Protocol Number: 01-C-0196

Title:

A Phase I Trial and Pharmacokinetic Study of R115777 in Pediatric Patients With Refractory Leukemias

Number:

01-C-0196

Summary:

This study will determine what dose of R115777 can safely be given to children with leukemia. R115777 interferes with the function of certain proteins that control cell growth. In many types of cancer, including leukemia, one of these proteins, called ras does not function properly, so that cell growth is unchecked. Besides determining a safe dose of R115777, this study will also look at the drug's side effects, its possible benefits in treating childhood leukemia, how the body uses and eliminates it, and what changes occur in leukemia cells and in the gene that produces the ras protein after giving R115777.

Patients 21 years of age or younger with acute lymphoblastic leukemia (ALL), acute non-lymphoblastic leukemia) ANLL), juvenile myelomonocytic leukemia (JMML), or chronic myelogenous leukemia (CML) who do not respond to standard therapy may be eligible for this study. Candidates will be screened with a history and physical examination, eye examination, blood and urine tests, lumbar puncture (spinal tap) and bone marrow aspiration. Lumbar puncture is done to examine the cerebrospinal fluid (CSF), which bathes the brain and spinal cord. After a local anesthetic is administered, a needle is inserted in the space between the bones in the lower back where the CSF circulates below the spinal cord. A small amount of fluid is collected through the needle. For the bone marrow test, the hip area is anesthetized and a special needle is used to draw bone marrow from the hipbone.

Patients enrolled in the study will take R115777 tablets every 12 hours for 21 days, followed by a 7-day rest period, completing one treatment cycle. To determine the highest dose of drug that can be given safely, the starting dose will be low and will be increased gradually in small groups of patients. Treatment cycles will continue unless unacceptable side effects occur or the leukemia does not respond to the drug. Patients will undergo the following tests and procedures to monitor for side effects and evaluate the response of the leukemia to treatment:

- Physical examinations - every week, initially

- Eye examinations - regularly

- Blood tests- periodically throughout treatment

- Bone marrow examination - before the start of each treatment cycle for three cycles and then less often

- Buccal swab (scraping the inside of the cheek with a tongue depressor to collect a cell sample) - before the first treatment dose and once during the first treatment cycle.

Additional blood samples will be collected as follows:

- To study the pharmacology of R115777, 12 small blood samples will be collected on days 1 and 2 after the first dose of R115777, and one sample will be taken between days 6 and 10 during the first treatment cycle only. If possible, the blood will be drawn through an indwelling catheter to avoid multiple needle sticks.

- Samples will be collected before the first treatment dose, once during the first treatment cycle, and before cycles 3,6, 9 and 12, to measure the effect of R115777 on a substance called nerve growth factor to see if it can predict which patients may be at risk for developing side effects from R115777

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION CRITERIA

Age: Patients must be less than or equal to 21 years of age.

Histological Diagnosis: Patients must have histologically-confirmed acute lymphoblastic leukemia (ALL), acute non lymphoblastic leukemia (ANLL), juvenile myelomonocytic leukemia (JMML), or chronic myelogenous leukemia (CML) in blast crisis.

Prior Therapy: The leukemia must be refractory to standard curative treatment regimens. Patients with acute promyelocytic leukemias (APL) must be refractory to treatment with retinoic acid and arsenic trioxide. Patients with Philadelphia (Ph) chromosome positive CML must be refractory to ST1571.

Patients must have had their last dose of radiation therapy at least four weeks prior to study entry, their last dose of chemotherapy, including corticosteroids, at least two weeks prior to study entry, and their last dose of retinoids 7 days prior to study entry. Patients who previously received myeloablative therapy followed by a bone marrow or stem cell transplant are eligible if the transplant was performed at least 3 months before study entry.

Patients must be off colony stimulating factors (with the exception of erythropoietin) such as filgrastim (granulocyte colony-stimulating factor), and GM-CSF for at least one week prior to study entry.

Patients must have recovered from the non-hematologic toxic effects of all prior therapy before entry onto this trial.

Disease Status: Patients must have greater than 25% blasts in the bone marrow (M3 bone marrow). Active extramedullary disease (except for leptomeningeal disease) may also be present.

Performance Status: Patients greater than 10 years must have a Karnofsky performance level greater than or equal to 50, and children less than or equal to 10 years must have a Lansky performance level greater than or equal to 50.

Hepatic Function: Patients must have adequate liver function, defined as bilirubin, SGPT, and SGOT within normal limits, and no recent history (within 1 month of trial entry) of significant elevation in bilirubin, SGPT, or SGOT to greater than or equal to 3.

Renal Function: Patients must have an age-adjusted normal serum creatinine OR a creatinine clearance greater than or equal to 60 mL/min/1.73 m(2).

Hematologic Function: Blood counts not required to be normal prior to entry on this trial.

Informed Consent: All patients or their legal guardians (if the patient is less than 18 years old) must sign a document of informed consent indicating their understanding of the investigational nature and the risks of this study before any protocol related studies are performed (this does not include routine laboratory tests or imaging studies required to establish eligibility). When appropriate, pediatric patients will be included in all discussions in order to obtain verbal assent.

Birth Control: Subjects of childbearing or child-fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while they are being treated on this study.

EXCLUSION CRITERIA

Patients with active leptomeningeal leukemia (CSF WB greater than 5 micrograms and unequivocal confirmation of leukemic blasts in the CSF by morphologic demonstration on a CSF cytocentrifuge specimen).

Patients with persistent grade greater than 2 sensory or motor neuropathy.

Patients with history of grand mal seizures (grade greater than or equal to 3) other than febrile seizures. No patients taking anti-convulsant medications, for any reasons.

Clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic, renal or other organ dysfunction) which in the judgement of the Principal or Associate Investigator would compromise the patient's ability to tolerate R115777 or are likely to interfere with the study procedures or results.

Pregnant or breast feeding females.

Patients currently receiving other investigational agents.

Inability to return for follow up visits.

Patients with an allergy to azoles (for example clotrimazole, fluconazole, ketoconazole, voriconazole).

Patients requiring total parenteral nutrition.

Special Instructions: Currently Not Provided

Keywords:

Farnesyltransferase

Inhibitor

RAS

Biologic Studies

Recruitment Keywords:

Leukemia

Pediatric

Children

Conditions:

Acute Lymphocytic Leukemia

Chronic Myelogenous Leukemia

Acute Nonlymphocytic Leukemia

Acute Myelomonocytic Leukemia

Chronic Myelomonocytic Leukemia

Chronic Myelogenous Leukemia

Investigational Drug(s):

R115777

Investigational Device(s):

None

Contacts:

Wendy Goodspeed, R.N.
National Institutes of Health
Building 10
Room 13C103
10 Center Drive
Bethesda, Maryland 20892
Phone: (301) 594-4762
Fax: (301) 480-8871

Electronic Address: goodspew@mail.nih.gov

Citations:

Farnesyltransferase inhibitors and anti-Ras therapy

Ras protein farnesyltransferase: A strategic target for anticancer therapeutic development

The potential of farnesyltransferase inhibitors as cancer chemotherapeutics

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