A Phase I Trial of Sirolimus (mTOR Inhibitor) or Vorinostat (HDAC Inhibitor) in Combination With Hydroxychloroquine (Autophagy Inhibitor) in Patients With Advanced Malignancies
The Study Drugs:
Sirolimus is designed to block a protein called mTOR inside the cancer cell. This may
interfere with the growth or spread of cancer cells or possibly kill the cancer cells.
Vorinostat is designed to cause chemical changes in different groups of proteins that are
attached to DNA (the genetic material of cells), which may slow the growth of cancer cells
or cause the cancer cells to die.
Hydroxychloroquine is designed to stop a cell process called autophagy (in which a cell
breaks down and recycles parts of itself) that cancer cells need to perform in order to
Study Drug Dose Level:
If you are found to be eligible to take part in this study, you will be assigned to a dose
level of hydroxychloroquine and either sirolimus or vorinostat, based on when you joined
this study, availability of spots for each drug combination, and what your doctor thinks is
in your best interest. Up to 11 dose levels of the sirolimus and hydroxychloroquine
combination and 9 dose levels of the vorinostat and hydroxychloroquine combination will be
tested. Three (3) to 6 participants will be enrolled at each dose level. The first group of
participants will receive the lowest dose level of the study drug combination. 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 each drug combination is
Once the highest tolerated dose of each drug combination is found, up to 28 more
participants (14 per combination) will be given this dose. The study doctor will decide
which drug combination each participant is given, based on their tumor type.
Study Drug Administration:
Each study "cycle" is 21 days.
You will take hydroxychloroquine and either vorinostat or sirolimus by mouth, 1 time a day,
every day. You should take the pills at about the same time each day with food and a cup (8
ounces) of water.
At every study visit, you will be asked about any health conditions you have, drugs you may
be taking, and if you have had any side effects.
Weekly During Cycle 1:
-Blood (about 2 teaspoons) will be drawn for routine tests.
At the beginning of each cycle beginning with 2:
- You will have a physical exam.
- Your medical history will be recorded.
- You will be asked if you have any muscle weakness or difficulty while moving.
Every 6 weeks, you will have an x-ray, CT scan, MRI scan, and/or PET/CT to check the status
of the disease. If the study doctor thinks it is needed, they will be performed more often.
If you are able to become pregnant, you will have a blood (about 1 teaspoon) or urine
About every 3 months, you will have an eye exam.
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 drug if the disease gets worse or
intolerable side effects occur.
This is an investigational study. Sirolimus is FDA approved and commercially available for
the treatment of patients with a kidney transplant. Vorinostat is FDA approved and
commercially available for the treatment of cutaneous T-cell lymphoma. Hydroxychloroquine is
FDA approved and commercially available to treat malaria. The use of these drugs
combinations is investigational.
Up to 236 patients will take part in this study. All will be enrolled at MD Anderson.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum Tolerated Dose (MTD)
Maximum tolerated dose (MTD) defined defined as the dose level below the dose at which 2 of 6 patients experience drug-related dose limiting toxicity (DLT) in the first treatment cycle.
21 day cycles, approximaely 4 weeks for DLT assessment
Filip Janku, MD, PHD
UT MD Anderson Cancer Center
United States: Food and Drug Administration
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