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Trial registered on ANZCTR


Registration number
ACTRN12620000767909
Ethics application status
Approved
Date submitted
11/06/2020
Date registered
27/07/2020
Date last updated
25/01/2023
Date data sharing statement initially provided
27/07/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Cancer Molecular Screening and Therapeutics (MoST) Program Substudy Addendum 9 substudy 21-22: Tucatinib andTrastuzumab
Scientific title
Single arm, open label, signal seeking, phase II trial of the activity of tucatinib plus trastuzumab in patients with tumours harbouring HER2 amplifications or mutations
Secondary ID [1] 301486 0
CTC0141- addendum 9
Universal Trial Number (UTN)
U1111-1182-6652
Trial acronym
MoST Addendum 9
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 317814 0
Condition category
Condition code
Cancer 315873 315873 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will receive 2 drugs:
1/ Trastuzumab, that will given to participants via subcutaneous injection by a qualified administrator at 600mg every 3 weeks.
2/ Tucatinib in the format of tablet, will be taken orally by participants at a dose of 300mg twice daily.

The trastuzumab may be withheld, whereas tucatinib dosage may be reduced to 250mg twice daily if participants experience intolerance toxicity. If participants experience further intolerance toxicity, tucatinib dosage may be reduced to 200mg twice daily, and then 150mg twice daily if the tucatinib dosage of 200mg twice daily also leads to intolerance toxicity.
Participants will receive both trastuzumab and tucatinib treatments until disease progression is documented or when the participants experience 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] 317795 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 324086 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 imaging scans (eg. CT and MRI), biomarker-based or qualitative clinical assessment of response may be included, such as European Leukemia Net (ELN) guidelines for acute myeloid leukemia (AML), Gynecologic Cancer Intergroup (GCIG) and Prostate Cancer Working Group 3 (PCWG3) criteria will be employed. 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] 324086 0
CT, MRI or PET (with CT function) scans for disease evaluation will take place every 9 weeks from the first dose of study treatment until disease progression. For participants with brain metastases, disease evaluation using MRI scans will take place every 6 weeks for 18 weeks from treatment initiation and then participants will be followed by MRI every 9 weeks until disease progression.
Secondary outcome [1] 383718 0
Overall survival (OS) (death from any cause)
Timepoint [1] 383718 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] 383720 0
Overall survival at 12 months
Timepoint [2] 383720 0
At 12 months from participant registration to date of death from any cause (or the date of last known vital status during follow up within 12 months from registration).
Secondary outcome [3] 383722 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 [3] 383722 0
CT, MRI or PET (with CT function) scans for disease evaluation will take place every 9 weeks from the first dose of study treatment until disease progression. For participants with brain metastases, disease evaluation using MRI scans will take place every 6 weeks for 18 weeks from treatment initiation and then participants will be followed by MRI every 9 weeks until disease progression.
Secondary outcome [4] 383724 0
Progression free survival (PFS) at 6 months. 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 [4] 383724 0
At 6 months post participant registration via CT, MRI or PET (with CT function) scans of disease evaluation.
Secondary outcome [5] 383725 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 [5] 383725 0
Adverse events will be recorded from the first dose of study treatment until 30 days after cessation of study treatment.
Secondary outcome [6] 383726 0
Health related quality of life during treatment. The EORTC QLQ-C30 and The Brief Pain Inventory Forms will be used to evaluate for this outcome.
Timepoint [6] 383726 0
Every 3 weeks from first dose of study treatment until participants stop treatment due to intolerable toxicity or withdraws for another reason apart from disease progression. After treatment discontinuation, the health related quality of life will be assessed at every 9 weeks until disease progression is recorded.

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. Tumours harbouring somatic HER2 amplification (in the absence of a HER2 mutation) or mutations (with or without concomitant amplification)
3. At least one measurable site of disease according to RECIST Version 1.1 or by RANO criteria if primary brain tumours.
4. Left ventricular ejection fraction >/= 50%.
5. Confirmation of molecular eligibility by the molecular tumour board.
6. ECOG 0 - 2.
7. Received and failed all standard anticancer therapy or have documented unsuitability for any further standard therapy, if standard therapy exists.
8. Clinical or radiological progression on or following last anticancer therapy unless such anticancer therapy stopped due to toxicity / treatment intolerance
9. 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 >/= 100 x 109/L, ANC >/= 1.5 x 109/L, and haemoglobin >/= 9g/dL (5.6mmol/L);
b. liver function; ALT/AST < /= 3 x ULN (in the absence of liver metastases, < /= 5 x ULN for patients with liver involvement) and total bilirubin < /= 1.5xULN
c. renal function; serum creatinine < /= 1.5xULN
10. For non central nervous system (CNS) cancers if brain metastases are present, patients must have either:
a. untreated brain metastases < /= 2.0 cm in size not needing immediate local therapy (at the discretion of the treating physician and adjudicated by the Principal Investigator).
b. previously treated brain metastases not needing immediate local therapy (at the discretion of the treating physician).
c. newly diagnosed brain metastases which require treatment with whole brain radiotherapy given >/= 21 days, stereotactic radiosurgery given >/= 7 days or surgery performed >/= 28 days prior to the first dose of treatment.
11. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments.
12. 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. Contraindications to investigational products.
2. Known history of hypersensitivity to active or inactive components of investigational products.
3. Previous treatment with the same agent or same class of agent e.g. other HER2-directed therapy.
4. Specific comorbidities or conditions (e.g. psychiatric) or concomitant medications which may interact with the investigational product(s)
5. 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.
6. Primary tumour histology is HER2 amplified breast adenocarcinoma or gastric adenocarcinoma.
7. Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment:
a. Radiation therapy, surgery, or tumour embolisation 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. Note additional requirements or exceptions in inclusion criteria 10c
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).
8. Administration of any investigational treatment within 30 days or 5 half-lives (whichever is longer) prior to receiving the first dose of study treatment.
9. Use of a strong CYP2C8 inhibitor within 5 half-lives of the inhibitor or use of a strong CYP3A4 or CYP2C8 inducer within 5 days prior to the first dose of study treatment. Use of sensitive CYP3A substrates should be avoided two weeks before enrolment and during study treatment
10. Ongoing treatment with corticosteroids at a total daily dose of > 2mg dexamethasone daily (or equivalent). Exceptions include use of dexamethasone up to 4mg /day within 14 days of initial treatment for patients with primary brain tumours.
11. Clinically significant cardiopulmonary disease.
12. Any untreated brain lesions >/=2.0 cm in size or any brain lesions requiring immediate local therapy.
13. Known leptomeningeal disease.
14. Have poorly controlled (> 1/week) generalized or complex partial seizures, or manifest neurologic progression due to brain metastases notwithstanding CNS-directed therapy.
15. Any unresolved toxicity (>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).
16. 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.
17. 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.
18. 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 participants each. Participants in group 1 will have tumours harbouring HER2 amplification and participants in group 2 will have tumours with harbouring HER2 mutations.

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
Recruiting
Date of first participant enrolment
Anticipated
30/09/2021
Actual
28/02/2022
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
32
Accrual to date
21
Final
Recruitment in Australia
Recruitment state(s)
NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 16864 0
The Canberra Hospital - Garran
Recruitment hospital [2] 16865 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [3] 16866 0
Linear Clinical Research - Nedlands
Recruitment hospital [4] 16867 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [5] 16868 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [6] 16869 0
Royal Hobart Hospital - Hobart
Recruitment hospital [7] 16870 0
Royal Darwin Hospital - Tiwi
Recruitment hospital [8] 23877 0
Prince of Wales Hospital - Randwick
Recruitment postcode(s) [1] 30513 0
2605 - Garran
Recruitment postcode(s) [2] 30514 0
3000 - Melbourne
Recruitment postcode(s) [3] 30515 0
6009 - Nedlands
Recruitment postcode(s) [4] 30516 0
5000 - Adelaide
Recruitment postcode(s) [5] 30517 0
4102 - Woolloongabba
Recruitment postcode(s) [6] 30518 0
7000 - Hobart
Recruitment postcode(s) [7] 30519 0
0810 - Tiwi
Recruitment postcode(s) [8] 39342 0
2031 - Randwick

Funding & Sponsors
Funding source category [1] 305927 0
Government body
Name [1] 305927 0
Office for Health and Medical Research
Country [1] 305927 0
Australia
Funding source category [2] 305935 0
Other Collaborative groups
Name [2] 305935 0
Australian Genomic Cancer Medicine Centre (AGCMC)
Country [2] 305935 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country
Australia
Secondary sponsor category [1] 306380 0
None
Name [1] 306380 0
Address [1] 306380 0
Country [1] 306380 0
Other collaborator category [1] 281362 0
Other Collaborative groups
Name [1] 281362 0
Australian Genomic Cancer Medicine Centre (AGCMC)
Address [1] 281362 0
Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst NSW 2010
Country [1] 281362 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306175 0
St Vincent's Hospital Ethics Committee
Ethics committee address [1] 306175 0
Ethics committee country [1] 306175 0
Australia
Date submitted for ethics approval [1] 306175 0
29/05/2020
Approval date [1] 306175 0
01/09/2020
Ethics approval number [1] 306175 0

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

Contacts
Principal investigator
Name 102970 0
Prof David Goldstein
Address 102970 0
320-346 Barker Street, Prince of Wales Hospital, Randwick, NSW 2031.
Country 102970 0
Australia
Phone 102970 0
+61 2 9382 5111
Fax 102970 0
Email 102970 0
david.goldstein@health.nsw.gov.au
Contact person for public queries
Name 102971 0
Lucille Sebastian
Address 102971 0
NHMRC Clinical Trials Centre,
Medical Foundation Building,
Levels 4-6,
92-94 Parramatta Road,
Camperdown NSW 2050
Country 102971 0
Australia
Phone 102971 0
+61 2 9562 5000
Fax 102971 0
Email 102971 0
most.study@sydney.edu.au
Contact person for scientific queries
Name 102972 0
David Goldstein
Address 102972 0
320-346 Barker Street, Prince of Wales Hospital, Randwick, NSW 2031.
Country 102972 0
Australia
Phone 102972 0
+61 2 9382 5111
Fax 102972 0
Email 102972 0
david.goldstein@health.nsw.gov.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.