Modulation of Autophagy With Hydroxychloroquine in Patients With Advanced/Recurrent Non-small Cell Lung Cancer - a Phase II Study. A Study of The Cancer Institute of New Jersey Oncology Group (CINJOG)
Phase: PHASE2
Conditions: 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

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:
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-
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Dnrg(s) Uuder Investigation: hy&'oxychloruquite. carbeiplatin, paclitaxel and bevacinunab
CONFIDENTIAL
Biostrtistical Centrr
Protocol Vexion:
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NCI
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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
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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
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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
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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
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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.
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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
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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
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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.
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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
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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
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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
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,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
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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.
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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.
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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.
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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.
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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
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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).
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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
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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.
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*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.
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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.
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