Sorafenib or Crizotinib and Vemurafenib in Advanced Cancer
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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 BRAF V600E 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 Drug: Crizotinib |
Phase 1 |
| Study Type: | Interventional |
| Study Design: | Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| 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 |
- Maximum Tolerated Dose (MTD) of Sorafenib or Crizotinib in Combination With Vemurafenib [ Time Frame: 4 weeks ] [ Designated as safety issue: Yes ]If not more than 33% of the participants in cohort develop dose limiting toxicity (DLT), this cohort considered the MTD. MTD defined by DLTs that occur in first cycle (4 weeks) (induction phase). Toxicities described according to the NCI-CTCAE Version 4.0. DLT defined as any clinically grade 3 or 4 non-hematologic toxicity as defined in NCI CTCAE v4.0, expected and believed to be related to study medications (except nausea and vomiting, electrolyte imbalances responsive to appropriate regimens or alopecia), any grade 4 hematologic toxicity lasting at least 3 weeks or longer (as defined by NCI-CTCAE v4.0) or associated with bleeding and/or sepsis; any grade 4 nausea or vomiting > 5 days despite maximum anti-nausea regimens, and any other grade 3 non-hematologic toxicity including symptoms/signs of vascular leak or cytokine release syndrome; or any severe or life-threatening complication or abnormality not defined in the NCI-CTCAE v4.0 that is attributable to therapy.
- 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 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 2018 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Vemurafenib + Sorafenib
There will be two treatment arms, Vemurafenib and Sorafenib and Vemurafenib and Crizotinib. Patients assigned to treatment arms per physician discretion. Dose Escalation Group Starting dose of Vemurafenib: 240 mg by mouth twice a day for 28 day cycle. Dose Escalation Group Starting dose of Sorafenib: 200 mg by mouth twice a day for 28 day cycle. Dose Expansion Group Starting Dose: Maximum tolerated dose (MTD) from dose escalation group. |
Drug: Vemurafenib
Dose Escalation Group Starting Dose: 240 mg by mouth twice a day for a 28 day cycle. Dose Expansion Group Starting Dose: Maximum tolerated dose (MTD) from dose escalation group. Other Names:
Drug: Sorafenib
Dose Escalation Group Starting Dose of Sorafenib: 200 mg by mouth twice a day for a 28 day cycle. Dose Expansion Group Starting Dose: Maximum tolerated dose (MTD) from dose escalation group. Other Names:
|
|
Experimental: Vemurafenib + Crizotinib
There will be two treatment arms, Vemurafenib and Sorafenib and Vemurafenib and Crizotinib. Patients assigned to treatment arms per physician discretion. Dose Escalation Group Starting Dose of Vemurafenib: 240 mg by mouth twice a day for 28 day cycle. Dose Escalation Group Starting dose of Crizotinib 250 mg by mouth daily for a 28 day cycle. Dose Expansion Group Starting Dose: Maximum tolerated dose (MTD) from dose escalation group. |
Drug: Vemurafenib
Dose Escalation Group Starting Dose: 240 mg by mouth twice a day for a 28 day cycle. Dose Expansion Group Starting Dose: Maximum tolerated dose (MTD) from dose escalation group. Other Names:
Drug: Crizotinib
Dose Escalation Group Starting dose of Crizotinib 250 mg by mouth daily for a 28 day cycle. Dose Expansion Group Starting Dose: Maximum tolerated dose (MTD) from dose escalation group. Other Names:
|
Show Detailed Description
Eligibility| Ages Eligible for Study: | 18 Years and older (Adult, Senior) |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- 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.
- 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.
- ECOG performance status </= 2
- Patients must be >/= 18 years of age.
- 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.
- Dermatology evaluation with excision of any suspicious lesions prior to initiation of therapy.
- 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.
- Women of childbearing potential must have a negative serum or urine pregnancy test within 2 weeks prior to initiation of therapy.
- Life expectancy >12 weeks in the opinion of the Investigator.
- Patients must be able to understand and be willing to sign a written informed consent document.
- Patient must be able to swallow pills.
Exclusion Criteria:
- Uncontrolled intercurrent illness, including, but not limited to, uncontrolled infection, uncontrolled asthma, need for hemodialysis, need for ventilatory support.
- Syndrome of congenital QTc prolongation or QTc >500 msec.
- 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.
- Pregnant or lactating women.
- History of hypersensitivity to vemurafenib.
- History of hypersensitivity to sorafenib for vemurafenib/sorafenib arm.
- History of hypersensitivity to crizotinib for vemurafenib/crizotinib arm.
- History of hypersensitivity to any component of the formulation.
- Patients unwilling or unable to sign informed consent document.
- Patients using any of the following medications: mesoridazine, dronedarone, thioridazine, ziprasidone, levomethadyl, and saquinavir for vemurafenib/sorafenib arm.
Contacts and LocationsPlease refer to this study by its ClinicalTrials.gov identifier: NCT01531361
| Contact: Filip Janku, MD, PHD | 713-563-1930 | ||
| Contact: MD Anderson Cancer Center | 1-855-873-4321 |
| United States, Texas | |
| University of Texas MD Anderson Cancer Center | Recruiting |
| Houston, Texas, United States, 77030 | |
| Principal Investigator: | Filip Janku, MD, PHD | M.D. Anderson Cancer Center |
More Information
Additional Information:
| 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: | June 20, 2016 |
| Health Authority: | United States: Food and Drug Administration |
Keywords provided by M.D. Anderson Cancer Center:
|
Advanced Cancers Advanced Malignancies Metastatic cancers Vemurafenib PLX4032 R05185426 Sorafenib Nexavar |
Bay 43-9006 Crizotinib PF-02341066 Xalkori Maximum tolerated dose MTD Dose limiting toxicity DLT |
Additional relevant MeSH terms:
|
Neoplasms Sorafenib Crizotinib Niacinamide Antineoplastic Agents Protein Kinase Inhibitors Enzyme Inhibitors |
Molecular Mechanisms of Pharmacological Action Vitamin B Complex Vitamins Micronutrients Growth Substances Physiological Effects of Drugs |
ClinicalTrials.gov processed this record on September 26, 2016