A Phase I Trial of Vemurafenib (BRAF Inhibitor) and Sorafenib (CRAF, BRAF, KIT, RET, VEGFR, PDGFR Inhibitor) in Patients With Advanced Malignancies
18 Years
N/A
Both
Advanced Cancers
Trial Information
A Phase I Trial of Vemurafenib (BRAF Inhibitor) and Sorafenib (CRAF, BRAF, KIT, RET, VEGFR, PDGFR Inhibitor) in Patients With Advanced Malignancies
Study Groups:
Dose escalation:
If you are found to be eligible to take part in this study, your doctor will decide if you
will receive vemurafenib either with sorafenib or crizotinib. Once it is decided which
combination you will receive, you will be assigned to a dose level based on when you join
the study.
Up to 6 dose levels of vemurafenib with sorafenib will be tested. Up to 5 dose levels of
vemurafenib with crizotinib will be tested. Up to 6 participants will be enrolled at each
dose level. The first group of participants will receive the lowest dose level. Each new
group will receive a higher dose than the group before it, if no intolerable side effects
were seen. This will continue until the highest tolerable dose of vemurafenib either with
sorafenib or crizotinib is found.
Dose expansion:
Once the highest tolerable dose of vemurafenib either with sorafenib or crizotinib is found,
up to 14 more participants may be enrolled. This will be to further study the safety of the
combination of drugs at that dose and the level of effectiveness of the study drugs in a
certain tumor group.
Study Drug Administration:
Each study cycle is 28 days.
You will take vemurafenib by mouth 2 times a day at the same time every day either with or
without food, swallowed whole with a glass of water. Tablets should not be chewed or
crushed. If you miss a dose, you can take it up to 4 hours before the next dose. You cannot
take both doses at the same time.
You will take sorafenib by mouth at the same time every day without food (at least 1 hour
before or 2 hours after a meal). Depending on which dose level you are enrolled in, you will
take sorafenib by mouth either 1 or 2 times a day. The doctor will discuss this with you.
You will take crizotinib by mouth at the same time every day consistently either with or
without food, swallowed whole with a glass of water. Depending on which dose level you are
receiving, you will take crizotinib by mouth either 1 or 2 times a day. The doctor will
discuss this with you.
Study Visits:
At every study visit, you will be asked if you have had any side effects.
Around Days 15-21 of Cycle 1:
- Your medical history will be recorded, including any cancer symptoms.
- You will have a physical exam, including measurement of your weight and vital signs.
- You will be asked about any health problems you may have and any other drugs or herbal
supplements you may be taking.
- Your performance status will be recorded.
- Blood (about 1 tablespoon) will be drawn for routine tests.
Before starting Cycles 2 and beyond:
- Your medical history will be recorded, including any cancer symptoms.
- You will have a physical exam, including measurement of your weight and vital signs.
- You will be asked about any health problems you may have and any other drugs or herbal
supplements you may be taking.
- Your performance status will be recorded.
- Blood (about 1 tablespoon) will be drawn for routine tests.
- If you are able to become pregnant, you will have a blood (about 1 teaspoon) or urine
pregnancy test.
Every other cycle (every 8 weeks):
- Blood (about 1 tablespoon) will be drawn to check your thyroid gland.
- You will have a skin exam by a skin doctor to check for any lesions that might have
skin cancer.
- You will have an x-ray, CT scan, MRI, and/or PET/CT scan to check the status of the
disease. Blood (about 1 tablespoon) will be drawn for tumor marker testing. After at
least 6 months of taking the study drugs, you may have CT, MRI, and/or PET/CT scans and
blood drawn every 3 cycles (every 12 weeks) if the study doctor thinks it is needed.
If the study doctor has to change your dose of study drugs, blood (about 1 tablespoon) will
be drawn to check for abnormal minerals.
Anytime during the study if your study doctor thinks it is needed:
- You will have an ECG to check your heart function.
- Blood (about 1 tablespoon) will be collected for abnormal mineral and digestive enzyme
testing.
- If you are taking the blood thinner warfarin, blood (about 1 teaspoon) will be drawn to
test how well your blood clots.
Length of Dosing:
You may continue taking the study drugs for as long as the doctor thinks it is in your best
interest. You will no longer be able to take the study drugs if the disease gets worse, if
intolerable side effects occur, or if you are unable to follow study directions.
Follow-up:
You will have a follow-up-visit within 30 days after your last dose of study drugs. You will
be asked about any health problems you may have and if you have had any side effects. If
your study doctor thinks it is needed, you may have follow-up for a longer period of time.
You may have a skin exam within 6 months after your last dose of study drugs to check for
any new lesions that may have skin cancer if the doctor thinks it is needed.
This is an investigational study. Vemurafenib is FDA approved and commercially available to
treat progressive melanoma with the BRAFV600E mutation. Sorafenib is FDA approved and
commercially available to treat progressive hepatocellular carcinoma and renal cell
carcinoma. Crizotinib is FDA approved and commercially available to treat locally advanced
or metastatic non-small lung cancer. Giving the combination of vemurafenib either with
sorafenib or crizotinib to patients with advanced cancer is investigational.
Up to 183 patients will be enrolled in this study. All will be enrolled at MD Anderson.
Inclusion Criteria:
1. Patients with advanced or metastatic cancers and BRAF mutations that are refractory
to standard therapy, relapsed after standard therapy, or who have no standard therapy
available that improves survival by at least three months.
2. Patients must be >/= 3 weeks beyond treatment with a cytotoxic chemotherapy regimen,
or therapeutic radiation, or major surgery. Patients may have received palliative
localized radiation immediately before or during treatment provided that radiation is
not delivered to the only site of disease being treated under this protocol. For
biologic/targeted agents patients must be >/= 5 half-lives or >/= 3 weeks from the
last dose (whichever comes first). Patients previously treated with vemurafenib
monotherapy do not have to stop medication before they start on the protocol.
3. ECOG performance status
4. Patients must be >/= 18 years of age.
5. Patients must have adequate organ and marrow function defined as: absolute neutrophil
count (ANC) >/= 1,000/mL, platelets >/=75,000/mL; creatinine bilirubin patients with liver metastasis: total bilirubin
6. Dermatology evaluation with excision of any suspicious lesions prior to initiation of
therapy.
7. Women of childbearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry, for
the duration of study participation, and for 30 days after the last dose.
8. Women of childbearing potential must have a negative serum or urine pregnancy test
within 2 weeks prior to initiation of therapy.
9. Life expectancy >12 weeks in the opinion of the Investigator.
10. Patients must be able to understand and be willing to sign a written informed consent
document.
11. Patient must be able to swallow pills.
Exclusion Criteria:
1. Uncontrolled intercurrent illness, including, but not limited to, uncontrolled
infection, uncontrolled asthma, need for hemodialysis, need for ventilatory support.
2. Syndrome of congenital QTc prolongation or QTc >500 msec.
3. Patients with clinically significant cardiovascular disease: history of
cerebrovascular accident (CVA) within 6 months, myocardial infarction or unstable
angina within 6 months, or unstable angina pectoris.
4. Pregnant or lactating women.
5. History of hypersensitivity to vemurafenib.
6. History of hypersensitivity to sorafenib for vemurafenib/sorafenib arm.
7. History of hypersensitivity to crizotinib for vemurafenib/crizotinib arm.
8. History of hypersensitivity to any component of the formulation.
9. Patients unwilling or unable to sign informed consent document.
10. Patients using any of the following medications: mesoridazine, dronedarone,
thioridazine, ziprasidone, levomethadyl, and saquinavir for vemurafenib/sorafenib
arm.
Type of Study:
Interventional
Study Design:
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Maximum Tolerated Dose (MTD) of Vemurafenib and Sorafenib
Outcome Description:
If more than 33% of enrolled at any particular dose level develop dose limiting toxicity (DLT), treatment will continue at dose level immediately below. If not more than 33% of cohort develop DLT, this cohort will be considered the MTD.
Outcome Time Frame:
8 weeks
Safety Issue:
Yes
Principal Investigator
Filip Janku, MD, PHD
Investigator Role:
Principal Investigator
Investigator Affiliation:
UT MD Anderson Cancer Center
Authority:
United States: Institutional Review Board
Study ID:
2011-1183
NCT ID:
NCT01531361
Start Date:
February 2012
Completion Date:
Related Keywords:
- Advanced Cancers
- Advanced Cancers
- Advanced Malignancies
- Metastatic cancers
- Vemurafenib
- PLX4032
- R05185426
- Sorafenib
- Nexavar
- Bay 43-9006
- Maximum tolerated dose
- MTD
- Dose limiting toxicity
- DLT
- Neoplasms
Name | Location |
|---|---|
| UT MD Anderson Cancer Center | Houston, Texas 77030 |
