IGF-MTX Conjugate in the Treatment of Myelodysplastic Syndrome

• ClinicalTrials.gov Identifier: NCT03175978
• Recruitment Status: Active, not recruiting
• First Posted: June 5, 2017
• Last Update Posted: October 23, 2020
• Sponsor: IGF Oncology, LLC
• Information provided by (Responsible Party): IGF Oncology, LLC

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Myelodysplastic Syndromes; Leukemia, Myelomonocytic, Chronic; Anemia, Refractory, With Excess of Blasts	Drug: IGF/MTX	Phase 1; Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 2 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pilot Study of IGF-Methotrexate Conjugate in the Treatment of Myelodysplastic Syndrome, CMML and Oligoblastic AML
• Actual Study Start Date: February 21, 2018
• Estimated Primary Completion Date: June 2021
• Estimated Study Completion Date: September 2021

Arms and Interventions

Arm

Intervention/treatment

Experimental: 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.

Drug: IGF/MTX; 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; Other Names: insulin-like growth factor-1/methotrexate conjugate; 765IGF-methotrexate

Outcome Measures

Primary Outcome Measures :

1. Incidence of Treatment-Emergent Adverse Events [ Time Frame: 3 cycles. 28 days each. ]
   Safety and tolerability

Secondary Outcome Measures :

1. Response criteria for AML, Complete Remission (CR) [ Time Frame: 3 cycles. 28 days each. ]
   Bone marrow blasts, platelet count, independence of red cell transfusions
2. Response criteria for AML, CR with incomplete recovery [ Time Frame: 3 cycles. 28 days each. ]
   All CR criteria except for residual neutropenia or thrombocytopenia
3. Response criteria for AML, Partial Remission (PR) [ Time Frame: 3 cycles. 28 days each. ]
   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%
4. Response criteria for AML, Cytogenetic CR (CRc). [ Time Frame: 3 cycles. 28 days each. ]
   Reversion to a normal karyotype at the time of morphologic CR in cases with an abnormal karyotype at the time of diagnosis.
5. Response criteria for AML, Treatment Failure, Resistant Disease. [ Time Frame: 3 cycles. 28 days each. ]
   Failure to achieve CR.
6. Response criteria for AML, Treatment Failure, Death in Aplasia. [ Time Frame: 3 cycles. 28 days each. ]
   Deaths occurring within 7 days completion of initial treatment with an aplastic or hypoplastic bone marrow obtained within 7 days of death.
7. Response criteria for AML, Treatment Failure, Death from Intermediate Cause [ Time Frame: 3 cycles. 28 days each. ]
   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.
8. Response criteria for AML, Relapse. [ Time Frame: 3 cycles. 28 days each. ]
   Bone marrow blasts greater the 5% or reappearance of blasts in the blood, or development of extramedullary disease.
9. Response criteria for MDS, Complete Remission [ Time Frame: 3 cycles. 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/L, neutrophils greater than or equal to 1.0*10^9/L, blasts equal to 0%.
10. Response criteria for MDS, Partial Remission (PR) [ Time Frame: 3 cycles. 28 days each. ]
    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.
11. Response criteria for MDS, Marrow CR [ Time Frame: 3 cycles. 28 days each. ]
    Bone marrow less than or equal to 5% myeloblasts and decreased by greater than 50% over pretreatment.
12. Response criteria for MDS, Stable Disease [ Time Frame: 3 cycles. 28 days each. ]
    Failure to achieve at least PR, but no evidence of progression for greater than 8 weeks
13. Response criteria for MDS, Failure [ Time Frame: 3 cycles. 28 days each. ]
    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
14. Response criteria for MDS, Relapse after CR or PR [ Time Frame: 3 cycles. 28 days each. ]
    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.
15. Response criteria for MDS, Cytogenetic Response [ Time Frame: 3 cycles. 28 days each. ]
    Complete; disappearance of the chromosomal abnormality without appearance of new ones. Partial; at least 50% reduction of the chromosomal abnormality.
16. Response criteria for MDS, Disease Progression, Blasts Measurements [ Time Frame: 3 cycles. 28 days each. ]
    Increase in blasts.
17. Response criteria for MDS, Disease Progression, Granulocytes/platelets [ Time Frame: 3 cycles. 28 days each. ]
    At least 50% decrement from maximum remission/response in granulocytes or platelets.
18. Response criteria for MDS, Disease Progression, Hgb [ Time Frame: 3 cycles. 28 days each. ]
    Reduction in Hgb.
19. Response criteria for MDS, Disease Progression, Transfusions [ Time Frame: 3 cycles. 28 days each. ]
    Transfusion dependence.
20. Response criteria for MDS, Survival, Death [ Time Frame: 3 cycles. 28 days each. ]
    Death from any cause.
21. Response criteria for MDS, Survival, Relapse [ Time Frame: 3 cycles. 28 days each. ]
    Time to relapse.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, Minnesota

Mayo Clinic

Rochester, Minnesota, United States, 55905

Regions Cancer Care Center

Saint Paul, Minnesota, United States, 55101

Sponsors and Collaborators

IGF Oncology, LLC

Investigators

• Principal Investigator: Mrinal S Patniak; Mayo Clinic

More Information

• Responsible Party: IGF Oncology, LLC
• ClinicalTrials.gov Identifier: NCT03175978
• Other Study ID Numbers: AML-03
• First Posted: June 5, 2017
• Last Update Posted: October 23, 2020
• Last Verified: October 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Preleukemia; Leukemia, Myelomonocytic, Chronic; Myelodysplastic Syndromes; Anemia, Refractory; Anemia, Refractory, with Excess of Blasts; Syndrome; Disease; Pathologic Processes; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Neoplasms; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Myelodysplastic-Myeloproliferative Diseases; Anemia; Methotrexate; Physiological Effects of Drugs; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Reproductive Control Agents; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Dermatologic Agents; Enzyme Inhibitors; Folic Acid Antagonists; Immunosuppressive Agents