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Funding
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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).
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| IGF/MTX | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| IGF/MTX | Drug | 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 |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events | Number of Participants with Treatment-Emergent Adverse Events through study completion, up to a maximum duration of 10 28-day cycles. | Up to 6 28-day cycles for one participant, and up to 10 28-day cycles for the other participant. |
| Measure | Description | Time Frame |
|---|---|---|
| Response Criteria for AML, Complete Remission (CR) | 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. | Assessed after 2 cycles of 28 days each. |
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Inclusion Criteria:
Exclusion Criteria:
ECOG PS >2.
Patients with active extramedullary disease.
Pleural effusions or ascites.
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.
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| Name | Affiliation | Role |
|---|---|---|
| Mrinal S Patniak | Mayo Clinic | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Mayo Clinic | Rochester | Minnesota | 55905 | United States | ||
| Regions Cancer Care Center |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. 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 |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. 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 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Participants With Treatment-Emergent Adverse Events | Number of Participants with Treatment-Emergent Adverse Events through study completion, up to a maximum duration of 10 28-day cycles. | Posted | Count of Participants | Participants | Up to 6 28-day cycles for one participant, and up to 10 28-day cycles for the other participant. |
|
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.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. 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 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Subcutaneous abscess | Skin and subcutaneous tissue disorders | Non-systematic Assessment | Subcutaneous abscess from an infection. The adverse event was unrelated to the study medication. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Lymphocyte count decreased | Blood and lymphatic system disorders | Systematic Assessment | Grade 3 event. Judged as possibly study medication related. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Hugh McTavish | IGF Oncology, LLC | 651-207-8270 | hmctavish@igfoncology.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Dec 6, 2018 | Aug 11, 2023 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D009190 | Myelodysplastic Syndromes |
| D015477 | Leukemia, Myelomonocytic, Chronic |
| D000754 | Anemia, Refractory, with Excess of Blasts |
| ID | Term |
|---|---|
| D001855 | Bone Marrow Diseases |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D007951 | Leukemia, Myeloid |
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| Response Criteria for AML, CR With Incomplete Recovery | All CR criteria except for residual neutropenia (<10(9)/L) or thrombocytopenia (<100x 10(9)/L). | Assessed after 2 cycles of 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 after complete remission or complete remission with incomplete recovery.. | Assessed after 6 cycles of 28 days each. |
| Response Criteria for MDS, Complete Remission (CR) | 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%. | Assessed after 6 cycles of 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. | Assessed after 2 cycles of 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 | Assessed after 6 cycles of 28 days each. Both patients had at least stable disease for at least 6 cycles. |
| Response Criteria for MDS, Failure | 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 | Assessed after 6 cycles of 28 days each. |
| Response Criteria for MDS, Disease Progression, Blasts Measurements | Absolute blast count. | Assessed after 2 cycles of 28 days each. |
| Response Criteria for MDS, Disease Progression, Hgb | Hemoglobin in g/dL | Assessed after 2 cycles of 28 days each. |
| Response Criteria for MDS, Disease Progression, Neutrophils | Neutrophil count in 10(9)/L | Assessed after 2 cycles of 28 days each. |
| Response Criteria for MDS, Survival, Death | Survival over the full study time period and follow up to 23 months after initiating treatment. | 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. |
| Saint Paul |
| Minnesota |
| 55101 |
| United States |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
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| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Secondary | Response Criteria for AML, Complete Remission (CR) | 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. | One of the two patients had oligoblastic AML in addition to MDS. Only that one patient is included in this analysis. | Posted | Count of Participants | Participants | Assessed after 2 cycles of 28 days each. |
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| Secondary | Response Criteria for AML, CR With Incomplete Recovery | All CR criteria except for residual neutropenia (<10(9)/L) or thrombocytopenia (<100x 10(9)/L). | One of the two patients had Oligoblastic AML in addition to MDS. Only that patient is included in the analysis. | Posted | Count of Participants | Participants | Assessed after 2 cycles of 28 days each. |
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| Secondary | Response Criteria for AML, Relapse. | 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.. | The one patient analyzed achieved complete remission after 2 cycles and relapse after 6 cycles. | Posted | Count of Participants | Participants | Assessed after 6 cycles of 28 days each. |
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| Secondary | Response Criteria for MDS, Complete Remission (CR) | 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%. | Posted | Count of Participants | Participants | Assessed after 6 cycles of 28 days each. |
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| Secondary | Response Criteria for MDS, Marrow CR | Bone marrow less than or equal to 5% myeloblasts and decreased by greater than 50% over pretreatment. | Posted | Count of Participants | Participants | Assessed after 2 cycles of 28 days each. |
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| Secondary | Response Criteria for MDS, Stable Disease | Failure to achieve at least PR, but no evidence of progression for greater than 8 weeks | Posted | Count of Participants | Participants | Assessed after 6 cycles of 28 days each. Both patients had at least stable disease for at least 6 cycles. |
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| Secondary | Response Criteria for MDS, Failure | 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 | Neither patient met the criteria of failure at any time point (after 2, 4, and 6 cycles of 28 days each). | Posted | Count of Participants | Participants | Assessed after 6 cycles of 28 days each. |
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| Secondary | Response Criteria for MDS, Disease Progression, Blasts Measurements | Absolute blast count. | 2 subjects overall are analyzed, one subject is analyzed per row of data. | Posted | Number | percentage of bone marrow blasts | Assessed after 2 cycles of 28 days each. |
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| Secondary | Response Criteria for MDS, Disease Progression, Hgb | Hemoglobin in g/dL | 2 subjects are analyzed overall, but one subject is analyzed per row of data. | Posted | Number | g/dl | Assessed after 2 cycles of 28 days each. |
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| Secondary | Response Criteria for MDS, Disease Progression, Neutrophils | Neutrophil count in 10(9)/L | 2 subjects are analyzed overall, but one subject is analyzed per row of data. | Posted | Number | neutrophils x10(9) per liter | Assessed after 2 cycles of 28 days each. |
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| Secondary | Response Criteria for MDS, Survival, Death | Survival over the full study time period and follow up to 23 months after initiating treatment. | Number of participants who survived for 23 months. | Posted | Count of Participants | Participants | 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. |
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| 0 |
| 2 |
| 2 |
| 2 |
| 2 |
| 2 |
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| Syncope | Nervous system disorders | Non-systematic Assessment | The syncope was judged possibly study medication related. |
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| Worsening anemia | Blood and lymphatic system disorders | Systematic Assessment | Grade 3. Judged as possibly study medication related. |
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| Peripheral motor neuropathy | Nervous system disorders | Non-systematic Assessment | Grade 2. Judged as possibly study medication related. |
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| D007938 | Leukemia |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D054437 | Myelodysplastic-Myeloproliferative Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D000753 | Anemia, Refractory |
| D000740 | Anemia |
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| Subject 102 baseline, 1 participant per row |
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| Subject 102, 8 weeks, 1 partipant per row |
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| Subject 102, baseline, 1 participant per row |
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| Subject 102, 8 weeks, 1 participant per row |
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| Subject 102, baseline, 1 participant per row |
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| Subject 102, 8 weeks, 1 participant per row |
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