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Trial registered on ANZCTR


Registration number
ACTRN12621000284864
Ethics application status
Approved
Date submitted
19/01/2021
Date registered
16/03/2021
Date last updated
16/03/2021
Date data sharing statement initially provided
16/03/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Cancer Molecular Screening and Therapeutics (MoST) Program Substudy Addendum 13 substudy 31: Entrectinib
Scientific title
A single-arm, open-label, phase II trial of the tumour response to entrectinib in patients with advanced tumours harbouring NTRK fusions or ROS1 gene rearrangements detected by comprehensive genomic profiling
Secondary ID [1] 303172 0
CTC0141-addendum 13
Universal Trial Number (UTN)
U1111-1182-6652
Trial acronym
MoST Addendum 13
Linked study record
This record is an addendum to the MoST framework protocol (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 is linked to ACTRN12616000908437.

Health condition
Health condition(s) or problem(s) studied:
Cancer 320293 0
Condition category
Condition code
Cancer 318218 318218 0 0
Lung - Non small cell
Cancer 318238 318238 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A group of 16 patients will be treated with Entrectinib. Entrectinib will be administered orally at a dose of 600 mg, once daily from days 1-28 on a 28-day treatment cycle until disease progression is documented, the patient experiences an intolerable toxicity, or withdraws for another reason. Clinical assessments will continue until disease progression if treatment is stopped for toxicity. Unacceptable toxicity is determined by the patient or site investigator or defined according to study protocol.

Participants will be followed up for at least 30 days after end of treatment for new adverse events and to follow up any adverse events which are ongoing at the end-of-treatment visit.
Patients will be followed up for disease progression, overall survival or subsequent anticancer
treatments at 8 weekly intervals until progression (if treatment stopped for reasons other than progression) and at 12 weekly intervals post progression.

Participant medication compliance will be determined at each clinic visit by return pill count.
Intervention code [1] 319479 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 326206 0
The primary end point is the objective tumour response (OTR)
Timepoint [1] 326206 0
Imaging (e.g. CT, MRI, Bone scan or PET-CT scans) for disease evaluation will take place every 8 weeks for 12 months, then 12 weekly until disease progression.
Primary outcome [2] 326791 0
The primary end point is the ratio to time to progression. Disease progression is defined according to RECIST v1.1, RANO guidelines.
Timepoint [2] 326791 0
Patients will be followed up for disease progression, overall survival or subsequent anticancer treatments at 8 weekly intervals until progression (if treatment stopped for reasons other than progression) and at 12 weekly intervals post progression.
Secondary outcome [1] 390513 0
Overall survival (OS) (death from any cause)
Timepoint [1] 390513 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] 390514 0
Progression free survival. 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] 390514 0
CT, MRI, Bone scan or PET-CT scans for disease evaluation will take place every 8 weeks for 12 months, then 12 weekly until disease progression.
Secondary outcome [3] 390579 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 [3] 390579 0
Adverse events will be recorded from the first dose of study treatment until 30 days after cessation of study treatment.
Secondary outcome [4] 390615 0
Health related quality of life during treatment will be assessed using a composite of the EORTC QLQ-C30 and The Brief Pain Inventory Forms.
Timepoint [4] 390615 0
While on treatment, health related quality of life will be assessed before commencing the next cycle of treatment. After treatment, this will be 8-weekly for 12 months, then 12-weekly until progression.
Secondary outcome [5] 390682 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. The entered data in the trial database will be used to evaluate this outcome. Participants who are still on study treatment at time of analysis will be censored on the date of their last reported study treatment.
Timepoint [5] 390682 0
Time to treatment failure analysis is performed at 12 months from last patient registration.
Secondary outcome [6] 390683 0
Depth response according to RECIST 1.1.
Timepoint [6] 390683 0
Imaging (eg. CT) scans for disease evaluation will take place every 8 weeks for 12 months, then 12 weekly until disease progression.
Secondary outcome [7] 390684 0
Progression free survival 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 [7] 390684 0
At 6 months post participant registration via CT, MRI or PET (with CT function) scans of disease evaluation.
Secondary outcome [8] 392693 0
Duration of response according to RECIST 1.1
Timepoint [8] 392693 0
Imaging (eg. CT) scans for disease evaluation will take place every 8 weeks for 12 months, then 12 weekly until disease progression.

Eligibility
Key inclusion criteria
1. Adults, aged 18 years and older with either pathologically confirmed:
a. newly diagnosed metastatic, non-squamous NSCLC identified through the ASPiRATION molecular screening program OR
b. advanced and/or metastatic solid cancer of any histologic type, refractory or unsuitable for standard therapies for that cancer type, identified through the MoST molecular screening program.
2. Harbouring an NTRK fusion or ROS1 activating gene alteration identified using CGP
3. NSCLC patients identified through the ASPiRATION molecular screening program must be FISH-negative, i.e. ineligible for PBS-reimbursed ROS1-targeted treatment
4. Confirmation of molecular eligibility by the molecular tumour board (MTB)
5. Measurable disease as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and/or RANO.
6. ECOG 0-2
7. If the CNS is involved (either primary or metastatic disease), this must be asymptomatic or previously treated and controlled either with local treatment or by steroids
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 90g/L;
b. liver function; ALT/AST less than or equal to 2.5 x ULN (in the absence of liver metastases, ALT/AST less than or equal to 5 x ULN for patients with liver metastases) and total bilirubin =1.5xULN;
c. renal function; serum creatinine less than or equal to 1.5xULN;
9. Prior anticancer therapy (excluding TRK or ROS1 inhibitors)
a. For newly diagnosed metastatic, non-squamous NSCLC:
i. Up to 2 cycles of systemic therapy while awaiting the results of CGP testing are permitted (but not required);
b. For advanced and/or metastatic treatment-refractory solid cancer of any histologic type:
i. Participants must have received and failed all standard anticancer therapy or have documented unsuitability for any further standard therapy, if standard therapy exists.
ii. Clinical or radiological progression on or following last anticancer therapy unless such anticancer therapy stopped due to toxicity / treatment intolerance
10. Life expectancy greater than or equal to 12 weeks
11. Willing and able to comply with all study requirements, including treatment (including ability to swallow whole capsules intact, without chewing, crushing, or opening the capsules/tablets), timing and/or nature of required assessments
12. Signed, written informed consent to participation in this 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 NTRK and/or ROS1 pathway inhibitor treatment (either approved or investigational)
2. Known history of hypersensitivity or contraindication to entrectinib
3. History of prolonged QTc interval (e.g. repeated demonstration of a QTc interval greater than 450 milliseconds from ECGs performed at least 24 hours apart) or use of medications that are known to prolong the QT interval.
4. History of additional risk factors for torsade de pointes (e.g. family history of long QT syndrome)
5. History of recent (within 3 months prior to screening) symptomatic congestive heart failure or clinically significant cardiac dysfunction, as determined by left ventricular ejection fraction (LVEF) less than 50%
6. Peripheral sensory neuropathy grade greater than or equal to 2
7. Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase inhibitor-induced pneumonitis
8. Radiation therapy, major surgery, or tumour embolization within 14 days prior to the first dose of entrectinib. Palliative radiotherapy (for analgesia) is acceptable only if the irradiated field does not include target lesions;
9. Any systemic therapy within 28 days prior to the first dose of entrectinib
10. Administration of any investigational treatment within 28 days prior to receiving the first dose of entrectinib
11. Specific comorbidities or conditions (e.g. psychiatric) or concomitant medications which may interact with entrectinib, including
a. Known active infections that would interfere with the assessment of safety or efficacy of entrectinib (bacterial, fungal, or viral, including HIV positive)
b. Active gastrointestinal disease (e.g. Crohn’s disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would reasonably affect drug absorption
12. 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;
13. Any unresolved toxicity (CTCAE v5.0 greater than grade 2) from previous anti-cancer therapy.
14. Prior or concurrent 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
15. Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal, infertile, or agree to use a highly effective form of contraception. Women of childbearing potential must have a negative pregnancy test done within 7 days prior to registration. Men with partners of childbearing potential must have been surgically sterilised or agree to use a highly effective form 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)
Statistical methods / analysis
A group of 16 patients will be recruited. 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] 18425 0
The Canberra Hospital - Garran
Recruitment hospital [2] 18426 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [3] 18427 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [4] 18428 0
Linear Clinical Research - Nedlands
Recruitment hospital [5] 18429 0
Royal Darwin Hospital - Tiwi
Recruitment hospital [6] 18432 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [7] 18433 0
Westmead Hospital - Westmead
Recruitment hospital [8] 18434 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [9] 18435 0
The Prince Charles Hospital - Chermside
Recruitment hospital [10] 18436 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [11] 18437 0
Royal Hobart Hospital - Hobart
Recruitment postcode(s) [1] 32536 0
0810 - Tiwi
Recruitment postcode(s) [2] 32539 0
2065 - St Leonards
Recruitment postcode(s) [3] 32540 0
2145 - Westmead
Recruitment postcode(s) [4] 32532 0
2605 - Garran
Recruitment postcode(s) [5] 32533 0
3000 - Melbourne
Recruitment postcode(s) [6] 32541 0
3065 - Fitzroy
Recruitment postcode(s) [7] 32542 0
4032 - Chermside
Recruitment postcode(s) [8] 32543 0
4102 - Woolloongabba
Recruitment postcode(s) [9] 32534 0
5000 - Adelaide
Recruitment postcode(s) [10] 32535 0
6009 - Nedlands
Recruitment postcode(s) [11] 32544 0
7000 - Hobart

Funding & Sponsors
Funding source category [1] 307579 0
Government body
Name [1] 307579 0
Office for Health and Medical Research
Address [1] 307579 0
Locked Bag 961 North Sydney NSW 2059
Country [1] 307579 0
Australia
Funding source category [2] 307585 0
Other Collaborative groups
Name [2] 307585 0
Australian Genomic Cancer Medicine Centre (AGCMC)
Address [2] 307585 0
Kinghorn Cancer Centre,
370 Victoria Street,
Darlinghurst NSW 2010
Country [2] 307585 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] 308266 0
Other Collaborative groups
Name [1] 308266 0
Australian Genomic Cancer Medicine Centre (AGCMC)
Address [1] 308266 0
Kinghorn Cancer Centre,
370 Victoria Street,
Darlinghurst NSW 2010
Country [1] 308266 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307638 0
St Vincent's Hospital Ethics Committee
Ethics committee address [1] 307638 0
Translational Research Centre,
97-105 Boundary Street,
Darlinghurst NSW 2010
Ethics committee country [1] 307638 0
Australia
Date submitted for ethics approval [1] 307638 0
26/06/2020
Approval date [1] 307638 0
26/08/2020
Ethics approval number [1] 307638 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 Entrectinib advanced cancers harbouring NTRK or ROS1 gene alterations identified using comprehensive genomic profiling.

Who is it for?
You may be eligible to join the study if you are aged 18 years and older, with pathologically confirmed advanced and/or metastatic solid cancer of any cell type or an earlier diagnosis of a poor prognosis cancer and have received all standard anticancer therapy, or if you have newly diagnosed metastatic non-small cell lung cancer. Your tumour will need to have an NTRK fusion or ROS1 gene alterations.


Study details
Participants will continue to receive Entrectinib orally at a dose of 600 mg every 28 days continuously as long as they and their doctor agree there is a benefit from treatment. Participants will undergo imaging assessments at 8 weekly intervals for 12 months and then 12 weekly, or as clinically indicated in order to evaluate tumour response. Safety and tolerability of treatment and health related quality of life during treatment will be assessed at 4 weekly intervals.

We cannot guarantee that patients 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 entrectinib 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 107958 0
Dr Subotheni Thavaneswaran
Address 107958 0
Garvan Institute of Medical Research
The Kinghorn Cancer Centre
370 Victoria St Darlinghurst NSW 2010
Country 107958 0
Australia
Phone 107958 0
+61 2 9355 5655
Fax 107958 0
+61 2 9355 5602
Email 107958 0
s.thavaneswaran@garvan.org.au
Contact person for public queries
Name 107959 0
Dr Lucille Sebastian
Address 107959 0
NHMRC Clinical Trials Centre,
Medical Foundation Building
Levels 4-6,
92-94 Parramatta Road,
Camperdown NSW 2050
Country 107959 0
Australia
Phone 107959 0
+61 2 9562 5000
Fax 107959 0
Email 107959 0
most@ctc.usyd.edu.au
Contact person for scientific queries
Name 107960 0
Dr Subotheni Thavaneswaran
Address 107960 0
Garvan Institute of Medical Research
The Kinghorn Cancer Centre
370 Victoria St Darlinghurst NSW 2010
Country 107960 0
Australia
Phone 107960 0
+61 2 9355 5655
Fax 107960 0
+61 2 9355 5602
Email 107960 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 other documents available
Summary results
No Results