Conditions: Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11 Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11 Adult Acute Myeloid Leukemia With t(8;21); (q22; q22.1); RUNX1-RUNX1T1 Adult Acute Myeloid Leukemia With t(9;11)(p22.3;q23.3); MLLT3-KMT2A Adult Acute Promyelocytic Leukemia With PML-RARA Alkylating Agent-Related Acute Myeloid Leukemia Chronic Myelomonocytic Leukemia Myelodysplastic Syndrome Previously Treated Myelodysplastic Syndrome Recurrent Adult Acute Myeloid Leukemia
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 29
Healthy volunteers: no

Brief summary:
This pilot phase II trial studies how well erlotinib hydrochloride works in treating patients with relapsed or refractory acute myeloid leukemia. Erlotinib hydrochloride may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the efficacy of erlotinib (erlotinib hydrochloride) in patients with refractory or relapsed acute myeloid leukemia (AML).

II. To determine the safety and tolerability of erlotinib in this patient population.

SECONDARY OBJECTIVES:

I. To investigate inhibitory effect of this drug on spleen tyrosine kinase (SYK) and its down-stream targets such as mitogen-activated protein kinase 8 (JNK), mitogen-activated protein kinase (MAPK) and mitogen-activated protein kinase 1 (Erk).

II. To evaluate its role in janus kinase (Jak)/signal transducer and activator of transcription (STAT) pathway and to investigate erlotinib-mediated cell death and/or differentiation.

III. To quantitate concentrations of plasma erlotinib.

OUTLINE:

Patients receive erlotinib hydrochloride orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

Arms:
arm 1: Patients receive erlotinib hydrochloride PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Erlotinib Hydrochloride intervention 2: Laboratory Biomarker Analysis
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies

Protocol document:
Prot_SAP_000.pdf: 
2012-0060
September 19, 2013
Page 1
Protocol Page
A Pilot Phase II Study of Erlotinib for the Treatment of Patients with 
Refractory/Relapsed AML
2012-0060
Core Protocol Information
Short Title 
Pilot Phase II - Erlotinib for AML
Study Chair: 
Jorge Cortes
Additional Contact:
Jane A. Autry
Rachel R. Abramowicz
Leukemia Protocol Review Group
Department:
Leukemia
Phone:
713-794-5783
Unit:
428
Full Title: 
A Pilot Phase II Study of Erlotinib for the Treatment of Patients with Refractory/Relapsed AML
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Terminated 10/25/2018
Version:
09
Submitted by:
Rachel R. Abramowicz--2/27/2018 3:50:31 PM
OPR Action:
Accepted by:  Melinda E. Gordon -- 3/2/2018 1:41:38 PM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


2012-0060
September 19, 2013
Page 2
Protocol Body
 


2012-0060 
September 19, 2013 
Page 1 of 28 
 
 
A Pilot Phase II Study of Erlotinib for the Treatment of Patients 
with Refractory/Relapsed AML 
 
 
1.0 
OBJECTIVES ..................................................................................................................... 2 
1.1 
Primary Objectives .......................................................................................................... 2 
1.2 
Secondary Objectives ...................................................................................................... 2 
2.0 
BACKGROUND ................................................................................................................ 2 
2.1 
Erlotinib .......................................................................................................................... 3 
2.2 
Rationale for Erlotinib in AML ...................................................................................... 7 
3.0 
STUDY DESIGN................................................................................................................ 8 
4.0 
PATIENT SELECTION ..................................................................................................... 8 
4.1 
Inclusion Criteria ............................................................................................................ 8 
4.2 
Exclusion Criteria ........................................................................................................... 9 
5.0 
TREATMENT PLAN ......................................................................................................... 9 
5.1 
General ............................................................................................................................ 9 
5.2 
Treatment Plan .............................................................................................................. 10 
6.0 
DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITIES…………………10  
6.1 
Dose Reduction Criteria for Hematologic Toxicity at Least Possibly Related to 
Erlotinib ...................................................................................................................... 10 
6.2 
Dose Reduction Criteria for Non-Hematologic Toxicity at Least Possibly Related to 
Erlotinib ...................................................................................................................... 11 
6.3 
Suggested Management of Toxicity ............................................................................. 12 
6.4 
Supportive Care Guidelines .......................................................................................... 14 
7.0 
AGENT FORMULATION AND PROCUREMENT ...................................................... 14 
7.1 
Formulation ................................................................................................................... 14 
7.2 
Packaging and Labeling ................................................................................................ 14 
7.3 
Storage and Handling .................................................................................................... 15 
7.4 
Administration .............................................................................................................. 15 
8.0 
PATIENT EVALUATION ............................................................................................... 15 
8.1 
Pre-Treatment Evaluation ............................................................................................. 15 
8.2 
Evaluation During Treatment ....................................................................................... 15 
8.3 
End of Treatment Visit.................................................................................................. 16 
9.0 
CRITERIA FOR RESPONSE .......................................................................................... 16 
9.1 
Response Criteria for MDS ........................................................................................... 16 
10.0 
ADVERSE EVENT REPORTING................................................................................... 17 
11.0 
STATISTICAL CONSIDERATIONS.............................................................................. 21 
11.1 
Safety Monitoring ......................................................................................................... 22 
11.2 
Statistical Analysis ........................................................................................................ 23 
12.0 
REFERENCES ................................................................................................................. 24 


2012-0060 
September 19, 2013 
Page 2 of 28 
 
 
 
1.0 
OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 To assess the efficacy of erlotinib in patients with refractory or relapsed 
AML.  
 
1.1.2 To determine the safety and tolerability of erlotinib in this patient 
population. 
 
1.2 
Secondary Objectives 
 
1.2.1 To investigate inhibitory effect of this drug on SYK and its down-stream 
targets such as JNK, MAPK and Erk.  
1.2.2 To evaluate its role in Jak/STAT pathway and to investigate erlotinib-
mediated cell death and/or differentiation.  
1.2.3 To quantitate concentrations of plasma erlotinib.   
 
2.0 
BACKGROUND 
 
Acute myeloid leukemia (AML) is a malignancy of immature granulocytes or monocytes. 
Malignancy is characterized by accumulation of leukemic blastocytes and blockade of 
normal bone marrow production resulting in thrombocytopenia, anemia, and neutropenia. 
In the U.S., approximately 11,930 new cases of AML are expected to be diagnosed in 
2006, with an estimated 9,040 deaths occurring in the same time period. Almost all newly 
diagnosed cases, as well as deaths, will be in adults.1 Standard treatment for AML 
includes systemic combination chemotherapy to control bone marrow and systemic 
disease. Treatment is generally divided into an induction phase, to attain remission, and a 
maintenance phase. Approximately 60% to 70% of adults with AML can be expected to 
attain complete remission status following appropriate induction therapy. Remission rates 
in adult AML are inversely related to age, with an expected remission rate of >65% for 
those younger than 60 years. Increased morbidity and mortality during induction appear 
to be directly related to age.2 
 
Standard therapy for hematologic malignancies, particularly acute leukemias, has 
changed little over the past 20-30 years. This is in part due to the lack of understanding, 
until recently, of the biology of the disease which has led to little change in the 
management of these patients. The treatment has been based on combination therapy with 
standard chemotherapy agents. In acute myeloid leukemia, typically with an 
anthracycline and cytarabine, and in acute lymphoblastic leukemia with multi-agent 
therapy. Recent advances in the discovery of important molecular abnormalities has led 
to the development of new agents that are likely to change the outcome of patients and 
the standard approach to the treatment of these patients. Some examples are already in 
clinical practice (eg, the use of all-trans retinoic acid-based therapy for patient with 
PML/RARα rearrangements) and others are in development with great possibilities of 


2012-0060 
September 19, 2013 
Page 3 of 28 
 
 
being approved in the near future (eg, FLT3 inhibitors, alone or in combination with 
chemotherapy). However, there is urgent need for identification of new therapeutic 
targets and agents that may be used for these patients.  
 
 
2.1 
Erlotinib  
 
Erlotinib, a potent, selective, and reversible inhibitor of tyrosine kinase activity 
associated with the HER1/EGFR, has demonstrated tumor growth inhibition both 
in vitro and in vivo. Erlotinib was designed to target the signaling pathway that 
mediates the effects of EGFR activation on cell proliferation. 
 
Erlotinib 150 mg orally once daily for the treatment of patients with locally 
advanced or metastatic NSCLC after failure of at least 1 prior chemotherapy 
regimen was approved in the US on 18 November 2004 and in the EU on 19 
September 2005, based on data from  the randomized, placebo-controlled Study 
BR.21. This trial demonstrated a statistically significant and clinically meaningful 
survival benefit, as well as delayed time to deterioration of lung cancer symptoms, 
in patients who received erlotinib. This indication has now been approved in 
multiple countries worldwide. 
 
Also, erlotinib 150 mg daily has been approved by European regulatory 
authorities for use as maintenance therapy in patients with advanced or recurrent 
NSCLC who had stable disease following 4 cycles of a platinum-based doublet 
chemotherapy. In the US, erlotinib 150 mg daily is approved for use as 
maintenance therapy in patients with advanced or recurrent NSCLC who have not 
progressed after 4 cycles of first-line platinum-based doublet chemotherapy. 
These indications are based on results from the SATURN study, a multicenter, 
double-blind, randomized phase 3 study that  demonstrated statistically significant 
and clinically relevant improvement in progression-free survival (PFS) and 
overall survival (OS). 
 
Two additional phase 3 clinical trials of erlotinib have been completed in NSCLC 
patients: 
•  First-line treatment of NSCLC, concurrently administered in combination 
with carboplatin/paclitaxel (Study OSI2298g); this trial showed no benefit 
of the addition of erlotinib to first-line chemotherapy for NSCLC. 
 
•  First-line treatment of NSCLC, concurrently administered in combination 
with cisplatin/gemcitabine (Study BO16411); this trial showed no benefit 
of the addition of erlotinib to first-line chemotherapy for NSCLC. 
  
2.1.1 Adverse Events 
 
As of 15 November 2010, more than 33,000 healthy subjects and cancer 
patients have participated in company-sponsored and investigator-


2012-0060 
September 19, 2013 
Page 4 of 28 
 
 
sponsored studies; more than 22,000 of these subjects or patients are 
estimated to have received erlotinib.   
 
The Global Drug Safety Database contains approximately 9243 unique 
clinical study serious adverse events assessed as related to erlotinib in a 
total of 5846 patients (see table below).   
 
MeDRA System Organ Class  
Preferred Terms 
Fatal 
Events 
Total 
Events 
Infections and infestations 
Pneumonia, pneumonia primary atypical, lung infections, 
upper/lower respiratory tract infection, bronchitis 
56 
230 
Cellulitis, infection, abscess, localized infection, folliculitis, 
skin infection 
8 
137 
Sepsis, staphylococcal sepsis, bacteremia, sepsis syndrome 
26 
64 
Neutropenic sepsis 
2 
5 
Pharyngitis, herpangina, tonsillitis 
- 
4 
Cellulitis orbital 
- 
1 
Endometritis 
- 
1 
Blood and lymphatic system disorder 
Neutropenia, leucopenia, agranulocytosis 
5 
104 
Febrile neutropenia 
- 
69 
Anemia 
3 
158 
Thrombocytopenia 
4 
73 
Pancytopenia, bone marrow failure 
2 
10 
Coagulopathy, disseminated intravascular coagulation, 
hemorrhagic diathesis 
8 
15 
Hemolytic uremic syndrome, TTP 
- 
3 
Leukocytosis 
- 
1 
Metabolism and nutrition disorders 
Dehydration 
7 
294 
Anorexia, failure to thrive, malnutrition, cachexia 
1 
243 
Hypokalemia 
- 
34 
Other electrolyte imbalance (Na+, Ca++, Mg++, phosphate) 
- 
86 
Hyperglycemia, hypoglycemia 
1 
18 
Psychiatric disorders 
Confusional state, mental status changes, disorientation 
- 
37 
Anxiety 
- 
2 
Depression 
- 
4 
Nervous system disorders 
CVA, cerebral infarction, hemorrhagic stroke, TIA, 
hemiparesis, cerebral artery embolism 
29 
93 
Headache 
1 
19 
Neuropathy peripheral, paraesthesia 
- 
14 


2012-0060 
September 19, 2013 
Page 5 of 28 
 
 
Lethargy, depressed consciousness 
1 
19 
Aphasia 
- 
4 
Coordination abnormal 
- 
1 
Dizziness, vertigo 
- 
34 
Syncope 
- 
17 
Myasthenia gravis 
- 
1 
Eye disorders 
Keratitis, keratoconjunctivitis sicca/dry eye, punctuate keratitis 
- 
12 
Conjunctivitis 
- 
14 
Ectropion 
- 
1 
Uveitis, iridocyclitis 
- 
5 
Vision blurred, visual disturbance, blindness 
1 
14 
Corneal erosion/ulceration/perforation 
- 
6 
Cardiac disorders 
Acute myocardial infarction, acute coronary syndrome, angina 
15 
57 
Cardiac arrest, cardio-respiratory arrest 
15 
17 
Cardiovascular disorder 
2 
2 
Atrial fibrillation/supraventricular tachycardia/tachycardia 
- 
27 
Cardiac failure acute, cardiac failure congestive, left 
ventricular failure, left ventricular systolic dysfunction 
5 
29 
Bradycardia 
1 
4 
Vascular disorders 
Deep vein thrombosis, phlebothrombosis, thrombosis, jugular 
vein thrombosis 
- 
81 
Hypotension, orthostatic hypotension 
4 
33 
Vasculitis, vasculitis necrotizing 
- 
7 
Peripheral embolism, embolism 
- 
9 
Hypertension, hypertensive crisis 
- 
18 
Peripheral ischemia 
- 
3 
Respiratory, thoracic, and mediastinal disorders 
 
 
Pneumonitis, interstitial lung disease, bronchiolitis obliterans 
and organizing pneumonia (BOOP), lung infiltration, alveolitis 
198 
621 
Dyspnea 
34 
218 
Pulmonary embolism 
17 
107 
Respiratory distress, acute respiratory distress syndrome 
14 
25 
Respiratory failure, respiratory arrest 
30 
37 
Anemic hypoxia, hypoxia 
3 
26 
Hemoptysis, pulmonary hemorrhage 
18 
48 
Epistaxis 
- 
20 
Pharyngolaryngeal pain 
- 
3 
Pulmonary fibrosis 
1 
21 
Cough 
1 
20 
Respiratory acidosis 
1 
1 


2012-0060 
September 19, 2013 
Page 6 of 28 
 
 
Gastrointestinal disorders 
Diarrhea 
16 
873 
Vomiting 
2 
332 
Nausea 
1 
269 
Gastrointestinal hemorrhage, melena, hematemesis, rectal 
bleeding 
21 
188 
Mouth hemorrhage 
- 
2 
Pancreatitis 
1 
24 
Stomatitis, mouth ulceration, glossitis 
- 
98 
Colitis, enterocolitis, cecitis 
2 
18 
Abdominal pain, dyspepsia 
2 
103 
Diarrhea hemorrhagic 
- 
4 
Intestinal ischemia 
1 
4 
Gastric Ulcer/Duodenal Ulcer 
1 
34 
Esophagitis, gastritis 
- 
33 
Intestinal perforation, gastrointestinal perforation, 
gastrointestinal ulcer perforation, diverticular perforation 
14 
37 
Constipation 
- 
30 
Dysphagia 
- 
27 
Pneumoperitoneum 
1 
4 
Hepatobiliary disorders 
Hyperbilirubinemia 
- 
51 
Cholecystitis 
- 
8 
Jaundice 
- 
8 
Hepatic function abnormal, liver disorder 
7 
112 
Hepatic steatosis 
1 
2 
Hepatitis, hepatic failure, hepatotoxicity 
15 
31 
Skin and subcutaneous tissue disorders 
Rash, dermatitis acneiform, exanthematous pustulosis, 
dermatitis, exanthema, acne, rash pustular, skin toxicity 
- 
698 
Dermatitis exfoliative 
- 
31 
Dermatitis bullous, blister 
1 
2 
Stevens Johnson syndrome, erythema multiforme, skin 
necrosis 
2 
9 
Dactylitis 
- 
2 
Pruritus 
- 
14 
Urticaria 
- 
8 
Eczema 
- 
14 
Hyperhidrosis 
- 
2 
Paronychia 
- 
22 
Palmar plantar erythrodysesthesia syndrome 
- 
14 
Alopecia 
- 
2 
Dry skin 
- 
8 


2012-0060 
September 19, 2013 
Page 7 of 28 
 
 
Nail disorder, ingrowing nail, hair growth abnormal 
- 
8 
Musculoskeletal and connective tissue disorders 
Muscular weakness 
- 
20 
Joint swelling 
- 
1 
Myalgia 
- 
9 
Osteonecrosis 
- 
2 
Renal and Urinary disorders 
Renal insufficiency, renal failure, nephrotic syndrome 
15 
96 
Reproductive system and breast disorders 
Vaginal hemorrhage, menorrhagia 
- 
3 
General disorders and administration site conditions 
Fatigue, asthenia, malaise, health deterioration, performance 
status decreased 
16 
325 
Pyrexia 
1 
190 
Mucosal inflammation 
1 
53 
Pain, chest pain 
2 
52 
Edema, peripheral edema 
- 
17 
Rigors, chills 
- 
12 
Enanthema 
- 
1 
Investigations 
Prothrombin time or INR prolonged 
- 
34 
Liver function test (eg, transaminases, AP) abnormal/increased 
- 
114 
Blood creatinine abnormal/increased 
- 
24 
Blood bilirubin increased 
- 
26 
Weight decreased 
1 
26 
Blood urea increased 
- 
3 
Ejection fraction decreased 
- 
2 
Fecal occult blood positive 
- 
1 
Hemoglobin decreased 
- 
20 
Neutrophil count decreased 
- 
18 
Amylase/Lipase increased 
- 
7 
Injury, poisoning, and procedural complications 
Radiation pneumonitis 
2 
12 
 
 
2.2 
Rationale for Erlotinib in AML 
 
Recently anecdotal reports have suggested that erlotinib can induce complete 
remission in patients with acute myeloid leukemia being treated for a concomitant 
non-small cell lung cancer.3,4 This was assumed to be an off target effect of 
erlotinib, but the exact mechanism was not clear. Previous reports had suggested 
that both gefitinib and erlotinib induced apoptosis in leukemic cell lines and cells 
obtained from patients with acute myeloid leukemia and myelodysplastic 


2012-0060 
September 19, 2013 
Page 8 of 28 
 
 
syndromes, while sparing normal CD34+ cells.5-8 Gefitinib was also found to 
have a differentiation effect.8 Using proteomic and RNA1-based approaches Syk 
was identified as the off target for these agents in AML.9 This effect was 
confirmed using a somewhat specific Syk inhibitor, R406 which demonstrated 
that Syk inhibition can trigger differentiation of AML and MDS cells.9 A similar 
effect was observed with gefitinib.9 Importantly, Syk mRNA and protein is 
widely expressed in AML,10 during B-cell development11, in myeloid and other 
hematopoietic cells12, and in primary CLL lymphocytes13. Inhibition of Syk with 
fostamatinib has also demonstrated significant antileukemia activity in chronic 
lymphocytic leukemia14,15 and acute lymphoblastic leukemia16. We thus 
hypothesize that erlotinib may have significant clinical activity in patients with 
AML, possibly through inhibition of Syk. 
 
3.0 
STUDY DESIGN 
 
 This will be a phase II, single-arm, open-label study. 
 
 All patients will receive therapy with erlotinib administered orally as a continuous 
daily dose in 28-day cycles. Patients will continue therapy until clinically significant 
progression of the disease or unacceptable toxicity. 
 
 The historical experience in this patient population is that response with standard 
therapy, when available, is less than 1%. In many instances (eg, patients with 
myelodysplastic syndrome failing hypomethylating agents), no standard therapy is 
even available. Thus, an overall response rate of 20% will be considered significant. 
 
4.0 
PATIENT SELECTION 
 
Patients must have baseline evaluations performed prior to the first dose of study drug 
and must meet all inclusion and exclusion criteria. Results of all baseline evaluations, 
which assure that all inclusion and exclusion criteria have been satisfied, must be 
reviewed by the Principal Investigator or his/her designee prior to enrollment of that 
patient. In addition, the patient must be thoroughly informed about all aspects of the 
study, including the study visit schedule and required evaluations and all regulatory 
requirements for informed consent. The written informed consent must be obtained from 
the patient prior to initiating treatment. The following criteria apply to all patients 
enrolled onto the study unless otherwise specified. 
 
4.1 
Inclusion Criteria 
 
4.1.1 Patients with AML who have either been refractory to prior therapy or 
have relapsed after prior therapy. Patients with MDS or CMML who 
received therapy with a hypomethylating agent and progress to AML are 
eligibleif they have received any therapy for MDS and failed (i.e., lack or 
loss of response) regardless of whether they have received therapy for 
AML or not.  The WHO classification will be used for AML.  


2012-0060 
September 19, 2013 
Page 9 of 28 
 
 
 
4.1.2 Age 18 years 
 
4.1.3 ECOG Performance Status 2  
 
4.1.4 Adequate liver (total bilirubin 2x ULN, ALT ≤2.5x ULN) and renal 
(creatinine 2x ULN) function. 
 
4.1.5 Patients must provide written informed consent. 
 
4.1.6 Patients must have been off chemotherapy for 2 weeks prior to entering 
this study, unless there is evidence of rapidly progressive disease, and 
must have recovered from the clinically significant toxic effects of that 
therapy to at least grade 1. Use of hydroxyurea for patients with rapidly 
proliferative disease is allowed before the start of study therapy and for the 
first four weeks on therapy.  
 
4.1.7 Patients – both males and females – with reproductive potential (ie, 
menopausal for less than 1 year and not surgically sterilized) must practice 
effective contraceptive measures throughout the study.  Women of 
childbearing potential must provide a negative pregnancy test (serum or 
urine) within 14 days prior to initiation of study. 
 
4.2 
Exclusion Criteria 
 
4.2.1 Patients with known allergy or hypersensitivity to erlotinib. 
 
4.2.2 Patients with any other known disease (except carcinoma in-situ) 
concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled 
diabetes; cardiovascular disease including congestive heart failure NYHA 
Class III or IV, myocardial infarction within 6 months, and poorly 
controlled hypertension; chronic renal failure; or active uncontrolled 
infection) which, in the opinion of the investigator could compromise 
participation in the study. 
 
4.2.3 Patients unwilling or unable to comply with the protocol. 
 
4.2.4 Significant gastrointestinal disorders that may interfere with absorption of 
erlotinib. 
 
4.2.5 Patients who can receive a stem cell transplant within 4 weeks. 
 
5.0 
TREATMENT PLAN 
 
5.1 
General: All patients should be registered in CORe. 
 


2012-0060 
September 19, 2013 
Page 10 of 28 
 
 
5.2 
Treatment Plan: Patients will receive erlotinib therapy according to the 
suggested guidelines below. Individual minor variations in the initiation of 
therapy, are acceptable as indicated by patient condition and physician judgment. 
These variations should be documented in the patient’s medical record. 
5.2.1 Therapy:  Patients will receive erlotinib at a dose of 150 mg orally, once 
daily in 28-day cycles. 
5.2.2 Dose Adjustments: Dose adjustments will be done as described below 
using the following dose-levels: 
 
Dose Level* 
Erlotinib daily dose 
0 
150 mg 
-1 
100 mg 
-2 
50 mg 
* Dose escalations/reductions different than those described in this table 
should be discussed with PI or Co-PI and documentation of the discussion 
made in the patient’s medical record. 
6.0 
DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITES 
 
6.1 
Dose Reduction Criteria for Hematologic Toxicity at Least Possibly Related 
to Erlotinib 
 
Patients with AML usually present with abnormal peripheral blood counts at the 
time therapy is started and myelosuppression is an expected event during the 
course of therapy for acute leukemias. Thus, no dose adjustments or treatment 
interruptions for myelosuppression will be planned for the first 4 weeks of therapy 
unless an adjustment or interruption is considered by the investigator to be in the 
best interest of the patient.  The reason for the variation should be documented in 
the patient’s medical record. After this time, treatment interruptions and dose 
adjustments may be considered on an individual basis. The following guidelines 
can be used to consider treatment: 
 
6.1.1 Patients with neutropenia or thrombocytopenia as a consequence of the 
disease do not require treatment interruptions for myelosuppression. Dose-
reductions in these patients should be considered in an individual case and 
discussed with the PI. The following guidelines can be used for these 
patients:  
 
6.1.1.1 Patients with a response and pre-cycle counts of neutrophils 
>1x109/L and platelets >50 x109/L who have sustained low 
counts of neutrophils <0.5 x109/L or a platelet count <20 x 
x109/L (eg, for more than 5 consecutive days) may have 
treatment interrupted. Upon recovery of counts to neutrophils 
>1x109/L and platelets to >50 x109/L treatment may be re-started 
with a 1 dose level reduction.  A reduction of 2 dose levels may 


2012-0060 
September 19, 2013 
Page 11 of 28 
 
 
be considered if the myelosuppression was deemed severe and 
life threatening by the treating physician, and if it is in the 
patient's best interest. 
 
6.1.1.2 If there are persistent peripheral blood blasts, or the bone marrow 
shows >5% blasts, may continue treatment regardless of 
neutrophil and platelet count and give supportive care as needed.  
 
6.1.1.3 If no marrow evidence of leukemia, may hold therapy until 
recovery of granulocytes to ≥1 x109/L and platelets ≥ 50 x109/L, 
then resume at same or 1 lower dose level according to 
guidelines mentioned above. 
 
6.2 
Dose Reduction Criteria for Non-Hematologic Toxicity at Least Possibly 
Related to Erlotinib 
 
Toxicity 
(NCI CTCAE v4.0) 
Dose Modificationa 
Diarrhea 
Grade 1 or 2 
None.  May initiate therapy with loperamide or alternate 
antidiarrheal.  See Section 6.3 for treatment details. 
Grade 3b or 4b 
a) 
Interrupt erlotinib until resolution to ≤ grade 2 and then restart 1 
dose level lower. If the event does not resolve to grade 2 within 
14 days, erlotinib will be discontinued. 
Rash 
Grade 1 
None 
Grade 2 
None.  Initiate treatment as outlined in Section 6.3.  If rash persists 
and is intolerable or worsens over 10 – 14 days, then reduce by 1 
dose level.  
Grade 3b 
Reduce by 1 dose level.  If rash persists or worsens over 10 – 14 
days, then interrupt erlotinib until resolution to ≤ grade 2 and then 
restart 1 dose level lower. If the event does not resolve to grade 2 
within 14 days, erlotinib will be discontinued. 
Grade 4 
Permanently discontinue erlotinib. 
Interstitial Lung Disease (ILD) 
Any Grade 
If ILD possibly related to study drug is suspected, erlotinib should be 
interrupted immediately  
pending diagnostic evaluation.  If ILD is diagnosed, erlotinib should 
be discontinued permanently and appropriate treatment instituted as 
necessary. 
Other Non-Hematologic Toxicities  
Grade 1 or 2 
None 
Grade 3b, c 
Interrupt erlotinib until resolution to ≤ grade 2 and then restart 1 dose 
level lower. 
Grade 4 
Permanently discontinue erlotinib 
a)  Doses that have been reduced 1 dose level for toxicity may be re-escalated to the previous 


2012-0060 
September 19, 2013 
Page 12 of 28 
 
 
dose level only if the toxicity abates or returns to baseline severity and the investigator 
believes it is in the best interest of the patient.  Doses that have been reduced 2 dose levels for 
toxicity may only be re-escalated to the previous dose level (ie, dose level at first reduction) 
and only if the toxicity abates or returns to baseline severity and the investigator believes it is 
in the best interest of the patient.  Doses that have been reduced 2 or more dose levels for 
toxicity may not be re-escalated to the starting dose level (or dose-escalated dose for tobacco 
smokers).  Any patient who fails to tolerate treatment at 50 mg/day will be discontinued from 
the study. 
b) 
If not responding to optimal treatment within 48 hrs. 
c) 
Only if  2 grade level change from baseline 
 
6.3 
Suggested Management of Toxicity: The following guidelines are offered as 
suggestions for the management of toxicity. Variations of these are acceptable 
based on the patient’s individual circumstances and physician preference.   
 
If a patient experiences several toxicities, dose adjustments are to be made based 
on the greatest degree of toxicity (ie, reducing the dose to the lowest level).  If 
significant toxicity is still apparent, the dose may be reduced a second time.  Any 
patient who fails to tolerate treatment of 50 mg/day will be withdrawn from the 
study.   
 
Antidiarrheal and antirash medications may be introduced at any time if clinically 
indicated. Previous phase 1 and 2 studies have demonstrated that the frequency 
and severity of diarrhea can be managed with loperamide.  The recommended 
dose of loperamide is 4 mg at first onset, followed by 2 mg every 2 to 4 hours 
until diarrhea resolves for 12 hours. Other antidiarrheal medications may be used 
as clinically indicated. 
 
In the event of severe or persistent diarrhea, nausea, anorexia, or vomiting 
associated with dehydration due to erlotinib therapy, erlotinib should be 
interrupted and appropriate measures should be taken to intensively treat the 
dehydration.   
 
Patients may be informed that skin toxicity is to be expected during treatment 
with erlotinib.  Skin toxicity may take the form of dry skin, rash, acneiform 
eruption, or hair or nail changes.  Prophylactic treatment of the skin may prevent 
or reduce skin toxicity.  The patient should be encouraged to use an alcohol-free, 
emollient cream applied twice a day to the entire body as soon as the patient starts 
therapy with erlotinib.  Creams and ointments are recommended because they 
have a greater ability to retain moisture than lotions.  Examples of suitable 
emollient creams include:  Neutrogena® Norwegian formula, SARNA® Ultra, 
Vanicream™, Aveeno® (fragrance-free formulation), and Eucerin® cream.  Other 
over-the-counter aqueous creams or emulsifying ointments may also provide 
symptomatic benefit.  Lotions are not recommended because they often contain 
alcohol, which may dry the skin.  Patients may also be encouraged to use a 
titanium dioxide or zinc oxide-based sunscreen product applied to sun-exposed 
areas twice per day. 
 


2012-0060 
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Patients who develop skin toxicity and are symptomatic may be treated with 
topical therapy such as hydrocortisone cream or clindamycin gel.  If needed, oral 
minocycline or oral doxycycline may be combined with the topical therapy.  A 
topical immodulating cream such as Elidel could also be considered.  For more 
severe rash, oral corticosteroids may be beneficial.  Patients who fail to respond to 
these measures may have the dose of erlotinib interrupted or reduced.  See Annex 
5 for more information on skin toxicity management. 
 
Minocycline may interfere with anticoagulants and oral contraceptives.  Patients 
treated with minocycline who are taking anticoagulants and/or oral contraceptives 
should be monitored accordingly. 
 
There have been infrequent reports of serious ILD, including fatal events, in 
patients receiving erlotinib for the treatment of NSCLC and other advanced solid 
tumors.  In the event of acute onset of new or progressive, unexplained pulmonary 
symptoms such as dyspnea, cough, and fever, where ILD is suspected, study drug 
should be interrupted pending diagnostic evaluation.  If ILD is diagnosed, study 
drug should be permanently discontinued and appropriate treatment instituted as 
necessary. 
 
Treatment with erlotinib should be used with extra caution in patients with total 
bilirubin > 3 x ULN. Patients with hepatic impairment (total bilirubin > ULN or 
Child-Pugh A, B and C) should be closely monitored during therapy with 
erlotinib.   
 
Gastrointestinal perforation (including fatalities) has been reported in patients 
receiving erlotinib.  Patients receiving concomitant anti-angiogenic agents, 
corticosteroids, NSAIDs, and/or taxane-based chemotherapy, or who have prior 
history of peptic ulceration ordiverticular disease are at increased risk.  
Permanently discontinue erlotinib in patients who develop gastrointestinal 
perforation.  
 
Bullous, blistering and exfoliative skin conditions have been reported, including 
cases suggestive of Stevens-Johnson syndrome/toxic epidermal necrolysis, which 
in some cases were fatal.  Interrupt or discontinue erlotinib treatment if the patient 
develops severe bullous, blistering, or exfoliating conditions.   
 
Ocular Disorders, including corneal perforation or ulceration have been reported 
during use of erlotinib.  Other ocular disorders including abnormal eyelash 
growth, keratoconjunctivitis sicca or keratitis have been observed with erlotinib 
treatment and are known risk factors for corneal ulceration/perforation.  Interrupt 
or discontinue erlotinib therapy if patients present with acute/worsening ocular 
disorders such as unexplained eye pain. 
 


2012-0060 
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Erlotinib dosing should be discontinued for any severe toxicity that does not 
respond to treatment or failure to recover within 14 days from hematological 
toxicity attributable to erlotinib. 
 
6.4 
Dose Escalation 
 
Patients who have had a prior dose reduction of erlotinib and who have no 
toxicity for at least 1 month of therapy may increase the dose of erlotinib provided 
they have experienced no grade ≥3 erlotinib-related toxicity. Dose escalation may 
be done by one dose level at a time and dose escalations should not be done more 
often than every 28 days. Patients may not escalate to a dose level they received 
earlier where the patient experienced grade 4 toxicity.  
 
6.5 
Supportive Care Guidelines 
  
Supportive measures including erythropoietin, analgesics, blood transfusions, 
antimicrobials, and hematopoietic colony stimulating factors for treatment of 
cytopenias are permitted.   
 
Prophylactic use of hematopoietic colony stimulating factors is not permitted.  
 
Other chemotherapy, investigational cytotoxic agents, radiation, or biologic 
therapy is prohibited while the patient is on study with the following exceptions 
during cycle 1: During the first 7 days of study only, patients may receive 
leukaphereses to control elevated blast and/or platelet counts and hydroxyurea is 
allowed for a maximum of the first 28 days on study.  Intrathecal chemotherapy to 
treat isolated CNS involvement of leukemia is allowable. 
 
6.6 
Patients may be taken off study at any time to receive a stem cell transplant as 
clinically indicated. 
 
 
7.0 
AGENT FORMULATION AND PROCUREMENT 
 
7.1 
Formulation 
 
The pharmaceutical preparations of erlotinib are formulations containing the 
hydrochloride salt.  Erlotinib is supplied as tablets containing erlotinib 
hydrochloride equivalent to 150 mg, 100 mg, and 25 mg of erlotinib.  All tablets 
are round, white, film-coated, bi-convex tablets without markings.  Additional 
information regarding erlotinib can be found in the Tarceva Package Insert.  
Erlotinib for this trial will be provided as investigational product. 
 


2012-0060 
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7.2 
Packaging and Labeling 
 
Erlotinib tablets are supplied in blue-white, high-density polyethylene (HDPE) 
bottles of 30 tablets each. 
 
7.3 
Storage and Handling 
 
Erlotinib tablets should be stored at 25°C (77°F); excursions permitted to 15° - 
30°C (59° - 86°F). 
 
7.4 
Administration 
 
Erlotinib tablets should be taken at approximately the same time of day.  Each 
erlotinib dose is to be taken with up to 200 mL (~ 1 cup or 8 oz) of water, and 
should be taken 1 hour before or 2 hours after meals.  Erlotinib should not be 
taken with grapefruit or grapefruit juice.  The entire dose must be taken at one 
time.  If the patient vomits after taking the tablet(s), the dose is replaced only if 
the tablet(s) can actually be seen and counted.  Missed doses will not be made up.  
Unused study drug returned by patients should be destroyed in accordance with 
the institution’s policy.  Patients will document self-administration by using the 
MDACC pill diary. 
 
8.0 
PATIENT EVALUATION 
 
8.1 
Pre-Treatment Evaluation: All pretreatment studies should be obtained within 
14 days (±3 days) of entry into the trial, unless otherwise stated. 
 
8.1.1 A complete history and physical, including assessment of baseline adverse 
events. 
 
8.1.2 CBC, platelet count, differential (differential can be omitted if WBC is 
≤0.5 x109/L). 
 
8.1.3 Creatinine, total bilirubin, ALT.  
 
8.1.4 Pregnancy test (urine or plasma) in females of childbearing potential 
should be performed within 14 days of  initiation of study. 
 
8.1.5 Bone marrow aspirate during the last 14 days preceding study initiation. 
Cytogenetics will be obtained prior to therapy (results from prior analysis 
can be used for this purpose). 
 
8.1.6 Pretreatment optional correlative studies (Appendix A). Every effort will 
be made to collect all samples at all time points for all patients; however, 
missing collection in one or more of these time points in occasional 
patients will not be considered a protocol deviation/violation. 


2012-0060 
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8.1.7 Chest x-ray 
 
8.2 
Evaluation During Treatment: All tests are ±5 days unless otherwise specified. 
 
8.2.1 Physical exam after 28 days of therapy (± 7 days), then every 2-3 months. 
 
8.2.2 Assessment of adverse events. 
 
8.2.3 CBC, platelet count, differential once weekly for the first 3 months, then 
every 2-4 weeks (differential can be omitted if WBC is ≤0.5 x109/L) until 
6 months of therapy, then every 6-8 weeks. 
 
8.2.4 Creatinine, total bilirubin, ALT weekly for the first 3 months, then every 
2-4 weeks until 6 months of therapy, then every 6-8 weeks. 
 
8.2.5 Bone marrow aspiration on day 28 (± 7 days), then every 2-3 months for 1 
year; then as clinically indicated.  Bone marrow aspirations to be 
performed at MDACC. 
 
8.2.6 
Correlative studies (Appendix A).   Every effort will be made to collect all 
samples at all time points for all patients; however, missing collection in 
one or more of these time points in occasional patients will not be 
considered a protocol deviation/violation. 
 
8.2.7 For patients that remain on study with no significant toxicity for more than 
12 months, subsequent evaluations during study may be modified after 
discussion with the principal investigator.  These include a decrease in 
frequency of correlative studies and other laboratory tests to once every 
one to three cycles. 
 
8.2.8 For patients receiving concomitant warfarin, PT at least every 4 
weeks for the first 6 months or more frequent if clinically indicated; 
after the first 6 months, PT as clinically indicated. 
 
8.3 
End of Treatment Visit 
 
8.3.1 To be completed 30 days (+/- 7 days) after the last dose of study drug.   
 
8.3.2 This visit will consist of a review of symptoms and adverse events.  This 
visit can be done by phone if patient unwilling or unable to do at 
MDACC. 
 
9.0 
CRITERIA FOR RESPONSE 
 


2012-0060 
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9.1 
Response criteria will be modified from the International Working Group for 
AML (JCO 2003; 21: 4642-9). Responders are patients who obtain a CR, CRi, or 
PR, with or without cytogenetic response, hematologic improvements, and 
morphologic leukemia-free state. Briefly, criteria are as follows: 
 
9.1.1 Complete Remission (CR):  
 
 
Peripheral blood counts: 
 
No circulating blasts 
 
Neutrophil count ≥1.0 x109/L  
 
Platelet count ≥100 x109/L 
 
 
Bone marrow aspirate and biopsy: 
 
≤5% blasts 
 
No Auer rods 
 
No extramedullary leukemia 
 
9.1.2 Complete remission with incomplete blood count recovery (CRi): 
 
 
Peripheral blood counts: 
 
No circulating blasts 
 
Neutrophil count <1.0 x109/L, or 
 
Platelet count <100 x109/L 
 
 
Bone marrow aspirate and biopsy: 
 
< 5% blasts 
 
No Auer rods 
 
No extramedullary leukemia 
 
9.1.3 Partial Remission (PR):  
 
All CR criteria if abnormal before treatment  except: 
 
50 % reduction in bone marrow blast but still >5% 
 
9.1.4 Morphologic Leukemia-Free State (MLF):  
 
Bone marrow: 5% myeloblasts   
 
9.1.5 Hematologic Improvement (HI): Hematologic response must be 
described by the number of positively affected cell lines. 
 
 
Erythroid response (E) (pretreatment Hgb <11 g/dL) 
 
Hgb increase by 1.5 g/dL 
 
 
Platelet response (P) (pretreatment platelets <100 x109/L) 
 
Absolute increase of 30 x 109/L for patients starting with >20 x 
109/L platelets, or 
Increase from < 20 x 109/L to > 20 x 109/L and by at least 100% 


2012-0060 
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Page 18 of 28 
 
 
 
 
Neutrophil response (N) (pretreatment ANC <1.0 x109/L) 
At least 100% increase and an absolute increase >0.5 x 109/L 
 
 
Blast response (B):  at least 50% reduction in blast percentage. 
 
9.1.6 Overall Response: An adequate response, included in the overall 
response rate (ORR) for this trial will include all of the following obtained 
within the first 3 months of therapy: CR, CRi, PR, MLF, HI. 
 
10.0 
ADVERSE EVENT REPORTING 
 
10.1 
Adverse event is any untoward medical occurrence that may present during 
treatment with a pharmaceutical product but which does not necessarily have a 
causal relationship with this treatment.  
 
 
Adverse drug reaction is a response to a drug which is noxious and unintended 
and which occurs at doses normally used in man for prophylaxis, diagnosis, or 
therapy of disease or for the modification of physiologic function.  
 
 
Assessing causal connections between agents and disease is fundamental to the 
understanding of adverse drug reactions. In general, a drug may be considered a 
contributory cause of an adverse event if, had the drug not been administered, 1) 
the event would not have happened at all, 2) the event would have occurred later 
than it actually did, or 3) the event would have been less severe. 
 
 
The Investigator or physician designee is responsible for verifying and providing 
source documentation for all adverse events and assigning the attribution for each 
event for all subjects enrolled on the trial. 
 
10.2 
Adverse Events (AEs) will be evaluated according to the CTC AE version 4.0 and 
documented in medical record.  Only unexpected AEs will be recorded in the 
Case Report Form (CRF).  PDMS/CORe will be used as the electronic case report 
form for this protocol.  Adverse events and protocol specific data will be entered 
into PDMS/CORe.  Expected events during leukemia therapy are: 
 
10.2.1 Myelosuppression related events (due to disease or leukemia therapy) 
 
10.2.1.1 
febrile or infection episodes not requiring management in the 
intensive care unit 
 
10.2.1.2 
epistaxis or bleeding except for catastrophic CNS or pulmonary 
hemorrhage 
 
10.2.1.3 
anemia, 
neutropenia, 
lymphopenia, 
thrombocytopenia, 
leukopenia 


2012-0060 
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10.2.2 Disease Related Events 
 
10.2.2.1 
Symptoms associated with anemia 
 
10.2.2.1.1 fatigue 
 
10.2.2.1.2 weakness 
 
10.2.2.1.3 shortness of breath 
 
10.2.2.2 
electrolyte abnormalities (sodium, potassium, bicarbonate, 
CO2, magnesium) 
 
10.2.2.3 
chemistry abnormalities (LDH, phosphorus, calcium, BUN, 
protein, albumin, uric acid, alkaline phosphatase, glucose) 
 
10.2.2.4 
coagulation abnormalities 
 
10.2.2.5 
disease specific therapy (induction, maintenance, salvage, or 
stem cell therapy) 
 
10.2.2.6 
alopecia 
 
10.2.2.7 
bone,  joint, or muscle pain 
 
10.2.2.8 
liver function test abnormalities associated with infection or 
disease progression 
 
10.2.2.9 
disease progression 
 
10.2.2.10 abnormal hematologic values  
 
10.2.3 General Therapy Related Events 
 
10.2.3.1 
catheter related events 
 
10.2.3.2 
renal failure related to tumor lysis syndrome or antibiotic/ 
antifungal therapy 
 
10.2.3.3 
rash related to antibiotic use 
 
10.2.4 Hospitalization for the management of any of the above expected events 
 


2012-0060 
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10.3 
Abnormal hematologic values will not be recorded on the case report form.  For 
abnormal chemical values, the apogee or nadir (whichever is appropriate) will be 
reported per course on the case report form. 
 
10.4 
Serious Adverse Event Reporting (SAE) 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the 
view of either the investigator or the sponsor, it results in any of the following 
outcomes: 
 
 Death 
 A life-threatening adverse drug experience – any adverse experience that 
places the patient, in the view of the initial reporter, at immediate risk of 
death from the adverse experience as it occurred. It does not include an 
adverse experience that, had it occurred in a more severe form, might have 
caused death. 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions. 
 A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, they may jeopardize the patient 
or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 
312.32). 
 
 Important medical events as defined above, may also be considered serious 
adverse events. Any important medical event can and should be reported as an 
SAE if deemed appropriate by the Principal Investigator or the IND Sponsor, 
IND Office. 
 
 All events occurring during the conduct of a protocol and meeting the 
definition of a SAE must be reported to the IRB in accordance with the 
timeframes and procedures outlined in “The University of Texas M. D. 
Anderson Cancer Center Institutional Review Board Policy for Investigators 
on Reporting Unanticipated Adverse Events for Drugs and Devices”. Unless 
stated otherwise in the protocol, all SAEs, expected or unexpected, must be 
reported to the IND Office, regardless of attribution (within 5 working days of 
knowledge of the event). 
 


2012-0060 
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Page 21 of 28 
 
 
 All life-threatening or fatal events, that are unexpected, and related to the 
study drug, must have a written report submitted within 24 hours (next 
working day) of knowledge of the event to the Safety Project Manager in the 
IND Office.  
 
 Unless otherwise noted, the electronic SAE application (eSAE) will be 
utilized for safety reporting to the IND Office and MDACC IRB.  
 
 Serious adverse events will be captured from the time of the first protocol-
specific intervention, until 30 days after the last dose of drug, unless the 
participant withdraws consent. Serious adverse events must be followed until 
clinical recovery is complete and laboratory tests have returned to baseline, 
progression of the event has stabilized, or there has been acceptable resolution 
of the event.  
 
 Additionally, any serious adverse events that occur after the 30 day time 
period that are related to the study treatment must be reported to the IND 
Office. This may include the development of a secondary malignancy. 
 
Reporting to FDA: 
 Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety 
Project Manager IND Office) according to 21 CFR 312.32. 
It is the responsibility of the PI and the research team to ensure serious 
adverse events are reported according to the Code of Federal Regulations, 
Good Clinical Practices, the protocol guidelines, the sponsor’s guidelines, 
and Institutional Review Board policy. 
 
Investigator Communication with Supporting Company: 
 
Serious adverse event will be reported by FAX concurrently to OSI Drug Safety 
(Fax number: 303-546-7706). Information not available at the time of the initial 
report (e.g., an end date for the adverse event or laboratory values received after 
the report) must be documented on a follow-up report.  A final report to document 
resolution of the SAE is required.  Hospitalizations for the management of any 
expected adverse events (previously described) will not have an expedited 
report but it will be included in the annual report via the SAE log. 
 
Pregnancies: Any pregnancy that occurs during study participation or within 4 
weeks of the patient’s last study drug administration should be reported using the 
MD Anderson SAE Form. To ensure patient safety each pregnancy must also be 
reported to OSI and the IND Office within 24 hours of learning of its occurrence.   
 


2012-0060 
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The Investigator will follow the pregnant female until completion of the 
pregnancy.  The Investigator will provide this information as a follow-up to the 
initial SAE. 
 
If the outcome of the pregnancy meets the criteria for immediate classification as 
a SAE (i.e., spontaneous abortion [any congenital anomaly detected in an aborted 
fetus is to be documented], stillbirth, neonatal death, or congenital anomaly), the 
Investigator should follow the procedures for Expedited Reporting of SAEs. 
 
11.0 
STATISTICAL CONSIDERATIONS17 
 
This is an open-label, to assess the efficacy and safety of erlotinib in patients with AML. 
The primary efficacy endpoint is overall response as defined in section 9.3. 
 
The historical experience in this patient population is that response with standard therapy, 
when available, is less than 1%. In many instances (eg, patients with myelodysplastic 
syndrome failing hypomethylating agents), no standard therapy is even available. Thus, 
an overall response rate of 20% will be considered significant.  For the purpose of this 
analysis, a response will be considered if occurring after 3 months of therapy (or earlier). 
 
The Simon’s optimal two-stage design will be used to implement the study. A total of 29 
patients will be enrolled to this study. These sample sizes are based on Simon’s optimal 
2-stage designs of alpha=0.05 with power of 95% (beta=0.05) to test the null hypothesis 
that the ORR will be ≤ 1%  versus the alternative hypothesis that ORR will be ≥ 20. At 
the first stage, 14 patients will be enrolled. If no response is observed among the 14 
patients, the trial will be terminated early for futility. If one or more patients have 
response, 15 more patients will be enrolled at the 2nd stage. If at least 2 responses 
achieved after the completion of the 2nd stage, the study will conclude that the treatment 
improves the response rate from 1% to 20%.  The probability of early termination under 
the null hypothesis is 87%. The probability of seeing at least 2 responses under the null 
(ORR = 1%) is 3% while the probability of seeing at least 2 with an event rate of 20% is 
94.8%. 
 
Further enrollment will continue during the interim analysis unless no responders 
(CR+PR+HI) have been reported by the time of enrollment of the 14th subject being 
analyzed. In this event, enrollment will be suspended and these 14 subjects will be 
followed to further assess their responses. During this follow-up period, as soon as one 
response is observed, enrollment will resume. If no response is observed after the 14 
subjects have been fully assessed, the trial will be terminated for futility. 
 
11.1  Safety Monitoring 
 
Toxicities will be monitored using the method of Thall, Simon, and Estey [1]. 
Toxicity is defined as clinically significant, non-hematologic grade 3 or 4 
toxicities at least possibly related to erlotinib. We would like to control the rate of 
clinically significant, non-hematologic grade 3 or 4 toxicities at least possibly 


2012-0060 
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Page 23 of 28 
 
 
related to erlotinib to be lower than 30% during the 1st 28 days. Using this 
information a non-informative flat prior distribution of Beta (0.6, 1.4) was chosen 
for the new combination treatment. 
 
The interim monitoring will be first conducted after the first 10 patients have been 
evaluated and then be repeated continuously. The monitoring rule for toxicity is 
Pr(E, Tox > 0.3 | data) > 0.90,  where E, Tox is the proportion of any grade 3 or 4 
clinically significant, non-hematologic toxicities at least possibly related to 
erlotinib. That is, the trial will be terminated if at any time during the study there 
is a more than 90% chance that the average rate of grade 3 or 4 non-hematologic 
adverse events is more than 30%.  
 
The stopping boundaries, based on these assumptions and monitoring conditions 
are shown in Table 1. For example, accrual will be stopped if 6 or more patients 
experience toxicity among the first 10 patients treated or if 7 or more patients 
experience toxicity in the first 13 patients. 
 
Table 1:  Stop accrual if the number of grade 3 or 4 non-hematologic adverse 
events is equal to or greater than indicated (i.e., # Grade 3 or 4 toxicity) among 
the number of patients accrued (i.e., # Patients) 
 
# Grade 3 or 4 toxicity 
6 
7 
8 
9 
10 
11 
12 
# Patients 
10 
13 
15 
18 
21 
23 
26 
 
 
Table 2 shows the operating characteristics for this stopping rule based on 10000 
simulations.  
 
Table 2:  Operating characteristics of toxicity monitoring (Based on 10000 simulations) 
 
True Toxicity 
Probability 
Stop Probability 
Trial Sample Size Percentile 
25% 
50% 
75% 
0.2 
3% 
29 
29 
29 
0.3 
21.50% 
29 
29 
29 
0.4 
57.50% 
11 
22 
29 
0.5 
88.50% 
10 
11 
19 
 
11.2 
Statistical Analysis 
 
The primary efficacy endpoint is the overall response (ORR) as assessed by 
investigators and defined in section 9.3. The overall response rate (ORR) will be 
calculated for Using the intent-to-treat (ITT) data. The corresponding 95% 
confidence interval will be derived.  
 
Safety summaries will include tabulations in the form of tables and listings. The 
frequency (number and percentage) of treatment-emergent AEs will be reported. 


2012-0060 
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Page 24 of 28 
 
 
Additional AE summaries will include AE frequency by AE severity and by 
relationship to study drug. Adverse events requiring discontinuation of study drug 
will be summarized separately, both overall and by AE severity and by 
relationship to study drug. Subjects found to have abnormal values considered 
clinically significant will be summarized. Laboratory shift tables containing 
counts and percentages will be prepared by laboratory parameter and time. 
Summary tables will be prepared for each laboratory parameter. Figures of 
changes in laboratory parameters over time will be generated. 
 
Subject demographics (including age, sex, and race/ethnicity) and other baseline 
characteristics (including ECOG performance status, disease burden, and number 
of prior therapies) will be summarized. Summary statistics will include: means, 
standard deviations, and medians for continuous variables and proportions for 
categorical variables. 
 
For secondary endpoints, descriptive statistics will be used to summarize the 
expression of biomarkers and the concentrations of plasma erlotinib.  The 
Wilcoxon rank sum test will be used to compare the expressions of biomarkers 
and concentrations of plasma erlotinib between patients with and without 
response. 
 
12.0 
REFERENCES 
 
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leukemia treated with erlotinib for non small-cell lung cancer. Blood. 2007;110:1079-
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leukemia and concomitant non-small-cell lung cancer. J Clin Oncol. 2008;26:3645-
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5. Boehrer S, Ades L, Braun T, et al. Erlotinib exhibits antineoplastic off-target effects 
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2012-0060 
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Appendix  A:  Pharmacodynamic Investigations During Erlotinib Oral Therapy in Patients 
with AML Who Have Failed Prior Therapy.  
 
The major objectives of the pharmacokinetic and pharmacodynamic investigations during this 
clinical trial are as follows: 
 
1. To unveil which one or all three distinct biologic processes are blocked by erlotinib such 
as cell death by apoptosis, irreversible cell cycle blockade or terminal differentiation in 
AML1. 
2. To determine the molecular mechanism involved in erlotinib induced off-target effect on 
numerous cell-cycle proteins and onco-proteins2. 
3. To determine the effect of erlotinib on Syk (a non-receptor tyrosine kinase) inhibition3, a 
recently identified novel target of AML.  
4. To relate plasma pharmacokinetic and cellular pharmacodynamic endpoints and to seek 
correlations between these measurements and response to therapy.  
 
Only patients entering at MD Anderson Cancer Center will be studied.  All patients with ≥5,000 
WBC/l of peripheral blood will be requested to participate in the cellular pharmacodynamic 
studies. Patients will sign consent forms to enter these investigations.   
 
Once a patient has consented to participate in the investigation, please contact Ms Yuling Chen 
(pager 713 404-2550) in The Laboratory of Cellular and Molecular Pharmacology (Dr. Gandhi, 
phone, 713 792-3336) to coordinate scheduling of blood samples.  To facilitate preparedness for 
laboratory studies, please plan on initiating therapy in the subsequent morning if the clinical 
situation allows and please inform us as soon as there is a possibility of patient entering the 
clinical trial.     
 
Blood samples will be collected at the following times during Cycle 1.**   
 
1. 0 (Pre-dose) 
2. 6 hour 
3. 24 hours 
4. Day 5 
5. Day 28  
 
Each blood sample will be collected in a Vacutainer green top tube.  The samples will be mixed 
and immediately put on ice-bath.  Samples will be brought to Dr. Gandhi’s laboratory in the Tan 
zone (T6.3932).   The blood will be centrifuged and plasma will be separated, transferred to 
storage tubes and immediately frozen, and stored until analysis.  After removal of plasma, the 
blood cells will be resuspended in PBS and CLL lymphocytes will be isolated by Ficoll-Hypaque 
density-gradient centrifugation procedures.  Cells will be used for the following laboratory 
endpoints.   
 
**Every effort will be made to collect all samples at all time points for all patients; however, 
missing collection in one or more of these time points in occasional patients will not be 
considered a protocol deviation/violation. 


2012-0060 
September 19, 2013 
Page 27 of 28 
 
 
 
NOTE:  We may not be able to do all studies in every patient.  This will be decided based on 
diagnosis and number of leukemia cells recovered from the peripheral blood sample.   
 
Plasma pharmacokinetics:  Plasma will be separated from the peripheral blood samples and 
analyzed by a reference laboratory for concentration of erlotinib.   
 
Cell death assay:  The leukemic blast cells before and during erlotinib therapy (1 x 106 cells) 
from real-time will be stained with Annexin V-FITC and propidium iodide to determine 
induction of apoptosis using FACS calibur/flow cytometry machine2.   
 
Mitochondrial outer membrane permeabilization assay:  The leukemic blast cells before and 
during erlotinib therapy (1 x 106 cells) obtained in real-time will be stained with DIOC6 and 
propidium iodide to determine the loss of mitochondrial outer membrane polarity using FACS 
calibur/flow cytometry machine2.   
 
Assessment of differentiation: Because preclinical studies illustrated either/or effect of apoptosis 
or differentiation caused by erlotinib in AML cell lines, we will determine if erlotinib can 
overcome the block of differentiation during erlotinib therapy1,2. The leukemic blasts before and 
during erlotinib therapy (1 x 106 cells) obtained in real-time will be washed and stained with PE-
conjugated anti-CD11b antibody (myelomonocytic marker from Becton Dickinson; clone 
ICRF44) and Isotypic mouse IgG1 (Becton Dickinson) to measure CD11b positive cells using 
flow cytometry. 
 
Measurement of cell cycle blockade: Phospho-proteome analysis revealed that off target effect of 
erlotinib can influence the phosphorylation status of numerous proteins including the 
retinoblastoma (Rb) protein which is critical for G1/S transition of the cell cycle1. Therefore, we 
plan to measure the total and phospho-Rb (Ser-807/811) before and during therapy using 
immunoblotting technique.  
 
Measurement of JAK/STAT proteins: Erlotinib is known to induce apoptosis via inhibiting the 
phosphorylation of oncogenic JAK2 kinase on Tyr 1007/1008 in AML cell lines, which 
otherwise would phosphorylate STAT-5 (Tyr-694), a transcription factor and a direct target of 
JAK21.  Therefore our plan is to measure the JAK2 and STAT-5 proteins and their post-
translational modification during erlotinib therapy using immunoblotting experiments.  
 
Measurement of NPM-1 and p14ARF:  In AML cell lines, the anti-neoplastic action of erlotinib 
was associated with redistribution of NPM-1 (nucleophosmin-1, a myelomonocytic master 
regulator) and p14ARF (a tumor suppressor protein) from nucleus to the cytoplasm1.  So we will 
be measuring these two proteins by immuno-fluorescence method and immunoblotting 
experiments by staining with antibodies specific for NPM-1 and p14ARF before and during 
erlotinib therapy. 
 
Measurement of Syk and the downstream molecules: Two recent important findings, one, 
erlotinib has off-target effect on Syk tyrosine kinase and two, inhibition of Syk protein induced 
cytotoxicity in AML - identified Syk as an AML target4,5. Therefore our plan is to monitor Syk 


2012-0060 
September 19, 2013 
Page 28 of 28 
 
 
phosphorylation during therapy and the consequent modulation in Syk-regulated pathways such 
as NFKB, PI3-K/AKT6,7, STAT-38, mTOR9 and MAPK/ERK pathways10.  In addition, inhibition 
of BCR-induced Syk activation down-regulates Mcl-111, so we will be evaluating the expression 
and functional role of all the above said proteins during erlotinib therapy.  
Correlative Studies References: 
 
1. 
Boehrer S, Ades L, Braun T, et al. Erlotinib exhibits antineoplastic off-target effects in 
AML and MDS: a preclinical study. Blood. 2008;111:2170-2180. 
2. 
Boehrer S, Ades L, Galluzzi L, et al. Erlotinib and gefitinib for the treatment of 
myelodysplastic syndrome and acute myeloid leukemia: a preclinical comparison. Biochem 
Pharmacol. 2008;76:1417-1425. 
3. 
Uckun FM, Ek RO, Jan ST, Chen CL, Qazi S. Targeting SYK kinase-dependent anti-
apoptotic resistance pathway in B-lineage acute lymphoblastic leukaemia (ALL) cells with a 
potent SYK inhibitory pentapeptide mimic. Br J Haematol;149:508-517. 
4. 
Tomasson MH, Xiang Z, Walgren R, et al. Somatic mutations and germline sequence 
variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia. 
Blood. 2008;111:4797-4808. 
5. 
Hahn CK, Berchuck JE, Ross KN, et al. Proteomic and genetic approaches identify Syk 
as an AML target. Cancer Cell. 2009;16:281-294. 
6. 
Beitz LO, Fruman DA, Kurosaki T, Cantley LC, Scharenberg AM. SYK is upstream of 
phosphoinositide 3-kinase in B cell receptor signaling. J Biol Chem. 1999;274:32662-32666. 
7. 
Moon KD, Post CB, Durden DL, et al. Molecular basis for a direct interaction between 
the Syk protein-tyrosine kinase and phosphoinositide 3-kinase. J Biol Chem. 2005;280:1543-
1551. 
8. 
Uckun FM, Qazi S, Ma H, Tuel-Ahlgren L, Ozer Z. STAT3 is a substrate of SYK 
tyrosine kinase in B-lineage leukemia/lymphoma cells exposed to oxidative stress. Proc Natl 
Acad Sci U S A;107:2902-2907. 
9. 
Leseux L, Hamdi SM, Al Saati T, et al. Syk-dependent mTOR activation in follicular 
lymphoma cells. Blood. 2006;108:4156-4162. 
10. 
Qin S, Minami Y, Hibi M, Kurosaki T, Yamamura H. Syk-dependent and -independent 
signaling cascades in B cells elicited by osmotic and oxidative stress. J Biol Chem. 
1997;272:2098-2103. 
11. 
Gobessi S, Laurenti L, Longo PG, et al. Inhibition of constitutive and BCR-induced Syk 
activation downregulates Mcl-1 and induces apoptosis in chronic lymphocytic leukemia B cells. 
Leukemia. 2009;23:686-697.