Recurrent Adult Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia, Untreated Adult Acute Myeloid Leukemia
Conditions
Brief summary
This pilot phase II trial studies whether biomarkers (biological molecules) in bone marrow samples can predict treatment response to sirolimus and chemotherapy (mitoxantrone hydrochloride, etoposide, and cytarabine \[MEC\]) in patients with acute myeloid leukemia (AML) that is likely to come back or spread (high-risk). Sirolimus inhibits or blocks the pathway that causes cancer cells to grow. Adding sirolimus to standard chemotherapy may help improve patient response. Studying samples of bone marrow from patients treated with sirolimus in the laboratory may help doctors learn whether sirolimus reverses or turns off that pathway and whether changes in biomarker levels can predict how well patients will respond to treatment.
Detailed description
PRIMARY OBJECTIVES: I. To test the association between biochemical response and clinical response. SECONDARY OBJECTIVES: I. To estimate complete response rate of sirolimus MEC in patients with high risk AML. II. To estimate progression free survival in this patient population. III. To collect further information on the safety, tolerability, and efficacy of sirolimus in combination with MEC in patients with relapsed or refractory myeloid malignancies. OUTLINE: Patients undergo collection of bone marrow samples prior to sirolimus dosing on day 4 and within 1 week and no later than day 45 of hematologic recovery. Patients receive sirolimus orally (PO) on days 2-9 (loading dose on day 1 only), and standard MEC chemotherapy comprising mitoxantrone hydrochloride intravenously (IV) over 15 minutes, etoposide IV over 1 hour, and cytarabine IV over 1 hour every 24 hours on day 4-8. After completion of study treatment, patients are followed up every 3 months for 2 years.
Interventions
DRUGSirolimus
Given PO
DRUGMitoxantrone
Given IV
DRUGEtoposide
Given IV
DRUGCytarabine
Given IV
Sponsors
Sidney Kimmel Comprehensive Cancer Center at Thomas Jefferson University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients must have histologic evidence of high risk acute myeloid leukemia defined as one of the following: 1. Primary refractory non-M3 AML * Residual leukemia after a minimum of 2 prior courses of chemotherapy (Same or different) * Evidence of leukemia recurrence after a nadir bone marrow biopsy demonstrates no evidence of residual leukemia. * Evidence of leukemia after induction therapy which, in the opinion of the investigator, would be appropriate for reinduction with sirolimus/MEC therapy. 2. Relapsed non-M3 AML 3. Previously untreated non-M3 AML age \>60 with no evidence of favorable karyotype defined by presence of t(8;21)(q22;q22) \[AML1-ETO\], inv16(p13;q22), or t(16;16)(p13;q22) \[CBFβ;MYH11\] by cytogenetics, FISH, or RT-PCR 4. Previously untreated secondary AML (from antecedent hematologic malignancy or following therapy with radiation or chemotherapy for another disease) with no evidence of favorable karyotype defined by presence of t(8;21)(q22;q22) \[AML1-ETO\], inv16(p13;q22), or t(16;16)(p13;q22) \[CBFβ;MYH11\] by cytogenetics, FISH, or RT-PCR 2. Subjects must be ≥ 18 years of age. 3. Subjects must have an ECOG performance status of 2 or less (see Appendix1). 4. Subjects must have a life expectancy of at least 4 weeks. 5. Subjects must be able to consume oral medication. 6. Subjects must have recovered from the toxic effects of any prior chemotherapy to =\< Grade 1 (except alopecia). 7. Required initial laboratory values: 1. Creatinine ≤ 2.0mg/dL 2. total or direct bilirubin ≤ 1.5mg/dL; SGPT (ALT) ≤ 3xULN 3. negative pregnancy test for women with child-bearing potential. 8. Patients must be able to sign consent and be willing and able to comply with scheduled visits, treatment plan and laboratory testing. 9. Subjects must have a left ventricular ejection fraction (LVEF) of ≥ 45%.
Exclusion criteria
1. Subjects with FAB M3 (t (15; 17) (q22; q21) \[PML-RARα\]) are not eligible. 2. Subjects must not be receiving any chemotherapy agents (except Hydroxyurea). a) Intrathecal methotrexate and cytarabine are permissible. 3. Subjects must not be receiving growth factors, except for erythropoietin. 4. Subjects with a "currently active" second malignancy, other than non-melanoma skin cancers are not eligible. 5. Subjects with uncontrolled high blood pressure, unstable angina, symptomatic congestive heart failure, myocardial infarction within the past 6 months or serious uncontrolled cardiac arrhythmia are not eligible. 6. Subjects taking the following are not eligible: 1. Carbamazepine (e.g., Tegretol) 2. Rifabutin (e.g., Mycobutin) or 3. Rifampin (e.g., Rifadin) 4. Rifapentine (e.g., Priftin) 5. St. John's wort 6. Clarithromycin (e.g., Biaxin) 7. Cyclosporine (e.g. Neoral or Sandimmune) 8. Diltiazem (e.g., Cardizem) 9. Erythromycin (e.g., Akne-Mycin, Ery-Tab) 10. Itraconazole (e.g., Sporanox) 11. Ketoconazole (e.g., Nizoral) 12. Telithromycin (e.g., Ketek) 13. Verapamil (e.g., Calan SR, Isoptin, Verelan) 14. Voriconazole (e.g., VFEND) 15. Tacrolimus (e.g. Prograf) Subjects taking fluconozole, voriconizole, itraconazole, posaconazole, and ketokonazole within 72 hours of study drug starting are not eligible. Reinstitution of fluconozole, voriconizole, itraconazole, posaconazole, ketokonazole and diltiazem is permissible 72 hours after the last dose of sirolimus.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Biochemical Response | Baseline to day 4 | Defined by change in phosphorylated ribosomal protein S6 (pS6) positive blasts, measured as the % reduction in pS6 positive blasts from baseline to day 4. Biochemical response will be described by mean, median, standard deviation, range and coefficient of variation. The association between biochemical response and clinical response will be tested by Fisher's exact test. |
| Clinical Response | Day 45 | Clinical response was assessed at Day 45 using IWG criteria: Complete Remission (CR), CR with incomplete platelet recovery (CRp), CR with incomplete hematologic recovery (CRi), Partial Remission (PR), or No Response (NR). CR requires normalized blood counts and bone marrow blasts \<5%. CRp meets CR except platelet recovery; CRi meets CR except incomplete neutrophil/platelet recovery. PR is ≥50% reduction in marrow blasts to 5-25% with partial blood count improvement. NR indicates failure to meet these criteria. Tumor response per RECIST v1.0: CR = disappearance of all target lesions; PR = ≥30% decrease in sum of longest diameters; Overall Response = CR + PR. Progression = ≥20% increase in sum of longest diameters, measurable increase in non-target lesion, or new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) (Complete Response [CR], CR With Incomplete Platelet Recovery [CRp], or Partial Response) | Day 45 | Fraction of patients who achieve CR, CRp, or PR will be assessed. ORR and 95% exact confidence interval will be computed for all patients and for sensitive and resistant subgroups. |
| Relapse Free Survival (RFS) | Time from study entry to first documented progression, death, or last contact, assessed up to 2 years | RFS will be estimated by the Kaplan-Meier method. A landmark analysis of RFS by clinical response (CR+CRp, CRi, PR or no response \[NR\]) will be computed from day 45 marrow assessment. Median values and 95% confidence intervals will be calculated. |
| Percentage of Participants by Risk Group | Up to 2 years | Overall Survival (OS) is defined as the time from study entry to death or last contact. OS will be analyzed by risk groups: Favorable, Intermediate, and Poor/Adverse, based on baseline factors such as cytogenetics, molecular markers, and clinical characteristics. These risk groups are used to predict clinical outcomes, with favorable indicating longer survival expectancy, intermediate suggesting moderate outcomes, and poor/adverse indicating more aggressive disease with lower survival rates. Results will be reported as the percentage of participants in each risk category. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORMargaret Kasner, MD
Thomas Jefferson University
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 8 Participants |
| Age, Categorical Between 18 and 65 years | 31 Participants |
| Age, Continuous | 59 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 36 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 26 Participants |
| Sex: Female, Male Female | 24 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 39 |
| other Total, other adverse events | 27 / 39 |
| serious Total, serious adverse events | 5 / 39 |
Outcome results
None listed