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IGF-MTX Conjugate in the Treatment of Myelodysplastic Syndrome

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03175978
Recruitment Status : Recruiting
First Posted : June 5, 2017
Last Update Posted : August 21, 2019
Sponsor:
Information provided by (Responsible Party):
IGF Oncology, LLC

Tracking Information
First Submitted Date  ICMJE May 25, 2017
First Posted Date  ICMJE June 5, 2017
Last Update Posted Date August 21, 2019
Actual Study Start Date  ICMJE February 21, 2018
Estimated Primary Completion Date June 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 31, 2017)
Incidence of Treatment-Emergent Adverse Events [ Time Frame: 3 cycles. 28 days each. ]
Safety and tolerability
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 31, 2017)
  • Response criteria for AML, Complete Remission (CR) [ Time Frame: 3 cycles. 28 days each. ]
    Bone marrow blasts, platelet count, independence of red cell transfusions
  • Response criteria for AML, CR with incomplete recovery [ Time Frame: 3 cycles. 28 days each. ]
    All CR criteria except for residual neutropenia or thrombocytopenia
  • 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%
  • 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.
  • Response criteria for AML, Treatment Failure, Resistant Disease. [ Time Frame: 3 cycles. 28 days each. ]
    Failure to achieve CR.
  • 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.
  • 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.
  • 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.
  • 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%.
  • 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.
  • 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.
  • 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
  • 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
  • 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.
  • 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.
  • Response criteria for MDS, Disease Progression, Blasts Measurements [ Time Frame: 3 cycles. 28 days each. ]
    Increase in blasts.
  • 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.
  • Response criteria for MDS, Disease Progression, Hgb [ Time Frame: 3 cycles. 28 days each. ]
    Reduction in Hgb.
  • Response criteria for MDS, Disease Progression, Transfusions [ Time Frame: 3 cycles. 28 days each. ]
    Transfusion dependence.
  • Response criteria for MDS, Survival, Death [ Time Frame: 3 cycles. 28 days each. ]
    Death from any cause.
  • Response criteria for MDS, Survival, Relapse [ Time Frame: 3 cycles. 28 days each. ]
    Time to relapse.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE IGF-MTX Conjugate in the Treatment of Myelodysplastic Syndrome
Official Title  ICMJE Pilot Study of IGF-Methotrexate Conjugate in the Treatment of Myelodysplastic Syndrome, CMML and Oligoblastic AML
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Myelodysplastic Syndromes
  • Leukemia, Myelomonocytic, Chronic
  • Anemia, Refractory, With Excess of Blasts
Intervention  ICMJE 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
Study Arms  ICMJE 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.
Intervention: Drug: IGF/MTX
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 31, 2017)
9
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 2020
Estimated Primary Completion Date June 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Mrinal S Patnaik 507-284-5096 patnaik.mrinal@mayo.edu
Contact: Aref Al-Kali 507-284-5096 al-kali.aref@mayo.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03175978
Other Study ID Numbers  ICMJE AML-03
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party IGF Oncology, LLC
Study Sponsor  ICMJE IGF Oncology, LLC
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Mrinal S Patniak Mayo Clinic
PRS Account IGF Oncology, LLC
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP