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Insufficient efficacy in Phase 1 dose-escalation portion of study
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This is a Phase 1/2a dose-escalation study of E6201, a dual mitogen-activated protein kinase/extracellular-signal regulated kinase 1 (MEK1) and FMS-like tyrosine kinase 3 (FLT3) inhibitor, in subjects with advanced hematologic malignancies with documented FLT3 and/or rat sarcoma (Ras) mutations. The Phase1 portion of the study will be a safety run-in (up to 30 subjects) to establish a recommended Phase 2 dose (RP2D). The Ph. 2a portion of the study will evaluate three specific patients groups: Cohort 1 will enroll patients with relapsed or refractory AML and confirmed FLT3 mutation (with or without a Ras mutation) without prior exposure to a FLT3 inhibitor; Cohort 2 will enroll patients with relapsed or refractory AML and confirmed FLT3 mutation (with or without a Ras mutation) with prior exposure to a FLT3 inhibitor; Cohort 3 will enroll patients with relapsed or refractory AML with a confirmed Ras mutation and no FLT3 mutation.
Phase 1 (Safety Run-In): Following Screening, a total of up to 30 subjects in up to 5 dose cohorts to establish the RP2D. The safety run-in phase will be a standard 3+3 cohort design.
Phase 2a (Expansion): Once the Phase 1 Safety Run-In portion of the study is complete and an RP2D is established, additional subjects will be enrolled into the Phase 2 Expansion portion in three cohorts. Cohort 1 will enroll up to 26 patients with relapsed or refractory AML and confirmed FLT3 mutation (with or without a Ras mutation) without prior exposure to a FLT3 inhibitor. Cohort 2 will enroll up to 26 patients with relapsed or refractory AML and confirmed FLT3 mutation (with or without a Ras mutation) with prior exposure to a FLT3 inhibitor. Cohort 3 will enroll up to 10 patients with relapsed or refractory AML with a confirmed Ras mutation and no FLT3 mutation. Cohort 1 and 2 of the Expansion Phase will incorporate a Simon 2-stage optimal design. Subjects with AML enrolled in the Phase 1 portion of the study at the RP2D will count towards the Phase 2a accrual for the appropriate cohort.
Subjects will receive E6201 weekly or bi-weekly on a 28-day schedule, with the schedule and dose level established in the Safety Run-In portion of the study. Disease assessments, including analysis of blood and bone marrow samples, will be performed at the end of Cycles 1 and 3 and every 2 cycles thereafter. Disease assessments may be made at other time points at the discretion of the Investigator.
Subjects who demonstrate clinical benefit (objective response or stable disease) will be allowed to continue therapy with E6201 until progression of disease, observation of unacceptable adverse events, intercurrent illness or changes in the patient's condition that prevents further study participation.
During the study, ECGs will be performed, blood will be collected for hematology, serum chemistry, pharmacokinetics and pharmacodynamics assessments, and bone marrow will be collected for the assessment of disease response and mutational status.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| E6201 240 mg/m^2 IV weekly | Experimental | E6201 240 mg/m^2 administered IV over 2 hours once weekly, on Days 1, 8, 15, and 22, repeated every 28 days (= 1 cycle) |
|
| E6201 320 mg/m^2 IV weekly | Experimental | E6201 320 mg/m^2 administered IV over 2 hours once weekly, on Days 1, 8, 15, and 22, repeated every 28 days (= 1 cycle) |
|
| E6201 160 mg/m^2 IV twice weekly | Experimental | E6201 160 mg/m^2 administered IV over 2 hours twice weekly, on Days 1, 4, 8, 11, 15, 18, 22 and 25, repeated every 28 days (= 1 cycle) |
|
| E6201 240 mg/m^2 IV twice weekly | Experimental | E6201 240 mg/m^2 administered IV over 2 hours twice weekly, on Days 1, 4, 8, 11, 15, 18, 22 and 25, repeated every 28 days (= 1 cycle) |
|
| E6201 320 mg/m^2 IV twice weekly | Experimental | E6201 320 mg/m^2 administered IV over 2 hours twice weekly, on Days 1, 4, 8, 11, 15, 18, 22, and 25, repeated every 28 days (= 1 cycle) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| E6201 | Drug | Single Group Assignment |
|
| Measure | Description | Time Frame |
|---|---|---|
| Maximum Tolerated Dose (MTD) of E6201 | Phase 1 (Safety Run-In) was conducted in 5 dose cohorts in up to 30 subjects in a standard 3+3 dose-escalation design to establish an MTD and recommended Phase 2 dose (RP2D). Safety assessed through the monitoring of adverse events (AEs), serious adverse events (SAEs), clinical laboratory parameters (hematology and serum chemistry), vital sign measurements, electrocardiograms (ECGs) and physical examinations. | Up to 6 weeks for each dose cohort |
| Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) | A DLT was defined as any one of the following events: prolonged myelosuppression (as defined by the National Cancer Institute [NCI] criteria specific for leukemia, i.e., marrow cellularity < 5% at ≥ 6 weeks from start of therapy without evidence of leukemia); ≥ Grade 3 non-hematologic toxicity (excluding Grade 3 nausea, vomiting or diarrhea that is adequately controlled with supportive care and resolves to ≤ Grade 2 within 48 hours, or Grade 3 electrolyte disturbances responsive to correction within 24 hours); ≥ Grade 3 liver function tests (LFTs) lasting > 7 days; treatment interruption > 14 days due to toxicity; or other important medical event. DLTs were collected to determine the MTD which is defined as the dose level below the dose at which ≥ 2 of 6 patients in a dose cohort experienced a DLT. | Up to 6 weeks for each dose cohort |
| Measure | Description | Time Frame |
|---|---|---|
| Overall Response Rate | For acute myeloid leukemia (AML): Revised Recommendations of the International Working Group (IWG) Response Criteria for AML: CR: Free of leukemia-related symptoms, absolute neutrophil count (ANC) > 1.0 x 10^9/L, platelet count ≥ 100 x 10^9/L, normal bone marrow with < 5% blasts and no Auer rods. CRi: As per CR but w/ residual thrombocytopenia (platelet count <100 x 10^9/L) or residual neutropenia (ANC <1.0 x 10^9/L). PR: ≥50% decrease bone marrow blasts to 5 - 25% abnormal cells, or CR w/ ≤ 5% blasts if Auer rods present. For myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML): Modified IWG Response Criteria for MDS: CR: Free of leukemia-related symptoms, ANC ≥1.0 x 10^9/L, platelet count ≥100 x 10^9/L, bone marrow ≤5% myeloblasts, normal maturation of all cell lines, hemoglobin ≥ 11g/dL, no blasts in the peripheral blood. PR: All CR criteria w/ ≥50% decrease in bone marrow blasts over pre-treatment, but still > 5%. |
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Inclusion Criteria:
Males and females ≥ 18 years of age
Phase 1: Confirmed relapsed or refractory AML with a documented FLT3 and/or Ras mutation, or ≥ 60 years with newly diagnosed FLT3+ and/or Ras+ AML and not eligible for standard induction chemotherapy or FLT3+ and/or Ras+ higher-risk MDS/CMML (defined as ≥ 10% marrow blasts or ≥ 5% peripheral blood blasts or Revised International Prognostic Scoring System [IPSS-R] score ≥ 3.5) and relapsed or refractory to prior therapy
Phase 2: Confirmed relapsed or refractory AML with a documented FLT3 and/or Ras mutation, or age ≥ 60 years with newly diagnosed FLT3+ and/or Ras+ AML and not eligible for standard induction chemotherapy
At least 3 weeks beyond the last cancer treatment for the disease under study, major surgery and recovered from all acute toxicities (≤ Grade 1) by first dose of study drug (C1D1). Hydroxyurea used to control peripheral blast counts is permitted during the first 2 cycles.
Adequate performance status Eastern Cooperative Oncology Group (ECOG) ≤ 2
Adequate renal and hepatic function:
Negative serum pregnancy test within 14 days prior to the first dose of study therapy for women of child-bearing potential (WCBP). Sexually active WCBP and male subjects must agree to use adequate methods to avoid pregnancy throughout the study and for 28 days after completion of study treatment.
Ability to provide written informed consent
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Gautam Borthakur, MD | MD Anderson Cancer Center Houston, TX 77030 | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Colorado Blood Cancer Institute | Denver | Colorado | 80218 | United States | ||
| H. Lee Moffitt Cancer Center & research Institute |
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| ID | Title | Description |
|---|---|---|
| FG000 | E6201 240 mg/m^2 Weekly | Cohort 1: Participants were administered E6201 240 mg/m^2 IV over 2 hours once weekly, on Days 1, 8, 15, and 22, repeated every 28 days (= 1 cycle) until progression of disease, toxicity or other reason for discontinuation of study drug, and followed for up to 6 months after the last dose. |
| FG001 | E6201 320 mg/m^2 Weekly | Cohort 2: Participants were administered E6201 320 mg/m^2 IV over 2 hours once weekly, on Days 1, 8, 15, and 22, repeated every 28 days (= 1 cycle) until progression of disease, toxicity or other reason for discontinuation of study drug, and followed for up to 6 months after the last dose. |
| FG002 | E6201 160 mg/m^2 Twice Weekly | Cohort 3: Participants were administered E6201 160 mg/m^2 IV over 2 hours twice weekly, on Days 1, 4, 8, 11, 15, 18, 22 and 25, repeated every 28 days (= 1 cycle) until progression of disease, toxicity or other reason for discontinuation of study drug, and followed for up to 6 months after the last dose. |
| FG003 | E6201 240 mg/m^2 Twice Weekly | Cohort 4: Participants were administered E6201 240 mg/m^2 IV over 2 hours twice weekly, on Days 1, 4, 8, 11, 15, 18, 22 and 25, repeated every 28 days (= 1 cycle) until progression of disease, toxicity or other reason for discontinuation of study drug, and followed for up to 6 months after the last dose. |
| FG004 | E6201 320 mg/m^2 Twice Weekly | Cohort 5: Participants were administered E6201 320 mg/m^2 IV over 2 hours twice weekly, on Days 1, 4, 8, 11, 15, 18, 22 and 25, repeated every 28 days (= 1 cycle) until progression of disease, toxicity or other reason for discontinuation of study drug, and followed for up to 6 months after the last dose. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Cohort 1: E6201 240 mg/m^2 Weekly |
|
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| Cohort 2: E6201 320 mg/m^2 Weekly |
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| Cohort 3: 160 mg/m^2 Twice Weekly |
| |||||||||||||||||||
| Cohort 4: 240 mg/m^2 Twice Weekly |
| |||||||||||||||||||
| Cohort 5: 320 mg/m^2 Twice Weekly |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Cohort 1: E6201 240 mg/m^2 Weekly | Cohort 1: Participants were administered E6201 240 mg/m^2 IV over 2 hours once weekly, on Days 1, 8, 15, and 22, repeated every 28 days (= 1 cycle) until progression of disease, toxicity or other reason for study drug discontinued, and followed for up to 6 months after the last dose. |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| 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 | Maximum Tolerated Dose (MTD) of E6201 | Phase 1 (Safety Run-In) was conducted in 5 dose cohorts in up to 30 subjects in a standard 3+3 dose-escalation design to establish an MTD and recommended Phase 2 dose (RP2D). Safety assessed through the monitoring of adverse events (AEs), serious adverse events (SAEs), clinical laboratory parameters (hematology and serum chemistry), vital sign measurements, electrocardiograms (ECGs) and physical examinations. | Full analysis set (FAS): All subjects who were administered any fraction of a dose of study medication | Posted | Number | E6201 MTD (mg/m^2) IV twice weekly | Up to 6 weeks for each dose cohort |
|
Adverse event data were collected for each subject from C1D1 to 6 months after the last dose of study drug. The total duration of the study was 26 months.
Adverse events were reported for all study participants who were administered any fraction of a dose of study medication.
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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 | E6201 240 mg/m^2 Weekly | E6201 240 mg/m^2 IV over 2 hours once weekly, on Days 1, 8, 15, and 22, repeated every 28 days (= 1 cycle) until progression of disease, toxicity or other reason for discontinuation of study drug, and followed for up to 6 months after the last dose. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| GI hemorrhage | Gastrointestinal disorders | MedDRA (15.0) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Febrile neutropenia | Blood and lymphatic system disorders | MedDRA (15.0) | Systematic Assessment |
Although E6201 exhibited an acceptable safety profile when administered at doses up to the MTD of 320 mg/m^2 IV twice weekly, insufficient efficacy was observed during the Phase 1 portion of the study. Thus, the Phase 2a portion was not initiated.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Chief Development Officer | Spirita Oncology, LLC | +1 (713) 898-8965 | linda.paradiso@spiritaoncology.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| SAP | No | Yes | No | Statistical Analysis Plan | Oct 19, 2017 | Nov 6, 2018 | SAP_000.pdf |
| Prot | Yes | No | No | Study Protocol | Oct 30, 2016 | Nov 6, 2018 | Prot_001.pdf |
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| ID | Term |
|---|---|
| C545120 | 14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione |
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|
| At the end of C1 and every 2 cycles thereafter through 6 months following last dose of study drug |
| Duration of Response | Length of time from the first evidence of objective response to the first evidence of progression | At the end of C1 and every 2 cycles thereafter through 6 months following last dose of study drug |
| Progression-Free Survival | Length of time from the date of first administration of study drug to the first evidence of disease progression or death, whichever is earlier | From Cycle 1 Day 1 (C1D1) until death or study closure, up to 26 months |
| Overall Survival | Length of time from the date of first administration of study drug to the date of death from any cause | From C1D1 until death or study closure, up to 26 months |
| Pharmacokinetic Profile of E6201 in Plasma: Cmax | Cmax: Maximum measured plasma concentration over the collection period | Assessed at Cycle 1 Days 1 and 15, Cycle 2 Day 1, pre-dose, 5 minutes following the end of the 2-hour infusion, 2, 4, 8 and 24 hours post-infusion. Summary PK parameters for Cycle 1 Day 1 reported. |
| Pharmacokinetics of E6201 in Plasma: Tmax | Tmax: Time to maximum measured plasma concentration | Assessed at Cycle 1 Days 1 and 15, Cycle 2 Day 1, pre-dose, 5 minutes following the end of the 2-hour infusion, 2, 4, 8 and 24 hours post-infusion. Summary PK parameters for Cycle 1 Day 1 reported. |
| Pharmacokinetic Profile of E6201 in Plasma: AUCT | Area under the plasma concentration versus time curve (AUC) to the last measurable concentration over the sampling time-interval. | Assessed at Cycle 1 Days 1 and 15, Cycle 2 Day 1, pre-dose, 5 minutes following the end of the 2-hour infusion, 2, 4, 8 and 24 hours post-infusion. Summary PK parameters for Cycle 1 Day 1 reported. |
| Pharmacokinetic Profile of E6201 in Plasma: AUCI | AUCI: The area under the concentration versus time curve from time 0 to infinity | Assessed at Cycle 1 Days 1 and 15, Cycle 2 Day 1, pre-dose, 5 minutes following the end of the 2-hour infusion, 2, 4, 8 and 24 hours post-infusion. Summary PK parameters for Cycle 1 Day 1 reported. |
| Pharmacokinetic Profile of E6201 in Plasma: T1/2 | T1/2: The apparent first-order elimination half-life | Assessed at Cycle 1 Days 1 and 15, Cycle 2 Day 1, pre-dose, 5 minutes following the end of the 2-hour infusion, 2, 4, 8 and 24 hours post-infusion. Summary PK parameters for Cycle 1 Day 1 reported. |
| Pharmacokinetic Profile of E6201 in Plasma: CLobs | Clearance observed (CLobs): Total body clearance for extravascular administration | Assessed at Cycle 1 Days 1 and 15, Cycle 2 Day 1, pre-dose, 5 minutes following the end of the 2-hour infusion, 2, 4, 8 and 24 hours post-infusion. Summary PK parameters for Cycle 1 Day 1 reported. |
| Pharmacokinetic Profile of E6201 in Plasma: VDobs | Measurement of apparent volume of distribution observed (VDobs) | Assessed at Cycle 1 Days 1 and 15, Cycle 2 Day 1, pre-dose, 5 minutes following the end of the 2-hour infusion, 2, 4, 8 and 24 hours post-infusion. Summary PK parameters for Cycle 1 Day 1 reported. |
| Number of Participants With Suppression of pERK at 4 Hours Post-dose | phospho-ERK (pERK) in blood assessed by Western blot at 4 hours post-dose | Cycle 1 Day 1, 4 hours post-dose. |
| Number of Participants With Suppression of pERK at 24 Hours Post-dose | Measurement of phospho-ERK (pERK) in blood assessed by Western blot at 24 hours post-dose | Cycle 1 Day 1, 24 hours post-dose. |
| Number of Participants With Suppression of pFLT3 at 4 Hours Post-dose | phospho-FLT3 (pFLT3) in blood assessed by Western blot at 4 hours post-dose | Cycle 1 Day 1, 4 hours post-dose. |
| Number of Participants With Suppression of pFLT3 at 24 Hours Post-dose | phospho-FLT3 (pFLT3) in blood assessed by Western blot at 24 hours post-dose | Cycle 1 Day 1, 24 hours post-dose. |
| Number of Participants With Suppression of pAKT at 4 Hours Post-dose | phospho-AKT (pAKT) in blood assessed by Western blot at 4 hours post-dose | Cycle 1 Day 1, 4 hours post-dose. |
| Number of Participants With Suppression of pAKT at 24 Hours Post-dose | phospho-AKT (pAKT) in blood assessed by Western blot at 24 hours post-dose | Cycle 1 Day 1, 24 hours post-dose. |
| Number of Participants With Suppression of pERK by PIA at 4 Hours Post-dose | Blood assay: Plasma inhibitory assay (PIA) measuring pERK in blood at 4 hours post-dose | Cycle 1 Day 1, 4 hours post-dose. |
| Number of Participants With Suppression of in pERK by PIA 24 Hours Post-dose | Blood assay: Plasma inhibitory assay (PIA) measuring pERK in blood at 24 hours post-dose | Cycle 1 Day 1, 24 hours post-dose. |
| Number of Participants With Suppression of pFLT3 by PIA at 4 Hours Post-dose | Blood assay: Plasma inhibitory assay (PIA) measuring pFLT3 in blood at 4 hours post-dose | Cycle 1 Day 1, 4 hours post-dose. |
| Number of Participants With Suppression of pFLT3 by PIA at 24 Hours Post-dose | Blood assay: Plasma inhibitory assay (PIA) measuring pFLT3 in blood at 24 hours post-dose | Cycle 1 Day 1, 24 hours post-dose. |
| Tampa |
| Florida |
| 33612 |
| United States |
| MD Anderson Cancer Center | Houston | Texas | 77030 | United States |
| Texas Transplant Institute | San Antonio | Texas | 78229 | United States |
| Lack of Efficacy |
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| Prepare for HSCT |
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| COMPLETED |
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| NOT COMPLETED |
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| COMPLETED |
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| NOT COMPLETED |
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|
| COMPLETED |
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| NOT COMPLETED |
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| COMPLETED |
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| NOT COMPLETED |
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|
| Cohort 2: E6201 320 mg/m^2 Weekly |
Cohort 2: Participants were administered E6201 320 mg/m^2 IV over 2 hours once weekly, on Days 1, 8, 15, and 22, repeated every 28 days (= 1 cycle) until progression of disease, toxicity or other reason for study drug discontinuation, and followed for up to 6 months after the last dose. |
| BG002 | Cohort 3: E6201 160 mg/m^2 Twice Weekly | Cohort 3: Participants were administered E6201 160 mg/m^2 IV over 2 hours twice weekly, on Days 1, 4, 8, 11, 15, 18, 22 and 25, repeated every 28 days (= 1 cycle) until progression of disease, toxicity or other reason for study drug discontinuation, and followed for up to 6 months after the last dose. |
| BG003 | Cohort 4: E6201 240 mg/m^2 Twice Weekly | Cohort 4: Participants were administered E6201 240 mg/m^2 IV over 2 hours twice weekly, on Days 1, 4, 8, 11, 15, 18, 22 and 25, repeated every 28 days (= 1 cycle) until progression of disease, toxicity or other reason for study drug discontinuation, and followed for up to 6 months after the last dose. |
| BG004 | Cohort 5: E6201 320 mg/m^2 Twice Weekly | Cohort 5: Participants were administered E6201 320 mg/m^2 IV over 2 hours twice weekly, on Days 1, 4, 8, 11, 15, 18, 22 and 25, repeated every 28 days (= 1 cycle) until progression of disease, toxicity or other reason for study drug discontinuation, and followed for up to 6 months after the last dose. |
| BG005 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Disease Type | Count of Participants | Participants |
|
| Eastern Cooperative Group (ECOG) Performance Status | ECOG Performance Status: 0 = Fully active, able to carry on all pre-disease performance without restriction
| Count of Participants | Participants |
|
| Prior Cancer Therapies | Median | Full Range | Number of treatment regimens |
|
| Units | Counts |
|---|---|
| Participants |
|
|
| Primary | Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) | A DLT was defined as any one of the following events: prolonged myelosuppression (as defined by the National Cancer Institute [NCI] criteria specific for leukemia, i.e., marrow cellularity < 5% at ≥ 6 weeks from start of therapy without evidence of leukemia); ≥ Grade 3 non-hematologic toxicity (excluding Grade 3 nausea, vomiting or diarrhea that is adequately controlled with supportive care and resolves to ≤ Grade 2 within 48 hours, or Grade 3 electrolyte disturbances responsive to correction within 24 hours); ≥ Grade 3 liver function tests (LFTs) lasting > 7 days; treatment interruption > 14 days due to toxicity; or other important medical event. DLTs were collected to determine the MTD which is defined as the dose level below the dose at which ≥ 2 of 6 patients in a dose cohort experienced a DLT. | Full analysis set (FAS): All subjects who were administered any fraction of a dose of study medication. | Posted | Number | Number of Participants with DLTs | Up to 6 weeks for each dose cohort |
|
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| Secondary | Overall Response Rate | For acute myeloid leukemia (AML): Revised Recommendations of the International Working Group (IWG) Response Criteria for AML: CR: Free of leukemia-related symptoms, absolute neutrophil count (ANC) > 1.0 x 10^9/L, platelet count ≥ 100 x 10^9/L, normal bone marrow with < 5% blasts and no Auer rods. CRi: As per CR but w/ residual thrombocytopenia (platelet count <100 x 10^9/L) or residual neutropenia (ANC <1.0 x 10^9/L). PR: ≥50% decrease bone marrow blasts to 5 - 25% abnormal cells, or CR w/ ≤ 5% blasts if Auer rods present. For myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML): Modified IWG Response Criteria for MDS: CR: Free of leukemia-related symptoms, ANC ≥1.0 x 10^9/L, platelet count ≥100 x 10^9/L, bone marrow ≤5% myeloblasts, normal maturation of all cell lines, hemoglobin ≥ 11g/dL, no blasts in the peripheral blood. PR: All CR criteria w/ ≥50% decrease in bone marrow blasts over pre-treatment, but still > 5%. | The analysis population was the per-protocol set (PPS). The PPS included all subjects in the FAS who had a valid baseline and one or more post-treatment assessments for a specified measure. | Posted | Number | Objective Responses | At the end of C1 and every 2 cycles thereafter through 6 months following last dose of study drug |
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|
| Secondary | Duration of Response | Length of time from the first evidence of objective response to the first evidence of progression | The analysis population was the per-protocol set (PPS). The PPS included all subjects in the FAS who had a valid baseline and one or more post-treatment assessments for a specified measure. No objective responses were observed. Therefore, duration of response could not be calculated. | Posted | At the end of C1 and every 2 cycles thereafter through 6 months following last dose of study drug |
|
|
| Secondary | Progression-Free Survival | Length of time from the date of first administration of study drug to the first evidence of disease progression or death, whichever is earlier | The analysis population was the per-protocol set (PPS). The PPS included all subjects in the FAS who had a valid baseline and one or more post-treatment assessments for a specified measure. For AML, MDS and CMML, progression was defined by relevant IWG criteria as failure to achieve at least a PR. No responses; PFS could not be calculated. | Posted | From Cycle 1 Day 1 (C1D1) until death or study closure, up to 26 months |
|
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| Secondary | Overall Survival | Length of time from the date of first administration of study drug to the date of death from any cause | The analysis population was the per-protocol set (PPS). The PPS included all subjects in the FAS who had a valid baseline and one or more post-treatment assessments for a specified endpoint. | Posted | Median | Standard Deviation | Days | From C1D1 until death or study closure, up to 26 months |
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| Secondary | Pharmacokinetic Profile of E6201 in Plasma: Cmax | Cmax: Maximum measured plasma concentration over the collection period | All subjects in the FAS who completed at least 1 pharmacokinetic (PK) assessment. | Posted | Mean | Standard Deviation | ng/mL | Assessed at Cycle 1 Days 1 and 15, Cycle 2 Day 1, pre-dose, 5 minutes following the end of the 2-hour infusion, 2, 4, 8 and 24 hours post-infusion. Summary PK parameters for Cycle 1 Day 1 reported. |
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| Secondary | Pharmacokinetics of E6201 in Plasma: Tmax | Tmax: Time to maximum measured plasma concentration | All subjects in the FAS who completed at least 1 pharmacokinetic (PK) assessment. | Posted | Mean | Standard Deviation | h | Assessed at Cycle 1 Days 1 and 15, Cycle 2 Day 1, pre-dose, 5 minutes following the end of the 2-hour infusion, 2, 4, 8 and 24 hours post-infusion. Summary PK parameters for Cycle 1 Day 1 reported. |
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| Secondary | Pharmacokinetic Profile of E6201 in Plasma: AUCT | Area under the plasma concentration versus time curve (AUC) to the last measurable concentration over the sampling time-interval. | All subjects in the FAS who completed at least 1 pharmacokinetic (PK) assessment. | Posted | Mean | Standard Deviation | h.ng/mL | Assessed at Cycle 1 Days 1 and 15, Cycle 2 Day 1, pre-dose, 5 minutes following the end of the 2-hour infusion, 2, 4, 8 and 24 hours post-infusion. Summary PK parameters for Cycle 1 Day 1 reported. |
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| Secondary | Pharmacokinetic Profile of E6201 in Plasma: AUCI | AUCI: The area under the concentration versus time curve from time 0 to infinity | All subjects in the FAS who completed at least 1 pharmacokinetic (PK) assessment. | Posted | Mean | Standard Deviation | h.ng/mL | Assessed at Cycle 1 Days 1 and 15, Cycle 2 Day 1, pre-dose, 5 minutes following the end of the 2-hour infusion, 2, 4, 8 and 24 hours post-infusion. Summary PK parameters for Cycle 1 Day 1 reported. |
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| Secondary | Pharmacokinetic Profile of E6201 in Plasma: T1/2 | T1/2: The apparent first-order elimination half-life | All subjects in the FAS who completed at least 1 pharmacokinetic (PK) assessment. | Posted | Mean | Standard Deviation | h | Assessed at Cycle 1 Days 1 and 15, Cycle 2 Day 1, pre-dose, 5 minutes following the end of the 2-hour infusion, 2, 4, 8 and 24 hours post-infusion. Summary PK parameters for Cycle 1 Day 1 reported. |
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| Secondary | Pharmacokinetic Profile of E6201 in Plasma: CLobs | Clearance observed (CLobs): Total body clearance for extravascular administration | All subjects in the FAS who completed at least 1 pharmacokinetic (PK) assessment. | Posted | Mean | Standard Deviation | L/h | Assessed at Cycle 1 Days 1 and 15, Cycle 2 Day 1, pre-dose, 5 minutes following the end of the 2-hour infusion, 2, 4, 8 and 24 hours post-infusion. Summary PK parameters for Cycle 1 Day 1 reported. |
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| Secondary | Pharmacokinetic Profile of E6201 in Plasma: VDobs | Measurement of apparent volume of distribution observed (VDobs) | All subjects in the FAS who completed at least 1 pharmacokinetic (PK) assessment. | Posted | Mean | Standard Deviation | L | Assessed at Cycle 1 Days 1 and 15, Cycle 2 Day 1, pre-dose, 5 minutes following the end of the 2-hour infusion, 2, 4, 8 and 24 hours post-infusion. Summary PK parameters for Cycle 1 Day 1 reported. |
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| Secondary | Number of Participants With Suppression of pERK at 4 Hours Post-dose | phospho-ERK (pERK) in blood assessed by Western blot at 4 hours post-dose | All subjects in the FAS who completed at least 1 PD assessment. Data obtained were not quantitative. | Posted | Count of Participants | Participants | Cycle 1 Day 1, 4 hours post-dose. |
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|
|
| Secondary | Number of Participants With Suppression of pERK at 24 Hours Post-dose | Measurement of phospho-ERK (pERK) in blood assessed by Western blot at 24 hours post-dose | All subjects in the FAS who completed at least 1 PD assessment. Data obtained were not quantitative. | Posted | Count of Participants | Participants | Cycle 1 Day 1, 24 hours post-dose. |
|
|
|
| Secondary | Number of Participants With Suppression of pFLT3 at 4 Hours Post-dose | phospho-FLT3 (pFLT3) in blood assessed by Western blot at 4 hours post-dose | All subjects in the FAS who completed at least 1 PD assessment. Data obtained were not quantitative. | Posted | Count of Participants | Participants | Cycle 1 Day 1, 4 hours post-dose. |
|
|
|
| Secondary | Number of Participants With Suppression of pFLT3 at 24 Hours Post-dose | phospho-FLT3 (pFLT3) in blood assessed by Western blot at 24 hours post-dose | All subjects in the FAS who completed at least 1 PD assessment. Data obtained were not quantitative. | Posted | Count of Participants | Participants | Cycle 1 Day 1, 24 hours post-dose. |
|
|
|
| Secondary | Number of Participants With Suppression of pAKT at 4 Hours Post-dose | phospho-AKT (pAKT) in blood assessed by Western blot at 4 hours post-dose | All subjects in the FAS who completed at least 1 PD assessment. Data obtained were not quantitative. | Posted | Count of Participants | Participants | Cycle 1 Day 1, 4 hours post-dose. |
|
|
|
| Secondary | Number of Participants With Suppression of pAKT at 24 Hours Post-dose | phospho-AKT (pAKT) in blood assessed by Western blot at 24 hours post-dose | All subjects in the FAS who completed at least 1 PD assessment. Data obtained were not quantitative. | Posted | Count of Participants | Participants | Cycle 1 Day 1, 24 hours post-dose. |
|
|
|
| Secondary | Number of Participants With Suppression of pERK by PIA at 4 Hours Post-dose | Blood assay: Plasma inhibitory assay (PIA) measuring pERK in blood at 4 hours post-dose | All subjects in the FAS who completed at least 1 PD assessment. Data obtained were not quantitative. | Posted | Count of Participants | Participants | Cycle 1 Day 1, 4 hours post-dose. |
|
|
|
| Secondary | Number of Participants With Suppression of in pERK by PIA 24 Hours Post-dose | Blood assay: Plasma inhibitory assay (PIA) measuring pERK in blood at 24 hours post-dose | All subjects in the FAS who completed at least 1 PD assessment. Data obtained were not quantitative. | Posted | Count of Participants | Participants | Cycle 1 Day 1, 24 hours post-dose. |
|
|
|
| Secondary | Number of Participants With Suppression of pFLT3 by PIA at 4 Hours Post-dose | Blood assay: Plasma inhibitory assay (PIA) measuring pFLT3 in blood at 4 hours post-dose | All subjects in the FAS who completed at least 1 PD assessment. Data obtained were not quantitative. | Posted | Count of Participants | Participants | Cycle 1 Day 1, 4 hours post-dose. |
|
|
|
| Secondary | Number of Participants With Suppression of pFLT3 by PIA at 24 Hours Post-dose | Blood assay: Plasma inhibitory assay (PIA) measuring pFLT3 in blood at 24 hours post-dose | All subjects in the FAS who completed at least 1 PD assessment. Data obtained were not quantitative. | Posted | Count of Participants | Participants | Cycle 1 Day 1, 24 hours post-dose. |
|
|
|
| 3 |
| 7 |
| 4 |
| 7 |
| 7 |
| 7 |
| EG001 | E6201 320 mg/m^2 Weekly | E6201 320 mg/m^2 IV over 2 hours once weekly, on Days 1, 8, 15, and 22, repeated every 28 days (= 1 cycle) until progression of disease, toxicity or other reason for discontinuation of study drug, and followed for up to 6 months after the last dose. | 4 | 10 | 10 | 10 | 10 | 10 |
| EG002 | E6201 160 mg/m^2 Twice Weekly | E6201 160 mg/m^2 IV over 2 hours twice weekly, on Days 1, 4, 8, 11, 15, 18, 22 and 25, repeated every 28 days (= 1 cycle) until progression of disease, toxicity or other reason for discontinuation of study drug, and followed for up to 6 months after the last dose. | 1 | 3 | 3 | 3 | 3 | 3 |
| EG003 | E6201 240 mg/m^2 Twice Weekly | E6201 240 mg/m^2 IV over 2 hours twice weekly, on Days 1, 4, 8, 11, 15, 18, 22 and 25, repeated every 28 days (= 1 cycle) until progression of disease, toxicity or other reason for discontinuation of study drug, and followed for up to 6 months after the last dose. | 0 | 3 | 2 | 3 | 3 | 3 |
| EG004 | E6201 320 mg/m^2 Twice Weekly | E6201 320 mg/m^2 IV over 2 hours twice weekly, on Days 1, 4, 8, 11, 15, 18, 22 and 25, repeated every 28 days (= 1 cycle) until progression of disease, toxicity or other reason for discontinuation of study drug, and followed for up to 6 months after the last dose. | 1 | 4 | 2 | 4 | 4 | 4 |
| Tumor lysis syndrome | Metabolism and nutrition disorders | MedDRA (15.0) | Systematic Assessment |
|
| Cellulitis | Infections and infestations | MedDRA (15.0) | Systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA (15.0) | Systematic Assessment |
|
| Multi-organ failure | General disorders | MedDRA (15.0) | Systematic Assessment |
|
| Sepsis | Infections and infestations | MedDRA (15.0) | Systematic Assessment |
|
| Alpha hemolytic Strep infection | Infections and infestations | MedDRA (15.0) | Systematic Assessment |
|
| Pseudomonal bateremia | Infections and infestations | MedDRA (15.0) | Systematic Assessment |
|
| ECG QTc prolonged | Investigations | MedDRA (15.0) | Systematic Assessment |
|
| Intracranial hemorrhage | Nervous system disorders | MedDRA (15.0) | Systematic Assessment |
|
| Klebsiella bacteremia | Infections and infestations | MedDRA (15.0) | Systematic Assessment |
|
| Respiratory tract infection fungal | Infections and infestations | MedDRA (15.0) | Systematic Assessment |
|
| Febrile neutropenia | Blood and lymphatic system disorders | MedDRA (15.0) | Systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA (15.0) | Systematic Assessment |
|
| Dyspnea | Respiratory, thoracic and mediastinal disorders | MedDRA (15.0) | Systematic Assessment |
|
| Epiglottitis | Infections and infestations | MedDRA (15.0) | Systematic Assessment |
|
| Non-cardiac chest pain | General disorders | MedDRA (15.0) | Systematic Assessment |
|
| Pyelonephritis | Infections and infestations | MedDRA (15.0) | Systematic Assessment |
|
| Perirectal abscess | Infections and infestations | MedDRA (15.0) | Systematic Assessment |
|
| Sinusitis | Infections and infestations | MedDRA (15.0) | Systematic Assessment |
|
| Lobar pneumonia | Infections and infestations | MedDRA (15.0) | Systematic Assessment |
|
| Asthenia | General disorders | MedDRA (15.0) | Systematic Assessment |
|
| Leucocytosis | Blood and lymphatic system disorders | MedDRA (15.0) | Systematic Assessment |
|
| Spleen disorder | Blood and lymphatic system disorders | MedDRA (15.0) | Systematic Assessment |
|
| Abdominal distension | Gastrointestinal disorders | MedDRA (15.0) | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA (15.0) | Systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | MedDRA (15.0) | Systematic Assessment |
|
| Dry mouth | Gastrointestinal disorders | MedDRA (15.0) | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA (15.0) | Systematic Assessment |
|
| Proctalgia | Gastrointestinal disorders | MedDRA (15.0) | Systematic Assessment |
|
| Stomatitis | Gastrointestinal disorders | MedDRA (15.0) | Systematic Assessment |
|
| Chills | General disorders | MedDRA (15.0) | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA (15.0) | Systematic Assessment |
|
| Non-cardiac chest pain | General disorders | MedDRA (15.0) | Systematic Assessment |
|
| Pyrexia | General disorders | MedDRA (15.0) | Systematic Assessment |
|
| Cellulitis | Infections and infestations | MedDRA (15.0) | Systematic Assessment |
|
| Diverticulitis | Infections and infestations | MedDRA (15.0) | Systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA (15.0) | Systematic Assessment |
|
| Pneumonia fungal | Infections and infestations | MedDRA (15.0) | Systematic Assessment |
|
| Sepsis | Infections and infestations | MedDRA (15.0) | Systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA (15.0) | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA (15.0) | Systematic Assessment |
|
| Fall | Injury, poisoning and procedural complications | MedDRA (15.0) | Systematic Assessment |
|
| ALT increased | Investigations | MedDRA (15.0) | Systematic Assessment |
|
| AST increased | Investigations | MedDRA (15.0) | Systematic Assessment |
|
| ECG QT prolonged | Investigations | MedDRA (15.0) | Systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | MedDRA (15.0) | Systematic Assessment |
|
| Dehydration | Metabolism and nutrition disorders | MedDRA (15.0) | Systematic Assessment |
|
| Fluid overload | Metabolism and nutrition disorders | MedDRA (15.0) | Systematic Assessment |
|
| Hypokalemia | Metabolism and nutrition disorders | MedDRA (15.0) | Systematic Assessment |
|
| Muscular weakness | Musculoskeletal and connective tissue disorders | MedDRA (15.0) | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA (15.0) | Systematic Assessment |
|
| Hemorrhage intracranial | Nervous system disorders | MedDRA (15.0) | Systematic Assessment |
|
| Confusional state | Psychiatric disorders | MedDRA (15.0) | Systematic Assessment |
|
| Mental disorder | Psychiatric disorders | MedDRA (15.0) | Systematic Assessment |
|
| Hematuria | Renal and urinary disorders | MedDRA (15.0) | Systematic Assessment |
|
| Pollakiuria | Renal and urinary disorders | MedDRA (15.0) | Systematic Assessment |
|
| Urinary retention | Renal and urinary disorders | MedDRA (15.0) | Systematic Assessment |
|
| Acute respiratory failure | Respiratory, thoracic and mediastinal disorders | MedDRA (15.0) | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (15.0) | Systematic Assessment |
|
| Dyspnea | Respiratory, thoracic and mediastinal disorders | MedDRA (15.0) | Systematic Assessment |
|
| Nasal congestion | Respiratory, thoracic and mediastinal disorders | MedDRA (15.0) | Systematic Assessment |
|
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA (15.0) | Systematic Assessment |
|
| Pruritis | Skin and subcutaneous tissue disorders | MedDRA (15.0) | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA (15.0) | Systematic Assessment |
|
| Rash maculo-papular | Skin and subcutaneous tissue disorders | MedDRA (15.0) | Systematic Assessment |
|
| Skin lesion | Skin and subcutaneous tissue disorders | MedDRA (15.0) | Systematic Assessment |
|
| Hypotension | Vascular disorders | MedDRA (15.0) | Systematic Assessment |
|
Not provided
Not provided