None listed
Conditions
Brief summary
The aim of the study is to assess the safety and efficacy of chemotherapy treatment with a combination of erlotinib and vemurafenib in patients with BRAF V600E mutant colorectal and non-small lung cancer. Who is it for? You may be eligible to join this study if you aged 18 years or more and have a confirmed diagnosis of metastatic colorectal cancer or non-small cell lung cancer with a BRAF V600E mutation of your primary cancer or related metastases. Study details: There are two parts to this study. In the first part, participants with metastatic colorectal cancer will be treated with erlotinib and vemurafenib daily until disease progression or unacceptable toxicities. Both of these chemotherapy drugs are administered in tablet form and taken orally. The dose administered will be increased in subsequent patient groups in order to determine the maximum tolerated dose to be used in the second part of the study. Patients with metastatic colorectal cancer or non-small cell lung cancer are eligible for the second part of the study. They will also be treated with oral erlotinib and vemurafenib daily until disease progression or unacceptable toxicities. All participants will be regularly monitored and assessed for a period of up to 18 months in order to evaluate the safety and efficacy of treatment.
Interventions
Tarceva (erlotinib) and Zelboraf (vemurafenib) are the intervention being studied. Both are provided in tablet form and are taken orally everyday until disease progression or unacceptable toxicity (anticipated this will be for approximately 6 months).
There will be 3 dose levels:
a) Dose level D-1 = erlotinib (100 mg/day) and vemurafenib (720 mg twice a day)
b) Dose level D1 = erlotinib (100 mg/day) and vemurafenib (960 mg twice a day)
c) Dose level D2 = erlotinib (150 mg/day) and vemura
Tarceva (erlotinib) and Zelboraf (vemurafenib) are the intervention being studied. Both are provided in tablet form and are taken orally everyday until disease progression or unacceptable toxicity (anticipated this will be for approximately 6 months). There will be 3 dose levels: a) Dose level D-1 = erlotinib (100 mg/day) and vemurafenib (720 mg twice a day) b) Dose level D1 = erlotinib (100 mg/day) and vemurafenib (960 mg twice a day) c) Dose level D2 = erlotinib (150 mg/day) and vemurafenib (960 mg twice a day). Please note; this is a dose escalation study in the first phase, proceeding to dose expansion in the second phase. Strategies used to monitor adherence will be via a patient diary, where patients are asked to complete a daily diary entry recording drug use, as well as, standard drug tablet return and accountability logs.
Sponsors
Peter MacCallum Cancer Centre
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. Male or female patients greater than or equal to 18 years of age at the time of study entry 2. All patients must have histological or cytological confirmed metastatic colorectal cancer with a BRAF V600E mutation of their primary cancer or related metastases. Patients with other tumour types with a proven BRAF V600E mutation can be considered for enrolment into the Expansion Phase exploratory cohort with the permission of the Study Chair. 3. Patients with BRAF V600E mCRC are permitted to have had a maximum of 2-lines of therapy for metastatic disease. A maintenance strategy post 1st-line treatment is not considered as an additional line of therapy, nor is rechallenge with oxaliplatin. Patients with lung adenocarcinoma are required to have received prior treatment with a platinum doublet. There is no requirement for previous treatment for other tumour types. 4. All patients must have measurable disease per RECIST 1.1 criteria. 5. A tumour paraffin tissue block or 20 - 30 unstained slides from the tumour tissue block must be available for the purpose of biomarker analyses. Obtaining archived tumour material or unstained slides from an archived tumour block will suffice to meet this requirement. The availability of the tumour tissue block must be confirmed at screening for a patient to be considered eligible. If no tissue block and fewer than 20 unstained slides are available, eligibility must be confirmed with the Study Chair or delegate. 6. ECOG performance status 0 to 1 inclusive. 7. Participants must have adequate organ and marrow function as defined below: a) Absolute neutrophil count greater than or equal to 1.5 x 109/L b) Platelets greater than or equal to 100 x 109/L c) ALT and AST less than or equal to 2.5 x upper limit of normal (ULN), or less than or equal to 5 x ULN if liver metastases are present d) Total serum bilirubin less than or equal to 1.5 x ULN e) Serum creatinine less than or equal to 1.5 x ULN, or creatinine clearance > 50ml/min 8. Participants must be suitable for oral drug administration. 9. Life expectancy > 3 months. 10. Female patients of childbearing potential (see below) must: a) Be on highly effective contraception. Highly effective contraception methods include: * total abstinence, or * sterilisation (see below), or * combination of any two of the following (a+b, or a+c, or b+c): * Use of oral, injected or implanted hormonal methods of contraception. Hormonal contraceptives include any marketed contraceptive agent that includes an oestrogen and/or a progestin. * Placement of an intrauterine device (IUD) * Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/cream/ vaginal suppository b) Have a negative serum or urine pregnancy test performed within the 7 days before start of treatment. c) Highly effective contraception for females of child bearing potential must be maintained throughout the study and for 6 months after study drug discontinuation. 11. Female patients not of child-bearing potential. Women are considered not of child bearing potential if they have had either: a) 12 months of natural (spontaneous) amenorrhoea with an appropriate clinical profile (eg. age appropriate, history of vasomotor symptoms), or b) A surgical bilateral oophorectomy (with or without hysterectomy), or c) Tubal ligation at least 6 weeks ago. In the case of unilateral oophorectomy alone, a woman is considered not of child-bearing potential only once the reproductive status has been confirmed by follow up hormone level assessment. 12. Sexually active males must use a condom during intercourse while taking the drug and for 6 months after stopping treatment and should not father a child in this period. A condom is required to be used also by vasectomised men in order to prevent delivery of the drug via seminal fluid. 13. Absence of any psychological, familial or sociological condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before trial entry. 14. Ability to understand and the willingness to sign a written informed consent. Before study entry, written informed consent must be obtained from patient prior to performing any study-related procedures.
Exclusion criteria
1. Active CNS lesions are excluded (i.e. those with radiographically unstable, symptomatic lesions). Patients treated with stereotactic therapy or surgery are eligible if patient remains without evidence of disease progression within the CNS for greater than or equal to 1 month. Previous whole brain radiotherapy is not allowed with the exception of patients who have had definitive resection or stereotactic therapy of all radiologically detectable parenchymal lesions. 2. History of or known spinal cord compression, or carcinomatous meningitis. 3. Patients who have had any systemic cytotoxic/biologic or investigational therapies within 4 weeks prior to study entry or who have not recovered from the side effects of such earlier therapy. 4. Previous malignancies within the past 5 years are excluded except for adequately treated carcinoma in-situ of the cervix. Isolated elevation in PSA in the absence of radiographic evidence of metastatic prostate cancer is allowed. 5. Participants who have had radiotherapy and/or major surgery within 2 weeks prior to study entry. 6. Anticipated or concurrent use of any other anti-cancer therapies or study agents. 7. Clinical significant cardiac disease including any of the following: a. unstable angina, b. symptomatic or otherwise uncontrolled arrhythmia requiring medication (does not include stable, lone atrial fibrillation), c. QTcF > 480 msecs or a history of congenital long QT syndrome, d. uncontrolled hypertension, e. symptomatic congestive heart failure f. myocardial infarction less than or equal to 6 months prior to first study treatment, g. serious uncontrolled cardiac arrhythmia. 8. Patients with active uncontrolled infection. 9. Known history of human immunodeficiency virus (HIV) infection. 10. Known history of active hepatitis B or C. 11. Other severe, acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, which in the judgment of the investigator would make the patient inappropriate for entry into this study. 12. Patients who are receiving treatment with medications known to be strong CYP3A4 inhibitors within 7 days before starting treatment with erlotinib and vemurafenib or strong inducers of CYP3A4 within 14 days before starting treatment with erlotinib and vemurafenib. A comprehensive list of inhibitors, inducers and substrates may be found at http://medicine.iupui.edu/flockhart/table.htm. 13. Nursing (lactating) women. 14. Severe hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of either erlotinib or vemurafenib. 15. Patients with EGFR mutant lung adenocarcinoma.
Outcome results
None listed