Clinical Trial of BP1001 (L-Grb-2 Antisense Oligonucleotide) in CML, AML, ALL & MDS

Study Overview
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Brief Summary
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The first goal of this clinical research study is to find the highest safe dose of BP1001, a liposomal Growth Factor Receptor Bound Protein-2 antisense oligodeoxynucleotide (L-Grb2 AS), for patients with Philadelphia Chromosome positive CML, AML, ALL and MDS. The response of the leukemia to this treatment will also be studied. The second goal of this clinical research study is to evaluate the safety and toxicity of the combination of BP1001 and concurrent low-dose ara-C (LDAC) in patients with AML.

Detailed Description
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The Philadelphia Chromosome is an unusual genetic trait found in 90-95% of patients with CML and approximately 20-25% of patients with ALL. 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) plays an important role in the rapid growth of leukemic cells. The study drug (BP1001) may be able to inhibit the cells from making Grb-2. Researchers hope that without this protein, the leukemia cells will die. Up to 60 patients are expected to be enrolled on this study. Part A: Dose escalation: Each cohort will receive BP1001 at a dose higher than the previous group. Part B: Dose-expansion Cohorts: Subjects with relapsed or refractory AML will receive escalating doses of BP1001 concurrently with fixed low-dose ara-C (LDAC) The study drug is an antisense molecule complementary to the messenger RNA (mRNA) 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 process and is done before the study drug is administered. The liposomes (which carry the study drug) will be administered intravenously twice a week for 28 days. Subjects enrolled in Part B of the study will receive study drug twice a week for 28 days concurrently with low dose ara-C, self administered twice daily for 10 consecutive days.

Official Title
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A Phase I Clinical Trial to Study the Safety, Pharmacokinetics, and Efficacy of BP1001 (L-Grb-2 Antisense Oligonucleotide) in Patients With Refractory or Relapsed Acute Myeloid Leukemia, Philadelphia Chromosome Positive Chronic Myelogenous Leukemia, or Acute Lymphoblastic Leukemia, and Myelodysplastic Syndrome

Conditions
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Recurrent Adult Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Myelodysplastic Syndrome, Ph1 Positive CML

Intervention / Treatment
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* Drug: BP1001
* Drug: BP1001 in combination with LDAC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Male or female patients 18 years of age or older A diagnosis of refractory or relapsed AML, 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. Patients with CML must have demonstrated resistance and/or intolerance to therapy with at least 2 tyrosine kinase inhibitors (TKI) Patients with AML and ALL should have received at least 1 prior treatment regimen and either failed to achieve response or relapsed on treatment Patients with MDS should have failed prior therapy with a hypomethylating agent or, if associated with a 5q- chromosomal abnormality, lenalidomide. NOTE: Patients with 5q- unable to receive or intolerant to lenalidomide are also eligible. Have clinically adequate hepatic and renal functions as defined by: ALT<2x ULN Serum creatinine concentration <2x ULN Serum bilirubin <2x ULN Patients must sign an informed consent Women of childbearing age must have a negative serum or urine pregnancy test prior to the initiation of study drug. Barrier contraceptive precautions are to be used throughout the trial by all study participants of child bearing potential. Have not received anti-cancer therapy for at least 2 weeks prior to study entry, with the exception of low dose ara-C (LDAC) given as subcutaneous injections (no less than 15 days prior), hydroxyurea or anagrelide (no less than 24 hours prior), TKI (no less than 5 days prior), and interferon (no less than 2 weeks prior) Have an ECOG Performance of 0-2 Have a life-expectancy ≥3 months Exclusion Criteria Serious intercurrent medical illnesses which would interfere with the ability of the patient to carry out the treatment program Pregnant or breastfeeding women Patients who have uncontrolled active infection Patients who have received another investigational product within the longer of 14 days or 5 half-lives of the previous product Any history of adverse reaction or hypersensitivity to LDAC Part B: BP1001 with Concurrent LDAC Dose-Expansion Cohorts Enrollment in the dose-expansion cohorts (DEC) will be limited to only those patients with a diagnosis of refractory or relapsed AML(except acute promyelocytic leukemia) or those who are refractory to at least 1 prior therapy regimen and no more than 1 prior salvage regimen.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BP1001<br>Subjects are treated with open-label study drug (BP1001) in a dose-escalation model. | Drug: BP1001<br>* Study drug (BP1001) is constituted in normal saline, administered by IV on twice weekly for 28 days.<br>* Other names: BP-100-1.01;|
| Experimental: BP1001 in combination with LDAC<br>AML subjects are treated with open-label escalating study drug (BP1001) in combination with low dose ara-C (LDAC) | Drug: BP1001 in combination with LDAC<br>* Study drug (BP1001) is constituted in normal saline, administered by IV twice weekly for 28 days. Low dose ara-C (LDAC) is self administered twice daily for 10 consecutive days during the 28 day cycle.<br>* Other names: low dose ara-C;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of BP1001 | Evaluate toxicity, tolerance, and MTD of escalating doses of BP1001 | 30 days | 
| Safety of BP1001 in combination with LDAC | Evaluate safety and toxicity of the combination of BP1001 and concurrent LDAC using non-hematologic and hematologic measures per NCI CTCAE criteria. | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Optimal biologically active dose | Determine the optimal biologically active dose of BP1001 defined as a 50% reduction in Grb-2 expression in circulating leukemia cells | 30 days | 
| In vivo pharmacokinetics | Evaluate the in vivo PK of BP1001 in all subjects using plasma and urine to compute half life and elimination | 30 days | 
| Correlate PK data with historical experience | Correlate the in vivo PK data with historical experience to demonstrate the liposomal delivery performs as expected for all subjects by comparing PK data (half life and elimination) obtained from each subject with historical experience | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liposomal Grb-2 treatment of CML, AML, CLL, MDS, Liposomal Grb-2 with LDAC for AML