ANZCTR - Registration

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

Date results information initially provided

21/01/2024

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]

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

non-small cell lung cancer

Condition category

Condition code

Cancer

Lung - Non small cell

Cancer

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]

Treatment: Drugs

Comparator / control treatment

No control group

Control group

Uncontrolled

Outcomes

Primary outcome [1]

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]

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]

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]

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]

Overall survival (OS) (death from any cause)

Timepoint [1]

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]

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]

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]

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]

Time to treatment failure analysis is performed at 12 months from last patient registration.

Secondary outcome [4]

Depth and duration of response according to RECIST 1.1

Timepoint [4]

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]

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]

At 6 months post participant registration via CT, MRI or PET (with CT function) scans of disease evaluation

Secondary outcome [6]

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]

Adverse events will be recorded from the first dose of study treatment until 30 days after cessation of study treatment.

Secondary outcome [7]

Health related quality of life during treatment will be assessed using the EORTC QLQ-C30 and The Brief Pain Inventory Forms

Timepoint [7]

Every 4 weeks from first dose of study treatment until end of treatment. Subsequently, at every 8 weeks until disease progression

Secondary outcome [8]

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]

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

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]

The Chris O’Brien Lifehouse - Camperdown

Recruitment hospital [2]

Royal Darwin Hospital - Tiwi

Recruitment hospital [3]

Royal Hobart Hospital - Hobart

Recruitment hospital [4]

Princess Alexandra Hospital - Woolloongabba

Recruitment hospital [5]

Linear Clinical Research - Nedlands

Recruitment hospital [6]

The Royal Adelaide Hospital - Adelaide

Recruitment hospital [7]

Peter MacCallum Cancer Centre - Melbourne

Recruitment hospital [8]

Westmead Hospital - Westmead

Recruitment hospital [9]

The Prince Charles Hospital - Chermside

Recruitment hospital [10]

St Vincent's Hospital (Melbourne) Ltd - Fitzroy

Recruitment hospital [11]

Austin Health - Austin Hospital - Heidelberg

Recruitment hospital [12]

Flinders Medical Centre - Bedford Park

Recruitment hospital [13]

Border Medical Oncology - Albury

Recruitment postcode(s) [1]

2050 - Camperdown

Recruitment postcode(s) [2]

0810 - Tiwi

Recruitment postcode(s) [3]

7000 - Hobart

Recruitment postcode(s) [4]

4102 - Woolloongabba

Recruitment postcode(s) [5]

6009 - Nedlands

Recruitment postcode(s) [6]

5000 - Adelaide

Recruitment postcode(s) [7]

3000 - Melbourne

Recruitment postcode(s) [8]

2145 - Westmead

Recruitment postcode(s) [9]

4032 - Chermside

Recruitment postcode(s) [10]

3065 - Fitzroy

Recruitment postcode(s) [11]

3084 - Heidelberg

Recruitment postcode(s) [12]

5042 - Bedford Park

Recruitment postcode(s) [13]

2640 - Albury

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

Office for Health and Medical Research

Country [1]

Australia

Funding source category [2]

Other Collaborative groups

Name [2]

Australian Genomic Cancer Medicine Centre (AGCMC)

Country [2]

Australia

Primary sponsor type

University

Name

University of Sydney

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Country [1]

Other collaborator category [1]

Other Collaborative groups

Name [1]

Australian Genomic Cancer Medicine Centre (AGCMC)

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

St Vincent's Hospital Ethics Committee

Ethics committee address [1]

Translational Research Centre, 97-105 Boundary Street, Darlinghurst NSW 2010

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

29/05/2020

Approval date [1]

17/08/2020

Ethics approval number [1]

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

Public notes

Contacts

Principal investigator

Name

Dr Antony Mersiades

Address

NHMRC Clinical Trials Centre
Medical Foundation Building
Levels 4-6, 92-94 Parramatta Rd,
Camperdown NSW 2050

Country

Australia

Phone

+61 2 9382 5000

Email

[email protected]

Contact person for public queries

Name

Dr Lucille Sebastian

Address

NHMRC Clinical Trials Centre,
Medical Foundation Building,
Levels 4-6,
92-94 Parramatta Road,
Camperdown NSW 2050

Country

Australia

Phone

+61 2 9562 5000

Email

[email protected]

Contact person for scientific queries

Name

Dr Antony Mersiades

Address

NHMRC Clinical Trials Centre
Medical Foundation Building
Levels 4-6, 92-94 Parramatta Rd,
Camperdown NSW 2050

Country

Australia

Phone

+61 2 9382 5000

Email

[email protected]

Trial Review

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