Acute Myeloid Leukemia, Myelodysplastic Syndrome
Conditions
Keywords
Acute myeloid leukemia, AML, salvage chemotherapy, CLAG-M, relapse acute myeloid leukemia, secondary acute myeloid leukemia, phase II, pharmacogenomics, myelodysplastic syndrome
Brief summary
This is a prospective phase II clinical study planned to be conducted at the Medical College of Wisconsin (MCW). After meeting the study criteria and enrollment, patients will be treated with a cladribine based salvage regimen and followed at periodic intervals to determine the primary and secondary objectives.
Detailed description
STUDY RATIONALE: The optimal treatment regimen for relapsed/refractory AML and high risk MDS progressing after hypomethylating agents is unknown. Although several chemotherapy options are available, there is no universally accepted regimen to date. Cladribine based salvage regimens have been frequently used at the investigators' center. However, it is uncertain to predict which patients are likely to respond to cladribine-based salvage or experience treatment-related toxicities. While studies have demonstrated that achievement of MRD negative complete remission (CR) is likely to be associated with a better overall survival (OS), there is limited prospective data evaluating the role of minimal residual disease (MRD) in the setting of relapsed/refractory disease. Through this study, the investigators aim to demonstrate the influence of achieving MRD negative CR on survival of patients with relapsed/refractory AML/high risk MDS treated with cladribine-based salvage therapy. In addition to the conventionally used predictive factors, we aim to incorporate pharmacogenomics to assess the efficacy and toxicity of therapy. PRIMARY OBJECTIVE: To determine the CR rate and achievement of MRD negativity after treatment with Cladribine based salvage chemotherapy regimen in patients with relapse/refractory AML/high risk MDS. SECONDARY OBJECTIVES: 1. To determine the progression free survival (PFS) and overall survival (OS) of patients treated with a cladribine based salvage chemotherapy regimen. 2. To study the pharmacogenomics of patients receiving a cladribine based salvage and determine its influence on survival, CR rate and MRD negativity. 3. Determination of disease- or patient-related factors that predict MRD negativity and survival with a cladribine based salvage regimen.
Interventions
Subjects will be started on CLAG-M regimen, which consists of the following: * Cladribine 5 mg/m\^2 IV over two hours on days 1-5; * Cytarabine 2 gm/m\^2 IV over four hours on days 1-5 * Mitoxantrone 10 mg/m\^2 IV on days 1-3; * G-CSF at a dose of 300 μg on days 0-5.
DRUGCladribine and Cytarabine (CLLDAC) Regimen
* Cladribine 5 mg/m\^2 IV over two hours on days 1-5; * Cytarabine 20 mg/m\^2 subcutaneous injection on days 1-10;
Sponsors
Medical College of Wisconsin
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥18 years at the time of informed consent. 2. Morphologically documented: * Primary Acute Myeloid Leukemia (AML) or * AML secondary to Myelodysplastic Syndrome (MDS) or myeloproliferative neoplasm (MPN), or * Therapy related AML (t-AML), as defined by World Health Organization (WHO) criteria. * Subjects with high risk MDS after failure of hypomethylating agents are also eligible. 3. Subjects must meet one of the following criteria: * In first or subsequent relapse or refractory status, with or without prior hematopoietic stem cell transplant (HSCT) OR * Subjects with MDS or MPN transformed to AML will be eligible even if they had not received prior therapy for AML. * Subjects with high risk MDS after failure of hypomethylating agents. 4. Eastern Cooperative Oncology Group (ECOG) performance score 0-3. 5. It is not known what effects this treatment has on human pregnancy or development of the embryo or fetus. Therefore, female subjects participating in this study should avoid becoming pregnant, and male subjects should avoid impregnating a female partner. Non- sterilized female subjects of reproductive age and male subjects should use effective methods of contraception through defined periods during and after study treatment as specified below. Female subjects must meet one of the following: * Postmenopausal for at least one year before the screening visit, or * Surgically sterile, or if they are of childbearing potential, agree to practice two effective methods of contraception from the time of signing of the informed consent form through 90 days after the last dose of study drug, AND * Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, or * Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, postovulation methods\] and withdrawal are not acceptable contraception methods.) Male subjects, even if surgically sterilized (i.e., status post vasectomy), must agree to one of the following: * Practice effective barrier contraception during the entire study treatment period and through 90 days after the last study drug dose, OR * Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR * Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, postovulation methods\] and withdrawal are not acceptable methods of contraception.) 6. Ability to understand a written informed consent document and the willingness to sign it. 7. Subjects must meet the following clinical laboratory criteria: CLAG-M Arm Only: For abnormalities in liver function tests, elevation thought to be due to hepatic infiltration by AML, Gilbert's syndrome or hemolysis would not be treated as
Exclusion criteria
. * Absolute neutrophil count ≥1,000/mm\^3 Unless related to AML * Platelets ≥75,000/mm\^3 Unless related to AML * Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN) (if elevated, then complete direct bilirubin). * AST(SGOT)/ALT Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN * Creatinine clearance ≥ 30 mL/min * Resting left ventricular ejection fraction ≥ 45% CLLDAC ARM ONLY: * Absolute neutrophil count ≥ 1,000/mm\^3 unless related to AML * Platelets ≥ 75,000/mm\^3 unless related to AML
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CLAG-M Arm: Minimal Residual Disease (MRD) Complete Remission (CR) | Day 35 | The number of participants who achieve MRD CR (see Cheson 2003, Cheson 2006 in the references below). |
| CLLDAC Arm: Minimal Residual Disease (MRD) Complete Remission (CR) | Day 35 | The number of participants who achieve MRD CR following one cycle of therapy (see Cheson 2003, Cheson 2006 in the references below). |
| CLLDAC Arm: Subjects Receiving a Second Cycle. | Day 70 | The number of subjects who require a second cycle of CLLDAC. |
| Overall Survival (OS) | Up to 4 Years | Duration of OS: Time from treatment initiation through death from any cause, up to 4 years |
| Progression-free Survival | Year 4 | Duration of PFS: Time from remission (date of bone marrow biopsy confirming CR/CRi) to relapse or death from any cause, whichever occurs first, up to 4 years |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATOREhab Atallah, MD
Medical College of Wisconsin
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 11 Participants |
| Age, Categorical Between 18 and 65 years | 31 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 38 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 | 0 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 | 0 Participants |
| Race (NIH/OMB) White | 48 Participants |
| Region of Enrollment United States | 53 participants |
| Sex: Female, Male Female | 23 Participants |
| Sex: Female, Male Male | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 32 / 40 | 13 / 13 |
| other Total, other adverse events | 40 / 40 | 13 / 13 |
| serious Total, serious adverse events | 8 / 40 | 8 / 13 |
Outcome results
None listed