Clinical Trial of BP1001 (Liposomal Grb2 Antisense Oligonucleotide) in Combination With LDAC in Patients With Previously Untreated AML

The Grb2 gene has been mapped to the human chromosome region 17q22-qter, a region that is
duplicated in leukemias and solid tumors, which may result in an increased copy number of the
Grb2 gene product. As Grb2 is important for the transformation of murine hematopoietic cells,
and the proliferation of human leukemia cells that express high levels of oncogenic tyrosine
kinases, inhibition of Grb2 may have a significant impact on the natural history of
leukemias. 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.

Low-dose cytarabine (Ara-C) (LDAC) has been used in a variety of schedules in several Phase
II trials in AML showing responses that include complete remission of disease. It is
generally well tolerated and can be given in an outpatient or home care setting. Researchers
hope that the combination of BP1001 and LDAC will result in greater response rates and
duration of response in participants with AML that cannot or elect not to be treated with
more intensive chemotherapy.

Decitabine is approved in Europe for the treatment of adult patients with newly diagnosed de
novo or secondary acute myeloid leukemia (AML). In vitro studies in AML cells co-incubated
with BP1001 and decitabine suggests that treatment of AML patients with decitabine followed
by BP1001 may be a combination that could benefit patients with AML.

This is a Phase IIa, multicenter, study of BP1001 in combination with LDAC or decitabine in
participants with previously untreated AML who are not otherwise eligible for standard or
high-intensity chemotherapy regimens or who have elected a low-intensity regimen

This trial will utilize an open label, two-stage design to assess the safety profile, PK, PD,
and efficacy of 60 mg/m2 of BP1001 in combination LDAC or decitabine to assess whether the
combination of either provides greater efficacy (Complete Remission [CR], Complete Remission
with incomplete platelet recovery [CRp], Complete Remission with incomplete hematologic
recovery [CRi], than LDAC or decitabine alone.

This 2-arm combination cohort study of either BP1001 with LDAC or decitabine will have 19
evaluable patients enrolled per cohort, with a decision to stop or proceed to 54 patients per
cohort, for a total of 108 additional de novo patients.

Inclusion Criteria:

1. Adults ≥18 years of age

2. Females must be of non-childbearing potential, surgically sterile, postmenopausal, or
practice adequate methods of contraception during the study and for 30 days after the
last dose of study drug, LDAC, or decitabine

3. Males must agree to use an adequate method of contraception during the study and for
at least 30 days after the last dose of study drug, LDAC, or decitabine

4. Histologically documented diagnosis (based on the 2008 World Health Organization [WHO]
Classification) (Vardiman 2009) of one of the following:

1. Newly diagnosed de novo AML; or

2. Untreated secondary AML, including AML that has progressed from myelodysplastic
syndrome (MDS)

3. In some cases of AML associated with specific genetic abnormalities, however, the
diagnosis of AML may be made regardless of the blast count in the PB or BM.

5. Investigator considers previously untreated participant ineligible for (or unwilling
to receive) intensive induction therapy based on medical reasons, disease
characteristics such as genetics, type of AML (de novo or secondary), or participant
characteristics such as age, performance status, co-morbidities, organ dysfunctions,
or patient election of low-intensity treatment.

6. Eligible for LDAC or decitabine therapy, based on Investigator assessment; although
decitabine is not approved by FDA for AML, it is commonly used in this patient
population

7. Adequate hepatic and renal functions as defined by:

1. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 times the upper
limit of normal (ULN); and

2. Usually total bilirubin ≤ 1.5 ULN. In specific cases the PI may request a waiver
of this requirement with medical justification and agreement with the medical
monitor and Bio-Path Holdings. And;

3. Estimated glomerular filtration rate (eGFR) of at least 50 ml/min. These
estimations can be calculated using the following methods (Appendix D):

i. Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) equation ii. Cockcroft
Gault equation iii. Modification of Diet in Renal Disease (MDRD study equation) iv.
Creatinine clearance estimated by 24-hr urine collection for creatinine clearance

8. Documented Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

9. Recovered from the effects of any prior surgery, radiotherapy, or antineoplastic
treatment (with the exception of alopecia), based on Investigator assessment

10. Willing and able to provide written informed consent

Exclusion Criteria:

1. Active non-hematologic or lymphoid malignancy other than AML treated with immuno- or
chemotherapy within the previous 12 months except active non-melanoma, non-invasive
skin cancer will be allowed.

2. Known, active leptomeningeal leukemia requiring intrathecal therapy. NOTE: Patients
with a history of CNS disease may be allowed to participate based on at least 1
documented, negative spinal fluid assessment within 28 days prior to Screening

3. Isolated potentially treatable extramedullary leukemia without also meeting bone
marrow criteria for acute leukemia (for AML usually = 20% blasts in bone marrow
aspirate or biopsy). Patients may have leukemia with lower blast counts (Dohner 2010).
Bio-Path Holdings and Investigator concurrence required.

4. Acute promyelocytic leukemia (APL) with t(15;17)(q22;q12) PML-RARA

5. Chronic myeloid leukemia (CML) in any phase

6. Receipt of any anti-cancer therapy within 14 days prior to C1D1, with the exception of
hydroxyurea or anagrelide (within 24 hours), TKI (within 1day), or single dose of
cytarabine (for proliferative disease)

7. Palliative treatment for high WBCs with hydroxyurea (HU) is allowed.

8. Uncontrolled active, untreated, or progressive infection

9. Receipt of any investigational agent or study treatment within 30 days prior to C1D1

10. Females who are pregnant, test positive for pregnancy, or are breast-feeding during
the Screening period, or intend to become pregnant or breast-feed during the course of
the study or within 30 days after last dose of study drug

11. Serious intercurrent medical or psychiatric illness which, in the opinion of the
Investigator, would interfere with the ability of the participant to complete the
study

12. Active hepatitis B infection (based on positive surface antigen [HBsAg]), hepatitis C
infection (based on positive antibody [HCV Ab]), or human immunodeficiency virus
(HIV-1 or HIV-2, based on positive antibody)

13. History of any hypersensitivity to cytarabine, unless reaction is deemed irrelevant to
the study by the Investigator and Medical Monitor

14. Presence of concurrent conditions that, in the opinion of the Investigator and/or
Medical Monitor, may compromise the participant's ability to tolerate study treatment
or interfere with any aspect of study conduct or interpretation of results. This
includes, but is not limited to, unstable or uncontrolled angina, New York Heart
Association (NYHA) class III or IV congestive heart failure, uncontrolled and
sustained hypertension, clinically significant cardiac dysrhythmia or clinically
significant baseline ECG abnormality (e.g., QTcF >470 msec)

15. Within the past 6 months, has had any of the following: myocardial infarction,
unstable angina pectoris, coronary/peripheral artery bypass graft, cerebrovascular
accident or transient ischemic attack

16. Uncontrolled seizure disorder (i.e., seizures within the past 2 months)

17. Unable or unwilling to communicate or cooperate with the Investigator or follow the
protocol for any reason