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Phase I/II Study of Hyper-CVAD Plus RAD001 (Everolimus) for Patients With Relapsed or Refractory Acute Lymphocytic Leukemia (ALL)

Phase 1/Phase 2
10 Years
Open (Enrolling)
Leukemia, Acute Lymphocytic Leukemia

Thank you

Trial Information

Phase I/II Study of Hyper-CVAD Plus RAD001 (Everolimus) for Patients With Relapsed or Refractory Acute Lymphocytic Leukemia (ALL)

The Study Drugs:

Everolimus is designed to stop cancer cells from multiplying. It may also stop the growth
of new blood vessels that help tumor growth, which may cause the tumor cells to die.

You will receive everolimus with 2 different chemotherapy combinations during alternating
cycles. This means that you will receive 1 combination on Cycles 1, 3, 5, and 7 and the
other combination during Cycles 2, 4, 6, and 8.

The first chemotherapy regimen is called hyper-CVAD. Hyper-CVAD includes cyclophosphamide,
vincristine, Adriamycin (doxorubicin), and dexamethasone. This combination is designed to
kill leukemia cells.

The other chemotherapy regimen includes the drugs methotrexate and ara-C (cytarabine). This
combination is also designed to kill leukemia cells.

Study Groups and Everolimus Dose Levels:

If you are found to be eligible to take part in this study, you will be assigned to a study
group based on when you joined this study. Up to 3 groups of 3-6 participants will be
enrolled in the Phase I portion of the study, and up to 30 participants will be enrolled in
Phase II.

If you are enrolled in the Phase I portion, the dose of everolimus you receive will depend
on when you joined this study. The first group of participants will receive the lowest dose
level of everolimus. Each new group will receive a higher dose of everolimus than the group
before it, if no intolerable side effects were seen. This will continue until the highest
tolerable dose of everolimus is found.

If you are enrolled in Phase II, you will receive everolimus at the highest dose that was
tolerated in the Phase I portion.

In this study, everolimus is the only study drug where different dose levels are being
tested and compared. All other drugs will be given at the same dose level.

Central Venous Catheter (CVC):

If you do not already have a CVC, you will have a CVC placed. A CVC is a plastic tube
usually placed under the collarbone. You will sign a separate consent for this procedure.
Some of the study drugs will be given through the CVC.

Everolimus Administration:

During all cycles, you will take everolimus once a day followed by a big glass of water. The
tablets must not be chewed, broken or crushed. You may either take everolimus on an empty
stomach or after a low fat meal. Taking everolimus after large, fatty meals is not advised
because it will lower the amount of everolimus your body absorbs. Some examples of a low fat
meal include: cereal with fat free milk, muffin/bagel with fat free spread, fruit salad, and
so on. Always follow the instructions for use of everolimus given to you by your study
doctor. Your first dose of everolimus will occur 1 day before you begin receiving

Do not miss any tablets/capsules. You should take everolimus about the same time each day
preferably in the morning.

If your study doctor thinks it is needed or if you experience severe side effects,
everolimus may be stopped and then started again with a lower dose or may be stopped

Chemotherapy Administration:

Each cycle will last about 21 days. The timing of each new cycle will depend on when your
blood counts recover.

Cycles 1, 3, 5, and 7:

During Cycles 1, 3, 5, and 7, you will receive hyper-CVAD. The drugs will be given at the
following times:

- On Days 1-3, you will receive cyclophosphamide by vein over 2-3 hours every 12 hours.

- On Days 1-4 and 11-14, you will receive dexamethasone by mouth or by vein. If by vein,
the infusion will take a few seconds.

- On Day 4, you will receive doxorubicin over 24 hours through a CVC.

- On Days 4 and 11, you will receive vincristine by vein over 2-3 hours.

Cycles 2, 4, 6, and 8:

During Cycles 2, 4, 6, and 8, you will receive the methotrexate and cytarabine by vein as

- On Day 1, you will receive methotrexate by vein over 24 hours.

- On Day 1, you may receive leucovorin (citrovorum) by vein (over 15 minutes) for 2-3
days. Leucovorin is given to help prevent methotrexate side effects.

- On Days 2-3, you will receive cytarabine by vein over 2 hours every 12 hours.

- On Days 1-3, you will receive methylprednisone over 2 hours every 12 hours for 6 doses.

Cycles 1-8:

You will also receive either Neupogen (filgrastim) or pegfilgrastim to help your bone marrow
recover from chemotherapy. Filgrastim or pegfilgrastim will be injected under the skin
within 72 hours after each cycle of chemotherapy. If you receive filgrastim, it will be
given daily until your counts recover. If you receive pegfilgrastim, it will be given 1

You will also receive small doses of methotrexate and Ara-C, one after the other, by a
spinal tap to help prevent the disease from coming back in the fluid surrounding your brain
during each cycle. During a spinal tap, a doctor or technician inserts a needle through the
skin and the soft tissues of the lower back to reach a pocket of fluid that is part of the
fluid space that surrounds the brain and the spinal cord. Once the fluid space is reached,
chemotherapy drugs can be administered. The procedure is done under local anesthesia. An
Ommaya reservoir (which holds the drugs being given) may also be implanted surgically if you
have difficulty with the spinal treatments. An Ommaya reservoir is a tube inserted under
the skin of the scalp that enters into the spinal fluid cavity of the brain. You will be
asked to sign a separate consent form for this procedure. The number of doses you receive
will depend on how many doses the study doctor thinks are needed. If you start with
leukemia in the brain, it will be given 2 times a week until there is no leukemia present
and then 1 time a week for 4 weeks. Sometimes, a sample of the spinal fluid collected from
the spinal taps may be tested to look for leukemia cells.

Maintenance Chemotherapy:

After you have completed 8 cycles, you will begin monthly (about every 28 days, depending on
your blood cell count recovery) maintenance chemotherapy for about the next 24 months. You
will take the following drugs:

- You will take 6-mercaptopurine by mouth with water every day.

- You will receive methotrexate by vein (over 2 hours) or mouth every week.

- You will receive vincristine by vein over 30 minutes every 28 days.

- You will take prednisone by mouth for 5 days every month.

Study Visits:

During Cycle 1, blood (about 1 tablespoon) will be drawn for routine tests 1-3 times every
week. During Cycles 2-8, blood (about 1 tablespoon) will be drawn for routine tests every
1-4 weeks.

During Cycles 1 and 2, you will have physical exam every week. After Cycle 2, you will have
a physical exam every 3-4 weeks.

At Weeks 2 and 3 of Cycle 1, you will have a bone marrow aspirate to check for response.
Depending on the results of the sample, this will be repeated every 1-2 weeks.

At Week 4-6 of Cycle 1, you will have a chest x-ray.

After Cycle 2 is over, the following tests and procedures will be performed:

- You will have a physical exam.

- Blood (about 8 teaspoons) and urine will be collected for routine tests.

- You will have a bone marrow aspirate.

- You will have a chest X-ray or computed tomography (CT) scan if needed.

If you had a positive hepatitis B test at screening, every month, blood (about 1
tablespoon) will be drawn to test the level of hepatitis B virus in your blood.

If your have risk factors and/or a positive Hepatitis C test results at screening, every
month, blood (about 1 tablespoon) will be drawn to test the level of Hepatitis C virus in
your blood.

Length of Study:

You may receive up to 32 cycles of study drugs. You will be taken off study early if the
disease gets worse, your doctor decides it is in your best interest to stop, or you have
intolerable side effects.

End-of-Study Visit:

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:

- You will have a physical exam.

- Blood (about 8 teaspoons) will be drawn for routine tests.

- You will have a bone marrow aspirate.

- If your doctor thinks it is needed, you will have a chest x-ray or CT scan.

Follow-up Visits:

You will have follow-up visits every 3 to 6 months. At these visits, the following tests
and procedures will be performed:

- You will have a physical exam.

- You will have a bone marrow aspirate.

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

- If your doctor thinks it is needed, you will have a chest x-ray.

This is an investigational study. All the chemotherapy drugs used on this study are FDA
approved and commercially available for treating ALL. Everolimus is FDA approved and
commercially available for the treatment of certain types of breast cancer. At this time,
the combination is only being used in research.

Up to 42 patients will take part in this study. All will be enrolled at MD Anderson.

Inclusion Criteria:

1. Refractory or relapsed acute lymphocytic leukemia (ALL) or lymphoblastic lymphoma
(LL). Patients expressing Philadelphia chromosome (Ph+) are eligible if they have
failed a prior tyrosine kinase-containing therapy.

2. Age >/= 10 years.

3. ECOG performance status
4. Adequate liver function with serum bilirubin alanine aminotransferase (ALT) and aspartate aminotransferase (AST) unless proven to be related to disease infiltration.

5. Adequate renal function with serum creatinine related to disease infiltration.

6. No symptomatic pulmonary disease. Forced expiratory volume in 1 s (FEV1), forced
vital capacity (FVC) and diffusion capacity of carbon monoxide (DLCO) >/= 50% of
expected, corrected for hemoglobin.

7. Fasting serum cholesterol patient can only be included after initiation of appropriate lipid lowering

8. Signed informed consent.

Exclusion Criteria:

1. Systemic chemotherapy within 7 days (with the exception of hydroxyurea and/or
dexamethasone) prior to starting therapy and recovered from persistent acute toxicity
(> grade 1) from that therapy, unless there is evidence of rapidly progressive
disease. Concurrent therapy for central nervous system (CNS) prophylaxis or treatment
for CNS relapse is permitted.

2. Prior treatment with or known hypersensitivity to an mTOR inhibitor (sirolimus,
temsirolimus, everolimus).

3. Major surgery within 4 weeks of start of study drug.

4. Other malignancies within the past 3 years except for adequately treated carcinoma of
the cervix, or basal or squamous cell carcinomas of the skin.

5. Severe and/or uncontrolled medical conditions or other conditions that could affect
participation in the study: a. Symptomatic congestive heart failure of New York Heart
Association Class III or IV. b. Unstable angina pectoris or myocardial infarction
within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia. c.
Uncontrolled severe infections. d. Liver disease such as cirrhosis, or severe hepatic
impairment (Child-Pugh class C).

6. continuation of #5: Note: A detailed assessment of Hepatitis B/C medical history and
risk factors must be done at screening for all patients. HBV DNA and HCV RNA PCR
testing are required at screening for all patients with a positive medical history
based on risk factors and/or confirmation of prior HBV/HCV infection.

7. Known history of HIV seropositivity.

8. Impairment of gastrointestinal function of gastrointestinal disease that may
significantly alter the absorption of RAD001 (e.g., ulcerative disease, malabsorption
syndrome or small bowel resection).

9. Female patients who are pregnant or breast feeding, or adults of reproductive
potential who are not using effective birth control methods. Childbearing potential
is a sexually mature woman who: 1)has not undergone a hysterectomy or bilateral
oophorectomy; 2)has not been naturally postmenopausal for at least 24 consecutive
months. Adequate contraception must be used throughout the trial and for eight weeks
after the last dose of study drug, by both sexes. (Women of child bearing potential
must have a negative urine or serum pregnancy test within 7 days prior to
administration of therapy.)

10. Male patient whose sexual partner(s) are women of child bearing potential who are not
willing to use adequate contraception, during the study and for 8 weeks after the end
of treatment.

11. Patients should not receive immunization with attenuated live vaccines within one
week of study entry or during study period. Close contact with those who have
received attenuated live vaccines should be avoided during treatment with everolimus.
Examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral
polio, BCG, yellow fever, varicella and TY21a typhoid vaccines.

12. Patients who have developed pleural effusion while on dasatinib therapy.

Type of Study:


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 Time Frame:

Following each dose cycles (21 days)

Safety Issue:


Principal Investigator

Marina Konopleva, MD, PHD

Investigator Role:

Study Chair

Investigator Affiliation:

UT MD Anderson Cancer Center


United States: Institutional Review Board

Study ID:




Start Date:

November 2009

Completion Date:

Related Keywords:

  • Leukemia
  • Acute Lymphocytic Leukemia
  • Acute Lymphocytic Leukemia
  • ALL
  • Hyper-CVAD
  • RAD001
  • Everolimus
  • 6-mercaptopurine
  • Citrovorum
  • Cyclophosphamide
  • Cytarabine
  • Dexamethasone
  • Doxorubicin
  • G-CSF
  • Methotrexate
  • Pegfilgrastim
  • Prednisone
  • Solumedrol
  • Vincristine Sulfate
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma



UT MD Anderson Cancer CenterHouston, Texas  77030