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A Phase I Dose-Escalation Study of the BRAF Inhibitor Vemurafenib (Zelboraf®) in Combination With an mTOR Inhibitor, Everolimus (Afinitor®) or Temsirolimus (Torisel®), in Subjects With Advanced Cancer


Phase 1
N/A
N/A
Open (Enrolling)
Both
Advanced Cancer, Solid Tumor

Thank you

Trial Information

A Phase I Dose-Escalation Study of the BRAF Inhibitor Vemurafenib (Zelboraf®) in Combination With an mTOR Inhibitor, Everolimus (Afinitor®) or Temsirolimus (Torisel®), in Subjects With Advanced Cancer


Study Drug Administration:

If you are found to be eligible to take part in this study, your doctor will decide whether
you will receive either everolimus or temsirolimus

You will be assigned to a dose level of vemurafenib based on when you join this study. Up
to 5 dose levels of vemurafenib 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 is
found.

Study Drug Administration:

You will take 3 vemurafenib tablets in the morning and 3 tablets in the evening.You will
take it every day during each 28-day study cycle. You will take vemurafenib in combination
with either 1 tablet of everolimus every day of each cycle or you will receive temsirolimus
by vein over 30-60 minutes on Days 1, 8, 15, and 22 of each cycle.

You will receive a dosing diary to record ONLY the date and times when you did NOT take a
scheduled dose of the study drug. You should bring this diary and any used or unused study
drug bottles to your next study visit (even empty bottles must be returned).

Study Visits:

At all study visits, you will be asked about any drugs you may be taking and if you have had
any side effects from them.

On Days 1 and 15 of Cycle 1 and Day 1 of Cycle 6:

- You will have a physical exam, including measurement of your vital signs.

- Your performance status will be recorded.

- Blood (about 3 teaspoons) will be drawn for routine tests.

On Day 1 of Cycles 2 and 5:

- You will have a physical exam, including measurement of your vital signs.

- Your performance status will be recorded.

- Blood (about 3 teaspoons) will be drawn for routine tests.

- You will have an ECG.

- Your skin will be checked.

On Day 1 of Cycle 3:

- You will have a physical exam, including measurement of your vital signs.

- Your performance status will be recorded.

- Blood (about 3 teaspoons) will be drawn for routine tests.

- You will have an ECG.

- You will have a CT scan or MRI scan to check the status of the disease.

On Day 1 of Cycle 4:

- You will have a physical exam, including measurement of your vital signs.

- Your performance status will be recorded.

- Blood (about 3 teaspoons) will be drawn for routine tests.

- You will have an ECG.

- You will have a head and neck exam to check the status of the disease.

On Day 1 of Cycle 7:

- You will have a physical exam, including measurement of your vital signs.

- Your performance status will be recorded.

- Blood (about 3 teaspoons) will be drawn for routine tests.

- You will have a CT scan or MRI scan to check the status of the disease.

- You will have a head and neck exam to check the status of the disease.

On Day 1 of Cycles 8 and beyond, blood (about 3 teaspoons) will be drawn for routine tests.

After Cycle 7, every 8 weeks:

- You will have a physical exam, including measurement of your vital signs.

- Your performance status will be recorded.

- Blood (about 3 teaspoons) will be drawn for routine tests.

- You will have an ECG.

After Cycle 7, every 12 weeks:

- You will have an ECG.

- You will have a head and neck exam to check the status of the disease.

- Your skin will be checked.

Length of Study:

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.

Your participation on the study will be over once you have completed the follow-up.

End of Study Drug Dosing Visit:

Once you are no longer taking the study drug, you will have a study visit. At this visit:

- You will be asked about any drugs you may be taking and if you have had any side
effects from them.

- You will have a physical exam, including measurement of your vital signs.

- Your performance status will be recorded.

- Blood (about 3 teaspoons) will be drawn for routine tests.

- You will have an ECG.

- You will have a CT scan or MRI scan to check the status of the disease.

- Your skin will be checked.

Safety Follow-Up Visit:

If you leave the study for any reason other than the disease getting worse, you will have a
follow-up visit about 28 days after your last dose. At this visit:

- You will be asked about any drugs you may be taking and if you have had any side
effects from them.

- You will have an ECG.

- Your skin will be checked.

- You will have a head and neck exam to check the status of the disease.

Follow-Up:

Every 3 months after the last dose of study drug (for up to 12 months) you will be contacted
by phone and asked about any new drugs you may be taking. This should take less than 5
minutes. This follow up may be during a regularly scheduled clinic visit.

Participant Responsibilities:

- Take the study drug as instructed by the study staff.

- Keep your study appointments. If you cannot keep an appointment, reschedule as soon as
you know that you will miss the appointment.

- Tell your doctor or study staff about any side effects, doctor visits, or
hospitalizations that you may have.

- Keep the study drug in a safe place, for your use only, and away from children. It must
be stored at room temperature but not warmer than 77 degrees F (25 degrees Celsius).

- Complete your diaries as instructed.

- While on this study, you cannot take part in any other research project without
approval from your doctor.

This is an investigational study. Vemurafenib is FDA-approved for metastatic melanoma. Its
use in other types of cancer is investigational. Everolimus and temsirolimus are FDA
approved kidney cancer. The combination of these drugs is investigational.

Up to 114 participants will be enrolled in this study. All will take part at MD Anderson.


Inclusion Criteria:



1. Confirmation of BRAF mutation-positive malignancy is required for selection of
patients for vemurafenib therapy

2. Measurable or non-measurable disease by RECIST 1.1.

3. Patients with advanced cancer should be refractory to standard therapy, relapsed
after standard therapy, or have no standard therapy available that improves survival
by at least three months.

4. Patients must be at least 3 weeks past receiving cytotoxic therapy and at least 5
half-lives after their previous treatment or 3 weeks, whichever is shorter, after
biologic therapy. Patients may receive palliative radiotherapy immediately or during
treatment provided that not all target lesions are radiated.

5. ECOG performance status /= 60%; Lansky Score >/= 50).

6. Patients must have normal organ and marrow function defined as: absolute neutrophil
count >/=1,000/mL; platelets >/=50,000/mL; creatinine < 2.0; total bilirubin < 2.0;
ALT(SGPT) X ULN.

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. Ability to understand and the willingness to sign a written informed consent
document.

Exclusion Criteria:

1. Patients with uncontrolled concurrent illness, including but not limited to: ongoing
or active infection requiring hospitalization; psychiatric illness/social situations
that would limit compliance with study requirements.

2. Exclusion of patients with creatinine >2.0 and bilirubin > 2.0.

3. Pregnant or lactating women.

4. Patients with a history of bone marrow transplant within the previous two years.

5. Patients with a known hypersensitivity to any of the components of the drug products.

6. Patients with major surgery within 30 days prior to entering the study.

7. Patients with a baseline QTc > 500 ms.

8. Patients who are unable to swallow pills.

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Maximum Tolerated Dose (MTD) of combination Vemurafenib

Outcome Description:

The MTD of combination Vemurafenib and Everolimus or Vemurafenib and Temsirolimus is defined as the highest dose studied in which the incidence of dose limiting toxicity (DLT) was less than one third (33%) of the participants at that dose level.

Outcome Time Frame:

First cycle of 28 day cycle

Safety Issue:

Yes

Principal Investigator

Vivek Subbiah, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

UT MD Anderson Cancer Center

Authority:

United States: Institutional Review Board

Study ID:

2012-0153

NCT ID:

NCT01596140

Start Date:

December 2012

Completion Date:

Related Keywords:

  • Advanced Cancer
  • Solid Tumor
  • Vemurafenib
  • Everolimus
  • Afinitor
  • RAD001
  • temsirolimus
  • BRAF gene mutation
  • solid tumor
  • relapsed BRAF mutation positive malignant melanoma
  • refractory BRAF mutation positive malignant melanoma
  • Neoplasms

Name

Location

UT MD Anderson Cancer Center Houston, Texas  77030