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Trial registered on ANZCTR


Registration number
ACTRN12620000861954
Ethics application status
Approved
Date submitted
11/06/2020
Date registered
28/08/2020
Date last updated
21/01/2024
Date data sharing statement initially provided
28/08/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Cancer Molecular Screening and Therapeutics (MoST) Program and ASPiRATION subprogram, Addendum 12 – substudies 27-30: Vemurafenib and Cobimetinib
Scientific title
Single arm, open label, phase II trial of vemurafenib and cobimetinib in patients with metastatic non-squamous non-small cell lung cancer and other tumours harbouring BRAF V600 mutations detected by comprehensive genomic profiling
Secondary ID [1] 301499 0
CTC 0141 / ALTG 20/002 – addendum 12
Universal Trial Number (UTN)
U1111-1182-6652
Trial acronym
MoST Addendum 12
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 317832 0
non-small cell lung cancer 318095 0
Condition category
Condition code
Cancer 315888 315888 0 0
Lung - Non small cell
Cancer 315889 315889 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will receive 2 drugs, vemurafenib and cobimetinib. Both drugs, in the format of tablet, are to be taken orally by participants, at a dose of 960mg twice daily (days 1 to 28 in a 28-day cycle) for vemurafenib and at 60mg daily (days 1 to 21 in a 28-day cycle) for cobimetinib.

If participants experience intolerance toxicity, vemurafenib dosage may be reduced to 720mg twice daily, and then to 480mg twice daily if participants experience further intolerance toxicity. For cobimetinib, the dosage may be reduced to 40mg daily for first event of intolerance toxicity and then to 20mg daily if participants experience further intolerance toxicity.

Participants will receive both vemurafenib and cobimetinib 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] 317805 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 324094 0
The primary end point for metastatic NSCLC is disease control and it is defined as the objective tumour response, based on complete or partial response using cancer specific response criteria. Where disease evaluation is not based on imaging scans (eg. CT), clinical assessment of response may be utilised. Response is assigned based on investigator discretion.
Timepoint [1] 324094 0
Imaging (eg. CT) scans for disease evaluation will take place every 8 weeks from first dose of study treatment until disease progression or commencement of non-protocol anti-cancer therapy, whichever occurs first.
Primary outcome [2] 324098 0
The primary end point for other cancers is disease control defined as: 1. Objective tumour response, based on complete and partial responses using cancer specific response criteria. 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 [2] 324098 0
Imaging (eg. CT) scans for disease evaluation will take place every 8 weeks from first dose of study treatment until disease progression or commencement of non-protocol anti-cancer therapy, whichever occurs first.
Secondary outcome [1] 383742 0
Overall survival (OS) (death from any cause)
Timepoint [1] 383742 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] 383743 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] 383743 0
Imaging (eg. CT) scans for disease evaluation will take place every 8 weeks from first dose of study treatment until disease progression or commencement of non-protocol anti-cancer therapy, whichever occurs first.
Secondary outcome [3] 383744 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 [3] 383744 0
Time to treatment failure analysis is performed at 12 months from last patient registration.
Secondary outcome [4] 383745 0
Depth and duration of response according to RECIST 1.1
Timepoint [4] 383745 0
Imaging (eg. CT) scans for disease evaluation will take place every 8 weeks until disease progression or commencement of non-protocol anti-cancer therapy, whichever occurs first.
Secondary outcome [5] 383746 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 [5] 383746 0
At 6 months post participant registration via CT, MRI or PET (with CT function) scans of disease evaluation
Secondary outcome [6] 383747 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 [6] 383747 0
Adverse events will be recorded from the first dose of study treatment until 30 days after cessation of study treatment.
Secondary outcome [7] 383748 0
Health related quality of life during treatment will be assessed using the EORTC QLQ-C30 and The Brief Pain Inventory Forms
Timepoint [7] 383748 0
Every 4 weeks from first dose of study treatment until end of treatment. Subsequently, at every 8 weeks until disease progression
Secondary outcome [8] 428477 0
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 (pan-cancer/solid tumour cohort only).
Timepoint [8] 428477 0
Imaging (eg. CT) scans for disease evaluation will take place every 8 weeks from first dose of study treatment until disease progression or commencement of non-protocol anti-cancer therapy, whichever occurs first.

Eligibility
Key inclusion criteria
1. Adults, aged 18 years and older, with either:
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 or another molecular screening program of equivalent standard (e.g. the Cancer Screening Protocol (CaSP) program);
2. A BRAF V600 mutation identified using CGP. Patients who have a positive BRAF V600E determined by immunohistochemistry must be confirmed by next generation sequencing (NGS);
3. Measurable disease as assessed by RECIST 1.1 and/or RANO (Exception: newly diagnosed metastatic, non-squamous NSCLC participants with evaluable but non-measurable disease may be approved on a case-by-case basis by contacting the study chair or delegate through the NHMRC CTC);
4. Confirmation of molecular eligibility by the molecular tumour board;
5. ECOG 0 to 2;
6. In patients with CNS metastases, the intracranial disease must be asymptomatic or previously treated and controlled either with local treatment and/or stable on corticosteroids;
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 greater than or equal to 100 x 109/L, ANC greater than or equal to 1.5 x 109/L, and haemoglobin greater than or equal to 90g/L (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;
8. Prior anticancer therapy:
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,
iii. Patients with cutaneous melanoma are ineligible;
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. Known history of hypersensitivity or contraindication to vemurafenib or cobimetinib;
2. History of prior BRAF and/or mitogen-activated protein kinase pathway inhibitor treatment;
3. Specific comorbidities or conditions (e.g. psychiatric) or concomitant medications which may interact with the investigational product(s);
a. History of clinically significant cardiac dysfunction, as determined by left ventricular ejection fraction (LVEF) < 40%;
b. QTc > 500 ms on baseline electrocardiogram;
c. Uncorrectable electrolyte abnormalities
d. History of retinal pathology on ophthalmological examination that is considered a risk factor for retinal detachment, retinal vein occlusion, or vascular-related macular degeneration;
e. History of uncontrolled glaucoma with intraocular pressure;
f. Uncontrolled systemic infections;
4. 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;
5. Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment:
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 study treatment;
6. Administration of any investigational treatment within 28 days prior to receiving the first dose of study treatment;
7. 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);
8. 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;
d. For participants with treatment-refractory solid tumours, a concurrent or past history of competing malignancy within 2 years, prior to molecular screening registration, is eligible, unless the competing malignancy is expected to lead to a shorter survival than the index BRAFV600-harbouring malignancy. The patient is ineligible if the concurrent malignancy harbours an activating RAS (i.e. KRAS, HRAS, or NRAS) mutation;
9. 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 (See Section 15.1 Acceptable Methods 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 64 patients harbouring a BRAF V600 mutation will be recruited for 4 substudies containing 16 participants each. Two substudies (32 participants) are for patients with pathologically confirmed metastatic non-squamous NSCLC and the other 2 substudies (32 participants) are for patients with solid tumour of any histologic type.

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
16/11/2020
Actual
12/07/2021
Date of last participant enrolment
Anticipated
Actual
19/12/2023
Date of last data collection
Anticipated
19/12/2025
Actual
Sample size
Target
64
Accrual to date
Final
64
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 21526 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment hospital [2] 21527 0
Royal Darwin Hospital - Tiwi
Recruitment hospital [3] 21528 0
Royal Hobart Hospital - Hobart
Recruitment hospital [4] 21529 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [5] 21530 0
Linear Clinical Research - Nedlands
Recruitment hospital [6] 21531 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [7] 21532 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [8] 21534 0
Westmead Hospital - Westmead
Recruitment hospital [9] 21535 0
The Prince Charles Hospital - Chermside
Recruitment hospital [10] 21536 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [11] 21537 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [12] 21538 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [13] 25801 0
Border Medical Oncology - Albury
Recruitment postcode(s) [1] 36433 0
2050 - Camperdown
Recruitment postcode(s) [2] 36434 0
0810 - Tiwi
Recruitment postcode(s) [3] 36435 0
7000 - Hobart
Recruitment postcode(s) [4] 36436 0
4102 - Woolloongabba
Recruitment postcode(s) [5] 36437 0
6009 - Nedlands
Recruitment postcode(s) [6] 36438 0
5000 - Adelaide
Recruitment postcode(s) [7] 36439 0
3000 - Melbourne
Recruitment postcode(s) [8] 36441 0
2145 - Westmead
Recruitment postcode(s) [9] 36442 0
4032 - Chermside
Recruitment postcode(s) [10] 36443 0
3065 - Fitzroy
Recruitment postcode(s) [11] 36444 0
3084 - Heidelberg
Recruitment postcode(s) [12] 36445 0
5042 - Bedford Park
Recruitment postcode(s) [13] 41626 0
2640 - Albury

Funding & Sponsors
Funding source category [1] 305937 0
Government body
Name [1] 305937 0
Office for Health and Medical Research
Country [1] 305937 0
Australia
Funding source category [2] 305939 0
Other Collaborative groups
Name [2] 305939 0
Australian Genomic Cancer Medicine Centre (AGCMC)
Country [2] 305939 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] 306394 0
None
Name [1] 306394 0
Address [1] 306394 0
Country [1] 306394 0
Other collaborator category [1] 281363 0
Other Collaborative groups
Name [1] 281363 0
Australian Genomic Cancer Medicine Centre (AGCMC)
Address [1] 281363 0
Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst NSW 2010
Country [1] 281363 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306183 0
St Vincent's Hospital Ethics Committee
Ethics committee address [1] 306183 0
Ethics committee country [1] 306183 0
Australia
Date submitted for ethics approval [1] 306183 0
29/05/2020
Approval date [1] 306183 0
17/08/2020
Ethics approval number [1] 306183 0

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

Contacts
Principal investigator
Name 103002 0
Dr Antony Mersiades
Address 103002 0
NHMRC Clinical Trials Centre
Medical Foundation Building
Levels 4-6, 92-94 Parramatta Rd,
Camperdown NSW 2050
Country 103002 0
Australia
Phone 103002 0
+61 2 9382 5000
Fax 103002 0
Email 103002 0
[email protected]
Contact person for public queries
Name 103003 0
Lucille Sebastian
Address 103003 0
NHMRC Clinical Trials Centre,
Medical Foundation Building,
Levels 4-6,
92-94 Parramatta Road,
Camperdown NSW 2050
Country 103003 0
Australia
Phone 103003 0
+61 2 9562 5000
Fax 103003 0
Email 103003 0
[email protected]
Contact person for scientific queries
Name 103004 0
Antony Mersiades
Address 103004 0
NHMRC Clinical Trials Centre
Medical Foundation Building
Levels 4-6, 92-94 Parramatta Rd,
Camperdown NSW 2050
Country 103004 0
Australia
Phone 103004 0
+61 2 9382 5000
Fax 103004 0
Email 103004 0
[email protected]

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.