Clinical Trial of L-Grb-2 Antisense Oligonucleotide in CML, AML, ALL & MDS

The goal of this clinical research study is to find the highest safe dose of a liposomal Growth Factor Receptor Bound Protein-2 antisense oligodeoxynucleotide (L-Grb2 AS) that can be given as treatment for patients with Philadelphia Chromosome positive CML, AML, CLL and MDS. The trade name of this drug is BP-100-1.01. The response of the leukemia to this treatment will also be studied. In addition, the time needed for the body to process this drug will be evaluated.

The Philadelphia Chromosome is an unusual genetic trait found in 90-95% of patients with CML. The protein created by this unusual trait causes normal cells within the body to become cancer cells, and then causes these cells to grow and divide at a rapid rate. Researchers think that the protein Growth Factor Receptor Bound Protein-2 (Grb-2) is necessary to the growth of these cancerous cells. The drug under study may be able to prevent the cells from making this protein. Researchers hope that without this protein, the leukemia cells will die.

Between 18 and 30 patients are expected to be enrolled on this study. Between 3 and 6 patients will be treated at each dose level. Each new group will be treated at a dose higher than the previous group. If the highest safe dose of the study drug is not found after the completion of this study, additional doses or another study may be considered.

The study drug is an antisense molecule complementary to the mRNA (messenger RNA) code for the cell's expression of the protein Grb-2. The study drug is incorporated into lipid (fat) particles known as liposomes. This incorporation process is part of the manufacturing procedure and is done before the drug is administered. The liposomes (which carry the study drug) will then be injected into a vein twice a week for at least 28 days.

Inclusion Criteria:

• 4.1.1 Male or female patients 18 years of age or older 4.1.2 A diagnosis of refractory or relapsed acute myeloid leukemia, or Ph+ CML, in chronic, accelerated or blast phase, or acute lymphoblastic leukemia, or myelodysplastic syndrome.

One of the following parameters is required to meet criteria for accelerated phase CML:

• Blasts in Peripheral Blood or Bone Marrow ≥15%
• Promyelocytes and Blasts in Peripheral Blood or Bone Marrow ≥30%
• PB or BM basophils ≥20%
• Thrombocytopenia <100 x 103/ml, not resulting from therapy

Blast phase is defined as ≥30% blasts in peripheral blood or bone marrow, or presence of extramedullary disease, except for liver or spleen.

4.1.2.1 Patients with CML must have demonstrated resistance and/or intolerance to therapy with at least 2 tyrosine kinase inhibitors (TKI) 4.1.2.2 AML and Ph+ ALL should have received at least one prior treatment regimen and either failed to achieve response or relapsed on treatment.

4.1.2.3 MDS patients should have failed prior therapy with a hypomethylating agent or, if associated with a 5q- chromosomal abnormality, lenalidomide. Patients with 5q- unable to receive or intolerant to lenalidomide are also eligible.

4.1.3 Patients must have clinically adequate hepatic and renal functions as defined by:

ALT<2x ULN Serum creatinine concentration <2x ULN Serum bilirubin <2x ULN 4.1.4 Patients must sign an informed consent. 4.1.5 Women of childbearing age must have a negative serum or urine pregnancy test prior to the initiation of study drug.

4.1.6 Barrier contraceptive precautions are to be used throughout the trial by all study participants of child bearing potential.

4.1.7 Patients must be off anti-cancer therapy for at least two weeks prior to study entry, with the exception of hydroxyurea or anagrelide (24 hours), TKI (5 days), and interferon (two weeks).

4.1.8 Patients with ECOG Performance of 0-2

Exclusion Criteria:

4.2.1 Serious intercurrent medical illnesses, which would interfere with the ability of the patient to carry out the treatment program.

4.2.2 Pregnant or breastfeeding women 4.2.3 Patients who have uncontrolled active infection 4.2.4 Patients who have received another Investigational product within the longer of 14 days or 5 half-lives of the previous product.

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