Acute Myeloid Leukemia, Essential Thrombocythemia
Conditions
Keywords
Acute Myeloid Leukemia, Myeloid Leukemia, Relapsed, Refractory
Brief summary
The purpose of this study is to determine a safe dose of LY573636-sodium to be given to patients with acute myeloid leukemia and to determine any side effects that may be associated with LY573636-sodium in this patient population. Efficacy measures will also be used to assess the activity of LY573636-sodium in acute myeloid leukemia and essential thrombocythemia patients.
Interventions
DRUGLY573636-sodium
Individualized dose is dependent on participant's height, weight, gender and is adjusted to target a specific exposure range corrected for a participant's laboratory parameters. Dosing will be done on Day 1 of a 35-day cycle for acute myeloid leukemia (AML) and Day 1 of a 28-day cycle for essential thrombocythemia (ET) for at least one cycle. A participant may have additional cycles of LY573636 if he or she is receiving benefit from the study drug and does not fulfill any of the criteria for study discontinuation.
Sponsors
Eli Lilly and Company
Study design
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants who have a diagnosis of either essential thrombocythemia or acute myeloid leukemia that is relapsed or refractory to at least one prior standard treatment. If participants have acute promyelocytic leukemia, they must be resistant and/or intolerant of both all trans retinoic acid (ATRA) and arsenic trioxide. * Are at least 18 years of age. * Have given written informed consent approved by Lilly and the ethical review board (ERB)/institutional review board (IRB) governing the site. * Must have adequate hepatic and renal function. * Have discontinued all previous therapies for cancer, including chemotherapy, radiotherapy, immunotherapy, cancer-related hormonal therapy, or other investigational therapy for at least 21 days for myelosuppressive agents (such as cytarabine, daunorubicin, and gemtuzumab ozogamicin) or 14 days for non-myelosuppressive agents prior to receiving study drug and recovered from the acute effects of therapy. Hydroxyurea used to control peripheral blood blast count is permitted within these respective periods, but it must be stopped at least 24 hours before study drug administration. * Males and females with reproductive potential must agree to use medically approved contraceptive precautions during the trial and for 6 months following the last dose of study drug. * Females of child bearing potential must have had a negative serum pregnancy test less than or equal to 7 days prior to the first dose of study drug. * Have a serum albumin level greater than equal to 3.0 grams/deciliter (g/L), less than or equal to 72 hour prior to dosing with LY573636-sodium.
Exclusion criteria
* Have received treatment with a drug that has not received regulatory approval for any indication within 14 or 21 days of the initial dose of study drug for a non-myelosuppressive or myelosuppressive agent, respectively. * Participants with myeloproliferative disorders (for example, chronic myeloid leukemia (CML), polycythemia vera and primary myelofibrosis) other than essential thrombocythemia. * Have received an autologous or allogenic stem cell transplant within 75 days of the initial dose of study drug for the dose escalation phase or within 60 days of the initial dose of study drug for the dose confirmation phase. Recipients of an allogeneic stem cell transplant must have discontinued immunosuppressive therapy at least 24 hours before study drug administration with no more than Grade 1 acute graft-versus-host disease. * Have previously completed or withdrawn from this study or any other study investigating LY573636 sodium. * Have serious preexisting medical conditions that in the opinion of the investigator would preclude participation in this study. * Have serious concomitant disorders, including active bacterial, fungal, or viral infection, incompatible with the study. * Have a second primary malignancy that could affect interpretation of results. * Have a known coagulopathy or bleeding disorder, other than leukemic related thrombocytopenia. Participants with severe or life-threatening bleeding refractory to platelet transfusions are also excluded from this study. * Major surgery within 4 weeks of study enrollment. * Are receiving warfarin (Coumadin). * Females who are pregnant or breast feeding. * Have known positive results of human immunodeficiency virus (HIV), hepatitis B surface antigen (HBSAg) or hepatitis C antibodies (HCAb). * Have received treatment within 28 days of the initial dose of study drug with an experimental agent for noncancerous indications that has not received regulatory approval for any indication. * Participants receiving amiodarone, quinidine, propofol, or clozapine. * Participants receiving treatment with strong or moderate inhibitors of cytochrome P450 (CYP)2C19, including proton-pump inhibitors (PPIs). Esomeprazole or pantoprazole are allowed if not administered within 72 hours before or after LY573636 administration
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recommended Phase 2 Dose of LY573636-Sodium in Participants With Relapsed or Refractory Acute Myeloid Leukemia (AML) and Essential Thrombocythemia (ET) | Predose up to 35 days postdose in Cycle 1 | Recommended Phase 2 dose was determined by maximum tolerated dose (MTD). MTD is the highest dose at which no more than 1 of 6 participants experienced a dose-limiting toxicity (DLT) and level immediately below that which had ≥2 instances of DLT. A DLT is an adverse event (AE) observed during the first cycle of treatment that is believed to be related to LY573636 and fulfills any of the following: ET only , Common Terminology Criteria for AE (CTCAE, Version 3.0) Grade (Gr) 4 hematologic toxicity for ≥3 days; For all, ≥Gr 3 nonhematological toxicity except for nausea/vomiting or diarrhea unless it fits the next criteria; ≥Gr 3 nausea, vomiting, or diarrhea that persists \>7 days despite maximal treatment; Gr 3 electrolyte disturbances that persist despite maximal measures; DLT can be declared if a participant experienced increasing toxicity during treatment. The primary outcome measure was not analyzed because the enrollment was stopped early before MTD was reached. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics Area Under the Curve(AUC) of LY573636 Above the Albumin-Corrected Threshold (AUCalb) | Predose,1h,2h,4h, 8d,14d,15d,21d,28d post dose | LY573636 has been found to be highly bound to albumin. AUCalb is a surrogate measure of exposure to unbound (free) LY573636. PK sample is withdrawn at any time on days 8,14,15,21,28. |
| Number of Participants With Bone Marrow (BM) Response | Baseline to measured progressive disease up to 70 days | The International Working Group's revised recommendations were used to assess response in acute myeloid leukemia (AML): complete response (CR) is \<5% blasts in BM and with a cell count ≥200 cells in BM, and with peripheral blood platelets ≥100x10⁹/liter (L) and absolute neutrophils ≥1x10⁹/L; CR with incomplete blood count recovery is defined as CRi; partial response (PR) is ≥5% blasts in BM but with ≥50% reduction in blast count. Number of responders for AML = CR+PR+ CRi. Result of a European Leukemia Net consensus conference was used to assess response in essential thrombocythemia (ET). CR is platelets ≤400x10⁹/L in peripheral blood, no disease-related symptoms, normal spleen size and white blood cells ≤10x10⁹/L in peripheral blood; PR has platelets ≤600x10⁹/L in peripheral blood or decrease \> 50% from baseline but does not meet CR criteria. Number of responders for ET = CR+PR. |
| Pharmacokinetics: Concentration Maximum (Cmax) of LY573636 | Predose,1h,2h,4h, 8d,14d,15d,21d,28d post dose | PK sample is withdrawn at any time on days 8,14,15,21,28. |
Countries
United States
Participant flow
Pre-assignment details
The reasons for discontinuation listed in the participant flow are the reasons the participant discontinued treatment. All participants who received at least 1 dose of study drug were considered to have completed the study.
Participants by arm
| Arm | Count |
|---|---|
| Cmax 250 μg/mL (AML) Participants diagnosed with acute myeloid leukemia (AML) dosed: LY573636 targeting a maximum concentration (Cmax) of 250 micrograms per milliliter (μg/mL) as a 24-hour infusion on Day 1 of a 35-day cycle. | 3 |
| Cmax 300 μg/mL (AML) Participants diagnosed with AML dosed: LY573636 targeting a Cmax of 300 μg/mL as a 24-hour infusion on Day 1 of a 35-day cycle. | 3 |
| Cmax 350 μg/mL (AML) Participants diagnosed with AML dosed: LY573636 targeting a Cmax of 350 μg/mL as a 24-hour infusion on Day 1 of a 35-day cycle. | 3 |
| Cmax 400 μg/mL (AML) Participants diagnosed with AML dosed: LY573636 targeting a Cmax of 400 μg/mL as a 24-hour infusion on Day 1 of a 35-day cycle. | 4 |
| AUCalb 5500 µg*hr/mL (AML) Participants diagnosed with AML dosed: LY573636 targeting an albumin-corrected exposure (AUCalb) 5500 micrograms\*hour per milliliter (µg\*hr/mL) as a 2-hour infusion on Day 1 of a 35-day cycle. | 8 |
| AUCalb 7000 µg*hr/mL (AML) Participants diagnosed with AML dosed: LY573636 targeting an AUCalb 7000 µg\*hr/mL as a 2-hour infusion on Day 1 of a 35-day cycle. | 1 |
| AUCalb 5500 µg*hr/mL (ET) Participants diagnosed with essential thrombocythemia (ET) dosed: LY573636 targeting an AUCalb 5500 µg\*hr/mL as a 2-hour infusion on Day 1 of a 28-day cycle. | 1 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Death due to Adverse Event | 0 | 0 | 0 | 2 | 2 | 0 | 0 |
| Overall Study | Death due to Study Drug Toxicity | 0 | 0 | 1 | 2 | 0 | 0 | 0 |
| Overall Study | Investigator Decision | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| Overall Study | Progressive Disease | 3 | 3 | 2 | 0 | 6 | 0 | 0 |
Baseline characteristics
| Characteristic | Cmax 300 μg/mL (AML) | Cmax 350 μg/mL (AML) | Cmax 250 μg/mL (AML) | Cmax 400 μg/mL (AML) | AUCalb 5500 µg*hr/mL (AML) | AUCalb 7000 µg*hr/mL (AML) | AUCalb 5500 µg*hr/mL (ET) | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 52.48 years | 66.62 years | 55.22 years | 55.46 years | 58.57 years | 81.19 years | 65.09 years | 56.86 years |
| Race/Ethnicity, Customized Race African | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Caucasian | 3 Participants | 3 Participants | 3 Participants | 2 Participants | 6 Participants | 1 Participants | 1 Participants | 19 Participants |
| Race/Ethnicity, Customized Race East Asian | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Missing | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment United States | 3 Participants | 3 Participants | 3 Participants | 4 Participants | 8 Participants | 1 Participants | 1 Participants | 23 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 2 Participants | 3 Participants | 4 Participants | 0 Participants | 1 Participants | 14 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 4 Participants | 1 Participants | 0 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 4 / 4 | 9 / 9 | 1 / 1 |
| serious Total, serious adverse events | 3 / 3 | 2 / 3 | 1 / 3 | 4 / 4 | 6 / 9 | 1 / 1 |
Outcome results
Primary
Recommended Phase 2 Dose of LY573636-Sodium in Participants With Relapsed or Refractory Acute Myeloid Leukemia (AML) and Essential Thrombocythemia (ET)
Recommended Phase 2 dose was determined by maximum tolerated dose (MTD). MTD is the highest dose at which no more than 1 of 6 participants experienced a dose-limiting toxicity (DLT) and level immediately below that which had ≥2 instances of DLT. A DLT is an adverse event (AE) observed during the first cycle of treatment that is believed to be related to LY573636 and fulfills any of the following: ET only , Common Terminology Criteria for AE (CTCAE, Version 3.0) Grade (Gr) 4 hematologic toxicity for ≥3 days; For all, ≥Gr 3 nonhematological toxicity except for nausea/vomiting or diarrhea unless it fits the next criteria; ≥Gr 3 nausea, vomiting, or diarrhea that persists \>7 days despite maximal treatment; Gr 3 electrolyte disturbances that persist despite maximal measures; DLT can be declared if a participant experienced increasing toxicity during treatment. The primary outcome measure was not analyzed because the enrollment was stopped early before MTD was reached.
Time frame: Predose up to 35 days postdose in Cycle 1
Population: No participants were analyzed since the MTD was not reached.
Secondary
Number of Participants With Bone Marrow (BM) Response
The International Working Group's revised recommendations were used to assess response in acute myeloid leukemia (AML): complete response (CR) is \<5% blasts in BM and with a cell count ≥200 cells in BM, and with peripheral blood platelets ≥100x10⁹/liter (L) and absolute neutrophils ≥1x10⁹/L; CR with incomplete blood count recovery is defined as CRi; partial response (PR) is ≥5% blasts in BM but with ≥50% reduction in blast count. Number of responders for AML = CR+PR+ CRi. Result of a European Leukemia Net consensus conference was used to assess response in essential thrombocythemia (ET). CR is platelets ≤400x10⁹/L in peripheral blood, no disease-related symptoms, normal spleen size and white blood cells ≤10x10⁹/L in peripheral blood; PR has platelets ≤600x10⁹/L in peripheral blood or decrease \> 50% from baseline but does not meet CR criteria. Number of responders for ET = CR+PR.
Time frame: Baseline to measured progressive disease up to 70 days
Population: All participants who received at least one dose of the study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cmax 250 μg/mL (AML) | Number of Participants With Bone Marrow (BM) Response | 0 Participants |
| Cmax 300 μg/mL (AML) | Number of Participants With Bone Marrow (BM) Response | 0 Participants |
| Cmax 350 μg/mL (AML) | Number of Participants With Bone Marrow (BM) Response | 1 Participants |
| Cmax 400 μg/mL (AML) | Number of Participants With Bone Marrow (BM) Response | 0 Participants |
| AUCalb 5500 µg*hr/mL (AML) | Number of Participants With Bone Marrow (BM) Response | 0 Participants |
| AUCalb 7000 µg*hr/mL (AML) | Number of Participants With Bone Marrow (BM) Response | 0 Participants |
| AUCalb 5500 µg*hr/mL (ET) | Number of Participants With Bone Marrow (BM) Response | 0 Participants |
Secondary
Pharmacokinetics Area Under the Curve(AUC) of LY573636 Above the Albumin-Corrected Threshold (AUCalb)
LY573636 has been found to be highly bound to albumin. AUCalb is a surrogate measure of exposure to unbound (free) LY573636. PK sample is withdrawn at any time on days 8,14,15,21,28.
Time frame: Predose,1h,2h,4h, 8d,14d,15d,21d,28d post dose
Population: Participants who received the study drug and had pharmacokinetic (PK) data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cmax 250 μg/mL (AML) | Pharmacokinetics Area Under the Curve(AUC) of LY573636 Above the Albumin-Corrected Threshold (AUCalb) | 6911 micrograms*hour/milliliter (µg*hr/mL) | Geometric Coefficient of Variation 86.8 |
Secondary
Pharmacokinetics: Concentration Maximum (Cmax) of LY573636
PK sample is withdrawn at any time on days 8,14,15,21,28.
Time frame: Predose,1h,2h,4h, 8d,14d,15d,21d,28d post dose
Population: Participants who received the study drug and had pharmacokinetic (PK) data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cmax 250 μg/mL (AML) | Pharmacokinetics: Concentration Maximum (Cmax) of LY573636 | 317 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 21 |