Conditions: Acute Biphenotypic Leukemia Acute Myeloid Leukemia de Novo Myelodysplastic Syndrome Myelodysplastic Syndrome Myeloproliferative Neoplasm
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 84
Healthy volunteers: no

Brief summary:
This phase I/II trial studies the side effects and best dose of filgrastim (granulocyte colony-stimulating factor \[G-CSF\]), cladribine, cytarabine, and mitoxantrone, when given together with sorafenib and to see how well they work in treating patients with newly-diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome (likely to be more aggressive). Drugs used in chemotherapy, such as cladribine, cytarabine, and mitoxantrone 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. Colony-stimulating factors, such as filgrastim, may increase the production of blood cells and may help the immune system recover from the side effects of chemotherapy. Sorafenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving filgrastim, cladribine, cytarabine, and mitoxantrone together with sorafenib may kill more cancer cells.

Detailed description:
OUTLINE: This is a phase I, dose-escalation study of mitoxantrone and sorafenib followed by a phase II study.

INDUCTION: Patients receive mitoxantrone intravenously (IV) over 60 minutes on days 1-3 and sorafenib orally (PO) twice daily (BID) on days 10-19 in the absence of disease progression or unacceptable toxicity. Patients also receive filgrastim subcutaneously (SC) once daily (QD) on days 0-5, cladribine IV QD over 2 hours on days 1-5, and cytarabine IV QD over 2 hours on days 1-5 in the absence of disease progression or unacceptable toxicity. Patients achieving partial remission (including MRD positive \[pos\] CR, CR with incomplete platelet recovery \[CRp\], and CR with incomplete count recovery \[CRi\]) or persistent AML may receive up to 2 cycles of induction therapy per the discretion of the treating physician.

POST-REMISSION: Patients receive sorafenib PO BID on days 8-27 or 3 days prior to next cycle of treatment, whichever occurs first. Patients also receive filgrastim subcutaneously SC QD on days 0-5, cladribine IV QD over 2 hours on days 1-5, and cytarabine IV QD over 2 hours on days 1-5 in the absence of disease progression or unacceptable toxicity. Patients achieving MRDneg CR may receive up to 4 cycles of post-remission therapy. Patients achieving disease response (MRDpos CR, CRi/CRp, or persistent disease) may receive up to two induction cycles and 1 cycle of post-remission therapy with mitoxantrone omitted in cycle 3. If they then enter MRDneg CR, they can proceed with up to a total of 4 cycles of post-remission therapy.

MAINTENANCE THERAPY: Patients achieving MRDneg CR may receive maintenance therapy of sorafenib PO BID for up to 1 year.

After completion of study treatment, patients are followed up every 3 months for up to 5 years.

Arms:
arm 1: See Detailed Description.

Interventions: intervention 1: Cladribine intervention 2: Cytarabine intervention 3: Filgrastim intervention 4: Laboratory Biomarker Analysis intervention 5: Quality-of-Life Assessment intervention 6: Mitoxantrone intervention 7: Sorafenib
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given SC intervention 4: Correlative studies intervention 5: Ancillary studies intervention 6: Given IV intervention 7: Given PO

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
Addition of Sorafenib to G-CSF, Cladribine, Cytarabine and 
Mitoxantrone (G-CLAM) in Adults with Newly-Diagnosed Acute 
Myeloid Leukemia (AML) Independent of FLT3-ITD status: A 
Phase 1/2 Study 
 
 
 
NCT02728050 
 
 
 
 
January 19, 2023 


9510 
 
 
Page 1 of 42 
FRED HUTCHINSON CANCER CENTER 
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE 
 
Current version: 12/29/2022  
Previous version: 7/12/2021 
 
 
Addition of Sorafenib to G-CSF, Cladribine, Cytarabine and 
Mitoxantrone (G-CLAM) in Adults with Newly-Diagnosed 
Acute Myeloid Leukemia (AML) Independent of 
 FLT3-ITD status: A Phase 1/2 Study 
 
Principal Investigator: Anna B. Halpern, MD, Assistant Professor, UW (206-606-1978) 
 
 
 
 
Emergency Phone (24 hours): 
Call the paging operator at the University of Washington Medical Center at 206-598-6190, and 
ask for the Fellow on call for Hematology/Oncology.  
FHCRC IRB Approval  
JAN 19 2023 
Document Released Date


9510 
Page 2 of 42 
OVERVIEW OF TREATMENT PLAN 
G-CSF
Cladribine 
Mitoxantrone* 
Cytarabine 
Sorafenib 
D 1 
D 5 
D 19 
D 10 
D 0 
D 35 
Response Assessment at 
whichever occurs first:  
1. Count recovery to
ANC > 1,000/μL and
platelets > 100,000/μL
OR
2. Between D27 and D35
Induction 
Schedule
(up to 2 courses)
* Mitoxantrone may be given for a maximum of two induction courses.
G-CSF
Cladribine 
Cytarabine 
Sorafenib 
D 1 
D 5 
D 27 or D-3* 
D 8 
D 0 
Post-Remission 
Schedule  
(up to 4 post-remission courses)
Begin next 
course (D 0) 


9510 
 
 
Page 3 of 42 
 
DOSE ESCALATION SCHEME 
 
Induction 
 
Level
G-CSF 
(SQ, D0-D5)1
Cladribine 
(IV, D1-D5)2
Cytarabine 
(IV, D1-D5)2,3 
Mitoxantrone 
(IV, D1-D3)2 
Sorafenib 
(PO, D10-D19) 
 1 
5 µcg/kg 
5 mg/m2 
2 g/m2 
10 mg/m2 
200 mg BID 
2 
5 µcg/kg  
5 mg/m2 
2 g/m2 
12 mg/m2 
200 mg BID  
3 
5 µcg/kg 
5 mg/m2 
2 g/m2 
15 mg/m2 
200 mg BID  
4 
5 µcg/kg 
5 mg/m2 
2 g/m2 
18 mg/m2 
200 mg BID 
5 
5 µcg/kg 
5 mg/m2 
2 g/m2 
18 mg/m2 
400 mg AM, 
200 mg PM 
6 
5 µcg/kg 
5 mg/m2 
2 g/m2 
18 mg/m2 
400 mg BID 
-1 
5 µcg/kg 
5 mg/m2 
2 g/m2 
10 mg/m2 
200 mg QD 
1Dosing based on actual patient weight, rounded to either 300 or 480 µcg, whichever is closer; 
D0 and D1 dose may be omitted if WBC >20,000/μL. 2Dosing based on body surface area (BSA) 
using actual patient weight. 3Starting approximately 2h after completion of cladribine.  
 
Post-Remission Therapy 
 
Level
G-CSF 
(SQ, D0-D5)1
Cladribine 
(IV, D1-D5)2
Cytarabine 
(IV, D1-D5)2,3 
Sorafenib 
(PO, D8 to D-3)4 
 1 
5 µcg/kg 
5 mg/m2 
2 g/m2 
200 mg BID 
2 
5 µcg/kg  
5 mg/m2 
2 g/m2 
200 mg BID  
3 
5 µcg/kg 
5 mg/m2 
2 g/m2 
200 mg BID  
4 
5 µcg/kg 
5 mg/m2 
2 g/m2 
200 mg BID 
5 
5 µcg/kg 
5 mg/m2 
2 g/m2 
400 mg AM,  
200 mg PM 
6 
5 µcg/kg 
5 mg/m2 
2 g/m2 
400 mg BID 
-1 
5 µcg/kg 
5 mg/m2 
2 g/m2 
200 mg QD 
1Dosing based on actual patient weight, rounded to either 300 or 480 µcg, whichever is closer; 
D0 and D1 dose may be omitted if WBC >20,000/μL. 2Dosing based on BSA using actual 
patient weight. 3Starting approximately 2h after completion of cladribine. 4D27 or D-3 (3 days 
before start of next treatment cycle), whichever occurs first 
 
 
 
*Whichever occurs first 


9510 
 
 
Page 4 of 42 
TABLE OF CONTENTS 
 
OVERVIEW OF TREATMENT PLAN  
 
 
 
 
 
 2 
DOSE-ESCALATION SCHEME  
 
 
 
 
 
 
 3 
 
1.0 Background and Rationale  
 
 
 
 
 
 
 5 
2.0 Objectives  
 
 
 
 
 
 
 
 
 9 
3.0 Patient Eligibility   
 
 
 
 
 
 
 
 9 
4.0 Evaluation and Counseling of Patient  
 
 
 
 
 
10 
5.0 Protocol Registration  
 
 
 
 
 
 
 
11 
6.0 Treatment Plan 
 
 
 
 
 
 
 
   
11 
7.0 Information on Study Drugs  
 
 
 
 
 
 
17 
8.0 Evaluations and Endpoint Definitions  
 
 
 
 
 
22 
9.0 Records 
 
 
 
 
 
 
 
 
 
24 
10.0 Correlative Studies 
 
 
 
 
 
 
 
24 
11.0 Protocol Enrollment and Special Considerations  
 
 
 
24 
12.0 Guidelines for Serious Adverse Event Reporting  
 
 
 
25 
13.0 Data and Safety Monitoring Plan  
 
 
 
 
 
26 
14.0 Ethical and Regulatory Considerations   
 
 
 
 
27 
15.0 Statistical Considerations for Phases 1 and 2 
 
 
 
 
28 
16.0 Study Termination  
 
 
 
 
 
 
 
29 
17.0 References  
 
 
 
 
 
 
 
 
30 
 
Appendix A:  Treatment-Related Mortality (TRM) Score  
 
 
33 
Appendix B:  Cardiotoxicity Index of Anthracyclines 
 
 
 
34 
Appendix C: European Organization for Research and Treatment of Cancer 
35 
QLQ-C30 questionnaire 
Appendix D:  Management of Toxicities Specific to Sorafenib 
 
 
37 
Appendix E: Study Medication Diary 
 
 
 
40 
 
 


9510 
 
 
Page 5 of 42 
1.0 
BACKGROUND AND RATIONALE 
Acute myeloid leukemia (AML) in adults remains difficult to treat, with only gradual 
improvements made over the last 3-4 decades [1, 2]. Although many patients will achieve a 
complete remission (CR) with 1 or 2 courses of intensive induction chemotherapy, the majority 
will ultimately relapse, and few patients will be alive 3-5 years after diagnosis [1, 2]. Therefore, 
the need for improved first-line therapies for AML is unquestioned. A major area of current 
interest is the use of small molecule inhibitors as a means to improve outcomes in AML. The 
major impetus for this current study are early results from a randomized trial reported by Röllig 
et al. at the 2014 annual meeting of the American Society of Hematology (ASH) [3] showing 
that the addition of the multikinase inhibitor sorafenib to standard induction therapy with 7+3 
improves event-free survival (EFS) in adults <60 years of age with newly-diagnosed AML 
compared to placebo independent of the FLT3/ITD mutation status. The latter is relevant since 
75-80% of patients with newly diagnosed AML do not harbor FLT3/ITD abnormalities. Two 
noteworthy aspects of this proposal are the use of G-CLAM (G-CSF, Cladribine, CytArabine, 
and Mitoxantrone) as the chemotherapy backbone and its choice of endpoints: CR without 
minimal residual disease (MRD) as primary efficacy endpoint and exploratory endpoints 
including quality of life (QOL) and healthcare resource utilization. 
 
G-CLAM 
The MRC/NCRI AML 15 trial involved approximately 3,200 newly diagnosed patients with 
AML and strongly suggested that FLAG-Ida (Fludarabine, CytArabine, G-CSF, and Idarubicin) 
is a more effective anti-AML regimen than daunorubicin with standard dose cytarabine (DA) or 
DA with addition of etoposide ([ADE]; 1,268 of these patients participated in the direct 
comparison of FLAG-Ida to ADE with a median age 48 [12-13% age 60+]) [4]. This study found 
that patients randomized to FLAG-Ida had a lower cumulative incidence of relapse than the other 
regimens (p<0.001; at 3 years: 38% vs. 55%), perhaps reflective of more patients achieving CR 
after 1 course of therapy. Death in CR was more common with FLAG-Ida (17% vs 11%), thus 
narrowing the difference in survival. However, given improvements in supportive care [5], it is 
likely only a matter of time before FLAG-Ida replaces 7+3 as the standard induction regimen for 
newly-diagnosed AML. 
 
At our institution, we have used G-CLAM rather than FLAG-Ida based on previously published 
data and our phase 1/2 trial experience using this regimen ( [6, 7]; additionally, an abstract based 
on the Phase I data for the relapsed/refractory arm has been accepted for presentation at ASH in 
December 2015). G-CLAM differs from FLAG-Ida in the use of mitoxantrone rather than 
idarubicin and, primarily, in the substitution of cladribine for fludarabine. Cladribine is a more 
active single agent in AML than fludarabine; a Polish 3-way randomized trial in 652 adults aged 
< 60 years found that while addition of fludarabine to 7+3 did not improve survival, addition of 
cladribine to 7+3 did, with results principally due to superior outcome in patients with adverse 
cytogenetics [8]. Single arm studies from the Moffitt Cancer Center suggest that cladribine plus 
high-dose cytarabine is more effective than mitoxantrone, etoposide and cytarabine (MEC) for 
relapsed/refractory disease [9], and the combination of cladribine, cytarabine, and mitoxantrone 
has produced encouraging results in similar patients at Moffitt [10] and in Poland [11].  
 
Since 2014, we have treated 61 patients with newly-diagnosed AML/high-risk MDS on our 
clinical trial with G-CLAM with dose-escalated doses of mitoxantrone. This cohort had a median 


9510 
 
 
Page 6 of 42 
age of 57 years with the following cytogenetic profiles by MRC criteria [12]: cytogenetically 
favorable (n=4), intermediate (n=43), adverse (n=13), and unknown (n=1). The study 
investigated mitoxantrone at 12 mg/m2, 14 mg/m2, 16 mg/m2, and 18 mg/m2 (rather than 10 
mg/m2 as used in the original G-CLAM regimen), and the highest dose level was found to have 
acceptable toxicity and tolerability. Among the 57 treated patients that are thus far evaluable for 
response, the overall response rate (ORR) was 87.7% with 75.4% achieving a CR, 5.3% a CR 
with incomplete platelet recovery (CRp), and 7.0% a CR with incomplete blood count recovery 
(CRi). Of the responders (including CRp/i), 90.0% had no evidence of MRD by flow cytometry 
at best response (MRDneg). Overall, the MRDneg CR rate for all patients was 68.4%. Generally, 
the regimen has been well tolerated, with neutropenic fever, rash, nausea, and hypoxia (fluid 
overload/infection-related) seen as the most common grade ≥3 adverse events. Our phase 2 study 
is now ongoing with mitoxantrone at the 18 mg/m2 dose level, and G-CLAM continues to serve 
as our principal treatment for newly-diagnosed AML. The MRDneg CR rate from this study will 
serve as the null rate for comparison with G-CLAM plus sorafenib. 
 
Sorafenib 
Sorafenib is an oral, small molecular, multikinase inhibitor which affects specific targets that are 
critical for tumor cell proliferation including the serine/threonine kinases c-Raf and B-Raf and 
the receptor tyrosine kinases RET, Flt-3 and c-Kit [13]. Sorafenib has potent in vitro activity 
against receptor tyrosine kinases important in tumor angiogenesis including the vascular 
endothelial growth factor receptor family (VEGFR1-3) and platelet derived growth factor-beta 
(PDGFR) [13]. In vivo, the anti-tumor activity of sorafenib is driven by its direct effects on 
tumor growth through its inhibition of the Raf/MEK/ERK pathway and the anti-angiogenic 
activity of the compound. Sorafenib demonstrates broad anti-tumor activity in human tumor 
xenograft models of liver, kidney, lung, prostate, breast and leukemia.  
 
Sorafenib as a single agent has been evaluated globally in multiple phase 1 and 2 trials in various 
malignancies. Two pivotal international, multi-institutional, single agent, randomized, placebo-
controlled trials led to sorafenib’s approval for renal cell carcinoma and hepatocellular 
carcinoma worldwide [14, 15]. Since then, sorafenib has also been approved for locally recurrent 
or metastatic differentiated thyroid cancer refractory to radioactive iodine (2013). In patients 
with AML, there is thus far some limited experience with sorafenib in combination with standard 
chemotherapy in early phase clinical trials in both younger and older age populations. In a phase 
1/2 study of sorafenib in combination with cytarabine (1.5g/m2 daily via continuous infusion x 4 
days) and idarubicin (IA) in patients <65 years with newly-diagnosed AML, Ravandi et al. 
demonstrated that sorafenib in doses up to 400 mg PO BID was safe and well tolerated. Among 
61 patients, a CR rate of 79% was observed. Overall, there was a 95% CR/CRp rate for FLT3-
mutated patients and an 84% CR/CRp rate for FLT3 wild-type patients. The median overall 
survival (OS) and disease-free survival were 29 and 13.8 months for mutated and wild-type 
patients, respectively [16, 17]. The most common grade 3 and 4 adverse events that were 
considered possibly associated with the addition of sorafenib to the induction regimen occurred 
in 15 patients and included nausea/vomiting, cardiac/hypertension, diarrhea, infections, hand and 
foot syndrome, liver toxicity, and pancreatitis.  
 
Likewise, in the abstract noted above by Röllig et al. [3], 276 younger adults with AML were 
randomized to either daunorubicin with cytarabine (or cytarabine and mitoxantrone [HAM] if no 
response to initial induction) with placebo or sorafenib at 800 mg PO daily on days 10-19 during 


9510 
 
 
Page 7 of 42 
induction, starting on day 8 up to 3 days prior to the next cycle during consolidation, and then 
daily for 12 months after the end of consolidation. CR rates were 59% vs. 60% in the placebo vs. 
sorafenib arm (p=0.76) but median event-free survival (EFS) was 9.2 months in placebo 
compared with 20.5 months in sorafenib arm, translating to a 3-year EFS of 22% vs. 40% 
respectively (p=0.013). Median OS has not yet been reached and is similar in both arms. There 
was a higher rate of fever, bleeding, and hand-foot syndrome in the sorafenib arm. Of note, the 
beneficial effect of sorafenib was due mostly to results in patients who were FLT3/ITD wild-type 
and who comprised the majority of patients in the study, as is true in the general AML 
population. In contrast, Serve et al. conducted a randomized trial with sorafenib, involving 211 
patients >60 years of age to either cytarabine, daunorubicin (7+3) and placebo or 7+3 in 
combination with sorafenib, and found higher treatment-related mortality (early death) for 
sorafenib vs. placebo (17% vs. 7%, p=0.052), and non-significantly lower CR rates in the 
sorafenib arm (48% vs 60%, p=0.12) [18]. Therefore, sorafenib given in combination with 
chemotherapy is not currently recommended for elderly patients with AML.  
 
The above considerations lead to this current trial in which the primary objective is to assess 
whether G-CLAM + sorafenib might improve MRDneg CR rates compared to G-CLAM alone in 
patients age ≤60. Because there is no experience with addition of sorafenib to G-CLAM, the first 
phase of the trial will involve both escalating the dose of mitoxantrone and establishing a 
maximally tolerated dose (MTD) of sorafenib when added to G-CLAM. The initial dose of 
mitoxantrone, 10 mg/m2 daily for 3 days, is below FDA-labeling for AML at 12mg/m2, and the 
initial dose of sorafenib is 50% that used by Röllig et al. We chose this mitoxantrone dose as the 
starting dose as it is the dose used in conjunction with G-CLAM as initially developed by the 
Polish AML group and published in the literature [11]. We are increasing the dose of 
mitoxantrone, as we did in G-CLAM alone,  due to past studies suggesting a benefit of escalated 
doses of anthracyclines in adults AML [19, 20] , as well as our own prior experience with 
tolerance and efficacy of escalated doses of mitoxantrone in G-CLAM. In the phase 1 portion of 
this study, we plan to determine if sorafenib can be added to G-CLAM and if the higher doses of 
mitoxantrone remain well tolerated when given in conjunction with sorafenib. After establishing 
tolerability and determining the MTD of both mitoxantrone and sorafenib, we will move to the 
phase 2 portion to assess the efficacy of this combination. Of note, as prior studies incorporating 
sorafenib in combination with chemotherapy had varying schedules of administration of 
sorafenib – either concurrent or starting after chemotherapy commencement – and while the 
optimal delivery of drug is unknown, our study will generally mimic the administration schedule 
used by Röllig et al. due to their success with this schedule.  
 
MRDneg CR 
Similar to other malignancies, overall survival is the most relevant drug efficacy endpoint in 
AML. However, events can occur in a relatively delayed fashion compared to the treatment 
under investigation, and surrogate endpoints are typically considered to render early phase drug 
testing more efficient [21]. For many years, CR was regarded as such an endpoint. Although 
achieving a CR appears necessary for long-term survival in AML after intensive chemotherapy, 
CR in itself is not sufficient to prolong survival [22, 23]. One plausible explanation is that 
conventionally defined CRs vary widely in their quality, with only high quality CRs translating 
into a survival advantage. In particular, presence of MRD at the time of CR (as contrasted with 
lesser degrees of response such as CR with incomplete platelet or neutrophil recovery 
[CRp/CRi], either of which is more prone to relapse than CR) is independently associated with 


9510 
 
 
Page 8 of 42 
relapse and thus indicates a poor quality CR [24]. Indeed, once account is made for response (CR 
vs CRp/CRi) and presence/absence of MRD at CR, pre-treatment covariates conventionally 
predictive of relapse (adverse cytogenetics, secondary AML, newly-diagnosed vs. relapsed 
disease) lose much of their significance. Consequently, the goal of induction therapy in AML 
might be attainment of a CR without MRD, with MRD defined by multi-parameter flow 
cytometry and/or persistent cytogenetic abnormalities. An attractive feature of CR without MRD 
is that this rate is only about 75% as high as CR rates, which in younger patients have averaged 
75-80%. Hence, the ability to detect improved rates of MRDneg CR is greater than the ability to 
do the same with CR. Therefore, the primary focus of this study is the MRDneg CR rate. 
 
QOL/Resource Utilization Endpoints 
In addition to using MRDneg CR as our primary endpoint, we will also plan to evaluate QOL 
and healthcare resource utilization as exploratory endpoints since, as we note above, some argue 
that an emphasis on endpoints other than survival - which can take years to demonstrate in AML 
- might facilitate faster drug development for this disease [25]. Given that improvements in 
survival have been difficult to demonstrate in AML, studies that measure QOL over time and in 
different phases of disease (remission vs. relapse), are critical to define criteria for non-survival 
benefits provided by AML therapies. For example, while response to a certain therapy may not 
prolong survival for a patient, being in a CR in itself might provide some QOL benefit. Thus far, 
the relationship between treatment response and better QOL has been poorly-studied [25, 26], 
although intuitively there would be a positive relationship given the high morbidity of this 
disease.  
 
Despite the acceptance of QOL as a valid endpoint for drug development, it is underutilized in 
AML as methodological limitations have historically impeded the use of QOL metrics in this 
disease. Due to the morbidity and mortality of AML, the dropout rate for use of these types of 
measures is high [25], requiring large sample sizes that often are not available in AML trials, 
especially if they are not tied to new therapeutic options. Additionally, while there are a number 
of clinical events associated with AML and its treatment that are objective, easily measured, and 
likely have a large impact on QOL - such as hospitalizations, infection rates, transfusion needs, 
or “healthcare resource utilization” - there is no currently available composite score that 
incorporates these measures and thus they can be difficult to compare across treatment regimens. 
We hope to address these historical limitations by incorporating the evaluations of QOL and 
resource assessments into an induction and remission therapy protocol with regular clinic visits 
tied to the patient’s therapy.  
 
It is conceivable that a reduction of the high burden of morbidity of AML and its treatment on 
both the patient and the healthcare system could lead to improvements in QOL and healthcare 
costs and therefore would be valuable. In our prior trial of G-CLAM alone, we have been 
tracking some healthcare resource utilization measures, such as time to blood count recovery, 
and its effect on infection rates, hospitalization duration and transfusion needs. We would like to 
expand this evaluation to the proposed trial on a larger scale and include QOL and cost analysis 
as well. 
 


9510 
 
 
Page 9 of 42 
2.0  
OBJECTIVES 
 
2.1  
Primary Objective 
2.1.1 
For phase 1, to assess the maximum tolerated dose (MTD) of sorafenib used in 
combination with dose-intensified mitoxantrone as part of the G-CLAM regimen 
in adults with newly-diagnosed AML/high-risk myelodysplastic syndromes 
(MDS).  
2.1.2 For phase 2, to determine if the addition of sorafenib to G-CLAM improves the 
rate of MRDneg CR compared with our center’s historical control of G-CLAM 
alone in adults with newly-diagnosed AML/high-risk MDS. 
 
2.2  
Secondary Objectives 
2.2.1 To estimate rates of CR, ORR, OS, EFS, and relapse-free survival (RFS) after the 
addition of sorafenib to G-CLAM in patients with newly-diagnosed AML/high-
risk MDS. 
2.2.2 To describe the toxicity profile and safety (rate of adverse events) of sorafenib in 
combination with G-CLAM.  
 
2.3 
Exploratory Objectives 
2.3.1 To assess the feasibility of incorporating QOL, cost and healthcare resource 
utilization endpoints in to a phase 1/2 clinical trial for newly diagnosed AML. 
 
2.3.2 To investigate, within the limits of a phase 1/2 trial, the impact of study treatment 
and response on quality of life, cost, and healthcare resource utilization for 
patients with AML undergoing intensive chemotherapy. 
 
 
3.0  
PATIENT ELIGIBILITY 
 
3.1  
Inclusion Criteria 
3.1.1 Age 18-60 years, inclusive 
3.1.2 Newly diagnosed disease with either a diagnosis of “high-risk” MDS (≥10% 
blasts in marrow or blood), high-risk myeloproliferative neoplasm (MPN; >10% 
blasts in blood or bone marrow), or AML other than acute promyelocytic 
leukemia (APL) with t(15;17)(q22;q12) or variants according to the 2008 WHO 
classification [27, 28]. Patients with biphenotypic AML are eligible. Such “high-
risk” MDS or MPN have natural history much closer to AML than to lower risk 
MDS or MPN and have responded similarly to “AML-type” therapy [29]. 
 3.1.3 Outside diagnostic material is acceptable as long as peripheral blood and/or bone 
marrow slides are reviewed at the study institution by appropriate clinical staff. 
Flow cytometric analysis of peripheral blood and/or bone marrow should be 
performed according to institutional practice guidelines. 


9510 
 
 
Page 10 of 42 
3.1.4 Treatment-related mortality (TRM) score ≤13.1as calculated with simplified 
model: https://cstaging.fhcrc-research.org/TRM/Default.aspx or APPENDIX A 
[30].  
3.1.5  The use of hydroxyurea prior to study registration is allowed. Patients with 
symptoms/signs of hyperleukocytosis, WBC >100,000/μL, or acute symptoms 
can be treated with leukapheresis or may receive up to 2 doses of cytarabine (up 
to 500 mg/m2/dose) prior to study day 0 enrollment. 
 
 
3.1.6 Adequate organ function: 
3.1.6.1 Bilirubin ≤2 times Institutional Upper Limit of Normal unless elevation is 
thought to be due to hepatic infiltration by AML, Gilbert’s syndrome, or 
hemolysis (assessed within 10 days prior to study day 0).  
3.1.6.2 Serum creatinine ≤2.0 mg/dL (assessed within 10 days prior to study day 
0). 
3.1.6.3 Left ventricular ejection fraction ≥45%, assessed within 3 months prior to 
study day 0, e.g. by MUGA scan or echocardiography, or other appropriate 
diagnostic modality and no clinical evidence of congestive heart failure.  
3.1.7 Women of childbearing potential and men must agree to use adequate 
contraception beginning at the signing of the consent until at least 3 months after 
the last dose of study drug.   
3.1.8    Provide written informed consent (or legal representative). 
 
3.2  
Exclusion Criteria   
3.2.1 Myeloid blast crisis of chronic myeloid leukemia (CML), unless patient is not 
considered candidate for CML-directed tyrosine kinase inhibitor treatment 
(excluding sorafenib). 
3.2.2 Concomitant illness associated with a likely survival of <1 year. 
3.2.3 Active systemic fungal, bacterial, viral, or other infection, unless disease is under 
treatment with anti-microbials and/or controlled or stable (e.g. if specific, 
effective therapy is not available/feasible or desired [e.g. chronic viral hepatitis, 
HIV]). Patient needs to be clinically stable as defined as being afebrile and 
hemodynamically stable for 24-48 hours prior to study day 0, unless fever is 
thought to be secondary to the underlying hematologic disease.  
3.2.4 Active or clinically significant (or symptomatic) cardiac disease, including active 
coronary artery disease, cardiac arrhythmias requiring anti-arrhythmic therapy 
other than beta blockers or digoxin within the last 3 months, unstable angina 
(anginal symptoms at rest), new-onset angina within 3 months before 
randomization, or myocardial infarction within 6 months before study day 0. 
 
3.2.5 Previous receipt of azacitidine, decitabine, anthracyclines, cytarabine, or other 
nucleoside analogues for treatment of AML or MPN/MDS other than as noted for 
cytarabine in 3.1.5. 
 
 
3.2.6  Pregnancy or lactation. 


9510 
 
 
Page 11 of 42 
3.2.7  Concurrent treatment with any other investigational agent that has anti-leukemia 
activity or another drug with anti-AML-activity. 
 
4.0  
EVALUATION AND COUNSELING OF PATIENT 
 
 
The patient will be completely evaluated with a history, physical examination, diagnostic 
testing if necessary, and review of outside slides and records if available. The protocol will be 
discussed thoroughly with the patient and family (if present), with description of all known risks 
to the patient. Alternative forms of treatment will be presented as objectively as possible, and the 
risks and hazards of the study explained to the patient. Consent will be obtained using forms 
approved by the local Institutional Review Board (IRB). 
 
 
5.0  
PROTOCOL REGISTRATION 
 
 
Subjects will be registered by the UW Study Coordinator and entered into the 
institutional clinical trials management system. A complete, signed, study consent and HIPAA 
consent are required for registration.  
 All eligibility requirements according to section 3.0 must be met. To complete the registration 
process, the Principal Investigator or her designee will assign a patient study number, and 
register the patient on the study.  
 
 
6.0  
TREATMENT PLAN 
 
 
This study is a single-center, open-label phase 1/2 study of sorafenib in combination with 
G-CLAM for adults with newly diagnosed AML or high-risk MDS/MPN at the Fred Hutchinson 
Cancer Research Center/University of Washington. It will employ a 6+6 dose escalation rule in 
phase 1 and a Simon 2-stage design in phase 2 as described in Section 15. 
 
Study Overview 
After study enrollment, patients will receive a first cycle of G-CLAM + sorafenib at one 
designated dose level. Post-induction bone marrows will be reassessed upon blood count 
recovery or between day Days +28 to +35 after start of chemotherapy, whichever occurs first, 
unless otherwise dictated by the patient’s course of clinical treatment. If the patient remains 
without count recovery (defined as ANC <500/µL and platelet count <50,000/µL) in the setting 
of an aplastic marrow (with <5% blasts), the next course of therapy will be held until (a) until 
bone marrow blasts are ≥5% OR (b) the patient has count recovery to ANC >500/µL and platelet 
count >50,000/µL.  Patients with MRDneg CR can go on to receive up to 4 courses of post-
remission therapy with G-CLA + sorafenib (i.e. with same regimen as used during induction but 
omission of mitoxantrone). Patients with partial remission (including MRDpos CR, CR with 
incomplete platelet recovery [CRp], CR with incomplete count recovery[CRi]) or persistent 
AML are eligible to receive a 2nd course identical to induction provided any extra-medullary 
toxicities have resolved to ≤grade 2 with appropriate dose reductions if extra- medullary 
toxicities ≥grade 3 occurred during cycle 1. Patients in MRDpos CR, CRp or CRi after a 2nd 
course may receive a 3rd course with G-CLA + sorafenib (mitoxantrone omitted) at their current 
dose level. Patients still not in MRDneg CR after this 3rd course are removed from study. Patients 
with MRDneg CR after completion of post-remission therapy are eligible to receive maintenance 
therapy for up to 1 year with daily sorafenib at the final dose they received during induction, 


9510 
 
 
Page 12 of 42 
with subsequent dose adjustments if necessary based on cytopenias and extra-medullary 
toxicities.  
 
6.1  
Baseline/Pre-Treatment Assessment 
The following studies should be obtained at baseline before initiation of study therapy to 
establish trial eligibility and allow patient characterization and disease prognostication. 
Results of tests and/or procedures conducted as per standard of care may be used to 
determine study eligibility if conducted within an appropriate window prior to screening. 
Outside testing and previously collected clinical data may be used if within the 
appropriate time frame. 
6.1.1 History and physical examination (assessed within 10 days prior to study day 0). 
6.1.2 Peripheral blood or bone marrow examination with morphologic and flow 
cytometric assessment, routine cytogenetic analysis, and molecular testing 
(FLT3/ITD, NPM1, CEBPA, or mutation profiling assay when available); a bone 
marrow biopsy should be obtained if spicules are absent from the aspirate sample 
(aspirate and biopsy to be assessed within 2 months prior to study day 0). 
6.1.2 Complete blood counts with differential blood count and platelet count (assessed 
within 10 days prior to study day 0). 
6.1.3 Metabolic panel, including bilirubin, albumin, and creatinine (assessed within 10 
days prior to study day 0). 
6.1.4 MUGA scan or echocardiography, or other appropriate diagnostic modality, to 
assess left ventricular ejection fraction (LVEF; assessed within 3 months prior to 
study day 0). 
6.1.5 For patients with a history of cardiac disease, a baseline ECG is recommended. 
Further ECG monitoring while taking sorafenib should be done at the discretion 
of the treating physician and PI, taking into account any concomitant QTc 
prolongation medications and electrolyte abnormalities.  
 
6.2 
Pre-Treatment 
 
 
At the discretion of the treating physician, allopurinol 300 mg PO daily (or equivalent 
dose adjusted for renal function) may be considered in all patients without known allergies to 
allopurinol to reduce the risk of tumor lysis. Higher doses of allopurinol are permitted if patients 
develop tumor lysis syndrome. Patients may receive rasburicase, a recombinant uric acid 
oxidase, for the prevention and/or treatment of tumor lysis syndrome at the discretion of the 
treating physician. All patients should be adequately hydrated and receive anti-emetics as 
necessary. 
 
6.3 
Administration of Sorafenib and Mitoxantrone 
 
 
6.3.1 For induction: patients will receive sorafenib and mitoxantrone at 1 of 6 total dose 
levels as allocated (see section Dose Escalation Scheme page 2 or 15.1.2). 
Mitoxantrone will be given IV daily over 60 minutes Days 1-3 and sorafenib 
orally Days 10-19 for all levels. Allowances of +/- 2 days for this window will be 
allowed for logistical purposes. Levels are as follows: Level 1, mitoxantrone 10 
mg/m2 with sorafenib 200 mg PO twice daily; Level 2, mitoxantrone 12 mg/m2 
with sorafenib 200 mg PO twice daily; Level 3, mitoxantrone 15 mg/m2 with 


9510 
 
 
Page 13 of 42 
sorafenib 200 mg PO twice daily; Level 4, mitoxantrone 18 mg/m2 with sorafenib 
200 mg PO twice daily; Level 5, mitoxantrone 18 mg/m2 with sorafenib 400 mg 
PO in the morning and 200 mg in the evening; Level 6, mitoxantrone 18 mg/m2 
with sorafenib 400 mg PO twice daily. Level -1, dosed at mitoxantrone 10 mg/m2 
and sorafenib 200 mg PO once daily will also be available for dose de-escalation 
due to toxicities, as described in Section 6.8. For baseline organ dysfunction 
within the allowable limits of the eligibility criteria, dose reduction of individual 
medications specific to the organ impairment (e.g. liver, kidney) are allowed but 
not required, as described in section 6.10, and should be done in conjunction with 
the Oncology Pharmacist and PI.  
 
 
6.3.2 The dose of mitoxantrone is calculated using the patient’s actual weight. 
 
 
6.3.3 For post-remission therapy: sorafenib will be given per dose level as above, 
starting on day 8 until day 27 or 3 days prior to next cycle of treatment, whichever 
occurs first. Allowances of +/- 3 days for this window will be allowed for 
logistical purposes (i.e. timing of clinic visit for count evaluation). 
6.3.4 For maintenance: sorafenib will be given daily for up to 12 months following 
post-remission at the final dose the patient received during induction, with 
subsequent dose adjustment based on blood counts and extra-medullary toxicities.  
6.3.5 All treatment is given as intent-to-treat; missed doses will not be made up. 
 
6.4 
Administration of G-CSF, Cladribine, and Cytarabine 
 
 
6.4.1  The doses of the elements of G-CLAM chemotherapy will be as follows: G-CSF 
5 µcg/kg rounded to 300 or 480 µcg daily subcutaneously daily on Days 0-5, 
Cladribine 5 mg/m2 IV daily over 2 hours on Days 1-5, and Cytarabine 2 g/m2 IV 
daily over 2 hours on Days 1-5.  
 
 
6.4.2 The doses of G-CSF, cladribine, and cytarabine are calculated using the patient’s 
actual weight. 
 
 
6.4.3 Days 0 and 1 G-CSF may be omitted at physician discretion for WBC 
>20,000/µL or signs/symptoms of leukostasis. 
 
 
6.4.4 Administration in the outpatient clinic can be considered but should be discussed 
with the study investigators. 
6.4.5 All treatment is given as intent-to-treat; missed doses will not be made up. 
6.4.6 No investigational or commercial agents or therapies other than those described 
herein may be administered with the intent to treat the patient's malignancy.  
 
6.5  
Monitoring during/after Induction and Post-Remission Therapy 
For patient monitoring, the following studies and study intervals are suggested: 
6.5.1 Complete blood counts with differential blood count, including immature 
cells/blasts, and platelet count at least 2 times weekly until ANC >1,000/µL and 
then at least weekly until platelet count >100,000/µL. 
6.5.2 Metabolic panel, including bilirubin, ALT/AST, and creatinine at least weekly 
until ANC >1,000/µL and platelet count >100,000/µL. 


9510 
 
 
Page 14 of 42 
6.5.3 Blood pressure monitoring on a weekly basis through the first 6 weeks of therapy 
is recommended. Thereafter, it is recommended that blood pressure should be 
monitored monthly as long as the patient remains on sorafenib. 
6.5.4 If patients develop signs or symptoms suggestive of cardiac dysfunction, LVEF 
should be assessed using the same method to evaluate baseline LVEF status 
(MUGA scan or echocardiography, or other appropriate diagnostic modality).   
 
6.6  
Assessment for Response after First Induction Course 
 
 
A bone marrow aspirate should be obtained upon blood count recovery (i.e. ANC 
>1,000/µL and platelet count >100,000/µL) or between Days +28 to +35 after start of G-CLAM 
chemotherapy, whichever occurs first; unless otherwise dictated by the patient’s course of 
clinical treatment (e.g. can be delayed per treating physician discretion if clinically indicated). A 
bone marrow biopsy need only be obtained during this procedure if spicules are absent from the 
aspirate sample.. MRD will be defined in all response assessments by evidence of disease on 
flow cytometry at any level greater than zero. 
6.6.1 Patients achieving MRDneg CR: Patients are eligible to receive up to 4 courses of 
post-remission therapy with G-CLA + sorafenib (mitoxantrone omitted).  
6.6.2 Patients achieving an MRDpos CR: Patients are eligible for a second course of 
therapy using the same dosing guidelines as course 1 (e.g. G-CLAM and 
Sorafenib given days 10-19) on their assigned dose level. If they again achieve an 
MRDpos CR, they can go on to receive a 3rd course, per discretion of the treating 
physician, with mitoxantrone omitted for course 3. If an MRDneg CR is not 
achieved after course 3, they will be removed from the study.  
6.6.3 Patients with CRi/CRp: Patients with incomplete blood count or platelet recovery, 
regardless of MRD status, are eligible for a second course of therapy using the 
same dosing guidelines as course 1 (e.g. G-CLAM and Sorafenib given days 10-
19) on their assigned dose level. If they again achieve a CRi/p (regardless of 
MRD), they can go on to receive a 3rd course, per discretion of the treating 
physician, with mitoxantrone omitted for course 3. If an MRDneg CR is not 
achieved after course 3, they will be removed from the study. 
6.6.4 Patients with persistent disease: Patients with persistent AML (≥5% blasts) are 
eligible for a second course of induction chemotherapy at the same dosing used in 
course 1 (e.g. G-CLAM and Sorafenib given days 10-19) on their assigned dose 
level, provided all non-hematologic toxicities have resolved to Grade <2. If they 
are not in CR after the 2nd induction course, they can go on to receive a 3rd course, 
per discretion of the treating physician, with mitoxantrone omitted for course 3. If 
an MRDneg CR is not achieved after course 3, they will be removed from the 
study. 
6.6.5 Patients with persistent aplasia without evidence of disease after Day +49: 
patients will be removed from protocol. 
6.6.6    For patients who experienced ≥Grade 3 non-hematologic toxicities excluding 
neutropenic fever and infections during the first induction, dose reductions are 
allowed but not required for this cycle as discussed in section 6.10. 
 
6.7  
Assessment for Response after a Second Induction Course 


9510 
 
 
Page 15 of 42 
If a patient receives a second induction course (s per section 6.6.2-6.6.4), a bone marrow  
aspirate should again be obtained upon blood count recovery (i.e. ANC >1,000/µL and 
platelet count >100,000/µL) or between Days +28 to +35 after start of G-CLAM  
chemotherapy, whichever occurs first, unless otherwise dictated by the patient’s course  
of clinical treatment. A bone marrow biopsy need only be obtained  
during this procedure if spicules are absent from the aspirate sample. 
 
6.7.1 Patients achieving MRDneg CR: Patients are eligible to receive up to 4 courses of 
post-remission therapy with G-CLA + sorafenib (mitoxantrone omitted).  
6.7.2 All other patients (MRDpos CR, CRi/CRp, persistent disease): Patients are 
eligible for a third course of therapy, per discretion of the treating physician, with 
mitoxantrone omitted for course 3 (G-CLA) and Sorafenib given on days 8-27 or 
3 days prior to next cycle of treatment, whichever occurs first. If an MRDneg CR 
is not achieved after course 3, they will be removed from the study.  
6.7.3 Patients with persistent aplasia without evidence of disease after Day +49: 
patients will be removed from protocol. 
 
6.8 
Post-Remission Therapy 
After achievement of an MRDneg CR with G-CLAM+sorafenib, patients are eligible for post-
remission therapy with G-CLA+sorafenib. 
 
 
6.8.1 The treatment is identical to the induction course but without mitoxantrone (i.e. 
G-CSF, cladribine, and cytarabine, or “G-CLA” + sorafenib, at same dose level as 
induction). If that patient had excessive toxicities (grade >3 non-hematologic 
toxicity excluding neutropenic fever and infections) during induction, doses 
should be reduced as described in section 6.10. 
 
 
6.8.2 Post-remission courses should start within 6 weeks of achieving CR once patients 
have recovered to ≤Grade 2 toxicities from the previous course of therapy. 
 
 
6.8.3 Patients can receive up to 4 courses of post-remission therapy.  
 
 
 
 
6.8.4 Patients can proceed to transplantation barring contraindications and if a suitable 
donor is available. 
 
6.9 
Maintenance Therapy 
6.9.1 Patients in MRDneg CR at the end of post-remission therapy with G-
CLA+sorafenib can continue to receive sorafenib for up to 12 months, as long as 
it is tolerated and as long as an MRDneg CR is maintained. Sorafenib will be 
given daily at the assigned dose level, unless dose reductions are needed for 
toxicity, in which case that dose would be continued. The MRDneg CR state 
should be confirmed every 3 months with bone marrow evaluations. 
 
6.10 
Dose Modifications of Chemotherapeutic Drugs for Baseline Organ Dysfunction or 
Subsequent Treatment Cycles  
 
 
For patients with baseline organ dysfunction within the allowed limits of the eligibility 
criteria, or for those who experienced ≥Grade 3 non-hematologic toxicities excluding 
neutropenic fever and infections during the first induction, a dose reduction is 


9510 
 
 
Page 16 of 42 
recommended. The following dose modifications are suggested for all subsequent 
treatment cycles: 
6.10.1 If a patient develops Grade ≥3 non-hematologic toxicity other than Grade 3 
infections within 28 days from the last dose of G-CLAM, the next course of G-
CLAM will be given once toxicity is < grade 2. The following dose reductions 
can be considered: cladribine 4 mg/m2 days 1-5, cytarabine 1.5 g/m2 days 1-4, 
mitoxantrone at one dose level below initial regimen days 1-3, G-CSF dose 
unchanged, and sorafenib at one dose level below their initial regimen. 
Additionally, the mitoxantrone may be omitted entirely if a 2nd induction course is 
indicated (any response less than CR without MRD) per treating physician 
discretion in discussion with the PI. Assuming these doses are well-tolerated the 
first course of G-CLA will be administered at these doses, omitting mitoxantrone. 
If Grade 3 non-hematologic toxicity occurs again, there will be a further 
reduction in doses of cladribine to 3 mg/m2 daily days 1-5 and cytarabine to 1 
g/m2 daily days 1-5 for the first cycle of G-CLA. Doses for subsequent courses of 
G-CLA will be discussed with the Principal Investigator. Patients who were 
receiving dose level -1 sorafenib or mitoxantrone when grade  3 toxicity 
occurred will be taken off study. 
 
6.10.2 Mitoxantrone: Reduce mitoxantrone dose by 50% if the bilirubin concentration is 
1.5-4.5 x IULN and to 25% if the bilirubin concentration is >4.5 x IULN. As per 
6.10.1 can omit mitoxantrone entirely if clinically indicated.  
 
6.10.3 Cladribine: If the serum creatinine exceeds 2.0 mg/dL and/or estimated creatinine 
clearance (calculated by Cockcroft-Gault) decreases to less than 50 mL/min 
during therapy, we will consider dose reduction in discussion with the Oncology 
Pharmacist. 
 
6.10.4 Cytarabine: If the serum creatinine exceeds 2.0 mg/dL and/or estimated creatinine 
clearance (calculated by Cockcroft-Gault) decreases significantly during therapy, 
we will consider dose reduction in discussion with the Oncology Pharmacist. 
 
6.10.5  Sorafenib: If transaminitis occurs with liver function tests exceeding 6 x IULN 
with concurrent hyperbilirubinemia (bilirubin concentration > 4.5 x IULN), and 
any evidence of hepatic injury such as elevated INR and ascites, sorafenib should 
be held/discontinued. Further therapy should be resumed based on physician 
discretion after discussion with Principal Investigator and the Oncology 
Pharmacist. 
 
6.11  Supportive Therapy 
 
 
6.11.1 All patients will be adequately hydrated and receive appropriate anti-emetics 
based upon institutional guidelines. 
 
 
6.11.2 Additional growth factors may be used according to institutional practice 
guidelines or the preference of the attending physician.  
 
 
6.11.3 Antimicrobial prophylaxis should be used according to institutional practice 
guidelines. In case of neutropenic fever, standard diagnostic testing will be 
performed, and empiric antibiotic coverage will be utilized as per usual care and 
standard institutional practices. 


9510 
 
 
Page 17 of 42 
 
 
6.11.4 Transfusional support should be carried out according to institutional practice 
guidelines. 
 
6.12 
Treatment of CNS Disease 
 
 
Treatment of CNS disease is done according to institutional practice guidelines or the  
 
 
preference of the attending physician.  
 
6.13 
Recommended Follow-up Care 
 
 
6.13.1 For patients who continue to receive sorafenib for up to 12 months after the 
completion of G-CLA+sorafenib, they should have complete blood counts and a 
metabolic panel (to include kidney and liver function) done at least monthly and a 
bone marrow exam every 3 months, including after the completion of sorafenib.  
 
 
 
6.13.2 While still on sorafenib, blood pressure should be monitored at least monthly. 
 
 
6.13.3  After completion of protocol treatment, patients should be evaluated by treating 
physicians according to institutional and/or national guidelines or the discretion of 
the attending physician. These evaluations may include peripheral blood studies 
and/or bone marrow examinations, as clinically indicated. 
 
6.14  Criteria for Removal from Treatment 
All reasons for discontinuation of treatment must be documented:   
6.14.1 Completion of protocol treatment. 
6.14.2 HCT after achievement of CR. 
6.14.3 Initiation of any other leukemia-directed therapy other than protocol therapy 
6.14.4 Failure to achieve MRDneg CR after 3 courses of therapy.  
6.14.5 Persistent aplasia (ANC <500/µL or platelets <50,000/ µL) without evidence of 
leukemia after Day +49. 
6.14.6 Relapse (including recurrence of MRD) after achievement of CR during 
treatment. 
6.14.7 Adverse toxicities that prevent continuation with study treatment. 
       6.14.8 Withdrawal of consent; the patient may withdraw from the study at any time for 
any reason.  
 
7.0  
INFORMATION ON STUDY DRUGS 
 
 
G-CSF, cladribine, cytarabine and mitoxantrone will be obtained commercially. 
Sorafenib will be provided free of charge by Bayer HealthCare Pharmaceuticals. 
 
7.1  
Drug Information on G-CSF (Granulocyte colony-stimulating factor) 
7.1.1 Mechanism of Action: G-CSF is a growth factor that stimulates the production, 
maturation, and activation of neutrophils. Further, it promotes premature release 
of neutrophils from the bone marrow and enhances their phagocytic capacity.  


9510 
 
 
Page 18 of 42 
7.1.2  Pharmacokinetics: Peak G-CSF concentrations after sub-cutaneous dosing occur 
in 2 to 8 hours, though the onset of action is approximately 24 hours, with plateau 
concentrations in 3-5 days, and elimination over an 11-20 day period. G-CSF is 
cleared by systemic degradation. Notably, as G-CSF binds neutrophils, plasma 
levels are controlled in large part by the absolute neutrophil count.[31]   
7.1.3  Adverse Effects (AEs): Common drug-related AEs (occurring in >10% of 
patients) include fever, petechiae, elevated uric acid, splenomegaly, bone pain, 
and epistaxis. Less common drug-related AEs (occurring in 1% -10% of patients) 
include hyper- or hypotension, arrhythmias, headache, nausea, vomiting, 
leukocytosis, and transfusion reaction. Infrequent drug-related AEs (occurring in 
<1% of patients) include acute respiratory distress syndrome, allergic reactions, 
alopecia, alveolar hemorrhage, arthralgia, bone density decrease, capillary leak 
syndrome, cerebral hemorrhage, vasculitis, dyspnea, edema, erythema nodosum, 
hematuria, hemoptysis, hepatomegaly, hypersensitivity, injection site reaction, 
pericarditis, proteinuria, psoriasis exacerbation, pulmonary infiltrates, renal 
insufficiency, sickle cell crisis, splenic rupture, Sweet’s syndrome, tachycardia, 
and thrombophlebitis. 
7.1.4 Recommended dose adjustments for organ dysfunction: There is limited or no 
data examining the toxicity of G-CSF in patients with renal or liver dysfunction. 
Therefore, administration of G-CSF to patients with liver or kidney disease must 
be done with caution. 
 
7.2  
Drug Information on Cladribine (2-chloro-2’-deoxyadenosnie, 2-CdA) 
7.2.1 Mechanism of Action: Cladribine is a prodrug that is converted to an adenosine 
deaminase-resistant triphosphate derivative (2-CdATP). This molecule is then 
activated by deoxycytidine kinase to a 5’-triphosphate derivative (2-CdAMP), 
which is incorporated into DNA where it acts as a transcription regulator. In 
addition to its cytotoxic properties in dividing cells, cladribine induces death in 
quiescent cells of lymphoid origin through an unknown mechanism.[32]  
7.2.2 Pharmacokinetics: Cladribine is renally excreted, with 18-35% as unchanged 
drug. It is able to penetrate the CSF, where it achieves 25% of plasma 
concentrations. It is 20% protein-bound. The half-life for elimination after a 2-
hour infusion is 6.72.5 hours in patients with normal renal function.   
7.2.3 Adverse Effects: Common adverse effects (occurring in >10% of patients) include 
fever, fatigue, headache, rash, nausea, anorexia, vomiting, myelosuppression 
(including grade 3/4 neutropenia/thrombocytopenia), injection site reaction, and 
infection. Less common adverse effects (occurring in 1 to 10% of patients) 
include edema, tachycardia, thrombosis, chills, dizziness, insomnia, malaise, 
diarrhea or constipation, weakness, myalgias and arthralgias, cough, dyspnea, 
epistaxis, and diaphoresis. Rare adverse effects (occurring in <1% of patients) 
include aplastic anemia, bacteremia, opportunistic infections, lymphocytopenia, 
altered mental status, hemolytic anemia, hypersensitivity, myelodysplastic 
syndrome, quadriparesis, and renal dysfunction/failure. 
7.2.4 Reconstitution: Cladribine is supplied as a sterile, preservative-free, isotonic 
solution containing 10 mg of cladribine (1 mg/mL) in 10 mL single-use vials. 


9510 
 
 
Page 19 of 42 
Cladribine should be passed through a sterile 0.22μm filter prior to introduction 
into the infusion bag containing 0.9% Sodium Chloride Injection, USP. 
7.2.5 Administration and Compatibility: The use of 5% dextrose is not recommended as 
a diluent because of increased degradation of cladribine. The infusion solution is 
stable for 24 hours at room temperature. 
7.2.6 Storage and Stability: Store refrigerated 2° to 8°C (36° to 46°F). Protect from 
light during storage. 
7.2.7 Recommended Dose Adjustments for Organ Dysfunction: Specific guidelines for 
cladribine dosing in patients with hepatic/renal dysfunction or hypoalbuminemia 
are not clearly defined. Because of the potential for compensatory elimination of 
cladribine in patients with hepatic and/or renal dysfunction, specific guidelines for 
dosing are difficult to define. Thus, when deciding whether to adjust cladribine 
doses for renal dysfunction, the risks for potential toxicities (e.g., 
myelosuppression, neurotoxicity) against the benefits and goals of treatment must 
be considered. 
 
7.3 
Drug Information on Cytarabine (Cytosine arabinoside) 
7.3.1  Mechanism of Action: Cytarabine is a synthetic pyrimidine analog, in which the 
sugar moiety (normally a ribose or deoxyribose) has been replaced with 
arabinose. Although its mechanism of action is not completely understood, the 
active form of cytarabine is probably incorporated into the DNA and interferes 
with DNA synthesis. As such, cytarabine has been found to primarily effect 
dividing cells, blocking their progression from G1 to S phase.  
7.3.2 Pharmacokinetics: Cytarabine is metabolized by deoxycytidine kinase and other 
kinases into its most active form (aracytidine triphosphate). Aracytidine 
triphosphate is converted to nontoxic uracil derivatives by pyrimidine nucleoside 
deaminases. This balance between the levels of kinases and deaminases is critical 
for regulating the sensitivity/resistance of cells to the drug. The plasma clearance 
of cytarabine is biphasic, with an initial rapid phase and more prolonged second 
clearance phase. The rapid clearance phase has a relatively short half-life (t1/2 = 
10 minutes), while the half- life of the second clearance phase is slightly longer 
(t1/2β = 1 – 3 hours). The nontoxic metabolites from the drug are excreted in the 
urine, and within 24 hours after the infusion, approximately 80% of these 
nontoxic metabolites can be recovered from the urine.  
7.3.3  Adverse Effects: The dose-limiting toxicity for cytarabine is myelosuppression. 
Adverse Events Associated with Standard Dose Cytarabine: Frequent AEs (not 
definitely quantified) include the following: myelosuppression (leucopenia, 
anemia, neutropenia, thrombocytopenia), pyrexia, rash, anorexia, diarrhea, 
nausea, vomiting, mucositis, anal inflammation or ulceration, hepatic dysfunction 
or increased liver enzymes, and local thrombophlebitis. Less frequent AEs (not 
definitely quantified) include chest pain, pericarditis, dyspnea dizziness, headache, 
neural toxicity, neuritis, alopecia, pruritis, skin freckling, skin ulceration, 
urticaria, abdominal pain, bowel necrosis, esophageal ulceration, esophagitis, 
pancreatitis, sore throat, urinary retention, jaundice/hyperbilirubinemia, local site 
cellulites, renal dysfunction, allergic edema or anaphylaxis, sepsis, and sudden 


9510 
 
 
Page 20 of 42 
respiratory distress syndrome. Infrequent AEs (not definitely quantified) include 
aseptic meningitis, cardiopulmonary arrest, cerebral dysfunction, cytarabine 
syndrome (bone pain, chest pain, conjunctivitis, fever, maculopapular rash, 
malaise, myalgia), exanthematous pustulosis, hyperuricemia, intestinal 
pneumonitis, increased lipase, paralysis with intrathecal and IV combination 
therapy, rhabdomyolysis, veno-occlusive disorder, and death. Adverse Events 
Associated with High Dose Cytarabine include cardiomegaly and 
cardiomyopathy, coma, severe neurotoxicity, personality change, somnolence, 
total body alopecia, severe rash or skin desquamation, gastrointestinal ulceration, 
peritonitis, intestinal pneumatosis, necrotizing colitis, liver abscess or damage, 
peripheral neuropathy, corneal toxicity, hemorrhagic conjunctivitis, pulmonary 
edema, sudden respiratory distress syndrome, and sepsis.  
7.3.4 Reconstitution: Cytarabine should be reconstituted in sterile water and can be 
further diluted using either 5% dextrose or sodium chloride solutions into 
appropriate concentrations for infusion.  
7.3.5  Administration and Compatibility:  The diluted cytarabine solution should be 
inspected for particulate matter, discoloration, and haze prior to infusion.  If there 
is evidence of particulate matter, discoloration, or haze the solution should not be 
infused. Patients should be medicated with standard anti-emetic therapy. 
Cytarabine is not compatible (1) during Y-site administration with allopurinol, 
amphotericin B, ganciclovir; (2) in syringe with metoclopropamide; or (3) 
admixed with fluorouracil, heparin, insulin (regular), nafcillin, oxacillin, 
penicillin G. Cytarabine may have variable compatibility when admixed with 
gentamycin, hydrocortisone, and methylpredinsone. 
7.3.6 Storage and Stability: Vials of non-reconstituted cytarabine should be stored at 
room temperature 15°C - 30°C (59°F - 86°F). The diluted cytarabine solution may 
be stable for up to 48 hours if stored at room temperature.  
7.3.7 Drug-Drug Interaction: Reversible decreases in the plasma steady-state 
concentration for digoxin and cardiac glycosides may occur. Cytarabine may 
diminish the therapeutic effect of flucytosine. There is ex vivo data suggesting that 
cytarabine may reduce the effectiveness gentamycin for killing K. pneumoniae.  
7.3.8  Warnings and Precautions: Ex vivo and in vivo studies have found that cytarabine 
causes extensive chromosomal damage and potential malignant transformation.  
Although there have been some case reports describing cytarabine use in pregnant 
humans, these cases reports are few. Thus, cytarabine is considered Pregnancy 
Category D. Women should be advised not to become pregnant while receiving 
cytarabine, and men should be advised not to father a child while receiving 
cytarabine and for at least 3 months after completing the therapy. It is not known 
whether cytarabine or its metabolites are excreted in breast milk; thus, it is not 
recommended for lactating females who are breast-feeding. As with any highly 
immunosuppressive medication, cytarabine may diminish the effectiveness of 
dead and live vaccines and enhance the toxic/adverse effect of live vaccines. One 
should avoid use of live vaccines while receiving it. A small percentage of 
patients will have a hypersensitivity reaction to cytarabine, and these individuals 
should not receive the drug again. 


9510 
 
 
Page 21 of 42 
7.3.9  Recommended Dose Adjustments for Organ Dysfunction: Guidelines for 
adjusting cytarabine dose due to renal or liver dysfunction are not standardized, 
but many clinicians will adjust the dose based upon the function of these organs.   
 
7.4 
Drug Information on Mitoxantrone 
7.4.1 Mechanism of Action: Mitoxantrone (dihydroxyanthracenedione) is an 
anthracenedione derivative that intercalates with DNA, resulting in inhibition of 
nucleic acid synthesis.  
7.4.2 Pharmacokinetics: Mitoxantrone is 78% bound to plasma proteins. A three-
compartment model was described after a single intravenous dose of 
mitoxantrone. The mean alpha half-life is 6 to 12 minutes, the mean beta half-life 
is 1.1 to 3.1 hours, and the mean terminal (gamma) or elimination half-life is 23 to 
215 hours (median 75 hours). Mitoxantrone has extensive distribution into body 
tissues and is metabolized in the liver to two main inactive metabolites 
(monocarboxylic acid derivative and dicarboxylic acid derivative). The major 
route of excretion for mitoxantrone appears to be biliary into the feces; 
approximately 11% of the dose is recovered in the urine within 5 days of drug 
administration, with 65% of this being unchanged drug. 
7.4.3 Adverse Effects: Common adverse effects (occurring in >10% of patients) include 
edema, fever, fatigue, headache, alopecia, nausea/vomiting, diarrhea, 
mucositis/stomatitis, myelosuppression, weakness, dyspnea, cough, and infection. 
Less common adverse effects (occurring in 1 to 10% of patients) include 
congestive heart failure, decreased left ventricular ejection fraction (LVEF), 
hypertension, chills, anxiety, cutaneous mycosis, hypcalcemia, hypokalemia, 
hyponatremia, menorrhagia, jaundice, myalgia, arthralgia, renal failure, 
proteinuria, rhinitis, diaphoresis, and infection.  
 
Mitoxantrone may cause cardiac toxicity with prolonged administration and doses 
exceeding 80 to 100 mg/m2; Appendix B provides an overview of the 
cardiotoxicity index of individual anthracyclines as well as mitoxantrone. When 
used after doxorubicin, cardiotoxicity is more frequent; an analysis by the 
Southwest Oncology Group revealed a risk of 6% at 134 mg/m2 prior doxorubicin 
and 60 mg/m2 mitoxantrone, rising to a 15% risk at 120 mg/m2 mitoxantrone. 
Cardiac events reported included arrhythmias, decreased left ventricular function, 
chronic heart failure, tachycardia, ECG changes, and, infrequently, myocardial 
infarction. Bradycardia has been rarely reported. Patients with prior treatment 
with anthracyclines, prior mediastinal radiotherapy, or with preexisting 
cardiovascular disease may have more frequent occurrences of cardiac toxicity. 
7.4.4 Reconstitution: Mitoxantrone must be diluted prior to use. The dose of 
mitoxantrone should be to at least 50 mL with either 0.9% Sodium Chloride 
Injection (USP) or 5% Dextrose Injection (USP). Mitoxantrone may be further 
diluted into Dextrose 5% in Water, Normal Saline or Dextrose 5% with Normal 
Saline and used immediately.  
7.4.5 Administration and Compatibility: Care in the administration of mitoxantrone will 
reduce the chance of extravasation. Mitoxantrone should be administered into the 
tubing of a freely running intravenous infusion of 0.9% Sodium Chloride 


9510 
 
 
Page 22 of 42 
Injection, USP or 5% Dextrose Injection, USP.  Care should be taken to avoid 
extravasation at the infusion site and to avoid contact of mitoxantrone with the 
skin, mucous membranes, or eyes. If any signs or symptoms of extravasation have 
occurred, including burning, pain, pruritis, erythema, swelling, blue discoloration, 
or ulceration, the injection or infusion should be immediately terminated and 
restarted in another vein. 
 
Mitoxantrone should not be mixed in the same infusion as heparin since a 
precipitate may form. 
7.4.6 Storage and Stability: Mitoxantrone should be stored between 15°C - 25°C (59°F 
- 77°F). 
 
7.4 
Drug Information on Sorafenib 
7.4.1 Mechanism of Action: Sorafenib is a kinase inhibitor that decreases tumor 
proliferation in vitro. Although in AML conventionally viewed as a FLT3 ITD kinase 
inhibitor, sorafenib inhibits multiple kinases (c-CRAF, BRAF, mutant BRAF, KIT, FLT-
3, RET, RET/PTC, VEGFR-1/2/3, PDGFR-β). Several of these kinases are thought to be 
in involved in tumor cell signaling, angiogenesis, and apoptosis.  
7.4.2 Pharmacokinetics: The mean elimination half-life of sorafenib is 25-48 hours.  
Steady-state plasma concentrations are achieved within 7 days. Following oral 
administration, sorafenib reaches peak concentrations in approximately 3 hours. With a 
high fat meal, bioavailability is reduced by 29% compared to that in the fasting state. 
Sorafenib undergoes oxidative metabolism via hepatic CYP3A4, as well as 
glucuronidation by UGT1A9. Inducers of CYP3A4 can decrease serum concentration of 
sorafenib.  
7.4.3 Adverse Effects: The most common adverse reactions (> 20%) for sorafenib are 
diarrhea, fatigue, infection, alopecia, hand-foot skin reaction, rash, weight loss, decreased 
appetite, nausea, gastrointestinal and abdominal pains, hypertension, and hemorrhage.  
When used in combination with chemotherapy for treatment of AML, the most common 
adverse reactions thought to be related to the addition of sorafenib include 
hyperbilirubinemia/transaminitis, nausea/vomiting, diarrhea, rash, hand-foot syndrome, 
pancreatitis/colitis, and cardiac/hypertension. Please see Appendix F for management of 
adverse events specific to sorafenib. 
7.4.4 Administration: Subjects will be instructed on the proper administration of 
sorafenib.  Sorafenib tablets should be taken 12 hours apart, at approximately the same 
time each morning and evening.  Sorafenib tablets should be taken without food, at least 
1 hour before or at least 2 hours after a meal, and with up to 240 mL (approximately 1 
cup or 8 oz.) of water.  Consumption of grapefruit and grapefruit juice should be avoided 
while receiving study drug. If a dose of sorafenib is missed, the next dose should be taken 
at the regularly scheduled time. 
7.4.5 Drug-Drug Interactions: Strong CYP3A4 inducers (such as carbamazepine, 
dexamethasone, phenobarbital, phenytoin, rifampin, rifabutin, St. John’s wort) can 
decrease systemic exposure to sorafenib, and concomitant use of these medications 
should be avoided whenever possible. Concomitant use of strong CYP3A4 inhibitors 
(such as azithromycin, ketoconazole, ritonavir) may be allowed, but patients should be 
closely monitored for signs/symptoms of toxicity from increased exposure to sorafenib. 


9510 
 
 
Page 23 of 42 
Interactions with strong CYP3A4 inhibitors has not been well studied, although 
ketoconazole administered at 400 mg once daily for 7 days did not alter the mean AUC of 
a single oral dose of sorafenib 50 mg in healthy volunteers. 
7.4.6 Storage and Stability: Sorafenib tablets do not need to be protected from light.  
They are sufficiently stable with regard to light, oxidation, thermal stress, and hydrolytic 
degradation.  The formulation is presented as an immediate release (IR) dosage form, i.e., 
the active ingredient is completely dissolved under in vitro test conditions within a short 
period of time. 
7.4.7 Recommended Dose Adjustments for Organ Dysfunction: Mild renal and hepatic 
dysfunction does not affect the pharmacokinetics of sorafenib, and drug adjustment is not 
necessary (See Section 6.8.5 for Dose Reduction for Subsequent Cycles.) 
 
 
8.0  
EVALUATION AND END POINT DEFINITIONS 
 
8.1 
Treatment Response and Outcome 
Treatment response (e.g. morphologic/cytogenetic/molecular complete remission, partial 
remission) or treatment failure (e.g. resistant disease, aplasia, morphological or 
molecular/cytogenetic relapse) as well as treatment outcome (e.g. overall survival, relapse-free 
survival, event-free survival, and remission duration) will be determine by peripheral blood 
count and bone marrow evaluation and categorized according to criteria recommended by 
International Working Groups [2, 33]. Patients are routinely assessed for the presence of minimal 
residual disease (MRD) as detected by multi-parameter flow cytometry and cytogenetic 
assessment, as per institutional practice.  
 
8.2 
Toxicity Criteria 
 
 
This study will use the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 5.0 for Toxicity and Adverse Event reporting. A copy of the CTCAE v5.0 can be 
downloaded from the CTEP home page (http://ctep.cancer.gov).  
 
8.3  
Definition of Dose-limiting Toxicities (DLTs) 
Reported adverse events and potential risks for G-CSF, cladribine, cytarabine, and 
mitoxantrone, are described in section 7. Dose-limiting toxicities (DLTs) used to guide dose 
escalation in this trial are defined as follows: 
8.3.1 Any Grade >3 non-hematologic toxicity lasting >48 hours that results in >7 day 
delay of the subsequent treatment cycle, with the exception of febrile neutropenia 
or infection. 
8.3.2 Any Grade ≥4 non-hematologic toxicity with the exception of febrile 
neutropenia/infection unless felt to be a direct consequence of treatment-related 
toxicity (e.g. intestinal infection following mucosal barrier breakdown), and with 
the exception of constitutional symptoms if no recovery to Grade ≤2 within 14 
days. 
8.3.3 Hematologic toxicity with ANC <500/ µL or platelet count <50,000/µL for >49 
days after initiation of G-CLAM, in conjunction with bone marrow showing no 
evidence of MRD or persistent AML. 


9510 
 
 
Page 24 of 42 
 
8.4 
Monitoring of Exploratory Endpoints 
 
 
We will plan to assess QOL and healthcare resource utilization. Cost data will be  
 
 
obtained at the conclusion of study therapy 
 
 
 
 
 
8.4.1 QOL:  QOL will be assessed after each cycle of remission induction and post-
remission therapy, then every 3 months if they remain on maintenance Sorafenib for up 
to 12 months, and at the conclusion of study treatment by the European Organization for 
Research and Treatment of Cancer QLQ-C30 questionnaire, a validated QOL 
measurement for oncology patients (Appendix C) [34]. These questionnaires will be 
distributed at clinic visits, which will be occurring at least monthly. 
 
 
8.4.2 Cost:  Cost records will be obtained at the conclusion of study treatment from the 
Financial Services Department.  
 
 
8.4.3 Healthcare resource utilization: This will be a composite measure. These 
variables will be recorded (at the end of the study due to time constraints of the data 
coordinator) to capture the period from the start of treatment to first response assessment 
(e.g. remission induction). The following variables will be collected:  total number of 
hospital admissions and duration of stays, days in the intensive care unit, number of 
blood product transfusions received, episodes of febrile neutropenia and days requiring 
antibiotic use, number of visits to the emergency department, and number of physician or 
advanced practice provider clinic visits. 
 
 
 
8.5 
Duration of Follow-up 
 
 
Patients will be followed after completion of study treatment to determine EFS and RFS 
(for patients achieving CR) as well as overall survival (for all patients) for a maximum of 5 
years. Follow-up may include periodic (e.g. every 3 months) review of medical records, and, if 
absolutely necessary, direct contact of the study participant. 
 
9.0  
RECORDS 
Research data will be recorded in a study-specific, password protected database using a 
unique study ID for each patient to assure patient confidentiality. Data from source documents 
will be transcribed into this database. Source documents are documents where patient data are 
recorded and documented for the first time. They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, quality of life assessments, pharmacy 
dispensing records, recorded data from automated instruments, copies of transcriptions that are 
certified after verification as being accurate and complete, X-rays, patient files, and records kept 
at the pharmacy, laboratories, and medico-technical departments involved in the clinical trial. 
 
Any publication or presentation will refer to patients by this number and not by name. The 
licensed medical records department, affiliated with the institution where the patient receives 
medical care, maintains all original inpatient and outpatient chart documents. Patient research 
files will be maintained under control of the Principal Investigator and/or study team and kept in 
a locked office or file room within a secure building. Access to the study database will be 
restricted by electronic password protection and restricted access to computers (i.e., locked 
offices).  
 


9510 
 
 
Page 25 of 42 
 
10.0 PROTOCOL ENROLLMENT AND SPECIAL CONSIDERATIONS 
All eligible patients will be included in this study without regard to gender or ethnicity. 
The incidence of AML is slightly higher in men, so it is expected that the distribution of these 
patients will reflect a slight male predominance of the disease as well as the general demographic 
distribution of AML patients seen at our institution. Up to 84 patients  with newly diagnosed 
AML/high-risk MDS/MPN will be enrolled in this study. This is an approximate number as it 
depends on the number of patients enrolled below the MTD in phase 1. 
Projected Target Accrual 
ETHNIC AND GENDER DISTRIBUTION CHART 
TARGETED / PLANNED ENROLLMENT:  Number of Subjects: 84 
 
 
Ethnic Category 
 
Sex / Gender 
 
Females 
Males 
Total 
Hispanic or Latino 
1
2
3
Not Hispanic or Latino 
33
48
81
Ethnic Category Total of All Subjects* 
34
50
84
 
                             Racial Categories 
 
American Indian / Alaska Native 
0
0
0
Asian 
1
1
2
Native Hawaiian or Other Pacific Islander 
0
0
0
Black or African American 
1
1
2
White 
32
48
80
Racial Categories:  Total of All Subjects* 
34
50
84
*The “Ethnic Category Total of All Subjects” must be equal to the “Racial Categories Total of 
All Subjects.” 
 
11.0  GUIDELINES FOR SERIOUS ADVERSE EVENT REPORTING 
 
11.1  Expedited Reporting Requirements 
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 (PI)  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 ten (10) 
calendar days of learning of the problem. Both the “Expedited Reporting Form for Unanticipated 
Problems or Noncompliance” and the “Adverse Event Reporting Form”, or equivalent forms, 
will be completed for this reporting.  
 
11.2 
Definitions 


9510 
 
 
Page 26 of 42 
11.2.1 Adverse Event (AE): Any harm or untoward medical occurrence in a research 
participant administered a medical product, medical treatment or procedure even 
if it does not necessarily have a causal relationship with the product, treatment, or 
procedure. An adverse event can be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease 
temporally associated with the use of a medical product, medical treatment, or 
procedure whether or not considered to be related. Mechanisms of obtaining 
information on AE include monthly transcripts, assessment forms obtained after 
each clinic visit, and hospital progress and discharge notes.  
11.2.2 Related or Possibly Related AE: An AE is “related or possibly related to the 
research procedures” if in the opinion of the principal investigator, it was more 
likely than not caused by the research procedures. AEs that are solely caused by 
an underlying disease, disorder or condition of the subject or by other 
circumstances unrelated to either the research or any underlying disease, disorder 
or condition of the subject are not “related or possibly related”. If there is any 
question whether or not an AE is related or possibly related, the AE should be 
reported. 
11.2.3 Serious AE (SAE): An adverse event that results in any of the following 
outcomes: 
• Death 
• Life-threatening adverse event (real risk of dying)  
• Prolongation of hospitalization* 
• Persistent or significant disability/incapacity/or change in psychosocial status 
• Congenital anomaly 
• Requirement of intervention to prevent permanent impairment of damage 
*Hospitalization itself will not be considered a serious adverse event if required 
for complications of AML or comorbid conditions. Hospitalization will be 
considered a SAE if it fulfills the criteria for a serious and unexpected adverse 
event as otherwise described. 
11.2.4 Unexpected AE: An AE is “unexpected” when its nature (specificity), severity, or 
frequency are not consistent with (a) the known of foreseeable risk of adverse 
events associated with the research procedures described in the protocol-related 
documents, such as the IRB-approved research protocol, informed consent 
document, and other relevant sources of information such as product labeling and 
package inserts. 
11.2.5 Management of Adverse Events. Please see Appendix D for 
prevention/management strategies for adverse events common with sorafenib. 
 
Grade ≥3 adverse events other than hematologic toxicities will be recorded, graded, and 
reported as appropriate. AEs will be collected from the time of consent until 60 days after 
day 1 of each cycle or until the patient receives an alternative anti-cancer therapy, 
whichever date comes first.  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. 
Myelosuppression and associated complications are expected events during leukemia 
therapy; therefore, myelosuppression and associated simple complications such as fever, 


9510 
 
 
Page 27 of 42 
infections, bleeding, and related hospitalizations will not be reported as individual AE but 
will be summarized in the annual report to the IRB.  
 
 
12.0.  DATA AND SAFETY MONITORING PLAN 
The Principal Investigator will carry out ongoing trial oversight and will meet frequently 
with the study team to review recently acquired data and adverse events. The data recorded 
within the research charts and protocol database is compared with the actual data that is available 
from the medical record and/or clinical histories. All investigators on the protocol have received 
formal training in the ethical conduct of human research. The Principal Investigator will receive 
monitoring support as described below. Institutional support of trial monitoring will be in 
accordance with the FHCRC/University of Washington Cancer Consortium Institutional Data 
and Safety Monitoring Plan. Under the provisions of this plan, FHCRC Clinical Research 
Support coordinates data and compliance monitoring conducted by consultants, contract research 
organizations, or FHCRC 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 per the institutional DSMP. In addition, protocols are 
reviewed at least annually and as needed by the Consortium Data and Safety Monitoring 
Committee (DSMC), FHCRC Scientific Review Committee (SRC) and the FHCRC/University 
of Washington Cancer Consortium Institutional Review Board (IRB). The review committees 
evaluate accrual, adverse events, stopping rules, and adherence to the applicable data and safety 
monitoring plan for studies actively enrolling or treating patients. The IRB reviews the study 
progress and safety information to assess continued acceptability of the risk-benefit ratio for 
human subjects. Approval of committees as applicable is necessary to continue the study. The 
trial will comply with the standard guidelines set forth by these regulatory committees and other 
institutional, state and federal guidelines. 
 
 
13.0  ETHICAL AND REGULATORY CONSIDERATIONS 
 
13.1  Institutional Review Board 
In accordance with federal regulations (21 CFR 312.66), an Institutional Review Board 
(IRB) that complies with regulations in 21 CFR 56 must review and approve this protocol and 
the informed consent form prior to initiation of the study. 
 
13.2  Consent 
The Principal Investigator or her designee must explain verbally and in writing the 
nature, duration, and purpose of the study and possible consequences of treatment. Patients must 
also be informed that they may withdraw from the study at any time and for any reason without 
jeopardizing their future treatment. In accordance with federal regulations (21 CFR 50), all 
patients enrolled in the study must sign the IRB-approved consent form. 
 
13.3  Confidentiality 
Patient medical information obtained for the purposes of this study is confidential, and 
disclosure to third parties, other than those noted below, is prohibited. Upon the patient’s request 
and written permission, medical information may be given to his/her personal physician or other 
appropriate medical personnel responsible for the patient’s welfare. Data generated for this study 


9510 
 
 
Page 28 of 42 
must be available for inspection on request to representatives of the national or local health 
authorities, and the associated IRB/IEC. Release of research results or data that reveal patient 
names or other identifiers, such as photographs, audio or videotapes, must be carried out in 
accordance with Department of Health and Human Services Final Standards for Privacy of 
Individual Health Information, 45 CFR 164.508. Written authorization must be obtained from 
the patient and IRB/IEC prior to the release of such information. Identifiable patient data may 
not be used for purposes of promoting any drugs used in this trial. 
 
13.4  Publication Statement 
The results of this clinical trial may be used for public dissemination in the form of 
papers, abstracts, posters, or other informational materials to be presented at scientific meetings, 
or published in professional journals, or as a part of an academic thesis by an investigator. 
Identifiable patient data may not be used for any of these presentations, manuscripts, or reports 
unless directed by law.  
 
 
 
14.0  STATISTICAL CONSIDERATIONS 
 
14.1 
Phase 1 
14.1.1 General Considerations: DLTs are defined in Section 8.3. DLTs occurring during 
Cycle 1 will be used to guide dose escalation. However, before the phase 2 
portion is begun, all grade >3 adverse events of all patients treated in the phase 1 
portion will be reviewed to assess for late and cumulative toxicities that were not 
captured during the phase 1 portion of the trial. The Principal Investigator 
reserves the right to modify the protocol to reduce the drug doses identified in the 
phase 1 portion if this assessment suggests a significant risk of late/cumulative 
toxicities. Patients will be considered evaluable for DLT if they received at least 
75% of the assigned doses of each chemotherapeutic during Cycle 1 or if they 
developed a DLT. If a patient does not develop a DLT but does not receive at 
least 75% of treatment during Cycle 1, the patient will be considered not 
evaluable for DLT and will be replaced. Maximum tolerated dose (MTD) is 
defined as the highest dose studied in which the incidence of DLT is <33% 
assuming at least 6 patients have been treated at this dose. 
14.1.2 Dose Escalation scheme: 
Starting with dose level K=1: 
A. Evaluate 6 patients at dose level K 
a. If 0 or 1 have DLT, increase dose to K+1 and go to A 
b. If 2 have DLT, stop dose escalation 
c. If >2 have a DLT, go to dose K-1 
The dose level below that which dose escalation was stopped is the 
potential MTD. 
 
In order to better define safety and initial evidence of anti-leukemia activity 
while waiting for patients to complete their treatment cycles to assess the 
MTD, any dose level cohort may be expanded up to 12 patients, provided that 


9510 
 
 
Page 29 of 42 
2 or fewer of 6 patients had DLT at that dose level (ie at last 4/6 have had no 
DLT).  the cohort is expanded to 7-11 patients, these patients will not count 
toward DLT and MTD evaluation. If a cohort is expanded to 12 patients, the 
following rules will determine further dose escalation: 
If 3 of fewer have DLT, increase dose to K+1 (go to A) 
If 4 or more have DLT, stop dose escalation 
 
Dose-finding for both mitoxantrone and sorafenib: 
Level 1
Mitoxantrone10 mg/m2
Sorafenib 200 mg BID
Level 2
Mitoxantrone12 mg/m2
Sorafenib 200 mg BID
Level 3
Mitoxantrone15 mg/m2
Sorafenib 200 mg BID
Level 4
Mitoxantrone18 mg/m2
Sorafenib 200 mg BID
Level 5 
Mitoxantrone18 mg/m2 
Sorafenib 400mg AM,  
200 mg PM 
Level 6
Mitoxantrone18 mg/m2
Sorafenib 400 mg BID
Level -1 
Mitoxantrone10 mg/m2 
Sorafenib 200 mg once 
daily
 
In addition to safety stopping rules in phase 1, we will also employ efficacy stopping 
rules to make sure that the regimen does not have lower response rates than our current standard. 
Among the first 57/61 evaluable patients treated with G-CLAM alone in our ongoing phase 1/2 
study, the MRDneg CR rate was 68%. We will assume that the G-CLAM+sorafenib regimen 
will not be of further interest if the true MRDneg CR rate is 60% or less (null hypothesis) and 
that that an MRDneg CR rate of 80% or more would be of interest for further investigation 
(alternative hypothesis). Therefore, if MRDneg CR is seen in < 5 of the first 11 patients, 
consideration will be given to stopping the study. An 80% confidence interval for an MRDneg 
CR rate of 4/11 is 0.17-0.60. Thus the upper bound of this limit is less than the current MRDneg 
CR rate with G-CLAM alone (68%). However, because the first 11 G-CLAM + sorafenib 
patients may differ with respect to cytogenetics/age etc. from the original 57 G-CLAM patients, 
a decision to stop would also depend on comparative examination of patient characteristics.   
 
14.2 
Phase 2 
The study will be conducted in two sequential parts. The phase 1 portion ends once an 
MTD is identified or dose level 6 has been completed, whichever occurs first. Patients enrolled 
in the Phase 1 portion and treated at the MTD dose of sorafenib and mitoxantrone will be 
included in the analysis of the Phase 2 portion. The primary objective of the Phase 2 portion is to 
evaluate the MRDneg CR rate after up to 2 courses of induction chemotherapy. 
 
A two-stage design will be used (Simon Optimal Two-Stage). As per the phase 1 section 
above, the MRDneg CR rate of our historical control of G-CLAM alone is 68%. G-
CLAM+sorafenib will not be of further interest if the true MRDneg CR rate is 60% or less (null 
hypothesis) and that that an MRDneg CR rate of 80% or more would be of considerable interest 
for further investigation (alternative hypothesis). Therefore, in the first stage, 19 eligible patients 
will be accrued. If necessary, the study may be temporarily closed while remission data is 
collected. If at least 12 of the first 19 patients achieved an MRDneg CR (63%), we will move to 
the second stage. The second stage would enroll another 22 patients (for a total of 41), with G-
CLAM + sorafenib considered of interest (at least 80% MRDneg CR rate) if at least 31/41 attained 


9510 
 
 
Page 30 of 42 
MRDneg CR. The probability of declaring a therapy of interest when it is not is 10% (type-1 error), 
and not of interest when it is, is 20% (power 80%).  Under the null hypothesis (true MRDneg CR 
rate 60%) the probability of termination before enrolling 41 patients is 51% and the average sample 
size is 29 patients.  Note that patients treated at the recommended sorafenib and mitoxantrone 
doses during the Phase 1 part of the study would count toward the first 19 patients. Patients will 
be considered not evaluable if they received less than 75% of the assigned doses of each 
chemotherapeutic agent during Cycle 1, and they will be replaced. If a patient does not receive at 
least 75% of their assigned dose of sorafenib but discontinues the drug due to toxicity, they will 
be considered evaluable as we want to capture this essential toxicity data (and its potential 
downstream effect on efficacy) and not be replaced.  
 
QOL scores, resource utilization, and cost variables will be recorded and summarized 
using descriptive methods including boxplots, histograms, and statistical summary measures 
(medians, means, standard deviation, N, and proportions). This study will not be powered to 
detect statistically significant differences between these endpoints for those with different 
responses; rather we will record these outcomes to inform a subsequent larger study, should 
follow up investigations be warranted. 
 
 
15.0 STUDY TERMINATION 
 
The study will terminate as described in section 15.0. The Principal Investigator, the IRB, 
and the FDA reserve the right to terminate this study at any time.  
16.0  REFERENCES 
 
1. Ferrara, F. and C.A. Schiffer, Acute myeloid leukaemia in adults. Lancet, 2013. 381(9865): p. 
484-95. 
2. Dohner, H., et al., Diagnosis and management of acute myeloid leukemia in adults: 
recommendations from an international expert panel, on behalf of the European 
LeukemiaNet. Blood, 2010. 115(3): p. 453-74. 
3. Rollig C, M.-T.C., Huttmann A, Noppeney R, Kunzmann V, Baldus CD, Brants CH, Kramer 
A, Schafer-Eckart K, Neubauer A, Krause SW, Giagounidis A, Aulitzky WE, Bornhauser M, 
Schaich M, Parmentier SB, Thied C, Von Bonin M, Schetelig J, Kramer M, Serve H, Berdel 
WE, Ehninger G. , Sorafenib Versus Placebo in Addition to Standard Therapy in Younger 
Patients with Newly Diagnosed Acute Myeloid Leukemia: Results from 267 Patients Treated 
in the Randomized Placebo-Controlled SAL-Soraml Trial. American Society of Hematology 
Annual Meeting, 2014. Abstract #6. 
4. Burnett, A.K., et al., Optimization of chemotherapy for younger patients with acute myeloid 
leukemia: results of the medical research council AML15 trial. J Clin Oncol, 2013. 31(27): p. 
3360-8. 
5. Othus, M., et al., Declining rates of treatment-related mortality in patients with newly 
diagnosed AML given 'intense' induction regimens: a report from SWOG and MD Anderson. 
Leukemia, 2014. 28(2): p. 289-92. 


9510 
 
 
Page 31 of 42 
6. Anwar A, H.A., Scott BL, Becker PS, Othus M, Hendrie PC, Ranker EM, Perdue A,  Chen 
TL, Buckley SA, Orlowski KF, Powell MA, Appelbaum FR, Estey EE, Walter RB. , Phase 1 
Trial of G-CSF, Cladribine, Cytarabine, and Dose-Escalated Mitoxantrone (G-CLAM) in 
Adults with Newly Diagnosed AML or High-Risk MDS. European Hematology Association 
(EHA) Annual Congress 2015. Abstract #P574. 
7. Halpern AB, A.A., Scott BL, Becker PS, Othus M, Hendrie PC, Ranker EM, Perdue A, 
Smith H, Chen TL, Buckley SA, Orlowski KF, Powell MA, Estey EE, Walter RB. , Phase 1 
Trial of G-CSF, Cladribine, Cytarabine, and Dose-Escalated Mitoxantrone (G-CLAM) in 
Adults with Newly Diagnosed AML or High-Risk MDS. Society of Hematologic-Oncology 
Annual Meeting, 2015. Abstract #208. 
8. Holowiecki, J., et al., Cladribine, but not fludarabine, added to daunorubicin and cytarabine 
during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, 
randomized phase III study. J Clin Oncol, 2012. 30(20): p. 2441-8. 
9. Price, S.L., et al., Salvage chemotherapy regimens for acute myeloid leukemia: Is one better? 
Efficacy comparison between CLAG and MEC regimens. Leuk Res, 2011. 35(3): p. 301-4. 
10. Jaglal, M.V., et al., Cladribine, cytarabine, filgrastim, and mitoxantrone (CLAG-M) 
compared to standard induction in acute myeloid leukemia from myelodysplastic syndrome 
after azanucleoside failure. Leuk Res, 2014. 38(4): p. 443-6. 
11. 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. Eur J Haematol, 2008. 80(2): p. 115-26. 
12. Grimwade, D., et al., Refinement of cytogenetic classification in acute myeloid leukemia: 
determination of prognostic significance of rare recurring chromosomal abnormalities 
among 5876 younger adult patients treated in the United Kingdom Medical Research 
Council trials. Blood, 2010. 116(3): p. 354-65. 
13. Wilhelm, S., et al., Discovery and development of sorafenib: a multikinase inhibitor for 
treating cancer. Nat Rev Drug Discov, 2006. 5(10): p. 835-44. 
14. Escudier, B., et al., Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med, 
2007. 356(2): p. 125-34. 
15. Llovet, J.M., et al., Sorafenib in advanced hepatocellular carcinoma. N Engl J Med, 2008. 
359(4): p. 378-90. 
16. Ravandi, F., et al., Phase I/II study of combination therapy with sorafenib, idarubicin, and 
cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol, 2010. 28(11): p. 
1856-62. 
17. Ravandi, F., et al., Final report of phase II study of sorafenib, cytarabine and idarubicin for 
initial therapy in younger patients with acute myeloid leukemia. Leukemia, 2014. 28(7): p. 
1543-5. 


9510 
 
 
Page 32 of 42 
18. Serve, H., et al., Sorafenib in combination with intensive chemotherapy in elderly patients 
with acute myeloid leukemia: results from a randomized, placebo-controlled trial. J Clin 
Oncol, 2013. 31(25): p. 3110-8. 
19. Fernandez, H.F., et al., Anthracycline dose intensification in acute myeloid leukemia. N Engl 
J Med, 2009. 361(13): p. 1249-59. 
20. Lowenberg, B., et al., High-dose daunorubicin in older patients with acute myeloid leukemia. 
N Engl J Med, 2009. 361(13): p. 1235-48. 
21. Walter, R.B., et al., Shortcomings in the clinical evaluation of new drugs: acute myeloid 
leukemia as paradigm. Blood, 2010. 116(14): p. 2420-8. 
22. Burnett, A.K., et al., The addition of gemtuzumab ozogamicin to low-dose Ara-C improves 
remission rate but does not significantly prolong survival in older patients with acute 
myeloid leukaemia: results from the LRF AML14 and NCRI AML16 pick-a-winner 
comparison. Leukemia, 2013. 27(1): p. 75-81. 
23. Burnett, A.K., et al., Clofarabine doubles the response rate in older patients with acute 
myeloid leukemia but does not improve survival. Blood, 2013. 122(8): p. 1384-94. 
24. Chen, X., et al., Relation of clinical response and minimal residual disease and their 
prognostic impact on outcome in acute myeloid leukemia. J Clin Oncol, 2015. 33(11): p. 
1258-64. 
25. Appelbaum, F.R., et al., End points to establish the efficacy of new agents in the treatment of 
acute leukemia. Blood, 2007. 109(5): p. 1810-6. 
26. Alibhai, S.M., et al., Quality of life beyond 6 months after diagnosis in older adults with 
acute myeloid leukemia. Crit Rev Oncol Hematol, 2009. 69(2): p. 168-74. 
27. Swerdlow SH, C.E., Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (Eds.), 
WHO Classification of Tumours and Haematopoietic and Lymphoid Tissues. . 4th Edition ed. 
2008, Lyon. 
28. Vardiman, J.W., et al., The 2008 revision of the World Health Organization (WHO) 
classification of myeloid neoplasms and acute leukemia: rationale and important changes. 
Blood, 2009. 114(5): p. 937-51. 
29. Estey, E., et al., Effect of diagnosis (refractory anemia with excess blasts, refractory anemia 
with excess blasts in transformation, or acute myeloid leukemia [AML]) on outcome of AML-
type chemotherapy. Blood, 1997. 90(8): p. 2969-77. 
30. Walter, R.B., et al., Prediction of early death after induction therapy for newly diagnosed 
acute myeloid leukemia with pretreatment risk scores: a novel paradigm for treatment 
assignment. J Clin Oncol, 2011. 29(33): p. 4417-23. 
31. Carton, E., A. Bellesoeur, and O. Mir, Colony-stimulating factors for febrile neutropenia. N 
Engl J Med, 2013. 369(3): p. 285-6. 


9510 
 
 
Page 33 of 42 
32. Reiss, A.L., et al., Neuroanatomy of fragile X syndrome: the posterior fossa. Ann Neurol, 
1991. 29(1): p. 26-32. 
33. Cheson, B.D., et al., Revised recommendations of the International Working Group for 
Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting 
Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol, 2003. 21(24): p. 
4642-9. 
34. Aaronson, N.K., et al., The European Organization for Research and Treatment of Cancer 
QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J 
Natl Cancer Inst, 1993. 85(5): p. 365-76. 
 
 
 


9510 
 
 
Page 34 of 42 
APPENDIX A: TREATMENT-RELATED MORTALITY (TRM) SCORE 
 
Calculation of Simplified Treatment-Related Mortality (TRM) Score 
 
Includes covariates: performance status (PS), age, platelet count, albumin, secondary AML, 
white blood cell count (WBC), peripheral blood blast percentage, and creatinine 
 
Score = 100/(1+e(-x)), with x = -4.08 + 0.89*PS + 0.03*age - 0.008*platelet count - 0.48*albumin 
+ 0.47*(have secondary AML) + 0.007*WBC - 0.007*(peripheral blood blast percentage) + 
0.34*creatinine 
 
 
Probability of TRM Above and Below Various Simplified TRM Score Cut-offs 
TRM Score 
Interval 
Patients below/ 
within/above TRM 
Score Interval (%) 
TRM Probability if 
below TRM Score 
Interval (%) 
TRM 
Probability if 
within TRM 
Score Interval 
(%) 
TRM 
Probability if 
above TRM 
Score Interval 
(%) 
0 – 1.9
0/20/80
-
1
12
1.91 – 3.9
20/20/60
1
2
16
3.91 – 6.9
40/20/40
1
7
20
6.91 – 9.2
60/10/30
3
7
24
9.21 – 13.1
70/10/20
4
12
31
13.11 – 22.8
80/10/10
5
20
41
22.81 – 100
90/10/0
6
41
-
 
From: Walter RB, Othus M, Borthakur G, Ravandi F, Cortes JE, Pierce SA, Appelbaum FR, 
Kantarjian HM, Estey EH. Prediction of early death after induction therapy for newly diagnosed 
acute myeloid leukemia with pretreatment risk scores: a novel paradigm for treatment 
assignment. J Clin Oncol. 2011;29(33):4417-4424.  
 
 
 


9510 
 
 
Page 35 of 42 
APPENDIX B: CARDIOTOXICITY INDEX OF ANTHRACYCLINES  
 
 
Drug 
Schedule 
Relative 
Myelosuppressive 
Potency1 
Approximate 
Relative 
Cardiotoxicity 
Cardiotoxicity 
Index2 
Doxorubicin
Rapid infusion
1
1
1
Doxorubicin
24hr infusion
1
0.62
0.62
Epirubicin
Rapid infusion
0.67
0.66
0.44
Mitoxantrone
Rapid infusion
5
0.5
2.5
Daunorubicin
Rapid infusion
0.67
0.75
0.5
Idarubicin
Rapid infusion
5
0.53
2.67
1Of single dose compared with doxorubicin administered by standard schedule. 2The 
cardiotoxicity index represents a factor by which to multiply the cumulative dose of a drug 
administered to obtain an approximation of toxicity that might be expected had the resultant 
amount of doxorubicin been given by rapid infusion 
 
Adapted from Holland J, et al. Cancer medicine, 5th ed. American Cancer Society. Hamilton and 
London: B.C. Decker, Inc. 2000. 
 
 
 


9510 
 
 
Page 36 of 42 
APPENDIX C: EUROPEAN ORGANIZATION FOR RESEACH AND 
TREATMENT OF CANCER QLQ-C30 QUESTIONNAIRE
 


9510 
 
 
Page 37 of 42 
 
 
 
 
Aaronson, N.K., et al., The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-
life instrument for use in international clinical trials in oncology. J Natl Cancer Inst, 1993. 85(5): p. 365-76. 


9510 
 
 
Page 38 of 42 
APPENDIX D: MANAGEMENT OF TOXICITIES SPECIFIC TO 
SORAFENIB 
I. Prevention/management strategies for diarrhea and fatigue 
Diarrhea and fatigue are common side effects of sorafenib.  The same dose-modification 
algorithm used for skin toxicities can be used to address these toxicities.  However, the 
preventive/management strategies for diarrhea and fatigue should be consistent with local 
standards (e.g., anti-diarrheals and optimized hydration status for diarrhea). 
II. Hand-foot-skin reaction: Suggested sorafenib dermatologic toxicity modification 
 
Recommended dose modification for hand foot skin reaction (HFSR) 
Toxicity Grade 
Suggested dose modification 
Grade 1 
Any occurrence 
Maintain dose level and consider topical therapy for 
symptomatic relief 
Grade 2 
1st occurrence 
Maintain dose level and consider topical therapy for 
symptomatic relief 
If no improvement within 7 days, see below
 
No improvement within 
7 days or 2nd occurrence
Interrupt until resolved to Grade 0-1 
When resuming treatment, decrease dose by one dose level
 
3rd occurrence  
Interrupt until resolved to Grade 0-1 
When resuming treatment, decrease dose by two dose levels
 
4th occurrence 
Discontinue treatment permanently 
Grade 3 
1st occurrence 
Interrupt until resolved to Grade 0-1 
When resuming treatment, decrease dose by one dose level
 
2nd occurrence 
Interrupt until resolved to Grade 0-1 
When resuming treatment, decrease dose by two dose levels
 
3rd occurrence 
Discontinue treatment permanently 
 
At first occurrence of HFSR, independent of grade, prompt institution of supportive 
measures such as topical emollients, low potency steroids, or urea-containing creams 
should be administered. 
Recommended prevention/management strategies for skin toxicities consistent with HFSR are 
summarized below. 


9510 
 
 
Page 39 of 42 
Recommended Prevention/Management Strategies for Skin Toxicities Consistent with Hand-Foot-Skin-
Reaction 
Toxicity Grade 
Practical Prevention / Management Strategies for HFSR  
Grade 0 (Preventive strategies) 
 Maintain frequent contact with trial physician to ensure early 
diagnosis of HFSR. 
 Practical prevention strategies 
o Pedicurea for subjects with pre-existing hyperkeratosis. 
o Subjects should avoid hot water, and clothing or activities that 
can cause friction on the skin. 
o Moisturizing cream should be applied sparingly. 
 Padded gloves and open shoes with padded soles should be worn 
to relieve pressure points. 
Grade 1  
Any occurrence 
 Continue preventive strategies and in addition: 
o Soak hands in cool water. 
o Apply petroleum jelly to moist skin. 
 In the case of hyperkeratotic lesions, exfoliate the hands or feet 
and apply moisturizing cream immediately afterwards. 
Grade 2 Any occurrence or 
Grade 3 Any occurrence 
 Continue supportive/management measures and add analgesic(s) 
for pain. 
a:  Pedicure should be done by a podiatrist. 
 
III. Treatment-emergent hypertension 
Hypertension is a known and potentially serious AE associated with sorafenib treatment. 
Subjects will undergo brief physical examinations, including blood pressure monitoring, on a 
weekly basis through the first 6 weeks of therapy.  Thereafter, blood pressure will be monitored 
on Day 1 of each cycle.  
Blood pressure measurements considered out of the normal range are diastolic pressure > 90 mm 
Hg and/or systolic pressure > 140 mm Hg, or a 20 mm Hg increase in diastolic pressure if the 
previous measurement was within normal limits. 
The dose-modification schedule to be followed in the event of treatment-emergent hypertension 
is outlined below.  The choice of anti-hypertensive medication to be used in cases of treatment-
emergent hypertension will be at the investigator's discretion and based on site-specific treatment 
guidelines as applicable.  All anti-hypertensive medications used for the management of 
treatment-emergent hypertension should be recorded in the subject’s records. 
Once a dose-reduction modification has been made for treatment-emergent hypertension, NO 
dose re-escalation will be allowed. 
 
 
 
 
 


9510 
 
 
Page 40 of 42 
Management of Treatment-Emergent Hypertension 
Grade of Event (NCI-CTCAE v4.0) 
Management/ Next Dose 
Grade 1 
Consider increasing blood pressure monitoring.  Continue 
sorafenib dosing as scheduled. 
Grade 2 asymptomatic and diastolic 
pressure 90-99 mm Hg  
Begin anti-hypertensive therapy.  Continue sorafenib dosing 
as scheduled. 
Grade 2 (symptomatic/persistent) 
OR 
Grade 2 symptomatic increase by > 
20 mm Hg (diastolic) or to > 140/90 mm Hg if 
previously within normal limits 
OR  
Grade 3 
Sorafenib should be helda until symptoms resolve and 
diastolic blood pressure < 90 mm Hg; also treat subject with 
anti-hypertensives and when sorafenib is restarted, reduce by 
1 dose level.b 
If diastolic blood pressure is not controlled (< 90 mm Hg) on 
anti-hypertensive therapy, reduce another dose level.b 
Grade 4 
Discontinue sorafenib
a:  Subjects requiring a delay of > 30 days (modify according to study specific cycle length) should discontinue 
sorafenib unless, in the opinion of the treating physician, the subject may benefit from continued treatment. 
b:  Subjects requiring dose reductions beyond 200 mg (1 placebo tablet) twice daily, every other day, should 
discontinue sorafenib. 
 
 
 


9510 
 
 
Page 41 of 42 
 Appendix E: Study Medication Diary 
 
Principal Investigator: 
Anna Halpern, MD 
Sponsor: 
Bayer Pharmaceuticals 
Protocol Number: 
9510 
Sponsor Study #: 
CC9510 
Title or Brief Description: 
G-CLAM+Sorafenib in Newly Diagnosed AML/High-grade Myeloid Neoplasms 
Subject Name  
 
 
 Date of Birth  
 
 
Study ID 
 
 
Study Medication 
Sorafenib   Dose 400 mg (2 tablets) twice daily Date Dispensed               
 
Patient instructions: 
 
Check the box each time you take your pills every day on the diary below. 
 
Please bring all unused study medication, along with this drug diary, if you go to the hospital for any 
reason.  
 
Please return your sorafenib pill bottle (even if empty) and this drug diary to your doctor at your 
next appointment following your last dose of sorafenib. 
 
If you have any questions on your sorafenib dose or schedule, you can page us 24 hours a day 
through the UW paging operator at 206-598-6190. From 8 am – 5 pm Monday-Friday ask to page 
Kelsey-Leigh Garcia (research coordinator). For after hours and on the weekends, ask to page Dr. 
Anna Halpern.   
Day of the week/ 
Date 
Check Column for Both 
AM Tablets Taken 
 
Check Column for Both 
PM Tablets Taken 
 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


9510 
 
 
Page 42 of 42 
 
 
 
Patient Signature 
 
Date 
**Do Not sign the diary until you have returned to your doctor** 
 
 
9510Study Medication Diary 
Page 42 of 42 
Version: 07/12/21