IGF-MTX Conjugate in the Treatment of Myelodysplastic Syndrome

This pilot study will evaluate use of IGF-Methotrexate conjugate (765IGF-MTX) in patients
with advanced, previously treated MDS, CMML and O-AML. 765IGF-MTX at a dose of 0.20 to 2.5
µequivalents per kg is administered as an IV infusion over 1.5 hours on days 1, 8 and 15 of a
28 day cycle. Treatment continues until disease progression, as assessed after 2 cycles,
unacceptable toxicity, or patient refusal. Assessment of response will be confirmed by bone
marrow studies performed at the end of cycles 2, 4, and 6 (each +/- 3 days).

Pharmacokinetics will be performed before and for up to 24 hours after drug administration on
days 1 (for 24 hrs) and 15 (for 24 hrs) of cycle 1. Pharmacodynamic samples will be assessed
pre-dosing on day 1 of cycle 1, pre-dosing on days 1 and 15 of cycle 2, and pre-dosing on day
15 of cycles 4 and 6.

Inclusion Criteria:

- Diagnosis of O-AML that is refractory to or intolerant to standard therapy and is no
longer likely to respond to such therapy (at least one line of therapy); or Diagnosis
of MDS/CMML that is refractory to or intolerant to standard therapy and is no longer
likely to respond to such therapy (at least one line of therapy)

- Confirmed histologic diagnosis on bone marrow biopsy and aspirate within 28 days of
trial entry prior to starting cycle 1.

- Platelets > 10 x 10^9/L

- ECOG performance status of 0, 1 or 2

- Prior systemic chemotherapy, immunotherapy, or biological therapy, radiation therapy
and/or surgery are allowed; prior use of systemic methotrexate > 1 month prior to
study entry is allowed. Intrathecal methotrexate is allowed prior to and during
treatment per investigator discretion.

- Patient must have recovered from the acute toxic effects (≤ grade 1 CTCAE v.4.0) of
previous anti-cancer treatment prior to study enrollment; the only exception is that
grade 2 neuropathy is permitted

- Adequate organ function within 14 days of study registration

- Negative serum pregnancy test in females. Male and female patients with reproductive
potential must use an approved contraceptive method if appropriate

Exclusion Criteria:

- ECOG PS >2.

- Patients with active extramedullary disease.

- Pleural effusions or ascites.

- Grade 3 peripheral neuropathy within 14 days before enrollment.

- Active uncontrolled infection or severe systemic infection (enrollment is possible
after control of infection).

- Myocardial infarction within ONE months prior to enrollment or has New York Heart
Association Class III or IV heart failure, 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.

- Pregnant or breastfeeding - methotrexate is Pregnancy Category X - has been reported
to cause fetal death and/or congenital abnormalities. Confirmation that the subject is
not pregnant must be established by a negative serum beta-human chorionic gonadotropin
(beta-hCG) pregnancy test result obtained during screening. Pregnancy testing is not
required for post-menopausal or surgically sterilized women.

- Uncontrolled diabetes mellitus defined as a Hemoglobin A1C≥ 10% in patients with a
prior history of diabetes, prior to study enrollment.

- Serious concomitant systemic disorders (e.g., active uncontrolled infection or
uncontrolled diabetes) or psychiatric disorders that, in the opinion of the
investigator, would compromise the safety of the patient or compromise the patient's
ability to complete the study.

- Other severe acute or chronic medical or psychiatric conditions, or laboratory
abnormality that may increase the risk associated with study participation or
investigational product administration or may interfere with the interpretation of
study results and, in the judgment of the investigator, would make the patient
inappropriate for enrollment in this study.

- Any history of epilepsy or a seizure disorder or any known prior seizures.

- Abnormalities on 12-lead electrocardiogram (ECG) considered by the investigator to be
clinical significant.

- Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to IGF or methotrexate.