Study of IGF-Methotrexate Conjugate in the Treatment of Advanced Tumors Expressing IGF-1R

Inclusion Criteria:

1. Diagnosis of advanced malignancy, refractory to or intolerant to standard therapy and
is no longer likely to respond to such therapy.

2. Tumor (tissue, bone marrow, or blood) must express IGF-1R, defined as 10% or higher
of cells expressing IGF-1R by IHC, or 0.1% or higher for IGF-1R expression by flow
cytometry (blood or bone marrow aspirate). Parafin-embedded tissue sections will be
stained with antibodies against IGFR-1 according to the manufacturer's recommended
protocols. IHC staining will be performed at the Pathology Department of the
University of Illinois Cancer Center.

3. Measurable or evaluable disease per RECIST 1.1 criteria for solid tumors & lymphoma.

4. Multiple Myeloma: Confirmed diagnosis of MM with relapsed or refractory disease.

5. Lymphoma: Previously treated, histologically confirmed lymphoma (RECIST 1.1) with
exception of lymphoplasmacytic lymphoma

6. Waldenstrom's Macroglobulinemia: Confirmed diagnosis with relapsed/refractory
disease, and measurable disease defined as atleast one lesion with a single diameter
of greater than 2cm by CT or bone marrow involvement with greater than 10% malignant
cells and immunoglobulin (IgM, IgG, IgA) greater than 1000mg/dL.

7. Hematologic malignancies including MDS, leukemia: Confirmed histologic diagnosis with
relapsed or refractory disease; measurable disease per RECIST 1.1 criteria is not
required.

8. Age ≥ 18 years.

9. ECOG performance status of 0, 1 or 2 (appendix IV).

10. Prior systemic chemotherapy, immunotherapy, or biological therapy, radiation therapy
and/or surgery are allowed; however prior use of methotrexate is not allowed.

Time since prior therapy and the first dose of study drug:

- At least 2 weeks since prior radiation, non cytotoxic small molecule drugs
(e.g., tyrosine kinase inhibitors such as erlotinib and hormonal agents such as
letrozole), prior major surgery (surgery (defined as a surgery involving a risk
to the life of the patient; specifically: an operation upon an organ within the
cranium, chest, abdomen, or pelvic cavity), prior systemic FDA approved therapy

- At least 3 weeks since prior antineoplastic therapy

- At least 4 weeks since exposure to monoclonal antibodies (chimeric or fully
human)

- At least 6 weeks since prior nitrosureas or mitomycin-C

11. Patient must have recovered from the acute toxic effects (≤ grade 1 CTCAE v4) of
previous anti-cancer treatment prior to study enrollment; the only exception is that
grade 2 neuropathy is permitted

12. Adequate organ function within 14 days of study registration defined as:

Absolute neutrophil count (ANC) > 1.5 X 109/L Hemoglobin1 > 9 g/dL Platelets1 > 100 X
109/L Total bilirubin < 1.5 x ULN Alkaline Phosphatase, AST and ALT < 3 X ULN (< 5 x
ULN is acceptable if liver has tumor involvement) Serum Creatinine ≤ 1.5 x ULN
Creatinine Clearance > 60 ml/min [or GFR > 60 ml/min or 24 Hr. Urine Creat Clearance
> 50 ml/min] Note: Patient may not have had a transfusion within 7 days of blood
draw.

13. Negative urine or serum pregnancy test in females. Male and female patients with
reproductive potential must use an approved contraceptive method if appropriate (for
example, abstinence, oral contraceptives, implantable hormonal contraceptives, or
double barrier methods) during and for 3 months after the last dose of 765IGF-MTX.

14. Voluntary written informed consent before performance of any study-related procedure
not part of normal medical care, with the understanding that consent may be withdrawn
by the patient at any time without prejudice to future medical care.

Exclusion Criteria:

1. Untreated or symptomatic CNS metastases.

2. Radiation therapy to more than 25% of the bone marrow. Whole pelvic radiation is
considered to be over 25%.

3. ≥ Grade 3 peripheral neuropathy within 14 days before enrollment.

4. Systemic infection requiring IV antibiotic therapy within 7 days preceding the first
dose of study drug, or other severe infection.

5. Myocardial infarction within 6 months prior to enrollment or has New York Heart
Association (NYHA) 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.

6. 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.

7. Uncontrolled diabetes mellitus defined as a Hemoglobin A1C≥ 7% in patients with a
prior history of diabetes, 28 days prior to study enrollment.

8. Serious concomitant systemic disorders (e.g., active infection, 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.

9. 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.

10. Recent (within 6 months) arterial thromboembolic events, including transient ischemic
attack (TIA), cerebrovascular accident (CVA), unstable angina, or myocardial
infarction (MI).

11. History of abdominal fistula, gastrointestinal perforation, or intra abdominal
abscess within 28 days prior to beginning study treatment.

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

13. History of cerebrovascular accident, pulmonary embolism or untreated deep venous
thrombosis (DVT) within the past 6 months. Note: Subjects with recent DVT who have
been treated with therapeutic anticoagulants for at least 6 weeks are eligible.

14. Presence of any non-healing wound, fracture, or ulcer within 28 days prior to the
first dose of study drug.

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