None listed
Conditions
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.
Interventions
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, t
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.
Sponsors
University of Sydney
Study design
Allocation
Non-randomised trial
Intervention model
Single group
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
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.
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).
Outcome results
None listed