Conditions: Acute Bilineal Leukemia Acute Biphenotypic Leukemia Acute Leukemia of Ambiguous Lineage Acute Undifferentiated Leukemia Mixed Phenotype Acute Leukemia Mixed Phenotype Acute Leukemia, B/Myeloid, Not Otherwise Specified Mixed Phenotype Acute Leukemia, T/Myeloid, Not Otherwise Specified Recurrent Mixed Phenotype Acute Leukemia
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 16
Healthy volunteers: no

Brief summary:
This phase II trial studies how well clofarabine, idarubicin, cytarabine, vincristine sulfate, and dexamethasone work in treating patients with mixed phenotype acute leukemia that is newly diagnosed or has returned after a period of improvement (relapsed). Drugs used in chemotherapy, such as clofarabine, idarubicin, cytarabine, vincristine sulfate, and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Detailed description:
PRIMARY OBJECTIVE:

I. To evaluate the response rate of the chemotherapy regimen in patients with mixed phenotype acute leukemia.

SECONDARY OBJECTIVE:

I. To evaluate the durability of response, the overall and event-free survival rates, and the safety profile of the regimen.

OUTLINE:

INDUCTION THERAPY: Patients receive clofarabine intravenously (IV) over 60 minutes on days 1-4 or 1-3; idarubicin IV over 30-60 minutes on days 1-3 or 1-2; cytarabine IV over 2 hours on days 1-4; vincristine sulfate IV over 15-30 minutes on days 1, 8, and 15; and dexamethasone IV over 10-30 minutes on days 1-4 and 15-18. Patients with a certain type of leukemia may receive rituximab IV over 4-6 hours on days 1 and 8 or sorafenib tosylate orally (PO) twice daily (BID) on days 1-14. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION THERAPY: Patients receive clofarabine IV over 60 minutes on days 1-3 or 1-2; idarubicin IV over 30-60 minutes on days 1-2; cytarabine IV over 2 hours on days 1-3 or 1-2; vincristine sulfate IV over 15-30 minutes on days 1, 8, and 15; and dexamethasone IV over 10-30 minutes on days 1-4 and 15-18. Patients with a certain type of leukemia may receive rituximab IV over 4-6 hours on days 1 and 8 of cycles 1-3 or sorafenib tosylate PO BID on days 1-28 of cycle 1-6 and beyond. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 6 months thereafter.

Arms:
arm 1: See Detailed Description.

Interventions: intervention 1: Clofarabine intervention 2: Cytarabine intervention 3: Dexamethasone intervention 4: Idarubicin intervention 5: Rituximab intervention 6: Sorafenib intervention 7: Sorafenib Tosylate intervention 8: Vincristine intervention 9: Vincristine Sulfate
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV intervention 5: Given IV intervention 6: Given PO intervention 7: Given PO intervention 8: Given IV intervention 9: Given IV

Protocol document:
Prot_SAP_000.pdf: 
Protocol 2013-0073 
August 8, 2019 
1 
 
A Phase 2 Study of Clofarabine, Idarubicin, Cytarabine, Vincristine, and 
Corticosteroids for Patients with Newly Diagnosed or Relapsed Mixed Phenotype 
Acute Leukemia 
 
I. Objectives 
Primary:  
To evaluate the response rate of the chemotherapy regimen in patients with mixed 
phenotype acute leukemia 
Secondary:  
To evaluate the durability of response, the overall and event-free survival rates, and the 
safety profile of the regimen 
 
II. Rationale  
The diagnosis of acute leukemia is typically based on an evaluation of the morphology, 
immunophenotype, karyotype, and molecular features of blast cells found in the bone 
marrow. Most often, the leukemia is clearly assigned to one of the following specific 
lineages: B-lymphoid, T-lymphoid, or myeloid. Diagnosis is usually unequivocally acute 
myeloid leukemia (AML), or acute lymphoid leukemia (ALL). ALL is further delineated 
into B- or T-cell groups. The therapeutic regimen is often designed based on the lineage 
of the leukemia. Nevertheless, rarely a patient cannot be readily classified due to 
immunophenotypic evidence of multiple lineages within the cell population [1]. 
Throughout the years, these leukemias have been referred to by a number of names, 
including mixed lineage leukemia, biphenotypic leukemia, bilineal leukemia, hybrid 
leukemia, undifferentiated leukemia, or leukemia of ambiguous lineage. This 
terminology has been used to describe leukemias with a single population of cells 
expressing markers from multiple lineages, as well as leukemias exhibiting two distinct 
blast populations each belonging to a distinct lineage. In 2008, the World Health 


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2 
 
Organization (WHO) grouped these processes together under the heading mixed 
phenotype acute leukemia (MPAL) [2].  
The definition of MPAL has evolved over the years, but most now accept the WHO 
definition published in 2008 [2]. Briefly, a blast population is myeloid if there is sufficient 
present of myeloperoxidase (MPO) or monocytic differentiation is present. The T 
lineage is defined by the presence of cytoplasmic or surface CD3. To assign the B 
lineage, a combination of the expression of several markers is used, including CD19, 
CD79a, CD22, and CD10.  
There is no standard therapy for the group of patients diagnosed with MPAL, and the 
situation presents a clinical challenge that has not been well studied. Most experience 
to date comes from the pediatric literature and from older case series. Killick and 
colleagues identified 25 cases of “biphenotypic” leukemia of 693 cases (3.6%) of acute 
leukemia over an 8 year period [3]. This cohort included pediatric patients as young as 3 
years of age, and adults up to age 46. A wide variety of induction regimens were used, 
including conventional ALL induction, conventional AML induction, as well regimens that 
used agents typically used to treat both lineages. Median overall survival (OS) for the 20 
de novo patients was 27.3 weeks, which is very poor considering a median age of 25.5 
years. Importantly, several patients also had the Philadelphia chromosome, and 
treatment was before the era of tyrosine kinase inhibitors.   
Recently, a group from Saudi Arabia described the clinical characteristics and outcome 
of 24 pediatric patients diagnosed with MPAL [4]. All patients were treated uniformly 
with a modified St. Jude Total Therapy-B HR regimen, which that group uses to treat 
high risk ALL [5]. This regimen involves at least six drugs with activity against lymphoid 
and myeloid leukemias. All patients were also considered for allogeneic stem cell 
transplantation (alloSCT) in first complete remission (CR). For patients not undergoing 
alloSCT, maintenance therapy was continued for 2.5 years. With a median follow up of 
four years, the survival was 75.7%, which is excellent, but must be interpreted keeping 


Protocol 2013-0073 
August 8, 2019 
3 
 
in mind that the median age was 8.7 years. AlloSCT did not improve the outcome in this 
small study.  
The St. Jude’s Children’s Research Hospital has recently published their own 
experience treating pediatric patients with mixed lineage acute leukemias [6]. Thirty-five 
patients were treated, and the median age was 10. Overall, 23 patients received AML 
induction (daunorubicin, cytarabine, etoposide), and 12 received standard ALL induction 
(vincristine, daunorubicin, L-asparaginase, prednisone). Patients receiving AML or ALL 
induction regimens up front achieved CR rates of 52% and 83%, respectively. Eighty 
percent of the patients not achieving CR after AML induction subsequently went into CR 
after ALL induction. The 5-year OS for patients with B/Myeloid or T/Myeloid was 47.8%.  
There is very little reported in the literature on adults with MPAL, and as a referral 
center, we may encounter these patients more often that other institutions. A 
contemporary regimen employing drugs active against both myeloid and lymphoid 
leukemias may be the optimal approach. AML is generally treated with anthracyclines 
combined with cytarabine [7-9]. Recently, the addition of a cladribine, a purine analog, 
to standard AML induction improved the survival of younger patients with newly 
diagnosed disease [10]. Clofarabine is also a purine analog that was rationally designed 
to optimize the pharmacologic shortcomings of two of its predecessors, fludarabine and 
cladribine [11]. The drug works through several mechanisms including inhibition of 
deoxyribonucleic acid (DNA) polymerases, inhibition of ribonucleotide reductase, and 
induction of apoptosis via DNA strand breaks and disruption of mitochondrial integrity 
[11]. Clofarabine is currently approved for pediatric patients with relapsed and refractory 
acute lymphoid leukemia after failure of two previous regimens [12].When administered 
three to six hours prior to cytarabine, in vitro both drugs induce a synergistic effect 
against AML cells, possibly due to the ability of clofarabine to efficaciously block 
ribonucleotide reductase [13]. These data have formed the basis for several clinical 
studies that we and others have conducted in an attempt to exploit this relationship, and 
hence, improve AML outcomes [14]. Currently, our frontline AML induction regimen of 
choice is a combination of clofarabine, cytarabine, and idarubicin.   


Protocol 2013-0073 
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4 
 
The frontline strategy for the management of adult ALL is similar to pediatrics, and 
involves induction chemotherapy, multiple rounds of consolidation, a prolonged 
maintenance phase, as well as central nervous system (CNS) prophylaxis. Most 
protocols call for approximately 3 years of therapy in total. There are several accepted 
regimens employed in the United States, and most involve the same key agents which 
include vincristine, anthracycline (e.g., doxorubicin or daunorubicin), corticosteroids 
(e.g., prednisone or dexamethasone), with or without some form of L-asparaginase [15-
17]. One such regimen is the hyperCVAD, which employs the combination of hyper-
fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone 
alternating with high dose methotrexate and cytarabine [18, 19]. Cycles are repeated 
approximately monthly for 8 cycles, a point at which patients move to the maintenance 
portion of the regimen with daily mercaptopurine, monthly vincristine, weekly 
methotrexate, and monthly pulses of prednisone (POMP). Long term outcomes have 
been published previously, with five year overall survival (OS) of 38%. Survival was 
influenced by several prognostic factors that were assessed using multivariable 
analysis. This is comparable to a number of other regimens that are used depending on 
center preference. 
At the M.D. Anderson Cancer Center (MDACC), MPAL has traditionally been treated 
with AML induction regimens. It may be optimal to also administer agents that are 
predominantly used against ALL. Therefore, we are proposing to use a hybrid regimen, 
with components of both AML and ALL therapy, to treat patients diagnosed with MPAL 
at MDACC. The backbone of the regimen will be our standard induction for AML, 
clofarabine, idarubicin, and cytarabine administered at attenuated doses. Importantly, all 
three of these drugs also have activity against ALL. In addition, we will add vincristine 
and corticosteroids to the regimen for enhanced lymphoid activity. These are ideal 
candidates for addition to the regimen for a number of reasons. First, the toxicity profiles 
do not overlap, allowing us to safely give all five agents during the same course of 
therapy. Second, corticosteroids are routinely used as a premedication to prevent 
toxicity induced by moderate to high doses of cytarabine, albeit at lower doses.  


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III. Background Drug Information 
All drugs used in this protocol are available commercially 
A. Idarubicin: 
Idarubicin is commercially available. 
Mechanism of action: 
Similar to doxorubicin and daunorubicin; inhibition of DNA and RNA synthesis by 
intercalation between DNA base pairs. 
Adverse effects: 
 Cardiovascular: Transient EKG abnormalities (supraventricular tachycardia, S-T 
wave changes, atrial or ventricular extrasystoles); generally asymptomatic and self-
limiting. Congestive heart failure, dose-related. The relative cardiotoxicity of 
idarubicin compared to doxorubicin is unclear. Some investigators report no increase 
in cardiac toxicity at cumulative oral idarubicin doses up to 540 mg/m2; other reports 
suggest a maximum cumulative intravenous dose of 150 mg/m2. 
 Central nervous system: Headache 
 Dermatologic: Alopecia (25% to 30%), radiation recall, skin rash (11%), urticaria 
 Gastrointestinal: Nausea, vomiting (30% to 60%); diarrhea (9% to 22%); stomatitis 
(11%); GI hemorrhage (30%) 
 Genitourinary: Discoloration of urine (darker yellow) 
 


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B. Cytarabine 
Cytarabine is commercially available. 
Mechanism of action: 
Cytarabine is an antimetabolite. Cytarabine is cell cycle–specific for the S phase of cell 
division. Activity occurs as the result of activation to cytarabine triphosphate in the 
tissues and includes inhibition of DNA polymerase and incorporation of cytarabine into 
DNA and RNA. 
Adverse effects: 
COMMON 
• Cardiovascular: Thrombophlebitis 
• Dermatologic: Rash, conjunctivitis 
• Endocrine metabolic: Hyperuricemia 
• Gastrointestinal: Anal inflammation, Diarrhea, Loss of appetite, Nausea, Stomatitis, 
Ulcer of anus, Ulcer of mouth, Vomiting 
• Hematologic: Decreased reticulocyte count, Megaloblastic anemia 
• Hepatic: Decreased liver function 
• Other: Fever 
SERIOUS 
• Hematologic: Anemia, Bleeding, Leukopenia, Thrombocytopenia 


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• Immunologic: Anaphylaxis 
• Neurologic: Neuropathy 
• Renal: Kidney disease 
• Other: Infectious disease, Sepsis 
C. Clofarabine 
Clofarabine is commercially available. 
Mechanism of action: 
Clofarabine potently inhibits DNA synthesis by inhibiting both DNA polymerase and 
ribonucleotide reductase. Clofarabine demonstrated the ability to disrupt mitochondrial 
integrity that results in the release of pro-apoptotic proteins, cytochrome C and 
apoptosis-inducing factor.  
Adverse effects:  
 Hematologic: Myelosuppression, infections 
 Hepato and Gastrointestinal: Nausea/vomiting, diarrhea, mucositis, 
stomatitis/pharyngitis, hyperbilirubinemia, increase of SGPT and/or SGOT, 
abdominal pain or cramping, peritonitis, pancreatitis, liver failure 
 Dermatologic: Skin rash with blisters (particularly hand-foot syndrome), Steven-
Johnson's syndrome, alopecia, conjonctivitis 
 Systemic: Fatigue, asthenia, anorexia, lethargy, malaise, mental status 
changes/coma, alopecia  
 Allergic reactions: (including fever, muscle aches, edema, dyspnea)  
 Cardiology: Congestive heart failure  


Protocol 2013-0073 
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 Nephrology: Kidney failure  
 Autoimmune reactions:  (antiplatelet antibodies, erythema nodosum) and/or 
chemical imbalances in the blood. 
 
D. Vincristine 
Vincristine is commercially available 
Mechanism of Action 
Binds to tubulin and inhibits microtubule formation; therefore arresting the cell at 
metaphase by disrupting the formation of the mitotic spindle. It is specific for the S and 
M phases of the cell cycle.  
Adverse Effects 
 Peripheral neuropathy 
 Constipation 
 Ileus 
 Loss of deep tendon relexes 
 Wrist and foot drop 
 Hyponatremia 
 Convulsions (rare) 
 Severe soft tissue damage if extravasated 
 Alopecia 
 Paresthesia  
 
E. Dexamethasone and Prednisone 
Dexamethasone and prednisone are commercially available 
 


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Mechanism of action 
Decreases inflammation by suppression of neutrophil migration. In leukemia cells, 
induces cell cycle arrest and apoptosis.  
Adverse Effects 
 Salt or fluid retention 
 Hypertension 
 Muscle weakness or loss of muscle mass 
 Osteoporosis 
 Aseptic necrosis of the heads of femur or humerus 
 Peptic Ulcer  
 Pancreatitis 
 Skin fragility 
 Acute psychosis (rare) 
 Elevated blood sugar 
 Increased intraocular pressure 
 
F. Methotrexate 
Methotrexate is commercially available 
Mechanism of Action 
Methotrexate is a folate antimetabolite that inhibits DNA synthesis. Methotrexate 
irreversibly binds to dihydrofolate reductase, inhibiting the formation of reduced folates, 
and thymidylate synthetase, resulting in inhibition of purine synthesis.  
Adverse Effects 
 Myelosuppression 
 Anorexia 


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 Mucositis 
 Alopecia 
 Rash 
 Photosensitivity 
 Infertility 
 Interstitial pneumonitis 
 Renal failure 
 Hepatic dysfunction 
 Leukoencephalopathy 
 Menstrual dysfunction 
 
G. 6-Mercaptopurine 
6-Mercaptopurine is commercially available 
Mechanism of Action 
Purine antagonist which inhibits DNA and RNA synthesis; acts as false metabolite and 
is incorporated into DNA and RNA, eventually inhibiting their synthesis.  
Adverse Effects 
 Myelosuppression 
 Liver failure 
 Diarrhea 
 Rash 
 Nausea and vomiting 
 
H. Rituximab 
Rituximab is commercially available 
 


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Mechanism of Action 
Rituximab is a monoclonal antibody that binds to the CD20 cell surface antigen. Binding 
of rituximab leads to antibody-dependent cellular cytotoxicity as well as complement 
mediated cytotoxicity. 
Adverse Effects 
 Infusion reactions (fever, chills, rigors, hypotension, tachycardia, shortness of 
breath) 
 Reactivation of hepatitis B 
 Dermatologic reactions 
 Lymphopenia  
 
IV. Eligibility Criteria 
Inclusion Criteria 
1. Sign an informed consent document  
2. Age 18 >/= 18 
3. Newly diagnosed or relapsed MPAL, which for this protocol, will be defined as 
follows: 
-Bone marrow result interpreted by the reading Pathologist  (or tissue biopsy for cases 
of extramedullary disease) as: biphenotypic leukemia, bilineal leukemia, undifferentiated 
leukemia, mixed lineage leukemia, leukemia of ambiguous lineage, T/Myeloid leukemia, 
B/Myeloid leukemia, or other diagnosis indicating the presence of multiple lineages 
within the cell population.  
Or 


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-Immunophenotype consistent with WHO definition of MPAL 
4. ECOG Performance Status of < 3 at study entry. 
5. Adequate organ function as outlined below (unless due to leukemia) 
 Serum creatinine < 3 mg/dL 
 Total bilirubin < 2.5 mg/dL 
 ALT (SGPT) and/or AST (SGOT) < 3 x ULN or < 5 x ULN if related to disease 
6. Women of childbearing potential must have a negative serum or urine pregnancy test 
within 7 days. Women of childbearing potential and men must agree to use 
contraception at study entry and for the duration of active study treatment. 
7. Cardiac ejection fraction ≥ 40% (by either cardiac echo or MUGA scan). 
Documentation of recent (≤ 6 months from screening) outside reports is acceptable. 
8.  If newly diagnosed, prior therapy with hydrea and/or steroid and the use of a single 
or a two day dose of cytarabine (up to 3 g/m2), for emergency use up to 24 hours prior 
to start of study therapy is allowed.  
 
Exclusion Criteria 
1. Breast feeding females 
2. Patients with active, uncontrolled infections  
3. Patients with active secondary malignancy will not be eligible unless approved by 
the Principal Investigator. 
 
 


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V. Treatment Plan 
1. Study Design 
This will be a phase II, single center, open label trial to assess the safety and efficacy of 
the regimen outlined below. Patients will be eligible if they are newly diagnosed or with 
relapsed disease, though these groups will be analyzed separately. We anticipate 
enrolling 10 – 20 patients per year.  
 
All drugs will be given using commercial supply.  For patients over the age of 80 years, 
further dose decrease beyond what is stated below is allowed at the discretion of the 
treating physician and if felt in the best interest of the patient. 
2. Induction 
 Clofarabine 15 mg/m2 IV daily over approximately 60 minutes for 4 days on days 
1 – 4 (for 3 days on days 1-3 for patients 61 – 80 years of age or with 
performance status (PS) of 2 or 3) 
 Idarubicin 10 mg/m2 IV over approximately 30 – 60 minutes daily for 3 days on 
days 1 – 3 (for 2 days on days 1-2 for patients 61-80 years of age or with PS 2 or 
3) 
o To start 1 – 2 hours after the clofarabine  
 Cytarabine 1,000 mg/m2 IV over approximately 2 hours daily for 4 days on days 1 
– 4 (for 3 days on days 1-3 for patients 61 – 80 years of age or with PS 2 or 3) 
o To start 3 – 6 hours after the clofarabine 


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 Vincristine 2 mg (FLAT dose) IV over approximately 15 – 30 minutes on days 1, 
8, and 15 
 Dexamethasone 40 mg IV daily for 4 days on days 1 – 4 and days 15 – 18  
o May be given 30 – 60 minutes prior to each dose of cytarabine during 
induction on days 1 – 4 (if rituximab given, can administer dexamethasone 
prior to rituximab on day 1) 
For patients with CD20 positive disease (> 10% of the lymphoid population), rituximab 
may be added to the regimen as follows: 
 Rituximab 375 mg/m2 IV infused according to package labeling on days 1 and 8. 
o Rituximab will be infused according to the package insert. Premedications 
will be administered according to departmental standard/prescribing 
information to prevent infusion related reactions. 
The doses and schedule can be modified for the following situations: 
 For patients 61 – 80 years of age or with performance status of 2 or 3: give 
clofarabine and cytarabine for 3 days; give idarubicin for 2 days as mentioned 
above.  
 Further dose reductions or modifications can be considered after discussion with 
the PI and the discussion documented in the patient’s medical record 


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 All patients will receive at least one lumbar puncture during the first cycle of 
induction. This is for diagnosis as well as for the application of prophylactic 
intrathecal chemotherapy (methotrexate 12 mg or cytarabine 100 mg). 
 The standard for ALL patients is to administer 8 prophylactic intrathecal 
chemotherapy treatments during induction and consolidation. Methotrexate is 
alternated with cytarabine, and patients typically receive two treatments per cycle 
for the first four cycles.  
 For this protocol, giving more than one intrathecal treatment will be at the 
discretion of the managing physician. This degree of flexibility is warranted due to 
the heterogeneity of patients with MPAL. 
Patients, who have not achieved a complete remission (CR)/complete remission without 
platelet (CRi) recovery following one induction course can receive a second induction 
course to optimize response if possible. A second induction course at the same dose as 
the previous course or in a dose-reduced fashion should not be given until at least 28 
days of course 1. If the bone marrow aspirate and/or biopsy(s) performed after the re-
induction cycle reveals a remission marrow (CR/CRi), then the patient may proceed with 
consolidation at the discretion of the treating investigator. In addition, any clinically 
significant drug-related, non-hematologic toxicity experienced by a patient should return 
to ≤ grade 2 or the baseline grade before the patient continues treatment. Should the 
patient not have achieved a remission, including CR and CRi after the re-induction 
course, he/she will be taken off study for failure to respond, unless the patient has 


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achieved clinical benefit or partial remission, at which time further therapy on protocol 
may be permitted with approval from the PI. 
3. Consolidation 
Patients in CR or CRi can continue with up to 6 consolidation cycles. 
 Clofarabine 15 mg/m2 IV daily over approximately 60 minutes for  3 days on days 
1 – 3 (for 2 days on days 1-2 in patients 61 – 80 years of age or with PS 2 or 3) 
 Idarubicin 6 mg/m2 IV over 30 – 60 minutes daily for  2 days on days 1 – 2 (3 
mg/m2 for 2 days on days 1-2 in patients 61-80 years of age or with PS 2 or 3) 
o To start 1 – 2 hours after the clofarabine  
 Cytarabine 1,000 mg/m2 IV over approximately 2 hours daily for  3 days on days 
1 – 3 (for 2 days on days 1-2 in patients 61 – 80 years of age or with PS 2 or 3) 
o To start 3 – 6 hours after the clofarabine  
 Vincristine 2 mg (FLAT dose) IV over 15 – 30 minutes on days 1, 8, and 15 
 Dexamethasone 40 mg IV daily for 4 days on days 1 – 4 and days 15 – 18  
o May be given 30 – 60 minutes prior to each dose of cytarabine during 
consolidation on days 1 – 3 (if rituximab given, can administer 
dexamethasone prior to rituximab on day 1) 
For patients with CD20 positive disease (> 10% of the lymphoid population), rituximab 
may be added to the regimen as follows during consolidation cycles 1 – 3:  
 Rituximab 375 mg/m2 IV infused according to package labeling on days 1 and 8 


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o Rituximab will be infused according to the package insert. Premedications 
will be administered according to departmental standard/prescribing 
information to prevent infusion related reactions. 
The doses and schedule can be modified for the following situations: 
 For patients 61 – 80 years of age or with performance status of 2 or 3: give 
clofarabine and cytarabine for 2 days; give idarubicin 3 mg/m2 for 2 days as 
mentioned above.  
 Further dose reductions can be considered after discussion with the PI 
Cycles may be repeated every 3 to 10 weeks based on leukemia response and 
resolution of clinically significant drug-related toxicities. Prior to each consolidation 
cycle, the ANC should be > 1.0 x 109/L, and the platelet count should be > 60 x 109/L 
(except for patients who are considered to have achieved a CRp following induction/re-
induction and in whom the platelet count may be lower). Patients with borderline values 
for ANC and platelet count (value up to 10% lower than recommended) can still proceed 
with the next consolidation cycle if this is judged to be in the best interest of the patients 
and after discussion with the principal investigator and the discussion documented in 
the patient’s medical record. In addition, any clinically significant drug-related non-
hematologic toxicity experienced by the patient must return to < grade 2 before 
receiving the next cycle. Doses missed or held during a cycle of treatment will not be 
made up and are recorded as being omitted. If patients experience multiple study drug-


Protocol 2013-0073 
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related toxicities or experience significant infections, dose adjustments may need to be 
made based on the most severe toxicity and based on the drug causing the toxicity. 
4. Dose Modifications 
Drug doses in subsequent consolidation cycles may be modified for clinically significant 
drug-related > grade 2 non-hematologic toxicities. Dose reductions can also be made in 
other clinical situations where this step is considered to be in the best interest for the 
patient and after discussion with the principal investigator and the discussion 
documented in the patient’s medical record.  Doses of each individual drug can be 
modified if a toxicity is considered due this particular drug. 
The following are suggestions for dose modifications in subsequent treatment courses: 
 Persistent neutropenia (< 1,000) or thrombocytopenia (< 50,000) greater than 42 
days from previous cycle: reduce doses of clofarabine, cytarabine and idarubicin 
by 20 – 25% 
 Clinically significant peripheral neuropathy persisting for > 2 weeks:  
- 
50% reduction of vincristine (1 mg) for Grade 2 persistent 
neuropathy 
- 
Eliminate vincristine for Grade 3-4 neuropathy, seizures and Ileus 
suspected to be related to vincristine 
Organ specific dose adjustments: 


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Cytarabine 
Idarubicin 
Clofarabine 
Vincristine 
Serum Creatinine 
(mg/dL) 
 
2.1 – 3 
75% of current 
dose 
75% of current 
dose 
75% of current 
dose 
100% of current dose 
Above 3 
Discuss with PI 
Bilirubin (mg/dL) 
 
2 – 3 
100% of 
current dose 
75% of current 
dose 
100% of current 
dose 
50% of current dose or 
omit 
3.1 – 5 
100% of 
current dose 
50% of current 
dose 
Discuss with PI 
Omit 
Above 5 
100% of 
current dose 
Omit 
Discuss with PI 
Omit 
 
5. Targeted therapy 
Approximately a third of patients with AML may harbor activating FLT3-ITD mutations; 
such mutations are also observed in patients with biphenotypic or mixed lineage 
leukemias.  We have previously shown that combining sorafenib with chemotherapy in 
patients with FLT3-ITD mutations is both safe and efficacious. (Ravandi et. al. JCO 
2010). Therefore, patients with known FLT3-ITD mutations will be allowed to receive 
sorafenib therapy at a dose of 400mg orally twice daily on days 1-14 during induction 


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and then continuously for 28 days per cycle starting with cycle 2, at the discretion of the 
treating physician.  Dose adjustments and interruptions of the sorafenib are per 
standard of care and at the discretion of the treating physician. These agents will require a 
separate consent to be completed by the patient and physician. Suggested dose adjustments 
are in the table below. 
Recently, the phase III randomized double-blind RATIFY study was completed and 
reported for patients with FLT3 mutated AML (Stone RM, et al. NEJM 2017) .  717 
patients with FLT3 mutated AML were randomized to receive araC + daunorubicin with 
or without midostaurin.  Midostaurin led to a significant improvement in survival (median 
74.7 months for midostaurin vs. 25.6 for placebo; P=0.007).  Based on this study, 
midostaurin was approved for the treatment of patients with FLT3 mutated AML in 
combination with chemotherapy, the first combination to show a survival benefit in 
several decades.  This has now become part of the standard of care in the treatment of 
FLT3-mutated AML.  Midostaurin has the additional benefit of targeting not only FLT3-
ITD mutations, but also point mutations in the FLT3 kinase, such as D835 mutations.  
Therefore, AML patients with known FLT3-ITD or FLT3 kinase domain mutations will be 
allowed to receive midostaurin at the recommended dose of 50mg orally twice daily on 
days 6-19 during induction, and then on days 6-19 during consolidation.  Dose 
adjustments and interruptions of the midostaurin are per standard of care and at the 
discretion of the treating physician.  Suggested dose adjustments are in the table below. 
Suggested Sorafenib Dosing Adjustments 


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Dose Level 
Sorafenib Dose and Schedule 
0 
400 mg PO Twice Daily 
-1 
400 mg PO Once Daily 
-2 
200mg PO Once Daily 
-3 
200mg PO Once Every Other Day 
 
Suggested Midostaurin Dosing Adjustments 
Dose Level 
Midostaurin Dose and Schedule 
0 
50 mg PO Twice Daily 
-1 
50mg PO Once Daily 
-2 
50mg PO Every other Day 
 
Other FDA-approved FLT3 inhibitors or targeted therapies (e.g. IDH1 or IDH2 inhibitors) 
are allowed at the discretion of the treating physician and after discussion with the PI for 
patients harboring corresponding mutations. 
Patients with the presence of the Philadelphia chromosome [translocation (9;22)] or the 
presence of the bcr-abl fusion gene (detected by PCR or FISH) – such as those with 
CML myeloid blast phase or ‘Philadelphia-positive AML’ – may benefit from concomitant 
therapy with an abl tyrosine kinase inhibitor (TKI).  Several orally bioavailable TKIs have 
now been FDA approved for Philadelphia positive CML and their selection is based on 
patient tolerance, comorbidities, and abl kinase domain mutations.  Patients with bcr-abl 
positive disease may receive concomitant therapy with an approved TKI, dosed orally, 


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continuously starting on day 1.  The choice and dose will be per the discretion of the 
treating physician according to standard practice. 
 
 
6. Central Nervous System (CNS) Prophylaxis and Treatment 
All patients will receive at least one lumbar puncture during the first cycle of induction. 
This is for diagnosis as well as for the application of prophylactic intrathecal 
chemotherapy (methotrexate 12 mg or cytarabine 100 mg). 
The departmental standard of care for ALL patients is to administer 8 prophylactic 
intrathecal chemotherapy treatments during induction and consolidation. Methotrexate 
is alternated with cytarabine, and patients typically receive two treatments per cycle for 
the first four cycles.  
For this protocol, giving more than one intrathecal treatment will be at the discretion of 
the managing physician. This degree of flexibility is warranted due to the heterogeneity 
of patients with MPAL. This will allow patients with predominantly myeloid disease to be 
spared unnecessary discomfort and risks. Patients that have predominantly lymphoid 
disease or others determined to be at high risk for developing CNS disease can receive 
up to 8 prophylactic intrathecal treatments.  


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Patients who are diagnosed with CNS disease at any point (cytologically or 
radiographically) will be managed according to the departmental standard of care with 
intensive intrathecal chemotherapy treatment.  
7. Maintenance Therapy 
Maintenance or continuation chemotherapy for up to 3 years is the standard of care for 
ALL patients. Furthermore, one of the larger experiences in MPAL gave all patients 
continuation therapy for 2.5 years. Other series have not included maintenance therapy. 
Therefore, maintenance therapy after the completion of consolidation will be at the 
discretion of the managing physician. Targeted therapy will continue during 
maintenance per the managing physician. 
Maintenance can be given for up to 30 months as follows: 
 Vincristine 2 mg (FLAT dose) IV over 15 – 30 minutes once monthly 
 Prednisone 200 mg (FLAT dose) PO daily for 5 days every month 
 Methotrexate 20 mg/m2 PO given once weekly 
 6-Mercaptopurine 50 mg PO three times daily 
Doses can be adjusted as clinically warranted at the discretion of the managing 
physician. In every day clinical practice, doses of methotrexate and 6-mercaptopurine 
are reduced for myelo- or hepato-toxicity. Vincristine is dose-reduced or omitted for 
clinically significant peripheral neuropathy. Corticosteroids are dose-reduced or omitted 


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in patients with active infectious issues. All dose adjustments in maintenance will be 
captured by research personnel for analysis.  
8. Supportive care 
Supportive measures such as prophylaxis for tumor lysis syndrome, anti-emetics, 
erythropoietin, analgesics, blood transfusions, antimicrobials and hematopoietic colony 
stimulating factors for treatment of cytopenias are permitted. The administration of anti-
leukemia therapies is not permitted, except for hydroxyurea which is allowed for up to 7 
days per cycle during cycles 1 – 3. The use of up to two doses of cytarabine (up to 3 
g/m2) for emergency use up to 24 hours prior to start of study therapy is also permitted. 
As stated above, intrathecal chemotherapy is allowed for the prevention and treatment 
of CNS disease. 
Patients may be concurrently enrolling in supportive care clinical trials.  Other 
investigational agents that are used for treatment of other cancers will not be allowed.  
Every effort will be made to adhere to the schedule of events and all protocol 
requirements. Variations in schedule of events and other protocol requirements that do 
not affect the rights and safety of the patient will not be considered as deviations.  Such 
variations may include laboratory assessments completed outside of schedule, 
occasional missed required research samples such as PK or PD.  All dose adjustments 
will be made according to the protocol unless otherwise specified. 
VI. PRETREATMENT AND POST-TREATMENT EVALUATION 


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Induction Treatment (Pre-treatment)  
1. CBC, differential, and platelet count.  
2. Creatinine, bilirubin, ALT (SGPT) and/or AST (SGOT) 
3. Echocardiogram or MUGA to assess left ventricular ejection fraction 
4. Bone marrow aspirate and/or biopsy with cytogenetics (if bone marrow not done within 
30 days or cytogenetics within 90 days. For patients with evidence of leukemia in the 
peripheral blood, the bone marrow may be omitted after discussion and approval with 
the principal investigator.) 
5. Informed consent 
6. Physical exam including vital signs and performance status 
7. Concomitant medications and medical history 
8. Pregnancy test (serum or urine) 
 
 
 
 
Pretreatment Evaluation 
Procedure 
Comments 
Schedule 
Informed 
Consent 
Obtain standard informed consent approved by 
IRB 
Within 14 days of therapy 
Medical History 
History of present illness, known allergies, prior 
cancer history as far as traceable, and past 
medical/ surgical history as far as relevant. 
Within 14 days of therapy 
Physical 
Examination 
Vital signs (temperature, heart rate, respiratory 
rate, blood pressure) and performance status. 
Within 14 days of therapy 
Concomitant 
Medications 
Document concomitant medications 
Within 14 days of therapy 
Hematology 
CBC, differential, and platelet count (the 
differential may be omitted when the  
WBC is < 500 
Within 14 days of therapy 
 


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Procedure 
Comments 
Schedule 
Biochemistry 
Creatinine, total bilirubin,  
ALT (SGPT) and/or AST (SGOT) 
Within 14 days of therapy 
 
Bone marrow 
Aspirate and/or biopsy 
To confirm complete remission  
 
Cytogenetics 
 
Within 30 days of therapy 
 
 
Within 90 days of therapy 
Echo or Muga 
Assessment of left ventricular ejection fraction 
Within 14 days 
Pregnancy test 
Serum or urine, if female and of child-bearing 
potential only 
Within 7 days of therapy 
 
During induction therapy 
1. CBC, differential, and platelet count every 3-7 days (the differential may be omitted when 
the WBC is < 500.). Creatinine, bilirubin, ALT (SGPT) and/or AST (SGOT) once weekly.  
2. Physical exam including vital signs (temperature, heart rate, respiratory rate, blood 
pressure) and performance status. Prior to each treatment course 
 
3. Bone marrow aspirate and/or biopsy on day 28 +/- 7 days to confirm complete remission. 
Cytogenetics as clinically indicated.  
 
 
During induction therapy 
Procedure 
Comments 
Schedule 
Hematology 
CBC, differential and platelet count 
Every 3-7 days (the 
differential may be omitted 
when WBC is ≤500) 
 
Biochemistry 
Creatinine, bilirubin, ALT (SGPT) and/or 
AST (SGOT) 
Once weekly 
 
Physical 
Examination 
Physical exam including vital signs 
(temperature, heart rate, respiratory rate, blood 
pressure) and performance status. 
Prior to each treatment 
course 


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Bone marrow 
Aspirate and/or biopsy to confirm complete 
remission. Cytogenetics as clinically indicated. 
On day 28 +/- 7 days  
 
During Post-Remission Therapy (Maintenance and consolidation) 
1. Physical exam including vital signs prior to each treatment course 
2. CBC, differential, and platelet count prior to each post-CR course  
3. Creatinine and bilirubin prior to each post-CR course  
4. Bone marrow aspirates as indicated, cytogenetics as clinically indicated. 
 
Long-term Follow-up 
Patients will be followed periodically every 6 months (+/- 3 months) for survival 
via brief phone call, even after being taken off treatment.  This may be done over 
the phone with a member of the study staff.  The phone call should last about 10 
minutes. 
VII. STUDY END POINTS 
Primary: 
1. Response rate achieved with the chemotherapy regimen 
Secondary: 
1. Event free survival at 2 years (events defined as death and relapses) 
2. Overall survival 
3. Remission duration 
4. Predictive factors for response and outcome 
5. Safety profile 
 
VIII. CRITERIA FOR WITHDRAWAL 


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Reasons for withdrawal include: 
 Withdrawal of consent or the subject refuses to continue treatment and/or 
procedures/observations. 
 Relapse unless the treating physician determines that the patient has achieved 
clinical benefit, at which time further therapy on protocol may be permitted with 
approval from the PI.  
 Failure to achieve at least a CRi after 2 induction courses 
 
IX. CRITERIA FOR RESPONSE 
The response criteria recommended by the NCI and the MDS International Working 
Group. 
Definitions: 
Complete Response (CR): 
 Neutrophil count ≥ 1.0 ×109/L 
 Platelet count ≥ 100 ×109/L 
 Bone marrow aspirate < 5% blasts 
 No extramedullary leukemia 
CRi: 
 Response as in CR but platelets <100 ×109/L 
Partial response (PR): 


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 Neutrophil count ≥ 1.0 ×109/L 
 Platelet count ≥ 100 ×109/L 
 ≥ 50% reduction in bone marrow blasts over baseline 
 
Clinical benefit:  
In addition to IWG criteria, in AML, a decrease in bone marrow blasts to <5% will also 
be considered clinical benefit. 
Stable Disease:  
In addition to IWG criteria and in absence of any of the above response criteria, patients 
will be considered to have stable disease if the bone marrow blast percent does not 
increase compared to pretreatment level. 
Relapse: 
Increase of bone marrow blasts to > 10% after an initial response. 
 
X. REPORTING REQUIREMENTS 
All adverse and serious adverse events will be recorded and reported according to the 
Department of Leukemia guidelines (appendix C) 
 
 
XI. STATISTICAL CONSIDERATIONS 


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This is a Phase II study of clofarabine, idarubicin, cytarabine, vincristine, and 
corticosteroids for patients with newly diagnosed or relapsed/refractory mixed 
phenotype acute leukemia 
The primary objective is to evaluate the efficacy, with primary endpoint of response (CR 
or CRi) during a 2 month window.  The two groups of patients will be evaluated 
separately; however accrual to both groups will be concurrent. 
Part I: Newly diagnosed patients 
A maximum of 40 newly diagnosed will be enrolled. The toxicity, 4-week mortality rate, 
and efficacy (response) will be monitored during the study, and all the data will be used 
to update the prior distributions for toxicity and efficacy parameters. The study will be 
stopped for toxicity, 4-week mortality and futility based on the following stopping rules.   
1.1 Response 
The historical data suggested that the response rate in the standard treatment for the 
study patient is about 50%, it is anticipated that with the study treatment the response 
rate will increase to 70%.   
Response will be monitored closely in all patients using the method of Thall et al (20).  
The interim monitoring will begin after 10 patients have been enrolled to the study, and 
then by a cohort of 5 patients. Denote the probabilities of response for the standard 
treatment and this experimental study by PS  and PE, respectively  We assume PS ~ 
beta(50, 50) to reflect the historical response rate and PE ~ beta (1, 1), which have the 


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same response rate but a bigger various.  We will stop the trial if at any point Pr (PE > 
PS  + 0.2 | data) < 0.01. That is, we will stop the trial if, at any time during the study, we 
determine that there is less than 1% chance that the response rate in the study is 20% 
more than that of  the standard treatment. Stopping boundaries corresponding to this 
stopping rule and operating characteristics are listed in table 1a and 1b respectively. For 
example, if 3 or fewer patients have response in the first 10 patients, the trial will be 
stopped.   
If the study is not stopped early and all 40 patients have been enrolled to the study and 
evaluated, and assuming that 28 out of the 40 patients have response to the treatment, 
then the 95% credible interval for the response rate will be (0.54, 0.82). 
Table 1a: The trial will be monitored according to the following stopping 
boundaries for CR/CRi. 
Number of Patients 
Evaluated 
Recommend Stopping if  Response Observed 
in n or less patients 
10 
3 
15 
5 
20 
8 
25 
11 
30 
13 
35 
16 
 
Table 1b: Operating characteristics for response monitoring 


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True CR 
Probability 
Probability of 
Early Stop 
Achieved Sample Size 
Percentile (10 25 50 75 
90) 
0.3 
0.99 
10  10  10  15  20 
0.4 
0.861 
 10  10  20  25  40 
0.5 
0.487 
10  20  40  40  40  
0.6 
0.137 
25  40  40  40  40 
0.7 
0.018 
 40  40  40  40  40 
0.8 
0.0009 
 40  40  40  40  40 
0.9 
<0.0001 
40 40  40  40  40 
 
1.2 4-week mortality  
Mortality in the first 4 weeks will be monitored closely in patients using the method of 
Thall et al (1995). Denote the probability of death within 4 weeks by DE.  We assume DE 
~ beta (0.2, 1.8).  We will stop the trial if at any point Pr(DE > 0.1 | data)  >0.90. That is, 
we will stop the trial if, at any time during the study, we determine that there is more 
than 95% chance that the mortality rate is more than 10%.  The trial will be stopped if 
(the number of death in the 1st 4 weeks observed) / (among the number of patients) ≥ 
3/10, 4/12, 5/19, 6/26 and 7/33. The operating characteristics are listed in table 2. 
Table 2: The operating characteristics for mortality monitoring are summarized in 
the following table 
True probability of death  
Probability of 
early stop 
Sample size 
percentiles (10, 25, 
50, 75, 90) 
0.01 
<0.0001 
40  40  40  40  40 


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0.05 
0.027 
40  40  40  40  40 
0.1 
0.191 
16  40  40  40  40 
0.15 
0.509 
10  15  39  40  40 
0.2 
0.782 
10  10  17  37  40 
0.25 
0.924 
10 10  11  22  36 
 
1.3 Toxicity 
Toxicity will be monitored closely in all patients using the method of Thall et al (1995). 
Denote the probability of toxicity by E, where toxicity is defined as any Grade 3 or 
greater clinically significant non-hematological toxicities related to the treatment.  We 
assume E ~ beta (0.6, 1.4).  We will stop the trial if we  Pr(E > 0.30 | data)  >0.92. That 
is, we will stop the trial if, at any time during the study, we determine that there is more 
than 95% chance that the toxicity rate is more than 30%. Stopping boundaries 
corresponding to this stopping rule and operating characteristics are listed in table 3a 
and 3b respectively.  
 
Table 3a:  The trial will be stopped according to the following boundaries for 
toxicities 
Number of Patients Evaluated 
Recommend Stopping if  Toxicity Observed in 
n or more patients 
10 
6 
15 
8 


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20 
10 
25 
12 
30 
14 
35 
16 
 
Table 3b: The operating characteristics for toxicity monitoring are summarized in 
the following table 
True toxicity probability  Probability of early 
stop 
Sample size percentiles 
(10, 25, 50, 75, 90) 
0.1 
0.0001 
40  40  40  40  40 
0.2 
0.011 
40  40  40  40  40 
0.3 
0.112 
30  40  40  40  40 
0.4 
0.446 
10  15  40  40  40  
0.5 
0.833 
10  10  15  30  40 
0.6 
0.981 
 10  10  10  15  25 
 
Analysis Plan: 
For discrete or categorical data, descriptive statistics will include tabulations of 
frequencies.  For continuous data, summary statistics including n, mean, standard 
deviation, median, minimum and maximum will be computed.  The posterior response 
rate their 95% credible intervals will be estimated.   
Part II: Relapsed patients 


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Up to 20 relapsed/refractory patients who have no other treatment options will be 
enrolled in the study. The descriptive analysis will be used to summarize the response 
data, and the Kaplan-Meier method will be applied to estimate the median survival and 
1-year survival rate. The study will monitor the 4-week mortality and toxicity use the 
method of Thall et al (1995).   
2.1. 4-week mortality  
Mortality in the first 4 weeks will be monitored closely in patients using the method of 
Thall et al (1995).  Denote the probability of death within 4 weeks by DE.  We assume 
DE ~ beta (0.2, 1.8).  We will stop the trial if at any point Pr(DE > 0.1 | data)  >0.8. That 
is, we will stop the trial if, at any time during the study, we determine that there is more 
than 80% chance that the mortality rate is more than 10%.  The trial will be stopped if 
(the number of death in the 1st 4 weeks observed) / (among the number of patients) ≥ 
3/10, 4/17. The operating characteristics are listed in table 4. 
Table 4: The operating characteristics for mortality monitoring are summarized in 
the following table 
True probability of death  Probability of 
early stop 
Sample size percentiles (10, 25, 
50, 75, 90) 
0.01 
0.001 
20  20  20  20  20 
0.05 
0.045 
20  20  20  20  20 
0.1 
0.218 
12  20  20  20  20 
0.15 
0.453 
10  12  20  20  20 


Protocol 2013-0073 
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0.2 
0.67 
10  10  14  20  20 
0.25 
0.826 
10 10  11  15  20 
 
2.2 Toxicity 
Toxicity will be monitored closely in refractory/relapsed patients using the method of 
Thall et al (1995). Denote the probability of toxicity by E, where toxicity is defined as 
any clinically significant Grade 3 or greater toxicities related to the treatment.  We 
assume E ~ beta (0.6, 1.4).  We will stop the trail if we Pr(E > 0.30 | data)  >0.8. That 
is, we will stop the trial if, at any time during the study, we determine that there is more 
than 80% chance that the toxicity rate is more than 30%. The trial will be stopped if (the 
number of patients with toxicity observed) / (among the number of patients) ≥ 5/10, 
6/12, 7/15 and 8/18. The operating characteristics are listed in table 5. 
Table 5: The operating characteristics for toxicity monitoring are summarized in 
the following table 
True toxicity probability  
Probability of early stop 
Sample size percentiles 
(10, 25, 50, 75, 90) 
0.1 
0.002 
20  20  20  20  20 
0.2 
0.071 
20  20  20  20  20 
0.3 
0.315 
10  14  20  20  20 
0.4 
0.65 
10  10  13  20  20  
0.5 
0.888 
10  10  10  13  20 
 


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diagnosed acute myeloid leukemia. Blood (ASH Annual Meeting Abstracts) 
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