Clinical trial NCT01649947
Conditions: Non-small Cell Lung Cancer Advanced Non-small Cell Lung Cancer Recurrent Non-small Cell Lung Cancer
Keywords: Lung cancer Non-small cell lung cancer Advanced non-small cell lung cancer Recurrent non-small cell lung cancer
Sponsor: Rutgers, The State University of New Jersey
Start date: 2011-12-23; Completion date: 2015-06-30
Enrollment: 32 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to examine the combination of one standard treatment for lung cancer plus an additional drug, hydroxychloroquine. The standard treatment for lung cancer being used includes 2 chemotherapy drugs, called paclitaxel and carboplatin. Some patients who have a specific type of lung cancer can also receive another drug, a drug that targets blood vessels, called bevacizumab (also known as avastin). Hydroxychloroquine is an FDA approved drug for the treatment of malaria, rheumatoid arthritis and lupus erythematosis.

Detailed description:

Arms: arm 1: Paclitaxel 200mg/m2 IV over 3 hours Carboplatin AUC= 6 IV over 15-30 min Hydroxychloroquine 200 mg PO BID arm 2: Paclitaxel 200mg/m2 IV over 3 hours Carboplatin AUC= 6 IV over 15-30 min Bevacizumab 15 mg/kg IV over 90 min for Hydroxychloroquine 200 mg PO BID
Interventions: intervention 1: Paclitaxel intervention 2: Carboplatin intervention 3: Hydroxychloroquine intervention 4: Bevacizumab
Intervention descriptions: intervention 1: Paclitaxel will be given at a dose of 200 mg/m2(by IV over 3 hours on Day 1). Cycles every 3 weeks for 4-6 Cycles.

Prior to receiving paclitaxel, all patients will receive the following premedication:

* Dexamethasone 20 mg po 12 and 6 hours prior to paclitaxel infusion (patients may be treated with dexamethasone 20 mg iv \< 1 hour prior to infusion with paclitaxel if the patient did not take the oral dexamethasone)
* Diphenydramine 50 mg iv (or equivalent) \< 1 hour prior to paclitaxel infusion
* Ranitidine 50 mg iv \< 1 hour prior to paclitaxel infusion (alternatively other H2-blockers may be used) intervention 2: Carboplatin will be given at AUC = 6 by IV over 15-30 minutes on Day 1 immediately following paclitaxel. Cycles every 3 weeks for 4-6 Cycles. intervention 3: Hydroxychloroquine will be given as a flat dose of 200 mg orally BID (total daily dose of 400 mg). Cycles every 3 weeks for 4-6 Cycles. intervention 4: Cohort 1 only:

Bevacizumab will be given by IV on Day 1 of each 21-day cycle at a dose of 15 mg/kg. Cycles every 3 weeks for 4-6 Cycles.

Protocol documents:
Prot_000.pdf: 
OtficialTitle:
"Modulation of Autophagy in Patients With
Advanced/Recurrent Non-small Cell Lung Cancer - phase
Protocol
toloel2oL4
NCT number:
0L649947
Document Tvpe:
Date of the
Document:


Modulatiou of autoplragy with hydroxychloroquine in patieuts with advanced/recurrent uon-
surall cell luug caucer - a Phase II study
Sub-iuvestigators:
nT
-
I
Dnrg(s) Uuder Investigation: hy&'oxychloruquite. carbeiplatin, paclitaxel and bevacinunab
CONFIDENTIAL
Biostrtistical Centrr
Protocol Vexion:
n
NCI
(nc'
:r
atl*qr**(k
thfht tr.*f+a#
fi*x}Srsb*is
t0i0913014
Page I of49


Modulation of autophagy with hydroxychloroquine in patients with advanced/recunent non-small cell lung cancer - a Phase II
studv
ftname:f
TABLE OF CONTENTS
1. PURPOSE/SPECIFICOBJECTIVES......
BACKGROUND AND SIGNIFICANCE
...........5
PARTICIPATING INSTITUTIONS.... 
.........."""""9
EXPERIMENTAL DESIGN AND METHODS
.9
5. PATIENT SELECTION CRITERIA.. 
"""""""""'11
5.2 INCLUSIoN oF woMEN AND MINoRITIES.".......'...... 
"""""""""""" 14
5.4 SouRcES OR METHODS OF RECRUITMENT............... 
"""""""""""" 14
5.5 STUDYENRoLLMENTPRoCEDURES 
"""""""""""""'14
3.
4.
7, TREATMENT PLAN...
8. TOXICITY MONITORING AND ADVERSE EVENT REPORTING 
"""""28
8.1 ADVERSE EVENT REPORTING REQUIREMENTS..........".' 
"""""""""'29
8.2 DEFDTITIoN oF SERIous ADVERSE EvENrs (SAES) 
""""""""""""29
9. TREATMENT EVALUATION/CRITERIA FOR RESPONSE. 
-"""""""""'30
9.5 GuIDELNES FoR EVALUATIoN oF MEASURABLE DISEASE'.. 
"""""'31
9.7 CoT.IFIRMAToRY MEAsuREMENT/DuMrloN oF RESPoNSE..........".."" 
""""""""'33
I0.REMoVALoFPATIENTSFROMSTUDY/oFFSTUDYCRITERIA.........................34
II. 
PHARMACEUTICALINFORMATION
------ --35
I1.3 BEVACZUMAB (CoHoRr I ONLY)... 
""""""""""""37
15
t6
Page 2 of 49
Protocol Version: l0/09/2014


Modulation ofautophagy with hydroxychloroquine in patients with advanced/recurrent non-small cell lung cancer - a Phase II
studv
-
ai
12. DATA COLLECTION AND RECORDS TO BE KEPT""""" 
"""""""""""""'tu
l2.l DATA REPoRTING To CooRDINATING CENTER 
""""40
13. DATA AND SAFETY MONITORING....
14. MULTI-INSTITUTIONAL GUIDELINES
I4.5 AMENDMENTS AND CONSENTS 
......'...4I
I4.7 DATA COLLECTION AND TOXICITY REPORTTNG..' 
""""""...."""'"'4I
14.8 DATA MoNIToRING AND SoLJRCE DocuMENT VERlFIcAnoN"" 
""""""""""""'41
15.
STATISTICAL CONSIDERATIONS...
...........................42
.-----43
16. HUMAN SUBJECTS..
I7. 
ECONOMIC/FINANCIAL CONSIDERATIONS......... 
""""44
18. 
PUBLICATION OF RESEARCH FINDINGS.. 
""""""""""'44
APPENDIX A - PERFORJVIANCE STATUS CRITERIA.. 
"""""""""48
APPENDIX B - NEW YORK HEART ASSOCIATION CLASSIFICATION OF CARDIAC DISEASE""""'49
4t
Page 3 of49
Protocol Version: I 0/09/20 I 4


Modulation ofautophagy with hydroxychloroquine in patients with advanced/recurrent non-small cell lung cancer - a Phase II
studv E
LIST OF ABBREVIATIONS
AE
ANC
CBC
CINJOG
CT
CR
CRF
CTCAE
DSMP
ECG
ECOG
FDA
HHS
IRB
kg
ML
mcdpg
NCI
NIH
OHRS
OHRP
PBMC
PD
PHI
PI
PR
RWJUH
SAE
SD
sCr
SGOT
SGPT
ULN
Adverse Event
Absolute neutrophil count
Complete blood count
Cancer Institute of New Jersey Oncolory Group
computer tomograPhY
Complete response
Case Report Form
Common Terminolory Criteria for Adverse Events
Data Safety Monitoring Plan
Electrocardiogram
Eastern Cooperative Oncology Group
Food and Drug Administration
Department of Health and Human Services
Institutional Review Board
kilograms
milliliters
Micrograms
National Cancer Institute
National Institutes of Health
Office of Human Research Services
Office of Human Research Protection
Peripheral blood mononuclear cells
Progressive disease
Protected health information
Principal Investigator
Partial response
Robert Wood Johnson University Hospital
Serious adverse event
Stable disease
Serum creatinine
Serum glutamic oxaloacetic transaminase
Serum glutamic pyruvic transaminase
Upper limit of normal
Page 4 of 49
Protocol Version: 1 0/09/20 I 4


Modulation ofautophagy with hydroxychloroquine in patients with advanced/recurrent non-small cell lung cancer - a Phase II
studv
-
1. Purpose/Specific Objectives
l.l Primary Endpoint
I . I . I The primary objective of this study is to assess the antitumor activity, as measured
by tumor response rate, of paclitaxel, carboplatin, Bevacizumab (for eligible
patients) and hydroxychloroquine in patients with advanced or recurrent NSCLC
cancer.
1.2 Secondary Endpoint(s)
1.2.1 To measure time to progression, percent one-year survival and overall survival
1.2.2 To assess toxicity of this regimen
1.2.3 To correlate clinical response with k-ras mutations
2, Background and Significance
Lung Cancer
Lung cancer is the number one cause of cancer-related mortality in the United States, with an
estimated 160,390 deaths in 2007.[] Over 85% of these patients will have non-small cell lung
cancer (NSCLC), and the majority of these patients have advanced disease at the time of
diagnosis. Patients with advanced disease who have an adequate performance status (PS) clearly
benefit from systemic chemotherapy, and many clinical trials were conducted to determine the
most effective regimen. In the late 1990's, the Eastern Cooperative Oncology Group (ECOG)
conducted a randomized phase III trial (E1594) to compare outcomes associated with several
platinum-based regimens: cisplatin * vinorelbine, cisplatin + paclitaxel, cisplatin * docetaxel,
and carboplatin + paclitaxel.[2] There were no significant differences in overall survival (OS)
between the 4 arms, with a median survival of 7.9 months and a l-year survival rate of 33Yo,
although patients receiving carboplatin + paclitaxel experienced the least toxicities. Similar
findings were observed in a trial conducted by the Southwest Oncology Group (SWOG), in
which carboplatin + paclitaxel was compared to cisplatin + vinorelbine.[3] Again median
survival was 8 months with a l-year survival rate of 36-38%. As many patients with NSCLC are
elderly or have co-morbidities that preclude the use of cisplatin, a large meta-analysis comparing
platinum-based doublet regimens to non-platinum based, third generation regimens revealed that
survival outcomes between these regimens were also not significantly different. [4] It was
proposed that the addition of a third cytotoxic agent could improve survival, a question that was
addressed in many clinical trials. However the majority of these studies demonstrated increased
toxicity without an additional statistically significant benefit in survival.[5-7] Therefore, the
current standard therapy includes two cytotoxic agents, one of which is usually a platinator if
tolerable. However, the poor outcomes still associated with advanced NSCLC clearly demanded
the need for continued improvements in treatment.
Angiogenesis and vascular endothelial growth factor
Scientific evidence supports the hypothesis that the growth of solid tumors is dependent on neo-
angiogenesis which led to the development of a novel approach in treatment.[8-10] Delivery of
oxygen and nutrients by the new vessels is a rate-limiting step for tumor cell proliferation and
growth. Thus, tumor-associated vasculature is a target for anti-tumor therapy. This concept of
Page 5 of49
Protocol Version: l0/09/20 l4
-


Modulation ofautophagy with hydroxychloroquine in patients with advanced/recurrent non-small cell lung cancer - a Phase II
studv
Itnamef
neo-angiogenesis led to the identification of factors responsible for stimulating new blood vessel
formation. Vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen, was
identified as a major regulator of angiogenesis implicated in turning on the angiogenic switch
necessary for progressive tumor growth.[ll] VEGF is a highly conserved, homodimeric
glycoprotein *hor. dominant isoform has a molecular mass of about 45 KD, and has a well-
defined role in normal and pathologic angiogenesis.fl2, l3] VEGF stimulates proliferation of
vascular endothelial cells, wiih u rn.in effective concentration (concentration resulting in 50Yo of
maximal achieved proliferation) of 10-50 pM. VEGF gene expression is substantially increased
in a majority of human tumors, including lung tumors, when compared with the surrounding
tumor-free tissues.[14] A correlation was noted between the degree of tumor vascularization and
the level of VEGF mRNA expression.ll5-19] In virtually all specimens examined, VEGF
mRNA is expressed in tumor .ellr but not endothelial cells. In contrast, mRNAs for two VEGF
receptors, VEGFRl and VEGFR2, are upregulated in endothelial cells associated with the tumor.
Theie findings are consistent with the hypothesis that VEGF is primarily a paracrine mediator
responsible for stimulating neo-angiogenesis and tumor propogation (18)
Targeting angiogenesis results in improved outcomes in select patients with NSCLC
Based on these data, investigators postulated that anticancer therapy could be significantly
improved by not only targiting the tumor cells directly, but also by targeting neo-
angiogenesir.lZOl S.uucizumab is a recombinant humanized monoclonal antibody that binds to
vici-a, preuenting: binding to VEGFR-I and -2 and downstream activation of endothelial
growth and migratiJn. In eaily clinical trials, bevacizumab demonstrated minimal toxicity in
combination with chemotherapy.[21 ,22] A randomized phase II trial demonstrated a significant
improvement in time to progieision (TTP) in patients receiving carboplatin, paclitaxel and
bevacizumab (15 mg/kg; compared to chemotherapy alone (7.4 mo vs' 4'2 mo, p=0'02)'123)
However, life-threa;ning and-fatal hemorrhage was observed in 9o/o of patients, and further
analysis iint.O this toxicity to tumors of squamous cell sub-histology. Thus patients with
cell tumors. as well as those with a p
t uu" U"o, .*clud.d f.orn ull further clinical trials using bevacizumab. The prospectively
randomized study of bevacizumab in NSCLC was conducted by ECOG (84599) in which
patients with advanced non-squamous NSCLC received carboplatin + paclitaxel with or without
tevacizumab.lz4lThis trial met its primary endpoint of an improvement in median OS (12.3 vs.
10.3 mo, HR 0.80, p:.013) in patients receiving chemotherapy plus bevacizumab as compared to
patients receiving ciemotheraiy alone. There was also an improvement in response rate (35% vs
i5%, p..g6t; and pFS (6.2 vs 4.5 mo, p<.0010). These significant improvements were
accomianiediy an increase in toxicity and tieatment related death (3ohvs l%o, p<.001). Based
on these results the combination of cartoplatin, paclitaxel and bevacizumab was approved by the
FDA in Oct 2006 for the first line treatment in patients with advanced non-squamous NSCLC
and has become a standard of care in the USA for these patients with a good PS'
Since wound healing requires neovascularization, in clinical practice, those patients who
underwent a recent procedure (such as port placement, recent invasive procedure where there is a
need for wound healing;, shouid receive Bevacizumab only aftet a 4 to 6 week delay for wound
healing.
Page 6 of49
Protocol Version: I 0/09/2014


Modulation ofautophagy with hydroxychloroquine in patients with advanced/recurrent non-small cell lung cancer - a Phase II
studv E
Bevacizumab Ineligible patients:
For these reasons, recent studies now distinguish patients with lung cancer into at least two
cohorts, those who are eligible for Bevacizumab and those who are not[25]. Typically, patients
with NSCLC without contraindications (hemoptysis, squamous histology, brain metastasis) are
considered as Bevacizumab eligible while the others are considered Bevacizumab ineligible.
Bevicizumab eligible patients will be defined as Cohort I in this study. These patients will
receive paclitaxel, carboplatin, bevacizumab and hydroxychloroquine.
Standard treatment for patients who are Bevacizumab ineligible is one of the standard
chemotherapies as per the ECOG 1594.2 Carboplatin and Paclitaxel is one of the standard
regimens and thus will be used as the back bone of the chemotherapy for Bevacizumab ineligible
patients as well. These patients will be defined as Cohort 2. These patients will receive
paclitaxel, carboplatin, and hydroxychloroquine.
Autophagy: a cell survival mechanism
While targeting angiogenesis has resulted in improved outcomes in NSCLC, the lack of durable
responses points towards resistance mechanisms. One such possible resistance mechanism is
through the activation of cell survival pathways such as autophagy. Autophagy is a normal, well-
regulated cellular response that is activated during times of nutrient deprivation. Autophagy is
effectively the cells recycling program whereby autophagosomes containing sequestered
cytoplasmic material fuse with lysosomes, resulting in digestion and reutilization of these
cellular contents.[26] This process temporarily conserves cellular energy, limits the accumulation
of damaged proteins and organelles during cellular stress, and thereby promotes cellular survival.
In tumor cells with defects in apoptosis (also known as programmed cell death) autophagy
allows for sustained viability and the ability to tolerate metabolic stresses.[27-31] This process
may allow cells to survive in a "spore-like" resistant state temporarily. This may eventually
result in cell death, but the restoration of nutrients allows these cells to regenerate.f27,29,32l In
those tumor cells with defects in apoptosis, and which rely on autophagy to survive, inhibitors of
autophagy can induce necrotic cell death.[30] Alternatively, in tumor cells with intact apoptotic
pathways, inhibition of autophagy can increase apoptotic cell death.[33] Thus blocking
autophagy has the potential to increase tumor cell death by several different pathways. Studies
by White laboratory [33a] in engineered mouse lung cancer models demonstrated that k-ras
mutant mice depend on autophagy, and autophagy inhibition inhibits tumor development and
progression.
Autophagy: potential mechanism of resistance to anti-angiogenic therapy
Recent studies have shown that K5 and endostatin, potent angiogenesis inhibitors, also induce
autophagy in endothelial cells of different tumor types.[34] If autophagy is induced by treatment
with angiogenesis inhibitors, the autophagic pathway may promote tumor escape from the effects
of antiangiogenic agents. A common feature of K5 and endostatin is upregulation of Beclinl, the
mammalian homologue of the yeast Atg6 autophagy gene involved in regulation of early
autophagosome formation, leading to alterations in the Beclinl-Bcl-2 complex. Interfering with
this autophagic response by knocking down Beclinl levels, thus abrogating autophagy,
dramatically increased apoptotic cell death of endothelial cells. Clinically antiangiogenic agents
PageT of49
Protocol Version: 1 0/09/20 I 4


Modulation of autophagy with hydroxychloroquine in patients with advanced/recurrent non-small cell lung ciulcer - a Phase II
studv
-
such as bevacizumab can induce metabolic stress through nutrient deprivation, a process that
may be enhanced using drugs that target autophagy.
Hydroxychloroquine is an agent that has been in use in the clinic for some time for the treatment
of malaria, rheumatoid arthritis, and systemic lupus erythematosus. This agent works through
inhibition of lysosomal acidification and blocks autophagy. Indeed the addition of chloroquine to
either antiangiogenic agents or cytotoxic agents significantly increases antitumor activity.l30,32,
351 In this trial we hypothesize that the addition of hydroxychloroquine to the standard regimen
of paclitaxel, carboplatin with or without bevacizumab will significantly increase antitumor
activity.
The initial phase I study of this combination defined the dose in the first cohort of patients (n:8)
and demonstrated toxicity similar to the chemotherapy combination without the addition of the
hydroxychloroquine. A review of the response data showed that 6 of the 8 patients achieved a
partial response by RECIST criteria. Subsequent interim analysis of this and the prior study
shows a composite 52o/o PR, and 25yo Stable disease rate. The progression free and overall
survival data are as yet ongoing but easily comparable to or better than historical data for stage
IV disease. Given the initial promising results in objective response, further phase II testing of
this combination seem warranted.
Hydroxychloroquine:
Hydroxychloroquine is a 4-aminoquinoline that has been in use for more than 30 years for the
treatment of malaria, rheumatoid arthritis, and systemic lupus erythematosus. A dose of 200 mg
po bid is well tolerated for chronic use and doses up to 1200 mg/day have been widely used
safely. Pharmacokinetic data from the Cancer Institute of New Jersey phase I studies, similar to
studies in Rheumatoid arthritis, have shown that with daily dosing, the hydroxychloroquine
remains membrane bound, but free levels are seen in 1200 mglday. A total equivalent daily
dose was well tolerated by patients with rheumatoid arthritis, without any reported adverse
events or need to discontinue-drug secondary to toxicity during the first year of treatment.al In
this study the majority of toxicity was attributable to gastrointestinal issues, anemia and rash. An
extremely rare toxicity of hydroxychloroquine is ocular toxicity that can result in retinopathy
with visual field deficits. This toxicity is related to the daily and cumulative dose of drug, as well
as the duration of therapy, and is .u.n *or. rare before 2 years of therapy.a' Giu"n the rarity of
this toxicity, the relatively short expected duration of therapy, and the lack of any adverse ocular
findings in our (and other's) oncology trials, we will forgo ocular monitoring, but remain
cognizant of this rare toxicity.
Hydroxychloroquine has dramatically entered cancer clinical trials and NCI lists 29 clinical trials
involving hydroxychloroquine. Addition of hydroxychloroquine to adjuvant chemotherapy and
radiotherapy for patients with glioblastoma multiforme in a small pilot study resulted in
prolongation of median survival, which though not statistically significant due to the small
number of patients enrolled, is worth further exploration in larger trials (49) At present,
hydroxychloroquine is being tested in combination with radiation therapy and temozolomide for
the treatment of patients with newly diagnosed glioblastoma multiforme in a large multi-center
NCl-sponsored clinical trial (NCT00486603), and in combination with bortezomib in patients
with relapsed or refractory multiple myeloma in another NCI-sponsored study (NCT00568880).
At the 
we have a portfolio of studies testing autophagy inhibition
Page 8 of49
Protocol Version: l0/09/2014


Mofulrtim of *ulophagr with hydroqrclrloroquine in patiorts with advancc#rccurrsrt non-suell ccll hng caaca * a Phasc II
studv
-
with hydroxychloroquine and we closed a dose fiading study in NSCLC rvhich prcvides the
dositg for this Fhase II study.
2.1 Study Rationnle
This is an open-label Phase tr study of paclitaxel, carboplatiu" and bevaeizumab (in
Bevacizumab eligible patients) plus hydroxychloroquine in the treatment of patients wifh
advanced NSCLC. Otu ltypothesis is that inhibitiou of autophagy using hydroxychloroquine
rvill iurprove the activity of standard chemotherapy +l. bevacizurnab in &is patient
population. Otu Phase I shrdy {030801) showed tolerability at standard doms of all agents
and also showed considerable activity in response (see statistical desigu).
Hydroxychloroquiue is a moder*te inhibitor of CYP ?D6 ald a urajor subskate of that
ell4nne, atd tlrere is both h*patic and renal claarauce of drug.a3 Paclitaxel is rnajor subskale
of CYP?C8 and 3A4, a ruiuor iad*cer of CYP3A4; carboplatin is subject to renal clearance;
bevacirumab is subjrct to proteolytic catabolism throtrglrout the body.
We will also perfonn exploratory correlative aoalyses of LC3 protein expressioa on
peripheral blood monoruclear cells, aud Beclin-l and p62 expression in pretreahuent tuuror
tissue, when available" LC3 is a marker of autophagosorne fonnation. Beclin-l is an essential
rcpnrlator of autophagy stld levels of this protein may correlate with and/or iudicate the
capacity for autopha$y, and p52 accumulation is associated with autophagy. These aualyses
will be considered exploratory as there are $o established mar*ers of autophagy.
{. Experimental Design and ${ethods
This is an open-label Phase II study of the combination of peclitaxel at ?00 mg/nf
inh'avenously over 3 houls on Day l; followed by carboplalin AUC = 6 intravenorxly over
15-30 mirutes on Day I followed by Bevaciaunab (for Cohort l) at 15 mdkg intravenously
(initial infrrsion over 90 minutes) on Day l; and hydroxychlorcquine orally (500 mg BID) on
Days l-21. Chemotherapy will be repeated every ?l days lbr a total of 6 cycles if tolerated.
The fotal utunber of cycles will be determined by tlrc treating physici*ns in aggeenent wifh
the Principal Im'estigator. Patients in Cohort I will then continue to receive bevaciaunab
every 2l days and hydroxycNoroquine daily up to I year until evidence of disease
proppession or unacceptable toxicily, while Cohort 2 will receive hydroxychloroquine *lone.
The continuation of the ltydroxychloroquine (with or without bevacizunab as per colrart) is
based on several recent studies suggestiug improved disease fi'ee and overall survival witl
maintenaree tlrerapy (24' 3s' 'o. *oi "ooiio,oiion of hydroxychloroguine could spare the
patietts the accumtrlating toxicity of coatimred cheurotherapy.
ASer baseliue evalustiouo tuncr response will be evaluated every 2 cycles (6 weeks) of
therapy. Resporses will be assessed using RECIST criteria. Patient sruvival will be follor.ved
every 2-3 urouth* after courpletion of initial cheurotherapy unfil progression of disease, a*d
followed for ovemll survival.
Protocol Version: I 0/09/?0 I 4
Institutions
Page 9 of49


Modulation ofautophagy with hydroxychloroquine in patients with advanced/reQunent non-small cell lung cancer - a Phase II
studv
elname:f
Schema:
Stage IIIB/IV or recurrent NSCLC
Cohort l: Bevacizumab Eligible Patients
Cohort 2: Bevacizumab Ineligible Patients
See Section 5 for eligibility criteria
Cohort 1: Bevacizumab Eligible Patients
All on DaY 1
Paclitaxel 200mg/m2lV over 3 hours
Carboplatin AUC= 6 lV over 15-30 min
Bevacizumab l5 mg&g IV over 90 min for
PLUS
Hydroxychloroquine 600 mg PO BID
Cohort 2: Bevacizumab Ineligible Patients
All on DaY I
Paclitaxel 200m{m2lV over 3 hours
Carboplatin AUC: 6 IV over l5-30 min
PLUS
Hydroxychloroquine 600 mg PO BID
Cycles every 3 weeks for 4-6 CYcles
See Section 7 for additional infusion guidelines
If a patient enrolled in
Cohort 1 is determined to
have:
CR, PR or SD
Bevacizumab 15 mg/kg IV q 3 weeks until
relapse/progression
PLUS
Hydroxycholorquine 600 mg PO BID
Note: No maintenance therapy will be given
for Cohort 2 enrolled Patients
Page l0 of49
Protocol Version: I 0/09/20 I 4


Modulation ofautophagy with hydroxychloroquine in patients with advanced/recurrent non-small cell lung cancer - a Phase II
studv E
4.1 Duration of StudY
The anticipated time a patient willbe on study will be up to approximately l2'18 months (6
cycles of chemoth 
"rupyl+l-B"vacizumab/ltydroxychloroquine 
followed by up to I year of
ciremotherapyl+l-Beiacizumab/hydroxychloroquine for Cohort I or 2 respectively. A longer
time on follow-up would be a reflection of a very positive outcome of the study.
Approximately 40 patients will be enrolled on this study. This study is expected to accrue
li-15 patients a yeai (based on prior accrual history, see protocol 030302) for 3 years.
5. Patient Selection Criteria
5.1 Inclusion Criteria
A patient is eligible for enrollment if all of the following inclusion criteria are met
5.1.1. Signed a protocol-specific informed consent'
5.1.2. I 8 years of age or older.
5.1.3. ECOG Performance Status 0 or 1. (see Appendix A)
5.1.4. Tumor assayed for k-ras and other tumor genomic mutations
Cancer criteria:
5.1J. Hirt"l"gically or cytologically confirmed non-small cell lung cancer. Mixed tumors
will be categorized by the predominant cell type unless small cell elements are
present, in which case the patient is ineligible. Cytologic or histologic elements can
6e established on metastatic tumor aspirate or biopsy. Sputum cytology alone is not
sufficient.
5.1.6. Advanced stage NSCLC (stage IVa ((malignant pleural effusion (is now staged as
stage IVa by tfie most recent staging system), or stage IV, or recurrent disease)).
5.1.7 . Measurable disease according to RECIST criteria'
5.1.8. patient with CNS metastasis are required to have stable disease documented by being
off treatment (surgery, or Whole Brain radiation therapy) for at least 2 weeks, and
four (4) weeks is preierred. No delay in onset of therapy is required for those patients
who undergo steriotactic RT to the brain lesion(s). A contrast enhanced brain CT or
brain MRI is required within 35 days of enrollment. Patients with brain metastases
who qualify for protocol therapy will be included in Cohort 2 (ineligible for treatment
with Bevacizumab)'
5.1.9. No prior cytotoxic chemotherapy or targeted therapy in the advanced or metastatic
setting. poit-operative adjuvant therapy for previously resected NSCLC is allowed as
long as the lait dose wai given greater than I year before study entry, and there is
current evidence of disease progression.
5.1.10. prior radiation to sites other tian the brqinls allowed, if completed at least 2 weeks
before treatment and provided that all radiation-related toxicities have resolved to
< Grade l. StereotactiC irradiation to any site excludes the need for a waiting period.
5.l.ll.No active malignancy other than NSCLC. Patients with a history of basal cell or
squamous cell carcinoma of the skin or carcinoma in situ of the cervix, or ductal or
lobular carcinoma in situ of the breast within the past 3 years must have been treated
Pagellof49
Protocol Version: l0/09/2014


Modulation ofautophagy with hydroxychloroquine in patients with advanced/recurrent non-small cell lung cancer - a Phase II
studv E
with curative intent. patients with a history of prior malignancy are eligible provided
they were treated with curative intent and have been free of disease for > 3 years'
Laboratory requirements
5.1.12. Ad.quit. orga, function, as evidenced by ALL the following:
o absolute neutrophil count (ANC) Z 1500/mm3
o platelet count > 100,000/mm3
o hemoglobinZ9gm/dl
o total Uiti*Uin < 1.5 x ULN; if patient has Gilbert's disease, then patient must have
isolated hypeJitirubinemia (e.g. no other liver function test abnormality), with
maximum bilirubin < 2 X institutional ULN'
o AST and ALT <2.5 x ULN in the absence of liver metastases;
AST and ALT < 5 x ULN in the presence of liver metastases
. alkaline phosPhatase <2.5 x ULN
o creatinini S t.5 X institutional ULN or calculated creatinine clearance
2 60 ml/min as estimated using the cockroft-Gault formula.
For Cohort l: (Bevacizumab ettstote,t
5.l.l3.No history of gr"tt-sis 
(defined as bright red blood of a half-teaspoon or
more) within 3 months prior to enrollment'
5.l.l4.None of the following conditions within 6 months prior to enrollment: myocardial
infarction, stroke or symptomatic peripheral vascular disease.
5.l.l5.For patients who have had un1uio. iurgical procedure, open biopsy, or significant
traumatic injury within 28 days prior to enrollment, or anticipate the need for such
while on active treatment, may participate and receive Bevacizumab at the start of the
second or third cycle as they would und.t standard care. Placement of vascular access
device is not considered major surgery, but the incision must have healed before
initiation of treatment.
5.l.16.Nohistoryofabdominalfistula,gastrointestinal
abscess within 6 months prior to enrollment'
perforation, or intra-abdominal
5.1.17. No serious non-healing wound, ulcer or bone fracture'
5.1.18. Patients musl have a-systolic blood pressure S 150 mm Hg and diastolic blood
pressure < 100 mm Hg (the use of antihypertensive medications to achieve these
goals is allowed).
5.1.19.patients must not have unstable angina or NYHA classification of congestive heart
failure of Grade Z 2 (see Appendix B)'
S.l.2O.No history of significant vasiular disease (eg aortic aneurysm).
5.l.2l.No current or "recent (within 28 days of enrollmenQ full dose anticoagulants or
thrombolYtic agents.
5.1.22. Adequate organ function
o INR < 1.5 and aPTT WNL.
o Urine Protein Creatinine (UPC) ratio < 1.0 or 24 hour urine protein ratio
< 1000 mg
Comorbidities
Protocol Version: I 0/09/20 14
Page 12 of 49


Modulation ofautophagy with hydroxychloroquine in patients with advanced/recurrent non-small oe, lung cancer - a Phase II
i?*L.,- 
,tr,ra
uPC ratio of spot urine is an estimation of the 24 urine protein excretton' A urv
ratio of I iiroughly equivalent to a 24-hour urine protein of I gm' To obtain a
UPC ratio:
. Obtain at least 4 mL of a random urine sample
o Determine protein and creatinine concentration
. Calculate the UPC using one of the followingformulae
[urine proteinJ/furine creatinine] - if bothvalues are reported in mg/dL
[(urine protein) x 0.088]/[urine ffeatinineJ - if urine creotinine is reported in
mmol/L
For Cohort 2 (Bevaclzttmab ineligible):
5.l.23.None of the following conditions within 6
infarction, stroke or symptomatic peripheral
5.1.24.Patients must not have unstable angina or
failure of Grade Z 2 (see Appendix B)'
5.l.25.Patients must not have hemoptysis, squamous histology, brain metastasis
For ALL (Cohort I and Cohort 2):
5J.26;,.Patients must not have psoriasis or porphyria'
5,l.2T,Noknownhypersensitivityto4-aminoquinolinecompound.
5.1.28. Patients must'not have known or suspected G-6P deficiency'
5.1.29.No know bleeding diathesis or coagulopathy'
5.1.30. No known GI pat"hology that would interfere with drug bioavailability'
5.1.31. No peripheral or sensory neuropathy > Grade.l at.study entry'
5.1.32. No known prior hyie.sensitivity to carboplatin, paclitaxel, bevacizumab or
hydroxychloroquine or any of their components'
5.1.33. l.io ongoing or active infection at study entry'
5.1.34.Patients must not be receiving treatment for rheumatoid arthritis or systemic lupus
erYthematosus.
5.1.35. Patients must not have HIV or be taking HAART therapy'
5.1.36. patients must not have a history of iny condition (social or medical) that, in the
opinion of the Investigator, miitrt interfere. with the patient's compliance with the
piotocol or pose additional or unacceptable risk to the patient.
5.l.37.Women rnuit NOt be pregnant or breastfeeding'
5.1.38. Women must :
o Have a negative serum or urine pregnancy test within 7 days prior to study
entry if shi is a woman of child-bearing potential' OR
o Be at least one year post-menopausal, OR
o Be surgicallY sterile
5.1.39.Patients or c[itauiaring or child fathering potential must be willing to use an
acceptable method of birttr control prior tJstudy entry and for the duration of the
months prior to enrollment: myocardial
vascular disease.
NYHA classification of congestive heart
Pagel3of49
Protocol Version: 1 0/09/2014
I


Modulctim of auiophEy wiih hydnqrcNoroquioc in patiants with sdvamadrrs1lrBt aon-rmall ccll tng cancrr - o Phast Il
ltrdy
PImmc:
ffi.eptable *itlgg tr :ont'1*:::T l]::l*,tornronal' 
bamier methods'
[ff*Ji"-ffi;;, ffi;t hs-tionrvasectom{ * .'b:lTi:
s . 1 . 40. il::l':,Tt"* iil[ rr*ffi ffi il;. ].'i,""r*-nt or propbvlaxis or malaria'
S.2Inclusion of Women and Minorities
Ttre National Institute of Health (NIH) and NCI lrave stressed the importance of gender
ard ruiaority io"i*ion in elinici u."il""* and reseatch- Fernale patients accormted for
5go,/o of c&neer p-ii*J seeu withi,'rir*-c**"r Institute of i{eq, Jersey's clinical
proltrams *irh*lil:'il;t y; ;;;;*1-Aillgrisans courprised 7%' Hispanics 80,'' and
Asiaus 3016 of female patients, ,r*p**tJfy' f*. *ff pll':"*- euteriug cliuical tials' tlre
percentages **rJiy"-womel}, 6rl"Ail;;-American, 5% Hispanic, and 396 Asian'
Nopersoushall,outheqoy|s3fage.race,color'orrratiorralorigur.beexcluded&on
participatioo io, o, u, J*ili"c tt * rr*""?ir of, eru'olhuent in this protocol'
i.3 Prrticipafion of Chiltlren 
r r, ,, c-^-.-. -r,,r,, norrir^inntion Lulr
patieuts urder ti;G;f lg will be excluded fronr sndy parlicipation" Lung cntrcer $
not seetr in the pediatric population
5.{ Sources or }lethods of Recruitment
-' - 
f*.i"iPuot*
treated at the
evaluatetl artd
document and written
rnust tle oq nle a!
tJ;:t*ii.j,il:,r,.ff 'x-TJ*x;:l:;:1-31:;liJ,:l!ff 'ffi"u{$:}11.1#i
for not st*rting protocol therapv will te iocumeuted i, the ';fo1ow'up eCRf*' Case report
form completion **t*"tio* "rro truirr.io!**il-r:* fiovlo.a to each participatlug institutiou
prl* t, tt tAV ac{ivatinu at the parlicipating institrrtios'
Protocol VersigUJ 01098911
Fage 14 of49
iufomred
consent
for this t


Mo&latim of autophegy uitlt hydre:rychloroquicc in paticnts *ith advaacrd/rccrhurt u rr-r:uall ccll lung cmcer _ a pha* II
studv
-
6. Study Partmeters
The followiug tests aud evaluations lvill be perfonned according to the schedule below.
Baselioe (i.e., pre-study) evolunfioils must Ue perfonne* no lougerihau 4 weeh (+1- 3 dap)
ior to
. urless otherwise indicated in one of the footnotes below the table
b May be perforuled 73lu prior to Day L Screening lab results are acceptable for Cycle l. Day I and do not need to be repeated.
c lacludes: Electrolytes. Calciust" BLtrN, Creatinine. Total Prctein, Glucose, Albumin, Totat liilirubin, AIk phosplratase,
ASTIALT
d For berarizurnab patierxr only - UPC to be obtained at baseline and at least every other cycte (Cycle Z, d 6, etc). If a IIpC is
$ot obtailed qn altEmare cycles (Cycle 3,5.?. etc.), a urine dip mrct be obtai$ed. If Upirxtio ir " t " 
24 how urjne for
proteil is to be collected
e Er.ery 3 monthr rnohile ocr trial regardless of phaee of treahneut
f. Wornen uu.ttl: Have a negative senun or rui$e pregrrfiEy test rvithin ? days prior to shrdy euby if she is a wonran of child-
bearing poteutiel IWOCBpJ, OR Be at leost one year post-rr}Eooprusal, OR Be nrgicalty rterile.
g Tunur as$etsros$t {at a 'ninirnpq CT Chesl with liver and a&enal windor*r, nith coutrast if uo containdicatioo) of all
known lesious are to be el.raluated according to R-ECIST. RECIST criteria u'ill be coupleted ou or before the day of heahuent
pnor to drug delitery. Any PR or CR ruust be confrrured byrepeat radiographic assessruent perfonned af teast 4 weeks (+A 3
days) a&er the prior scan. This confirnratory scan will serve as a nerry baselite, and fumor assessrnertt cau be perfonned every
3 cycles starling from the tfune &e confinnatory scan is obtained.
h Patienrs may receive up ts 6 cycles as deterurined appropriate by rhe atterrding physician in aggcssleot with the principal
lnvestigator.
i INR will be determined for tevacizumab patients only.
j' "Access archived hrnor tissue *t time of diagprosis or repeai diagrrostic biopsy al screeuing, where approprirte (e.g. when tiale
Sorn diagrroris to preserrtation nray u'arrorl)
Page 15 of49
Protocol Version: I 0109/!014


Modulation of autophagy with hydroxychroroquine in patients with advanced/recurrent non'smarl cell lung cancer - a Phase II
i,Tl'".",!!t!
1. Treatment Plan
i;1"9.,i]1il11,fff;1;?:',:,T.d on an outpatienftasis- A cvcre is o.r,.L.g as an interval or 21
days (a delay of 2 days due to holidayJ, rLrr.."o. und bad weather will be permitted and will
not be counted as a protocol violation]. N" irr.rug",ional or commercial agents or therapies
other than those described below ,r"y ;;;;iniJtered with the intent to treat the patient's
malignancy. Patients will receive treit.""t until it is no longer of benefit to them or until 1
y"url Patients may discontinue therapy at any time for any reason'
7.2 StudY Agents
ffiillbeobtainedcommerciallyandisavailableina200mgtabletthatis
equivalent to i!J-,,,f rryarorycttio-.ili;; U."* *9,, 250 mg chloroquine phosphate'
Hydroxychlo.oquin. riay'Ue ,ur..r-*ilii- food or milk at any time of the day' Once
hydroxychororofiri,i" 1t-],#4, p"ients should take hydroxychloroquine around the same
time every daY.
Forpatientsthatareunabletoswallowcapsulesortablets,thetabletmayberemovedandbe
dissolved in 5 ml of water or mixed in a imall amount of liquid or f99!. However' the drug
may be bitter-tasting. The drug may u. oittoruto in 5 ml of water for NG administration'
Patients receiving antacids, sucralfate, cholestyramine'. and/or bicarbonate should have the
study drug dor. u-d*inistered at teast-i'trour beiore or 2 hours after these medications'
ffi-illbeobtainedcommerciallyandisavailableasapremixedsterileaqueouS
solution of l'mgiml ready for dilution uno pur.nreral.administratiin' vials are available in
50, 150,450 and 600 mg sirer,.o'rituin no'ptt"rvative' and are for single use only' For
fuither details, refer to the Paraplatin6 luttugt Insert and institutional standards'
Bffiwill 
be obtained commercialry and isavailable as a concentrated solution of 6
mg/ml in polyoxyethylated-cas.t "ii1Cr.i*"pf,or 
EL) 50% and dehydrated alcohol 50% in 5'
16.7 and50 ml vials. For further o.tuilr, refer to the Taxol@ Package Insert and institutional
standards.
ffiinCohort1willreceiveBevacizumab.Bevacizumabwillbeobtained
commercially and is available ur- u .t.ut to slightly opalescent'. sterile liquid ready for
parenteral uo*irirt ution. Each 400 or 100 mg (25 mg/m) glass vial contains bevacizumab
with a vehicle consisting of sodiurir pf,"tpt'"i irehal;se' polysorbate 20'.and Sterile Water
for Injection, USp. VialJ contai" ,; ;;;;;;vaiiye and.are for single use only' Vials should be
refrigerated at2"C_g.c(36.F-46"F, inJshould remain refrigerated.unti use. vials should be
protected from light, not frozen, and not shaken. po. r,rrtri., details, refer to the Avastin@
Fackage Insert and institutional standards'
Protocol V.ttlgtil 0/0%9]i
Page 16 of 49


Modulation ofautophagy with hydroxychloroquine in patients with advanced/recurrent non-small cell lung cancer- a phase II
study
PIname:f
7.3 Dose Calculation
Hvdroxvchloroquine
Hydroxychloroquine will be given as a flat dose of 600 mg orally BID (total
1200 mg). Missed Doses
If patients vomit after taking hydroxychloroquine, patients should be instructed
the dose. Patients should take the next dose at the scheduled time.
daily dose of
not to retake
If a scheduled dose is missed, patients should be instructed to take the dose as soon as
remembered. If it is near the time of their next dose they should be instructed to skip the
dose and resume their usual dosing schedule. Patients should not double their dose to catch
up missed doses.
Paclitaxel
Paclitaxel will be given at a dose of 200 mg/mz. The dose will be based on the patient's
actual weight at screening in the determination of body surface area. A variance of SYo of the
calculated total dose will be allowed.
BSA (m2;:
lnrigni1rwrishptbt)
1/ 
3r3r 
or
I he i g h t 1c m1 ii, i sh t (ks)
1/ 
3600
Carbonlatin
The dose will be AUC : 6 Carboplatin dose will be based on the Calvert formula:
Carboplatin dose (mg) = AUC x (GFR* +25)
*GFR is estimated using the Cockoft-Gault formula for creatinine clearance and the
patient's corrected body weight (lean):
{(140 - patient's age) x (patient's conected body weight in kilograms)}f
(7 2 x patient's serum creatinine)
#Forfemales, multiply the result by 0.85
Ideal body weight : (2.3 * {inches over 5 feet}) + 45 kg for females
(2.3 * {inches over 5 feet}) + 50 kg for males
Corrected or Lean Body Weight =
({Total Body Weight - Ideal Body Weight} * 0.4) + Ideal Body Weight
Page 17 of 49
Protocol Version: l0/09/2014


Modulation of autophagy with hydroxychloroquine in patients with advanced/recunent non'small cell lung cancer - a Phase II
i?i'...,-
ffinCohortlwillreceiveBevacizumab.Bevacizumabwillbegivenatadoseof
15 mg/kg. Doses *ifi U" calculated UurJ on the patient's actual weight in kilograms at
screening. A variance oiiy"of the calculated total dose will be allowed'
7.4 Treatment Administration
This study will be open to the GINJOG Network hospital(s) and investigator offices"
Patients will be .nroif.O in one of two cohorts as determined by their type of cancer'
cohort 1 patients will be Bevicizumac.rGui. pr,ient and cohort 2 will be Bevicizumab
ineligible Patients.
Cohort 1 @evicizumab eligible)
Patients will be given paclitaxel at 200 mglm2,-bevacizumab 15 mdkg' carboplatin
AUC :6 and hydroxychloroquine 600 mg ora-lly BID (total daily dose of 1200 mg)'
once hydroxycholoroquine is started, patients should take hydroxychloroquine around
the same time everY daY'
paclitaxel will be given by IV over 3 hours on Day I (see Section 7 '4'l fot premedication
guid.lin., and Section 7 '3 for dosing information)'
Carboplatin will be given at AUC - 6 by IV over 15-30 minutes on Day 1 immediately
iollowing paclitaxel (see Section 7'3 for dosing information)'
Bevacizumab will be given by IV as detailed below on Day 1 immediately following
carboplatin 1r". S..iion 7.a fbr-;;ti;t information; Section 7'4'2 for intusion
information). For patients that have had a recent surgery, or invasive procedure'
Bevacizumab can beitarted at Cycle 2 or Cycle 3'
If a patient enrolled in cohort 1 is determined to have complete response (cR)' partial
response (PR) or stable disease tspittrev will.be given bevacizumab 15 mgikg IV every
3 weeks and hydroxychloroquine OO'O mi orally BiD until relapse or progression occurs'
Cohort 2 @evicizumab ineligible)
patients will be given paclitaxel at 200 mglm2, carboplatin AUC = 6 and
hydroxychloroqiin.?oo mg oratty BID (total daily dose of 1200 mg).
once hydroxycholoroquine is started, patients should take hydroxychloroquine around
the same time everY daY'
PaclitaxelwillbegivenbylVover3hoursonDayl(seeSection7.4.|forpremedication
guidelines and Seclion 7 '3 fot dosing information)'
Carboplatin will be given at AUC, = 6 by IV over 15-30 minutes on Day 1 immediately
following paclitaxet isee Section 7 .3 for dosing information).
Protocol Vttt-191, I 0/0%9li
Page 18 of49


Modulation ofautophagy with hydroxychloroquine in patients with advanced/recurrent non-small cell lung cancer - a Phase II
studv E
7.4.3. Paclitaxel premedications
prior to receiving paclitaxel, all patients will receive the following premedication:
o Dexamethasone 20 mg po 12 and 6 hours prior to paclitaxel infusion (patients
may be treated with deiamethasone 20 mg iv < I hour prior to infusion with
paclitaxel if the patient did not take the oral dexamethasone)
o Diphenydramine 50 mg iv (or equivalent) < I hour prior to paclitaxel infusion
. Ranitidine 50 mg iv < t hour prior to paclitaxel infusion (alternatively other H2-
blockers maY be used)
T.4.l.Bevacizumab infusion (Cohort I - Bevacizumab eligibte patients Only)
Bevacizumab will be given on Day I of each Zl-day cycle. The initial bevacizumab dose
will be delivered or.r 90 (+10) minutes as a continuous infusion. If a patient experiences
an infusion-associated adverse event, he or she may be premedicated for the next drug
infusion. However the infusion time may not be decreased for the subsequent infusion. If
a patient continues to experience infusion-associated adverse events with the 9O-minute
infusion, the patient's symptoms should be managed per institutional guidelines. If the
first infusion is tolerated without infusion-associated adverse events, the second infusion
may be delivered over 60 (tl0) minutes. If a patient experiences infusion-associated
adverse events with the 60-minute infusion, all subsequent doses will be given over 90
minutes. If the 60-minute infusion is well tolerated, all subsequent infusions may be
delivered over 30 (*10) minutes. If a patient experiences infusion-associated adverse
events with the 30-minuie infusion, all su-bsequent doses will be given over 60 minutes'
Monitoring for and management of anaphylactic reactions will be performed according to
institutional guidelines.
7.5 Dose Modifications
Dose Modifications General Guidelines Cycles 1-6
All toxicities should be graded using common Terminology criteria for Adverse Events
(CTCAE) Version 4.0
DOSE MODIFICATIONS FOR ALL DRUGS WILL BE MADE USTNG THE
FOLLOWING GENERAL GUIDELINES:
o The guidelines below are recommendations. Any toxicities observed should be
manfued according to institutional guidelines and the clinical judgment of the
treating phYsician.
. All dose reductions are permanent.
o Dose modifications of any one drug will not affect the dose of the other 3 drugs'
o There are no dose reductions for bevacizumab. lf adverse events occur that
necessitate holding bevacizumab, the dose will remain unchanged once treatment
resumes.
Page 19 of49
Protocol Version: 1 0/09/20 I 4


Modulation of autophagy with hydroxychloroquine in patients with advanced/recunent non-small cell lung cancer - a Phase II
studv E o If a dose is delayed due to toxicity, labs/toxicity should be_ reevaluated at least
weekly until recovery to treatment ievels, or as indicated in the dose modification
tables.
. Regardless of the reason for holding any study {rug {eatr.n91t, the maximum
allowable length of treatment intemrplion is 3 weeks. If the delivery of any study
drug due to foxicity is delayed foi more than 3 weeks, that drug should be
permanentlY discontinued.
o Dose delay of either carboplatin, bevacizumab or paclitaxel will result in delay of
the other drug (to ensure all drugs are delivered on the same day).
. Day I of each cycle will be based on the day that carboplatin and/or paclitaxel are
delivered.
o If either paclitaxel or carboplatin are discontinued due to toxicity, day one_of the
cycle will be the day thl remaining chemotherapy dryg is delivered. The
maximum delay of both drugs while monitoring toxicity is 3 weeks.
o If both chemotherapy drugs are discontinued due to toxicities despite. dose
reductions, the pafiint *itt come off study, and 1ll therapy, including
bevacizumab and hydroxychloroquine, will be discontinued.
o No more than 2 dose reductions for each chemotherapy drug will be allowed, and
no more than one dose reduction of hydoxychloroquine. Bevacizumab dose
reductions will not be allowed. Further need for dose reduction will result in
discontinuation of that drug.
Dose Levels (CYcles I to 6)
Starting dose
Paclitaxel dose
200 mglm2
Carboplatin
dose
AUC :6
Hydroxychloroquine
600 mg PO bid
Dose Level -1
175 mglm2
AUC=5
400 mg PO bid
Dose Level-2
150 mg/m2
AUC :4
400 mg PO bid
7.5.1 Hematologic ToxicitY
Absolute neutrophil count (paclitaxel- carboplatin)
o ANC must be > 1500/mm3 on Day 1 of each cycle'
. If ANC < 1500/mm3 on Day 1, treatment should be delayed by I week. Maximum
delay is < 3 weeks. Treatment should be restarted without dose modification,
unless criteria in the table below are met.
o Dose modifications should be based on the nadir ANC and/or occurrence of
febrile neutropenia during the previous cycle. For guidelines regarding the use of
growth factors, see Section 7.7
Page 20 of 49
Protocol Version: l0/09/2014


Modulation ofautophagy with hydroxychloroquine in patients with advanced/recurrent non-small cell lung cancer - a Phase II
studv
-
Event during previous cycle
Nadir ANC < 500/mm3 or
febrile neutropenia (ANC
< 1000/mm'and fever
>38.5"C)
Paclitaxel
First occurrence:
decrease dose by
I dose level
Second
occuffence: may
use CSFs in
accordance with
ASCO guidelines
Third occurrence:
decrease dose by
I dose level
Carboplatin
First occurrence:
decrease dose by I
dose level
Second
occurence: may
use CSFs in
accordance with
ASCO guidelines
Third occurrence:
decrease dose by I
dose level
Bevacizumab/
Hydroxy-
chloroquine
No change
Thrombocvtopenia (paclitaxel. carEoplatin)
Plateletcountmustbmofeachcycle.lfplatelet<100,000/mm3,
treatment should be delayed by I week. Dose modifications should be based on the nadir
platelet count during the previous cycle.
Event during previous cYcle
Nadir platelet count
< 50,000/mm3
Bevacizumab
/Hydroxy-
chloroquine
No change
Paclitaxel
Decrease dose by I
dose level
Carboplatin
Decrease dose
by I dose level
Anemia
No dose reductions will
including erythropoietin,
Section 7.7.
be made for anemia. Patients should
at the treating physician's discretion
receive supportive care,
and as per guidelines in
Page 2l of 49
Protocol Version: I 0/09/20 I 4


Modulation ofautophagy with hydroxychloroquine in patients with advanced/recurrent non'small cell lung cancer - a Phase II
studv E
7.5.2 Non-Hematologic ToxicitY
Hvpertension (Bevacizumab-Cohort I onlv)
o Dose modifications for hypertension are applicable to bevacizumab dosing.
No dose modifications 
-are required for paclitaxel and carboplatin for
hypertension.
o See Section 7.6 regarding concomitant medications (metoprolol)
Event during previous cYcle
Hypertension
Dose Modification of Bevacizumab
Grade 0 - 2
No change, control hypertension with medications as per
general therapy guidelines.
Grade 3
Hold drug until blood pressure can be controlled to
S 150/100 with standard medication. Restart drug at same
dose.
Grade 4
Bevacizumab must be permanently discontinued.
Heoatic (naclitaxel)
o Liver function test will be evaluated prior to treatment on Day I of each cycle.
This value should be used in determining the dose
sGoT (ASr)
Bilirubin
Paclitaxel dose to give
(ms/m2)
<5xULN
AND
WNL
200
>5xULN
OR
>ULN-l.5xULN
150
> 1.5 x ULN
0
Gastrointestinal toxicitv (all drues)
. A"y bowel obstruction Z Grade 2 will result in holding bevacizumab until
resolution of symptoms. Patient may be restarted on bevacizumab at the
discretion of the investigator
. Any GI perforation will result in discontinuation of patient from the study.
o Nausea andlor vomiting should be controlled with adequate_ antiemetics.
Nausea anJvomiting mu-st be < Grade I on Day I of each cycle. If nausea and
vomiting are > Gracl-'e I on Day 1, then treatment will be delayed for up to 3
weeks.
. If the patient has any grade stomatitis or mucositis on Day I of any cycle,
treatment will be withheld until full recovery'
Page 22 of 49
Protocol Version: 1 0/09/20 l4


Modulation ofautophagy with hydroxychloroquine in patients with advanced/recunent non'small cell lung cancer - a Phase II
studv
rtnime:f
o Diarrhea should be treated with standard medications to avoid dose
modification or inteffuption, if possible.
Event during previous cYcle
Nausea or
Vomiting
Grade 3-4
despite
antiemetics
Paclitaxel Carboplatin Bevacizumab
First occurrence : Hold treatment until resolved to
< Grade 1, resume at previous dose
Second occurrence : Hold treatment until resolved
to <Grade l, resume at Previous dose
Hydroryehloroquine
First occurrence : Hold
treatment until resolved
to < Grade 1, resume at
50% dose
Discontinue drug
Stomatitis or
mucositis
Grade 3-4
Decrease 1
dose level
Decrease 1
dose level
No change
No change
Diarrhea
Grade 3-4
No change
No change
No change
Hold until resolved to
< Grade I then resume
at 50% dose.
If>Grade3toxicitY
recurs at reduced dose,
hydroxychloroquine
must be permanently
discontinued
a
o
Neurologic toxicity must be < Grade I on Day l.
If neurologic toxicity > Grade I on Day l, treatment should be delayed by.-l week'
Maximumlelay is i 3 weeks. Treatment should be restarted after dose modifications
per guidelines below
o Dose reductions should be based on the most severe grade of toxicity experienced
during the previous cycle of treatment or on Day 1.
Event during previous cYcle
Paclitaxel
Allow recovery to
< Grade l.
Decrease by I
dose level.
Carboplatin
Bevacizumab/
Hydroxy-chloroquine
Grade2
No change
No change
Allow recovery to
No change
No change
Grade 3
Page 23 of 49
Protocol Version: I 0/09/20 l4


Modulation ofautophagy with hydroxychloroquine in patients with advanced/recurrent non-small cell lung cancer- a Phase II
studv E
Event during previous cycle
Grade2
Paclitaxel
Allow recovery to
< Grade l.
Decrease by I
dose level.
Carboplatin
No change
No change
Bevacizumab/
Hydroxy-chloroquine
< Grade l.
Decrease by 2
dose levels.
Anaphvlaxis/Hypersensitivity (paclitaxel. carboplatin. bevacizumab)
Caution: patients who had a mild to moderate hypersensitivity reaction have been
successfully rechallenged, but careful attention to prophylaxis and bedside monitoring of
vital signs is recommended.
Event
Paclitaxel or Carboplatin or Bevacizumab lnfusion
Mild (e.g., mild
flushing, rash, pruritis,
drug fever, ie. Grade 1)
No treatment needed. Supervise at bedside and complete
infusion.
Moderate (e.g.,
moderate flushing,
rash, mild dyspnea,
allergy related edema,
ie. Grade 2)
Stop drug infusion. Administer diphenhydramine 25-50
mg and dexamethasone l0 mg IV. After recovery, resume
infusion per institutional guidelines. If no further
symptoms occur, complete the infusion at the full dose
rate. Report as an adverse event. Consider additional
premedication with all subsequent doses of drug. If
symptoms recur, permanently stop drug.
Severe (e.g.,
hypotension requiring
pressors, angioedema,
symptomatic
bronchospasm: ie.
Grade 3-4)
Stop drug infusion. Administer diphenhydramine 25-50
mg and dexamethasone 10 mg IV. Add epinephrine or
bronchodilators as needed. Report as an adverse event.
Permanently stop drug.
Page 24 of 49
Protocol Version: I 0/09/20 I 4


Modulation ofautophagy with hydroxychloroquine in patients with advanced/recurrent non-small cell lung cancer - a Phase II
studv
ftna-":f
Hemorrhage
Arterial Thrombosis (Bevacizumab - Cohort I only)
. Cardiac ischemia/ infraction
. CNS ischemia (TIA, CVA)
. Any peripheral or visceral arterial ischemia/thrombosis
Event
Bevacizumab (Cohort I only)
Grade 1 pulmonary
Hold drug and evaluate for source. If resolved within I week, and
no source, resume full dose. If recurrent, discontinue drug
pennanently.
Grade > 2 pulmonary or CNS
Grade 3 all other sites
- there is no anatomic or pathologic condition
increase the risk of hemorrhage recurrence
Patients who experience recurrence of Grade 3
discontinue study therapy.
Patients receiving full-dose anticoagulation must discontinue
bevacizumab.
. For patients not on full-dose anticoagulation, hold bevacizumab
until ALL of the following criteria are met:
- the bleeding has resolved and hemoglobin is stable
- there is no bleeding diathesis that would increase the risk of
therapy
that could
hemorrhage must
Grade 4
Discontinue bevacizumab permanently.
Event
Bevacizumab
Grade 2 (if new or worsened since
bevacizumab therapy)
Discontinue bevacizumab permanently.
Grade 3-4
Discontinue bevacizumab permanently.
Page 25 of 49
Protocol Version: I 0/09/20 1 4


Modulation ofautophagy with hydroxychloroquine in patients with advanced/recurrent non-small cell lung cancer - a Phase II
studv
-
Yenous Thrombosis (Bevacizumab - Cohort 1 onlv)
Protein
Skin Toxicities (hydroxvchloroquine)
o Rash should be assessed as soon as possible to evaluate for possible rare side effects
o Sun protective measures should be encouraged
o If Grade :2, hold drug until rash has resolved to Grade I or less and resume at
previous dose. If rash then worsens to > Grade l, hold drug until rash resolved to
grade 1 or less and resume at 50% dose.
. If Grade ) 3, discontinue drug permanently and manage according to standard of
care.
Event
Bevacizumab
Grade 3 OR asymptomatic Grade 4
Hold bevacizumab treatment. If the planned duration of full-
dose anticoagulation is < 14 days, bevacizumab should be
held until the full-dose anticoagulation period is over.
If the planned duration of full-dose anticoagulation is >14
days, bevacizumab may be resumed during the period of
full-dose anticoagulation IF all of the criteria below are met:
o The patient must have an in-range INR (usually 2-3) on a
stable dose of warfarin, or on stable dose of heparin prior
to restarting bevacizumab.
o The patient must not have pathological conditions that
carry high risk of bleeding (e.g. tumor involving major
arteries or other conditions)
o The patient must not have had hemorrhagic events while
on study
If thromboemboli worsen/recur upon resumption of study
therapy, discontinue bevacizumab
Grade 4
Discontinue bevacizumab permanently.
urla
mab- Cohort
Event
Bevacizumab
Grade3(UPC>3.5)
Hold drug until UPC < 3.5. If therapy is held for > 2
months due to proteinuria, discontinue drug
oermanently.
Nephrotic syndrome
Manage per standard of care. Discontinue drug
oermanently.
Page26 of 49
Protocol Version: I 0/09/20 l4
lttf 
t


Modulation ofautophagy with hydroxychloroquine in patients with advanced/recurent non-small cell lung cancer - a Phase II
studv
ftnume:f
MYopathv (hvdroxvchloroq uine)
. If Grada:2, hold drug until symptoms resolved to Grade I or less and resume at
previous dose. If symptoms worsen to > Grade l, hold drug until symptoms resolved
to grade I or less and resume at 50% dose.
. [f grade > 3, discontinue drug permanently and manage according to standard of care.
Ocular Reactions (hvdroxvchloroquine)
. Any change in vision or any new visual symptoms (other than blurred vision, < Grade
l) should result in holding drug until evaluation by an opthalmologist. Any findings
attributable to drug will result in permanent discontinuation of drug. Management of
symptoms should be per standard of care.
Other
. Any grade arterial thrombosis will result in permanent discontinuation of
bevacizumab.
o Wound dehiscence requiring medical or surgical therapy will result in discontinuation
of bevacizumab.
. Any Grade 3 or 4 congestive heart failure will result in discontinuation of
bevacizumab.
o For Grade 3 AE attributable to bevacizumab and not listed above:
' 
Hold bevacizumab until symptoms resolve to < Grade 1
. [f treatment delay is >14 days due to toxicity, discontinue bevacizumab
o For Grade 4 AE attributable to bevacizumab and not listed above:
. Discontinuebevacizumab
. Upon consultation with the PI, resumption of bevacizumab may be
considered if a patient is benefiting from therapy, and the G4 toxicity is
transient, has recovered to < Grade I and unlikely to recur with retreatment.
r Bevacizumab should be held in patients with symptoms/signs suggestive of
Reversible Posterior Leukoencephalopathy Syndrome (RPLS), pending work-up and
management, including control of blood pressure. Bevacizumab should be
discontinued upon diagnosis of RPLS.
7.6 Concomitant Medications
In general, concomitant medications and therapies deemed necessary for the supportive care
and safety of the patient are allowed. All concomitant medications must be documented in
the patient's medical records.
Because of the inherent risk of either reduced activity or enhanced toxicity of the
concomitant medication and/or hydroxychloroquine, drugs known to interact with the same
CYP450 isoenzymes as hydroxychloroquine should be used with caution.
Page27 of49
Protocol Version: I 0/09/20 I 4


Modulation ofautophagy with hydroxychloroquine in patients with advanced/recurrent non-small cell lung cancer - a Phase II
studv E
Medications known to have significant interactions with hydroxychloroquine:
Digoxin: Concurrent digoxin and hydroxychloroquine therapy has been reported to result in
increased serum digoxin concentrations. Patients that take digoxin while on this study must
monitor digoxin levels.
Metoprolol: Concurrent use of metoprolol, a CYP2D6 enzyme substrate, and
hydroxychloroquine, a potent CYP2D6 enzyme inhibitor, may increase metoprolol exposure.
Use caution when metoprolol is administered concomitantly with hydroxychloroquine, and
monitor closely for metoprolol adverse effects (such as bradycardia).
Aurothioglucose: The concurrent use of aurothioglucose and antimalarial agents is
contrainilicated.Bothaurothioglucose and antimalarial agents are capable of inducing blood
dyscrasias, and concurrent use might result in an additive risk of this effect
7.7 Supportive Care Guidelines
All supfortive measures consistent with optimal patient care will be given throughout the
study. ihe clinical tolerance of the patients, the overall tumor response and the medical
judgment of the investigator will determine if it is in the patient's best interest to continue or
discontinue treatment. If treatment is discontinued due to any toxicity, the patient must be
followed to monitor duration of toxicity, response and time to progression or survival and
initiation of any new systemic therapy.
Recombinant erythropoietin may be administered for symptomatic and/or progressive z
Grade 2 anemia per the investigator's discretion and should be used as per approved
prescribing information. Dosing recommendations for target hemoglobin must be followed.
Alternative methods for managing hemoglobin, such as transfusions may be considered when
medically appropriate.
Colony stimulating factors (filgrastim, pegfilgrastim, GM-CSF) should only be used if a
neutropenic complication occurs after the first cycle despite dose reduction. If colony-
stimulating factois are used, they must be used in accordance with the American Society of
Clinical Oncology (ASCO) guidelines.
8. Toxicity Monitoring and Adverse Event Reporting
All patients who receive one dose of protocol therapy will be evaluable for assessment of
toxicity. Prior to each cycle the treating physician will fully assess the patient's condition
with respect to possible treatment related toxicities. All adverse events, whether observed by
the physician or reported by the patient, occurring during the active portion of therapy, or up
to 3b days after thi last dose of treatment will be graded by a numerical score according to
the NCI's Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0
(http:/ictep.cancer.eovireportins/ctc.html) and recorded in the patient's medical record.
Adverse events will be recorded on electronic case report forms in accordance with a study-
specific data capture Plan.
PageZ8 of 49
Protocol Version: l0/09/20 l4


Modulrrim of autophaSy *.ith hydraqrcNorcquinc in patiorts witlr advmecd,lrcwnrni uon-srull ccll ltmg cancu - a PhasE II
strdv
PI;".:n
A preexisting corditiou is one that is present at the start of the shrdy. A preexirtiog cooditiou
wiil be r*"*dud as an adverse event if the frequency, intelrsity, or the character of the
condition worsetls dutng the shrdyperiod.
8.1 Adverse Event Reportiug Requirements
An adverse exprience is defiued a$ auy uniutended or abnotmal clinical observation that is
11ot of benefit to the patieut. Either the condition was not preserrt prior to exposure to the
shrdy therapy. or it has worseted in iutensity or frequency following exposure to the study
therapy.
" (defined below) au#or "serious" (defrned be
adverse events
Copies
repod sent to
In addition to reporting to tbe local IRB, reporting to external bodies suclr as indtrsky and/or
the FDA nray be required.
Rcporting SAEs using commerci*lly svsiluble drugr:
m aOeition, arry urexpected (rol listed in the pac.kage inserl) serious adverse events that are
associated (def*tety, probably or possibly rnlated) with the trse of cartoplatin, paclitaxel,
t *"u.i**uU or hydroxychloroquine, must be reported to the FDA withirr l0 buriuess days
usiug a FDA Forrn tr,tedWatc[ 3500 fonu htto:llwww.fda"sovlu]edrvatchisafetvf3500.Ddf
({h.r # I -800-rDA-01 78}.
8"2 Defixition of $erious Adverse Events (SAE$)
A seriotu odverse event (experience) is one occurring at any dose level fhat results in ouy of
. Death
. Lifetlreatening- irumediate risk of death froru tbe reaction-
. Requires inpatie,nt hospitalization or prolongation of existing hospitalizatiou-
. Results in persistent or significant disability/incapacity.
. Results iu a congenital auomcly/birth defect.
. Requires intervention to prevent one of the outcomes listed in this defurition"
Tlre definitioa of serious adverse event (experieace) also ineludes imporlant medical #str/s"
Medic*l altl scientific judgneut will be exercised in deciding whether expedited reporliug is
All
Page 29 of49
Protocol Version: I 0r 09/?0 1 4


Mo&rlstioo of autoplragpr rvi& hy&oqrcNoroquinc h patiorts with advanecd/rccurml aon-susll ccll lung cmccr * a Phrst II
studv
-
appropriate iu otlrer situ*tions, such ns important medical syErts that may rCIt be irnmediately
lilb{lueatening or result in death or hospitalizatiou but may jeopardize tlre patient or nrsy
require interyeution to prevent one of tlre other outcomes listed iu the definition above.
Thene eveut$ will rcually be considsred serious. Examples of such evm*s ure irtmrive
treahneat iu an emergeucy room or at home for allergic broachospasm; blood dyscrasias or
couvulsions tlmt do not result in hospitalization.
Hospitalization: Any adverse event leading to hospitalization or prolongation of
hospitalization will be considered as Serioux, UNTESS at least ona of tbe following
exceptions are met:
The admission re*ults in a hoqpital stay of less than 12 horus.
OR
The a&nissioo is pre-plarured (ia, electivs or scheduled argery arranged prior to the start of
the stud$.
OR
The adrnission is not associeted with an adverse event (eg, social hospitalization for purposes
ofrespite care).
83 Delinition of Relstrd
There is a reasonable possibility that the dnrg caused the adverse experience. That is, the
event is judged by the investip;ator to be possibly, probably or definifely related to the
treafunent.
8.4 Definition of Unexpected
Any adverse drug experience andlor specificity, that is not included in tlre culrenf
investigdor's brochue a$d/or package iusert.
9. Trectment Evrlurtion/Criteris fior Besponsr
For the purposes of this study, patiants should be reevaluated for respo$se following eyery
2 cycles of therapy drring the Iirst 6 cycles. ln addition to baseline scan(s), confirmatory
scans should also be obtained not less tban 4 weeks following initial documentation of
objective response.
9.1 M*asursble Disense
Measruable lesions are defiued a* tlrsse that can be accurately measured in at least one
dimensisu (longest diameter to be recorded) as >?0 nrm with conveutional techniques (CT,
MRI, x-ray) or as:10 uun with spiral CT scal" All tumor rleasurements mtxt be reeorded
irr nrillirneters (or decinral fiactions of centirneters).
Page 30 of49
Protocol Version: ! 0/09/30 1 4


Modulation of autophagy with hydroxychloroquine in patients with advanced/reculrent non-small cell lung cancer - a Phase II
studv
flname:f
9.2 Non-Measurable Disease
All other tesions 1or sites of disease), including small lesions (longest diameter <20 mm
with conventionai techniques or <10 mm using spiral CT scan), are considered non-
measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial
effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses (not
followed by CT o. trtRt;, and cystic lesions are all non-measurable'
9.3 Target Lesions
All measuruUt, i.rion, up to a maximum of five lesions per organ and 10 lesions in total'
representative of all involved organs, will be identified as target lesions and recorded and
measured at baseline. Target lesions will be selected on the basis of their size (lesions with
the longest diameter) and their suitability for accurate repeated mgas{em.:nts (either by
imaging techniques or clinically). A sum of the longest diameter (LD) for all target lesions
will be calculated and reported as the baseline sum LD' The baseline sum LD will be used
as reference by which to characterize the objective tum-or.response. There-may be occasions
when progressive disease is suspected but iannot be fully characterized. In these cases the
treating physician may decide to continue treatment for one or two cycles before
reassessment, if he/she feels it is in the patients' best interest and the patient agrees to
continue treatment.
9.4 Non-Target Lesions
All other lesions (or sites of disease) will be identified as non-target lesions and will be
recorded at baseline. Non-target fesions include measurable lesions that exceed the
maximum numbers per organ or total of all involved organs as well as non-measurable
lesions. Measurements of these lesions are not required, but the presence or absence of each
will be noted throughout follow-up.
9.5 Guidelines for Evaluation of Measurable Disease
All measurements will be taken and recorded in metric notation using a ruler or calipers' All
baseline evaluations will be performed as closely as possible to the beginning of treatment
and never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique will be used whenever possible to
characterize each identified and reported lesion at baieline and during follow-up' Imaging-
based evaluation is preferred to evaluation by clinical examination when both methods have
been used to assess the antitumor effect of a treatment'
9.5.1 Clinical lesions- Clinical lesions will only be considered measurable when they are
superficial (e.g., skin nodules and palpable lymph -nodes). In the case of skin lesions'
documentation-Uy color photography, including aruler to estimate the size of the lesion'
9.5.2 Chest x-ray- Lesions on chest x-ray are acceptable as measurable lesions when
they are clearly defined and surrounded by aerated lung. However, CT is preferable'
9.S.3 Conventional CT and MRI- These techniques will be performed with cuts of l0
Protocol Version: 1 0/09/2014
Page 3l of49


Modulation of autophagy with hydroxychloroquine in patients with advanced/recurrent non-small cell lung cimcer - a Phase II
study
PI name: JosePh Aisner, MD
mm or less in slice thickness contiguously. Spiral CT will be performed using a 5 mm
contiguous reconstruction algorithrn. fnit applies to tumors of the chest, abdomen, and
pelvis.
9.5.4 Ultrasound (US)- Because one of the endpoints of the study is objective response
evaluation, US will not be used to measure tumor lesions. US might be used, at the
discretion of the investigator, to confirm the complete disappearance of superficial
lesions assessed by clinical examination.
9.5.6 Tumor markers- Tumor markers alone will not be used to assess response. If
markers are initially above the upper normal limit, they must normalize for a patient to be
considered in complete clinical response.
9.5.7 Cytology, histology- These techniques may be used to differentiate between partial
..rporrl, @R) and complete responses (CR) if necessary and determined by the
invistigator. Cytological confirmation of the neoplastic origin of any effusion that
appears o. *o.r.n, during treatment when the measurable tumor has met criteria for
response or stable disease is mandatory to differentiate between response or stable
disiase (an effusion may be a side effect of the treatment) and progressive disease.
9.6.l Evaluation of T
t Lesio
Lesions
9.6 Response Criteria
ns
Complete Response
(CR):
Disappearance of all target lesions
Partial Response
(PR):
ffi 
the sum of the longest diameter (LD) of target
lesions, taking as reference the basellne sum LD
Progressive Disease
(PD):
At t."st " 
20./. irc...se in the sum of the LD of target lesions, taking as
reference the smallest sum LD recorded since the treatment started or the
appearance of one or more new lesions.
Stable Disease (SD):
Neittler suffuienl shrinkage to qualiff for PR nor sufficient increase to
qualiff for PD, taking as reference the smallest sum LD since the treatment
started.
9-6.2 Evaluation of Non
Complete Response (CR):
Disappearance of all non-target lesions and
*normalization of tumor marker level.
Incomplete Response/
Stable Disease (SD):
Persiste*e of one or more non-target lesion(s) and/or
maintenance of tumor marker level above the normal
limits.
Progressive Disease (PD):
Appearance of one or more new lesions and/or
uneq u ivocal pro gression of existing non:!qlg9!-le$ens'
et" lesions only is exceptional, in such
circumstances the opinion of the investigator will prevail.
Page 32 of 49
Protocol Version: I 0/09/20 I 4


Modulation ofautophagy with hydroxychloroquine in patients with advanced/recunent non-small cell lung cancer - a Phase II
studv
rtnime:J
*Note: If tumor markers are initially above the upper normal limit, they must
normalize for a patient to be considered in complete clinical
9.6.3 Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment
until disease progression/recurrence (taking as reference for progressive disease the
smallest measurements recorded since the treatment started). The patient's best
response assignment will depend on the achievement of both measurement and
confirmation criteria.
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
PR
SD
PD
Any
CR
Incomplete
response/SD
Non-PD
Non-PD
Any
PD
Any
Yes or No
Yes or No
Yes
No
No
No
No
CR
PR
PR
SD
PD
PD
PD
Any
Notes:
Patients with a global deterioration of health status requiring discontinuation of
treatment without objective evidence of disease progression at that time should be
classified as having "symptomatic deterioration." Every effort will be made to
document the objective progression.
In some circumstances, it may be difficult to distinguish residual disease from normal
tissue. When the evaluation of complete response depends on this determination. The
residual lesion will be investigated (fine needle aspirate/biopsy if possible) before
confirming the complete response status.
9.7 Confirmatory MeasuremenUDuration of Response
9.7.1 Confirmation
To be assigned a status of PR or CR, changes in tumor measurements must be
confirmed by repeat assessments that will be performed no less than 4 weeks after the
criteria for response are first met. In the case of SD, follow-up measurements must
have met the SD criteria at least once after study entry after a minimum interval of 2
cycles of treatment.
Page 33 of49
Protocol Version: 1 0/09/20 I 4


Modulation ofautophagy with hydroxychloroquine in patients with advanced/recurrent non-small cell lung cancer- a Phase II
studv
-
9,7,2 Duration of Overall Response
The duration of overall response is measured from the time measurement criteria are
met for CR or PR (whichever is first recorded) until the first date that recurrent or
progressive disease is objectively documented (taking as reference for progressive
disease the smallest measurements recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first
met for CR until the first date that recurrent disease is objectively documented.
9.7.3 Duration of Stable Disease
Stable disease is measured from the start of the treatment until the criteria for
progression are met, taking as reference the smallest measurements recorded since the
treatment started.
10. Removal of Patients from Study/Off Study Criteria
In the absence of treatment delays due to adverse events, treatment may continue until one of
the following criteria applies:
a) 
Disease progression/relapse during active treatment,
b) 
Intercurrent illness that prevents further administration of treatment,
c) 
Unacceptable adverse event(s).
d) 
In the event of any drug-related life-threatening toxicity or laboratory abnormality the
patient will be withdrawn from further treatment,
e) 
Patient decides to withdraw from the study,
0 
Noncompliance with treatment plan,
g) 
General or specific changes in the patient's condition render the patient unacceptable
for further treatment in the judgment of the investigator, or
h) 
Protocol violation - any patient found to have entered this study in violation of the
protocol might be discontinued from the study at the discretion of the Principal
Investigator.
Page 34 of 49
Protocol Version: l0/09/2014

SAP_001.pdf: 
Official Title:
"Modulation of Autophagy in patients With
Advanced/Recurrent Non-small cell Lung cancer - phase
il:'
NCT number:
0L649947
Document Type:
SAP p.42
Date of the
Document:
LOl0el2Ot4


Y;1u'ut'o' 
ofautophagy with hydroxychloroquine in patients with advanced/recurrent non-smail celr lung cancer - a phase II
t'lname:f
I l. Pharmaceutical Information
11.1 Carboplatin
carboplatin is a second'generation organic platinum and chemotherapeutic agent and is cell
cycle non-specific' Like' cisplatin it iroauces predominurrry interstrand DfA cross links,
causing DNA lesions.and biological effects. i"rb"pi;;i; exhibits linear pharmacokinetics
and is excreted lainly by t[e kidneys. r, p;i;;;; with creatinine clearances of
approximately 60 ml/min or greater, 7l%o of the iose is excreted within 24 hours. Dosing
formulas' which incorporate- estimates of glomerular filtration rates (GFR), provide
predictable AUC estimates and should be uJed to caiculate doses, especially in elderly
patients where renal function may be decreased.
Packaging and Labeling
Investigators should re'Gw the approved. Package Insert (pf as per the current version and
applicable manufacturer, for full iniormation on io.uge irirdling, preparation and stability.
How Supplied
carboplatin is commercially available from multiple commercial manufacturers in the United
States' carboplatin may be supplied as a sterile'10 mglmi aqueous solution or as a sterile
lyophilized white powder in 5o mg, 150 mg and +s6 mg vials containing equal parts of
carboplatin and mannitol by weight.
Handling and Dispensing
ltoy8e Req uirements/Stability
carboplatin may be supplied as a sterile l0 mg/ml aqueous solution and stable to the date on
the package when 
-stored at room temperature of zj"c (77"F) [excursions permitted from
l5'-30oC (59.-86"F)1, and should be protected from light.
carboplatin may be supplied as a sterile lyo.philized white powder in 50mg, 150 mg and 450
mg vials containing eqllalpar.t: of carboplatin and mannitol'by weight. Reconstituted vials do
not contain any antimicrobial agents and should be discarded within g hours of
reconstitution' unopened vials u.. itubl. to the date on the package when stored at room
temperature of 25oC (77"F), and should be protected from light. Solutions for infusion should
be discarded 8 hours after preparation.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration. Procedrr., fo, proper haniling'and disposal or urti-.urcer drugs
:ii:X',li,i.frli,L?ii3;;:i"ilJ,'trijL't*; pubrished'and strourd be rererenc.o uy ,tuiy
Page 35 of49
Protocol Y ersion: l0 /09 /20 I 4


y;X''-Ytutophagy with hydroxychloroquine in patients with advanced/recurrenr non-smalr celr lung cancer - a phase II
ftname;f
Preparation and Administration
carboplatin should be administered under the supervision of a qualified physician
experienced in the use of antineoplastic uggnir. afpffiiut. management of comprications is
possible only when adequate diagnostic ura t..utr.nifucilities are readily available.
Solutions can be further diluted to a concentration as low as 0.5 mg/mL with 5%oDextrose in
ffift:::;fjodium 
chloride Injection, usp. Ad;;nister by.Jnii*our'inrusion over 15
Needles or IV administration sets containing aluminum parts should not be used for the
preparation or administration of the drug as u-iu,ninu, caninteract with carboplatin causing
precipitation or loss of potency.
Drug should be disposed of or destroyed as per written institutional policies and per
recommendations in the current approved-package tnsert.
11.2. Paclitaxel
Paclitaxel (NSC #125973) is commercially available.
How supplied
A concentrated sterile solution, 6 mglml,: 5. Tl y1t f:o mglvial) in polyoxyethylated castor oil
(cremophor EL) 50%o and dehydra:ted alcohol, usp, sozr] rn. contents of the vial must be
diluted just prior to infusion.
Reported Toxicities
Myelosuppression' N&v, diarrhea, stomatitis,.mucositis, pharyngitis, sinus bradycardia, heart
block, ventricular 
, tachycardia, myocardiar 
. 
- 
infarction ' rt rl, tiypot"nrion,- 
- 
,.rrory (taste),
peripheral neuropathy, seizures, rnooo alterations, "r"p-ivil.,oid and uticariai reactions (acute),
flushing, rash, pruritus, aropecia, fatigue, arthrargia,rnvurgiu, right-headedner; urd myopathy.
Solution Preparation and Administration
The total calculated dose of paclitaxel will be diluted in 500 ml of 5% Dextrose injection, USp
(D5w) or 0'9Yo Sodium chloride for injection, ysP (NSS). paclitaxel must be prepared in glass
or polyolefin containers due to leachlng of diethy)hrrvi pr,tr,urate (DEHp) plasticizer from
polyvinyl chloride (PVC) bags and intravenous tubing by the cremophor vehicle in which
paclitaxel is solubilized. Paclitaxel will be administer"eo as a l-hour infusion weekly via an
infusion control device (pump). Nothing else is to be infused through the line while paclitaxel is
being administered.
NorE: Formation of a small number of -!!er9 in solution (within acceptable limits established
by the USP Particulate Matter Test for LVP's) has been observeo after preparation of paclitaxel.
Therefore' in-line filtration. is necessary for administration of paclitaxel solutions. In-line
filtration should be accomplished by incorporating_ a hydrophiric, microporous filter of pore size
not greater than 0'22 microns (e.g. IVEX-it, tvg'x-rf, oilluiuurrnt) into trr. iv nuia pathway
distal to the infusio:.P.'}p. Although particulate formatifn does not indicate loss of drug
potency, solutions exhibiting excessive particulate matter formation should not be used.
Page 36 of 49
Protocol Version: I 0/09/20 I 4


Modulation ofautophagy with hydroxychloroquine in patients with advanced/recurrent non-small cell lung cancer- a phase II
study
llname:f
Storage
The intact vial should be stored at room temperature. Each baglbottle should be prepared
immediately before administration.
Stability
All solutions of paclitaxel exhibit a slight haziness directly proportional to the concentration of
drug and the time 9lryryd after preparation, although *t "n 
prepared as described above,
solutions of paclitaxel (0.3-l .2 mglml) are physically an-<l chemicaily ,tubt" for 4g hours.
11.3 Bevacizumab (Cohort I Only)
Bevacizumab is supplied as a clear to slightly opalescent, sterile liquid ready for parenteral
administration in vials of two sizes:
Each 100 mg (25 mglmL - 4 mL fill) glass vial contains bevacizumab with phosphate,
trehalose, polysorbate 20, and sterile watei for Injection, usp.
Each 1000 mg(25 mg/mL - 40 mL fill) glass vial contains bevacizumab with phosphate,
trehalose, polysorbate 20, and Sterile water for Injection, USp.
Preparation
opened vials must be used within 8 hours. vials contain no preservative and are intended for
single use only. The calculated dose should be diluted in 100 mL of 0.g% sodium chloride
for IV infusion.
Administration
See Section 7.4.2.
Toxicities
The most common adverse events associated with bevacizumab have been hypertension and
proteinuria. Other less common events, some of which have been fatal, inJude bleeding,
thrombosis, elevated liver function tests, and bowel perforation, and anastomatic dehiscence.
Infusion-related or allergic reactions may also o..ur. These include fever, chills, rigor, rash,
urticaria, and dyspnea. Treatment for such reactions should be done per institutional
guidelines.
Hypertension is among the most common adverse events associated with bevacizumab to
d-ate' Both new hypertension and worsenilq of existing hypertension have been reported.
Hypertension may require treatment; acp intriuitori calcium channel blockers, beta
blockers (note alternatices to metoprolol are suggested as there are interactions with
hydroxychloroquine, see SectionT.6) and, diuretics fiave all been reported to be effective in
this setting' Although most hypertension can be controlled by medication, hypertensive crises
have been reported in several studies, and the end organ consequences included CNS
bleeding and ischemia, and congestive heaft failure
Page 37 of 49
Protocol Version: I 0/09/2014


Modulation ofautophagy with hydroxychloroquine in patients with advanced/recurrent non-small cell lung cancer- a phase II
study
-
Proteinuria, ranging from asymptomatic abnormal urinalysis to nephrotic syndrome, has been
described in l0o/o or more of patients receiving bevacizumab. Proteinuria is managed with
dose modifications as described in the dose modification section.
Bleedine, including fatal CNS hemorrhage, has been reported. DIC has been described in a
few patients receiving bevacizumab in combination with oxaliplatin, fluorouracil and
leucovorin. Bleeding at tumor sites or at sites of other pre-existing abnormalities (e.g.,
diverticulosis, hemorrhoids) has also been described. Further toxicity observed in a Phase III
study included fatal hemoptysis in 2 of 55 patients with non-small cell lung cancer, both of
whom had a history of hemoptysis. Although most episodes of epistaxis were short-lived and
resolved without treatment, some required medical intervention.
Thrombosis/embolism Both arterial and venous thromboses (including pulmonary embolism,
mesenteric vein thrombosis, ischemic bowel, and cerebral vascular accident) have been
described in patients receiving bevacizumab. Fatal pulmonary embolus has also been
described.
Hepatic Dysfunction: Reversible and marked elevations of liver function tests (total bilirubin
and/or transaminase and AP) have been rarely reported when bevacizumab is used in
combination with chemotherapy or concurently with other drugs that are potentially
hepatotoxic. The mechanism of such hepatic toxicities is unclear. It is possible that in rare
occasions, bevacizumab may potentiate the liver side effect of a concurrent medication,
although it is unclear at this time whether bevacizumab alone can cause LFT derangement.
Bowel perforation and bowel anastomotic dehiscence have been reported in clinical trials
using bevacizumab alone or in combination with chemotherapy. Although these events were
likely related to co-existing factors such as tumor involvement, chemotherapy, recent
invasive procedures or bowel inflammation, contribution of bevacizumab to these events
cannot be excluded. A fatal bowel perforation has been described. Partial delay in wound
healing has been demonstrated in animal models treated with anti-VEGF antibodies and it is
possible that bevacizumab may delay or compromise wound healing in patients.
Other toxicities Other reported or potential toxicities associated with bevacizumab include:
Constitutional-Headache, infection without neutropenia, asthenia;
cardiovascular-Hypotension, pericardial effu sion Skin-Rash, urticaria;
Gastrointestinal-Nausea, vomiting, stomatitis/pharyngitis, colitis, intestinal obstruction;
Pulmonary-Pulm onary infi ltration, dyspnea;
Musculoskeletal-Arth ralgia, chest pain.
I 1.4 Hydrorychloroquine
Product Description: Hydroxychloroquine is a colorless crystalline solid, soluble in water
to at least 20 percent; chemically the drug is 2-tt4-l(7-Chloro-4-quinolyl)
aminolpentyllethylaminolethanol sulfate (l:l). Hydroxychloroquine sulfate tablets contain
200 mg Hydroxychloroquine sulfate, equivalent to 155 mg base, and are for oral
administration.
Page 38 of49
Protocol Version: I 0/09/20 I 4


Modulation ofautophagy with hydroxychloroquine in patients with advanced/recurrent non-small cell lung cancer - a phase II
study
flname:f
Product Name: hydroxychloroquine
Product Dosing: 1200 mg per day
How Supplied: Hydroxychloroquine tablets, USP of 200 mg (equivalent to 155 mg of base),
white, unscored, film-coated, capsule-shaped tablets debossed 0,93,, and *g774- on one side
and plain on the other side in bottles of 100 and bottles of 500.
Storage Requirements/Stabitity: Tablets are stable at room temperature. Storage
temperatures should be between 20" and25"C. Store away from light and moisture. Dispenie
in a tight, light-resistant container.
Route of Administration:
The dose of hydroxychloroquine will be 600 mg PO BID as determined by protocol 030g01.
Hydroxychloroquine should be taken at the same time each day. Hydrory.ilo.oquine may be
given orally or via NG tube. The dose may be given with a meal o. milk. For patients that
can't swallow capsules or tablets, the tablet may be removed and be dissolved in 5 ml of
water or mixed in a small amount of liquid or food. However, the drug may be bitter-tasting.
The drug may be dissolved in 5 ml of water for NG administration. Fatients receiving
antacids, sucralfate, cholestyramine, and/or bicarbonate should have the study drug dose ai
least I hour before or 2 hours after these medications.
Drug Interactions: There are known drug interactions with the following medications:
penicillamine, telbivudine, botulinum toxins, digoxin, and propafenone. Def,ending on the
specific drug, hydroxychloroquine increases the Lvels of these other drugs, or interferes with
the activity of the agent (specifically with botulinum toxin).
Toxicity:
Anorexia, nausea, vomiting, diarrhea, abdominal cramps, alteration of retinal pigmentation,
visual scotoma (visual field defects), disturbance ol accommodation with symptoms of
blurred vision, halos around light, photophobia, corneal deposits, rash, hemolysis in patients
with G6PD deficiency.
Extraocular muscle palsy, skeletal muscle weakness, absent or hypoactive deep tendon
reflexes.
Irritability, neryousness, emotional changes, nightmares, psychosis, headache, dizziness,
vertigo, tinnitus, nystagmus, nerve deafness, convulsions, aiaxia. Neuromyotoxicity is rare.
Weight loss, lassitude, exacerbation or precipitation of porphyria, and nonlight-sensitive
psoriasis. Cardiomyopathy has been rarely reported and the relationship with
hydroxychloroquine is unclear.
Page 39 of 49
Protocol Version: 10/09/2014


Modutarim of autoglagy *'ith hy&oxlrcNoroquinc ir paticnrs witl advauedircerurcat uoa-rnuall ccll 1mg cmccr - a phasc Ir
sfirdv
-
12. Drta Colle$ion snd Reeords to be Kept
I2.l Data Reporting to Coordinating Center
A snbset of the NCI's crMS ease report fonus, iu el*chouic
The Priucipal &rvestigator at each institution will be responsi6le for assuri*g that all the
required data is entered onto the e-CRFs accurately aud rnil.thiu Z weeks of the d*te in which
tlre previous cycle was conrpleted.
PeriodicallS monitoring andlor auditing visits will be conducted by staff from the
Coordiaating Celter. The Principal [rvestigator at each participating cinter will provide
access to his&er original records to perurit verificafion data enhy.
12"2 Research Chsrts
A research chart (i.e-, shadorv chart) ir nraiutained at OIIRS for eoch patiert ennrlled.
Copies of the most sipnificanf study soluce docuuents will be ruaiutained in tlre research
th*rt Examples of source documeut copies fhat will be maintained in the reseaxch chsrt
include: signed infonned cousent forur. docrunents that verify eligibiht aud ireatrnent and
docunerls thnt veri$, Grade 3-4 adverse events and respon*., this iuformation will be
updated otr a pro$pective basis arrd will be confidentially maintained at tlre OHRS.
12.3 treports
Publicstions aud anuual repofis for sulrnrission to the IRB aud FDA will be unitteu by the
hincipal Investigator using the data caphred ou the CRFs. Study progtress reports will be
provided to participating instihrtions for submission to local IRBs.
13. Drta and Safety lt{onitoring
utilized-
provided try
data caphue
Oncology
caleudar
are reqrired
findiogs from the initiation audit were sa
conduct will occur if
fonnat (e-CRfg will be
witb the instnrctions
irr a study-specilic
via fhe On-line Clinical
in the shrdy specific
user to the fonns that
audits of
data and
$eorch Environnrent (OuCore). The e-CRFs are fo
has treen created in OaCore. The systeu will prornpt
ient's euollurent and
2rnved Data and Safety Monitoring Plau (DSMP). An "inifiation audit" will be 
"oodo.
orIRS Quality Assurance staffin accordance with the DSMP following eruollnent of
Page 4.0 of 49
Iv""iEigg33!,11


b{o&rlatiou of autophqy with hydroxycbloroquinc irr paticntr rdth advarccd/rccurcnt uon-srnall ccll lung canco - a phasc Ir
studv
-
1{. Multi-Institutionnl Guidelires
14.3 Initiation Meeti&gs
A shrdy inifiatisu meeting will tle conducted with each participatilg instifutioa prior to
enrulhnent of patients froru tlre instifution" 0IIRS staff will conduci the study initiation
ueeting ia close proxiurity to IRB approval of the sttrdy at the participatiag ca*er. Iu most
situation the study initiatiou meeting rvill b,e conducted via teleconferi**u. Web-based
trainirrgregardiog e-cR-F corupletion will be utilized as apprcpriate.
l{.4 IRB Continuing Approvnls
hrvestigaton frour participating iustitutions must provicle to the OIIRS. a copy of the
institution's approved coritiurring review docrunentaiioa. Regishation will be halted at any
icipating institutiou in wbich a cunent continuins a
is not ori file.
nrd Consentr
l{.6 Psfient Regirtration
All patients &om participating institutions urust register patieuts with fhe OI{RS ceukal
regisfration desk, as described in Section 5.? of this prntocoi
14.7 Dst* Collection and Toxicity Reporting
The PI at each institution rvill be responsible for
collected and eutered onto the eCR-Fs accuately
descr:ibed in Sectiou 13.
assrutng that all the requiled d*ta is
and cornpleted eCRFs submitted as
I{,8 Dats Monitoring and $ource Document verilicttion
Each site participating in the accnul of patieuts to this protocol will be audited for protocol
aud regllatory compliance, data verification aud source documentation.
ivill uraintain a copy of all ameudments, conseut forms and
instihrtion. Consent flcnns will be reviewed and
Protocol Versiol: I 0i09i?0 1 4


lv{o&rlation of autoplrag u'ith hy&oxyclrloroquine it patiarts t{rh adyancrdirccurrcat nor-q,sll ccll lung cancc - a phasc II
studv
-
15" Statisticsl Considemtions
The primaly objective of this study is to assess the antitumor activify" as messured by tumor
response rate, of p*clitaxel, carboplatiu. Bevaciaunab (for eligible patients) a&d
hydroxychloroquine in patients with advanced or recurrent NSCLC cancer. The null hypothesis
of reslrouse rate for the paclitaxel, carboplatin, Bevacizuurab combination therapy for luag
cancer is 30%. Based ou the previous study "Modulafion of autophagy with hydroxychlonrquine
iu patients wittrr advancedlrecurrerrt non-srnall cell lung sallcer - a Phase VII study", we would
like to detennine if ihe *ddifion of hytlroxychloroquine cau incrense this respotrse rate to 60Yo.
We will use a Simon's two-stage rninimax desipr with a 5% significance l*vel and 80od power.
This procedure calls for 10 patients in the first stage and 7 h fhe *econd) so that the maximum
sample size is 17. If 2 or fewer responses are obssrvsd in the first stage, the trial will be stopped
and the addition of lrydroxyehloroquine to the paclitaxel. carboplatin, Bevacirumab combiuation
will be deeured not worthy of furlher shrdy. If the kial coutinues to the second stage, aud I or
fewer responses are observed out of fhe total of 17, addition of hydroxychloroquine will not be
considered worthy of fiuther shrdy iu these patients. But if 9 or more respouse$ are observed
frrhue study is warrauted.
For the above two-stage minirnax design, if the true response rate is 30016, the expected sample
size is 14.32, aad the probability of early termination is 0.38. In the event that other updated
iufonnation {$i"S tlre sfudy monitoring uray affect tlre study's desipp, we will use the ruefhod of
Wu and Shih" as a gruide when necessary.
The pafients accrued in the Phase I dose escalatiou shrdy (protocol 03S801) will be included in
final results of this Phase II study. Evaluoble patients for fhe Phase II portiou are those who have
received at least two cycles of treahuent.
The secondary endpoints of this shrdy are to assess time to progpession and oneaear sruvival,
and overall survival in pafients receiviug this regirnen. Time to progression will be calculated
based on the time behveen ttrre lirst day of keatment and the date of disease progression. Overall
sruvival will be calculated based on the time betweeu the first day of fieatmeut and the date of
death frour fiuy cause.
14"9 trsts snd CenterAudits
Page 42 of49
Versiau: l0l09l?014
:


}{o&rlatioq of autophagy witlr hy&oxyc}rloruquinc in patiants wi& adr.aucc#recurrcnl r}on-$uall ccll lung cmccr * a pharc II
study
-
lhe yre-year survival rafe will be estimnted rvith the prcseutatio$ of its g5% confideuce htsrval.
For the assessment of progressiou &ee survival and overall sruvir.al" Kaplan-Meier esfimates of
ilrvival fu[ction aud the $audard emor$ will be calculafed. The median survival times and g5go
confideoce intervals wll be pre$eufed. In additiou, toxicity of rhis ,*gi** *iff U. assessed. Any
relatiooship between baseline beclirr-l and p62 expressiou, changes io rc:-n protein expression,
and tumor response will be shrdied based on descriptive analyses"
For the added cohort of 20 patienfs to be keafe.d with 600 mg bid:
The [ull hypothesis response rate will be taken fo be 309o, u* tAr the previors eohort. Tlis is the
response mte for the therapy without hydroxyclrloroquine. We would like to detemrine if the
addition o{fhe higher dose of hydroxychloroquiu*lnniit increase this response rate fo 60%. we
will use a Simon's two-stage ruiuirnardesigrr ivith a 5% significance level aud g5?6 power. This
procedure calls for I pati-euts during tlre first stage and lii patients in the sectxrd, so that the
ma lltrum saurple size is ?0. If 2 orhwer re*pous*s are observed during stage i then the trial
yitl!" stopped early for firtility. If there ar1 3 or ruore respouses, the triai'wilicontinue to Stagp
II' If a total of g or fewer rcspor$e$ are observed by ttre end of Stage II, out of a total of 20
patients, then no fruther investigation of the combiuation will be corriidered. If tiere are l0 or
more responses out of ?0, the courbi*ntion incruding hydroxychloroqrdus will be cousidered for
fruther study.
A secondary ob.iective wiII be to assess fhe dru"ation of response amonli respo*ders. This will be
assessed by compufing a Kaplan Meier survival eurve.
16. Hurnan $ubjects
16.1 Prtient Population
See Section 5.
16.2 Poteutial Risks
The major risk to the patients involved_ in this study is ttrat tlre bydroxychloroquine may
decrease the effectiveness or iucrease the toxicity of m* standard r"giro*, of paclitaxel,
callmplatin and bevazicumab. In addition, patients may experience uapleisant and potentially
fatal side effects from the ruedications used.
16"3 Consent Proccdures
Informed consent must bs gbtained prior to comrqenciufi aty research procedures. Tbe pI
shall seek such consent only rurder such circtunstances irat provide &e prospeciive patient
opportunify to corsider whether or not to parficipate aud thit nrinimizes the possibiity or
eoe'reion or urdue influence. The infonnation given to the patient, or the rryru*Jot*tiv*, slmll
!e i& a langnrage understaudable to the patieut or represettative. Tlre infonled cousent
docuruent ,moy not - include any exculpatory laugrrage tluoupft whic[ fhe patient or
represeutative is made to waive any of the patieut'* t.!"t rtghtslor rr*leases, ; ;e*}* ;;
release the invesfigator, tlrc $pousor or the iusiitutiou torir tatltity for oeg{igence.
Page 43 of49
Protocol Versiau: I 0/09/30 I 4


16.4 Potentiol Benelits
Patients may expericnce improved rc$po$se rates of their disease as well as a cl*oce to
increare thefu ovefall surrrivat.
16.5 Risk-Benelit Rstio
Tlre rnajor risk of participatiug in this study versus receiving staudard care is that tbere may
be increa$ed ttrxicity of the r"$** or decreased e{fectivene,ss" Altenrafive therapiee include
stadard che.urothuapy with bevaciaunab or obseruation
16.6 Grnder snd Minorities
Female patieats accotmted for 58% of cs$cer patients seen within the Caucer Inetitute of
New Jersey's clinical ptr}gr?ms within the last year. African-Aruericaarconrpri sed Tva,
Hispatics 89/o, and Asians 3?6 of female patienis, reqpectivety. For all patients entering
clinical trials. the perceutages were 52?o women, dx iihi"un-America& Syo Hispanic, and
3Yo Asian.
No person slmll, on the grounds of age, race, color, or national origirl be excluded &onr
parficip*tion in, or be deuied ttre benefiis o,f, enrol&neut in this protocoi. 
"
I 7. Economic/Tinsnciol Considmtions
Patients and/or their insruance carriers will,be expected to pay fbr all costs of therapy.
monitoring, and follow-up. Pntierrts will not be chaiged ibr the cost of laboratory comelate
Moddatiu of aubphegry with hy&nxychloroquinc in patiants *itb advamrd/rceurult noa-.*rll ccll lung cmccr - a phasr tr
study
!g}g13!Sry conelate resring will be frrnded bi
18. Pu$iqllon of Ressarck
Page 44 of49
Protocol Versiou: I 0r'09/30 I 4


Y;y'u"oll 
of autophagy with hydroxychloroquine in patients with advanced/recurrent non-small cell lung cancer - a phase II
Ptname:J
REF'ERENCES
1. 
Figures,A.C.S.C.F.a.,No. 500g06.2007.
2' 
Schiller, J.H., et al,, Comparison offour chemotherapy regimensfor advanced non-
small-cell lung cancer. N Engl J Med, 2002.346e): p. 92_g.
3' 
Kelly, K., et al., Randomized phase III triat oTpicitaxa phs carboplatin versus
vinorelbine plus cisplatin in the treatment oYpitien* with advanced non--small-cell
lung cancer: a southwest oncology Groupliiot.l clin oncol,2ool,lg(13): p.3210-g.
4' 
DrAddario, G., et al., Platinum-bised ruiru, non-platinum-based chemotherapy in
advanced no1llall'cell lung cancer a meto-onatysis of the published lirerature. J
Clin Oncot, 2005. 23(13): p.2926-36.
5' 
Alberola, V., et al., Cisptotin plus gemcitabine versus a cisplatin-based rriplet versus
nonplatinum sequential doublets in advanced non-small-"ilt luog cancer: o Spanish
Lung Cancer Group phose III randomized trial. J Clin Oncol, ZO'OS. 2l(17)z p.SZOI-
13.
6' 
Comella, P., et al., Randomized trial comparing cisplatin, gemcitabine, and vinorelbine
with either cisplatin and gemcitobine or cispkiin aid vinorelbine in advonced non-
smoll-cell lung cancer: interim analysis of o phase III triat of the Southern Italy
cooperative oncologt Group. J crin oncoL)000. rg(7): p.ilst-1.
7 ' 
Favaretto, A., et al., Paclitaxel and carboplatin in combiiution wirh gemcitabine: a
phase I-II trial in patients with advanced non-smoll-cell lung cancer. Gruppo Studio
Tumori Potmonari veneto Gsrpry. Ann oncor,2000. lr(t1): p. 142r-6.
8' 
Folkman, J., Tumor angiogenesis: therapeutic implicarions. N fngl J Med, 1971.
285(21): p. il82-6.
9' 
Folkman, J., Seminars in Medicine of the Beth Israel Hospital, Boston, Clinical
applications of research on angiogenesr& N Engl J tvteO, iggS. 333e6)z p.1757-63.
l0' 
Folkman, J,rAngiogenesis und angiogenests inlruuun: an overvieru. Exi, 1997.79: p.
t-8.
11' Carmeliet, P. and R.K. Jain, Angiogenesis in cancer and other diseases. Nature,2000.
407(6801): p.249-57.
12' Dvorak, H.F., et al,, Vosculor permeability focror/voscular endorhelial growth factor:
an importont mediator of angiogenesis in malignancy and inflommatioi,Int Arch
Allergy Immunol, 1995. 107(l_3): p.233_5.
13' tr'errara, N,, Vascular endotheliot growth factor: molecular and biotogical aspects,
Curr Top Microbiol Immunol, 1999,23i: p. l-30.
14' Mattern, J., R. Koomagi, and M. Volm,,4 isociation of vascular endotheliol growth
factor expression with intratumoral microvessel density and tumour celt protiferation
in human epidermoid rung carcinomo. Br J cancer, 1996.73(7): p. 93r-1.
15' Berkman, R.A., et al., Expression of the vascular pirmeabiliry jaitor/vascular
endothelial growth factor gene in centrol nervousiystem neoplasms. J CIin Invest,
1993.91(t): p. 153-9.
16' Ferrara, N. an! !. Davis-Smyth,The biologt of voscular endothelial growrhfactor.
Endocr Rev, 1997. l8(l): p.4-25.
17' Ferrara, N., et al., Expression of vascular endothelial growth factor does not promote
transformotion but confers a growth advantage in vivo to Chinese hamster ovory cells.
J Clin Invest, 1993. 91(l): p. 160-70.
Page 45 of 49
Protocol Version: I 0/09/2014


Modulation ofautophagy with hydroxychloroquine in patients with advanced/recurrent non-small cell lung cancer - a Phase II
study
-
18. Plate, K.H., et al., Vascular endothelial growth factor and glioma angiogenesis:
coordinate induction of WGF receptors, distribution of VEGF protein and possible in
vivo regulotory mechanisms.Int J Cancer,1994.59(a): p. 520-9.
19. Yoshiji, H., et al., Expression of vascular endothelial growth factor, its receptor, ond
other angiogenicfactors in human breast concen Cancer Res, 1996. 56(9): p. 2013-6.
20. Teicher, B.A.rA systems approach lo cancer therapy. (Antioncogenics * standard
cytotoxics-->mechanism(s) of interaction). Cancer Metastasis Rev, 1996. 15(2): p.
247-72.
21. Gordon, M.S., et al., Phase I safety and pharmacokinetic study of recombinant human
anti-vascular endothelisl growthfactor in patients with advanced cancer. J Clin
Oncol,2001. 19(3): p. 843-50.
22. Margolin, K., et al., Phase Ib trial of intravenous recombinant humanized monoclonal
antibody to vascular endothelial growth factor in combination with chemotherapy in
patients with advanced cancer: pharmacologic and long-term safety dota. J Clin
Oncol,2001. 19(3): p. 851-6.
23. Johnson, D.H., et al., Randomized phase II triol comparing bevacizumob plus
carboplatin and poclitaxel with carboplatin and paclitaxel alone in previously
untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol,
2004. 22(tt): p. 2184-91.
24, Sandler, A., et al., Paclitoxel-carboplotin alone or with bevacizumabfor non-small-cell
lung cancer. N Engl J Med, 2006. 355(2 4)z p.2542-50.
25, Clinicaltrials.gov. Randomized Double-Blind Placebo Controlled Phase II Trial
Evaluating Erlotinib in Non-Smoking Potients lhth (Bevacizumab-Eligible and
Ineligible) Advanced Non-Small Cell Lung Cancer (NSCLC). 2010 [cited 2010
032620101; Available from :
http://clinicaltrials.sov/ct2lshow/NCT00976677?term=bevacizumab+elisible&rank=
1.
26. Levine, B. and D.J. Klionsky, Development by self-digestion: molecular mechanisms
ond biological functions of autophagt. Dev Cell, 2004. 6(4): p. 463-77.
27. Degenhardt, K., et al., Autophaglt promotes tumor cell survival and restricts necrosis,
inJlammation, and tumorigenesis. Cancer Cell, 2006. 10(1): p. 5l-64.
28. Karantza-Wadsworth, V., et al., Autophagy mitigates metabolic stress and genome
damage in mammary tumorigenesis. Genes Dev,2007.21(13): p. 1621-35.
29. Lum, J.J., et al., Growth factor regulation of outophagt and cell survival in the
absence of apoptosis. Ce|I,2005. 120(2): p.237-48.
30. Mathew, R., Y. Karantza-Wadsworth, and E. White, Role of autophag in cancer.
Nat Rev Cancer, 2007.7(12): p.961-7.
31. Mathew, R., et al., Autophagy suppresses tumor progression by limiting chromosomal
instabilily. Genes Dev, 2007. 2f (1 1): p. 1367-81.
32. Jin, S., et al., Metabolic catastrophe as a means to cancer cell deuth, J Cell Sci,2007.
120(Pt 3): p.379-83.
33. Boya, P., et al., Inhibition of macroautophagt triggers apoptosis, Mol Cell Biol, 2005.
25(3): p.1025-40.
33a. Guo, J.Y., et al., Activated Ras requires autophagy to maintain metabolism and
tumorigenesis. Genes Dev. 2011 25(5): p.460-70
Protocol Version: I 0/09/20 I 4
I
Page 46 of 49


Modulation ofautophagy with hydroxychloroquine in patients with advanced/recurrent non-small cell lung czurcer - a phase II
study
PIname:f
34' Ramakrishnjln, S.' et al., Autophogy ond angiogenesis inhibition.Autophagy rz00T.
3(5): p. sl2-s.
35' Ciuleananu T, Brodowicz T, Zielinski C, et al : Maintenance pemetrexed plus best
supportive care versus placebo plus best supportive care for non-small-cell lung
cancer: a randomised, double_blind, phase 3 study
36' capptzzo,T. ciuleanu, L. stelmathf S.et al saruRN: A double-blind, randomized,
phase IIr study of maintenance erlotinib versus placebo following nonfrogression
with first-line platinum-based chemotherapy in patients with advanced NSCLC. J
Clin Oncot 2009,27: l5s (abst g00f)
37' Wu, Y' and W.J. Shih,Approaches to handling dsru when a phose II trial deviates
from the pre'specilied simon's two-stoge desigi. stat Med, zilot. zllzl): p. 6190-20g.
Page47 of49
Protocol Version: I 0/09/201 4


ffi''u* 
"r"utophagy with hydroxychlorcqrrific irl paticnts with advanccdtccurrcil rlou-$rlall ccll lung cmccr - a pha.sc II
-
Appardix A
Perfonnnace Statrs Criteria
ECOG Perfonnance Stafus Scale
x,amofsky Perfoiuauee Scale
Grade
Descriptious
Percenl
0
Nonnal actir,,{ty.-rdtfrffiffi
carr;i on all predisease performauce
$'itlroril restriction.
100
Nonnal,nocoffi
disease.
90
Able tocarryonno"roGm;
signs or slar.lptonrs of disease.
I
^:-
syolprouls. but aurbulatory.
Restricted in phXsically strernrors
activity, but anrbulatoryand ablE to
carry orrt uork of a liglri or sedurtary
nahre (e.9., ligdrt housework office
wort).
80
Nomral actirttywith e{fort so@ffii
syutptonrs ofdisease.
70
Cares for seld rmabie ro carry tn rorffat
actil.ity or to do acfiye r*ork.
)
and capable of all self..care. but unabie
to earry out aay tork actir.ities. Up
ard about n:ore th6n S0% ofnxking
hours.
OU
Requires occasioual assistanie, ffiE
ro care for most of hisher needs.
.50
Requires eoniide*He u;iffia
freq*eni medical care.
J
onty timited self-care, ""#Hi:"#a
or chair more thm 50yo of u.aking
hours.
40
Disabled- requires specialiareffi
asristauce.
30
Severely disatlea. lro*piEtizatioi
indicated. Death,not iurndnent^
4
l00Yo bedriddarl C,or$i*
disabled. Camot caflyon any self,
ca.re. Totally c$nfined lo bed or chair.
30
Very sick. hospiralizaiionffi
Deathnot iuutinent
l0
hlori-brurd, atat procisrer proffi
rapidly.
5
t.Ieao.
0
Dead.
Page 48 of49
Protocol Versicn: I 0l0g&0 I 4


Modulation of autophagy with hydroxychloroquine in patients with advanced/recurrent non-smail celr rung cancer - a phase II
Uname:f
Appendix B
New York Heart Association classification of cardiac Disease
Functional Capacity
Patients with cardiac disease but without resulting limitations of
physical activity. Ordinary physical activity does not cause
,ndr. fatigue, palpitation, dyspnea, or anginal pain.
No objective evidence of
cardiovascular disease.
Patients with cardiac disease resulting in slight limitation of
physical activity. They are comfortable at rest. Ordinary
physical activity results in fatigue, palpitation, dyspnea, or
anginal pain.
Objective evidence of
minimal cardiovascular
disease.
Patients with cardiac disease resulting in marked limitation of
physical activity. They are comfortable at rest. Less than
ordinary activity causes fatigue, palpitation, dyspne4 or anginal
pain.
Objective evidence of
moderately severe
cardiovascular disease.
Patients with cardiac disease resulting in inability to carry on any
physical activity without discomfort. Symptoms of heart failure
or the anginal syndrome may be present even at rest. If any
physical activity is undertaken, discomfort is increased.
Objective evidence of
severe cardiovascular
disease.
Page 49 of 49
Protocol Version: I 0/09/2014