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A Phase I Trial of Vemurafenib in Combination With Cetuximab and Irinotecan in Patients With BRAF V600 Mutant Advanced Solid Malignancies


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Advanced Cancers

Thank you

Trial Information

A Phase I Trial of Vemurafenib in Combination With Cetuximab and Irinotecan in Patients With BRAF V600 Mutant Advanced Solid Malignancies


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 9 participants will be enrolled at each dose level. The first group will
receive the lowest dose and the 3rd group will receive the FDA-approved dose. The 2nd group
will receive a dose in between Dose Levels 1 and 3.

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 1 of 2 expansion groups and will receive the study drug combination at that
dose. 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 cancers.

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.

Study Visits:

During Week 3 of all cycles:

- You will have a physical exam.

- Your medical history will be recorded.

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

- Blood (about 2 teaspoons) will be drawn for biomarker testing.

- You will have an EKG.

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

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) and urine will be collected for routine tests.

- Blood (about 2 teaspoons will be drawn for biomarker testing.

- Women who are able to become pregnant will have a blood (about 2 teaspoons) or urine
pregnancy test.

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

At Week 2 of Cycle 2, 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.

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 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) and urine 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 the doctor thinks it is needed, 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.

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 63 patients will be enrolled in this study. All will be enrolled at MD Anderson.


Inclusion Criteria:



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

2. Cancers with positive BRAF V600 mutation detected by an FDA-approved test in 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 normal organ and marrow function as defined below, within 14 days:
• Absolute neutrophils count >,=1000/mcl • Platelets >,=75000/mcl • Hb >,=8 mg/dl •
Total bilirubin =,<2.0 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

7. Current treatment may cause harm to the developing human fetus. For this reason 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 30 days 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

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

9. Expansion cohort: We propose 2 final expansion cohorts for this study in subsets of
interest utilizing the recommended dosing of combination. These cohorts 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 an
FDA-approved test in a CLIA-certified laboratory. These cohorts will include patients
with one of the following conditions: • Cohort 1: patients with positive BRAF (V600)
/ negative K-RAS mutation solid cancers • Cohort 2: patients with positive BRAF
(V600E) / negative K-RAS mutation colorectal cancer

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

5. Prolonged QTc interval (>,=500 msec) as calculated by Bazett's formula

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

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

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

9. Patient is pregnant or lactating

10. 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

11. Patient is not able to swallow oral medication

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

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

14. Patients with BRAF WT cancers

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum Tolerated Dose (MTD)

Outcome 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.

Outcome Time Frame:

After 3, 14 day cycles

Safety Issue:

Yes

Principal Investigator

David S. Hong, MD

Investigator Role:

Study Director

Investigator Affiliation:

UT MD Anderson Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

2012-0748

NCT ID:

NCT01787500

Start Date:

February 2013

Completion Date:

Related Keywords:

  • Advanced Cancers
  • 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
  • Neoplasms

Name

Location

UT MD Anderson Cancer CenterHouston, Texas  77030