Clinical Trials /

Vemurafenib, Cetuximab, and Irinotecan Hydrochloride in Treating Patients With Solid Tumors That Are Metastatic or That Cannot Be Removed by Surgery

NCT01787500

Description:

This phase I trial studies the side effects and best dose of vemurafenib when given together with cetuximab and irinotecan hydrochloride in treating patients with solid tumors that have spread to other parts of the body or cannot be removed by surgery. Vemurafenib and irinotecan hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as cetuximab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving vemurafenib with cetuximab and irinotecan hydrochloride may be a better treatment for solid tumors.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Vemurafenib, Cetuximab, and Irinotecan in Advanced Solid Cancers
  • Official Title: A Phase I Trial of Vemurafenib in Combination With Cetuximab and Irinotecan in Patients With BRAF V600 Mutant Advanced Solid Malignancies

Clinical Trial IDs

  • ORG STUDY ID: 2012-0748
  • SECONDARY ID: NCI-2013-00541
  • NCT ID: NCT01787500

Conditions

  • Advanced Cancers

Interventions

DrugSynonymsArms
VemurafenibPLX4032, RO5185426Vemurafenib + Cetuximab + Irinotecan
CetuximabC225, Erbitux, IMC-C225Vemurafenib + Cetuximab + Irinotecan
IrinotecanCPT-11, CamptosarVemurafenib + Cetuximab + Irinotecan

Purpose

The goal of this clinical research study is to find the highest tolerable dose of vemurafenib that can be given in combination with cetuximab and irinotecan to patients with advanced cancer. The safety of this drug combination will also be studied. Vemurafenib is designed to block BRAFV600 inside the cancer cells, which is involved in cancer cell growth. Cetuximab is designed to block proteins inside the cancer cell, which may prevent or slow the growth of cancer cells and leads to cell death. Irinotecan is designed to stop cancer cells from making new DNA (the genetic material of cells). If the cancer cells cannot make DNA, they cannot divide into new cells and may die. This is an investigational study. Vemurafenib is FDA approved and commercially available for the treatment of certain types of melanoma in patients with BRAF mutation. Cetuximab is FDA approved and commercially available for the treatment of KRAS wild type, EGFR expressing metastatic colorectal cancer and squamous cell carcinoma of the head and neck. Irinotecan is FDA approved and commercially available for the treatment of metastatic colorectal cancer. The use of these drugs together in advanced cancer is investigational. Up to 33 patients will be enrolled in this study. All will be enrolled at MD Anderson.

Detailed Description

      Study Groups:

      If you are found to be eligible to take part in this study, your doctor will decide which
      dose level of vemurafenib you will receive. All participants will receive the standard dose
      of cetuximab and irinotecan.

      Dose Escalation Group:

      Up to 3 dose levels of vemurafenib will be tested in combination with cetuximab and
      irinotecan. Up to 6 participants will be enrolled at each dose level.

      The dose of any of the study drug combinations that you receive may be lowered if you have
      intolerable side effects.

      Dose Expansion Group:

      After the highest tolerable dose of vemurafenib is found, additional participants will be
      enrolled in the expansion group and will receive the study drug combination at that dose.
      This group will have up to 15 participants with BRAF mutant, KRAS wild type colorectal
      cancer.

      Study Drug Administration:

      You will take vemurafenib by mouth 2 times a day. If the doctor thinks it is needed, you may
      take it less often. Vemurafenib can be taken with or without food. Always take it with food
      or always take on an empty stomach. Take with full glass of water.

      You will receive cetuximab and irinotecan by vein over 90 minutes on Day 1 of each cycle. You
      will be monitored for at least 1 hour after the end of drug infusion.

      Study Visits:

      During Week 1 of Cycles 2 and beyond:

        -  You will have a physical exam and your skin will be checked.

        -  Your medical history will be recorded.

        -  Blood (about 4 teaspoons) will be collected for routine tests.

        -  You will be asked about any drugs you may be taking and side effects you may be having.

      At Week 1 of Cycles 1-2, if you are in a certain group on study, blood (about 2 teaspoons
      each time) will be drawn before your dose of irinotecan and 8 more times over the next 24
      hours for pharmacokinetic (PK) testing. PK testing measures the amount of study drug in the
      body at different time points.

      If you are enrolled in the colorectal cancer dose expansion group, you will have a biopsy for
      biomarker testing on Day 14 of Cycle 2.

      Beginning at Week 1 of Cycle 3, you will have EKG every other cycle (once monthly) for 3
      months, and then once every 3 months until the end of the study.

      Beginning at Week 1 of Cycle 3, blood (about 2 teaspoons) will be drawn for biomarker testing
      every other cycle (once monthly).

      Beginning at Week 1 of Cycle 3, women who are able to become pregnant will have a blood
      (about 2 teaspoons) or urine pregnancy test every other cycle.

      At Week 1 of Cycle 3 and Cycle 5, urine will be collected for routine tests.

      At Week 1 of Cycle 3, if you are in a certain group on study, blood (about 2 teaspoons) will
      be drawn for PD testing.

      Every 3 Cycles, you will have imaging to check the status of the disease. These tests can
      include some or all of the following: a CT scan, MRI scan, PET scan, and/or bone scan. You
      will also have a chest x-ray.

      You will have an additional head and neck exam every 12 weeks while on study.

      All patients will have a chest CT 6 months after their last dose of vemurafenib. SCC patients
      will have additional chest CTs at screening and every 6 months while on study.

      Length of Study:

      You may continue taking the study drugs for as long as your doctor thinks it is in your best
      interest. You will be taken off study early if the disease gets worse, if you continue to
      have intolerable side effects, or if you are unable to follow study directions.

      Your participation on the study will be over once you have completed the end-of-study visit.

      End-of-Study Visit:

      Within 30 days after your last dose of study drugs, you will have an end-of-study visit. At
      this visit, the following tests and procedures will be performed:

        -  Your medical history will be recorded.

        -  You will have a physical exam, including measurement of your vital signs and weight.
           °Your skin will be checked. You will also have a head and neck exam.

        -  You will be asked about any drugs you may be taking and side effects you may be having.

        -  Your performance status will be recorded.

        -  Blood (about 4 teaspoons) will be collected for routine tests.

        -  If the doctor thinks it is needed, blood (about 2 teaspoons) will be drawn to measure
           tumor markers.

        -  If you are in a certain group on study, blood (about 2 teaspoons) will be drawn for PK
           testing.

        -  You will have imaging to check the status of the disease. These tests can include some
           or all of the following: a chest x-ray, CT scan, MRI scan, PET scan, and/or bone scan.

        -  If you are in the Dose Expansion group and the disease got worse while you were on
           study, blood (about 2 teaspoons) will be drawn for biomarker testing.
    

Trial Arms

NameTypeDescriptionInterventions
Vemurafenib + Cetuximab + IrinotecanExperimentalPhase I Dose Escalation: All groups treated. Starting dose of Vemurafenib 480 mg by mouth twice daily of a 14 Day cycle. Cetuximab 500 mg/m2 by vein every 2 weeks on Day 1 of each 14 Day cycle. Irinotecan 180 mg/m2 by vein every 2 weeks on Day 1 of each 14 Day cycle. Dose Expansion Groups: Once the maximum tolerated dose has been defined, patients enrolled in two expansion cohorts. One group will have up to 18 participants with BRAF mutant, KRAS wild type colorectal cancer. The other group will have up to 18 participants with BRAF mutant, KRAS wild type solid tumor cancers. Starting dose of Vemurafenib is maximum tolerated dose from Dose Escalation Group. Cetuximab and Irinotecan dosages and administration remain the same.
  • Vemurafenib
  • Cetuximab
  • Irinotecan
Dose Expansion Group - Colorectal CancerExperimentalDose Expansion Groups: Once the maximum tolerated dose has been defined, patients enrolled in two expansion cohorts. One group will have up to 18 participants with BRAF mutant, KRAS wild type colorectal cancer. Starting dose of Vemurafenib is maximum tolerated dose from Dose Escalation Group. Cetuximab 500 mg/m2 by vein every 2 weeks on Day 1 of each 14 Day cycle. Irinotecan 180 mg/m2 by vein every 2 weeks on Day 1 of each 14 Day cycle.
  • Vemurafenib
  • Cetuximab
  • Irinotecan
Dose Expansion Group - Solid CancersExperimentalOnce the maximum tolerated dose has been defined, patients enrolled in two expansion cohorts. This group will have up to 18 participants with BRAF mutant, KRAS wild type solid cancers. Starting dose of Vemurafenib is maximum tolerated dose from Dose Escalation Group. Cetuximab 500 mg/m2 by vein every 2 weeks on Day 1 of each 14 Day cycle. Irinotecan 180 mg/m2 by vein every 2 weeks on Day 1 of each 14 Day cycle.
  • Vemurafenib
  • Cetuximab
  • Irinotecan

Eligibility Criteria

        Inclusion Criteria:

          1. Patients must have histologically confirmed malignancy that is metastatic or
             unresectable

          2. Cancers with positive BRAF V600 mutation detected by a CLIA-certified laboratory

          3. Age 18 years or older

          4. ECOG performance status of 0 to 2

          5. Life expectancy of greater than 3 months

          6. Patients must have measurable disease per RECIST 1.1 criteria

          7. Patients must have a K-RAS WT tumor

          8. Patients must have normal organ and marrow function as defined below, within 14 days:
             • Absolute neutrophils count >,=1500/mcl • Platelets >,=100000/mcl • Hb >,=9 mg/dl •
             Total bilirubin =,<1.5 mg/dl • AST/ALT =,<5x upper limit of normal if liver metastases
             present; otherwise, then =,< 2.5x upper limit • Estimated creatinine clearance by
             Cockcroft-Gault equation > 30 mL/min

          9. Current treatment may cause harm to the developing human fetus. For this reason women
             of child-bearing age must have a negative pregnancy test at screening and both women
             of child-bearing potential and men must agree to use adequate contraception (hormonal
             or barrier method of birth control; abstinence) prior to study entry and for the
             duration of study participation, and for 6 months after last dose. Should a woman
             become pregnant or suspect she is pregnant while she or her partner is participating
             in this study, she should inform her treating physician immediately

         10. Signed informed consent approved by the Institutional Review Board prior to patient
             entry

         11. Expansion cohort: We propose a final expansion cohort for this study in a subset of
             interest utilizing the recommended dosing of combination. This cohort will include
             patients harboring characteristics that may predict response of combination or with
             clinical features that proved to derive most benefit of the study combination during
             preclinical studies. Cancers with positive BRAF (V600) mutation detected by a
             CLIA-certified laboratory.

        Exclusion Criteria:

          1. Patient receiving any concurrent chemotherapy

          2. Concurrent severe and/or uncontrolled medical disease including, but not limited to,
             ongoing or active infection requiring intravenous antibiotics, bowel obstruction

          3. Symptomatic congestive heart failure (NYHA Class III or IV), or unstable angina
             pectoris

          4. Patients who have had a myocardial infarction, transient ischemic attack, unstable
             angina, or CVS within 6 months before treatment

          5. Presence of symptomatic pleural and/or pericardial effusion not appropriately treated

          6. Prolonged QTc interval (>,=450 msec) as calculated by Bazett's formula, or patients
             with a history of congenital long QT syndrome or uncorrectable electrolyte
             abnormalities

          7. Medical and/or psychiatric problems of sufficient severity to limit full compliance
             with the study or expose patients to undue risk

          8. Known anaphylactic or severe hypersensitivity to the study drugs or their analogs

          9. Patient has failed to recover from any prior surgery within 4 weeks of study entry

         10. Patient is pregnant, lactating, or breastfeeding

         11. Patient has had any treatment specific for tumor control within 3 weeks of dosing with
             investigational drugs and cytotoxic agents, or within 2 weeks of cytotoxic agent given
             weekly, or within 6 weeks of nitrosoureas or mitomycin C, or within 5 half-lives of
             biological targeted agents with half-lives and pharmacodynamic effects lasting less
             than 5 days

         12. Patient is not able to swallow oral medication

         13. Patients receiving any medications or substances that are strong inhibitors or
             inducers of CYP3A4 complex are ineligible

         14. Patients with known K-RAS mutant (codon 12 or 13) detected by an FDA-approved test in
             a CLIA-certified laboratory

         15. Patients with BRAF WT cancers
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD)
Time Frame:After 3, 14 day cycles
Safety Issue:
Description:Maximum tolerated dose (MTD) defined as highest dose studied in which the incidence of dose-limiting toxicity (DLT) was less than 33%. DLT is defined as: Any clinically grade 3 or 4 non-hematologic toxicity. Any grade 4 neutropenia (with or without fever and/or sepsis) or thrombocytopenia (with or without bleeding) lasting at least 1 week or longer Any grade 3 or 4 nausea or vomiting lasting more than 5 days despite anti-emetics regimens or grade 3 or 4 diarrhea refractory to anti-diarrhea medications 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 the therapy Any toxicity that does not resolve within 7 days of aggressive supportive measures or causes suspension of the drug (except allergy) or a dose reduction should be counted as a DLT.

Secondary Outcome Measures

Measure:Clinical Response
Time Frame:Every 4 weeks while participant is on study until 30 days after last dose of study drugs
Safety Issue:
Description:Response evaluated using the new international criteria proposed by revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline version 1.12. Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Trial Keywords

  • Advanced Cancers
  • Advanced Solid Cancers
  • BRAF V600 Mutant Advanced Solid Malignancies
  • Metastatic
  • Unresectable
  • BRAF mutant, KRAS wild type colorectal cancer
  • BRAF mutant, KRAS wild type solid tumor cancers
  • Vemurafenib
  • PLX4032
  • RO5185426
  • Cetuximab
  • C225
  • Erbitux
  • IMC-C225
  • Irinotecan
  • CPT-11
  • Camptosar

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