Clinical trial NCT02551718
Conditions: Recurrent Acute Leukemia of Ambiguous Lineage Recurrent Acute Lymphoblastic Leukemia Recurrent Acute Myeloid Leukemia Refractory Acute Lymphoblastic Leukemia Refractory Acute Myeloid Leukemia Refractory Acute Leukemia of Ambiguous Lineage
Sponsor: University of Washington
Start date: 2015-09-11; Completion date: 2021-05-13
Enrollment: 34 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This pilot clinical trial studies the feasibility of choosing treatment based on a high throughput ex vivo drug sensitivity assay in combination with mutation analysis for patients with acute leukemia that has returned after a period of improvement (relapsed) or does not respond to treatment (refractory). A high throughput screening assay tests many different drugs individually or in combination that kill leukemia cells in tiny chambers at the same time. High throughput drug sensitivity assay and mutation analysis may help guide the choice most effective for an individual's acute leukemia.

Detailed description:
PRIMARY OBJECTIVES:

I. To test patient cells in a high throughput assay against individual drugs and drug combinations within 21 days to enable optimal choice of drug combinations for therapy.

II. To test gene expression that reveals activation of druggable pathways or mutations in genes that confer susceptibility to specific agents may also be considered in choice of treatment.

SECONDARY OBJECTIVE:

I. To evaluate the response to the chosen therapy.

OUTLINE:

Leukemia cells obtained from blood or bone marrow are analyzed for sensitivity to both individual drugs and drug combinations via high throughput chemotherapy sensitivity assay and next generation sequencing assays. Doctors will then recommend chemotherapy regimens based on the results.

After completion of the chemotherapy regimen, patients are followed up at 2-4 weeks for response, and then every 3 months for 2 years for duration of response and survival.

Arms: arm 1: Leukemia cells purified from blood or bone marrow samples are analyzed for sensitivity to individual drugs and drug combination and by next generation sequencing.
Interventions: intervention 1: Chemosensitivity Assay intervention 2: Cytology Specimen Collection Procedure intervention 3: Gene Expression Analysis intervention 4: Genetic Variation Analysis intervention 5: In Vitro Sensitivity-Directed Chemotherapy
Intervention descriptions: intervention 1: Lab test in which leukemia cells obtained from blood or bone marrow are tested for sensitivity to 115 drugs individually and in certain combinations intervention 2: Undergo blood or bone marrow collection intervention 3: Analysis of leukemia cell genes to identify possible drug targets intervention 4: Analysis of leukemia cell genes to identify possible drug targets intervention 5: Receive personalized chemotherapy with one or more of the following drugs:

Afatinib Arsenic trioxide Axitinib Azacitidine Bexarotene Bortezomib Bosutinib Busulfan Cabazitaxel Cabozantinib Carfilzomib Ceritinib Cladribine Clofarabine Crizotinib Cytarabine HCl Dabrafenib Dasatinib Daunorubicin HCl Decitabine Erlotinib Etoposide Everolimus Fludarabine Gefitinib Gemcitabine HCl Hydroxyurea Imatinib Irinotecan Lapatinib Lomustine Melphalan Mercaptopurine Methotrexate Mitoxantrone Nelarabine Nilotinib Paclitaxel Pazopanib Pentostatin Ponatinib Pralatrexate Rapamycin Regorafenib Romidepsin Ruxolitinib Sorafenib Sunitinib Temsirolimus Thioguanine Topotecan HCl Trametinib Tretinoin

Protocol documents:
Prot_SAP_000.pdf: 
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Fred Hutchinson Cancer Research Center 
University of Washington 
Seattle Cancer Care Alliance 
Seattle Children’s 
Current Version: 07/14/2020, v 9.0 
Previous Version: 04/27/2020 
Individualized Treatment for Relapsed/Refractory Acute Leukemia Based on 
Chemosensitivity and Genomics/Gene Expression Data 
Principal Investigator: 
Mary-Elizabeth Percival 
University of Washington 
Assistant Professor of Medicine, UW 
Assistant Professor, Fred Hutchinson Cancer Research Center 
825 Eastlake Avenue East 
Campus Box CE3-300 
Seattle, WA 98109 
Tel:  206-606-1320 
Fax:  206.606.6984 
Email:  mperciva@seattlecca.org 
IRO REC'D 08/20/2020
FHCRC IRB Approval  
AUG 21 2020 
Document Released Date
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TABLE OF CONTENTS 
 
SECTION 
 
 
 
 
 
 
 
 
 
 
PAGE 
TABLE OF CONTENTS .................................................................................................................2 
1. Study Objective ............................................................................................................................4 
 
1.1 Primary Objective ..........................................................................................................4 
 
1.2 Secondary Objective ......................................................................................................4 
2. Background ..................................................................................................................................4 
3. Patient Eligibility .........................................................................................................................8 
 
3.1 Inclusion Criteria ...........................................................................................................8 
 
3.2 Exclusion Criteria ..........................................................................................................9 
4. Study Drug Information ...............................................................................................................9 
5. Pretreatment Evaluations ...........................................................................................................14 
 
5.1 Screening Evaluations / Procedures .............................................................................14 
6. Plan of Treatment .......................................................................................................................14 
 
6.1 Chemosensitivity Assay ……………………………………………………………..14 
 
6.2 Drug Choice …………………………………………………………………………14 
 
6.3 Drug Dosing …………………………………………………………………………15 
 
6.4 Consent for Individual Regimens …………………………………………………...15 
 
6.5 Duration of Therapy………………………………………………………………….15 
7. On Study Evaluations ................................................................................................................15 
8. Follow Up ..................................................................................................................................16 
9. Criteria for Response .................................................................................................................16 
 
9.1 Definition of Response ................................................................................................16 
 
9.2 Degree of Cytoreduction ..............................................................................................16 
 
9.3 Duration of Response  ..................................................................................................16 
10. Registration of Patients  ...........................................................................................................16 
11. Forms to be Kept ......................................................................................................................16 
12. Regulatory and Reporting Requirements .................................................................................16 
 
12.1 Adverse Event Monitoring and Reporting .................................................................16 
 
12.2 Serious Adverse Events .............................................................................................17 
 
12.3 Reporting Serious Adverse Events ............................................................................17 
13. Data and Safety Monitoring Plan .............................................................................................17 
 
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14. Statistical Considerations .........................................................................................................18 
 
14.1 Experimental Design ..................................................................................................18 
14.2 Stopping Rules ……………………………………………………………………..18 
15. References ................................................................................................................................19 
APPENDICES  
Appendix A – Performance Status Criteria ...................................................................................21 
Appendix B – Study Calendar .......................................................................................................22 
Appendix C – Response Criteria ....................................................................................................23 
Appendix D – Research Subject Registration Form ......................................................................24 
Appendix E – Drug Dosing and References……………………………………………………..25 
Protocol Eligibility Form ...............................................................................................................37 
FAX Cover Letter ..........................................................................................................................39 
 
 
 
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1. STUDY OBJECTIVE 
 
This study will utilize an in vitro high throughput chemosensitivity assay, mRNA expression 
microarray data, and patient mutational analysis, as available, to choose specific drugs or drug 
combinations for the treatment of patients with relapsed (2nd salvage or greater) or refractory (to 
at least 2 inductions) acute leukemias.   
  
1.1.The primary objective is to test patient cells in a high throughput assay against 
individual drugs and drug combinations within 21 days to enable optimal choice of 
drug combinations for therapy.  In addition, gene expression that reveals activation 
of druggable pathways or mutations in genes that confer susceptibility to specific 
agents may also be considered in choice of treatment.  
 
 1.2.The secondary objective is to evaluate the response to the chosen therapy. 
 
2. BACKGROUND 
 
Current approaches to acute leukemia result in complete remission for most children and the 
majority of adults. Approximately 50% to 70% of patients can achieve long-term disease control 
when undergoing transplantation in early phases of the disease (De Lima et al. 2004). However, 
despite a high rate of complete remission to induction chemotherapy, the majority of patients 
with acute leukemia will relapse. Even in acute lymphocytic leukemia (ALL), which is generally 
responsive to chemotherapy, nearly 10% to 30% of children are at risk for relapse (Tzortzatou-
Stathopoulou et al. 2001). It is generally believed that patients who undergo allogeneic 
hematopoietic cell transplant have a high likelihood of cure. However, those transplanted with 
detectable minimal residual disease (MRD) have a high risk of relapse after transplant. MRD 
tends to be proportional to risk of relapse (Campana, 2009).  In fact, most adults and some 
children will relapse with acute leukemia within 6 to 24 months. For patients diagnosed with 
acute myeloid leukemia (AML), the projected 5-year survival is only 25% (American Cancer 
Society, 2015). For patients who have failed multiple attempts at induction, or those who have 
failed 2 salvage regimens for relapsed AML, or those with initial remission duration of less than 
six months, the results of treatment are very poor (Estey et al. 1996). For patients with a first 
complete remission duration of less than 12 months or no initial CR, there was a 0% chance of 
achieving CR with second salvage induction. Consequently, for patients unable to achieve an 
initial remission, the 4-year survival rate is 23% (Othus et al. 2015). Even for patients being 
treated with a first salvage regimen, a poor risk group can be identified by criteria including 
relapse free interval, age at relapse, cytogenetics, and whether they had a prior stem cell 
transplant. These patients had a 12 month survival of only 16%, and a 5 year survival of 4% 
(Breems et al. 2005). There are numerous conventional and experimental chemotherapy 
regimens available for such patients, but with few exceptions, we cannot predict response. 
Furthermore, traditional regimens are known to fail in patients who have had two or more 
salvage regimens.  
This, in combination with the morbidity and mortality associated with side effects of 
chemotherapeutic agents, is why we pursued a prior feasibility trial utilizing a high throughput 
 
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chemosensitivity assay to guide individual drug selection for relapsed/refractory acute myeloid 
leukemia. Entitled “Treatment for Relapsed AML Based on a High Throughput Drug Sensitivity 
Assay” (NCT # 01872819), this trial finished patient accrual in October 2015. 
The in vitro high throughput drug sensitivity assay used in this initial trial was comprised of both 
investigational drugs and FDA approved drugs. This assay is CLIA-certified for patient 
diagnostic purposes and testing was performed in the Quellos High Throughput Core Facility, 
University of Washington Medicine, Seattle WA.  Thus far, we have tested a total of 46 AML 
patient blood samples (30 preclinical and 16 on the prior trial) enriched for blasts to exceed 80-
90%, using magnetic bead isolation methods when needed.  Two 384-well plates accommodate 
testing of 80 drugs at 8 concentrations each plus controls.  Cells were added to matrix protein 
coated non-tissue culture-treated 384-well plates at a density of 5,000 cells per well in 50µL of 
complete media (containing pen/strep and 10mM HEPES buffer) using a Thermo Scientific 
Matrix WellMate, and incubated overnight to allow adhesion.  Compounds (50nL) were added 
(ranging from 5 pM to 100 µM) to patient samples using the CyBio CyBi-Well Vario and 
incubated at 37°C, 5% CO2 for 96 hours.  The final solvent concentration, (DMSO) in the assay 
was 0.1%.  CellTiter-Glo (Promega) was dispensed into the individual wells with the WellMate 
following the manufacturer’s recommended procedures and, following 20 minutes incubation on 
an orbital shaker, luminescence was measured on a Perkin Elmer EnVision Multi-label plate 
reader to assess viable cells.  Measurements were corrected for background luminescence and 
percentage cell viability is reported as relative to the DMSO solvent control. IC50 values were 
calculated by fitting data using least squares method to the standard four-parameter logistic 
model where: 
“Y” = (“Ymin”+(“Ymax”/(1+((“X”/”IC50”)Slope), and Y = % viability, Ymin = minimal % viability, 
Ymax = maximal % viability, X = compound concentration, IC50 = concentration of compound 
exhibiting 50% inhibition of cellular viability, Slope = the slope of the resultant curve.  Curve 
fitting was performed using idbs XLFit software (Microsoft Excel). 
The novel aspect of the assay is that the cell survival is measured on a substratum to which the 
cells are adherent, a property which confers drug resistance for all hematologic malignancies. 
Recent studies (McMillin et al. 2010 and Straussman et al. 2012) demonstrate the importance of 
the microenvironment in drug sensitivity testing.  Our adherence strategy, although it does not 
substitute for microenvironment, is a component previously demonstrated sufficient to reproduce 
drug resistance in AML (Becker et al. 2009).    
Preliminary testing of 46 patients’ leukemic blasts confirmed that each patient’s cancer has 
unique in vitro chemotherapeutic susceptibility (Figure 1). By comparing the EC50 of each drug 
across all 46 patients, we are able to discern an individual patient’s relative in vitro susceptibility 
to any given drug.  
 
 
 
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Figure 1. In-vitro high throughput sensitivity data for 0.3 micromolar drug concentration for 24 
patients and 160 drugs. Red = cell death, Green = cell survival. Hierarchical clustering is shown 
for patients and drugs. Note that each patient exhibits a unique pattern of drug susceptibility.  
 
Fifteen patients were enrolled in the initial feasibility study. Individual drugs were chosen on the 
basis of EC50 and drug availability, and patients received the single agents at the accepted 
maximal tolerated dose. Within an average of 11.6 (median 9, range 4-28) days, 13 patients 
received single drugs to which their cells appeared to be sensitive with an EC50 range of 0.026-
0.175umol/L, including cladrabine, mitoxantrone, bortezomib or vinblastine. All patients 
exhibited a decline in blast number after receipt of the indicated drug, on average, by 92.6% 
(range 80.5-99.8%) (Figure 2). One patient achieved CR and 2 patients achieved partial complete 
remission (Becker et al. 2014).  
 
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Figure 2. Peripheral blast counts following drug sensitivity guided therapy in 11 of our initial 13 
AML patients who had circulating blasts. Patients received a single drug at time points indicated 
by arrows. 
 
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Other groups have used similar assay based approaches to profile in vitro chemosensitivity of an 
individual patient’s AML blasts to traditional chemotherapy (Bennett et al. 2014). In vitro 
chemosensitivity assays may also be useful for estimating a novel agent’s utility in AML. 
Pemovska et al (2013) identified targeted agents both investigational and approved for other 
indications that exhibited significant cytotoxicity in an in-vitro assay. Several of these agents (ex 
dasatinib, sunitinib and temsirolimus) were employed in assay-guided treatment resulting in brief 
but marked reduction in leukemic burden. Recognizing the inherent limitations of in vitro 
testing, two separate groups have developed systems to perform sensitivity testing of several 
chemotherapeutic agents simultaneously within living solid tumors (Klinghoffer et al. 2015; 
Jonas et al. 2015). 
The incorporation of mutational analysis and gene expression data in the choice of chemotherapy 
has the potential to further refine the approach. Specific mutations in genes implicated in AML 
can determine responsiveness to certain therapeutic agents.  For example, prior studies 
demonstrated that tyrosine kinase domain (TKD) mutations found in the FLT3 gene confer 
chemotherapy resistance to some FLT-3 inhibitors such as sorafenib, but not to others such as 
crenolanib (Zimmerman et al. 2013; Zhang et al 2014).  
Our group is currently analyzing our own in vitro assay data for correlations between gene 
expression and in vitro drug sensitivity. To this end, we developed a novel computational 
method, named SPARROW, to reduce the dimensionality of gene expression data by identifying 
genes that represent important molecular events in publicly available AML expression data 
(Logsdon et al. 2015). In particular, it aims to identify hub regulators whose expression levels 
are predictive of many downstream gene expression levels. We have found that high expression 
of several hub regulators correlates well with increased sensitivity to certain classes of drugs. As 
would be expected, high expression of FLT3 was associated with increased sensitivity to FLT3 
inhibitors sunitinib, AP24534 and tandutinib. High expression of SMARCA4 and TRF2 were both 
associated with increased sensitivity to topoisomerase inhibitors daunorubicin, mitaxantrone, 
etopsoside and topotecan. (Lee et al. 2014). 
We now propose a second assay-directed therapy trial in adult and pediatric refractory acute 
leukemia that will utilize drug combinations and incorporate genetic information in the choice of 
drugs. 
 
3. PATIENT ELIGIBILITY 
 
  
3.1. Inclusion Criteria 
(1) Diagnosis of acute leukemia by WHO criteria (e.g.-acute myeloid leukemia, acute 
lymphoblastic leukemia, acute leukemia of ambiguous origin). 
(2) Either:  
a)  relapsed after or refractory to prior treatment with at least two regimens or 
lines of treatment;. 
b)  prior failure of at least one regimen or line of treatment, with poor cytogenetic 
or other risk factors, and ineligible for other clinical trials. 
 
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(3) Age  ≥ 3 years old 
(4) ECOG Performance Status 0 – 3. 
(5) Expectation that we can obtain about 10 million blasts from blood and/or marrow 
(e.g., circulating blast count of 5,000 or greater or cellular marrow with greater than or 
equal to 20% blasts).  
(6) Adequate renal and hepatic function as defined below (or more stringent, depending 
on the individual drugs). 
• Bilirubin ≤ 1 .5 x Upper Limit of Normal (ULN) unless elevation is thought to 
be due to Gilbert’s syndrome, hemolysis, or hepatic infiltration by the 
hematologic malignancy.  
• SGOT (AST) and SPGT (ALT) ≤  2.5 x ULN, unless elevation is thought to be 
due to hepatic infiltration by the hematologic malignancy, 
• Alkaline Phosphatase ≤ 2.5 X ULN, unless elevation is thought to be due to 
hepatic infiltration by the hematologic malignancy 
• Serum creatinine ≤ 2.0 mg/dL 
 
 
(7) Informed consent. 
(8) Willing to use contraception when appropriate. 
(9)   Expected survival is greater than 100 days. 
 
3.2. Exclusion Criteria 
(1) No other active cancer that requires systemic chemotherapy or radiation. 
(2) Active systemic fungal, bacterial, viral or other infection, unless disease is under 
treatment with antimicrobials and considered controlled in the opinion of the investigator.  
(3) Significant organ compromise that will increase risk of toxicity or mortality. 
(4) Pregnancy or lactation. 
4. STUDY DRUG INFORMATION 
 
Our original drug sensitivity assay included 115 investigational drugs and 45 FDA approved 
drugs. Approximately 60 of these exhibited activity against at least half the 46 patient samples 
tested to date. The second-generation assay includes 77 investigational drugs and 70 FDA 
approved drugs. The latter FDA approved drugs are approved for oncologic indications though 
not necessarily acute leukemia. Several of these drugs are tested in combination mirroring 
frequently used anti-leukemic regimens. Table 1 is a list of the drugs included in the 147-drug 
panel and their mechanisms of action. If mutational analysis reveals an aberrant pathway for 
which there is an available targeted inhibitor, such a drug will be added to the assay if it can be 
obtained. 
Table 1. The 70 FDA approved and 77 investigational agents and their mechanisms of 
action comprising the second generation drug sensitivity assay. 
Drug 
Mechanism of Action 
Panel 
 
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Acrichine 
Suppresses NF-kB pathway and activates p53 pathway 
FDA Approved 
Afatinib 
Inhibitor of epidermal growth factor receptors 1 (ErbB1; EGFR), 
2 (ErbB2; HER2), and 4 (ErbB4; HER4), and certain EGFR 
mutants 
FDA Approved 
Arsenic trioxide 
Degrades aberrant PML-retinoic acid receptor α fusion protein 
FDA Approved 
Axitinib 
VEGF and PDGF receptor inhibitor  
FDA Approved 
Azacitidine 
Inhibits DNA methyltransferase and tRNA cytosine-5-
methyltransferase 
FDA Approved 
Belinostat 
Histone deacetylase inhibitor 
FDA Approved 
Bexarotene 
Activates retinoid X receptors  
FDA Approved 
Bortezomib 
Reversibly inhibits 26S proteosome  
FDA Approved 
Bosutinib 
Dual kinase inhibitor of both Abl and Src kinases 
FDA Approved 
Busulfan 
Cross-links A-G and G-G 
FDA Approved 
Cabazitaxel 
Inhibits microtubule depolymerization 
FDA Approved 
Cabozantinib 
Inhibits MET, RET, VEGF, FLT3, KIT, TRKB and other tyrosine 
kinase associated receptors 
FDA Approved 
Carfilzomib 
Inhibits 20S proteosome  
FDA Approved 
Ceritinib 
Inhibitor of ALK 
FDA Approved 
Cladribine 
Purine nucleoside antimetabolite  
FDA Approved 
Clofarabine 
Purine nucleoside analog that inhibits ribonucleotide reductase 
and DNA polymerase 
FDA Approved 
Crizotinib 
Inhibitor of ALK 
FDA Approved 
Cytarabine HCl 
Antimetabolite analog that competes with cytidine for 
incorporation into DNA and inhibits DNA replication in S phase 
FDA Approved 
Dabrafenib 
inhibitor of BRAF 
FDA Approved 
Dasatinib 
Inhibitor of SRC-family protein-tyrosine kinases 
FDA Approved 
Daunorubicin HCl 
Inhibits DNA replication through topoisomerase-mediated 
action 
FDA Approved 
Decitabine 
Inhibits DNA methyltransferase  
FDA Approved 
Erlotinib 
Inhibits EGFR 
FDA Approved 
Etoposide 
Inhibits topoisomerase II 
FDA Approved 
Everolimus 
Binds FKBP-12, which binds and inhibits mTOR 
FDA Approved 
Fludarabine 
Inhibits DNA Polymerase alpha, ribonucleotide reductase, and 
DNA Primase 
FDA Approved 
Gefitinib 
Inhibits EGFR and other TKIs 
FDA Approved 
Gemcitabine HCl 
Converted to dFdCDP, which inhibits ribonucleotide reductase 
FDA Approved 
Hydroxyurea 
Inhibits ribonucleotide diphosphate reductase 
FDA Approved 
Ibrutinib 
Bruton's tyrosine kinase inhibitor 
FDA Approved 
Idarubicin 
Inhibits DNA replication through topoisomerase-mediated 
action 
FDA Approved 
Imatinib 
Inhibits TKs encoded by bcr-abl, PDGFR, and c-kit genes 
FDA Approved 
Irinotecan 
Inhibits topoisomerase I 
FDA Approved 
Lapatinib 
Blocks phosphorylation of EGFR, Erb82, Erk, and AKT 
FDA Approved 
 
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Lomustine 
Cross-links and carbamoylates DNA 
FDA Approved 
Lenalidomide 
Promotes G0-G1 cell cyle arrest 
FDA Approved 
Melphalan 
Alkylates DNA at N7 of guanine and induces interstrand cross-
links 
FDA Approved 
Mercaptopurine 
Inhibits nucleotide interconversion and de novo purine 
synthesis 
FDA Approved 
Methotrexate 
Inhibits dihydrofolate reductase  
FDA Approved 
Mitoxantrone 
Intercalates into DNA and induces cross-linking 
FDA Approved 
Nelarabine 
Converted to ara-G and inhibits DNA synthesis at S phase 
FDA Approved 
Nilotinib 
Inhibits Bcr-abl, PDGFR, and c-kit 
FDA Approved 
Olaparib 
PARP inhibitor 
FDA Approved 
Omacetaxine 
Binds 80S ribosome and inhibits protein synthesis 
FDA Approved 
Paclitaxel 
inhibits disassembly of microtubules 
FDA Approved 
Palbociclib 
CDK4 and 6 inhibitor 
FDA Approved 
Panobinostat 
HDAC inhibitor 
FDA Approved 
Pazopanib 
Inhibits VEGFR-1,2,3, c-kit, and PDGFR 
FDA Approved 
Pemetrexed 
Inhibits thymidylate synthase 
FDA Approved 
Pentostatin 
Inhibits adenine deaminase 
FDA Approved 
Pomalidomide 
Promotes G0-G1 cell cyle arrest 
FDA Approved 
Ponatinib 
Previously called AP24534:  Inhibits Bcr-abl, FLT3, VEGFR, FGFR 
FDA Approved 
Pralatrexate 
Inhibits dihydrofolate reductase  
FDA Approved 
Rapamycin 
Binds FKBP-12, which binds and inhibits mTOR 
FDA Approved 
Regorafenib 
Inhibits VEGFR-2 &3, Ret, Kit, Raf, and PDGFR 
FDA Approved 
Romidepsin 
Inhibits HDAC and depletes Hsp90 dependent oncoproteins 
FDA Approved 
Ruxolitinib 
Inhibits JAK 1 and 2, VEGFR and EGFR 
FDA Approved 
Selumetinib 
Inhibitor of MEK MAPK/ERK Kinase 
FDA Approved 
Sorafenib 
Inhibits Raf kinase, VEGFR, and PDGFR; BRAF and MAP Kinase 
pathway 
FDA Approved 
Sunitinib 
Inhibits VEGFR, PDGFRb, and c-kit; disrupts microtubules and 
glutamic acid metabolism 
FDA Approved 
Temsirolimus 
Inhibits mTOR, tubulin polymerization and Hedgehog ligand 
surface receptors PCTH and SMO 
FDA Approved 
Thioguanine 
Inhibits DNA and RNA synthesis by incorporating into DNA and 
RNA, HDAC inhibitor 
FDA Approved 
Topotecan HCl 
Inhibits relegation of topoisomerase I mediated single strand 
DNA breaks 
FDA Approved 
Trametinib 
Inhibitor of MEK MAPK/ERK Kinase 
FDA Approved 
Tretinoin 
Activates retinoid receptors and also inhibits telomerase 
FDA Approved 
Vandetanib 
Inhibits EGFR and VEGFR 
FDA Approved 
Vinblastine 
Causes metaphase cell cycle arrest via microtubule assembly 
inhibition 
FDA Approved 
Vincristine 
Causes metaphase cell cycle arrest via microtubule assembly 
inhibition 
FDA Approved 
 
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Vinorelbine 
Causes metaphase cell cycle arrest via microtubule assembly 
inhibition 
FDA Approved 
Vorinostat 
HDAC inhibitor 
FDA Approved 
Alisertib 
Aurora A kinase inhibitor 
Investigational 
AMG232 
MDM2 inhibitor (p53) 
Investigational 
AMG900 
Pan-aurora kinase inhibitor 
Investigational 
AT-7519 
Inhibits CDK 
Investigational 
AT9283 
Inhibits Aurora kinases A & B, JAK2, and bcr-abl 
Investigational 
Avagacestat 
Gamma secretase inhibitor 
Investigational 
AZD-7762 
Inhibits checkpoint kinases 
Investigational 
AZD-8055 
mTOR inhibitor 
Investigational 
AZD-8330 
MEK1 and 2 inhibitor 
Investigational 
BAY 11-7082  
IKK inhibitor 
Investigational 
BAY 11-7085  
IkBa inhibitor 
Investigational 
Birinapant 
IAP inhibitor 
Investigational 
Buparlisib 
PI3K inhibitor 
Investigational 
BMS-754807 
Inhibits IGF-1R and InsR tyrosine kinases 
Investigational 
Cediranib 
Inhibits VEGFR 1,2,3 
Investigational 
Crenolanib 
PDGFR inhibitor 
Investigational 
Dactolisib  
PI3K and mTOR inhibitor 
Investigational 
Dinaciclib 
CDK inhibitor 
Investigational 
DMH1 
BMP inhibitor 
Investigational 
Doramapimod 
Pan-p38 MAPK inhibtor 
Investigational 
Dorsomorphin 
BMP inhibitor 
Investigational 
Dovitinib 
VEGFR, FGFR inhibitor 
Investigational 
Entinostat 
HDAC inhibitor 
Investigational 
EPZ-5676 
DOT1L inhibitor 
Investigational 
Flavopiridol 
CDK inhibitor 
Investigational 
Ganetespib 
Hsp90 inhibitor 
Investigational 
GDC-0152 
IAP inhibitor 
Investigational 
Gedatolisib 
Dual PI3K/mTOR inhibitor 
Investigational 
Gliteritinib 
Inhibits FLT3, AXL, ALK 
Investigational 
GSK1210151A 
bromodomain BET inhibitor 
Investigational 
I-BET762 
bromodomain BET inhibitor 
Investigational 
Idelalisib 
PI3K inhibitor 
Investigational 
Iniparib 
PARP inhibitor 
Investigational 
KPT-185 
CRM1 inhibitor 
Investigational 
Lenvantinib 
VEFGR2 tyrosine kinase inhibitor 
Investigational 
Lisitinib 
IGF-1R inhibitor 
Investigational 
Luminespib 
Hsp90 inhibitor 
Investigational 
Masitinib 
Inhibits c-Kit, FGFR3, FAK, and PDGFR 
Investigational 
MG-132 
Proteosome inhibitor 
Investigational 
 
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Midostaurin 
PKC inhibitor 
Investigational 
MK-1775 
WEE1 tyrosine kinase inhibitor 
Investigational 
MK2206 
Akt inhibitor 
Investigational 
Mocetinostat 
HDAC inhibitor 
Investigational 
Nintedanib 
Inhibits Src, VEGFR, PDGFR, FGFR 
Investigational 
NVP-BGJ398 
FGFR inhibitor 
Investigational 
NVP-BYL719 
PI3k inhibitor 
Investigational 
Obatoclax 
Bcl-2 inhibitor 
Investigational 
Otava 
7070707035 
CDK4 inhibitor 
Investigational 
OTX015 
BRD 2,3,4 inhibitor 
Investigational 
Pacritinib 
Dual jak2/flt3 inhibitor 
Investigational 
Panobinostat 
HDAC inhibitor 
Investigational 
PD-0325901  
MEK inhibitor 
Investigational 
PF-04691502 
PI3K and mTOR inhibitor 
Investigational 
PFI-1 
Bromodomain BET inhibitor 
Investigational 
Pictilisib  
PI3K inhibitor 
Investigational 
Pimasertib 
Inhibits MEK1 and 2 (AS703026) 
Investigational 
Pexidartinib 
KIT, CSF1R, FLT3 inhibitor 
Investigational 
PLX-4720 
BRAF V600E inhibitor 
Investigational 
Pp242 
mTOR/C1/C2 inhibitor 
Investigational 
Quizartinib 
FLT3 inhibitor 
Investigational 
Rigosertib 
Plk-1 inhibitor 
Investigational 
SB 218078 
ATP-competitive inhibitor of Chk1 
Investigational 
Selinexor 
CRM1 inhibitor 
Investigational 
SGI-1776 
PIM kinase inhibitor 
Investigational 
SNS-032 
Multiple CDK, GSK-3 inhibitor 
Investigational 
Sonidegib 
SMO inhibitor 
Investigational 
Staurosporine 
Multiple kinases 
Investigational 
Tanespimycin 
HSP90 inhibitor 
Investigational 
Tepotinib 
MET tyrosine kinase inhibitor 
Investigational 
Tipifarnib 
Farnesyl transferase inhibitor 
Investigational 
Tivantinib 
Inhibits c-Met 
Investigational 
Tosedostat 
Aminopeptidase inhibitor 
Investigational 
Tozasertib 
Aurora A, B, C, Flt3, Abl 
Investigational 
Vemurafenib 
BRAF V600E inhibitor 
Investigational 
Venetoclax 
Bcl-2 inhibitor 
Investigational 
Vismodegib 
PTCH and SMO inhibitor 
Investigational 
Volasertib 
PLK 1, 2, 3 inhibitor 
Investigational 
YM-155 
Survivin inhibitor 
Investigational 
 
 
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5. PRETREATMENT EVALUATION 
 
5.1. Screening Evaluations/Procedures 
1. 
Signed, written informed consent: Consent must be completed prior to performing 
any study-related procedures.  
2. 
The following standard of care evaluations, if done, may be reviewed within the 
electronic medical record to assist with determining eligibility for the study, unless 
required per the inclusion/exclusion criteria: 
a.      Medical history: Detailed documentation of disease and treatment history with    
outcomes 
b.     ECOG performance status (Appendix A)  
c.      Concurrent medical conditions.   
d.     Serum chemistries: Electrolytes (sodium, potassium, chloride, and bicarbonate), 
blood urea nitrogen (BUN), creatinine, glucose, and liver function tests (aspartate 
aminotransferase (AST) and/or alanine aminotransferase (ALT), alkaline phosphatase 
(ALP), total bilirubin 
e.      Initial standard of care diagnostic bone marrow reports, may include 
hematopathology, cytogenetics / FISH, flow cytometry and mutation status. 
f. MUGA scan may be performed prior to treatment for participants receiving 
anthracycline therapy 
 
6. PLAN OF TREATMENT  
6.1. Chemosensitivity Assay 
A blood sample of 25 cc in sodium heparin will be sent to the research laboratory for 
testing in the high throughput assay, and results will be available in about a week. For 
patients with less than an absolute blast count in the peripheral blood of 5.0 X 109/L, a 
bone marrow sample of 10 cc will be sent. If this aspirate contains an inadequate number 
of blasts, another bone marrow aspirate may be obtained with patient approval.  
Investigator discretion will be used for analyzing the adequacy of the cell counts .  Gene 
expression data will be obtained via methods described elsewhere (Logsdon et al. 2015). 
Mutational analysis will be performed with the MyAMLTM, CLIA validated next 
generation sequencing assay, which screens for mutations in 196 genes associated with 
AML. (www.genection.com/myaml.html).  
1. Treatment with any chemotherapeutic agent necessary to control leukemic 
burden is permitted during the time of testing and drug procurement. These 
agents must be stopped prior to initiation of assay-guided therapy.  
2. If leukemia is present in a location other than the blood or bone marrow, a 
sample of fluid or a biopsy from that location (for example, a skin or tumor 
sample or spinal fluid) may be sent to the research laboratory for testing in the 
high throughput assay. 
 
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6.2. Drug Choice 
A drug or combination of 2-3 drugs tested in combination will be chosen from only the 
FDA approved drugs listed in Table 1 based on availability, insurance clearance, degree 
of apparent in vitro response (lowest absolute EC50 or lowest EC50 relative to other 
patients for individual drugs), prior publication of drug or drug combination use in other 
leukemia patients and difference in class of drug compared to the drugs to which the 
patient has previously not responded. In addition, gene expression that reveals activation 
of druggable pathways or mutations in genes that confer susceptibility to specific agents 
may also be considered in choice of treatment. If an inhibitor is available that has the 
same target (e.g.-a specific kinase) as the one tested, this drug may be substituted. For 
combination regimens, we intend to only utilize regimens for which there are clinical data 
in humans. Additional  FDA approved drugs or combinations of drugs may be added to 
the assay panel in the future if there is evidence to suggest efficacy in leukemia patients. 
However, the protocol will be amended to include these drugs prior to their use in any 
assay-guided treatment regimen.   
6.3. Drug Dosing 
Individual drugs will be used in doses that have been utilized in humans with anti-cancer 
response, at standard or maximum tolerated dose. Drug combinations will be used at 
standard doses or doses for which there is published experience. Appendix E contains a 
list of sample dosages, though they may change if new data emerges showing superior 
outcomes with alternative dosing strategies.  
6.4. Consent for Individual Regimens 
In addition to the consent for this study, there will be an individual general clinical 
consent for treatment that is not considered a research consent and may include printed 
information that describes the drug or drug combination, mechanisms of drug action in 
lay terms and applicable side effects, this activity is considered standard practice and is 
not strictly performed for research, these consents may vary in appearance. Additionally, 
an alternative clinical trial consent may be used if the patient is found to be eligible for a 
clinical trial which may contain an assay-guided regimen or agent. These consents will be 
signed after assignment of the drug or drug combination. These consents will be obtained 
for the first two treatment regimens directed by the study, and afterward consent will be 
obtained only as required per institutional policy by treating physicians. 
6.5. Duration of Therapy 
Subjects may receive up to two distinct assay-guided regimens that will be monitored for 
response and adverse events for the study. Treating physicians have discretion to 
continue treatment thereafter based on data from the study and the responses and survival 
of the patients will be monitored, but not the adverse events. 
7. ON STUDY EVALUATIONS 
1. 
The on-study period begins at initiation of study procedures and response data to 
any study directed therapies will be collected for a period up to 2 years. Adverse events 
 
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will be collected from the time of start of assay guided therapy through 14 days after 
completion of the first or second drug regimen, as applicable. 
 
2. 
Hematology: CBC with differential and platelet count and peripheral blood smear 
at frequency per standard of care.   
3.  
Serum chemistries: Electrolytes (sodium, potassium, chloride, and bicarbonate), 
BUN, creatinine, glucose, and liver function tests (AST, ALT, ALP, total bilirubin, LDH) 
per standard of care. 
4.   
Bone marrow aspirations by standard practice with measure of cellularity and 
percent of blasts, bone marrow at blood count recovery to document remission status. 
Reports for subsequent bone marrow evaluations throughout period of treatment. See 
Appendix B for the study calendar.   
5.   
Grade 3 and higher adverse events will be recorded using the NCI CTCAE, 
Version 4.0 
8. FOLLOW-UP 
1. 
Response data. All reports for bone marrow evaluations done as standard of care 
following this treatment, including morphology, flow cytometry, cytogenetics/FISH and 
mutation studies, will be collected.   
2. 
Subsequent complete blood count, renal function, and liver function tests obtained 
for clinical reasons for a period of up to one month post the last consolidation 
chemotherapy cycle, as needed to define toxicity or duration of response.  
3. 
Reports on each patient’s course post stem cell transplant, if applicable, will be 
reviewed to determine response and duration of remission.  
4. 
Disease free and overall survival data will be assessed by contacting the referring 
MD or the patient every three months for the first two years.  
9. CRITERIA FOR RESPONSE 
Responses to treatment will be on the basis of 1) standard criteria as well as 2) the degree of 
cytoreduction.  
9.1. Definition of Response by standard criteria 
Response will be evaluated using European LeukemiaNet criteria, which are outlined in  
Appendix C. 
 
9.2. Degree of Cytoreduction 
 
 
The percent cellularity of the bone marrows obtained within 2-3 weeks of treatment and 
 
the percent leukemia by morphology and flow cytometry will be monitored by the study 
 
team, and compared to the pre-treatment levels.  
 
9.3. Duration of Response 
 
Time to progression will be noted for patients, regardless of whether they undergo stem 
 
cell transplant.  
 
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10. REGISTRATION OF PATIENTS 
Patients who fulfill eligibility criteria and who signed consent will be enrolled by the study 
coordinator. See Appendix D for the registration form.  
11. FORMS TO BE KEPT 
Case report forms, diagnostic pathology reports, and laboratory test results will be kept in a 
secure location that protects confidential information or electronically with security access.  
Follow up information regarding survival and information about time of relapse and subsequent 
therapy will also be maintained.  
 
12. REGULATORY AND REPORTING REQUIREMENTS  
 
12.1. Adverse Event Monitoring and Reporting 
The principal investigator is responsible for monitoring the safety of patients who enroll 
in the study.  The descriptions and grading scales found in the NCI CTCAE version 4.0 
will be used for adverse event reporting.  Non-hematologic toxicities >grade 3 will be 
recorded from assay-guided therapy administration through 14 days after last 
administration of study therapy and will be followed until resolution. 
 
12.2. Serious Adverse Events 
A serious adverse event (SAE) is any adverse drug experience that occurs at any dose 
that results in any of the following outcomes: 
• Death. 
• Life threatening adverse event. 
• Hospitalization or prolongation of hospitalization* 
• Persistent of significant disability/incapacity. 
• A congenital anomaly/birth defect. 
• Requires surgical intervention to prevent one of the outcomes listed above. 
*For the purposes of this study, hospitalizations or prolongation of 
hospitalizations  for protocol-scheduled procedures, blood product transfusions, or 
for social reasons (i.e. awaiting transport home) will not be considered a SAE; 
hospitalization or prolongation of hospitalizations for fever and/or infection will 
be considered expected, and not be considered a SAE. 
12.3. Reporting Serious Adverse Events 
In accordance with FHCRC/UW Cancer Consortium IRB policy, all adverse events (AEs; 
whether occurring on-site or off-site), which in the opinion of the principal investigator 
are (1) unexpected, and (2) related or possibly related to the research, and (3) serious or 
suggests that the research places research participants or others at a greater risk of 
physical or psychological harm than was previously known or recognized, will be 
submitted to the IRB within 10 calendar days of learning of the problem. 
 
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AEs that do not meet the requirement for expedited reporting will be reported to the IRB 
as part of the annual renewal of the protocol. 
 
 
13. DATA AND SAFETY MONITORING PLAN 
Ongoing trial oversight is carried out by the principal investigator, Dr. Percival and the primary 
research coordinator.  These individuals will meet regularly to review recently acquired data, and 
adverse events.  
Institutional support of trial monitoring is provided in accordance with the Fred Hutch/University 
of Washington Cancer Consortium Institutional Data and Safety Monitoring Plan.  Under the 
provisions of this plan, Fred Hutch Clinical Research Support (CRS) coordinates data and 
compliance monitoring by consultants, contract research organizations, or CRS employees 
unaffiliated with the conduct of the study. Independent monitoring visits occur at specified 
intervals determined by the assessed risk level of the study and the findings of previous visits.  In 
addition, protocols are reviewed at least annually by the Fred Hutch/ UW Cancer Consortium 
Data and Safety Monitoring Committee (DSMC) and the Fred Hutch Institutional Review Board 
(IRB). The DSMC reviews accrual, adverse events, stopping criteria, and adherence to the data 
and safety monitoring plan. The Fred Hutch IRB reviews the study progress and safety 
information to assess continued acceptability of the risk-benefit ratio for human subjects. 
Approval of both committees is necessary to continue the study.  
 
14. STATISTICAL CONSIDERATIONS 
14.1. Experimental Design 
This is a feasibility study with the primary objective of combining drug treatments and 
initiating therapy based on the results of the drug screen for poor risk patients with any 
refractory or relapsed acute leukemia.  The sample size is determined by funding and 
time constraints, rather than testing of specific hypotheses.  Information from this study 
will enable us to determine effective combinations of drug treatments based on in vitro 
response and mutational analyses.  
Given the large expenditure of time and funds for each patient, we would like to see the 
primary objective achieved in at least 40-50% of the patients. We will consider the study 
successful (feasibility demonstrated) if we are able to choose and initiate a combination 
drug regimen within 21 days in 9 out of 15 patients. With that outcome, we could say 
with 90% confidence that the true feasibility rate is at least 40%.  Based on our previous 
study, where 14 of 15 patients were successfully tested and treated within 21 days, we 
believe that the true feasibility rate in this study could be 70% or more. In that case, we 
have an 87% chance of observing a 9 out of 15 success rate or better.  
Although efficacy is not a primary endpoint, the overall objective of individualized 
therapy is to increase the rate of CR, and ultimately survival.  However, the goal of this 
study is to establish feasibility, and subsequent trials will be needed to validate the 
approach and establish superiority over current standard of care.  
 
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Patients who sign consent can be screened for eligibility. Part of the definition of 
eligibility is to be able to obtain ~10 million leukemia blasts for analysis (or per lab 
ability to assay). Patients for which enough cells are not obtained will be considered 
screen failures.  
Patients who receive assay results and do not receive drug due to other circumstances, 
such as inability to return to center, patient/doctor decision to not be treated per study 
recommendation, or patient/doctor preference for palliative care, will be considered 
discontinuation.  Patients who discontinue for this rationale will be replaced in order to 
complete all objectives of this study; we will continue to follow outcomes of patients who 
discontinue. 
14.2. Stopping Rules 
The study will be stopped if we fail to demonstrate feasibility. Operationally, this will be 
triggered if the 7th patient  fails to receive treatment, indicating that the objective of 
treating 9 of 15 patients will not be met. 
 
15. REFERENCES 
American Cancer Society, Cancer Facts and Figures 2015 
 
Becker PS, Kopecky KJ, Wilks AN, Chien S, Harlan JM, Willman CL, Petersdorf SH, Stirewalt 
DL, Papayannopoulou T, Appelbaum FR. Very late antigen-4 function of myeloblasts correlates 
with improved overall survival for patients with acute myeloid leukemia.  Blood, 22; 113(4):866-
74, Jan 2009. 
 
Becker PS, Oehler V, Estey E, Martins T, Perdue A, David J, Chien S, Hendrie P, Ostronoff F, 
Blau A. Feasibility trial of individualized therapy for relapsed or refractory acute myeloid 
leukemia based on a high throughput in vitro drug sensitivity assay. Poster session presented at: 
American Society of Hematology Annual Meeting; 2014 December 6-9; San Francisco, CA. 
 
Breems DA, van Putten WLJ, Huugens PC, Ossenkoppele GJ, Verhoef GEG, Verdonck LF, 
Vellenga E, de Greef GE, Jacky E, van der Lelie J, Roogaerts MA, Lowenberg B. Prognostic 
index for adult patients with acute myeloid leukemia in first relapse.  J Clin Oncol, 23: 1969-
1978, 2005.   
 
Bennett TA, Montesinos P, Moscardo F. Pharmacological profiles of acute myeloid leukemia 
treatments in patient samples by automated flow cytometry: a bridge to individualized medicine. 
Clin Lymphoma Myeloma Leuk, 14(4):305-318, Aug 2014 
 
Campana, Dario. "Minimal Residual Disease in Acute Lymphoblastic Leukemia." Seminars in 
Hematology 46.1 (2009): 100-06. ASH. Web. 17 July 2014. 
De Lima, Marcos et. al. "Nonablative versus Reduced-intensity Conditioning Regimens in the  
Treatment of Acute Myeloid Leukemia and High-risk Myelodysplastic Syndrome: Dose Is 
Relevant for Long-term Disease Control after Allogeneic Hematopoietic Stem Cell 
 
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Transplantation." Blood Journal 104.3 (2004): n. pag. ASH Academy. American Society of 
Hematology, 1 Aug. 2004. Web. 08 July 2014. 
Döhner H, Estey E, Amadori S, Appelbaum F, Büchner T, Burnett A, Dombret H, Fenaux P, 
Grimwade D, Larson R, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele G, Sanz M, Sierra J, 
Tallman M, Löwenberg B, Bloomfield C. Diagnosis and management of acute myeloid leukemia 
in adults: recommendations from an international expert panel, on behalf of the European 
LeukemiaNet. Blood, 115:453-474, 2010. 
Estey E, Kornblau S, Pierce S, Kantarjian H, Beran M, Keating M. A stratification system for 
evaluating and selecting patients with relapsed or primary refractory acute myelogenous 
leukemia.  Blood, 88:756, 1996.  
O. Jonas, H. M. Landry, J. E. Fuller, J. T. Santini, J. Baselga, R. I. Tepper, M. J. Cima, R. 
Langer, An implantable microdevice to perform high-throughput in vivo drug sensitivity testing 
in tumors. Sci. Transl. Med. 7, 284ra57 (2015). 
Klinghoffer RA, Bahrami SB, Hatton BA et al. A technology platform to assess multiple cancer 
agents simultaneously within a patient’s tumor. Sci. Transl. Med. 7, 284ra58 (2015). 
Lee S, Logsdon B, Saxena A, Oehler V, Miller P, Blau A, Becker P. Big data approach to 
identify molecular basis of drug sensitivity phenotypes in acute myeloid leukemia. Paper 
presented at: American Society of Hematology Annual Meeting; 2014 December 6-9; San 
Francisco, CA 
Logsdon BA, Gentles AJ, Miller CP, Blau CA, Becker PS, et al. Sparse expression bases in 
cancer reveal tumor drivers. Nucleic acids research. 2015; 43(3):1332-44.  
McMillan DW, Delmore J, Weisberg E, Negri JM, Geer DC, Klippel S, Mitsiades N, 
Schlossman RL, Munshi NC, Kung AL, Griffin JD, Richardson PG, Anderson KC, Mitsiades 
CS. Tumor cell-specific bioluminescence platform to identify stroma-induced changes to 
anticancer drug activity.  Nat Med, 16(4):483-9, 2010. 
Othus M, Appelbaum FR, Petersdorf SH, Kopecky KJ, Slovak M, Nevill T, Brandwein J, Larson 
RA, Stiff PJ, Walter RB, Tallman MS, Stenke L, Erba HP. Fate of patients with newly diagnosed 
acute myeloid leukemia who fail primary induction therapy. Biol Blood Marrow Transplant, 
21(3): 559-64, 2015. 
Pemovska T, Kontro M, Yadav B et al. Individualized systems medicine strategy to tailor 
treatments for patients with chemorefractory acute myeloid leukemia. Cancer Discov, 
3(12):1416-29, 2013. 
Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, Davis A, Mongare MM, 
Gould J, Frederick DT, Cooper ZA, Chapman PB, Solit DB, Ribas A, Lo RS, Flaherty KT, 
Ogino S, Wargo JA, Golub TR. Tumour micro-environment elicits innate resistance to RAF 
inhibitors through HGF secretion. Nature, 487:500-4, 2012. 
Tzortzatou-Stathopoulou, Fotini, Athina L. Papadopoulou, Maria Moschovi, Athanasios 
Botsonis, and George T. Tsangaris. "Low Relapse Rate in Children With Acute Lymphoblastic 
Leukemia After Risk-Directed Therapy." Journal of Pediatric Hematology/Oncology 23.9 
(2001): 591-97. OvidSP. Web. 17 July 2014. 
 
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Zimmerman, E. I., D. C. Turner, J. Buaboonnam, S. Hu, S. Orwick, M. S. Roberts, L. J. Janke, 
A. Ramachandran, C. F. Stewart, H. Inaba, and S. D. Baker. "Crenolanib Is Active against 
Models of Drug-resistant FLT3-ITD-positive Acute Myeloid Leukemia." Blood 122.22 (2013): 
3607-615. American Society of Hematology. Web. 
Zhang, W., C. Gao, M. Konopleva, Y. Chen, RO Jacomo, G. Borthakur, JE Cortes, F. Ravandi, 
A. Ramachandran, and M. Andreeff. Clinical Cancer Research 20.9 (2014): 2363-374. Clinical 
Cancer Research. 11 Mar. 2014. Web. 10 July 2014. 
 
 
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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
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). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 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. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
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APPENDIX B:   
STUDY CALENDAR 
Assessment 
Screening 
 
Treatment Phase 
 
End of 
Treatment 
Long Term 
Follow-up 
Informed Consent 
X 
 
 
 
 
Medical History/Concurrent Conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG Performance Status 
X 
 
 
X 
 
Hematology 
X 
 
Xd 
X 
X 
Serum Chemistriesa  
X 
X 
Xd 
X 
 
Bone Marrow Biopsy, Aspirate and Smear Results 
Xb 
 
Xd 
X 
X 
MUGAc 
Xc 
 
 
 
 
Response Assessment/ 
Confirmation of Continued Remission Status 
 
 
 
X 
X 
Drug Administration 
 
 
X 
 
 
 
 
 
 
 
 
Adverse Event Assessment 
X 
 
X 
X 
 
a Electrolytes (sodium, potassium, chloride and bicarbonate), BUN, creatinine, glucose, AST, ALT, alkaline phosphatase, total bilirubin and LDH. 
b Review of the initial standard of care bone marrow,aspirate and smear results.   
C For patients receiving anthracycline therapy 
d According to standard of care 
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APPENDIX C 
RESPONSE CRITERIA IN AML:  FROM DÖHNER ET AL. 2010 
Abbreviations:  AML acute myelogenous leukemia; EMD, extramedullary disease; CR, complete remission 
 
 
Response Criterion 
 
Time of Assessment 
 
Neutrophils  
(µ L)` 
 
Platelets (µ L) 
 
Bone Marrow Blasts (%) 
 
Other 
Morphologic leukemia-free 
state 
Varies by protocol 
NA 
NA 
< 5 
Absence of blasts w/ Auer 
rods; Absence of EMD 
CR w/ incomplete recovery 
(CRi) 
Varies by protocol 
<1,000 
<100,00 
< 5 
Absence of blasts w/ Auer 
rods; Absence of EMD 
Morphologic CR 
Varies by protocol 
>1,000 
> 100,000 
< 5 
RBC transfusion 
independence; Absence of 
EMD 
Cytogenetic CR (CRc) 
Varies by protocol 
>1,000 
> 100,000 
< 5  
Reversion to normal 
karyotype at time of CR in 
cases w/ abnormal 
karyotype at diagnosis; 
absence of EMD 
Molecular CR (CRm) 
Varies by protocol 
> 1,000 
> 100,000 
< 5 
No standard definition; 
depends on molecular target 
Partial remission (PR) 
Varies by protocol 
> 1,000 
> 100,000 
decrease to 5-25 
Decrease of pretreatment 
bone marrow blast 
percentage by at least 50% 
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Appendix D 
Protocol 9226 Patient Demographics and Eligibility Form 
Please Fax this completed form to 206-606.6984 for patient registration. 
Questions regarding eligibility should go to Mary-Elizabeth Percival, MD  206-606-1320 
Research Subject Registration Form 
 
1.1 
UPN#:_____________________________________ 
 
Patient Name:  
___________________  
_____________ 
___ 
 
 
 
Last 
 
 
 
First 
 
 
MI 
Date of Birth:    
___  ___/___ ___/ ___ ___ ___ ___ 
 
 
 
Month     Day          Year 
 
Ethnicity (choose one): instruct the patient to select one of the following: 
 
  Hispanic or Latino  (A person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race.  Term “Spanish Origin” can also be used 
in addition to “Hispanic” or “Latino”  
 
 
 
  Not Hispanic or Latino 
 
 
 
  Declined to Report 
Race (check all that apply): instruct the patient to select one or more of the following: 
 
  American Indian/Alaska Native  (A person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or community 
attachment) 
 
 
 
  Asian  (A person having origins in any of the original peoples of the Far East, Southeast, Asia, or 
the Indian subcontinent including, for example, Cambodia, China, India Japan, Korea, Malaysia, Pakistan, 
the Philippine Islands, Thailand and Vietnam) 
  Native Hawaiian/Pacific Islander (A person having origins in any of the original 
peoples of Hawaii, Guam, Samoa or other Pacific Islands) 
 
 
 
  Black/African American (A person having origins in any of the black racial groups of 
Africa.   
  White  (A person having origins in any of the original peoples of Europe, the Middle East or 
North Africa) 
 
 
 
 
 
  Research Subject does not know race 
 
 
  Declined to Report 
Gender: 
 
  Male 
 
 
 
  Female 
  Unknown 
 
 
 
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Appendix E: Drug Dosing and References 
 
Drug or Drug 
Combination 
Dosing 
Reference(s) 
Afatinib 
Adult: 40mg PO qd x14 
days 
Pediatric: not studied 
Gordon S, et al. A phase I, open-label, dose-
escalation study of continuous once-daily oral 
treatment with afatinib in patients with advanced 
solid tumors. Invest New Drugs. 2013 Apr; 
31(2):409-416 
Arsenic trioxide 
Adult: 0.15mg/kg/day IV 
until bone marrow 
remission 
 
Pediatric: 0.15 mg/kg IV 
qday for 5days/week x 2 
weeks 
Powell et al. Arsenic trioxide improves event-
free and overall survival for adults with acute 
promyelocytic leukemia: North American 
Leukemia Intergroup Study C9710. Blood. 2010 
Nov 11;116(19):3751-7 
 
Fox E et al. Phase 1 trial and pharmacokinetic 
study of arsenic trioxide in children and 
adolescents with refractory or relapsed acute 
leukemia, including acute promyelocytic 
leukemia or lymphoma. Blood 2008 Jan; 111(2): 
566-573 
Axitinib 
Adult: 5 mg PO BID x 14 
days 
Pediatric: not studied 
Rugo HS, et al. A Phase I trial of the oral 
antiangiogenesis agent AG-013736 in patients 
with advanced solid tumors: pharmacokinetic 
and clinical results. J Clin Oncol. 2005 Aug 
20;23(24):5474-83. 
Azacitidine 
Adult: 100 mg/m2 IV or 
SC daily Days 1-7 
 
Pediatric: not studied 
 
Package Insert 
 
 
Belinostat 
Adult: 1gm/m2 IV daily 
on Days 1-5 
 
Pediatric: not studied 
Kirschbaum MH et al. A phase 2 study of 
belinostat (PDX101) in patients with relapsed or 
refractory acute myeloid leukemia or patients 
over 60 with newly-diagnosed acute myeloid 
leukemia: A California Cancer Consortium 
study. Leuk Lymphoma; 2014 Oct: 55(10): 
2301-2304 
Bexarotene 
Adult: 400mg/m2 PO 
qday x 14 days 
 
Pediatric: 309mg/m2 PO 
qday x 14 days 
 
Tsai DE, Luger SM, Andreadis C, Vogl DT, 
Kemner A, Potuzak M, et al. A phase I study of 
bexarotene, a retinoic X receptor agonists, in 
non-M3 myeloid leukemia. Clin Cancer Res 
2008;14:5619–25 
 
 
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Mehta N, et al. Bexarotene is active against 
subcutaneous panniculitis-like T-cell lymphoma 
in adult and pediatric populations. Clin 
Lymphoma Myeloma Leuk. 2012 Feb; 12(1):20-
25 
Bortezomib 
Adult: 1.25 mg/m2 IV 
twice weekly x 2 weeks 
 
Pediatric: not studied 
Cortes J, et al. Phase I study of bortezomib in 
refractory or relapsed acute leukemias.Clin 
Cancer Res. 2004;10(10):3371-6. 
Bosutinib 
Adult: 500 mg PO qday x 
14 days 
 
Pediatric: not studied 
Daud AI, et al. Phase I Study of Bosutinib, a 
Src/Abl Tyrosine Kinase Inhibitor, Administered 
to Patients with Advanced Solid Tumors.  Clin 
Cancer Res 2012;18(4):1092-1100 
Busulfan 
Adult: 1.8mg/m2 PO 
qday x 14 days 
 
Pediatric: same as adult 
Product Information: MYLERAN(R) oral 
tablets, busulfan oral tablets. GlaxoSmithKline, 
Research Triangle Park, NC, 2005.  
Cabazitaxel 
Adult: 25mg/m2 IV 
q3weeks 
 
Pediatric: not studied 
Dieras V, et al. Cabazitaxel in patients with 
advanced solid tumors: results of a Phase I and 
pharmacokinetic study. Eur J Cancer. 2013 Jan; 
49(1):25-34 
Cabozantinib 
Adult: 175mg PO qday x 
14 days 
 
Pediatric: not studied 
Kurzrock R, Sherman SI, Ball DB, et al. (2011) 
Activity of XL184 (cabozantinib), an oral 
tyrosine kinase inhibitor, in patients with 
medullary thyroid cancer. J Clin Oncol 29:2660–
2666  
Carfilzomib 
Adult: 15mg/m2 IV on 
days 1-5 of 14 day cycles 
 
Pediatric: not studied 
O’Connor, O. A phase 1 dose escalation study of 
safety and pharmacokinetics of the novel 
proteasome inhibitor carfilzomib (PR-171) in 
patients with hematologic malignancies. Clin 
Cancer Res. 2009 Nov 15; 15(22): 7085-91  
Ceritinib 
Adult: 750mg PO qday x 
14 days 
 
Pediatric: not studied 
Shaw AT, et al. Ceritinib in ALK-rearranged 
non-small-cell lung cancer. N Engl J Med. 2014 
Mar 27; 370(13):1189-97 
Cladribine 
Adult: 21.5 mg/m2/day 
IV over 1 hr Days 1-5 
 
Pediatric: 8.9mg/m2/d 
continuous IV for 5 days 
Larson RA, et al. Dose-escalation trial of 
cladribine using five daily intravenous infusions 
in patients with advanced hematologic 
malignancies. J Clin Oncol. 1996;14:188-95. 
 
Krance RA et al. Experience with 2-
chlorodeoxyadenosine in previously untreated 
children with newly diagnosed acute myeloid 
leukemia and myelodysplastic diseases. J Clin 
Oncol. 2001 Jun 1;19(11):2804-11 
 
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Clofarabine 
Adult: 40 mg/m2/day IV 
Days 1-5 
 
Pediatric: 52mg/m2/day 
IV for 5 days 
Kantarjian HM, et al. Phase I clinical and 
pharmacology study of clofarabine in patients 
with solid and hematologic cancers. J Clin 
Oncol. 2003;21(6):1167-73. 
 
Jeha S et al. Clofarabine, a novel nucleoside 
analog, is active in pediatric patients with 
advanced leukemia. Blood. 2004 Feb 
1;103(3):784-9 
Crizotinib 
 
Adult: 250mg PO BID x 
14 days 
 
Pediatric: 280mg/m2 PO 
BID x 14 days 
 
Kwak E, Bang Y, Camidge R, et al. Anaplastic 
lymphoma kinase inhibition in non-small-cell 
lung cancer. N Engl J Med 2010; 363: 1693–703 
 
Mosse YP, et al. Safety and efficacy of crizotinib 
for paediatric patients with refractory solid 
tumours or anaplastic large-cell lymphoma: a 
children’s oncology group phase 1 consortium 
study. Lancet Oncol. 2013 May; 14(6):472-80 
Cytarabine HCl 
≤ 60 years old:  3gm/m2 
every 12 hr Days 1-6 
> 60 years old: 1.5gm/m2 
every 12 hr Days 1-6 
Herzig RH, et al.  High-dose cytosine 
arabinoside therapy for refractory leukemia.  
Blood 1983,62:361-369 
Dabrafenib 
Adult: 150mg PO q12hrs 
x 14 days 
 
Pediatric: not studied 
Falchook GS et al. Dabrafenib in patients with 
melanoma, untreated brain metastases, and other 
solid tumours: a phase 1 dose escalation trial. 
Lancet. 2012 May 19;379(9829):1893-901 
Dasatinib 
 
Adult: 140mg PO qday x 
14 days 
 
Pediatric: 60 or 80mg/m2 
PO qday x 14 days 
Product Information: SPRYCEL(R) oral tablets, 
dasatinib oral tablets. Bristol-Myers Squibb 
Company (per FDA), Princeton, NJ, 2013. 
 
Zwaan CM, et al. Dasatinib in children and 
adolsescents with relapsed or refractory 
leukemia: results of the CA180-018 phase 1 
dose-escalation study of the Innovative 
Therapies for Children with Cancer Consortium. 
J Clin Oncol 2013 Jul 1;31(19): 2460-8 
Daunorubicin 
HCl 
Adult: 90 mg/m2 IV Days 
1-3 
 
Pediatric: not studied 
Fernandez, HG, et al. Anthracycline Dose 
Intensification in Acute Myeloid Leukemia. N 
Engl J Med 2009;361:1249-59. 
 
Lowenberg, B, et al. High-Dose Daunorubicin in 
Older Patients with Acute Myeloid Leukemia. N 
Engl J Med 2009;361:1235-48. 
Decitabine 
Adult: 20mg/m2 IV qd 
for 5 days q4weeks 
Kantarjian HM, et al: Results of a randomized 
study of 3 schedules of low-dose decitabine in 
 
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Pediatric: 10mg/m2/d IV 
for 10 days 
higher-risk myelodysplastic syndrome and 
chronic myelomonocytic leukemia. Blood 2007 
January; 109(1): 52-57 
 
Phillips CL et al (2013), Low dose decitabine in 
very high risk relapsed or refractory acute 
myeloid leukaemia in children and young adults. 
British Journal of Haematology, 161: 406–410. 
Erlotinib 
Pediatric: 125mg/m2 PO 
qday x 14 days 
 
Adult : 150mg PO qday x 
14 days 
Geoerger B, et al. Innovative Therapies for 
Children with Cancer pediatric phase I study of 
erlotinib in brainstem glioma and 
relapsing/refractory brain tumors. Neuro Oncol. 
2011 January; 13(1):109-118 
 
Hidalgo M et al. Phase I and pharmacologic 
study of OSI-774, an epidermal growth factor 
receptor tyrosine kinase inhibitor, in patients 
with advanced solid malignancies. J Clin Oncol. 
2001 Jul 1;19(13):3267-79. 
Etoposide 
Adult: 100mg/m2 IV on 
days 1-5 in combination 
with other approved 
chemotherapeutic agents 
 
Pediatric: same as above 
Product Information: TOPOSAR(TM) 
intravenous injection, etoposide intravenous 
injection. Teva Parenteral Medicines, Inc. (per 
DailyMed), Irvine, CA, 2011. 
 
Horton, T. M., et al (2014), A Phase 2 study of 
bortezomib combined with either 
idarubicin/cytarabine or cytarabine/etoposide in 
children with relapsed, refractory or secondary 
acute myeloid leukemia: A report from the 
Children's Oncology Group. Pediatr. Blood 
Cancer, 61: 1754–1760. 
Everolimus 
Adult: 10mg PO qday x 
14 days 
 
Pediatric: not studied 
Tabernero J, et al. Dose- and schedule-dependent 
inhibition of the mammalian target of rapamycin 
pathway with everolimus: a phase I tumor 
pharmacodynamic study in patients with 
advanced solid tumors. J Clin Oncol. 2008 Apr 
1;26(10):1603-10. 
Fludarabine 
Adult: 75mg/m2 IV daily 
Days 1-5 
 
Pediatric: not studied 
Warrell LP JR, et al. Phase I and 2 study of 
fludarabine phosphate in leukemia: therapeutic 
efficacy with delayed central nervous system 
toxicity. J Clin Oncol. 1986 Jan;4(1):74-9. 
Gefitinib 
Pediatric: 400mg/m2 PO 
qday x 14 days 
 
Adult: 500mg PO qday x 
14 days 
Daw NC, et al. Phase I and pharmacokinetic 
study of gefitinib in children with refractory 
solid tumors: a Children's Oncology Group 
Study. J Clin Oncol. 2005 Sep 1; 23(25):6172-80 
 
 
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Lorusso PM. Phase I studies of ZD1839 in 
patients with common solid tumors. Semin 
Oncol. 2003 Feb; 30(1 suppl 1):21-9 
Gemcitabine 
HCl 
Adult: 10 mg/m2 IV over 
12hrs on day 1 
 
Pediatric: not studied 
Advani AS, et al. A phase II trial of gemicitabine 
and mitoxantrone for patients with acute myeloid 
leukemia in first relapse. Clin Lymphoma 
Myeloma Leuk. 2010 Dec; 10(6):473-6 
Hydroxyurea 
Adult: 20 to 30mg/kg PO 
qday x 14 days 
 
Pediatric: not studied 
Product Information: HYDREA(R) oral 
capsules, hydroxyurea oral capsules. Bristol-
Myers Squibb Company, Princeton, NJ, 2005 
Ibrutinib 
Adult: 420mg PO qday 
x14 days 
 
Pediatric: not studied 
O’Brien S et al. Ibrutinib as initial therapy for 
elderly patients with chronic lymphocytic 
leukemia or small lymphocytic lymphoma: an 
open-label, multicenter, phase 1b/2 trial. Lancet 
Oncol 2014 Jan; 15(1) 48-58 
Idarubicin 
Adult: 12mg/m2/day x 3 
days (in combination w/ 
cytarabine) 
 
Pediatric: same as adult 
Wiernik P.H., et al. (1992) Cytarabine plus 
idarubicin or daunorubicin as induction and 
consolidation therapy for previously untreated 
adult patients with acute myeloid leukemia. 
Blood 79: 313–319 
 
Creutzig U et al. Randomized trial comparing 
liposomal daunorubicin with idarubicin as 
induction for pediatric acute myeloid leukemia: 
results from study AML-BFM 2004. Blood. 
2013 July; 122(1):37-43 
Imatinib 
Adult: 600mg PO qday x 
14 days 
 
Pediatric: 340mg/m2 PO 
qday x 14 days 
Cohen MH, et al. Approval summary for 
imatinib mesylate capsules in the treatment of 
chronic myelogenous leukemia. Clin Cancer 
Res. 2002 May; 8(5):935-42 
 
Schultz KR, et al. Improved early event-free 
survival with imatinib in Philadelphia 
chromosome-positive acute lymphoblastic 
leukemia: a Children’s Oncology Group Study. J 
Clin Oncol. J Clin Oncol 2009; 27: 5175–5181 
 
Irinotecan 
Adult: 250mg/m2 IV on 
days 1 and 15  
 
Pediatric: not studied 
Rothenberg ML, et al. Phase I dose-finding and 
pharmacokinetic trial of irinotecan (CPT-11) 
administered every two weeks. Ann Oncol. 2001 
Nov; 12(11):1631-41 
Lapatinib 
Pediatric: 900mg/m2 PO 
BID x 14 days 
 
Fouladi M, et al. Phase I trial of lapatinib in 
children with refractory CNS malignancies: a 
Pediatric Brain Tumor Consortium study. J Clin 
Oncol. 2010 Sep 20;28(27):4221-7 
 
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Adult: 1600mg PO qday 
x 14 days 
 
Burris HA, et al. Phase I safety, 
pharmacokinetics and clinical activity study of 
lapatinib (GW572016), a reversible dual 
inhibitor of epidermal growth factor receptor 
tyrosine kinases, in heavily pretreated patients 
with metastatic carcinomas. J Clin Oncol. 2005 
Aug 10;23(23):5305-13 
Lenalidomide 
Adult: 50mg PO qday 
x14 days 
 
Pediatric: 116mg/m2 PO 
qday x 14 days 
Fehniger TA et al. A phase 2 study of high-dose 
lenalidomide as initial therapy for older patients 
with acute myeloid leukemia. Blood 2011 Feb; 
117(6): 1828-1833 
 
Warren KE et al. Phase I trial of lenalidomide in 
pediatric patients with recurrent, refractory or 
progressive primary CNS tumors: Pediatric 
Brain Tumor Consortium study PBTC-018. J 
Clin Oncol. 2011 Jan; 29(3): 324-9 
Lomustine 
Adult: 130mg/m2 PO 
once 
 
Pediatric: same as adult 
Product Information: Gleostine(TM) oral 
capsules, lomustine oral capsules. NextSource 
Biotechnolgy, LLC (per FDA), Miami, FL, 
2014. 
Melphalan 
Adult: 70 mg/m2 IV once 
 
Pediatric: not studied 
Sonneveld P, et al. Intermediate-dose melphalan 
compared with myeloablative treatment in 
multiple myeloma: long-term follow-up of the 
Dutch Cooperative Group HOVON 24 trial. 
Haematologica 2007 July; 92(7): 928-935 
Mercaptopurine 
Adult: 75mg/m2 PO qday 
x 14 days 
 
Pediatric: same as adult 
Product Information: PURINETHOL(R) oral 
tablets, mercaptopurine oral tablets. Gate 
Pharmaceuticals (per FDA), Sellersville, PA, 
2011. 
 
Stock W, La M, Sanford B, et al, “What 
Determines the Outcomes for Adolescents and 
Young Adults With Acute Lymphoblastic 
Leukemia Treated on Cooperative Group 
Protocols? A Comparison of Children's Cancer 
Group and Cancer and Leukemia Group B 
Studies,” Blood, 2008, 112(5):1646-54. 
Methotrexate 
Adult: MTX 200 mg/m2 
IV over 2 hours followed 
by 800 mg/m2 IV over 24 
hours on day 1 
Pediatric: not studied 
Kantarjian HM, et al. Results of treatment with 
hyper-CVAD, a dose-intensive regimen, in adult 
acute lymphocytic leukemia. J Clin Oncol 2000; 
18(3): 547-61 
 
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Mitoxantrone 
≤ 60 years old:  15mg/m 
m2  Days 1-3 
> 60 years old: 12mg/ m2 
Days 1-3 
Feldman EJ, et al. Phase I Clinical and 
Pharmacokinetic Evaluation of High-Dose 
Mitoxantrone in Combination With Cytarabine 
in Patients With Acute Leukemia. J Clin Oncol. 
1993 Oct;11(10):2002-9. 
 
Nelarabine 
Adult: 1500mg/m2 IV on 
days 1,3,5  
 
Pediatric: 650mg/m2 IV 
qday for 5 consecutive 
days 
Kurtzberg J, Ernst TJ, Keating MJ, et al. Phase I 
study of 506U78 administered on a consecutive 
5-day schedule in children and adults with 
refractory hematologic malignancies. J Clin 
Oncol 2005;23:3396-3403 
Nilotinib 
Adult: 400mg PO BID x 
14 days 
 
Pediatric: not studied 
Tanaka C, et al. (2010), Clinical 
Pharmacokinetics of the BCR–ABL Tyrosine 
Kinase Inhibitor Nilotinib. Clin Pharmacol Ther, 
87: 197–203 
Olaparib 
Adult: 400mg PO BID x 
14 days 
 
Pediatric: not studied 
Audeh MW, Carmichael J, Penson RT, et al. 
Oral poly(ADP-ribose) polymerase inhibitor 
olaparib in patients with BRCA1 or BRCA2 
mutations and recurrent ovarian cancer: a proof-
of-concept trial. Lancet. 2010;376(9737):245-
251 
 
Omacetaxine 
Adult: 1.25mg/m2 BID 
x14 days 
 
Pediatric: not studied 
Cortes JE, et al. Subcutaneous omacetaxine in 
chronic or accelerated chronic myeloid leukemia 
resistant to two or more tyrosine-kinase 
inhibitors including imatinib. Blood. 
2011;118:3761. 
 
Paclitaxel 
Pediatric: 430mg/m2 IV 
once 
 
Adult: 390mg/m2 IV over 
24hrs x 2 doses 
Horton, T. M et al. (2008), A Phase 1 and 
pharmacokinetic clinical trial of paclitaxel for 
the treatment of refractory leukemia in children: 
A Children's Oncology Group study. Pediatr. 
Blood Cancer, 50: 788–792. 
 
Rowinsky EK et al. Phase 1 and 
pharmacodynamic study of taxol in refractory 
acute leukemias. Cancer Res. 1989 Aug 
15;49(16): 4640-7 
Palbociclib 
Adult: 125mg PO qday 
x14 days 
 
Pediatric: not studied 
Flaherty KT et al. Phase I, Dose-Escalation Trial 
of the Oral Cyclin-Dependent Kinase 4/6 
Inhibitor PD 0332991, Administered Using a 21-
Day Schedule in Patients with Advanced Cancer. 
Clin Cancer Res  January 15, 2012  18;  568 
Panobinostat 
Adult: 60mg PO M-W-F 
x 2 weeks 
DeAngelo DJ et al. Phase Ia/II, two-arm, open-
label, dose-escalation study of oral panobinostat 
 
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Pediatric: not studied 
administered via two dosing schedules in 
patients with advanced hematologic 
malignancies. Leukemia (2013) 27, 1628–1636 
Pazopanib 
Adult: 800mg PO qday x 
14 days 
 
Pediatric: not studied 
Hurwitz HI, et al. Phase I trial of pazopanib in 
patients with advanced cancer. Clin Cancer Res. 
2009 Jun 15; 15(12):4220-7 
Pemetrexed 
Adult: 2700mg IV over 
25min once 
 
Pediatric: 1910mg/m2 
over 10min once 
Abdel-Karim I et al. A phase 1 study of 
pemetrexed in patients with relapsed or 
refractory acute leukemia. Invest New Drugs 
2011 April;29(2):323-31 
 
Malempati S et al. Phase I trial and 
pharmacokinetic study of pemetrexed in children 
with refractory solid tumors: the Children’s 
Oncology Group. J Clin Oncol. 2008 Jan 
1;26(1):165 
Pentostatin 
Adult: 4mg/m2 IV x 2 
doses 
 
Pediatric: not studied 
Product Information: NIPENT(R) IV injection, 
pentostatin IV injection. Hospira, Inc, Lake 
Forest, IL, 2007. 
Pomalidomide 
Adult: 4mg PO qday x 14 
days 
 
Pediatric: not studied 
Richardson PG et al. Pomalidomide alone or in 
combination with low-dose dexamethasone in 
relapsed and refractory multiple myeloma: a 
randomized phase 2 study. Blood. 
2014;123(12):1826-1832 
Ponatinib 
Adult: 45mg PO qday x 
14 days 
 
Pediatric: not studied 
Cortes MD et al. Ponatinib in refractory 
Philadelphia chromosome-positive leukemias. N 
Engl J Med 2012; 367:2075-2088 
Pralatrexate 
Adult: 15 mg/m² IV 
qweek 
 
Pediatric: not studied 
Horwitz SM, et al. Identification of an active, 
well tolerated dose of pralatrexate in patients 
with relapsed or refractory cutaneous T-cell 
lymphoma. Blood 2012;119(18):4115-22  
Rapamycin 
Adult: 2mg PO qday x 14 
days w/ dose adjustment 
to reach target serum 
concentration of 10-
20pg/ml 
 
Pediatric: not studied 
Sillaber, C., et al (2008), Evaluation of 
antileukaemic effects of rapamycin in patients 
with imatinib-resistant chronic myeloid 
leukaemia. European Journal of Clinical 
Investigation, 38: 43–52. 
Regorafenib 
Adult: 160 mg PO daily 
x 14 days 
 
Pediatric: not studied 
Mross K, et al. A phase 1 dose-escalation study 
of regorafenib (Bay 73-4506), an inhibitor of 
oncogenic, angiogenic, and stromal kinases, in 
patients with advanced solid tumors. Clin Cancer 
Res 2012;18(9):2658-67  
 
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Romidepsin 
Adult: 7 mg/m² IV over 4 
hours on days 1, 3, & 5 
 
Pediatric: not studied  
Amiri-Kordestani L, et al. Phase I trial of a new 
schedule of romidepsin in patients with advanced 
cancers. Clin Cancer Res 2013;19(16):4499-
507(solid tumors) 
Ruxolitinib 
Adult: 25 mg PO BID x 
14 days 
 
Pediatric: not studied 
Eghtedar A, et al. Phase 2 study of the JAK 
kinase inhibitor ruxolitinib in patients with 
refractory leukemias, including 
postmyeloproliferative neoplasm acute myeloid 
leukemia. Blood 2012;119(20):4614-8  
 
Selumetinib 
Adult: 100mg PO BID x 
14 days 
 
Pediatric: not studied 
Jain N et al. Phase II Study of the Oral MEK 
Inhibitor Selumetinib in Advanced Acute 
Myelogenous Leukemia: A University of 
Chicago Phase II Consortium Trial. Clin Cancer 
Res Jan 2014 15;20(2): 490-98 
 
Sorafenib 
Adult: 400 mg PO BID x 
14 days 
 
Pediatric: 150mg/m2 PO 
BID x 14 days 
Borthakur G, et al. Phase 1 study of sorafenib in 
patients with refractory or relapsed acute 
leukemias. Haematologica 2011;96(1):62-8  
 
Widemann BC, et al. A phase 1 trial and 
pharmacokinetic study of sorafenib in children 
with refractory solid tumors or leukemias: a 
Children’s Oncology Group Phase 1 Consortium 
report. Clin Cancer Res. 2012 Nov 1; 
18(21):6011-22 
Sunitinib 
Adult: 50 mg PO qd x 14 
days 
 
Pediatric: 15mg/m2 PO 
qday x 14 days 
Fiedler W, et al. A phase 1 study of SU11248 in 
the treatment of patients with refractory or 
resistant acute myeloid leukemia (AML) or not 
amenable to conventional therapy for the disease. 
Blood 2005;105:986–993. 
 
Dubois SG, et al. Phase 1 and pharmacokinetic 
study of sunitinib in pediatric patients with 
refractory solid tumors: a children’s oncology 
group study. Clin Cancer Res. 2011 Aug 1; 
17(15):5113-22 
Temsirolimus 
Adult: 15 mg/m² IV 
qweek x 2 doses 
 
Pediatric: not studied 
Fujisaka Y, et al. A phase 1 clinical study of 
temsirolimus (CCI-779) in Japanese patients 
with advanced solid tumors. Jpn J Clin Oncol 
2010;40(8):732-8  
Thioguanine 
Adult: 2 mg/kg PO daily 
x 14 days 
 
Pediatric: not studied 
Micromedex  
 
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Topotecan HCl 
Adult: 6 mg/m² IV daily 
over 30 mins on days 1, 
8, 15  
 
Pediatric: 2.4mg/m2/d IV 
for 9 days 
Masuda N, et al. Phase 1 and pharmacologic 
study of weekly bolus topotecan for advanced 
non-small cell lung cancer. Clin Lung Cancer 
2010;11(4):271-9 (NSCLC)  
FDA approved: 1.5 mg/m² IV daily over 30 mins 
x 5 days every 21 day cycle (NSCLC) 
 
Furman WL et al. Protracted intermittent 
schedule of topotecan in children with refractory 
acute leukemia: a pediatric oncology group 
study. J Clin Oncol. 2002 Mar;20(6):1617-24 
Trametinib 
Adult: 2 mg PO qd x 14 
days 
 
Pediatric: not studied 
Infante JR, et al. Safety, pharmacokinetic, 
pharmacodynamics. And efficacy data for the 
oral MEK inhibitor trametinib: a phase 1 dose-
escalation trial. Lancet Oncol 2012 13(8):773-81  
Tretinoin 
Adult: 150 mg/m² PO qd 
x 14 days 
 
Pediatric: 25mg/m2 PO 
BID x 14 days 
Lee JS, et al. Phase I evaluation of all-trans-
retinoic acid in adults with solid tumors. J Clin 
Oncol 1993;11(5):959-66  
 
Testi AM et al. GIMEMA-AIEOPAIDA 
protocol for the treatment of newly diagnosed 
acute promyelocytic leukemia (APL) in children. 
Blood. 2005 Jul 15;106(2):447-53. 
Vandetanib 
Adult: 300mg PO qday 
 
Pediatric: not studied 
 
Caprelsa (vandetanib) [prescribing information]. 
Wilmington, DE: AstraZeneca Pharmaceuticals; 
March 2014 
Vinblastine 
Adult: 6mg/m2 IV on 
days 1 and 15 
 
Pediatric: same as adult 
 
Vinblastine (prescribing information). 
Schaumburg, IL: APP Pharmaceuticals, LLC; 
October, 2011 
Vincristine 
Adult: 2mg IV on days 4 
and 11 
 
Pediatric: 1.5 to 2mg/m2 
IV once weekly, varies 
per protocol 
Kantarjian, H et al (2004), Long-term follow-up 
results of hyperfractionated cyclophosphamide, 
vincristine, doxorubicin, and dexamethasone 
(Hyper-CVAD), a dose-intensive regimen, in 
adult acute lymphocytic leukemia. Cancer, 101: 
2788–2801. 
 
Product Information: vincristine sulfate 
injection, vincristine sulfate injection. Mayne 
Pharma (USA) Inc., Paramus, NJ, 2004 
Vinorelbine 
Adult: 30mg/m2 IV on 
days 1 and 8 
 
Vinorelbine (prescribing information). New 
York, NY: Pfizer; February, 2012. 
 
 
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Pediatric: 20mg/m2 IV on 
days 1 and 8 
Shukla N, Kobos R, Renaud T, et al. Phase II 
trial of clofarabine with topotecan, vinorelbine 
and thiotepa for pediatric patients with relapsed 
or refractory acute leukemia. Pediatr Blood 
Cancer. 2014;61:431-435 
Vorinostat 
Adult: 400mg PO qd x 
14 days 
 
Pediatric: 230mg/m2 PO 
qd x 14 days 
Kelly WK et al. Phase I study of an oral histone 
deacetylase inhibitor, suberoylanilide 
hydroxamic acid, in patients with advanced 
cancer. J Clin Oncol. 2005 Jun 10;23(17):3923-
31 
 
 Fouladi M et al. Pediatric phase I trial and 
pharmacokinetic study of vorinostat: a Children's 
Oncology Group phase I consortium report. J 
Clin Oncol. 2010 Aug 1;28(22):3623-9  
Methotrexate + 
cytarabine 
Adult: MTX 200 mg/m2 
IV over 2 hours followed 
by 800 mg/m2 IV over 24 
hours on day 1; 
cytarabine 3 g/m2 over 2 
hours every 12 hours × 4 
on days 2 and 3  
 
Pediatric: not studied 
Kantarjian HM, et al. Results of treatment with 
hyper-CVAD, a dose-intensive regimen, in adult 
acute lymphocytic leukemia. J Clin Oncol 2000; 
18(3): 547-61 
Mitoxantrone + 
etoposide + 
cytarabine 
Adult: (Mitoxantrone 
6mg/m2 IV bolus, 
etoposide 80mg/m2 IV 
over 1hr, cytarabine 
1g/m2 IV over 6hrs) x 6 
days 
 
Pediatric: mitoxantrone 
12mg/m2 IV D1,3,5; 
cytarabine 100mg/m2 IV 
D1-10, etoposide 
100mg/m2 IV D1-5 
Amadori S, et al. Mitoxantrone, etoposide, and 
intermediate-dose cytarabine: an effective and 
tolerable regimen for the treatment of refractory 
acute myeloid leukemia. J Clin Oncol 1991; 
9(7):1210-1214 
 
Gibson, B. E. S., et al for the United Kingdom 
Childhood Leukaemia Working Group and the 
Dutch Childhood Oncology Group (2011), 
Results of a randomized trial in children with 
Acute Myeloid Leukaemia: Medical Research 
Council AML12 trial. British Journal of 
Haematology, 155: 366–376. 
Cladribine + 
cytarabine + 
mitoxantrone + 
filgrastim 
Adult: Cladrabine 
5mg/m2 IV days 1-5, 
cytarabine 2gm/m2 IV 
days 1-5, mitoxantrone 
10mg/m2 IV days 1-3, 
filgrastim 300 mcg SC 
days -1 through 5 
 
Pediatric: not studied 
Wierzbowska A, et al. Cladribine combined with 
high doses of arabinoside cytosine, mitoxantrone 
and G-CSF (CLAG-M) is a highly effective 
salvage regimen in patients with refractory and 
relapsed acute myeloid leukemia of the poor risk: 
a final report of the Polish Adult Leukemia 
Group. 
 
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Clofarabine + 
cytarabine 
Adult: Clofarabine 
40mg/m2 IV days 2-6, 
cytarabine 1gm/m2 IV 
days 1-5 
 
Pediatric: clofarabine 
52mg/m2 IV days 1-5, 
cytarabine 1gm/m2 IV 
days 1-5  
Faderl S, et al. Clofarabine and cytarabine 
combination as induction therapy for acute 
myeloid leukemia (AML) in patients 50 years of 
age or older. Blood, July 2006, 108(1):45-51 
 
Cooper, T. M., et al (2014), AAML0523: A 
report from the Children's Oncology Group on 
the efficacy of clofarabine in combination with 
cytarabine in pediatric patients with recurrent 
acute myeloid leukemia. Cancer, 120: 2482–
2489 
Fludarabine + 
cytarabine + 
idarubicin + 
filgrastim 
Adult: Fludarbine 
30mg/m2 IV days 1-4, 
cytarabine 2gm/m2 IV 
days 1-4, idarubicin 
12mg/m2 IV days 2-4, 
filgrastim 200mcg SC 
starting day -1 through 
neutrophil recovery 
 
Pediatric: same as above 
Estey E et al. Randomized Phase II Study of 
Fludarabine + Cytosine Arabinoside + Idarubicin 
± All-Trans Retinoic Acid ± Granulocyte 
Colony-Stimulating Factor in Poor Prognosis 
Newly Diagnosed Acute Myeloid Leukemia and 
Myelodysplastic Syndrome. Blood, Apr 1999, 
9(8): 2478-2484 
 
Fleischhack, et al. (1998), IDA-FLAG 
(idarubicin, fludarabine, cytarabine, G-CSF), an 
effective remission-induction therapy for poor-
prognosis AML of childhood prior to allogeneic 
or autologous bone marrow transplantation: 
experiences of a phase II trial. British Journal of 
Haematology, 102: 647–655. 
Fludarabine + 
cytarabine + 
filgrastim 
Adult: Fludarabine 
30mg/m2 IV days 1-5, 
cytarabine 2mg/m2 IV 
days 1-5, filgrastim 
300mcg SC or IV starting 
day -1 through neutrophil 
recovery 
 
Pediatric: same as above 
Virchis, A et al. (2004), Fludarabine, cytosine 
arabinoside, granulocyte-colony stimulating 
factor with or without idarubicin in the treatment 
of high risk acute leukaemia or myelodysplastic 
syndromes. British Journal of Haematology, 124: 
26–32. 
 
McCarthy, A.J., Pitcher, L.A., Hann, I.M. and 
Oakhill, A. (1999), FLAG (fludarabine, high-
dose cytarabine, and G-CSF) for refractory and 
high-risk relapsed acute leukemia in children. 
Med. Pediatr. Oncol., 32: 411–415. 
Azacitidine + 
sorafenib 
Adult: Azacitidine 
75mg/m2 IV qday for 
7days, sorafenib 400mg 
PO BID x 14 days 
 
Pediatric: not studied 
Ravandi, F et al. Phase 2 study of azacytidine 
plus sorafenib in patients with acute myeloid 
leukemia and FLT-3 internal tandem duplication 
mutation. Blood. 2013 Jun 6; 121(23): 4655-
4662 
Idarubicin + 
Bortezomib 
Adult: idarubicin 8mg/m2 
IV and bortezomib 
Howard DS et al. A phase I study using 
bortezomib with weekly idarubicin for treatment 
 
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1.2mg/m2 IV on days 
1,8,15 and 22 
 
Pediatric: not studied 
of elderly patients with acute myeloid leukemia. 
Leuk Res. 2013 Nov; 37(11):1502-8 
 
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Protocol 9226 Eligibility 
I) Inclusion Criteria:    
Each of the following questions (1-9) must be marked "Yes" for the patient to enroll on 
Protocol  9226  
1)  Yes 
 No 
 
Capable of understanding the investigational nature, potential risks and 
benefits of the study, and able to provide valid informed consent. 
Patient signed and dated consent form and HIPAA authorization.    
           
 
 
Date:  ___________  
             
Date of IRB approval of consent form:  __________  
 
 
 
 
2)  Yes 
 No 
 
Diagnosis of acute leukemia by WHO criteria (e.g. acute myeloid leukemia, 
acute lymphoblastic leukemia, acute leukemia of ambiguous origin). 
3)  Yes 
 No 
           Either:  relapsed after or refractory to prior treatment with  at least two 
regimens or lines of treatment. 
 
 
 
Or:  Prior failure of at least one regimen or line of treatment, with 
poor cytogenetic or other risk factors, and ineligible for other clinical 
trials. 
4) Yes 
 
No 
 
Age > 3    
5) Yes 
 
No 
 
ECOG Performance status of 0-3. 
6) Yes 
 
No 
 
Expectation that we can obtain about 10 million blasts from blood and/or 
marrow (e.g., circulating blast count of 5,000 or greater or cellular marrow 
with greater than or equal to 20% blasts). 
7) Yes 
 
No 
 
Adequate renal and hepatic function as defined below (or more stringent 
depending on the individual drugs) function. Please check yes if patient 
meets all of the following criteria: 
 
 
Yes 
 No 
 Bilirubin ≤  1 .5 x Institutional Upper Limit of Normal 
(IULN) unless elevation is thought to be due to Gilbert’s syndrome, 
hemolysis, or hepatic infiltration by the hematologic malignancy, 
 
Yes 
 No 
 SGOT (AST) and SPGT (ALT) ≤  2.5 x IULN, unless 
elevation is thought to be due to hepatic infiltration by the hematologic 
malignancy, 
Yes 
  No 
  Alkaline Phosphatase < 2.5 X ULN, unless elevation is 
thought to be due to hepatic infiltration by the hematologic malignancy, 
Yes 
 No 
 Serum creatinine ≤ 2.0 mg/dL 
 
 
8) Yes 
    No 
 
Willing to use contraception. 
9) Yes 
    No 
 
Expected survival is greater than 100 days. 
 
II) Exclusion Criteria: 
Each of the following questions (10- 13) must be marked "No" for the patient to enroll on 
 
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Document Release Date: 08/21/2020
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Protocol 9226  
10)  Yes  
    No 
 
Active systemic fungal, bacterial, viral or other infection, unless disease is 
under treatment with antimicrobials and considered controlled in the 
opinion of the investigator. 
11) Yes    
   No 
      No other active cancer that requires systemic chemotherapy or radiation     
                                         therapy 
12)  Yes 
     No 
 
Significant organ compromise that will increase risk of toxicity or mortality.  
13)  Yes 
     No 
 
Pregnancy or lactation. 
 
Date of eligibility assessment: _________________ 
 
Name of person completing form:___________________________Phone number:____________ 
 
Signature of person completing form:___________________________Date:___________       
 
Signature of FHCRC Investigator:___________________________Date:___________ 
 
 
ATTACH SIGNED CONSENT AND HIPAA AUTHORIZATION FORMS, AND SEND TO STUDY COORDINATOR< FHCRC 
WITHIN 24 HOURS OF CONFIRMED ELIGIBILITY FOR STUDY TREATMENT. 
 
IRB Approved 
Document Release Date: 08/21/2020
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FAX COVER LETTER 
 
DATE:_______________ 
 
TO: Cody Hammer, Study Coordinator 
 
FAX: (206) 288-6354 
 
RE: RESEARCH SUBJECT REGISTRATION FORM 
PROTOCOL 9226 
Total # of pages (including cover): __________ 
 
FROM:____________________________________ 
 
FAX:______________________________________ 
 
PHONE:___________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRB Approved 
Document Release Date: 08/21/2020
Printed on 9/28/2020