Anemia, Refractory, With Excess of Blasts, Leukemia, Myelomonocytic, Chronic, Myelodysplastic Syndromes
Conditions
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.
Interventions
DRUGIGF/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
Sponsors
IGF Oncology, LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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 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, Blasts Measurements | Assessed after 2 cycles of 28 days each. | Absolute blast count. |
| Response Criteria for MDS, Disease Progression, Hgb | Assessed after 2 cycles of 28 days each. | Hemoglobin in g/dL |
| Response Criteria for MDS, Disease Progression, Neutrophils | Assessed after 2 cycles of 28 days each. | Neutrophil count in 10(9)/L |
| 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 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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 | 2 |
| Total | 2 |
Baseline characteristics
| Characteristic | IGF/MTX | — |
|---|---|---|
| Age, Categorical <=18 years | 0 Participants | — |
| Age, Categorical >=65 years | 2 Participants | — |
| Age, Categorical Between 18 and 65 years | 0 Participants | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment United States | 2 participants | — |
| Sex: Female, Male Female | 0 Participants | — |
| Sex: Female, Male Male | 2 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 2 |
| other Total, other adverse events | 2 / 2 |
| serious Total, serious adverse events | 2 / 2 |
Outcome results
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.
Time frame: Up to 6 28-day cycles for one participant, and up to 10 28-day cycles for the other participant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IGF/MTX | Number of Participants With Treatment-Emergent Adverse Events | 2 Participants |
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.
Time frame: Assessed after 2 cycles of 28 days each.
Population: One of the two patients had oligoblastic AML in addition to MDS. Only that one patient is included in this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IGF/MTX | Response Criteria for AML, Complete Remission (CR) | 0 Participants |
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).
Time frame: Assessed after 2 cycles of 28 days each.
Population: One of the two patients had Oligoblastic AML in addition to MDS. Only that patient is included in the analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IGF/MTX | Response Criteria for AML, CR With Incomplete Recovery | 1 Participants |
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..
Time frame: Assessed after 6 cycles of 28 days each.
Population: The one patient analyzed achieved complete remission after 2 cycles and relapse after 6 cycles.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IGF/MTX | Response Criteria for AML, Relapse. | 1 Participants |
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%.
Time frame: Assessed after 6 cycles of 28 days each.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IGF/MTX | Response Criteria for MDS, Complete Remission (CR) | 0 Participants |
Secondary
Response Criteria for MDS, Disease Progression, Blasts Measurements
Absolute blast count.
Time frame: Assessed after 2 cycles of 28 days each.
Population: 2 subjects overall are analyzed, one subject is analyzed per row of data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IGF/MTX | Response Criteria for MDS, Disease Progression, Blasts Measurements | Subject 101 baseline, 1 participant per row | 22 percentage of bone marrow blasts |
| IGF/MTX | Response Criteria for MDS, Disease Progression, Blasts Measurements | Subject 101, 8 weeks, 1 participant per row | 5 percentage of bone marrow blasts |
| IGF/MTX | Response Criteria for MDS, Disease Progression, Blasts Measurements | Subject 102 baseline, 1 participant per row | 17 percentage of bone marrow blasts |
| IGF/MTX | Response Criteria for MDS, Disease Progression, Blasts Measurements | Subject 102, 8 weeks, 1 partipant per row | 17 percentage of bone marrow blasts |
Secondary
Response Criteria for MDS, Disease Progression, Hgb
Hemoglobin in g/dL
Time frame: Assessed after 2 cycles of 28 days each.
Population: 2 subjects are analyzed overall, but one subject is analyzed per row of data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IGF/MTX | Response Criteria for MDS, Disease Progression, Hgb | Subject 101, baseline, 1 participant per row | 7.3 g/dl |
| IGF/MTX | Response Criteria for MDS, Disease Progression, Hgb | Subject 101, 8 weeks, 1 participant per row | 8.9 g/dl |
| IGF/MTX | Response Criteria for MDS, Disease Progression, Hgb | Subject 102, baseline, 1 participant per row | 9.7 g/dl |
| IGF/MTX | Response Criteria for MDS, Disease Progression, Hgb | Subject 102, 8 weeks, 1 participant per row | 9.9 g/dl |
Secondary
Response Criteria for MDS, Disease Progression, Neutrophils
Neutrophil count in 10(9)/L
Time frame: Assessed after 2 cycles of 28 days each.
Population: 2 subjects are analyzed overall, but one subject is analyzed per row of data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IGF/MTX | Response Criteria for MDS, Disease Progression, Neutrophils | Subject 101, baseline, 1 participant per row | 0.04 neutrophils x10(9) per liter |
| IGF/MTX | Response Criteria for MDS, Disease Progression, Neutrophils | Subject 101, 8 weeks, 1 participant per row | 0.75 neutrophils x10(9) per liter |
| IGF/MTX | Response Criteria for MDS, Disease Progression, Neutrophils | Subject 102, baseline, 1 participant per row | 0.38 neutrophils x10(9) per liter |
| IGF/MTX | Response Criteria for MDS, Disease Progression, Neutrophils | Subject 102, 8 weeks, 1 participant per row | 1.29 neutrophils x10(9) per liter |
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
Time frame: Assessed after 6 cycles of 28 days each.
Population: Neither patient met the criteria of failure at any time point (after 2, 4, and 6 cycles of 28 days each).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IGF/MTX | Response Criteria for MDS, Failure | 0 Participants |
Secondary
Response Criteria for MDS, Marrow CR
Bone marrow less than or equal to 5% myeloblasts and decreased by greater than 50% over pretreatment.
Time frame: Assessed after 2 cycles of 28 days each.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IGF/MTX | Response Criteria for MDS, Marrow CR | 1 Participants |
Secondary
Response Criteria for MDS, Stable Disease
Failure to achieve at least PR, but no evidence of progression for greater than 8 weeks
Time frame: Assessed after 6 cycles of 28 days each. Both patients had at least stable disease for at least 6 cycles.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IGF/MTX | Response Criteria for MDS, Stable Disease | 2 Participants |
Secondary
Response Criteria for MDS, Survival, Death
Survival over the full study time period and follow up to 23 months after initiating treatment.
Time frame: 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.
Population: Number of participants who survived for 23 months.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IGF/MTX | Response Criteria for MDS, Survival, Death | 2 Participants |