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Closed (no longer recruiting)Last updated: 20 December 2023

MoST Addendum 12 (substudies 27-30): This phase II trial is evaluating how safe and effective a combination of two targeted therapies (vemurafenib and cobimetinib) are in people with metastatic non-squamous non-small cell lung cancer and other solid cancers with BRAF V600 mutationsSingle 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

Clinical summary

Summary

This is a substudy of the Cancer Molecular Screening and Therapeutic (MoST) Program (ACTRN12616000908437). In this randomised trial, participants will receive 2 drugs, vemurafenib and cobimetinib. Both drugs will be administered orally, at a dose of 960mg twice daily (days 1 to 28 in a 28-day cycle) for vemurafenib and 60mg daily (days 1-21 in a 28-day cycle) for cobimetinib. Participants will continue to receive treatment until toxicity or disease progression. Dosages may be reduced if participants experience toxicity.

Conditions

This trial is treating patients with non-squamous non-small cell lung cancer and solid cancers.

Cancer

Multi-Cancer Multi-Cancer

Age

People18+

Phase

II

Trial Acronym

MoST Addendum 12 (substudies 27-30)

More information

Trial Identifiers

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Trial sponsor

University of Sydney, Australian Genomic Cancer Medicine Centre

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

Eligibility

Inclusion

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;
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;
4. Confirmation of molecular eligibility by the molecular tumour board;
5. ECOG 0 to 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 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;
iv. Advanced thyroid cancers must be radioiodine-refractory and have previously progressed on or intolerant of oral angiogenesis inhibitor;
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.

Exclusion

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).

Inclusion

  • You are able to swallow medication by mouth.
  • You have been diagnosed with cancer, but have not received any treatment.
  • You have had treatment but your cancer has gotten worse or has not responded to the treatment you have been given.
  • Your cancer has not spread to other parts of the body.
  • Your cancer has spread to other parts of the body.

Exclusion

  • You have been diagnosed with a prior or secondary type of cancer.
  • You have certain types of non-cancer medical conditions.
  • You have had certain treatments, surgical procedures or drugs.
Message

Clinical trials have complex eligibility criteria.

Ask your doctor if this trial could be right for you.

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