswaran@garvan.org.au
Contact person for public queries
Name 91959 0
Lucille Sebastian
Address 91959 0
NHMRC Clinical Trials Centre,
Medical Foundation Building
Levels 4-6,
92-94 Parramatta Road,
Camperdown NSW 2050
Country 91959 0
Australia
Phone 91959 0
+61 2 9562 5000
Fax 91959 0
Email 91959 0
most@ctc.usyd.edu.au
Contact person for scientific queries
Name 91960 0
Subotheni Thavaneswaran
Address 91960 0
Garvan Institute of Medical Research,
The Kinghorn Cancer Centre,
370 Victoria Street,
Darlinghurst NSW 2010
Country 91960 0
Australia
Phone 91960 0
+61 2 9355 5655
Fax 91960 0
+61 (0)2 9355 5872
Email 91960 0
s.thavaneswaran@garvan.org.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 Supporting Document Provided


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.