Phase I / II Adaptive Randomized Trial of Vorinostat, Isotretinoin and Temozolomide in Adults With Recurrent Glioblastoma Multiforme
Temozolomide is designed to kill cancer cells by damaging DNA (the genetic material of
cells). The damaged DNA may cause tumor cell death. Isotretinoin is designed to decrease
the growth rate of gliomas and may decrease the blood supply to the tumor. Vorinostat is
designed to change the levels of production of several proteins in the tumor cells and
either kill or stop their growth. Researchers hope that it may improve the effects of
isotretinoin and temozolomide on malignant gliomas.
There are 2 phases to this study. In Phase 1, researchers are trying to find the highest
tolerable dose of the study drugs that can be given together in each of the 3 study groups.
Up to the first 54 participants enrolled in this study will be enrolled in Phase 1. If you
have an anaplastic glioma you are only allowed to participate in the Phase I part of this
study. In Phase 2, researchers will be trying to find out which of the 3 groups is best for
the treatment of gliomas.
If you are found to be eligible to take part in this study and you are enrolled in Phase 1,
you may be assigned to either Group 1 or Group 2. Group 1 will receive vorinostat and
isotretinoin. Group 2 will receive temozolomide and isotretinoin. If you enter the study
after the highest tolerable doses for Groups 1 and 2 are found, you will be assigned to
Group 3 and will receive vorinostat, isotretinoin, and temozolomide. No matter which group
you are assigned to, every 28 days will be called a study "cycle. During Days 21-28, you
will not receive any study drugs. This is called the "rest" period.
The first 3 participants in each study group will receive the lowest dose levels of the
study drugs. If there are no intolerable side effects seen at that dose level after 4 weeks
(or, 1 study "cycle"), the next 3 participants enrolled to each study group will receive a
higher dose of the study drugs. If there are no intolerable side effects at that second
dose level, 3 more participants will be enrolled in each study group at the next (higher)
dose level. In any study group, if 1 participant has intolerable side effects, another 3
participants will be enrolled at the same dose level. If a second participant at that dose
level has intolerable side effects, another group of 3 participants will then be enrolled in
that study group at the earlier (lower) dose level, to make sure that it is the highest safe
dose combination that can be given.
Once the phase I portion of the study is completed, the Phase II portion will begin. If you
are found to be eligible to take part in this study and are 1 of the first 30 participants
in Phase II, you will be randomly assigned (as in the roll of dice) to 1 of the same 3
groups as participants in the Phase I portion of the study.
If you are found to be eligible to take part in this study and you are not one of the first
30 participants assigned to Phase II, you will be assigned to a study group based on how
well each group is performing. If each group is about as effective as the other groups, you
may still have an equal chance of being assigned to each group. If 1 or 2 groups appear to
be more effective, you will have a higher chance of being assigned to the more effective
If you are eligible to participate in the Phase II portion of the study but your doctor has
recommended that you have surgery to remove a tumor that has come back, you would have the
surgery before being assigned to a study group. This part of the study is done to learn the
effects of vorinostat on tumor tissue and blood cells. Up to 10 participants will take part
in this portion of the study.
If you participate in this part of the study, you will be given vorinostat by mouth once
daily for 3 days in a row before your surgery. The last dose of the drug will be given the
morning of surgery. After the surgery, a portion of the remaining tumor tissue will be used
to measure the drug levels and the effects of vorinostat on the tumor. Blood (about 1
teaspoon) will be drawn before and after the first dose of vorinostat, and at the same time
as the tissue removal during surgery. This blood will be used to study the drug levels and
the effects of the drug in normal blood cells and to match these findings with that in the
After you have recovered from the effects of surgery (about 2 weeks), you will then be
randomly assigned or assigned based on known effectiveness as all other members of the Phase
All participants, regardless of being assigned to Phase 1 or 2, will receive the same study
drugs (based on the group they are assigned to) and the same procedures and testing.
If you are assigned to Group 1, you will take vorinostat by mouth once a day during Days
1-14. You will also take isotretinoin by mouth 2 times a day on Days 1-21.
If you are assigned to Group 2, you will take isotretinoin by mouth 2 times a day on Days
1-21. You will take temozolomide by mouth once a day on Days 1-7 and Days 15-21.
If you are assigned to Group 3, you will take vorinostat by mouth once a day during Days 1-7
and Days 15-21. You will also take isotretinoin by mouth 2 times a day on Days 1-21. You
will also take temozolomide by mouth once a day on Days 1-7 and Days 15-21.
About every week during Cycle 1 and about every 2 weeks after that, blood (less than 1
tablespoon) will be drawn for routine tests. Blood (about 2 tablespoons) will also be drawn
about every 2 weeks during Cycle 1 and then at the end of every cycle to check your liver
and kidney function and to see how well you blood clots.
At the end of Cycle 1 and the at the end of every odd numbered cycle (Cycles 3, 5, 7 and so
on), blood (about 1 teaspoon) will be drawn for lipid testing (a check of different types of
fat in the blood, such as cholesterol).
Women who are able to have children must have a negative blood (about 1 teaspoon) pregnancy
test before each new cycle. If at any point during the study your treatment is delayed, you
will also have a pregnancy test before restarting therapy.
You will have a complete physical and neurological exam at the end of Cycle 1 and 2, then
at the end of every other cycle (Cycles 4, 6, 8 and so on). These tests may be performed
more often if your doctor thinks it is necessary. Your performance status will be recorded.
You will have a complete medical history and physical exam, including measurement of your
weight. You will have a neurological exam.
You will have an MRI scan at the end of every other cycle (Cycles 2, 4, 6, 8 and so on).
These tests may be performed more often if your doctor thinks it is needed.
You will receive the treatment for up to 1 year, after which you will continue to be
monitored on the study provided your disease does not get worse. You may continue to receive
treatment beyond 1 year and remain on study if your doctor decides that it is in your best
Once you are no longer receiving the study drugs, you will have an end-of-study visit. At
this visit, you will have another complete physical exam. Blood (less than 2 tablespoons)
will be drawn for routine tests, to check your liver and kidney function, to check your
bloods ability to clot, and for lipid testing. You will have an MRI.
After you have your end-of-study visit, you will have a follow-up evaluation (a clinic visit
or telephone call) about every 3 months to find out how you are feeling. These visits/calls
will continue indefinitely. The phone calls will take about 15 minutes.
This is an investigational study. Isotretinoin, temozolomide, and vorinostat are FDA
approved drugs and commercially available. The use of these drugs in this combination is
investigational. Up to 189 patients will take part in this study. All will be enrolled at
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose (MTD)
Each 4 week period to accomodate 28 day cycles
Marta Penas-Prado, MD
M.D. Anderson Cancer Center
United States: Institutional Review Board
|UT MD Anderson Cancer Center||Houston, Texas 77030|