Study of VELCADE® With Mitoxantrone and Etoposide for Leukemias

Phase I/II Trial of VELCADE® (Bortezomib) in Combination With Mitoxantrone and Etoposide for Relapsed or Refractory Acute Leukemias

Based on what is known about it's mechanism of action, bortezomib is presumed to make other chemotherapy drugs work better. This study examines the use of bortezomib in combination with an already effective chemotherapy regimen that is used to treat leukemias that have relapsed or been refractory to treatment.

VELCADE is a drug that blocks growth of cancer cells and helps destroy them. This research will help us to determine if VELCADE when combined with chemotherapy is useful in treating the leukemia with which you have been diagnosed. Your leukemia is a type that did not respond to chemotherapy or has come back after successful therapy.

VELCADE is approved by the Food and Drug Administration (FDA) for the treatment of multiple myeloma for patients that have received at least one prior therapy. Multiple Myeloma is a type of cancer that develops from blood cells. The dose of the drug being used in this research study is the same as what is used for the treatment of myeloma but the number of injections is less. VELCADE has, however not been approved by the FDA for use in acute leukemia. Mitoxantrone and etoposide, the other two chemotherapy drugs are also used for treating leukemia.

In the first part of the study, we are going to test the safety of VELCADE at different doses when given with mitoxantrone and etoposide. You may be enrolled at any one of three doses. In the second part, we are going to assess the response to the combination of VELCADE and chemotherapy drugs. You will receive VELCADE at the chosen dose based on safety assessment from Phase I. It will be administered as an intravenous (through the vein) injection on day-1 and day-4 of the 5-day schedule. In addition, you will also receive mitoxantrone over 15 minutes and etoposide over 45 minutes from days 1-5. The first 28 days from the beginning of the treatment will be called a treatment cycle.

On day-14 of the treatment cycle, you will have a bone marrow biopsy done to see if all the leukemia cells have disappeared. If there is no evidence of leukemia, then you may receive growth factors to help your marrow recover faster. If there is still presence of leukemia, in the same amount or more, then the treatment will be considered a failure and you will not receive any more of this treatment.

If there is a partial improvement then you will receive additional cycles of VELCADE with chemotherapy as described above until there are no signs of your disease. This is called a complete remission.

Therapy will be withheld at any time if there is concern that you are having side-effects that are not medically acceptable. Once the side-effects have resolved, VELCADE therapy may be re-started at a lower dose.

It is estimated that you may require about two to three cycles of therapy.

Inclusion Criteria:

• Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (ie, a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study.

• Male subject agrees to use an acceptable method for contraception for the duration of the study.

• Patients who have had a diagnosis of Acute Myeloid Leukemia (AML) or Acute Lymphoblastic Leukemia (ALL) will be eligible for the study.

  • Patients must have failed initial therapy that may manifest in either of the following ways:

    • Demonstration of Primary Refractory Disease (Primary Induction Failure) as evidenced by a mid-cycle bone marrow analysis showing lack of complete tumor clearance (CTC).
    • Relapse of initial disease after a period of attaining complete remission.

• Patients must be > 18 years of age, with no upper age limit.

• ECOG performance status of 0 or 1.

• Patients have no symptomatic cardiac or pulmonary disease and adequate hepatic and renal function as measured by the following criteria:

  • Cardiac: Left ventricular ejection fraction at rest must be >40% (MUGA preferred)
  • Hepatic: ALT and AST < 3x the upper limits of normal range as specified by the institution's clinical laboratory.
  • Renal: Serum creatinine within the normal range (< 1.4 mg/dL) or if creatinine outside normal range then creatinine clearance > 60 mL/min/m2

• Patients who have had a diagnosis of Acute Myeloid Leukemia (AML) or Acute Lymphoblastic Leukemia (ALL) will be eligible for the study.

• Patients must have failed initial therapy that may manifest in either of the following ways:

  • Demonstration of Primary Refractory Disease (Primary Induction Failure) as evidenced by a mid-cycle bone marrow analysis showing lack of complete tumor clearance (CTC).
  • Relapse of initial disease after a period of attaining complete remission.

• Patients must be > 18 years of age, with no upper age limit.

• ECOG performance status of 0 or 1.

• Patients have no symptomatic cardiac or pulmonary disease and adequate hepatic and renal function as measured by the following criteria:

  • Cardiac: Left ventricular ejection fraction at rest must be >40% (MUGA preferred)
  • Hepatic: ALT and AST < 3x the upper limits of normal range as specified by the institution's clinical laboratory.
  • Renal: Serum creatinine within the normal range (< 1.4 mg/dL) or if creatinine outside normal range then creatinine clearance > 60 mL/min/m2

Exclusion Criteria:

• Patient has > Grade 2 peripheral neuropathy within 14 days before enrollment.
• Myocardial infarction within 6 months prior to enrollment or has New York Hospital Association (NYHA) Class III or IV heart failure (see section 8.4), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at screening has to be documented by the investigator as not medically relevant.
• Patient has hypersensitivity to bortezomib, boron or mannitol.
• Female subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum or urinary pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women.
• Patient has received other investigational drugs within 14 days before enrollment
• Serious medical or psychiatric illness likely to interfere with participation in this clinical study.