Vemurafenib and Sorafenib in Advanced Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by M.D. Anderson Cancer Center
Sponsor:
Information provided by (Responsible Party):
M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:
NCT01531361
First received: February 6, 2012
Last updated: May 16, 2014
Last verified: May 2014
  Purpose

The goal of this clinical research study is to find the highest tolerable dose of the combination of ZelborafTM (vemurafenib) with Nexavar® (sorafenib) or Xalkori® (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.


Condition Intervention Phase
Advanced Cancers
Drug: Vemurafenib
Drug: Sorafenib
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Trial of Vemurafenib (BRAF Inhibitor) and Sorafenib (CRAF, BRAF, KIT, RET, VEGFR, PDGFR Inhibitor) in Patients With Advanced Malignancies

Resource links provided by NLM:


Further study details as provided by M.D. Anderson Cancer Center:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) of Vemurafenib and Sorafenib [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Tumor Response [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    Tumor response defined as one or more of the following: (1) stable disease for more than or equal to 4 months, (2) decrease in measurable tumor (sentinel lesions) by more than or equal to 20% by RECIST criteria, (3) decrease in tumor markers by more than or equal to 25% (for example, a >/= 25% decrease in CA125 for patients with ovarian cancer), or (4) a partial response according to the Choi criteria, i.e., decrease in size by 10% or more, or a decrease in the tumor density, as measured by Hounsfield units (HU), by more than or equal to 15%.


Estimated Enrollment: 183
Study Start Date: February 2012
Estimated Primary Completion Date: February 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Vemurafenib + Sorafenib
Starting dose of Vemurafenib 240 mg by mouth twice a day for 28 day cycle. Starting dose of Sorafenib 200 mg by mouth twice a day for 28 day cycle. Expansion group starting dose: Maximum tolerated dose (MTD) from dose escalation group.
Drug: Vemurafenib

Starting Dose: 240 mg by mouth twice a day for a 28 day cycle.

Expansion group starting dose: Maximum tolerated dose (MTD) from dose escalation group.

Other Names:
  • PLX4032
  • R05185426
Drug: Sorafenib

Starting dose: 200 mg by mouth twice a day for a 28 day cycle.

Expansion group starting dose: Maximum tolerated dose (MTD) from dose escalation group.

Other Names:
  • Nexavar
  • Bay 43-9006

  Hide Detailed Description

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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; 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01531361

Contacts
Contact: Filip Janku, MD, PHD 713-563-1930

Locations
United States, Texas
UT MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Investigators
Principal Investigator: Filip Janku, MD, PHD UT MD Anderson Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT01531361     History of Changes
Other Study ID Numbers: 2011-1183, NCI-2012-00217
Study First Received: February 6, 2012
Last Updated: May 16, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by M.D. Anderson Cancer Center:
Advanced Cancers
Advanced Malignancies
Metastatic cancers
Vemurafenib
PLX4032
R05185426
Sorafenib
Nexavar
Bay 43-9006
Maximum tolerated dose
MTD
Dose limiting toxicity
DLT

Additional relevant MeSH terms:
Neoplasms
Sorafenib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 01, 2014