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 immuno-histochemistry (IHC), or 0.1% or higher for IGF-1R
expression by flow cytometry (blood or bone marrow aspirate).
3. Paraffin-embedded tissue sections will be stained with antibodies against insulin-like
growth factor receptor 1 (IGFR-1) according to the manufacturer's recommended
protocols. IHC staining and flow cytometry will be performed at the Pathology
Department of the University of Illinois Cancer Center.
4. Measurable or evaluable disease per RECIST 1.1 criteria for solid tumors and lymphoma
as defined in the protocol. For other hematologic malignancies, see below (measurable
disease per RECIST 1.1 criteria not necessary).
5. Multiple Myeloma: Confirmed diagnosis of multiple myeloma as defined in the protocol
with relapsed or refractory disease, and measurable disease defined as one of below:
- Serum monoclonal protein > 500mg/dL by serum protein electrophoresis (SPEP)
- Urine monoclonal protein > 200mg/24 hours by urine protein electrophoresis (UPEP)
- Measurable free light chain by free light chain assay > 10mg/dL with abnormal
kappa to lambda light chain ratio
- Measurable bone disease by > 1 bone lesion which is > 20 mm on conventional
techniques or > 10 mm with spiral CT (for lytic lesions)
- Monoclonal bone marrow plasmacytosis > 30%
6. Lymphoma: Previously treated, histologically confirmed lymphoma with measurable
disease via RECIST 1.1, with the exception of lymphoplasmacytic lymphoma, which can be
diagnosed based on morphologic evidence in the bone marrow plus the appropriate
7. Waldenstrom's Macroglobulinemia: Confirmed diagnosis with relapsed or refractory
disease, and measurable disease defined as at least 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.
8. Hematologic malignancies including myelodysplastic syndrome(MDS), leukemia: Confirmed
histologic diagnosis with relapsed or refractory disease; measurable disease per
RECIST 1.1 criteria is not required.
9. Age ≥ 18 years
10. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
11. Prior systemic chemotherapy, immunotherapy, or biological therapy, radiation therapy
and/or surgery are allowed; however prior use of methotrexate allowed if > 6 months
prior to study entry. Intrathecal methotrexate is allowed prior to and during
treatment per investigator discretion. Time since prior therapy and the first dose of
- 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
- At least 6 weeks since prior nitrosureas or mitomycin-C
12. 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
13. Adequate organ function within 14 days of study registration defined as the following
- Absolute neutrophil count (ANC) ≥ 1.5 X 10^9/L
- Hemoglobin ≥ 9g/dL* (Patient may not have had a transfusion within 7 days of
- Platelets ≥ 100 X 10^9/L* (Patient may not have had a transfusion within 7 days
of blood draw.)
- Total bilirubin ≤ 1.5 X upper limit of normal (ULN)
- Alkaline phosphatase, aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) ≤ 3 X ULN < 5 X ULN is acceptable if liver has tumor
- Serum creatinine ≤ 1.5 X ULN
- Creatinine clearance ≥ 60 ml/min^2 or glomerular filtration rate (GFR) ≥ 60
ml/min^2 or 24 hour urine creatinine clearance ≥ 50 ml/min
- Laboratory values for lymphoma patients:
- Absolute neutrophil count (ANC) ≥ 1.0 X 10^9/L
- Hemoglobin ≥ 8g/dL
- Platelets ≥ 50 X 10^9/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^2 or GFR ≥ 60 ml/min^2 or 24 hour urine
creatinine clearance ≥ 50 ml/min
14. 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.
15. 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.
1. Untreated central nervous system (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
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
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
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