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A Phase I Study of Epigenetic Immunomodulation Through the Use of Azacitidine, Lenalidomide, and Grifola Frondosa in Patients With Advanced Malignancy


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

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Trial Information

A Phase I Study of Epigenetic Immunomodulation Through the Use of Azacitidine, Lenalidomide, and Grifola Frondosa in Patients With Advanced Malignancy


Study Drugs:

Azacitidine is designed to block certain proteins in cancer cells whose job is to stop the
function of the tumor-fighting proteins. By blocking the "bad" proteins, the tumor-fighting
genes may be able to work better.

Lenalidomide is designed to change the body's immune system. It may also interfere with the
development of tiny blood vessels that help support tumor growth. This may decrease the
growth of cancer cells.

Grifola frondosa extract is a natural substance taken from maitake mushrooms. Researchers
want to learn if it can cause the body's immune system to react against cancer.

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to receive
either azacitidine and lenalidomide, azacitidine and Grifola frondosa, or azacitidine,
lenalidomide, and Grifola frondosa at a dose level based on when you joined this study.

Up to 4 dose levels of azacitidine and lenalidomide will be tested. Up to 2 dose levels of
azacitidine and Grifola frondosa will be tested. At the beginning of the study, 3-6
participants will be enrolled at each dose level of the study drug combinations. The first
group of participants will receive the lowest dose level of azacitidine and lenalidomide.
Each new group will receive a higher dose of the study drug combination than the group
before it, if no intolerable side effects were seen. This will continue until the highest
tolerable dose of the study drug combination is found. After enrollment in the azacitidine
and lenalidomide group is completed, the next group of participants will receive the lowest
dose level of azacitidine and Grifola frondosa. Each new group will receive a higher dose of
the study drug combination than the group before it, if no intolerable side effects were
seen. This will continue until the highest tolerable dose of the study drug combination is
found.

After the highest dose of the azacitidine and lenalidomide or Grifola frondosa combinations
are found, new participants enrolling in this study will begin receiving Grifola frondosa
along with azacitidine and lenalidomide. Up to 2 dose levels will be tested. The first group
of participants will receive the lowest dose level of lenalidomide. The next group will
receive a higher dose of lenalidomide than the group before it, if no intolerable side
effects were seen. The doses of azacitidine and Grifola frondosa will stay the same.

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

Study Drug Administration:

A study drug "cycle" is 28 days.

On Days 1-5 of each Cycle, you will receive azacitidine either under the skin or by vein.
If you receive azacitidine as an injection under the skin, you will receive it over 10
minutes. If you receive azacitidine by vein, you will receive it over 40 minutes.

On Day 2 of Cycle 1, you will begin taking lenalidomide 1 time each day until Day 21, then
you will have a 7 day-rest period. For Cycle 2 and every cycle after that, you will take
lenalidomide 1 time each day on Days 1-21 followed by a 7-day rest period. Lenalidomide is
a capsule that you will take by mouth with water. The capsules should be swallowed whole.
You should not break, chew, or open the capsules.

If you are assigned to receive Grifola frondosa, you will also begin taking Grifola frondosa
2 times each day on Day 2 of Cycle 1 if you are also taking azacitidine. If you are also
taking azacitidine and lenalidomide, you will begin taking Grifola frondosa on Day 3 of
Cycle 1. Depending on the dose level you are assigned to, you will either take Grifola
frondosa 2 times each day until Day 21 followed by a 7-day rest period, or you will take
Grifola frondosa 2 times daily during all cycles. Grifola frondosa is a liquid extract that
comes in a glass bottle. Your dose of Grifola frondosa will be based on when you joined the
study and your body weight.

Expansion Groups:

After the highest tolerable dose of each study drug combination is found, 42 additional
participants will be enrolled in 3 expansion groups (14 in each group), one group for each
study drug combination at the highest tolerable dose or a dose level that has been shown to
be safe.

Study Visits:

The following tests and procedures will be performed within 7 days before your first dose of
study drug:

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

- Your performance status will be recorded.

- Blood (about 2 teaspoons) and urine will be collected for routine tests.

Women who are able to have children must have a negative blood (about 1 teaspoon) pregnancy
test within 10 to 14 days before the first dose of the study drug combination and again
within 24 hours before receiving lenalidomide.

Before you begin each cycle, the following tests and procedures will be performed:

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

- Your performance status will be recorded.

- Blood (about 2 teaspoons) and urine will be collected for routine tests.

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

- If the study doctor thinks it is needed, blood (about 1 teaspoon) will be drawn to
measure tumor markers.

- Women who are able to have children will have a blood pregnancy test.

Every week during Cycles 1 and 2, blood (about 2 teaspoons) will be drawn for routine tests.

Women who are able to have children will have a blood (about 1 teaspoon) pregnancy test
every week during Cycle 1.

At the end of every 2 cycles (Cycles 2, 4, 6, and so on), you will have a CT, MRI, PET scan,
and/or x-ray to check the status of the disease.

If you are in the one of the Expansion Groups, blood (about 6 teaspoons each time) will be
drawn for biomarker testing before you take the first dose of study drug, on Days 21 and 28
of Cycle 1, 1 time during each cycle after that, and at the end-of-study visit.

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 or
intolerable side effects occur.

End-of-Study Visit:

Within 30 days after your last dose of the study drug combination, you will have an
end-of-study visit. The following tests and procedures performed:

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

- Your performance status will be recorded.

- Blood (about 2 teaspoons) and urine will be collected for routine tests.

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

- If the study doctor thinks it is needed, blood (about 1 teaspoon) will be drawn to
measure tumor markers.

- If the study doctor thinks it is needed, you will have a chest x-ray, CT, MRI, and/or
PET scan to check the status of the disease.

- Women who are able to have children will have a blood pregnancy test.

This is an investigational study. Grifola frondosa extract is not FDA approved for any
usage. Its use in this study is investigational. Azacitidine and lenalidomide are FDA
approved and commercially available for the treatment of multiple myeloma and
myelodysplastic syndrome. The use of the study drug combination (Grifola frondosa,
azacitidine, and lenalidomide) is currently being used for research purposes only.

Up to 102 patients will take part in this study. All will be enrolled at M. D. Anderson.


Inclusion Criteria:



1. Patients must have histologically or cytologically confirmed diagnosis of an advanced
solid tumor refractory to standard treatment or for which no standard therapy is
available.

2. Patients must have ECOG performance status 2 or better (0-2).

3. Patients must have normal organ and marrow function as defined: Absolute lymphocyte
count > 1,000 /uL, Absolute neutrophil count > 1,500 /uL, Platelets > 75,000 /uL,
Bilirubin normal (ULN), normal limits; if abnormal, then a calculated creatinine clearance >/= 50 mL/min

4. Patients must be able to understand and be willing to sign an IRB-approved written
informed consent document.

5. Females of childbearing potential (FCBP) must have a negative serum or urine
pregnancy test with a sensitivity of at least 50 mlU/mL within 10-14 days prior to
and again within 24 hours of prescribing lenalidomide (prescriptions must be filled
within 7 days) and must either commit to continued abstinence from heterosexual
intercourse or begin TWO acceptable methods of birth control, one highly effective
method and one additional effective method AT THE SAME TIME, at least 28 days before
she starts taking lenalidomide.FCBP must also agree to ongoing pregnancy testing. Men
must agree to use a latex condom during sexual contact with a FCBP even if they have
had a successful vasectomy. A female of childbearing potential is a sexually mature
woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has
not been naturally postmenopausal for at least 24 consecutive months (ie, has had
menses at any time in the preceding 24 consecutive months).

6. Patients must be 18 years of age or older since the safety and dosages of these study
drugs has not been demonstrated in the pediatric population. Exception: patients who
are 13 years old or older and have more than 50 kg of body weight will be eligible
after consultation with their pediatric attending.

7. Life expectancy greater than 3 months based on the attending physician's discretion.

8. All study participants must be registered in the mandatory RevAssist program, and be
willing and able to comply with the requirements of RevAssist.

Exclusion Criteria:

1. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure (NYHA Class III or IV), unstable
angina pectoris, symptomatic cardiac arrhythmia, active bleeding, active thrombosis,
or psychiatric illness/social situations that would limit compliance with study
requirements.

2. History of stroke or transient ischemic attack within 6 months prior to study
enrollment and significant vascular disease (e.g., aortic aneurysm, aortic
dissection) and symptomatic peripheral vascular disease.

3. History of allergic reactions to the study drugs or their analogs.

4. Patients that have had any treatment specific for tumor control within 3 weeks of
study drug treatment or: a. within 2 weeks if cytotoxic agents were given weekly b.
within 6 weeks for nitrosoureas or mitomycin C c. within 4 half-lives for targeted
agents with half lives and pharmacodynamic effects lasting less than 5 days (that
includes, but is not limited to, erlotinib, sorafenib, sunitinib, bortezomib, and
other similar agents) d. failed to recover from toxic effects of any therapy prior to
study entry

5. Concurrent known immunosuppressors.

6. Inability to swallow oral medication.

7. Pregnant or breastfeeding women.

8. Concurrent enrollment on another research study.

9. Known hepatitis B and C infection, HIV infection and autoimmune disorders.

10. Subjects with known moderate or severe renal impairment will be excluded if
creatinine clearance < 60 ml/min.

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)

Outcome Description:

MTD defined by patient dose limiting toxicities (DLTs) that occur in the first cycle (4 weeks).

Outcome Time Frame:

4 weeks

Safety Issue:

Yes

Principal Investigator

Siqing Fu, MD, PHD

Investigator Role:

Principal Investigator

Investigator Affiliation:

UT MD Anderson Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

2010-0076

NCT ID:

NCT01200004

Start Date:

April 2012

Completion Date:

Related Keywords:

  • Advanced Cancers
  • Advanced solid tumor
  • Azacitidine
  • Grifola frondosa
  • Basidiomycete fungus
  • Lenalidomide
  • Neoplasms

Name

Location

UT MD Anderson Cancer CenterHouston, Texas  77030