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Trial registered on ANZCTR


Registration number
ACTRN12619001265167
Ethics application status
Approved
Date submitted
16/08/2019
Date registered
12/09/2019
Date last updated
27/05/2024
Date data sharing statement initially provided
12/09/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Cancer Molecular Screening and Therapeutics (MoST) Program Substudy Addendum 8 substudy 19: T-DM1
Scientific title
Single arm, open label, signal seeking, phase IIa trial of the activity of Trastuzumab emtansine (T-DM1) in patients with tumours harbouring HER2 amplifications or mutations
Secondary ID [1] 298894 0
CTC0141-addendum 8
Universal Trial Number (UTN)
U1111-1182-6652
Trial acronym
MoST Addendum 8
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 313869 0
Condition category
Condition code
Cancer 312281 312281 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Trastuzumab emtansine will be administered intravenously at a dose of 3.6 mg/kg every 21 days continuously until disease progression is documented, the patient experiences an intolerable toxicity, or withdraws for another reason.
Intervention code [1] 315171 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 320919 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 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 patient 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] 320919 0
CT or MRI scans for disease evaluation will take place every 9 weeks until disease progression
Secondary outcome [1] 373327 0
Overall survival (OS) (death from any cause).
Timepoint [1] 373327 0
For the duration of the study.
Secondary outcome [2] 373328 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. AEs reported by participants will be documented by study site staff and subsequently transcribed 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] 373328 0
Adverse events will be recorded from the first dose of study treatment until 30 days after cessation of study treatment.
Secondary outcome [3] 373329 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 [3] 373329 0
Every 3 weeks during treatment and every 9 weeks during follow-up until disease progression

Eligibility
Key inclusion criteria
1. Adults, aged 18 years and older, with either pathologically confirmed:
a. advanced and/or metastatic solid cancer of any histologic type, refractory or unsuitable for standard therapies for that cancer type; or
b. metastatic, non-squamous NSCLC
2. Patients with tumours harbouring HER2 mutations or amplification (in the absence of a mutation) (Groups 1 and 2) or HER2 mutation with/without amplification (Groups 3 and 4) identified using comprehensive genomic profiling (CGP) and determined by the molecular tumour board.
3. Confirmation of molecular eligibility by the molecular tumour board
4. Measurable disease as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and/or RANO. (Exception: ASPiRATION participants with evaluable but non-measurable disease may be approved on a case-by-case basis by contacting the ASPiRATION study chair or delegate through the NHMRC CTC).
5. ECOG 0-2
6. 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
7. 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 equal or more than 100 x 10^9/L, ANC equal or more than 1.5 x 10^9/L, and haemoglobin equal or more than 9g/dL (5.6mmol/L);
b. liver function; ALT/AST equal or less than 2.5 x ULN and total bilirubin equal or less than 1.5xULN;
c. renal function: creatinine clearance greater than 50 mL/min based on Cockcroft-Gault glomerular filtration rate (GFR) estimation: (140 - Age) × (weight in kg) × (0.85 if female)/(72 × serum creatinine);
8. Prior anticancer therapy (excluding HER2 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 second or subsequent line metastatic, non-squamous NSCLC:
i. Clinical or radiological progression on, or following last anticancer therapy unless such anticancer therapy stopped due to toxicity / treatment intolerance
c. 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
9. ALP equal or less than 2.5 ×ULN with the following exception: patients with bone metastases: ALP equal of less than 5 ×ULN
10. INR and aPTT less then 1.5 x ULN (unless on therapeutic coagulation)
11. Albumin equal or more than 25mg/dL
12. Life expectancy greater than or equal to 12 weeks
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Known history of hypersensitivity or contraindication to T-DM1;
2. Prior treatment with T-DM1, or other HER2-directed therapy;
3. HER2-amplified breast and gastric cancer (breast and gastric cancer with HER2 mutations are permitted);
4. Peripheral neuropathy of grade 2 or higher (according to National Cancer Institute Common Terminology Criteria for Adverse Events [CTCAE], version 5);
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. Currently diagnosed with interstitial lung disease, interstitial fibrosis or history of tyrosine kinase inhibitor-induced pneumonitis
7. Specific comorbidities or conditions (e.g. psychiatric) or concomitant medications which may interact with the investigational product(s);
8. 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;
9. Radiation therapy, major surgery or tumour embolization within 14 days prior to the first dose of T-DM1;
10. Any systemic therapy within 28 days prior to the first dose of T-DM1. Any systemic therapy within 21 days prior to the first dose of T-DM1 for ASPiRATION cohort participants who received systemic therapy while awaiting the results of CGP testing.;
11. Any unresolved toxicity ( greater than CTCAE v5.0 grade 2) from previous anti-cancer therapy;
12. 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
13. Pregnancy, lactation, or inadequate 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 64 patients will be recruited for 4 substudies containing 16 subjects each.

Subjects in group 1 will have tumours with activating HER2 mutations in treatment-refractory solid cancers (recruitment complete).
Subjects in group 2 will have tumours with HER2 amplifications in the absence of a HER2 mutation in treatment-refractory solid cancers (recruitment complete).
Subjects in group 3 and 4 will have HER2 activating mutation with/without amplification in metastatic non-squamous NSCLC.

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
1/03/2020
Actual
25/06/2020
Date of last participant enrolment
Anticipated
31/12/2024
Actual
Date of last data collection
Anticipated
30/06/2025
Actual
Sample size
Target
64
Accrual to date
53
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 14366 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [2] 14367 0
St George Hospital - Kogarah
Recruitment hospital [3] 14368 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment hospital [4] 14369 0
The Canberra Hospital - Garran
Recruitment hospital [5] 14370 0
Linear Clinical Research - Nedlands
Recruitment hospital [6] 14371 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [7] 14372 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [8] 14373 0
Royal Hobart Hospital - Hobart
Recruitment hospital [9] 14374 0
Royal Darwin Hospital - Tiwi
Recruitment hospital [10] 14375 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [11] 22422 0
Westmead Hospital - Westmead
Recruitment hospital [12] 22423 0
The Prince Charles Hospital - Chermside
Recruitment hospital [13] 22424 0
The Alfred - Melbourne
Recruitment hospital [14] 22425 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [15] 24941 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [16] 24942 0
Flinders Medical Centre - Bedford Park
Recruitment postcode(s) [1] 27368 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 27369 0
2217 - Kogarah
Recruitment postcode(s) [3] 27370 0
2050 - Camperdown
Recruitment postcode(s) [4] 27371 0
2605 - Garran
Recruitment postcode(s) [5] 27372 0
6009 - Nedlands
Recruitment postcode(s) [6] 27373 0
3000 - Melbourne
Recruitment postcode(s) [7] 27374 0
5000 - Adelaide
Recruitment postcode(s) [8] 27375 0
7000 - Hobart
Recruitment postcode(s) [9] 27376 0
0810 - Tiwi
Recruitment postcode(s) [10] 27377 0
4102 - Woolloongabba
Recruitment postcode(s) [11] 37586 0
2145 - Westmead
Recruitment postcode(s) [12] 37587 0
4032 - Chermside
Recruitment postcode(s) [13] 37588 0
3004 - Melbourne
Recruitment postcode(s) [14] 37589 0
3084 - Heidelberg
Recruitment postcode(s) [15] 40592 0
3065 - Fitzroy
Recruitment postcode(s) [16] 40593 0
5042 - Bedford Park

Funding & Sponsors
Funding source category [1] 303437 0
Government body
Name [1] 303437 0
Office for Health and Medical Research
Country [1] 303437 0
Australia
Funding source category [2] 303440 0
Other Collaborative groups
Name [2] 303440 0
Australian Genomic Cancer Medicine Centre (AGCMC)
Country [2] 303440 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] 303581 0
None
Name [1] 303581 0
Address [1] 303581 0
Country [1] 303581 0
Other collaborator category [1] 280903 0
Other Collaborative groups
Name [1] 280903 0
Australian Genomic Cancer Medicine Centre (AGCMC)
Address [1] 280903 0
Kinghorn Cancer Centre,
370 Victoria Street,
Darlinghurst NSW 2010
Country [1] 280903 0
Australia
Other collaborator category [2] 282702 0
Other Collaborative groups
Name [2] 282702 0
Thoracic Oncology Group of Australasia (TOGA)
Address [2] 282702 0
PO Box 1103
Thornbury
VIC 3071
Country [2] 282702 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303971 0
St Vincent's Hospital Ethics Committee
Ethics committee address [1] 303971 0
Ethics committee country [1] 303971 0
Australia
Date submitted for ethics approval [1] 303971 0
26/07/2019
Approval date [1] 303971 0
19/09/2019
Ethics approval number [1] 303971 0

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

Contacts
Principal investigator
Name 95410 0
Dr Subotheni Thavaneswaran
Address 95410 0
Garvan Institute of Medical Research
The Kinghorn Cancer Centre
370 Victoria St Darlinghurst NSW 2010
Country 95410 0
Australia
Phone 95410 0
+61 2 9355 5655
Fax 95410 0
+61 2 9355 5602
Email 95410 0
s.thavaneswaran@garvan.org.au
Contact person for public queries
Name 95411 0
Sarah Chinchen
Address 95411 0
NHMRC Clinical Trials Centre,
Medical Foundation Building
Levels 4-6,
92-94 Parramatta Road,
Camperdown NSW 2050
Country 95411 0
Australia
Phone 95411 0
+61 2 9562 5000
Fax 95411 0
Email 95411 0
most.study@sydney.edu.au
Contact person for scientific queries
Name 95412 0
Subotheni Thavaneswaran
Address 95412 0
Garvan Institute of Medical Research
The Kinghorn Cancer Centre
370 Victoria St Darlinghurst NSW 2010
Country 95412 0
Australia
Phone 95412 0
+61 2 9355 5655
Fax 95412 0
+61 2 9355 5602
Email 95412 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.