COVID-19 studies are our top priority.

For new and updated trial submissions, we are processing trials as quickly as possible and appreciate your patience. We recommend submitting your trial for registration at the same time as ethics submission.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12620000861954p
Ethics application status
Submitted, not yet approved
Date submitted
11/06/2020
Date registered
28/08/2020
Date last updated
28/08/2020
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 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 [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
Response duration according to RECIST1.1
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

Eligibility
Key inclusion criteria
Inclusion criteria – ASPIRATION subprogram (newly diagnosed metastatic non-squamous NSCLC):
1. Adults, aged 18 years and older, with newly diagnosed metastatic non-squamous NSCLC;
2. A BRAF V600 mutation identified using CGP;
3. Measurable disease as assessed by RECIST 1.1;
4. Confirmation of molecular eligibility by the molecular tumour board;
5. ECOG 0 to 2;
6. 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 =/> 90g/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;
7. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments;
8. Signed, written informed consent to participation in the specific treatment substudy.

Inclusion criteria – Pan cancer subprogram (solid tumour of any histologic type):
1. Adults, aged 18 years and older, with pathologically confirmed advanced and/or metastatic solid tumour of any histologic type or an earlier diagnosis of a poor prognosis cancer, identified through the MoST molecular screening program;
2. Confirmation of BRAF V600 mutation (V600E/K) in the tumour tissue by the next generation sequencing (NGS) panel. Patients who have a positive BRAF V600E determined by immunohistochemistry must be confirmed by NGS;
3. Confirmation of molecular eligibility by the molecular tumour board;
4. ECOG 0 to 2;
5. Life expectancy greater than or equal to 12 weeks;
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. Measurable disease as assessed by RECIST 1.1;
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 =/> 90 g/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. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments;
11. Signed, written informed consent to participation in the specific treatment substudy.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria - ASPiRATION subprogram (newly diagnosed metastatic non-squamous NSCLC):
1. Contraindications to investigational product;
2. Prior systemic therapy for advanced disease; Up to two cycles of systemic therapy while awaiting the results of CGP testing are permitted;
3. Known history of hypersensitivity to active or inactive components of investigational product;
4. History of prior BRAF and/or mitogen-activated protein kinase pathway inhibitor treatment;
5. 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. History of retinal pathology on ophthalmological examination that is considered a risk factor for retinal detachment, retinal vein occlusion, or vascular-related macular degeneration;
d. History of uncontrolled glaucoma with intraocular pressure;
e. Uncontrolled systemic infections;
6. 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;
7. 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;
8. Administration of any investigational treatment within 28 days prior to receiving the first dose of study treatment;
9. CNS involvement. However, 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;
10. 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;
11. 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.

Exclusion Criteria – Pan cancer subprogram (solid tumour of any histologic type):
1. Contraindications to investigational product;
2. Known history of hypersensitivity to active or inactive components of investigational product;
3. History of prior BRAF and/or mitogen-activated protein kinase pathway inhibitor treatment;
4. Patients with cutaneous melanoma are ineligible;
5. Advanced thyroid cancers must be radioiodine-refractory and have previously progressed on or intolerant of oral angiogenesis inhibitor;
6. 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. History of retinal pathology on ophthalmological examination that is considered a risk factor for retinal detachment, retinal vein occlusion, or vascular-related macular degeneration;
d. History of uncontrolled glaucoma with intraocular pressure;
e. Uncontrolled systemic infections;
7. 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;
8. 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. Immunotherapy within 28 days prior to the first dose of study treatment;
c. Chemotherapy, biologic therapy or hormonal therapy within 28 days of a drug prior to the first dose of study treatment or until recovery from previous therapy (whichever is longer);
d. 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);
9. Administration of any investigational treatment within 30 days or 5 half-lives (whichever is longer) prior to receiving the first dose of study treatment;
10. 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;
11. Prior or concurrent malignancy. 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;
12. 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 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
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)
NSW
Recruitment hospital [1] 16889 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [2] 16890 0
St George Hospital - Kogarah
Recruitment postcode(s) [1] 30539 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 30540 0
2217 - Kogarah

Funding & Sponsors
Funding source category [1] 305937 0
Government body
Name [1] 305937 0
Office for Health and Medical Research
Address [1] 305937 0
Locked Bag 961 North Sydney NSW 2059
Country [1] 305937 0
Australia
Funding source category [2] 305939 0
Other Collaborative groups
Name [2] 305939 0
Australian Genomic Cancer Medicine Centre (AGCMC)
Address [2] 305939 0
Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst NSW 2010
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
Submitted, not yet approved
Ethics committee name [1] 306183 0
St Vincent's Hospital Ethics Committee
Ethics committee address [1] 306183 0
Translational Research Centre, 97-105 Boundary Street, Darlinghurst NSW 2010
Ethics committee country [1] 306183 0
Australia
Date submitted for ethics approval [1] 306183 0
29/05/2020
Approval date [1] 306183 0
Ethics approval number [1] 306183 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 combination of vemurafenib and cobimetinib in a population of participants with newly diagnosed metastatic non-squamous small cell lung cancer (NSCLC) or other tumours harbouring BRAF V600 mutations detected 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 NSCLC or solid tumour of any histologic type or an earlier diagnosis of a poor prognosis cancer. Your tumour will need to express a BRAF V600 mutation.

Study details:
Participants will receive both vemurafenib and cobimetinib treatments. The vemurafenib and cobimetinib are to be taken orally, at 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.
Both vemurafenib and cobimetinib will be given to participants continuously as long as they and their doctor agree there is a benefit from treatment. Participants will undergo imaging assessments at 8 weekly intervals from first treatment until progression. Safety and tolerability of treatment will be assessed at 4 weekly intervals. Health related quality of life during treatment will be assessed at 4 weekly intervals and then every 8 weeks after end of treatment until progression.
We cannot guarantee that participants 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 vemurafenib and cobimetinib 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 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
antony.mersiades@ctc.usyd.edu.au
Contact person for public queries
Name 103003 0
Dr 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
most@ctc.usyd.edu.au
Contact person for scientific queries
Name 103004 0
Dr 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
antony.mersiades@ctc.usyd.edu.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