Sorafenib or Crizotinib and Vemurafenib in Advanced Cancer
Information source: M.D. Anderson Cancer Center
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Advanced Cancers
Intervention: Vemurafenib (Drug); Sorafenib (Drug); Crizotinib (Drug)
Phase: Phase 1
Status: Recruiting
Sponsored by: M.D. Anderson Cancer Center Official(s) and/or principal investigator(s): Filip Janku, MD, PHD, Principal Investigator, Affiliation: M.D. Anderson Cancer Center
Overall contact: Filip Janku, MD, PHD, Phone: 713-563-1930
Summary
The goal of this clinical research study is to find the highest tolerable dose of the
combination of ZelborafTM (vemurafenib) with NexavarŽ (sorafenib) or XalkoriŽ (crizotinib)
that can be given to patients with advanced cancer. The safety of these drugs will also be
studied.
Vemurafenib is designed to block a protein called BRAFV600E inside the cancer cells, which
is involved in cancer cell growth.
Sorafenib is designed to block the function of important proteins in and outside of cancer
cells. These proteins are involved in cancer cells growth and new blood vessel development.
Crizotinib is designed to block certain abnormal genes found in cancer cells. This may
cause the cancer cells to die.
Clinical Details
Official title: A Phase I Trial of Sorafenib (CRAF, BRAF, KIT, RET, VEGFR, PDGFR Inhibitor) or Crizotinib (MET, ALK, ROS1 Inhibitor) in Combination With Vemurafenib (BRAF Inhibitor) in Patients With Advanced Malignancies
Study design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Maximum Tolerated Dose (MTD) of Sorafenib or Crizotinib in Combination With Vemurafenib
Secondary outcome: Tumor Response
Detailed description:
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 1, 8, 15, and 22 of Cycle 1 and Day 1 of Cycles 2 and beyond:
- Blood (about 2-4 tablespoons) will be drawn for mutation/genetic testing.
Mutation/genetic testing looks at whether specific genes are changed (mutated) in the
tumor.
- Urine will be collected for mutation/genetic testing. You may collect your first urine
of the morning, anytime during the day, or you may collect urine for 24 hours. You
will be given containers to collect the urine and will be told how to use them.
If you collect your urine over 24 hours, the study staff will give you a large (3-liter)
urine storage container and a small (7-ounce) plastic collection container. You will
urinate into the small collection container and then pour the urine into the large urine
storage container within 10 minutes after the collection. You should write down the time of
the first and last collections in the large storage container and return it to the study
staff at the end of the 24-hour period.
If you collect your first urine of the morning, the study staff will give you 3 plastic
collection cups and 3 small tubes filled with a preservative solution. To collect your
first morning urine, you will fill the collection cup with urine up to the 100 mL
(milliliter) line, add 1 of the small tubes of preservative to the cup within 10 minutes,
and then mark on the container that this is your first morning urine. If possible, fill the
other 2 collection cups, adding a tube of preservative to each as just described and mark
them as part of your first morning urine. You will return the collection cups to the study
staff at your next visit.
If you collect your urine anytime it suits you, the study staff will give you 3 plastic
collection cups and 3 small tubes filled with a preservative solution. To collect your
urine, you will fill the collection cup with urine up to the 100 mL line, add 1 of the small
tubes of preservative to the cup within 10 minutes, and then mark on the container that this
is your first morning urine. If possible, fill the other 2 collection cups, adding a tube
of preservative to each as just described and mark them so the study doctor will know the
time when you collected your urine. You will return the collection cups to the study staff
at your next visit. Your study doctor or staff will give you more details, if needed.
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. The
following tests and procedures will be performed:
- You will be asked about any health problems you may have and if you have had any side
effects.
- If the disease has gotten worse, blood (about 2-4 tablespoons) will be drawn for
mutation/genetic testing.
- If the disease has gotten worse, urine will be collected for mutation/genetic testing.
You may collect your first urine of the morning, anytime during the day, or you may
collect urine for 24 hours.
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.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
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. Patients with BRAF
mutation in cell free DNA (tested in CLIA lab) are also eligible.
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 = 2
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 = 2 X ULN; total
bilirubin = 2 X ULN (exceptions may apply to benign non-malignant indirect
hyperbilirubinemia such as Gilbert syndrome); ALT (SGPT) and/or AST (SGOT) = 5 X
ULN Exception for patients with liver metastasis: total bilirubin = 3 x ULN; ALT
(SGPT) = 8 X ULN.
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.
Locations and Contacts
Filip Janku, MD, PHD, Phone: 713-563-1930
University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States; Recruiting
Additional Information
University of Texas MD Anderson Cancer Center Website
Starting date: February 2012
Last updated: May 14, 2015
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