IGF-MTX Conjugate in the Treatment of Myelodysplastic Syndrome

Phase 1

Terminated

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

Interventions: Drug: IGF/MTX

Registration Number: NCT03175978

Lead Sponsor: IGF Oncology, LLC

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 2

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
IGF/MTX	IGF/MTX	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Treatment-Emergent Adverse Events	Up to 6 28-day cycles for one participant, and up to 10 28-day cycles for the other participant.	Number of Participants with Treatment-Emergent Adverse Events through study completion, up to a maximum duration of 10 28-day cycles.

Secondary Outcome Measures

Name	Time	Method
Response Criteria for AML, Complete Remission (CR)	Assessed after 2 cycles of 28 days each.	Bone marrow blasts, platelet count, independence of red cell transfusions. Bone marrow blasts \<5%, absence of blasts with Auer rods, absence of extramedullyary disease, absolute neutrophil count \>1.0 x 10(9)/L, independence of red cell transfusions.
Response Criteria for MDS, Disease Progression, Hgb	Assessed after 2 cycles of 28 days each.	Hemoglobin in g/dL
Response Criteria for AML, CR With Incomplete Recovery	Assessed after 2 cycles of 28 days each.	All CR criteria except for residual neutropenia (\<10(9)/L) or thrombocytopenia (\<100x 10(9)/L).
Response Criteria for MDS, Disease Progression, Blasts Measurements	Assessed after 2 cycles of 28 days each.	Absolute blast count.
Response Criteria for MDS, Survival, Death	All-cause mortality was assessed up to 23 months, and serious and Other (Not Including Serious) Adverse Events were assessed for up to 22 months.	Survival over the full study time period and follow up to 23 months after initiating treatment.
Response Criteria for AML, Relapse.	Assessed after 6 cycles of 28 days each.	Bone marrow blasts greater the 5% or reappearance of blasts in the blood, or development of extramedullary disease after complete remission or complete remission with incomplete recovery..
Response Criteria for MDS, Complete Remission (CR)	Assessed after 6 cycles of 28 days each.	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 platelets/L, neutrophils greater than or equal to 1.0\10\^9 neutrophils/L, blasts equal to 0%.
Response Criteria for MDS, Marrow CR	Assessed after 2 cycles of 28 days each.	Bone marrow less than or equal to 5% myeloblasts and decreased by greater than 50% over pretreatment.
Response Criteria for MDS, Stable Disease	Assessed after 6 cycles of 28 days each. Both patients had at least stable disease for at least 6 cycles.	Failure to achieve at least PR, but no evidence of progression for greater than 8 weeks
Response Criteria for MDS, Failure	Assessed after 6 cycles of 28 days each.	Death during treatment or disease progression characterized by worsening of cytopenias, increase in percentage of bone marrow blasts, or progression to a more advanced MDS FAB subtype than pretreatment
Response Criteria for MDS, Disease Progression, Neutrophils	Assessed after 2 cycles of 28 days each.	Neutrophil count in 10(9)/L