Lestaurtinib, Cytarabine, and Idarubicin in Treating Younger Patients With Relapsed or Refractory Acute Myeloid Leukemia
Study Details
Study Description
Brief Summary
RATIONALE: Lestaurtinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine and idarubicin, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving lestaurtinib together with cytarabine and idarubicin may kill more cancer cells.
PURPOSE: This phase I/II trial is studying the side effects and best dose of lestaurtinib when given together with cytarabine and idarubicin and to see how well they work in treating younger patients with relapsed or refractory acute myeloid leukemia.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1/Phase 2 |
Detailed Description
OBJECTIVES:
Primary
- Determine a safe, tolerable, and biologically active dose of lestaurtinib in combination with chemotherapy comprising cytarabine and idarubicin in younger patients with relapsed or refractory FLT3-mutant acute myeloid leukemia.
Secondary
-
Determine the overall response rate in patients treated with this regimen.
-
Optimize dosing of lestaurtinib based primarily on biologic activity rather than toxicity.
-
Correlate the clinical response to this regimen with the ability to achieve adequate FLT3 plasma inhibitory activity levels and the in vitro sensitivity of pretreatment leukemic cells to lestaurtinib in these patients.
-
Determine the mechanisms of resistance to lestaurtinib in these patients.
-
Assess the feasibility of using rapid central determination of FLT3 mutation status at study entry to determine induction therapy in future upfront protocols.
OUTLINE: This is a multicenter, dose-finding study of lestaurtinib followed by an efficacy study.
-
Dose-finding phase:
-
Course 1: Patients receive cytarabine IV over 2 hours twice daily on days 1-4, idarubicin IV over 15 minutes on days 2-4, and oral lestaurtinib twice daily on days 5-28. Patients achieving complete or partial response proceed to course 2.
Cohorts of 6 patients receive escalating doses of lestaurtinib until a tolerable and biologically active dose (TBAD) is determined. The TBAD is defined as the dose at which no more than 2 of 6 patients experience DLT and biologic activity is confirmed by plasma inhibitory activity (PIA) assay.
-
Course 2: Patients receive high-dose cytarabine IV over 3 hours twice daily on days 1-4 and oral lestaurtinib (at the dose determined in course 1) twice daily on days 5-28. Patients achieving complete or partial response proceed to continuation therapy.
-
Continuation therapy: Patients receive oral lestaurtinib twice daily on days 1-28. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
-
Efficacy phase: Once the TBAD is determined, subsequent patients receive treatment as in course 1 and 2 with lestaurtinib at the TBAD. Patients may also receive continuation therapy as in the dose-finding phase.
Blood samples are collected periodically during study treatment for pharmacokinetic and PIA assays.
After completion of study treatment, patients are followed periodically for up to 5 years.
PROJECTED ACCRUAL: A total of 37 patients will be accrued for this study.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Group 1 (Lestaurtinib dose 50 mg/m2 DOSE-FINDING PHASE: COURSE 1: Patients receive cytarabine IV over 2 hours twice daily on days 1-4, idarubicin IV over 15 minutes on days 2-4, and oral lestaurtinib twice daily on days 5-28. Patients achieving complete or partial response proceed to course 2. Cohorts of 6 patients receive escalating doses of lestaurtinib until a TBAD is determined. The TBAD is defined as the dose at which no more than 2 of 6 patients experience DLT and biologic activity is confirmed by PIA assay. COURSE 2: Patients receive high-dose cytarabine IV over 3 hours twice daily on days 1-4 and oral lestaurtinib (at the dose determined in course 1) twice daily on days 5-28. Patients achieving complete or partial response proceed to continuation therapy. CONTINUATION THERAPY: Patients receive oral lestaurtinib twice daily on days 1-28. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Continued (see detailed description) |
Drug: cytarabine
given IV
Other Names:
Drug: idarubicin
Given IV
Other Names:
Drug: lestaurtinib
Given orally
Other Names:
|
| Experimental: Group 2 (Lestaurtinib: Dose 62.5 mg/m2 DOSE-FINDING PHASE: COURSE 1: Patients receive cytarabine IV over 2 hours twice daily on days 1-4, idarubicin IV over 15 minutes on days 2-4, and oral lestaurtinib twice daily on days 5-28. Patients achieving complete or partial response proceed to course 2. Cohorts of 6 patients receive escalating doses of lestaurtinib until a TBAD is determined. The TBAD is defined as the dose at which no more than 2 of 6 patients experience DLT and biologic activity is confirmed by PIA assay. COURSE 2: Patients receive high-dose cytarabine IV over 3 hours twice daily on days 1-4 and oral lestaurtinib (at the dose determined in course 1) twice daily on days 5-28. Patients achieving complete or partial response proceed to continuation therapy. CONTINUATION THERAPY: Patients receive oral lestaurtinib twice daily on days 1-28. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Continued (see detailed description) |
Drug: cytarabine
given IV
Other Names:
Drug: idarubicin
Given IV
Other Names:
Drug: lestaurtinib
Given orally
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Dose-limiting Toxicity [28 days]
Number of patients with dose-limiting toxicity (DLT)
- >80% Inhibition of FLT3 Phosphorylation in a Majority of Post-treatment Trough Time Points [Course 1 day 7, day 14, day 21, and day 28.]
FLT3 inhibition is determined in patients receiving lestaurtinib by measuring FLT3 plasma inhibitory activity (PIA). For PIA predictive modeling, a random effects linear regression model will be used to describe the relationship between PIA and Pharmacokinetic (PK) levels for each of the 5 trough plasma samples collected for each patient
Eligibility Criteria
Criteria
DISEASE CHARACTERISTICS:
-
Diagnosis of acute myeloid leukemia (AML) according to FAB classification
-
At least 5% blasts in the bone marrow, with or without extramedullary disease
-
In first relapse after induction therapy OR refractory to induction therapy with ≤ 1 attempt at remission induction
-
Patients who are in a first relapse > 1 year from their initial diagnosis of AML are excluded from the dose-finding phase of the study, but are eligible for the efficacy phase
-
First relapse after hematopoietic stem cell transplantation (HSCT) allowed provided patient has no evidence of active graft-versus-host disease (GVHD) and is at least 4 months posttransplantation
-
Positive for a FLT3 activating mutation (internal tandem duplication or kinase domain point mutation) using standard polymerase chain reaction-based procedures at any time in the course of illness
-
Treatment-related AML allowed
PATIENT CHARACTERISTICS:
-
Karnofsky performance status (PS) 50-100% (> 16 years of age) OR Lansky PS 50-100% (≤ 16 years of age)
-
Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR serum creatinine based on age and gender as follows:
-
Creatinine no greater than 0.4 mg/dL (1 month to < 6 months of age)
-
Creatinine no greater than 0.5 mg/dL (6 months to < 1 year of age)
-
Creatinine no greater than 0.6 mg/dL (1 year to < 2 years of age)
-
Creatinine no greater than 0.8 mg/dL (2 years to < 6 years of age)
-
Creatinine no greater than 1 mg/dL (6 years to < 10 years of age)
-
Creatinine no greater than 1.2 mg/dL (10 years to < 13 years of age)
-
Creatinine no greater than 1.4 mg/dL (females) or 1.5 mg/dL (males) (13 years to < 16 years of age)
-
Creatinine no greater than 1.4 mg/dL (females) or 1.7 mg/dL (males) (16 years of age and over)
-
Bilirubin ≤ 1.5 times upper limit of normal (ULN)
-
ALT < 5 times ULN (unless it is related to leukemic involvement)
-
Not pregnant or nursing
-
Negative pregnancy test
-
Fertile patients must use effective contraception
-
Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 50% by radionuclide angiogram
PRIOR CONCURRENT THERAPY:
-
Recovered from all prior therapy
-
No prior cumulative anthracycline doses exceeding 450 mg/m^2 daunorubicin equivalents
-
Patients who relapse after receiving treatment on protocol COG-AAML03P1 or COG-AAML0531 (300 mg/m2 of daunorubicin hydrochloride and 48 mg/m2 of mitoxantrone hydrochloride) allowed provided they have not received any additional anthracyclines
-
At least 14 days since prior cytotoxic therapy
-
Hydroxyurea allowed to decrease the WBC prior to starting protocol treatment
-
No concurrent hydroxyurea
-
At least 7 days since prior biologic agents
-
At least 14 days since prior monoclonal antibody therapy
-
Radiotherapy to chloromas allowed
-
Irradiated lesion may not be used to assess tumor response
-
No other concurrent chemotherapy, investigational therapy, immunomodulating agents, or steroids
-
Steroids used as an antiemetic allowed
-
Prophylactic intrathecal cytarabine allowed
-
No concurrent CYP3A4,5 inhibitors, including any of the following:
-
Azole antifungals (e.g., fluconazole or voriconazole)
-
Cyclosporine
-
Erythromycin
-
Clarithromycin
-
Troleandomycin
-
HIV protease inhibitors
-
Nefazodone
-
No concurrent CYP3A4,5 inducers, including any of the following:
-
Carbamazepine
-
Dexamethasone
-
Rifampin
-
Phenobarbital
-
Phenytoin
-
Hypericum perforatum (St. John's wort)
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham | Birmingham | Alabama | United States | 35294 |
| 2 | Children's Hospital of Orange County | Orange | California | United States | 92868 |
| 3 | Children's National Medical Center | Washington | District of Columbia | United States | 20010-2970 |
| 4 | Winship Cancer Institute of Emory University | Atlanta | Georgia | United States | 30322 |
| 5 | Children's Memorial Hospital - Chicago | Chicago | Illinois | United States | 60614 |
| 6 | Indiana University Melvin and Bren Simon Cancer Center | Indianapolis | Indiana | United States | 46202-5289 |
| 7 | Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Baltimore | Maryland | United States | 21231-2410 |
| 8 | Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute | Boston | Massachusetts | United States | 02115 |
| 9 | C.S. Mott Children's Hospital at University of Michigan Medical Center | Ann Arbor | Michigan | United States | 48109-0286 |
| 10 | Masonic Cancer Center at University of Minnesota | Minneapolis | Minnesota | United States | 55455 |
| 11 | Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis | St. Louis | Missouri | United States | 63110 |
| 12 | Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center | New York | New York | United States | 10032 |
| 13 | Cincinnati Children's Hospital Medical Center | Cincinnati | Ohio | United States | 45229-3039 |
| 14 | Knight Cancer Institute at Oregon Health and Science University | Portland | Oregon | United States | 97239-3098 |
| 15 | Children's Hospital of Philadelphia | Philadelphia | Pennsylvania | United States | 19104-9786 |
| 16 | Children's Hospital of Pittsburgh | Pittsburgh | Pennsylvania | United States | 15213 |
| 17 | St. Jude Children's Research Hospital | Memphis | Tennessee | United States | 38105 |
| 18 | Vanderbilt-Ingram Cancer Center | Nashville | Tennessee | United States | 37232-6838 |
| 19 | Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas | Dallas | Texas | United States | 75390 |
| 20 | Baylor University Medical Center - Houston | Houston | Texas | United States | 77030-2399 |
| 21 | Children's Hospital and Regional Medical Center - Seattle | Seattle | Washington | United States | 98105 |
Sponsors and Collaborators
- Children's Oncology Group
- National Cancer Institute (NCI)
Investigators
- Study Chair: Patrick A. Brown, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
- Study Chair: Donald Small, MD, PhD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- AAML06P1
- CDR0000543398
- COG-AAML06P1
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Group 1 (Lestaurtinib Dose 50 mg/m2) | Group 2 (Lestaurtinib: Dose 62.5 mg/m2) |
|---|---|---|
| Arm/Group Description | COURSE 1: Cytarabine IV over 2 hours twice daily days 1-4, idarubicin IV over 15 minutes days 2-4, and oral lestaurtinib twice daily days 5-28. Patients achieving complete or partial response proceed to course 2. Cohorts of 6 patients receive escalating doses of lestaurtinib until a safe, tolerable and biologically active dose (TBAD) is determined. The TBAD is defined as the dose at which no more than 2 of 6 patients experience DLT and biologic activity is confirmed by PIA assay. COURSE 2: Patients receive high-dose cytarabine IV over 3 hours twice daily days 1-4 and oral lestaurtinib (at the dose determined in course 1) twice daily days 5-28. Patients achieving complete or partial response proceed to continuation therapy. CONTINUATION THERAPY: Patients receive oral lestaurtinib twice daily days 1-28. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Continued (see detailed description) | COURSE 1: Cytarabine IV over 2 hours twice daily days 1-4, idarubicin IV over 15 minutes days 2-4, and oral lestaurtinib twice daily days 5-28. Patients achieving complete or partial response proceed to course 2. Cohorts of 6 patients receive escalating doses of lestaurtinib until a safe, tolerable and biologically active dose (TBAD) is determined. The TBAD is defined as the dose at which no more than 2 of 6 patients experience DLT and biologic activity is confirmed by PIA assay. COURSE 2: Patients receive high-dose cytarabine IV over 3 hours twice daily days 1-4 and oral lestaurtinib (at the dose determined in course 1) twice daily days 5-28. Patients achieving complete or partial response proceed to continuation therapy. CONTINUATION THERAPY: Patients receive oral lestaurtinib twice daily on days 1-28. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Continued (see detailed description) cytarabine |
| Period Title: Overall Study | ||
| STARTED | 6 | 8 |
| COMPLETED | 6 | 6 |
| NOT COMPLETED | 0 | 2 |
Baseline Characteristics
| Arm/Group Title | Group 1 (Lestaurtinib Dose 50 mg/m2 | Group 2 (Lestaurtinib: Dose 62.5 mg/m2 | Total |
|---|---|---|---|
| Arm/Group Description | COURSE 1: Patients receive cytarabine IV over 2 hours twice daily on days 1-4, idarubicin IV over 15 minutes on days 2-4, and oral lestaurtinib twice daily on days 5-28. Patients achieving complete or partial response proceed to course 2. Cohorts of 6 patients receive escalating doses of lestaurtinib until a TBAD is determined. The TBAD is defined as the dose at which no more than 2 of 6 patients experience DLT and biologic activity is confirmed by PIA assay. COURSE 2: Patients receive high-dose cytarabine IV over 3 hours twice daily on days 1-4 and oral lestaurtinib (at the dose determined in course 1) twice daily on days 5-28. Patients achieving complete or partial response proceed to continuation therapy. CONTINUATION THERAPY: Patients receive oral lestaurtinib twice daily on days 1-28. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Continued (see detailed description) | COURSE 1: Patients receive cytarabine IV over 2 hours twice daily on days 1-4, idarubicin IV over 15 minutes on days 2-4, and oral lestaurtinib twice daily on days 5-28. Patients achieving complete or partial response proceed to course 2. Cohorts of 6 patients receive escalating doses of lestaurtinib until a TBAD is determined. The TBAD is defined as the dose at which no more than 2 of 6 patients experience DLT and biologic activity is confirmed by PIA assay. COURSE 2: Patients receive high-dose cytarabine IV over 3 hours twice daily on days 1-4 and oral lestaurtinib (at the dose determined in course 1) twice daily on days 5-28. Patients achieving complete or partial response proceed to continuation therapy. CONTINUATION THERAPY: Patients receive oral lestaurtinib twice daily on days 1-28. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Continued (see detailed description) | Total of all reporting groups |
| Overall Participants | 6 | 8 | 14 |
| Age (Count of Participants) | |||
| <=18 years |
6
100%
|
8
100%
|
14
100%
|
| Between 18 and 65 years |
0
0%
|
0
0%
|
0
0%
|
| >=65 years |
0
0%
|
0
0%
|
0
0%
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
4
66.7%
|
2
25%
|
6
42.9%
|
| Male |
2
33.3%
|
6
75%
|
8
57.1%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||
| Hispanic or Latino |
1
16.7%
|
0
0%
|
1
7.1%
|
| Not Hispanic or Latino |
4
66.7%
|
8
100%
|
12
85.7%
|
| Unknown or Not Reported |
1
16.7%
|
0
0%
|
1
7.1%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
| Asian |
1
16.7%
|
2
25%
|
3
21.4%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
1
16.7%
|
1
12.5%
|
2
14.3%
|
| White |
4
66.7%
|
5
62.5%
|
9
64.3%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| Region of Enrollment (participants) [Number] | |||
| United States |
6
100%
|
8
100%
|
14
100%
|
Outcome Measures
| Title | Dose-limiting Toxicity |
|---|---|
| Description | Number of patients with dose-limiting toxicity (DLT) |
| Time Frame | 28 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Group 1 (Lestaurtinib Dose 50 mg/m2 | Group 2 (Lestaurtinib: Dose 62.5 mg/m2 |
|---|---|---|
| Arm/Group Description | COURSE 1: Patients receive cytarabine IV over 2 hours twice daily on days 1-4, idarubicin IV over 15 minutes on days 2-4, and oral lestaurtinib twice daily on days 5-28. Patients achieving complete or partial response proceed to course 2. Cohorts of 6 patients receive escalating doses of lestaurtinib until a TBAD is determined. The TBAD is defined as the dose at which no more than 2 of 6 patients experience DLT and biologic activity is confirmed by PIA assay. COURSE 2: Patients receive high-dose cytarabine IV over 3 hours twice daily on days 1-4 and oral lestaurtinib (at the dose determined in course 1) twice daily on days 5-28. Patients achieving complete or partial response proceed to continuation therapy. CONTINUATION THERAPY: Patients receive oral lestaurtinib twice daily on days 1-28. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Continued (see detailed description) | COURSE 1: Patients receive cytarabine IV over 2 hours twice daily on days 1-4, idarubicin IV over 15 minutes on days 2-4, and oral lestaurtinib twice daily on days 5-28. Patients achieving complete or partial response proceed to course 2. Cohorts of 6 patients receive escalating doses of lestaurtinib until a TBAD is determined. The TBAD is defined as the dose at which no more than 2 of 6 patients experience DLT and biologic activity is confirmed by PIA assay. COURSE 2: Patients receive high-dose cytarabine IV over 3 hours twice daily on days 1-4 and oral lestaurtinib (at the dose determined in course 1) twice daily on days 5-28. Patients achieving complete or partial response proceed to continuation therapy. CONTINUATION THERAPY: Patients receive oral lestaurtinib twice daily on days 1-28. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Continued (see detailed description) |
| Measure Participants | 6 | 6 |
| Number [participants] |
0
0%
|
0
0%
|
| Title | >80% Inhibition of FLT3 Phosphorylation in a Majority of Post-treatment Trough Time Points |
|---|---|
| Description | FLT3 inhibition is determined in patients receiving lestaurtinib by measuring FLT3 plasma inhibitory activity (PIA). For PIA predictive modeling, a random effects linear regression model will be used to describe the relationship between PIA and Pharmacokinetic (PK) levels for each of the 5 trough plasma samples collected for each patient |
| Time Frame | Course 1 day 7, day 14, day 21, and day 28. |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Group 1 (Lestaurtinib Dose 50 mg/m2 | Group 2 (Lestaurtinib: Dose 62.5 mg/m2 |
|---|---|---|
| Arm/Group Description | COURSE 1: Patients receive cytarabine IV over 2 hours twice daily on days 1-4, idarubicin IV over 15 minutes on days 2-4, and oral lestaurtinib twice daily on days 5-28. Patients achieving complete or partial response proceed to course 2. Cohorts of 6 patients receive escalating doses of lestaurtinib until a TBAD is determined. The TBAD is defined as the dose at which no more than 2 of 6 patients experience DLT and biologic activity is confirmed by PIA assay. COURSE 2: Patients receive high-dose cytarabine IV over 3 hours twice daily on days 1-4 and oral lestaurtinib (at the dose determined in course 1) twice daily on days 5-28. Patients achieving complete or partial response proceed to continuation therapy. CONTINUATION THERAPY: Patients receive oral lestaurtinib twice daily on days 1-28. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Continued (see detailed description) | COURSE 1: Patients receive cytarabine IV over 2 hours twice daily on days 1-4, idarubicin IV over 15 minutes on days 2-4, and oral lestaurtinib twice daily on days 5-28. Patients achieving complete or partial response proceed to course 2. Cohorts of 6 patients receive escalating doses of lestaurtinib until a TBAD is determined. The TBAD is defined as the dose at which no more than 2 of 6 patients experience DLT and biologic activity is confirmed by PIA assay. COURSE 2: Patients receive high-dose cytarabine IV over 3 hours twice daily on days 1-4 and oral lestaurtinib (at the dose determined in course 1) twice daily on days 5-28. Patients achieving complete or partial response proceed to continuation therapy. CONTINUATION THERAPY: Patients receive oral lestaurtinib twice daily on days 1-28. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Continued (see detailed description) |
| Measure Participants | 6 | 6 |
| Number [participants] |
5
83.3%
|
5
62.5%
|
Adverse Events
| Time Frame | ||||
|---|---|---|---|---|
| Adverse Event Reporting Description | ||||
| Arm/Group Title | Group 1 (Lestaurtinib Dose 50 mg/m2 | Group 2 (Lestaurtinib: Dose 62.5 mg/m2 | ||
| Arm/Group Description | COURSE 1: Patients receive cytarabine IV over 2 hours twice daily on days 1-4, idarubicin IV over 15 minutes on days 2-4, and oral lestaurtinib twice daily on days 5-28. Patients achieving complete or partial response proceed to course 2. Cohorts of 6 patients receive escalating doses of lestaurtinib until a TBAD is determined. The TBAD is defined as the dose at which no more than 2 of 6 patients experience DLT and biologic activity is confirmed by PIA assay. COURSE 2: Patients receive high-dose cytarabine IV over 3 hours twice daily on days 1-4 and oral lestaurtinib (at the dose determined in course 1) twice daily on days 5-28. Patients achieving complete or partial response proceed to continuation therapy. CONTINUATION THERAPY: Patients receive oral lestaurtinib twice daily on days 1-28. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Continued (see detailed description) | COURSE 1: Patients receive cytarabine IV over 2 hours twice daily on days 1-4, idarubicin IV over 15 minutes on days 2-4, and oral lestaurtinib twice daily on days 5-28. Patients achieving complete or partial response proceed to course 2. Cohorts of 6 patients receive escalating doses of lestaurtinib until a TBAD is determined. The TBAD is defined as the dose at which no more than 2 of 6 patients experience DLT and biologic activity is confirmed by PIA assay. COURSE 2: Patients receive high-dose cytarabine IV over 3 hours twice daily on days 1-4 and oral lestaurtinib (at the dose determined in course 1) twice daily on days 5-28. Patients achieving complete or partial response proceed to continuation therapy. CONTINUATION THERAPY: Patients receive oral lestaurtinib twice daily on days 1-28. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Continued (see detailed description) | ||
All Cause Mortality |
||||
| Group 1 (Lestaurtinib Dose 50 mg/m2 | Group 2 (Lestaurtinib: Dose 62.5 mg/m2 | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
| Group 1 (Lestaurtinib Dose 50 mg/m2 | Group 2 (Lestaurtinib: Dose 62.5 mg/m2 | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 2/6 (33.3%) | 6/8 (75%) | ||
| Blood and lymphatic system disorders | ||||
| Anemia | 1/6 (16.7%) | 0/8 (0%) | ||
| Disseminated intravascular coagulation | 0/6 (0%) | 1/8 (12.5%) | ||
| Febrile neutropenia | 0/6 (0%) | 1/8 (12.5%) | ||
| Cardiac disorders | ||||
| Cardiac disorders - Other | 0/6 (0%) | 1/8 (12.5%) | ||
| Left ventricular systolic dysfunction | 0/6 (0%) | 1/8 (12.5%) | ||
| Pericardial effusion | 0/6 (0%) | 1/8 (12.5%) | ||
| Sinus tachycardia | 0/6 (0%) | 1/8 (12.5%) | ||
| Gastrointestinal disorders | ||||
| Abdominal pain | 0/6 (0%) | 2/8 (25%) | ||
| Ascites | 0/6 (0%) | 1/8 (12.5%) | ||
| Colitis | 0/6 (0%) | 1/8 (12.5%) | ||
| Diarrhea | 0/6 (0%) | 1/8 (12.5%) | ||
| Mucositis oral | 1/6 (16.7%) | 0/8 (0%) | ||
| Typhlitis | 0/6 (0%) | 1/8 (12.5%) | ||
| Infections and infestations | ||||
| Appendicitis perforated | 0/6 (0%) | 1/8 (12.5%) | ||
| Infections and infestations - Other | 1/6 (16.7%) | 4/8 (50%) | ||
| Investigations | ||||
| Activated partial thromboplastin time prolonged | 1/6 (16.7%) | 0/8 (0%) | ||
| Alanine aminotransferase increased | 0/6 (0%) | 1/8 (12.5%) | ||
| Aspartate aminotransferase increased | 0/6 (0%) | 1/8 (12.5%) | ||
| Lymphocyte count decreased | 0/6 (0%) | 1/8 (12.5%) | ||
| Neutrophil count decreased | 0/6 (0%) | 1/8 (12.5%) | ||
| Platelet count decreased | 0/6 (0%) | 1/8 (12.5%) | ||
| Weight gain | 0/6 (0%) | 1/8 (12.5%) | ||
| White blood cell decreased | 0/6 (0%) | 2/8 (25%) | ||
| Metabolism and nutrition disorders | ||||
| Acidosis | 0/6 (0%) | 1/8 (12.5%) | ||
| Alkalosis | 0/6 (0%) | 1/8 (12.5%) | ||
| Anorexia | 0/6 (0%) | 3/8 (37.5%) | ||
| Hyperglycemia | 1/6 (16.7%) | 0/8 (0%) | ||
| Hyperkalemia | 1/6 (16.7%) | 1/8 (12.5%) | ||
| Hypoalbuminemia | 0/6 (0%) | 1/8 (12.5%) | ||
| Hypokalemia | 1/6 (16.7%) | 4/8 (50%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| Chest wall pain | 0/6 (0%) | 1/8 (12.5%) | ||
| Pain in extremity | 0/6 (0%) | 1/8 (12.5%) | ||
| Nervous system disorders | ||||
| Intracranial hemorrhage | 0/6 (0%) | 1/8 (12.5%) | ||
| Seizure | 0/6 (0%) | 1/8 (12.5%) | ||
| Psychiatric disorders | ||||
| Anxiety | 0/6 (0%) | 1/8 (12.5%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Dyspnea | 0/6 (0%) | 1/8 (12.5%) | ||
| Epistaxis | 1/6 (16.7%) | 1/8 (12.5%) | ||
| Hypoxia | 0/6 (0%) | 3/8 (37.5%) | ||
| Pneumonitis | 0/6 (0%) | 1/8 (12.5%) | ||
| Skin and subcutaneous tissue disorders | ||||
| Rash maculo-papular | 0/6 (0%) | 1/8 (12.5%) | ||
| Vascular disorders | ||||
| Hypotension | 0/6 (0%) | 1/8 (12.5%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Group 1 (Lestaurtinib Dose 50 mg/m2 | Group 2 (Lestaurtinib: Dose 62.5 mg/m2 | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 6/6 (100%) | 8/8 (100%) | ||
| Blood and lymphatic system disorders | ||||
| Anemia | 3/6 (50%) | 6/8 (75%) | ||
| Febrile neutropenia | 1/6 (16.7%) | 3/8 (37.5%) | ||
| Gastrointestinal disorders | ||||
| Abdominal pain | 0/6 (0%) | 1/8 (12.5%) | ||
| Hemorrhoids | 1/6 (16.7%) | 0/8 (0%) | ||
| Nausea | 1/6 (16.7%) | 1/8 (12.5%) | ||
| Rectal pain | 1/6 (16.7%) | 0/8 (0%) | ||
| Upper gastrointestinal hemorrhage | 0/6 (0%) | 1/8 (12.5%) | ||
| Vomiting | 0/6 (0%) | 1/8 (12.5%) | ||
| General disorders | ||||
| Fever | 0/6 (0%) | 1/8 (12.5%) | ||
| Infections and infestations | ||||
| Infections and infestations - Other | 1/6 (16.7%) | 2/8 (25%) | ||
| Investigations | ||||
| Alanine aminotransferase increased | 2/6 (33.3%) | 1/8 (12.5%) | ||
| Aspartate aminotransferase increased | 1/6 (16.7%) | 1/8 (12.5%) | ||
| Lipase increased | 0/6 (0%) | 1/8 (12.5%) | ||
| Lymphocyte count decreased | 1/6 (16.7%) | 5/8 (62.5%) | ||
| Neutrophil count decreased | 4/6 (66.7%) | 5/8 (62.5%) | ||
| Platelet count decreased | 4/6 (66.7%) | 6/8 (75%) | ||
| Weight loss | 0/6 (0%) | 1/8 (12.5%) | ||
| White blood cell decreased | 4/6 (66.7%) | 3/8 (37.5%) | ||
| Metabolism and nutrition disorders | ||||
| Anorexia | 1/6 (16.7%) | 1/8 (12.5%) | ||
| Hypertriglyceridemia | 0/6 (0%) | 1/8 (12.5%) | ||
| Hypoalbuminemia | 0/6 (0%) | 2/8 (25%) | ||
| Hypokalemia | 1/6 (16.7%) | 2/8 (25%) | ||
| Hyponatremia | 0/6 (0%) | 1/8 (12.5%) | ||
| Hypophosphatemia | 1/6 (16.7%) | 0/8 (0%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| Bone pain | 1/6 (16.7%) | 0/8 (0%) | ||
| Psychiatric disorders | ||||
| Depression | 1/6 (16.7%) | 0/8 (0%) | ||
| Reproductive system and breast disorders | ||||
| Uterine hemorrhage | 1/6 (16.7%) | 0/8 (0%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Adult respiratory distress syndrome | 0/6 (0%) | 1/8 (12.5%) | ||
| Hypoxia | 0/6 (0%) | 2/8 (25%) | ||
| Pharyngolaryngeal pain | 0/6 (0%) | 1/8 (12.5%) | ||
| Skin and subcutaneous tissue disorders | ||||
| Erythema multiforme | 0/6 (0%) | 1/8 (12.5%) | ||
| Rash maculo-papular | 1/6 (16.7%) | 1/8 (12.5%) | ||
| Vascular disorders | ||||
| Hypertension | 0/6 (0%) | 1/8 (12.5%) | ||
| Hypotension | 1/6 (16.7%) | 0/8 (0%) | ||
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Must obtain prior Sponsor approval.
Results Point of Contact
| Name/Title | Results Reporting Coordinator |
|---|---|
| Organization | Children's Oncology Group |
| Phone | 626-447-0064 |
| resultsreportingcoordinator@childrensoncologygroup.org |
- AAML06P1
- CDR0000543398
- COG-AAML06P1