Clinical trial NCT03839446
Conditions: Acute Myeloid Leukemia
Keywords: cytogenetic status mitoxantrone etoposide gemtuzumab ozogamicin bone marrow
Sponsor: Robert Redner, MD
Start date: 2019-02-28; Completion date: 2024-12-22
Enrollment: 16 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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.

Arms: arm 1: 10 mg/m2 mitoxantrone days 1-5 + 100mg/m2 etoposide days 1-5 + 3mg/m2 gemtuzumab ozogamicin on day 6
Interventions: intervention 1: mitoxantrone + etoposide + gemtuzumab ozogamicin
Intervention descriptions: intervention 1: 10 mg/m2 mitoxantrone days 1-5 + 100mg/m2 etoposide days 1-5 + 3mg/m2 gemtuzumab ozogamicin on day 6.

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
Phase II Study of the Combination of Mitoxantrone, Etoposide and Gemtuzumab 
Ozogamicin (MEGO) for Patients with Acute Myeloid Leukemia Refractory to 
Initial Standard Induction Therapy 
 
July 25, 2022 
Version 5 
 
 
PRINCIPAL INVESTIGATOR 
Robert Redner, MD 
Clinical Instructor, Division of Hematology/Oncology 
UPMC Cancer Pavilion 
5115 Centre Avenue, 4th 
Floor Pittsburgh, PA 15232 
Phone: 412-864-6625 
Email: rednerrl@upmc.edu 
 
 
 
 
BIOSTATISTICIAN 
Daniel P. Normolle, PhD 
Biostatistics Facility 
UPMC Hillman Cancer Center 
Suite 325 Sterling Plaza 
201 
North Craig St. 
Pittsburgh, PA 15213 
Phone: 412-383-1581 
Email: dpn7@pitt.edu 


2 
 
Table of Contents 
Page 
1.0 INTRODUCTION 
4 
1.1 
Study objectives…………………………………………………………… 
4 
1.2 
Background and Rationale ………………………………………………. 
4 
2.0 ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1 
Eligibility Criteria…………………………………………………………..... 
9 
2.2 
Exclusion criteria………………………………………………………….... 
10 
2.3 
Eligibility evaluation……………………………………………………....... 
11 
3.0 STUDY IMPLEMENTATION 
3.1 
Study design and treatment plan ……………………………………….. 
12 
3.2 
Off study criteria for the trial ……………………………………………... 
13 
3.3 
Off treatment criteria for the trial ………………………………………… 
13 
4.0 ON STUDY EVALUATION ……………………………………………………... 
13 
5.0 STATISTICAL CONSIDERATIONS AND METHODOLOGY 
5.1 
Number and evaluability of patients ……………………………………… 
14 
5.2 
Sample size / Accrual rate ……………………………………………....... 
15 
5.3 
Study Design………………………………………………………………… 
15 
5.4 
Statistical Analysis Plan…………………………………………………..... 
17 
7.0 ADVERSE EVENT REPORTING ………………………………........................ 
20 
8.0 DATA SAFETY MONITORING PLAN…………………………………………... 
23 


3 
 
9.0 STUDY EVALUATION, TREATMENT SCHEMA AND FLOW CHART…..... 
25 
10.0 Drug information ........................................................................................ 
32 
11.0 References ………………………………………………………………………… 
40 


4 
 
 
 
 
1.0  INTRODUCTION 
 
 
1.1 Study objectives 
 
Primary Objective: To evaluate the response rate and toxicity of the combination of 
mitoxantrone, etoposide and gemtuzumab ozogamicin 
as second line therapy in patients with acute myeloid leukemia (AML) 
who have failed the first induction therapy. 
 
Secondary Objectives: To assess the progression-free survival, overall survival and treatment 
related mortality in patients with AML treated with the combination of 
mitoxantrone, etoposide and gemtuzumab ozogamicin. 
To explore if age, cytogenetic status, percent of blast in the bone 
marrow prior to therapy or percent expression of CD33 in the 
leukemia blasts are predictive of complete remission, overall survival 
or progression-free survival in patients with AML treated with the 
combination 
of 
mitoxantrone, 
etoposide 
and 
gemtuzumab 
ozogamicin. 
 
 
 
1.2 
Background and Rationale 
 
 
Acute myeloid leukemia (AML) is a disease characterized by a clonal proliferation of myeloid 
precursors with reduced capacity to differentiate into more mature cellular elements. As a 
result, there is an accumulation of leukemic forms in the bone marrow, peripheral blood and 
other tissues, with a marked reduction in red cells, platelets, and neutrophils. The increased 
production of malignant cells, along with reduction in these mature elements, results in a 


5 
 
variety of systemic symptoms and signs. These include anemia, bleeding and an increased 
risk of infection. If left untreated, AML can lead to death within weeks1. 
The standard treatment for newly diagnosed AML has not changed appreciably over the last 
few decades and consists primarily of an anthracycline (e.g. daunorubicin, idarubicin) 
combined with a nucleoside analogue, cytarabine. The goal of remission induction 
chemotherapy is the rapid restoration of normal bone marrow function2. Obtaining complete 
remission (CR) varies substantially depending on several factors, most notably age and 
cytogenetic abnormalities at the time of AML diagnosis. CR rates of 65-80% can be expected 
in younger patients (variably defined as < 55-60 years). CR rates decrease to 30% to 50% in 
older patients3. 
There is no agreed standard of care for AML patients that do not respond to initial first line 
induction therapy. Although remission after second-line therapy may occur, the CR rate is 
considerably lower. A number of chemotherapy regimens have been used in patients with 
resistant disease with overall CR rates of 20-40%. These regimens include different 
combinations and doses of agents that are effective in the treatment of AML such as 
fludarabine, cytarabine, etoposide, and mitoxantrone4. 
Gemtuzumab ozogamicin (GO) is an antibody drug conjugate consisting of a recombinant 
humanized antibody to CD33 which is linked to calicheamicin5. Calicheamicin is a potent 
antitumor antibiotic that cleaves double-stranded DNA at specific sequences6. Approximately 
90% of AML patients have myeloid blast cells expressing the CD33 surface antigen7. 
Monotherapy with GO resulted in CR of 20-25% in adults with CD33 positive AML in first 
relapse8. GO was approved by the United States Food and Drug Administration (FDA) for use 
in patients age 60 or older with CD33+ AML in first relapse who were not considered 
candidates for cytotoxic chemotherapy in 20009. However, due to early deaths in a prospective 
phase 3 randomized study which incorporated GO in the induction phase in one of the arms 
(SWOG S0106)10 the manufacturer withdrew the product from the American market in 2010. 
The SWOG S0106 study used 6 mg/m2 of GO on day 4 of induction with cytarabine, 
daunorubicin. The treatment-related mortality (TRM) was 5% on the GO arm vs 1% on the 
other arm. In 2017, FDA again approved GO for induction therapy in combination with 
chemotherapy based on a phase 3 prospective randomized, open-label study (ALFA-0701 
trial11) and as monotherapy for patients unfit for intensive treatment based on the phase 3 


6 
 
randomized EORTC-GIMEMA AML-19 trial12. The ALFA-0701 trial randomized 280 patients 
50-70 year-old to receive induction with daunorubicin and cytarabine or daunorubicin, 
cytarabine and GO 3mg/m2 on days 1,4,7 of induction. It showed that the addition of GO to 
the induction chemotherapy improved event-free survival. The AML-19 trial randomized 237 
patients unfit for induction chemotherapy to receive either best supportive care or GO 6mg/m2 
on day 1 and 3mg/m2 on day 8. It showed that GO improved the overall survival in patients 
unfit for intensive treatment when compared to best supportive care with no difference in the 
adverse events. The NCRI AML17 trial13 studied further the dose of GO with induction 
chemotherapy showing that 3mg/m2 has the same efficacy but better safety profile than 
6mg/m2. The dosing regimen of GO as it is currently approved by the US FDA is 3mg/m2 
(maximum dose 4.5mg) on days 1,4,7 with induction chemotherapy or 6mg/m2 on day 1 
followed by 3mg/m2 on day 8 if used as monotherapy. 
The 
most 
important 
GO-associated 
hematologic 
toxicity 
is 
myelosuppression 
(thrombocytopenia, neutropenia). Infusion-related adverse reactions are similar to those of 
other monoclonal antibodies (fever, chills, cutaneous rash, hypotension, hypertension, 
dyspnea, nausea, emesis and headache). They are usually transient and respond well to 
symptomatic therapy14. 
Hepatic veno-occlusive disease or sinusoidal obstructive syndrome (VOD/SOS) is the most 
frequently reported life-threatening non-hematological adverse event. Overall, among all adult 
GO- treated AML patients evaluated in the clinical trial setting, SOS occurred at a rate of 3% 
when GO was administered as monotherapy at the initial FDA approved dose and schedule 
(for relapsed AML, 9 mg/m2 on day 1 and 14); 7% when the drug was used in conjunction with 
other chemotherapeutic agents that are not known to be hepatotoxic; and 28% when GO was 
combined with thioguanine, a hepatotoxic chemotherapeutic agent. SOS rates were between 
15% and 40% if stem cell transplantation was performed within 3 months of GO 
administration15. Another observational study showed an overall 9.1% risk of SOS with GO 
and 2.7% risk of death from SOS16. During the early 2000s when GO was used at higher 
doses it was observed that patients that received GO <3.5 months before allogeneic stem cell 
transplantation had much higher incidence of SOS17, which was no longer observed in the 
modern era of lower GO fractionated doses18. 


7 
 
Various clinical trials have evaluated the efficacy of GO as monotherapy in newly-diagnosed 
AML, refractory/relapsed AML and in combination with chemotherapy for induction. Different 
dosing schedules of GO were used in these trials. In addition to grade 3/4 neutropenia and 
thrombocytopenia some patients also develop transaminitis and VOD (Table 1). 
Table 1: Clinical trials with gemtuzumab ozogamicin 
Trial 
No. of 
pts 
State of 
disease 
GO Dosing 
Therapy 
Results 
Ref 
EORTC- 
GIMEMA 
AML-19 
237 
New diagnosis, 
unwilling or unfit 
for treatment 
Induction: 6 mg/m2 
on day 1 and 3 
mg/m2 
on day 8. Maintenance:
2mg/m2 monthly up to 
8 doses 
Best 
Supportive 
Care 
GO +/- 
CR/CRi 27% on the GO arm.
OS improvement at 1 year 
with GO 
(4.9 vs 3.6 months, p=0.005)
12 
LRF AML 
14 
and 
NCRI 
AML 16 
495 
New diagnosis, 
unfit for intensive 
treatment 
5 mg (fixed dose) on 
day 1 of 42-day 
cycles for a 
maximum of four 
cycles 
LDAC 20mg 
BID on days 
1-10 of 
42-day cycles 
+/- 
GO 
Improved CR with GO 
(21% vs 11%, P= .002). 
No difference in OS. 
Patients in the GO arm had 
more nausea and vomiting, 
required more platelet 
transfusions and longer 
duration of antibiotics. 
No episodes of VOD were 
reported. 
19 
MRC 
AML-15 
1113 
New diagnosis 3mg/m2 on the first day 
of induction. 
DA or DAE or 
FLAG-IDA 
+/- 
GO 
No difference is OS but 
improved 5-year OS in 
patients with favorable 
cytogenetics. No excess 
hematologic or liver 
toxicity on the GO arm 
20 
ALFA-0701 278 
New diagnosis 
Induction: 3mg/m2 on 
days 1,4,7 
Consolidation: 
3mg/m2 on day 1 for 
up to two cycles 
Induction 
DA +/- GO 
Consolidation: 
DA +/- GO 
Improved EFS, DFS on the 
intervention arm but no 
difference in OS. Prolonged 
thrombocytopenia and 
neutropenia on the GO 
arm.3 cases of VOD were 
reported on the GO arm. 
11,21 
NCRI 
AML16 
1115 
New diagnosis 
Induction: 3 mg/m2 
on day 1 
DA +/- GO 
Improved OS on the 
treatment arm and similar 
TRM 
22 
SWOG 
S0106 
595 
New diagnosis 
Induction 6 mg/m2 
on day 4 
DA (with D at 
60 mg/m2) vs 
DA (with D at 
45mg/m2) plus GO 
No difference in OS with 
increased TRM in the GO 
arm (6% vs 1%) 
10 


8 
 
EORTC- 
GIMEMA 
AML-17 
472 
New diagnosis 
Induction: 6mg/m2 
on days 1 and 15 
MEC +/- GO 
Similar CR rate and OS. 
Higher TRM with GO 
(22% vs 18%) mainly 
driven by patients >70 
years old 
23 
NCRI 
788 
New diagnosis 
Induction: 
randomization To 3 or 
6 mg/m2 
Randomi- zation 
No difference in OS. 
Increased TRM with higher 
13 
AML17 
on day 1 
to ADE or DA , 
both + GO 
GO dose. 
HOVON-43 232 
Consolidation 
6 mg/m2 every 4 
weeks, up to 3 cycles Observation vs GO 
No difference in OS 
24 
 
Abbreviations: CR, complete remission; CRi, complete remission with incomplete hematologic recovery; GO, 
Gemtuzumab Ozogamicin; OS, overall survival; LDAC, low-dose cytarabine; VOD, veno-occlusive disease, 
DA, daunorubicin + cytarabine, DAE, daunorubicin + cytarabine + etoposide; FLAG-IDA, fludarabine + 
cytarabine + G-CSF + idarubicin; EFS, event-free survival; DFS, disease-free survival; TRM, treatment-related 
mortality; MEC, mitoxantrone + etoposide + cytarabine; ADE, cytarabine + daunarubicin + etoposide 
 
 
Rationale 
 
The combination of mitoxantrone and etoposide is an active regimen in refractory/relapsed 
AML patients25. In a retrospective study, we evaluated the efficacy and toxicity of mitoxantrone 
and etoposide in AML patients treated at our institution who did not respond to first induction 
therapy with cytarabine and an anthracycline. A total of thirty-five AML patients were treated 
with mitoxantrone (10 mg/m2/d) on days 1-5 and etoposide (100 mg/m2/d) on days 1-5. 
Thirteen of thirty-five patients (37%) achieved CR. There were no grade 3/4 hepatic toxicities. 
The median duration of neutropenia in patients achieving CR was 29 days after reinduction. 
14% of patients died from infectious complications. 
In order to increase the efficacy of mitoxantrone and etoposide as second line therapy in 
patients with AML we propose to conduct a phase II clinical trial evaluating the safety and 
efficacy of the combination of GO, mitoxantrone and etoposide. A similar trial was open in our 
institution before Pfizer withdrew the drug from the market in 201026. Before the withdrawal 5 
patients were treated with a regimen consisted of mitoxantrone 10 mg/m2 administered 
intravenously on days 1–3, etoposide 100 mg/m2 administered on days 1–5 and on day 6 GO 
3 mg/m2. Three of the five patients achieved a CR. There were no treatment-related deaths. 
All patients developed grade 3–4 neutropenia and thrombocytopenia, with complete 
responders requiring a median of 19 days (range, 17–34 days) from the completion of 


9 
 
treatment to recover their neutrophils and a median of 24 days (range, 17–34 days) to recover 
their platelets. One patient developed grade 3 ALT transaminitis that resolved within 24 h and 
one patient developed a transient ischemic attack. No patient developed clinical signs or 
symptoms of veno-occlusive disease. 
It has been demonstrated that high peripheral CD33-antigen load is an independent adverse 
prognostic factor in AML patients treated with GO. Data indicate that a high peripheral 
CD33antigen load consumes a large portion of the GO, which results in reduced GO 
penetration into the bone marrow 27. As a consequence, CD33 saturation of AML blast cells 
present in the bone marrow is incomplete, which may hamper subsequent cell kill. 
Administration of GO may be more effective after reduction of the leukemic cell burden with 
conventional chemotherapy. Thus, we plan to administer the GO after the administration of 
mitoxantrone and etoposide. Furthermore, since enrolled patients in the study will already be 
treated with combination of cytarabine and an anthracycline (1st regimen) and mitoxantrone 
and etoposide (2nd regimen) and GO has been associated with neutropenia and 
thrombocytopenia, we plan to use a single dose of GO 3 mg/m2 the day after the completion 
of the 5 days of etoposide and mitoxantrone. 
 
2.0 ELIGIBILITY ASSESSMENT AND ENROLLMENT 
 
 
2.1 Eligibility 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). The bone marrow aspiration and/or biopsy will be evaluated 
by the Hematopathology Division of the University of Pittsburgh. In order to prevent any 
delays in starting therapy for eligible patients, a preliminary evaluation of the bone marrow 
will be sent by the hematopathologist via e-mail to the investigator. 


10 
 
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: 
a. 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). 
b. 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. 


11 
 
 
2.2 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). 
 
2.3 Eligibility evaluation 
The following clinical and laboratory assessments must be performed for all eligible patients 
within 14 days of study enrollment and consent: 


12 
 
1. Complete medical history and physical examination, including height, weight, body surface 
area (BSA), ECOG performance status, and a neurological evaluation. 
2. Echocardiogram to evaluate cardiac ejection fraction. 
3. CBC with differential and platelets. 
4. Complete metabolic panel (Na, K, Cl, CO2, glucose, BUN, Cr, Ca, total protein, albumin, 
total bilirubin, AST, ALT, and alkaline phosphatase) and magnesium level. 
5. LDH, uric acid, and phosphorus levels. 
6. PT/INR, PTT. 
7. Urinalysis. 
8. PA and lateral chest x-ray. If clinically indicated CT Chest/Abdomen/Pelvis can be 
performed. 
9. EKG. 
 
10. Urine pregnancy test for all women ≤ 60 years old. 
 
The following clinical and laboratory assessments must have been performed for all eligible 
patients within 12 weeks from initiation of treatment: 
1. Hepatitis B surface antigen. 
2. Hepatitis C antibody and if positive HCV RNA. 
 
 
3.0 STUDY IMPLEMENTATION 
 
 
3.1 Study design and treatment plan 
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. 
 
 
Treatment plan 
 
Eligible patients will be treated at the UPMC Hillman Cancer Center inpatient leukemia 
service. Patients will receive mitoxantrone 10mg/m2 administered intravenous piggyback 


13 
 
(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. 
 
3.2 Off study criteria for the study 
1. Request by the patient at any time for any reason. 
2. The patient may at any time be removed from the trial at the principal investigator’s 
discretion if the principal investigator deems the patient to be at unacceptable risk to remain 
on the study. Reasons for this action may include (but are not limited to) disease progression 
with declining organ function/performance status before treatment; inadequate 
family/caregiver support; noncompliance. 


14 
 
3.3 Off treatment criteria for the study 
1. Unacceptable adverse event(s) due to the infusion of any of the three antineoplastic agents 
which necessitates the termination of the therapy. 
2. Intercurrent disease that prevents the administration of treatment. 
 
 
4.0 ON STUDY EVALUATION 
All patients enrolled in the study will have the following evaluations: 
1. History and physical examination will be performed daily during the hospital stay and then 
weekly (± 4 days) as an outpatient for 4 weeks after discharge and then every 2 weeks until 
count recovery (defined as ANC ≥1000 with or without PLT ≥ 100,000). Daily weight will be 
measured (if clinically possible) while in the hospital and at each outpatient visit. 
2. If patients develop grade 3 or 4 non-hematologic toxicity during their treatment, they will be 
followed weekly after discharge until resolution of toxicity or improvement to grade 2 or less. 
3. CBC with differential, complete metabolic panel (Na, K, Cl, CO2, glucose, BUN, Cr, Ca, total 
protein, albumin, total bilirubin, AST, ALT, and alkaline phosphatase), phosphorus, uric acid, 
magnesium level and LDH will be performed daily while in the hospital. After discharge, CBC 
with differential and complete metabolic panel as defined above will be obtained weekly (± 4 
days) until count recovery (defined as ANC ≥1000 with or without PLT ≥ 100,000). 
4. Bone marrow biopsy and/or aspirate will be performed no earlier than 7 days after the therapy 
completion to evaluate disease response. 
5. Bone marrow biopsy/aspiration to test for remission will be performed once hematopoietic 
 
recovery (defined as ANC ≥1000 with or without PLT ≥ 100,000) has been achieved. It can 
be performed in the inpatient or outpatient setting. If the bone marrow is consistent with 
morphologic complete remission, minimal residual disease testing will be performed with flow 
cytometry. If, on diagnosis, the NPM1 mutation was detectable by PCR or next-generation 
sequencing, then NPM1 PCR will be performed as well if morphologic complete remission is 
achieved. If hematopoietic recovery has not been achieved by 5 weeks (± 7 days) after the 
completion of therapy, bone marrow biopsy and/or aspiration for disease evaluation will be 


15 
 
performed. If there is no evidence of leukemia, subsequent bone marrow biopsies will be 
performed based on count recovery. 
6. After the assessment of the recovery marrow patients will be followed remotely from chart 
review to evaluate the disease-free survival and the overall survival. If information cannot be 
obtained from the chart patients may be contacted by telephone. 
 
 
5.0  STATISTICAL CONSIDERATIONS AND METHODOLOGY 
 
5.1 Number and evaluability of patients 
This is a phase II study of the combination therapy of GO, mitoxantrone and etoposide as 
second line therapy in patients with acute myeloid leukemia. The study is designed to assess 
the therapeutic efficacy and the toxicity profile using Simon’s optimal two-stage phase II design 
to permit early stopping of the trial if there is strong evidence that the studied treatment is 
inefficacious. 
To be evaluable for clinical response, a patient must: 
1. Receive a total of 5 days of mitoxantrone and etoposide, 
2. Receive 1 dose of GO and 
3. Have a follow-up bone marrow biopsy to evaluate the response to therapy. 
Additional participants will be recruited to replace those who are not evaluable for clinical 
response. The accrual target is a maximum of 44 response-evaluable patients. All participants 
who begin treatment will be counted in the interim analysis for excess mortality. 
 
5.2. Sample Size/Accrual rate 
5.2.1 Sample size 
This study is expected to require a minimum of 16 patients (at the interim evaluation of 
response) and a maximum of 44 response-evaluable patients unless undue toxicity is 
encountered. We anticipate accruing up to 9 additional patients (~20%) to account for patients 
who may prove unevaluable (i.e. ineligibility, cancellations, death or major violations). 
Therefore, our overall sample size will be a maximum of 53 patients. 


16 
 
5.2.2. Accrual time and study duration 
Based on previous efforts in recruiting patients at the UPMC Hillman Cancer Center, it is 
anticipated that at least thirty patients per year will be enrolled in the protocol and the accrual 
will be completed within two years. The final evaluation of the study to assess overall survival 
will be conducted at 5 years or if all subjects expire, whichever comes first. 
 
5.3. Study design 
5.3.1 Definition of complete remission (CR): An evaluable patient will be classified as 
having complete remission if they meet the criteria in Appendix II. 
Decision Rule (Simon two-stage design): The largest CR rate where the proposed treatment 
regimen would be considered ineffective in this population is 35%. Subsequent studies will 
be warranted if the CR rate is 50% or higher or the CR rates are similar to historical data but 
the disease-free survival and the overall survival are improved in comparison to our 
institution’s historical cohort. The following optimal Simon two stage design uses 44 patients 
to test the null hypothesis that the true CR rate in the given patient population is at most 35%. 
Stage 1: Enter 16 evaluable patients. If 5 or fewer patients have a CR in this timeframe, we 
will consider this early evidence that this treatment regimen is not sufficiently 
efficacious in this patient population, and the accrual of patients will be stopped. If 
6 or more patients have a CR, then accrual will continue in the second stage of this 
trial. 
Stage 2: Enter an additional 28 evaluable patients to the trial. If 19 or more patients achieve a 
complete remission, the treatment will be promoted for further consideration. This design has 
α=0.15 and β=0.20; the large value of α is appropriate in an early phase trial. If the probability 
of CR is 35%, the expected sample size is 30.3 patients, i.e., the probability that the trial will 
be halted after 16 patients is 48.9%. 
 
 
 
 
5.3.2 Monitoring for treatment-induced mortality 
The trial will be continually monitored to ensure that treatment-induced mortality is not 
excessive, defined as >0.20 of patients treated. A safety-evaluable patient is a patient 


17 
 
who was consented and started the protocol chemotherapy. All safety-evaluable 
patients, not just those evaluable for clinical response, are counted in the interim 
analysis for mortality. The cutpoints are listed in Table 2. 
 
Table 2. Stopping rule for excessive mortality. The trial will be halted if, for the number of 
patients in the following table, the number of deaths is greater than or equal to the given number. 
 
# Patients # Deaths # Patients # Deaths 
4 
3 
24 
7 
6 
3 
26 
8 
8 
3 
28 
8 
10 
4 
30 
8 
12 
4 
32 
9 
14 
5 
34 
9 
16 
5 
36 
10 
18 
6 
38 
10 
20 
6 
40 
11 
22 
7 
42 
11 
 
Justification of the stopping rule: It was assumed that under standard of care, the 
probability of death is π=0.2. A beta-binomial model is assumed with α=2 and β=8. If 
the number of deaths, x, is greater than the value in the Stopping Rule table for the 
number of patients, n, then: 
 
P(π>0.2|α,β,x,n)>0.75. 
 
Under different assumptions of the true probability of death (True P(Death)), the 
expected number of patients (E(n)) and the probability of the trial stopping early (P(Stop 
Early)) were determined by Monte Carlo simulation: 
 
True P(Death) E(n) P(Stop Early) 
0.20 
28.3 
0.513 
0.25 
22.9 
0.720 
0.30 
15.8 
0.900 
0.35 
11.5 
0.973 
0.40 
8.4 
0.994 
0.45 
6.9 
0.996 


18 
 
5.4. 
Statistical analysis plan 
5.4.1. Analysis of complete remission 
 
The probability of complete remission (CR, Appendix II) will be estimated by the number 
of CR divided by the total number of patients evaluable for response. A 95% one-sided 
exact binomial confidence interval of the form (πL,1) for the true probability of CR will be 
calculated. 
 
5.4.2 Analysis of secondary endpoints 
Overall and progression-free survival functions will be estimated by the product limit 
(Kaplan-Meier) method. The median survival and its 90% confidence interval will also be 
reported. 
Proportional hazards (Cox) regression will be used to describe the relationship between 
age, cytogenetic status (poor, intermediate, favorable), percent of blast in the bone 
marrow prior to therapy and percent expression of CD33 in the leukemia blasts to overall 
and progression-free survival. Likelihood ratio tests will be used to identify statistically 
significant ratios and profile likelihood confidence intervals will be estimated for hazard 
ratios of statistically significant predictors. Logistic regression will be applied in a similar 
fashion to determine predictors of complete remission. 
 
6. ADVERSE EVENT REPORTING 
Definitions 
The following definitions of terms apply to this section: 
 
Adverse event: Any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. 
Life-threatening adverse event or life-threatening suspected adverse reaction: An adverse 
event or suspected adverse reaction is considered "life-threatening" if, in the view of either 
the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
Serious adverse event or serious suspected adverse reaction: An adverse event or 


19 
 
suspected adverse reaction is considered "serious" if, in the view of either the investigator 
or sponsor, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life functions, 
or a congenital anomaly/birth defect. Important medical events that may not result in death, 


20 
 
be life-threatening, or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
Suspected adverse reaction: Any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. Suspected adverse reaction implies a lesser degree 
of certainty about causality than adverse reaction, which means any adverse event caused 
by a drug. 
Adverse reaction means any adverse event caused by a drug. Adverse reactions are a 
subset of all suspected adverse reactions where there is reason to conclude that the drug 
caused the event. 
Unexpected adverse event or unexpected suspected adverse reaction: An adverse event or 
suspected adverse reaction is considered "unexpected" if it is not listed in the investigator 
brochure or is not listed at the specificity or severity that has been observed; or, if an 
investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application, as 
amended. For example, under this definition, hepatic necrosis would be unexpected (by virtue 
of greater severity) if the investigator brochure referred only to elevated hepatic enzymes or 
hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected 
(by virtue of greater specificity) if the investigator brochure listed only cerebral vascular 
accidents. "Unexpected," as used in this definition, also refers to adverse events or suspected 
adverse reactions that are mentioned in the investigator brochure as occurring with a class of 
drugs or as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 
Eliciting AE Information 
Research subjects will be routinely questioned about AEs at study visits. 
 
Recording Requirements 


21 
 
All observed or volunteered adverse events (serious or non-serious) and abnormal test 
findings, regardless of study group or suspected causal relationship to the study drug(s) will 
be recorded in the subjects’ case histories. For all adverse events, sufficient information will 
be pursued and/or obtained so as to permit 1) an adequate determination of the outcome of 
the event (i.e., whether the event should be classified as a serious adverse event) and; 2) 
an assessment of the casual relationship between the adverse event and the study drug(s). 
AEs or abnormal test findings felt to be associated with the investigational drug or study 
treatment(s) will be followed until the event (or its sequelae) or the abnormal test finding 
resolves or stabilizes at a level acceptable to the Sponsor-Investigator. 
Abnormal Test Findings 
An abnormal test finding will be classified as an adverse event if one or more of the following 
criteria are met: 
• 
The test finding is accompanied by clinical symptoms. 
• 
The test finding necessitates    additional diagnostic 
evaluation(s) 
or 
medical/surgical intervention; including significant additional concomitant drug 
treatment or other therapy. 
Note: simply repeating a test finding, in the absence of any of the other listed criteria, 
does not constitute an AE. 
• 
The test finding leads to a change in study dosing or discontinuation of subject 
participation in the clinical study. 
REPORTING OF SERIOUS ADVERSE EVENTS 
All events meeting the definition of a serious adverse event, from the date of first dose of 
study drug until 30 days after last dose, should be reported according to the departmental 
SAE checklist and SAE form. The initial SAE form should be sent to the following within 
24 business hours / 1 business day of the Principal Investigator becoming aware: 
1.  Robert Redner, MD 
2. CRSSafetySubmissions@upmc.edu 
3. Local Institutional Review Board when reporting requirements are met. 
4. Pfizer Safety @ SAEFaxmailbox@Pfizer.com 


22 
 
 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include as applicable the following information that is 
available at the time of report within the Sections B and C of the departmental SAE form: 
 
• 
CTCAE(5.0) term(s) and grade(s) 
• 
current status of study drug 
• 
all interventions to address the AE (testing and result, treatment and response) 
• 
hospitalization and/or discharge dates 
• 
event relationship to study drug 
 
Follow-up reports: 
Additional information may be added to a previously submitted report by adding to the 
original departmental SAE form and submitting it as follow-up or creating supplemental 
summary information and submitting it as follow-up with the original departmental SAE form. 
Special Interest Serious Adverse Events 
 
The following events also require reporting to Pfizer at the fax number provided above. 
 
1. Exposure during Pregnancy, Exposure during Lactation, Occupational Exposure, and Lack of 
Effect. Even though there may not be an associated SAE, exposure to the Pfizer drug product 
during pregnancy, exposure to the Pfizer drug product during lactation, and occupational exposure 
to the Pfizer drug product are reportable, and lack of effect od rh Pfizer drug product may also be 
reportable. The term SAE is understood to include exposure during pregnancy, exposure during 
lactation, occupational exposure, and reportable instances of lack of effect. 
2. Hy’s Law Cases. Cases of potential drug-induced liver injury as assessed by laboratory test values 
are reportable. If a Subject develops abnormal lab values in aspartate transaminase (AST) or 
alanine transaminase (ALT) or both, concurrent with abnormal elevations in total bilirubin and no 
other known cause of liver injury, that event would be classified as a Hy’s Law Case. The term 
SAE is understood to include Hy’s Law Cases. 
 
7. DATA SAFETY MONITORING PLAN 
 
Investigator/Sub-investigators, 
regulatory, 
CRS management, 
clinical 
research coordinators, clinical research associates, data managers, and clinic staff meet 
regularly in the disease center Data Safety Monitoring Board (DSMB) to review and 
discuss study data to include, but not limited to, the following: 


23 
 
• 
serious adverse events 
• 
subject safety issues 
• 
recruitment issues 
 
• 
accrual 
 
• 
protocol deviations 
• 
unanticipated problems 
• 
breaches of confidentiality 
Minutes from the disease center DSMB meetings are available to those who are unable to 
attend in person. 
All toxicities encountered during the study will be evaluated on an ongoing basis according 
to the NCI Common Toxicity Criteria Version 5.0. All study treatment associated adverse 
events that are serious, at least possibly related and unexpected will be reported to the IRB. 
Any modifications necessary to ensure subject safety and decisions to continue or close the 
trial to accrual are also discussed during these meetings. If any literature becomes available 
which changes the risk/benefit ratio or suggests that conducting the trial is no longer ethical, 
the IRB will be notified in the form of an Unanticipated Problem submission and the study 
may be terminated. 
All study data reviewed and discussed during these meetings will be kept confidential. Any 
breach in subject confidentiality will be reported to the IRB in the form of an Unanticipated 
Problem submission. The summaries of these meetings are forwarded to the UPMC Hillman 
Cancer Center DSMC which also meets monthly following a designated format. 
For all research protocols, there will be a commitment to comply with the IRB’s policies for 
reporting unanticipated problems involving risk to subjects or others (including adverse 
events). DSMC progress reports, to include a summary of all serious adverse events and 
modifications, and approval will be submitted to the IRB at the time of renewal. 
Protocols with subjects in long-term (survival) follow-up or protocols in data analysis only, will 
be reviewed bi-annually. 


24 
 
Both the UPMC Hillman Cancer Center DSMC as well as the individual disease center 
DSMB have the authority to suspend accrual or further investigate treatment on any trial 
based on information discussed at these meetings. 
All records related to this research study will be stored in a locked environment. Only the 
researchers affiliated with the research study and their staff will have access to the research 
records. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8. STUDY EVALUATION, TREATMENT SCHEMA AND FLOW CHART 
 
 
Pre-treatment evaluation 
Within last 6 weeks 
from 
day of consent 
Anti-Hepatitis C antibody and if positive HCV RNA PCR 
X 


25 
 
Hepatitis B surface antigen 
X 
Within 14 days from 
day of consent 
Medical history and physical examination 
X 
Height, weight, BSA, ECOG performance status 
X 
Toxicities from prior therapies 
X 
Cardiac echocardiogram 
X 
Bone marrow biopsy and aspiration 
X 
Urine βHCG in women ≤ 60 years old (pregnancy test) 
X 
PT/INR, PTT 
X 
Complete metabolic panel (Na, K, Cl, CO2, glucose, BUN, Cr, Ca, 
total protein, albumin, total bilirubin, AST, ALT and alkaline 
phosphatase) 
X 
Magnesium, Phosphorous, Uric Acid, LDH 
X 
CBC with differential 
X 
Urinalysis 
X 
Electrocardiogram (12 lead) 
X 
Chest radiograph 
X 
CT Chest, Abdomen and/or Pelvis if indicated 
X 
 
Treatment Schema 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Mitoxantrone 
X 
X 
X 
X 
X 
Etoposide * 
X 
X 
X 
X 
X 
Gemtuzumab 
ozogamicin ** 
X 
 
* Dose modification of etoposide for patients who develop elevated total bilirubin and/or AST 
or decrease in creatinine clearance 


26 
 
 
Adverse event 
Dose modification of etoposide 
CrCl 10 – 50 ml/min 
administer 75% of normal dose 
CrCl < 10 ml/min 
administer 50% of normal dose 
CrCl <50 ml/min 
AND 
Total bilirubin >3 mg/dL or AST >3 
times ULN 
Hold etoposide 
 
**If enrolled patients on day 6 of therapy have levels of aspartate aminotransferase 
(AST) ≥ 2.5 x UNL or alanine aminotransferase (ALT) ≥ 2.5 x UNL or total bilirubin ≥ 2 
x ULN the administration of GO will be on hold until recovery of total bilirubin to less 
than or equal to 2 × ULN and AST and ALT to less than or equal to 2.5 × ULN prior to 
each dose. Daily values of LFTs will be obtained. The GO dose can be delayed up to 
the 10th day after the initiation of therapy due to toxicity or unexpected events (ie 
infection). Doses of GO will be capped at 4.5mg. Administration of a FLT3 inhibitor will 
be prohibited until CR is achieved. The use of a FLT-3 inhibitor is not prohibited after CR 
has been achieved for patients with FLT3-ITD or FLT-TKD mutations. 
 
ON STUDY EVALUATION 
TIMING 
History and physical examination 
Daily during the hospital stay at UPMC 
Shadyside Hospital and then weekly as 
outpatient for 4 weeks, and then every 2 
weeks until count recovery 
CBC with differential 
CBC with differential will be performed daily 
during the inpatient stay and weekly as 
outpatient until count recovery 


27 
 
Complete metabolic panel including LFTs 
Complete metabolic panel including liver 
function tests (LFTs) will be performed daily 
during the admission. After discharge, they 
will be followed weekly as outpatient until 
count recovery 
Bone marrow aspiration and biopsy (to 
evaluate disease status) 
At least 7 days after the completion of 
treatment 
Weight 
Daily (if clinical possible) while in 
hospital and during each visit outpatient 
 
Bone marrow biopsy, aspirate with flow cytometry studies, cytogenetics and molecular studies 
will be performed no earlier than 7 days after the completion of treatment. Once hematopoietic 
recovery has been achieved patients will undergo bone marrow biopsy and/or aspiration for 
disease evaluation which can be performed in the inpatient or outpatient setting. If the bone 
marrow is consistent with morphologic complete remission, minimal residual disease testing 
will be performed with flow cytometry. If on diagnosis the NPM1 mutation was detectable by 
PCR or next-generation sequencing then NPM1 PCR will be performed as well if morphologic 
complete remission is achieved If hematopoietic recovery has not been achieved by 5 weeks 
after the completion of therapy bone marrow biopsy and/or aspiration for disease evaluation 
will be performed. 
 
 
 
Study Flow Chart 
Screening Period 
Treatment Days 
Post-treatment 
Main 
Study 
Screening 
1 
2 
3 
4 
5 
6 
Daily 
during 
Inpatient 
stay 
Follow 
Up 
Visits 
Survival 
Follow 
upa 
Scheduling Window 
(Days) 
-14 to 0 
Can delay each dose 
up to 3 days. 
Up to 5 days 
from the last 
dose of 
etoposide/ 
mitoxantroneb 
Weeklyc 
Informed Consent 
X 
Inclusion/Exclusion 
Criteria 
X 


28 
 
Medication 
Reviewd 
X 
X 
X 
X 
X 
X 
X 
X 
Trial Treatment 
Administration 
X 
X 
X 
X 
X 
X 
Post-study 
anticancer therapy 
status 
X 
Survival Status 
X 
Review Adverse 
Events 
X (from 1st 
induction 
therapy) 
X 
X 
X 
X 
X 
X 
X 
X 
Full Physical 
Examination 
X 
X 
Directed Physical 
Examination 
X 
X 
X 
X 
X 
X 
X 
Vital Signs and 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG 
Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine or Serum β- 
HCG 
X 
PT/INR and aPTT 
Xe 
CBC with 
differential 
Xe 
X 
X 
X 
X 
X 
X 
X 
Xf 
Comprehensive 
Serum 
Chemistry Panelg 
Xe 
X 
X 
X 
X 
X 
X 
X 
Xf 
Magnesium, 
Phosphorus, 
Uric Acid, LDH 
Xe 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
Xe 
Chest Radiograph 
Xe 
Echocardiogram 
Xh 
EKG 
Xe 
Bone Marrow 
Biopsy 
Xi 
Xj 
Archival or Newly 
X 
Obtained Tissue 
Collection 
 
a Survival will be assessed daily during inpatient stays and then in the follow up visits. After the 
assessment of the recovery marrow or the marrow after 5 weeks from the completion of therapy patients 
will be followed remotely from chart review to evaluate the disease-free survival and overall survival. If 
information cannot be obtained from the chart, patients may be contacted by telephone. b Administration 
of a FLT3 inhibitor will be prohibited until CR is achieved. The use of a FLT-3 inhibitor is not prohibited 
after CR has been achieved for patients with FLT3-ITD or FLT-TKD mutations. 


29 
 
c After discharge the patient will be followed weekly for 4 weeks and then every 2 weeks until count 
recovery (defined as ANC ≥ 1000 with or without PLT ≥ 100,000). If patients develop grade 3 or 4 
nonhematologic toxicity during their treatment they will be followed weekly after discharge until resolution 
of toxicity or improvement to grade 2 or less. There is ± 4 days window for each visit. d Medication review 
will be performed from the day of screening until the day of discharge. e All screening laboratory 
assessment must occur within 14 days after consent is signed. f After discharge, CBC with differential 
and complete metabolic panel will be obtained weekly until count recovery (defined as ANC ≥ 1000 with 
or without PLT ≥ 100,000). g Includes Na, K, Cl, HCO3, BUN, Cr, glucose, Ca, total protein, albumin, total 
bilirubin, AST, ALT, alkaline phosphatase. h Transthoracic Echocardiogram must be performed after the 
administration of 7 days of cytarabine with 3 days of idarubicin and before the first day of the study 
treatment. i Bone marrow with persistent disease as described in eligibility criteria section and CD33 
expression in ≥ 30% leukemic blasts on the bone marrow. j Bone marrow biopsy and/or aspirate will be 
performed no earlier than 7 days after the therapy completion to evaluate disease response. Bone 
marrow biopsy/aspiration to test for remission once hematopoietic recovery has been achieved will be 
performed in the inpatient or outpatient setting. If hematopoietic recovery has not been achieved by 5 
weeks after the completion of therapy bone marrow biopsy/aspiration for disease evaluation will be 
performed. If the recovery bone marrow is consistent with morphologic complete remission, minimal 
residual disease testing will be performed with flow cytometry. If at AML diagnosis the NPM1 mutation 
was detectable by PCR or next generation sequencing then NPM1 PCR will be performed as well. k Blood 
will be collected prior to the initiation of therapy with mitoxantrone and etoposide, prior to the initiation of 
therapy with GO, after the administration of GO and weekly while in the hospital. Blood and bone marrow 
aspirate will be collected at the time of bone marrow evaluation following therapy and at the time of bone 
marrow evaluation following hematopoietic recovery or prolonged cytopenias. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX I 
 
 
Performance Status Criteria 


30 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to 
carry on all pre-disease performance 
without restriction. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or sedentary 
nature (e.g., light housework, office 
work). 
2 
In bed <50% of the time. Ambulatory 
and capable of all self-care, but 
unable to carry out any work activities. 
Up and about more than 50% of 
waking hours. 
3 
In bed >50% of the time. Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
4 
100%     bedridden. 
Completely 
disabled. 
Cannot 
carry 
on 
any 
selfcare. Totally confined to bed or 
chair. 
5 
Dead. 
 
 
 
APPENDIX II 
 
 
RESPONSE CRITERIA FOR ACUTE LEUKEMIA 
 
 
Morphologic leukemia-free state 
Bone marrow < 5% blasts in an aspirate with spicules 


31 
 
No blasts with Auer rods or persistence of extramedullary disease 
Absolute neutrophil count < 1000/mcL AND platelets <100,000/mcL 
 
Complete remission 
Bone marrow < 5% blasts in an aspirate with spicules Absolute 
neutrophil count > 1000/mcL 
Platelets ≥100,000/mcL 
No residual evidence of extramedullary disease 
Morphologic CR - patient independent of transfusions 
Cytogenetic CR - cytogenetics normal (in those with previously abnormal cytogenetics) 
Molecular CR - molecular studies negative 
 
Complete remission with incomplete hematologic recovery 
Bone marrow < 5% blasts in an aspirate with spicules 
No residual evidence of extramedullary disease 
Absolute neutrophil count > 1000/mcL or platelets ≥100,000/mcL 
No residual evidence of extramedullary disease 
 
 
Partial remission 
Decrease of at least 50% in the percentage of blasts to 5 to 25% in the bone marrow 
Patients failing to achieve a complete remission are considered treatment failures 
 
Relapse 
Relapse following complete remission is defined as reappearance of leukemic blasts in 
the peripheral blood or the finding of more than 5% blasts in the bone marrow, not 
attributable to another cause (eg, bone marrow regeneration after consolidation therapy) 
 
Cheson BD, Bennett JM, Kopecky KJ et al. J Clin Oncol 2003;21 (24):4642-4649 
 
 
9. DRUG INFORMATION 


32 
 
Gemtuzumab Ozogamicin 
 
 
Other Names: Mylotarg 
 
 
Classification: Antibody-drug conjugate 
 
 
Mechanism of Action: Antibody-drug conjugate to CD33 antigen. Binding results in 
internalization of the antibody-antigen complex. Following internalization, the 
calicheamicin derivative is released inside the myeloid cell. The calicheamicin derivative 
binds to DNA resulting in double strand breaks and cell death. Pluripotent stem cells and 
nonhematopoietic cells are not affected. 
 
Storage and Stability: GO is supplied as a sterile, pyrogen-free, unpreserved, white 
lyophilized powder in amber glass vials. The unopened vials of GO should be stored at 
2 - 8° C (refrigerated) and protected from light and should be used within 8 hours of 
reconstitution. GO is light sensitive and should be reconstituted, prepared, and 
administered under protection from direct/indirect sunlight and Ultraviolet (UV) light. 
 
Dose Specifics: GO will be administered at 3 mg/m2 (cap at 4.5mg) on day 6. BSA will be 
calculated based on actual body weight. 
 
Preparation: GO is light sensitive and must be protected from direct and indirect sunlight 
and unshielded fluorescent light during the preparation and administration of the infusion. 
ALL PREPARATION SHOULD BE DONE IN A BIOLOGIC SAFETY HOOD WITH 
FLUORESCENT LIGHT OFF. Prior to reconstitution, allow vials to come to room 
temperature for approximately 5 minutes. Reconstitute the contents of each vial with 5 
mL sterile water for injection, USP, using sterile syringes. Gently swirl each vial. The final 
concentration is 1 mg/mL. Use reconstituted solution immediately or after being 
refrigerated at 2-8°C for up to 1 hour. Protect reconstituted solution from light. Do not 
freeze reconstituted solution. Dilute the desired volume of GO into a 50-milliliter 


33 
 
intravenous bag of 0.9% sodium chloride injection or other appropriate volume of 0.9% 
sodium chloride to make a final GO concentration between 0.075 mg/ml to 0.234 mg/mL. 
Gently invert the infusion container to mix the diluted solution. Do not shake. Following 
dilution with 0.9% sodium chloride injection, GO solution should be infused immediately. 
If not used immediately, store at room temperature (15–25°C; 59–77°F) for up to 6 hours, 
which includes the 2-hour infusion time and 1-hour, if needed, to allow the refrigerated 
diluted solution to equilibrate to room temperature. The diluted solution can be 
refrigerated at 2– 8°C (36–46°F) for up to 12 hours which includes up to 1-hour in the vial 
post-reconstitution. 
 
Route of Administration: GO is administered as a 2 hour IV infusion. A 0.2-micron 
polyethersulfone filter is required on the IV line. The IV bag must be protected from light 
using a light-blocking cover during infusion. The infusion line does not need to be 
protected from light. 
 
Compatibilities: No information; infuse via separate line. 
 
 
Availability: Commercially available 
 
 
Side Effects: 
 
 
Common (occurs in more than 10% of people - more than 10 out of 100 people): 
fever (79%), infection (42%), increased AST (40%), sepsis (32%), bleeding (23%), 
nausea and vomiting (21%), constipation (21%), mucositis (21%), headache (19%), 
increased ALT (16%), rash (16%) 
 
 
Infrequent (occurs in 1% to 10% of people - from 1 to 10 out of 100 people): 
pneumonia (7%), bleeding (7%), hyperbilirubinemia (7%), mucositis (4%), pain (4%), 
diarrhea (2%), headaches (2%), tachycardia (2%), lung edema (2%) 
 
 
Rare (occurs in <1% of people, mainly identified in post-marketing surveillance): 


34 
 
neutropenic colitis, interstitial pneumonia, hemorrhagic cystitis 
 
 
Nursing Implications: Patients should be premedicated prior to administration of GO 
with methylprednisolone 1 mg/kg IV, diphenhydramine 50 mg IV or PO and 
acetaminophen 650 mg PO 30 minutes prior to start of the infusion. Additional doses of 
acetaminophen and diphenhydramine may be administered every 4 hours after the initial 
pretreatment dose. Repeat with the same dose of methylprednisolone for any sign of an 
infusion reaction, such as fever, chills, hypotension, or dyspnea during the infusion or 
within 4 hours afterwards. 
 
During and after the infusion patients will be monitored with vital signs recorded every 
30 minutes during the infusion and for 1 hour after completion of the infusion. 
 
GO should be administered in a setting where appropriate medical support, including life 
support equipment, is available in case of an unexpected adverse event. 
 
 
 
Etoposide 
 
 
Other Names: Toposar 
 
 
Classification: Podophyllotoxin Derivative 
 
Mechanism of Action: Etoposide has been shown to delay transit of cells through the S 
phase and arrest cells in late S or early G2 phase. The drug may inhibit mitochondrial 
transport at the NADH dehydrogenase level or inhibit uptake of nucleosides into HeLa cells. 
It is a topoisomerase II inhibitor and appears to cause DNA strand breaks. Etoposide does 
not inhibit microtubular assembly. 
 
Storage and Stability: Unopened vials of etoposide are stable for 24 months at room 
temperature (25 degrees Celsius). Vials of etoposide are stable at room temperature for 96 


35 
 
hours when diluted to concentrations of 0.2 milligrams/milliliter (mg/mL); stability is 24 hours 
with concentrations of 0.4 mg/mL at room temperature. The manufacturer does not 
recommend that etoposide be administered at concentrations greater than 0.4 mg/mL 
because time to precipitation is highly unpredictable and precipitate formation has been 
reported to occur earlier than the utility times listed above. Etoposide 20 mg/ml is stable in 
a plastic syringe for 5 days when stored at room temperature under fluorescent light. 
 
Dose Specifics: Patients will receive etoposide 100 mg/m2 administered intravenously in 
500 ml of 0.9% sodium chloride over 2 hours on days 1-5 (for patients who have elevated 
total bilrirubin, AST or reduced creatinine clearance during the etoposide infusion see 
treatment schema for dose modification of the etoposide). BSA will be calculated based on 
actual body weight. 
 
Preparation: Etoposide Injection must be diluted prior to use with either 5% Dextrose 
Injection, or 0.9% Sodium Chloride Injection, to give a final concentration of 0.2 to 0.4 
mg/mL . If solutions are prepared at concentrations above 0.4 mg/mL, precipitation may 
occur. Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration whenever solution and container permit. 
 
Route of Administration: Etoposide should be given as a diluted solution via the IV route. 
 
Compatibilities: Variable stability (consult detailed reference) in D5W, LR, NS.Y-site 
administration: Compatible: Allopurinol, amifostine, aztreonam, cladribine, doxorubicin 
liposome, fludarabine, gemcitabine, granisetron, melphalan, ondansetron, paclitaxel, 
piperacillin/tazobactam, sargramostim, sodium bicarbonate, teniposide, thiotepa, 
topotecan, vinorelbine. Incompatible: Cefepime, filgrastim, idarubicin. 
 
Compatibility when admixed: Compatible: Carboplatin, cisplatin, cisplatin with 
cyclophosphamide, cisplatin with floxuridine, cytarabine, cytarabine with daunorubicin, 
floxuridine, fluorouracil, hydroxyzine, ifosfamide, ifosfamide with carboplatin, ifosfamide 


36 
 
with cisplatin, ondansetron. Variable (consult detailed reference): Cisplatin with mannitol 
and potassium chloride, doxorubicin with vincristine. 
 
Availability: Commercially available 
 
 
Side Effects: 
 
 
Common (occurs in more than 10% of people - more than 10 out of 100 people): 
Alopecia (8% to 66%), ovarian failure (38%), Nausea/vomiting (31% to 43%), anorexia 
(10% to 13%), diarrhea (1% to 13%), leukopenia (60 to 91%), thrombocytopenia (22% 
to 41%), anemia (up to 33%), mucositis 
 
Infrequent (occurs in 1% to 10% of people - from 1 to 10 out of 100 people): 
Hypotension (1% to 2%), stomatitis (1% to 6%), abdominal pain (up to 2%), hepatic 
toxicity (up to 3%), peripheral neuropathy (1% to 2%), anaphylactic-like reaction (IV 
infusion 1% to 2%) 
 
Rare (occurs in fewer than 1% of people – fewer than 1 out of 100 people): 
Congestive heart failure, hyperpigmentation, rash, radiation-recall reaction, 
StevensJohnson Syndrome, pruritus, toxic epidermal necrolysis, cyanosis, optic neuritis, 
transient blindness, diaphoresis, interstitial pneumonitis, pulmonary fibrosis, metabolic 
acidosis, thrombophlebitis, extravasation 
 
Nursing Implications: For IV use only; may cause severe local tissue damage if 
extravasation occurs. Do not administer intrathecally; may cause serious and permanent 
neurologic damage. Should be administered under the supervision of an experienced 
cancer chemotherapy physician. 
 
 
Mitoxantrone 


37 
 
Other Names: Dihydroxyanthracenedione, DHAD 
 
 
Classification: Anthracenedione 
 
 
Mechanism of Action: Analogue of the anthracyclines, mitoxantrone intercalates DNA; 
binds to nucleic acids and inhibits DNA and RNA synthesis by template disordering and 
steric obstruction; replication is decreased by binding to DNA topoisomerase II and seems 
to inhibit the incorporation of uridine into RNA and thymidine into DNA; active throughout 
entire cell cycle 
 
Storage and Stability: Intact vials should be stored between 15 and 25 degrees Celsius 
(59 and 77 degrees Fahrenheit). DO NOT FREEZE. After penetration of the stopper, store 
the remaining solution of undiluted mitoxantrone for no longer than 7 days between 15 to 
25 degrees Celsius (59 to 77 degrees Fahrenheit) or for no longer than 14 days under 
refrigeration (2 to 8 degrees Celsius or 36 to 46 degrees Fahrenheit). Mitoxantrone must 
be further diluted for infusion. 
 
Dose Specifics: Patients will receive mitoxantrone 10mg/m2 administered IVPB in 50ml 
0.9% sodium chloride over 15 minutes on days 1-5. (Refer to Treatment Plan of Phase I 
and II sections). BSA will be calculated based on actual body weight. 
 
Preparation: MITOXANTRONE CONCENTRATE MUST BE DILUTED PRIOR TO USE. 
Dilute the dose with at least 50 milliliters (mL) of 0.9% sodium chloride or 5% dextrose in 
water. Dilution in volumes greater than 50 mL may be done in 5% dextrose in water, 0.9% 
sodium chloride, or dextrose 5% with 0.9% sodium chloride. Parenteral drug products 
should be inspected visually for particulate matter and discoloration prior to administration 
whenever solution and container permit. 
 
Route of Administration: Mitoxantrone should be given as a diluted solution via the IV 
route. 


38 
 
Compatibilities: Stable in D5NS, D5W, NS Y-site administration: Compatible: Allopurinol, 
amifostine, cladribine, etoposide phosphate, filgrastim, fludarabine, gatifloxacin, 
gemcitabine, granisetron, linezolid, melphalan, ondansetron, sargramostim, teniposide, 
thiotepa, vinorelbine. Incompatible: Amphotericin B cholesteryl sulfate complex, 
aztreonam, cefepime, doxorubicin liposome, paclitaxel, piperacillin/tazobactam, propofol. 
 
Compatibility when admixed: Compatible: Cyclophosphamide, cytarabine, fluorouracil, 
hydrocortisone sodium succinate, potassium chloride. Incompatible: Heparin. Variable 
(consult detailed reference): Hydrocortisone sodium phosphate. 
 
Availability: Commercially available 
 
 
Side Effects: 
 
 
Common (occurs in more than 10% of people - more than 10 out of 100 people): 
Arrhythmia (3% to 18%), ECG changes (11%), fatigue (up to 39%), fever (6% to 78%), 
headache (6% to 13%), alopecia (20% to 61%), nail bed changes (11%), amenorrhea 
(28% to 53%), menstrual disorder (26% to 61%), hyperglycemia (10% to 31%), 
abdominal pain (9% to 15%), anorexia (22% to 25%), nausea (26% to 76%), 
constipation (10% to 16%), diarrhea (14% to 47%), GI bleeding (2% to 16%), mucositis 
(10% to 29%), stomatitis (8% to 29%), vomiting (6% to 11%), urinary tract infection (7% 
to 32%), neutropenia (79% to 100%), leukopenia (9% to 100%), lymphopenia (72% to 
95%), anemia (5% to 75%), thrombocytopenia (33% to 39%), petechiae/bruising (6% to 
11%), alkaline phosphatase increased (37%), transaminases increased (5% to 20%), 
creatinine increased (13%), hematuria (11%), dyspnea (6% to 18%), upper respiratory 
tract infection (7% to 53%), fungal infection (9% to 15%), infection (4% - 18%), sepsis 
(31% to 34%) 
 
 
Infrequent (occurs in 1% to 10% of people - from 1 to 10 out of 100 people): LVEF 
decreased ( 5%), CHF (2% - 5%), depression (5%), seizure (2% - 4%), hypocalcemia 


39 
 
(10%), hypokalemia (7% - 10%), hyponatremia (9%), menorrhagia (7%),impotence 
(7%), jaundice (3% to 7%), myalgia (5%), arthralgia (5%), conjunctivitis 
(5%), blurred vision (3%), renal failure (8%), proteinuria (6%), rhinitis (10%), pneumonia 
(9%), sinusitis (6%), diaphoresis (9%) 
 
 
Rare (occurs in fewer than 1% of people – fewer than 1 out of 100 people): 
Blue skin discoloration, rash, interstitial pneumonitis, hypersensitivity, extravasation 
 
 
May cause myocardial toxicity and potentially-fatal congestive heart failure (CHF); risk 
increases with cumulative dosing. Predisposing factors for mitoxantrone-induced 
cardiotoxicity include prior anthracycline therapy, prior cardiovascular disease, 
concomitant use of cardiotoxic drugs, and mediastinal/pericardial irradiation. Not 
recommended for use when left ventricular ejection fraction (LVEF) <50%. 
 
Nursing implications: For IV use only; may cause severe local tissue damage if 
extravasation occurs. Do not administer intrathecally; may cause serious and permanent 
neurologic damage. May cause urine, saliva, tears, and sweat to turn blue-green for 24 
hours post infusion. Whites of eyes may have blue-green tinge. Has been associated with 
the development of secondary acute myelogenous leukemia and myelodysplasia. Should 
be administered under the supervision of an experienced cancer chemotherapy 
physician. 
 
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