Acute Myeloid Leukemia
Conditions
Keywords
cytogenetic status, mitoxantrone, etoposide, gemtuzumab ozogamicin, bone marrow
Brief summary
This study is an open-label, single arm phase II study which will examine the efficacy and toxicity of the combination therapy of GO, mitoxantrone and etoposide in patients who did not respond to first line induction therapy.
Detailed description
Eligible patients will be treated inpatient. Patients will receive mitoxantrone 10mg/m2 administered intravenous piggyback (IVPB) in 50ml 0.9% normal saline over 15 minutes on days 1-5 and etoposide 100 mg/m2 administered intravenously in 500 ml of 0.9% sodium chloride over 2 hours on days 1-5. On day 6, patients will receive a single dose of GO 3mg/m2 (maximum dose 4.5mg). Patients will be pre-medicated 1 hour prior to the GO infusion with diphenhydramine 50mg administered orally or intravenously, acetaminophen 650 mg administered orally or intravenously and 1mg/kg methylprednisolone or an equivalent dose of alternative corticosteroid administered IV within 30 minutes prior to infusion of GO. GO will be administered intravenously in 50 ml (or other suitable volume resulting in a final GO concentration between 0.075 mg/mL to 0.234 mg/mL) of 0.9% sodium chloride over 2 hours. Doses of GO will be based on BSA calculated using actual body weight with a cap of 4.5mg. Vital signs will be recorded within one hour prior to the infusion and then every 30 minutes during the infusion and 30 minutes and one hour after completion of infusion. An additional dose of methylprednisolone 1 mg/kg IV may be given for any sign of infusion reaction, such as fever, chills, hypotension, or dyspnea occurring during the GO infusion or within 4 hours after the GO infusion. For dose modifications based on kidney and liver function please see the treatment schema at the end of the study. Supportive care including blood product transfusions, antiemetic medications, antiviral and antifungal medications, growth factor support, tumor lysis syndrome prophylaxis, or empiric antibiotics may be used at the clinical discretion of the provider.
Interventions
DRUGmitoxantrone + etoposide + gemtuzumab ozogamicin
10 mg/m2 mitoxantrone days 1-5 + 100mg/m2 etoposide days 1-5 + 3mg/m2 gemtuzumab ozogamicin on day 6.
Sponsors
Pfizer
Robert Redner, MD
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open label single arm
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Able to understand and have the ability to provide written consent. 2. Age: ≥18 and ≤75 years-old 3. Patients with newly diagnosed AML based on the World Health Organization classification who have persistent disease after their first course treatment with an anthracycline and cytarabine (the diagnosis of persistent disease, which is defined as ≥10% blasts by morphology for this trial or \>5% blasts if they have had an increase in blasts from the last bone marrow biopsy, will be based on their assessment after bone marrow aspiration and/or biopsy after initial treatment). 4. Patients with myelodysplastic syndrome (MDS) based on the World Health Organization classification who have persistent disease after their treatment with an anthracycline and cytarabine (the diagnosis of persistent disease, which is defined as ≥10% blasts by morphology for this trial or \>5% blasts if they have had an increase in blasts from the last bone marrow biopsy, will be based on their assessment after bone marrow aspiration and/or biopsy after initial treatment). 5. CD33 expression in ≥ 30% of leukemic blasts on the bone marrow. 6. Eastern Cooperative Oncology Group Performance Status of 0 -2 (see Appendix I). 7. Patients must have the following laboratory values prior to beginning protocol treatment: * Calculated creatinine clearance ≥ 30 mL/min (using the Cockcroft-Gault equation CL creatinine = ((140-age) x body mass X 0.85 if female)/72 x creatinine where age is given in years, body mass is given in Kg and creatinine is given in mg/dl). * Aspartate aminotransferase (AST) ≤ 2.5 x upper normal limit. * Alanine aminotransferase (ALT) ≤ 2.5 x upper normal limit. * Total bilirubin ≤ 2 x upper normal limit. Note: As many eligible patients will be pancytopenic secondary to their disease or prior treatments, hematologic abnormalities will not be used as criteria for entry or exclusion. 8. Left ventricular ejection fraction (LVEF) ≥50 %. 9. Females of child-bearing potential must have a negative pregnancy test during screening and all subjects must agree to use an effective method of contraception. A woman is eligible to enter and participate in the study if she is of: 1. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant) including any female who has had a hysterectomy or has had a bilateral oophorectomy (ovariectomy). 2. Childbearing potential, has a negative serum pregnancy test during the screening period and agrees to avoid sexual activity or use contraception from screening through follow-up (method of birth control if the patient is not neutropenic include the use of a diaphragm, intrauterine device, contraceptive sponge and/or usage of male condom with a spermicide from the partner). A man with a female partner of childbearing potential is eligible to enter and participate in the study if he has either had a prior vasectomy or agrees to avoid sexual activity or use adequate contraception (as described above) from screening through follow-up.
Exclusion criteria
1. Patients with a diagnosis of Acute Promyelocytic Leukemia (APL) as defined by the World Health Organization. 2. Relapsed acute leukemia. 3. Bi-lineage or bi-phenotypic leukemia. 4. Prior use of mitoxantrone or etoposide or GO. 5. Previous allogeneic hematopoietic cell transplantation. 6. First induction course of acute myeloid leukemia with CPX-351. 7. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of treating investigator. 8. Has known history of active Hepatitis B (HBsAg reactive) or Hepatitis C (detectable HCV RNA). 9. Uncontrolled, life-threatening infection that is not responding to antimicrobial therapy. 10. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 11. Patient may have not received any other investigational anti-neoplastic agents within 4 weeks from the start of therapy. 12. Concurrent active malignancy; exceptions include patients who have been disease free for 5 years, patients with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma, or patients with another malignancy with better prognosis than AML. 13. Women who are pregnant or breastfeeding. 14. Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory or cardiac disease).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Remission Rate | Up to six weeks | The estimated percentage of patients with Complete Responses (CR / total response-evaluable patients x 100). CR in AML is defined as: 1. Normal values for absolute neutrophil count (\>1000/microL), platelet count (\>100,000/microL), independence from red cell transfusion. 2. Bone marrow biopsy reveals no clusters or collections of blast cells. Extramedullary leukemia (eg, central nervous system or soft tissue involvement) must be absent. 3. Bone marrow aspiration reveals normal maturation of all cellular components (ie, erythrocytic, granulocytic, and megakaryocytic series). No requirement for bone marrow cellularity. 4. \< 5 percent blast cells are present in the bone marrow, and none can have a leukemic phenotype (eg, Auer rods). 5. The absence of a previously detected clonal cytogenetic abnormality (ie, complete cytogenetic remission, CRc) confirms the morphologic diagnosis of CR but is not currently required. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Up to five years | The length of time during and after the treatment that a patient lives with Acute Myeloid Leukemia disease that does not progress. |
| Overall Survival (OS) | Up to five years | The length of time from the start of treatment that patients are still alive. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Mitoxantrone + Etoposide + Gemtuzumab Ozogamicin 10 mg/m2 mitoxantrone days 1-5 + 100mg/m2 etoposide days 1-5 + 3mg/m2 gemtuzumab ozogamicin on day 6
mitoxantrone + etoposide + gemtuzumab ozogamicin: 10 mg/m2 mitoxantrone days 1-5 + 100mg/m2 etoposide days 1-5 + 3mg/m2 gemtuzumab ozogamicin on day 6. | 16 |
| Total | 16 |
Baseline characteristics
| Characteristic | Mitoxantrone + Etoposide + Gemtuzumab Ozogamicin |
|---|---|
| Age, Continuous | 59 years |
| Cytogenetic Status Intermediate / Favorable | 3 Participants |
| Cytogenetic Status Poor | 13 Participants |
| ECOG Status ECOG = 0 | 1 Participants |
| ECOG Status ECOG = 1 | 15 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Percent bone marrow blasts | 50.9 Percent bone marrow blasts |
| Percent CD33 expression in leukemia blasts | 100 % CD33 expression |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 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 | 15 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 7 / 16 |
| other Total, other adverse events | 16 / 16 |
| serious Total, serious adverse events | 2 / 16 |
Outcome results
Primary
Complete Remission Rate
The estimated percentage of patients with Complete Responses (CR / total response-evaluable patients x 100). CR in AML is defined as: 1. Normal values for absolute neutrophil count (\>1000/microL), platelet count (\>100,000/microL), independence from red cell transfusion. 2. Bone marrow biopsy reveals no clusters or collections of blast cells. Extramedullary leukemia (eg, central nervous system or soft tissue involvement) must be absent. 3. Bone marrow aspiration reveals normal maturation of all cellular components (ie, erythrocytic, granulocytic, and megakaryocytic series). No requirement for bone marrow cellularity. 4. \< 5 percent blast cells are present in the bone marrow, and none can have a leukemic phenotype (eg, Auer rods). 5. The absence of a previously detected clonal cytogenetic abnormality (ie, complete cytogenetic remission, CRc) confirms the morphologic diagnosis of CR but is not currently required.
Time frame: Up to six weeks
Population: To be evaluable for clinical response, a patient must have received a total of 5 days of mitoxantrone and etoposide, received 1 dose of GO and had a follow-up bone marrow biopsy to evaluate the response to therapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mitoxantrone + Etoposide + Gemtuzumab Ozogamicin | Complete Remission Rate | 36 percentage of participants |
Secondary
Overall Survival (OS)
The length of time from the start of treatment that patients are still alive.
Time frame: Up to five years
Population: All treated patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Mitoxantrone + Etoposide + Gemtuzumab Ozogamicin | Overall Survival (OS) | 17.4 months |
Comparison: Cytogenetic statusp-value: 0.80195% CI: [0.17, 3.86]Regression, Cox
Comparison: % bone marrow blastsp-value: 0.16895% CI: [0.95, 1.01]Regression, Cox
Comparison: % CD33 expression in leukemia blastsp-value: 0.01595% CI: [0.94, 0.99]Regression, Cox
Secondary
Progression-free Survival (PFS)
The length of time during and after the treatment that a patient lives with Acute Myeloid Leukemia disease that does not progress.
Time frame: Up to five years
Population: Patients who were evaluable for response to treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Mitoxantrone + Etoposide + Gemtuzumab Ozogamicin | Progression-free Survival (PFS) | 3.27 months |
Comparison: Cytogenetic statusp-value: 0.77795% CI: [0.18, 3.65]Regression, Cox
Comparison: Percent of blasts present in the bone marrow.p-value: 0.295% CI: [0.96, 1.01]Regression, Cox
Comparison: % CD33 expression in leukemia blastsp-value: 0.01495% CI: [0.94, 0.99]Regression, Cox