IGF-MTX Conjugate in the Treatment of Myelodysplastic Syndrome

Study Overview
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Brief Summary
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The primary objective of this study is to determine the safety and tolerability of utilizing the insulin-like growth factor-1-methotrexate conjugate, 765IGF-MTX for the treatment of advanced, previously treated myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) and oligoblastic acute myelogenous leukemia (oligoblastic AML or O-AML), including determining the maximum tolerated dose (MTD).

Detailed Description
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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.

Official Title
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Pilot Study of IGF-Methotrexate Conjugate in the Treatment of Myelodysplastic Syndrome, CMML and Oligoblastic AML

Conditions
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Myelodysplastic Syndromes, Leukemia, Myelomonocytic, Chronic, Anemia, Refractory, With Excess of Blasts

Intervention / Treatment
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* Drug: IGF/MTX


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IGF/MTX<br>This arm 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. | Drug: IGF/MTX<br>* 765IGF-MTX is supplied as a 5 ml sterile solution at 4.0 µeq per ml 765IGF-MTX concentration in aqueous 10 mM HCl in a 10 ml glass vial<br>* Other names: 765IGF-methotrexate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events | Safety and tolerability | 3 cycles. 28 days each. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response criteria for AML, Complete Remission (CR) | Bone marrow blasts, platelet count, independence of red cell transfusions | 3 cycles. 28 days each. | 
| Response criteria for AML, CR with incomplete recovery | All CR criteria except for residual neutropenia or thrombocytopenia | 3 cycles. 28 days each. | 
| Response criteria for AML, Partial Remission (PR) | All hematologic criteria of CR; decreased bone marrow blast percentage (5% to 25%), and decrease of pretreatment bone marrow blast percentage by at least 50% | 3 cycles. 28 days each. | 
| Response criteria for AML, Cytogenetic CR (CRc). | Reversion to a normal karyotype at the time of morphologic CR in cases with an abnormal karyotype at the time of diagnosis. | 3 cycles. 28 days each. | 
| Response criteria for AML, Treatment Failure, Resistant Disease. | Failure to achieve CR. | 3 cycles. 28 days each. | 
| Response criteria for AML, Treatment Failure, Death in Aplasia. | Deaths occurring within 7 days completion of initial treatment with an aplastic or hypoplastic bone marrow obtained within 7 days of death. | 3 cycles. 28 days each. | 
| Response criteria for AML, Treatment Failure, Death from Intermediate Cause | Deaths occurring before completion of therapy or within 7 days of completion of therapy, with no blasts in the blood, but no bone marrow examination available. | 3 cycles. 28 days each. | 
| Response criteria for AML, Relapse. | Bone marrow blasts greater the 5% or reappearance of blasts in the blood, or development of extramedullary disease. | 3 cycles. 28 days each. | 
| Response criteria for MDS, Complete Remission | Bone marrow less than 5% myeloblasts with normal maturation of all cell lines. Persistent dysplasia will be noted. Peripheral blood values of Hgb greater than or equal to 11 d/dL, platelets greater than or equal to 100*10^9/L, neutrophils greater than or equal to 1.0*10^9/L, blasts equal to 0%. | 3 cycles. 28 days each. | 
| Response criteria for MDS, Partial Remission (PR) | All CR criteria if abnormal before treatment except; bone marrow blasts decreased by greater than or equal to 50% over pretreatment but still greater than 5%. Cellularity and morphology not relevant. | 3 cycles. 28 days each. | 
| Response criteria for MDS, Marrow CR | Bone marrow less than or equal to 5% myeloblasts and decreased by greater than 50% over pretreatment. | 3 cycles. 28 days each. | 
| Response criteria for MDS, Stable Disease | Failure to achieve at least PR, but no evidence of progression for greater than 8 weeks | 3 cycles. 28 days each. | 
| Response criteria for MDS, Failure | Death during treatment or disease progression characterized by worsening of cytopenis, increase in percentage of bone marrow blasts, or progression to a more advanced MDS FAB subtype than pretreatment | 3 cycles. 28 days each. | 
| Response criteria for MDS, Relapse after CR or PR | At least 1 of the following: return to pretreatment bone marrow blast percentage, decrement of greater than or equal to 50% from maximum remission/response levels in granulocytes or platelets, reduction in Hgb concentration by greater than or equal to 1.5 g/dL or transfusion dependence. | 3 cycles. 28 days each. | 
| Response criteria for MDS, Cytogenetic Response | Complete; disappearance of the chromosomal abnormality without appearance of new ones. Partial; at least 50% reduction of the chromosomal abnormality. | 3 cycles. 28 days each. | 
| Response criteria for MDS, Disease Progression, Blasts Measurements | Increase in blasts. | 3 cycles. 28 days each. | 
| Response criteria for MDS, Disease Progression, Granulocytes/platelets | At least 50% decrement from maximum remission/response in granulocytes or platelets. | 3 cycles. 28 days each. | 
| Response criteria for MDS, Disease Progression, Hgb | Reduction in Hgb. | 3 cycles. 28 days each. | 
| Response criteria for MDS, Disease Progression, Transfusions | Transfusion dependence. | 3 cycles. 28 days each. | 
| Response criteria for MDS, Survival, Death | Death from any cause. | 3 cycles. 28 days each. | 
| Response criteria for MDS, Survival, Relapse | Time to relapse. | 3 cycles. 28 days each. |