Clinical trial NCT04386057
Conditions: Pancreatic Cancer Advanced Cancer
Keywords: Pancreatic Cancer Advanced Cancer Extracellular Signal-Regulated Kinases Cell Growth Inhibitors
Sponsor: Kimberly Perez, MD
Start date: 2020-05-27; Completion date: 2024-02-05
Enrollment: 52 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is evaluating the safety and efficacy of combining the study drug LY3214996 with hydroxychloroquine sulfate (HCQ) in patients with advanced pancreatic cancer.

Detailed description:
* This is an open label, randomized, two arm, phase II with safety lead- in study exploring the anti-tumor activity of the extracellular signal-regulated kinase (ERK) inhibitor LY3214996 with and without hydroxychloroquine (HCQ) in patients with advanced pancreatic cancer.
* The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits.

  * The safety lead-in will test the safety of a combination of investigational drugs and also try to define appropriate dosage. The names of the study drugs involved in this study are:

    * LY3214996
    * Hydroxychloroquine Sulfate (HCQ)
  * Following completion of a brief combination treatment safety lead-in cohort, participants will be randomized 1:1 for enrollment to one of two treatment arms:

    * Arm 1: receiving combination treatment with LY3214996 and HCQ
    * Arm 2: receiving monotherapy treatment with LY3214996

It is expected that about 52 people will take part in this research study

The U.S. Food and Drug Administration (FDA) has not approved LY3214996 as a treatment for any disease.

The U.S. Food and Drug Administration (FDA) has not approved HCQ for your specific disease but it has been approved for other uses.

Arms: arm 1: The research study procedures include screening for eligibility and study treatment. Study treatment will include evaluations, biopsies, and follow up visits. A treatment cycle will be defined as 28 consecutive days. Treatment will be administered on an outpatient basis.

Test the safety of study drugs in combination and define dose levels.

* LY3214996
* HCQ arm 2: The research study procedures include screening for eligibility and study treatment. Study treatment will include evaluations, biopsies, and follow up visits. A treatment cycle will be defined as 28 consecutive days. Treatment will be administered on an outpatient basis. Combined dosage per determined Lead-In Cohort

* LY3214996
* HCQ arm 3: The research study procedures include screening for eligibility and study treatment. Study treatment will include evaluations, biopsies, and follow up visits. A treatment cycle will be defined as 28 consecutive days.Treatment will be administered on an outpatient basis.

-LY3214996 arm 4: Participants who are enrolled to Arm 2 who experience radiologic disease progression on monotherapy will have the option to cross-over to receive treatment with the combination. Crossover will occur at the treating investigator's discretion following consultation and approval from the overall principal investigator. Combined dosage per determined Lead-In Cohort

* LY3214996
* HCQ
Interventions: intervention 1: Hydroxychloroquine Sulfate intervention 2: LY3214996
Intervention descriptions: intervention 1: HCQ will be administered by mouth twice daily continuously throughout each treatment per 28 day cycle intervention 2: LY3214996-daily oral dosage per protocol per 28 day cycle

Protocol documents:
Prot_SAP_000.pdf: 
Page 1
 NCI Protocol #: 04386057
DF/HCC Protocol #: 19-529
TITLE:  Phase II Trial of ERK Inhibition Alone and in Combination with Autophagy Inhibition 
in Patients with Metastatic Pancreatic Cancer
Coordinating Center:
Dana-Farber Cancer Institute
Principal Investigator (PI):
Kimberly Perez, MD
Dana-Farber Cancer Institute
Kimberly_Perez@DFCI.HARVARD.EDU
Other Investigators:
Andrew Aguirre, MD, PhD
Dana-Farber Cancer Institute
Andrew_Aguirre@dfci.harvard.edu
Srivatsan Raghavan, MD, PhD
Dana-Farber Cancer Institute
Srivatsan_Raghavan@DFCI.HARVARD.EDU
Brian Wolpin, MD, MPH
Dana-Farber Cancer Institute
Brian_Wolpin@dfci.harvard.edu
Ashwin Somasundaram, MD
University of North Carolina at Chapel Hill
ashwin@med.unc.edu
Statistician:
 
Hui Zheng, PhD
Massachusetts General Hospital
Hzheng1@partners.org
NCI-Supplied Agent: N/A
Other Agent: LY3214996 – Eli Lilly and Company; Hydroxychloroquine Sulfate (HCQ, 
Plaquenil®) – Commercial 
IND #: 145184
IND Sponsor: DF/HCC Investigator – Kimberly Perez, MD 
Protocol Type / Version # / Version Date: Revised / Version 13 / June 27, 2023


Page 2
SCHEMA
Informed 
consent and 
confirmation 
of eligibility 
for study 
treatment
Enrollment to 
Arm 1: 
LY3214996 + HCQ
1 cycle = 28 days
 (20 patients)
Enrollment to 
Arm 2: 
LY3214996 
1 cycle = 28 days
(20 patients)
At Disease 
Progression: 
Cross-over at 
treating investigator 
discretion
Assessment 
of 
treatment 
response
Pre-Treatment
Biopsy 
(prior to C1D1)
1:1 
Randomization 
Assessment 
of 
treatment 
response
Progression 
Biopsy
(optional)
Note: The trial will begin with a safety lead-in cohort to evaluate 
the LY3214996 + HCQ combination. Refer to Section 5.1 for 
details.
Following discontinuation of study treatment, participants in all 
arms will be followed for a maximum of 6 months.
Treatment will continue until disease progression, unacceptable 
toxicity, the participant decides to withdraw, intercurrent illness or 
condition prevents further administration of study treatment, or 
subject non-compliance with study requirements. Refer to Section 
5.5.


Page 3
TABLE OF CONTENTS
SCHEMA.........................................................................................................................................2
1.
OBJECTIVES......................................................................................................................7
1.1
Study Design............................................................................................................7
1.2
Primary Objective....................................................................................................7
1.3
Secondary Objective................................................................................................7
1.4
Exploratory Objectives ............................................................................................7
2.
BACKGROUND .................................................................................................................7
2.1
Study Disease and Rationale....................................................................................7
2.2
LY3214996 ............................................................................................................10
2.3
Hydroxychloroquine Sulfate..................................................................................17
2.4
Correlative Studies Background ............................................................................17
3.
PARTICIPANT SELECTION...........................................................................................23
3.1
Eligibility Criteria..................................................................................................23
3.2
Exclusion Criteria ..................................................................................................24
3.3
Inclusion of Women and Minorities ......................................................................25
4.
REGISTRATION PROCEDURES ...................................................................................26
4.1
General Guidelines for DF/HCC Institutions ........................................................26
4.2
Registration Process for DF/HCC Institutions.......................................................26
4.3
General Guidelines for Non-DF/HCC Investigative Sites.....................................26
4.4
Registration Process for Non-DF/HCC Investigative Sites...................................27
5.
TREATMENT PLAN........................................................................................................27
5.1
Treatment Regimen................................................................................................27
5.2
Pre-Treatment Criteria ...........................................................................................31
5.3
Agent Administration.............................................................................................31
5.4
General Concomitant Medication and Supportive Care Guidelines......................32
5.5
Criteria for Taking a Participant Off Protocol Therapy.........................................35
5.6
Duration of Follow Up...........................................................................................35
5.7
Criteria for Taking a Participant Off Study ...........................................................36
6.
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................36
6.1
Dosing Delays........................................................................................................36
6.2
Dose Modifications................................................................................................36
6.3
Toxicity Management Guidelines..........................................................................37
6.4
Overdose ................................................................................................................39
7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................40
7.1
Expected Toxicities................................................................................................40
7.2
Adverse Event Characteristics...............................................................................42
7.3
Serious Adverse Events .........................................................................................42
7.4
Adverse Event Reporting.......................................................................................43


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7.5
Reporting to the Food and Drug Administration (FDA) .......................................44
7.6
Reporting to Hospital Risk Management...............................................................44
7.7
Routine Adverse Event Reporting .........................................................................45
8.
PHARMACEUTICAL INFORMATION..........................................................................45
8.1
LY3214996 ............................................................................................................45
8.2
Hydroxychloroquine Sulfate (HCQ, Plaquenil®)..................................................47
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................48
9.1
Tumor Biopsy Collection.......................................................................................48
9.2
Pharmacodynamic Marker Collection ...................................................................49
9.3
Pharmacokinetic (PK) Sample Collection .............................................................49
10.
STUDY CALENDAR .......................................................................................................50
11.
MEASUREMENT OF EFFECT .......................................................................................55
11.1
Antitumor Effect – Solid Tumors ..........................................................................55
12.
DATA REPORTING / REGULATORY REQUIREMENTS...........................................62
12.1
Data Reporting.......................................................................................................62
12.2
Data Safety Monitoring..........................................................................................63
12.3
Multi-Center Guidelines ........................................................................................63
13.
STATISTICAL CONSIDERATIONS...............................................................................63
13.1
Study Design/Endpoints ........................................................................................63
13.2
Sample Size, Accrual Rate and Study Duration ....................................................63
13.3
Analysis of Primary Endpoint................................................................................64
13.4
Analysis of Secondary Endpoints..........................................................................64
13.5
Analysis of Exploratory Endpoints........................................................................64
13.6
Reporting and Exclusions ......................................................................................65
14.
PUBLICATION PLAN .....................................................................................................65
REFERENCES ..............................................................................................................................66
APPENDIX A
PERFORMANCE STATUS CRITERIA ..................................................69
APPENDIX B
LIST OF DRUGS KNOWN TO PREDISPOSE TO TORSADE DE 
POINTES
70
APPENDIX C
RASH MANAGEMENT GUIDELINES ..................................................71
APPENDIX D
DF/HCC MULTI-CENTER DATA AND SAFETY MONITORING 
PLAN
72
15.
INTRODUCTION .............................................................................................................73
15.1
Purpose...................................................................................................................73
15.2
Multi-Center Data and Safety Monitoring Plan Definitions..................................73


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16.
GENERAL ROLES AND RESPONSIBILITIES .............................................................74
16.1
DF/HCC Sponsor...................................................................................................74
16.2
Coordinating Center...............................................................................................74
16.3
Participating Institution..........................................................................................75
17.
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS .............................76
17.1
Protocol Distribution..............................................................................................76
17.2
Protocol Revisions and Closures ...........................................................................76
17.3
Informed Consent Requirements ...........................................................................76
17.4
IRB Documentation ...............................................................................................77
17.5
IRB Re-Approval...................................................................................................77
17.6
Participant Confidentiality and Authorization Statement......................................77
17.7
DF/HCC Multi-Center Protocol Registration Policy.............................................78
17.8
DF/HCC Protocol Case Number............................................................................78
17.9
Safety Assessments and Toxicity Monitoring .......................................................79
17.10 Data Management..................................................................................................80
18.
REQUISITIONING INVESTIGATIONAL DRUG..........................................................81
19.
MONITORING: QUALITY CONTROL..........................................................................81
19.1
Ongoing Monitoring of Protocol Compliance.......................................................81
19.2
Monitoring Reports................................................................................................82
19.3
Accrual Monitoring................................................................................................82
20.
AUDITING: QUALITY ASSURANCE ...........................................................................82
20.1
DF/HCC Internal Audits........................................................................................82
20.2
Audit Notifications.................................................................................................83
20.3
Audit Reports.........................................................................................................83
20.4
Participating Institution Performance ....................................................................83


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LIST OF TABLES
Table 1: LY3214996 Related TEAEs in ≥ 10% of Patients ..........................................................16
Table 2: Safety Lead-in Cohort Dose Plan....................................................................................28
Table 3: Dose Escalation Decision Criteria for Safety Lead-in Cohort ........................................28
Table 4: Treatment Regimen Description......................................................................................31
Table 5: HCQ Dose Reductions ....................................................................................................37
Table 6: LY3214996 Dose Reductions..........................................................................................37
Table 7: Hematologic Toxicity Management................................................................................38
Table 8: Non-Hematologic Toxicity Management........................................................................38
Table 9: HCQ Toxicities Considered Expected.............................................................................40
Table 10: Pharmacokinetic Blood Sample Collection1,2 ...............................................................49
Table 11: Study Calendar for the Safety Lead-in Cohort, Arm 1, and Cross-Over Participants∞.51
Table 12: Study Calendar for Arm 2 Participants .........................................................................53
Table 13: For Participants with Measurable Disease (i.e., Target Disease)..................................61
Table 14: For Participants with Non-Measurable Disease (i.e., Non-Target Disease)..................61
Table 15: Safety Lead-in Probability Table...................................................................................64


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1.
OBJECTIVES
1.1
Study Design
This is an open label, randomized, two arm, phase II study exploring the anti-tumor activity of 
the extracellular signal-regulated kinase (ERK) inhibitor LY3214996 with and without 
hydroxychloroquine (HCQ) in patients with advanced pancreatic cancer. Following completion 
of a brief combination treatment safety lead-in cohort, participants will be randomized 1:1 for 
enrollment to one of two treatment arms: 

Arm 1: receiving combination treatment with LY3214996 and HCQ

Arm 2: receiving monotherapy treatment with LY3214996
1.2
Primary Objective
Evaluate the anti-tumor activity of LY3214996 alone and in combination with HCQ in patients 
with metastatic pancreatic tumors. Anti-tumor activity will be measured via disease control rate 
(DCR), which will be defined as the proportion of patients with complete response (CR), partial 
response (PR) or stable disease (SD) that persists for ≥ 4 months. Radiologic response will be 
assessed using RECIST v1.1 criteria.
1.3
Secondary Objective
Examine the objective response rate (ORR), progression-free survival (PFS), and overall survival 
(OS) following treatment in these patient populations.
1.4
Exploratory Objectives

Develop multivariate predictive models for response to LY3214996 alone and in 
combination with HCQ via integration of correlative assays, sequencing data, organoid 
therapeutic response measurements, and clinical data including prior regimens of 
therapy.

Explore biomarker indicators of target engagement, response, and resistance.

Investigate resistance mechanisms via repeat molecular analyses and organoid 
derivation at the time of progression.

Assess the pharmacokinetic (PK) properties of LY3214996 when combined with HCQ 
in this patient population.
2.
BACKGROUND
2.1
Study Disease and Rationale


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Pancreatic ductal adenocarcinoma (PDAC) is the third-leading cause of cancer-related death in 
the United States and is projected to become the second leading cause by 2030.1 Fifteen to 
twenty percent of PDAC patients are diagnosed with clinically localized disease that is amenable 
to potentially curative surgical resection.2,3 Following surgical resection, the majority of patients 
will have local or distant recurrence and succumb to the disease.4 Systemic treatment, in the form 
of neoadjuvant or adjuvant cytotoxic chemotherapy, is used in conjunction with oncologic 
resection but only adds a modest benefit in survival.5,6 
Most patients are not surgical candidates and are diagnosed with locally advanced or metastatic 
disease. Therapeutic options for these patients include the combination chemotherapy regimens 
gemcitabine/nab-paclitaxel7 or FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, 
oxaliplatin).8 Despite therapeutic intervention, median overall survival is 6.7 – 11.1 months (PFS 
= 3.3 – 6.4) for advanced disease,7,8 compared to 25 – 28 months (PFS = 13.1 – 13.9) in 
surgically resected patients.5 Current therapeutic selection for metastatic pancreatic cancer 
patients is often based on patient performance status and co-morbidities. This highlights the 
unmet clinical need to define responsive subgroups to inform treatment selection and to 
nominate alternative treatment options for patients who are resistant to currently approved 
treatment regimens. 
Approximately 95% of PDAC tumors harbor KRAS mutations,9 and those with wild-type KRAS 
often harbor alterations in other RAS pathway genes such as BRAF.10 Despite this, inhibition of 
MEK downstream of KRAS hasn’t resulted in significant clinical benefit to most patients with 
PDAC. One promising approach to treatment might be to target ERK alone or in combination 
with inhibition of the metabolic functions that support the increased energy needs of PDACs.
Macroautophagy (autophagy) is a lysosome-mediated process that permits cells to degrade 
organelles and macromolecules and recycle cellular waste. The resulting products are used to 
sustain cellular metabolic needs.9,11 Pancreatic tumors have high basal levels of autophagy, and 
Figure 1: KRAS suppression or 
ERK inhibition enhances 
autophagic flux. a: PDAC cell 
lines stably infected with lentiviral 
vector encoding mCherry-EGFP-
LC3B and then transiently 
transfected with siRNA targeting 
KRAS or a mismatch control oligio 
(MM) (72 h). Area ratios of 
mCherry+ punctae to EGFP+ 
punctae were determined. Mean 
autophagic index is plotted, each 
data point representing 1 field 
containing at least 10 analyzed 
cells. b: PDAC cell lines stably 
infected with lentiviral vector 
encoding mCherry-EGFP-LC3B 
and then treated with ERK 
inhibitor or DMSO for 24 h. c: 
Representative images of cells 
described and quantified in b, 
scale bar 20 µm.9 
b
c


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inhibition of autophagy has been shown to inhibit growth both in cell line and animal models.11 
Unfortunately, this did not translate clinically when autophagy was inhibited with single-agent 
hydroxychloroquine (HCQ). HCQ is an FDA approved autophagy inhibitor commonly used in 
rheumatoid arthritis and as an antimalarial agent. A phase II monotherapy study conducted at 
Dana-Farber using HCQ in 20 patients with metastatic pancreatic cancer demonstrated negligible 
therapeutic efficacy. Only two patients were without progressive disease at two months, and 
median PFS and OS were 46.5 and 69 days, respectively. The trial did identify LC3-II as a 
candidate clinical pharmacodynamic marker, but otherwise determined that autophagy inhibition 
alone with HCQ was not sufficient to affect tumor growth.11
The theory that RAS pathway signaling regulates autophagy led researchers Bryant and Kinsey 
to independently explore both the mechanism driving the autophagic flux and the potential 
combination of MEK/ERK and autophagy inhibition. The authors determined that KRAS 
suppression elevated autophagic flux, and that treatment with a RAF pathway inhibitor 
phenocopied KRAS suppression (Figure 1). This elevation serves as a protective mechanism for 
the survival of the cell in the face of RAF/MEK/ERK pathway inhibition. Consistent with this, 
both authors reported synergistic anti-proliferative effects with combination treatment both in 
vitro and in vivo (Figure 2).9,12  
Based on these discoveries, Kinsey’s team went on to compassionately treat a single patient with 
the MEK inhibitor trametinib (2 mg daily) and HCQ (escalated to 600 mg BID). The patient had 
failed three prior treatment regimens, with a best response of stable disease with the first two 
lines and disease progression with the last. Kinsey reported the patient achieved a PR by 
RECIST 1.1 criteria, with a decrease in tumor burden of approximately 50% at 4 months 
following initiation of therapy. The patient tolerated the treatment well with only grade 1 rash 
and fatigue noted, no ocular or cardiac toxicity was observed.12
Figure 2: ERK inhibition with HCQ is effective pre-
clinically. a: hM1A subject-derived organoids grown 
for 10 days in the presence of indicated concentrations 
of CQ and ERK inhibitor (0.039 to 2.5 µM). Growth 
curve is representative of 5 independent experiments. 
b: Heatmap representing BLISS independence scores 
corresponding to representative growth curve shown 
in a. c: NSG mice implanted with KRAS-mutant PDX 
tumor (AZ1013) were treated with ERK inhibitor 
alone or in combination with HCQ for 22 days. Mean 
tumor volume plotted, error bars denote s.e.m. d: 
Quantitation of AZ1013 tumor weights, P value is 
from two-sided, unpaired t-test comparing ERK 
inhibitor-treated to ERK inhibitor + HCQ-treated 
tumors; error bars denote s.e.m.9
a
b
c
d
Further investigation of the combination of ERK and autophagy inhibition in PDAC is 


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warranted. The combination may provide significant clinical benefit in a patient population with 
incredible need. 
2.2
LY3214996
LY3214996 is a small molecule that selectively inhibits the extracellular signal-regulated kinase 
(ERK; ERK1/2), a key downstream node of the RAS/RAF/MEK signaling pathway. The MAPK 
pathway is a key regulator of cellular proliferation and survival. Abnormalities of the MAPK 
pathway are common in many cancers, including PDAC, cutaneous melanoma, uveal melanoma, 
colorectal cancer (CRC), non-small cell lung cancer (NSCLC), breast cancer, ovarian cancer, and 
many others. Extracellular signal-regulated kinase is a downstream member of this pathway and 
plays a central role in transmitting extracellular signals from activated receptor tyrosine kinases 
(RTKs) such as epidermal growth factor receptor (EGFR), fibroblast growth factor receptor 
(FGFR), platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor 
receptor (VEGFR), and others. This pathway is a 3-tiered kinase cascade consisting of the RAF, 
MEK, and ERK kinases and activation of this pathway begins with activation of RAS, a small 
guanosine triphosphate hydrolase. Activation of RAS leads to the recruitment of RAF, a 
serine/threonine kinase, to the cell membrane and its activation. Activated RAF then 
phosphorylates and activates MEK1/2, which in turn phosphorylates and activates ERK1/2. 
When activated, ERK1/2 phosphorylates p90 ribosomal S6 kinase 1 (RSK1), and regulates 
several additional downstream cytoplasmic and nuclear targets involved in the cell cycle, cell 
proliferation, cell growth, and cell survival.
The feasibility of pharmacologic inhibition of the MAPK pathway in cancer has been shown 
through the success of BRAF and MEK inhibitors in the treatment of patients with various 
cancer subtypes, especially patients who harbor BRAF mutations. However, while BRAF and 
MEK inhibitors have proven effective in patients with BRAF V600E/K melanoma and 
BRAFV600E NSCLC, most patients eventually develop drug resistance, which leads to disease 
relapse.13,14 Most resistance mechanisms to RAF and MEK inhibitors result in reactivation of 
ERK1/2;15 therefore, a blockade of ERK1/2 is directly postulated to overcome many of the 
current limitations of RAF and MEK inhibitors. In addition, RAF and MEK inhibitors remain 
ineffective in RAS-mutant cancers. Neurofibromin-1, a tumor-suppressor gene is a negative 
regulator of RAS. Loss of function of NF1 has been linked to the development of tumors in 
mice.16 Neurofibromin-1 deletions and mutations are common in cancers and may recapitulate 
RAS mutations and represent an attractive target in the MAPK pathway.16,17
The current mechanistic paradigm suggests that the drug resistance could be due to reactivation 
of the MAPK pathway through RAS-/RAF-dependent mechanisms such as activating mutation 
in NRAS or MEK1,18,19 expression of truncated forms of BRAF or upregulation of CRAF, or 
COT1.20-23 Moreover, the persistent expression of the RTKs PDGFR-β and insulin-like growth 
factor 1 receptor (IGF-1R) conferred BRAF inhibitor resistance that may involve enhanced 
phosphatidylinositol 3-kinase (PI3K)/AKT pathway activation.18,24,25 In addition, RAS-mutant 
tumors, especially those that harbor KRAS and NRAS mutations that account for a larger 
proportion of cancer patients, remain refractory to BRAF and/or MEK inhibitors. Loss of MEK 
function can also be overcome by ERK activation. Therefore, the mechanisms of resistance to 
ERK inhibitors will be different from those that arise from MEK inhibitors.13 Furthermore, the 


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acquired resistance to BRAF and MEK inhibition in BRAF-mutant tumors and the inherent lack 
of response in RAS cancers present a significant therapeutic challenge. LY3214996 is a potent 
inhibitor of ERK1/2 kinases that can potentially obviate resistance mechanisms in cancers that 
harbor BRAF, RAS, NF1, MEK, and other MAPK mutations and alterations.
LY3214996 is being evaluated as monotherapy and in combination in the first-human-dose 
(FHD) Phase 1 Study I8S-MC-JUAB (hereafter “JUAB”) to determine the safety, 
pharmacokinetic (PK) profile, and pharmacodynamic (PD) relationships of LY3214996 in 
patients with advanced/metastatic solid tumors refractory to standard therapy. Please refer to the 
LY3214996 investigator’s brochure (IB) for complete background information.
2.2.1
Pre-Clinical Summary
2.2.1.1 Summary of Absorption, Distribution, Metabolism, and Excretion
Please refer to the LY3214996 IB for complete background information. Pharmacokinetic 
parameters of LY3214996 were examined in mice, rats, and dogs following an oral gavage dose, 
and in rats and dogs following an intravenous (IV) dose. The data indicate high bioavailability in 
both rats and dogs. Following infusion, clearance of LY3214996 was low to moderate (i.e., 
slower than hepatic blood flow) in both rats and dogs. 
The plasma toxicokinetics of LY3214996 were evaluated in rats and dogs following single and 
repeated oral doses for up to 4 weeks. Exposure increased with dose in both species, but the 
increase was not always dose-proportional. No accumulation in plasma of LY3214996 was noted 
following repeated dosing to rats and dogs. In the rat, sex differences in exposures were 
approximately 2-fold, with females showing higher exposure. There was no sex difference in 
exposure noted in the dog.
In vitro protein binding data indicated low protein binding in all matrices examined. From 
radiolabel studies conducted in rats and dogs, [14C]LY3214996 was identified as the 
predominant drug-related peak in plasma, urine, and feces of both species. In the plasma, 
[14C]LY3214996 accounted for >64% of the systemic exposure (area under the concentration-
time curve from time zero till infinity [AUC0-∞]) of the total radioactivity, both in rats and dogs. 
Minor metabolism, which was primarily oxidative in nature, was observed in both species. 
Metabolites were identified in rat and dog plasma, bile, urine, and feces. Fecal elimination was 
the predominant route of excretion (>77%) in both rats and dogs. Excretion of total radioactivity 
into the urine was approximately 8% in rats and ranged from approximately 11% to 14% in dogs.
2.2.1.2 Summary of Non-Clinical Safety Studies
Please refer to the LY3214996 IB for complete background information. LY3214996 was 
evaluated in 1-month daily oral-dosing toxicity studies in Sprague-Dawley rats and Beagle dogs 
(with 1-month reversibility in mid-dose rats and dogs) at tolerated dose levels, as well as at dose 
levels that exceeded the MTD. Safety pharmacology parameters were evaluated in vitro (human 
ether á-go-go–related gene [hERG]) and as part of the repeat-dose toxicity study in dogs. Genetic 
toxicity was evaluated in a bacterial mutation (Ames) assay. Results from these studies have 
allowed for identification of a starting dose that is anticipated to be safe in patients. Based on 


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nonclinical study findings, potential toxicities include GI inflammation, fecal changes, emesis, 
dehydration, sores on gums, scabs on skin, and clinical pathology changes, including increased 
neutrophils and monocytes, decreased lymphocytes, decreases in red cell mass, decreased 
albumin, increased globulin, and/or increases in serum phosphorus. Injury to the long bones 
(femur and tibia), female reproductive tract (ovary), and effects in the skin were also observed 
only in rats. With the exception of effects on skin, bone, and ovaries, all findings either 
recovered or showed evidence of recovery after a 1-month reversal period.
2.2.1.3 Mechanism of Action
Please refer to the LY3214996 IB for complete background information:

LY3214996 is an adenosine triphosphate (ATP)-competitive, selective inhibitor of ERK1 
(inhibitory constant [Ki] for ERK1-2P=650 pM) and ERK2 (Ki for ERK2-2P=64 pM), 
with biochemical IC50 values of 5 nM for each kinase.

LY3214996 inhibits cellular phospho-RSK1 (T359/S363) in RAF- and RAS-mutant 
cancer cell lines with sub-μM potency. It also inhibits transcriptional output mediated by 
ERK in regulating expression of several target genes. Among 48 genes tested, 16 genes 
(EGR1, SPRY4, DUSP6, ETV5, FOSL1, IER3, ETV4, FOS, GPR3, MAFF, DUSP4, 
GDF15, LIF, IL8, TNFRF12A, and PLK3) were downregulated more than 4-fold and 20 
genes (PHLDA2, ETV1, CCND1, SPRED2, CDC45L, SPRED1, CCNB1, TNC, LNK, 
JUN, SLC2A1, SPC25, CCNA2, SPRY2, MAD2L1, ETS1, MYC, SLC4A7, HMGA2, and 
MKI67) were downregulated 2-fold to 4-fold with LY3214996 treatment.
2.2.1.4 In Vitro and In Vivo Summary
Please refer to the LY3214996 IB for complete background information:

In CRC BRAF V600E-mutant COLO 205 cells, LY3214996 inhibits cell proliferation 
with an IC50 value of 186 nM in vitro, and exhibits significant tumor growth 
inhibition/regression at 12.5 to 100 mg/kg in vivo. LY3214996 may show anti-tumor 
activity in CRC patients with BRAF V600E mutation.

In preclinical models, LY3214996 was demonstrated to be active against a vemurafenib-
resistant A375 melanoma model with ERK reactivation. These resistance mechanisms 
include NRAS mutation, BRAF splice variants, CRAF elevations, and FGFR3 activation. 
Therefore, LY3214996 may show activity in patients who had progressive disease after 
prior BRAF and MEK inhibitor treatment.

In preclinical models of NRAS-mutant melanoma, LY3214996 inhibits cell proliferation 
and induces tumor cell apoptosis, whereas vemurafenib was inactive. Similar activities 
are also observed for other NRAS-mutant tumor cells, including the AML cell line HL60. 
LY3214996 has also significantly inhibited SK-MEL-30 (melanoma) and HL-60 (AML) 
xenograft tumor growth in vivo in mice.

In cancer cell sensitivity profiling of 535 cell lines, cell lines that harbor MAPK pathway 
mutations are more sensitive to LY3214996 compared to cell lines that do not harbor 
MAPK pathway mutations.

In a subsequent, in-house profiling of LY3214996 in a panel of 62 cell lines from 
colorectal, lung, and pancreatic cancers, mutations of KRAS, NRAS, BRAF, and MEK1 
appear to predict cell growth inhibition to LY3214996.


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
In a preclinical model of MEK1-mutant SW48 CRC cells, LY3214996 led to better 
inhibition of cell proliferation and in vivo tumor growth compared to a MEK inhibitor.

In in vivo efficacy studies, LY3214996 demonstrated significant tumor growth inhibition 
and regression at a 25- to 100-mg/kg once-daily dose schedule in a CRC HCT 116 
xenograft model. In xenograft models of KRAS-mutated NSCLC and pancreatic cancer, 
LY3214996 showed significant tumor growth inhibition at a 50-mg/kg to 100-mg/kg 
once-daily dose schedule. In an HCT 116 xenograft PD model in mice, LY3214996 
demonstrated a dose- and time-dependent inhibition of phospho-RSK1 and a PK/PD 
correlation with absolute threshold effective dose of 50% inhibition (TED50) and 
threshold effective dose of 80% inhibition (TED80) of 16 mg/kg and 38 mg/kg, and 
threshold effective concentration of 50% inhibition (TEC50) and threshold effective 
concentration of 80% inhibition (TEC80) of 1107 nM and 3758 nM, respectively. In an 
HCT 116 CRC xenograft PD model in rats, LY3214996 inhibited phospho-RSK with 
absolute TED50 and TED80 of 9 mg/kg and 22 mg/kg, and TEC50 and TEC80 of 559 nM 
and 2032 nM, respectively. Overall, LY3214996 has demonstrated a PK/PD correlation 
in HCT 116 xenograft tumors implanted in mice as well as rats. Data suggest that ≥50% 
phospho-RSK1 (PD biomarker) inhibition for 6 to 8 hours in a once-daily schedule is 
sufficient to yield significant tumor growth inhibition/regression in BRAF-, KRAS-, or 
MEK1-mutant models.

LY3214996 is tolerated in combination with targeted agents such as abemaciclib (cyclin-
dependent kinase [CDK]4/6 inhibitor) and chemotherapeutic agents (gemcitabine and 
paclitaxel), and has shown additive or synergistic effect in 1 or more models.
2.2.2
Clinical Summary
2.2.2.1 Pharmacokinetics
LY3214996 PK data are available from 20 patients after QD dosing and from 9 patients after 
BID dosing. Please refer to the LY3214996 IB for complete background information.
After oral administration, maximum plasma concentrations of LY3214996 were reached 
approximately 1 to 2 hours post dose. The mean t1/2 was approximately 3 to 5 hours, suggesting 
little to no accumulation upon multiple QD and BID dosing. Exposures increased with dose from 
25 to 400 mg, and AUCτ at steady state on Day 15 was similar to AUC0-∞ on Day 1, suggesting 
that the PK of LY3214996 did not change with time at these doses. The variability in exposures, 
assessed by percentage coefficient of variation (%CV), ranged from 3% to 98% for both Cmax 
and AUC, and did not display any apparent trend with dose. These variabilities are most likely 
associated with the all-comer patient population and small numbers of patients per dose level.
2.2.2.2 Distribution
Protein-binding assessments of LY3214996 were conducted in human plasma at concentrations 
of 0.1, 1, and 10 μM and in human liver microsomes using equilibrium dialysis. The results 
indicate that LY3214996 is 52.0% to 54.9% bound to plasma proteins over the concentration 
range investigated. LY3214996 was predominantly bound to albumin to an extent similar to 
human plasma protein binding, with lower binding to α1-acid glycoprotein (AAG).


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2.2.2.3 Metabolism
Exploratory metabolite profiling of human plasma samples collected from patients after single 
(Day 1) and repeat (Day 15) 200-mg doses of LY3214996 identified LY3214996 as the 
predominant circulating component based on qualitative assessments (ion peak intensity in mass 
spectrometry analysis). Eight metabolites, mainly oxidative, were also identified in plasma. The 
2 most predominant metabolites observed at Cmax and AUC0.5-12hr pools on both Day 1 and Day 
15 were a lactam on the morpholine ring (LSN3310162) and a hydroxyl glucuronide.
2.2.2.4 Effect of Other Drugs on the PK of LY3214996
A substrate-depletion approach using recombinant human cytochrome P450s (CYPs) was used to 
identify CYPs metabolizing LY3214996 and to predict the relative contributions of these CYPs 
to hepatic CYP-mediated clearance. These studies indicated that CYP2J2, CYP3A4, and 
CYP3A5, respectively, are responsible for 12%, 88%, and <1% of hepatic CYP-mediated 
clearance of LY3214996. The magnitude of the contribution of these CYPs toward the overall 
clearance of LY3214996 is unknown since the in vivo clearance pathways of LY3214996 have 
not yet been determined.
The transport of LY3214996 was evaluated at 5 μM in vitro using Madin-Darby canine kidney 
(MDCK) cells transfected with human of P-glycoprotein (P-gp) or breast cancer-resistance 
protein (BCRP) transporters. LY3214996 was found to be a substrate of P-gp and BCRP 
transporters. The clinical relevance of the in vitro transport of LY3214996 is currently unknown.
2.2.2.5 Effect of LY3214996 on the PK of Other Drugs
The ability of LY3214996 to reversibly inhibit the metabolism of probe substrates of CYP1A2, 
CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A in vitro was examined in 
human liver microsomes over the concentration range 0.15 to 200 μM. The results indicate that 
LY3214996 reversibly inhibits the metabolism of CYP2C8, CYP2C9, and CYP3A substrates, 
although at relatively high concentrations of LY3214996 (all IC50 values ≥19 μM). To predict the 
likelihood of a clinically relevant drug-drug interaction (DDI), the predicted ratio of a victim 
drug (R) was calculated using a static model, R=1+(Imax,u/Ki), where Imax,u = unbound Cmax from 
the 400-mg QD cohort and Ki,u is the most potent observed unbound reversible inhibition 
constant for CYP2C9 at 34.5 μM (Ki×fraction unbound in microsomes = 35.8 μM×0.964). The 
current Cmax concentration observed for the 400-mg QD cohort is 1.39 μM. The calculated R 
value is 1.04. Therefore, the current risk of a DDI mediated by reversible CYP2C9 inhibition is 
low. Additionally, Ki values for the other CYP enzymes evaluated were higher than that of 
CYP2C9. Therefore, the risk of a DDI mediated by reversible CYP inhibition of those isoforms 
is unlikely.
The potential of LY3214996 to cause time-dependent inhibition of CYP3A4-mediated 
metabolism was also evaluated in vitro using human liver microsomes. The results indicate that 
LY3214996 is a time-dependent inhibitor of CYP3A4 metabolism. Assuming this is due to 
mechanism-based inhibition, LY3214996 appears to be a less efficient inhibitor than 
erythromycin, a known moderate in vivo time-dependent inhibitor of CYP3A. The clinical 


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relevance of this apparent mechanism-based inhibition cannot be fully assessed by this estimate 
alone, since it is influenced by multiple factors, including the circulating plasma concentrations, 
protein binding in plasma and microsomes, interactions at the gut wall, and other factors. 
Therefore, the risk of competitive and mechanism-based inhibition of CYP3A is planned to be 
clinically evaluated in an Eli Lilly sponsored trial.
An in vitro study to investigate the effects of LY3214996 on the expression of CYPs was 
conducted at concentrations of 0.1 to 10 μM of LY3214996 in 3 individual lots of cryopreserved 
human hepatocytes. LY3214996 was not an inducer of CYP1A2, CYP2B6, or CYP3A4 
messenger ribonucleic acid (mRNA) or activity. LY3214996 was also not an inducer of 
CYP2C8, CYP2C9, or CYP2C19 mRNA. However, LY3214996 did induce CYP2D6 and 
CYP3A5 mRNA, but did not induce the activity of CYP2D6. CYP3A5 is considered less 
responsive to induction than CYP3A4. The clinical relevance of the in vitro induction of 
CYP2D6 and CYP3A5 by LY3214996 is currently unknown.
2.2.2.6 Safety 
Please refer to the LY3214996 IB for complete background information. As of 30 June 2018, 
validated safety data for 39 patients enrolled and treated with LY3214996 were available from 
ongoing clinical study JUAB.
Dose-Limiting Toxicities
A total of 5 (12.8%) of the 39 patients experienced at least 1 DLT; 2 patients (7.7%) receiving 
QD dosing (Part A) and 3 patients (23.1%) receiving BID dosing (Part A2). In Part A, DLTs 
were observed at a dose levels of 400 and 600 mg QD (1 patient, each). These included Grade 3 
fatigue and cough at 400 mg QD and Grade 3 dehydration at 600 mg QD. In Part A2, 2 patients 
at 200 mg BID experienced DLTs of Grade 3 blood creatinine increased, renal failure, and rash 
maculo-papular and 1 patient at 300 mg BID experienced Grade 3 blood creatinine 
phosphokinase increased.
Deaths
As of 30 June 2018, 5 deaths (12.8%) were reported in Study JUAB; 3 in Part A and 2 in Part 
A2. Of these, 4 deaths occurred within 30 days of treatment discontinuation and 1 death occurred 
after 30 days of treatment discontinuation. All of these deaths were due to patient’s disease.
Serious Adverse Events
Four patients (10.3%) experienced a serious adverse event (SAE):

1 patient in Part A Cohort 5 (400 mg QD) experienced Grade 3 cellulitis, not considered 
to be related to the study treatment.

2 patients in Part A Cohort 6 (600 mg QD) experienced Grade 3 non-cardiac chest pain 
and dehydration (n=1). Non-cardiac chest pain was not considered to be related to the 
study treatment, whereas dehydration was considered to be related to the study treatment.

1 patient in Part A2 Cohort 6 (300 mg BID) experienced Grade 3 hepatic enzyme 


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increased, which was considered to be related to the study treatment. This completely 
reversed when study drug was discontinued.
Treatment-Emergent Adverse Events
Of the 39 patients, 38 (97.4%) experienced at least 1 treatment-emergent adverse event (TEAE); 
17 patients had Grade 3 or higher TEAE. Of the total TEAEs, the most commonly reported 
TEAEs in 10 or more patients included nausea, vomiting, fatigue, anemia, and rash maculo-
papular.
There were 34 patients (87.2%) who experienced at least 1 related TEAE, of whom 8 patients 
(20.5%) experienced TEAEs that were Grade 3 or above. The commonly reported related TEAEs 
in 10 or more patients included nausea, rash maculo-papular, and vomiting.
Table 1: LY3214996 Related TEAEs in ≥ 10% of Patients 
Preferred Term
Total All Grades
N=39
n (%)
Total Grade ≥ 3
N=39
n (%)
Nausea
12 (30.8)
0 (0)
Rash maculo-papular
10 (25.6)
3 (7.7)
Vomiting
10 (25.6)
1 (2.6)
Diarrhea
8 (20.5)
0 (0)
Pruritus
7 (17.9)
1 (2.6)
Dermatitis acneiform
6 (15.4)
0 (0)
Blood creatinine phosphokinase increased
5 (12.8)
1 (2.6)
Rash
4 (10.3)
1 (2.6)
Vision blurred
4 (10.3)
0 (0)
Alanine aminotransferase increased
4 (10.3)
1 (2.6)
Hyperkalemia
4 (10.3)
0 (0)
Discontinuations due to Adverse Events or Death
As of the data cut-off date, 33 patients (84.6%) discontinued the study treatment; 22 patients in 
Part A and 11 in Part A2. The most common reason for treatment discontinuation was 
progressive disease (64.1%) followed by AE (12.8%), withdrawal by subject (5.1%), and 
physician decision (2.6%).
Maximum Tolerated Dose
The MTD for LY3214996 was originally declared to be 600 mg by mouth once daily, or 200 mg 
by mouth twice daily. Once daily dosing was better tolerated than twice daily dosing, and 600 
mg once daily was better tolerated than 300 mg twice daily. In both 600 mg once daily and 300 
mg twice daily, 100% pRSK PD inhibition in tumor are observed. PK exposures increased with 
dose (25 to 800 mg once daily) in a fairly dose-proportional manner. There was no apparent 
time-dependent inhibition of CYP3A4 up to 800 mg. In a limited set of highly heterogeneous 
cancer patients, a best overall response of stable disease (SD) was observed with some patients 


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showing tumor regressions.  Tumor regressions were observed in both once daily and twice daily 
doses, but treatment duration appears to be better in those treated with once daily doses. There 
were no dose reductions in any patients treated at the once daily dose who achieved SD and 3 
participants remain on treatment as of the data cut-off date. The once daily dosing schedule was 
selected for this trial as once daily dosing was better tolerated. 
Eli Lilly has since determined that despite anti-emetic premedication, issues with unexpected 
toxicity have continued at the 600 mg once daily dose. They have thus advised a reduction in 
dose to 400 mg once daily.
2.2.2.7 Efficacy
Efficacy has not been established at this time.
2.2.2.8 Marketing Experience
LY3214996 is not approved or marketed in any country.
2.3
Hydroxychloroquine Sulfate
Please refer to the FDA package insert for complete background information on 
hydroxychloroquine sulfate (HCQ). HCQ is an FDA approved autophagy inhibitor. It has been 
tested as monotherapy in patients with advanced pancreatic cancer at doses of 400 and 600 mg 
twice daily. Out of 20 enrolled patients with metastatic pancreatic cancer, 2 (10%) were without 
progressive disease at 2 months, and median PFS and OS were 46.5 and 69 days, respectively. 
Grade 3/4 treatment-related adverse events in this patient population included lymphopenia and 
elevated alanine aminotransferase. Tolerability and efficacy were similar at both doses levels.11  
Subsequent studies in patients with pancreatic cancer have evaluated gemcitabine or gemcitabine 
and nab-paclitaxel with HCQ at 600 mg PO BID.26-28
2.4
Correlative Studies Background
2.4.1
Organoid Culture Generation and Compound Sensitivity Testing
Approaches that predict the most effective chemotherapeutic regimen should improve patient 
care. To enable precision medicine in PDAC patients at Dana-Farber Cancer Institute (DFCI), a 
biopsy-based program for genomic and functional characterization of patient specimens was 
established. It was recently demonstrated that approximately 30% of PDAC patients have 
clinically relevant genomic lesions that could be used to guide clinical trial selection for 
molecularly targeted therapies.10,29,30
However, additional strategies for therapeutic selection are needed for the majority of patients 
who do not have clearly actionable genomic lesions. Treatment responsiveness likely represents 
a multi-factorial phenotype that is not well described by either genomic or transcriptomic 
assessment alone. We hypothesize that effective prediction of therapeutic responses in a 
clinically useful manner will require implementation of ex vivo functional profiling of PDAC 
tumor cell sensitivity.


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At DFCI, we have established a robust translational pipeline to perform genomic analysis on 
biopsy specimens and functional therapeutic profiling on patient-derived PDAC organoid models 
in real-time.30,31 In ongoing work, we have demonstrated successful whole exome or targeted 
panel genomic sequencing from small needle biopsies in 90% of patients with advanced 
PDAC.30 For patients with previously untreated advanced PDAC, we have demonstrated 
successful organoid culture and therapeutic sensitivity profiling on 65% of biopsy specimens. 
Organoids are treated over a 12-point dose range, with estimation of the half maximal inhibitory 
concentration (IC50) and area under the curve (AUC) from dose response curves (Figure 3A, 
3B). Treatments are performed with single agent compounds as well as with relevant 
combinations. Each individual patient’s tumor is evaluated in the context of all other patients for 
whom we have tested therapeutic sensitivity (Figure 3C).
Figure 3: PDAC organoid drug testing protocol and example report. A. Protocol for initiation, expansion, 
and organoid drug testing. B. Dose-response curves and C. Relative sensitivity to MAPK inhibitors. Each 
small dot represents a unique patient, and the large dot is the patient of interest. D. Example report 
summarizing results which suggest sensitivity to MAPK inhibitors.


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Across our initial PDAC organoid cohort of 56 patients, we have identified coherent patterns of 
therapeutic response with two primary clusters of sensitivity to one or more of over 20 drugs that 
we routinely profile. These two sensitivity clusters include a subset of patients with increased 
sensitivity to MAPK pathway inhibition with MEK or ERK inhibitors (Figure 4).  Here, we 
propose to apply our robust translational infrastructure to correlate observed clinical response to 
treatment with LY3214996 alone and in combination with HCQ to organoid sensitivity profiling 
performed on pre-treatment and time of progression biopsy samples. This study will lay the 
foundation for subsequent PDAC organoid platform trials of novel therapeutic agents.
Several recent studies have demonstrated that drug sensitivity testing in organoid models 
correlates with clinical responses to standard-of-care therapies. Vlachogiannis and colleagues 
recently reported that patient-derived organoids modeled the treatment response of metastatic 
gastrointestinal cancers. The team grew organoids from a total of 110 fresh biopsies obtained 
from 71 patients with metastatic colorectal cancer (mCRC), metastatic gastroesophageal cancer 
(mGOC), and cholangiocarcinoma. Organoids were grown from 70% of biopsies with a 
cellularity of 2+ and above, and their establishment rate correlated strongly with tumor 
cellularity of the parental biopsy (χ2 test, P < 0.0001). All the organoids were established as part 
of a co-clinical trial, allowing for direct comparison between clinical and pre-clinical response.32 
Histological comparison confirmed notable morphological similarities between the organoids 
and parental biopsies, routine immunohistochemistry markers (CDX-2 and CK7) verified that the 
parental tumor’s expression pattern was maintained in the organoids, and the results of next 
generation sequencing (NGS) demonstrated a 96% overlap in mutation spectrum between the 
organoids and parental biopsies. The team examined the predictive value of organoids in 21 
comparisons of clinical response observed in patients with ex vivo response data available 
(Figure 5). Overall, the organoids that were analyzed had a 100% sensitivity, 93% specificity, 
and 88% positive predictive value in forecasting treatment response to targeted agents or 
chemotherapy in patients (Fisher’s exact test, P < 0.0001).32
Figure 4. Patient-specific PDAC organoid therapeutic profiling reveals functional subclasses of patients. 
Heatmap demonstrates variance from mean AUC, with negative variance (red) indicating greater sensitivity.


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Figure 5: Organoid based ex vivo co-clinical trials in mGOC and 
mCRC. A) Cell viability upon paclitaxel treatment was compared in 
baseline and progression organoids from patient F-014 and organoids 
from patients that exhibited primary (F-015) or acquired (F-012) 
resistance to paclitaxel in the clinic. Organoids derived from the 
responsive metastasis showed a concentration that inhibits growth by 
50% (GI50) of ~1/4th that for organoids derived at progression; 
resistant organoid demonstrated identical paclitaxel concentration-
response profile to the 2 organoids established from refractory 
patients. Viability data shown are means ± SEM of indicated 
independent experiments. B) Concentration-dependent DNA damage 
observed in F-014 baseline organoid in response to paclitaxel but not 
in organoids from the same patient established at progression. C) 
Organoids established from baseline (C-003 and C-004) and 
progression (C-001 and C-002) biopsies from patients treated with 
cetuximab. Two organoids established from baseline showed no 
response to cetuximab, keeping with the primary resistance observed 
in the two patients in the clinic. C-002 possessed molecular markers 
indicating response to cetuximab, but organoid showed no response, 
and the patient did not respond clinically. Organoids treated with 
cetuximab in vitro; data shown are means ± SD from independent 
experiments performed in triplicate. Vlachogiannis et al., Science 359, 
920-926 (2018).  
A
B
C
Correlation of organoid results and clinical response was also reported by Tiriac et al. in PDAC. 
The team obtained 159 biopsy samples from primary tumors and metastases in 138 patients for 
generation of organoids. A total of 114 organoid cultures were successfully generated from 101 
patients (73% of patients). Whole genome sequencing (WGS) was performed on a subset of 
PDAC organoids and matched primary tumor (bulk), both were germline corrected with normal 
tissue (n = 13). An average of 97.43% of the mutations detected in the parental tumor specimen 
were also detected in the organoids. In 11 of the 13 cases, the organoid cultures completely 
recapitulated the core mutation profile found in the patient, and the primary tumor specimens 
from the two sample pairs that did not overlap had extremely low purity (<15%) and no 
alterations in PDAC core genes were detected in the parental biopsies.31
The team generated drug sensitivity signatures by correlating organoid transcriptional profiles 
with pharmacotyping results. For each chemotherapeutic agent, the Spearman correlation was 
computed between organoid gene expression and the AUC for each drug, defining distinct 
transcriptional signatures. The signatures were refined to include genes that increased in 
expression when AUC decreased (negative rho value), which is indicative of increased drug 
sensitivity. By clustering the organoid cultures using the individual drug response signatures, the 
organoids could be grouped into sensitive or non-sensitive classes for each individual 
chemotherapeutic signature. This signature was then used to evaluate patient response in a 


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subgroup of 55 patients who received gemcitabine monotherapy, and it was determined that 
patients with enrichment for the gemcitabine sensitivity signature had a significantly better 
progression free survival (772 v. 373 days, HR = 0.54, P = 0.04) and a trend toward improved 
overall survival.31
In the proposed study, patient-derived pancreatic tumor organoids will be grown from tumor 
tissue obtained from mandatory pre-treatment and optional time of progression biopsies 
following published protocols.33 After several rounds of organoid expansion, sensitivity will be 
evaluated to LY3214996, as well as additional RAS-MAPK pathway inhibitors. Additionally, 
organoid sensitivity to HCQ alone or in combination with LY3214996 will be evaluated. For 
each single agent, 12-point dose response curves measured in triplicate, as illustrated in Figure 
3. Moreover, combination therapy with LY3214996 and HCQ will be investigated through 
measuring dose response curves across a range of LY3214996 and HCQ in a 10-day assay with 
patient-derived organoid models.9 Determinations of synergy will be assessed by Bliss 
independence scores, as previously described.9 
AUCs will calculated from the dose response curves, and these AUC estimates are used for 
comparison with other patients’ samples as a measure of relative sensitivity to each agent 
(Figure 6). The percent sensitivity statistic is a measure of where the patient’s AUC 
measurement for each drug occurs within the population tested (n), with higher percentages 
indicating greater sensitivity to that particular agent. This trial will retrospectively assess the 
correlation of organoid drug sensitivity screening with ERK inhibition ± HCQ clinical treatment 
response.
2.4.2
Targeted DNA Sequencing
Next generation sequencing will be performed at the Center for Advanced Molecular Diagnostics 
Figure 6: Example Drug Sensitivity Profiling. AUC estimates are used for comparison with other patients’ samples as a measure of 
relative sensitivity to each agent.


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(CAMD) at Brigham and Women’s Hospital (BWH). CAMD has developed a cancer genomic 
assay to detect somatic mutations, copy number variations and structural variants in tumor DNA 
extracted from fresh, frozen or formalin-fixed paraffin-embedded samples. The OncoPanel assay 
surveys exonic DNA sequences of over 440 cancer genes and over 190 regions across 
approximately 60 genes for rearrangement detection. DNA is isolated from tissue containing at 
least 20% tumor nuclei and analyzed by massively parallel sequencing using a solution-phase 
Agilent SureSelect hybrid capture kit and an Illumina HiSeq 2500 sequencer. 
The pre-treatment biopsy will be submitted for OncoPanel testing. Somatic genetic alterations in 
oncogenes and tumor-suppressor genes contribute to the pathogenesis and evolution of human 
cancers. These alterations can provide prognostic and predictive information and stratify cancers 
for targeted therapeutic information.34
2.4.3
Whole Transcriptome Sequencing 
Each patient enrolled on the study will have whole transcriptome sequencing (WTS) by RNA-
sequencing (RNAseq) performed on their pre-treatment biopsy and organoid specimens to assess 
for baseline transcriptional signatures that may correlate with treatment response. RNA will be 
obtained from tumor cellular material using standard operating procedures, and RNAseq will be 
performed at the Broad Institute as previously described.30 Multiple transcriptional subtypes have 
been described for pancreatic cancer, and these subtypes may have prognostic and predictive 
therapeutic implications.10,31,35-38 Of notable importance to this ERK inhibitor based trial, these 
pancreatic cancer transcriptional subtypes have previously been shown to correlate with 
differences in dependency on KRAS and MAPK signaling.38 RNA-sequencing will enable a 
comprehensive analysis of RNA expression features in human tumor samples in both parental 
tumor biopsies as well as organoid cultures to investigate the fidelity of organoid cultures to 
represent subtype-specific transcriptional signatures.  Furthermore, using our patient-specific 
organoid models, we will also perform RNA-sequencing on post-treatment samples to measure 
transcriptional signatures 24 hours after treatment with LY3214996 ± HCQ to investigate the 
ability of dynamic expression changes to serve as a biomarker for therapeutic response. In these 
analyses, we will employ our own RAS-MAPK pathway transcriptional signatures,39 as well as 
other published signatures40 and those defined by colleagues at Eli Lilly (see above, section 
2.2.1.3). The identification of dynamic alterations in RAS-MAPK transcriptional signatures in 
post-treatment early passage organoid samples may enable early identification of patients who 
are likely to respond to treatment with LY3214996 ± HCQ. Thus, these data may fuel additional 
prospective utilization of organoid-based transcriptional profiling, in addition to conventional 
viability testing, as a potential biomarker-driven strategy for stratification onto future 
LY3214996-based clinical trials. 
2.4.4
Evaluation of Resistance Mechanisms
Participants will be offered an optional biopsy at the time of disease progression. Time of 
progression biopsies will undergo repeat molecular analyses and organoid derivation to 
investigate mechanisms of resistance using organoid-based sensitivity profiling as well as DNA 
and RNA sequencing as noted above.


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2.4.5
Confirmation of Target Engagement
Wolpin et al. identified LC3-II in peripheral lymphocytes as a candidate pharmacodynamic 
marker to monitor autophagy inhibition.11 Tumor tissue and serial blood samples will be 
collected from all study participants to evaluate LC3-II levels at the Wolpin Laboratory at Dana-
Farber Cancer Institute, additional or alternate markers may be explored as considered 
appropriate at the time of analysis. 
2.4.6
Immunohistochemistry
During the pre-screening and post-treatment biopsy, an additional core will be obtained 
following standard institutional procedures. FFPE samples from this core will be evaluated for 
target inhibition including ERK inhibition (pERK, pRSK, MYC) and autophagy inhibition (p62 
and LC3B) via immunohistochemistry (IHC). 
3.
PARTICIPANT SELECTION
3.1
Eligibility Criteria
3.1.1
Participants must have histologically or cytologically confirmed adenocarcinoma or 
poorly differentiated carcinoma of the pancreas.
3.1.2
Age ≥ 18 years. 
3.1.3
ECOG performance status ≤ 1 (see Appendix A)
3.1.4
Participants must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded for non-
nodal lesions and short axis for nodal lesions) as ≥ 20 mm with conventional techniques 
or as ≥ 10 mm with spiral CT scan, MRI, or calipers by clinical exam.  See Section 11 for 
the evaluation of measurable disease.
3.1.5
Participants must have received at least one but no more than two prior lines of systemic 
therapy for metastatic pancreatic cancer. Perioperative treatment (chemotherapy and/or 
radiation) is not considered a prior line of therapy. 
3.1.6
Participants must have adequate organ and marrow function as defined below:
Absolute Neutrophil Count
≥ 1,500/mcL
Platelet Count
≥ 100,000/mcL
Total Bilirubin
≤ 1.5 × institutional upper limit of normal 
(ULN)
AST (SGOT) / ALT(SGPT)
≤ 2.5 × institutional ULN, OR
AST (SGOT) / ALT (SGPT)
≤ 5 × institutional ULN if elevation is a result 
of metastases
Creatinine
≤ 1.5 × institutional ULN, OR


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Creatinine Clearance
≥ 60 mL/min/1.73 m2 for participants with 
creatinine levels above 1.5 × institutional 
normal (calculated via the Cockcroft-Gault 
equation)
3.1.7
The effects of LY3214996 or HCQ on the developing human fetus are unknown.  For this 
reason and because anti-cancer agents are known to be teratogenic, women of child-
bearing potential and men must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) prior to study entry and for the duration of study 
participation.  Should a woman become pregnant or suspect she is pregnant while she or 
her partner is participating in this study, she should inform her treating physician 
immediately.  Men treated or enrolled on this protocol must also agree to use adequate 
contraception prior to the study, for the duration of study participation, and 6 months 
after completion of LY3214996 or HCQ administration.
3.1.8
Ability to understand and the willingness to sign a written informed consent document.
3.1.9
Ability to swallow and retain oral medication.
3.1.10 Baseline QTcB of ≤ 470 msec on screening EKG.
3.1.11 Participants must be able and willing to undergo the pre-treatment biopsy procedure, and 
have a cancer site amenable to biopsy.
3.2
Exclusion Criteria
3.2.1
Participants with pancreatic histologies other than adenocarcinoma or poorly 
differentiated carcinoma, such as neuroendocrine or acinar cell carcinoma.
3.2.2
Participants who have received a prior MAPK pathway inhibitor, including but not 
limited to LY3214996.
3.2.3
Participants who have had systemic chemotherapy, other investigational therapy, or 
immunotherapy within 3 weeks prior to the first dose of study medication. 
3.2.4
Participants who have received oral tyrosine kinase inhibitors (TKIs) within 5 half-lives 
of the first dose of study medication.
3.2.5
Participants who have received radiation therapy within 2 weeks prior to the first dose of 
study medication.
3.2.6
Participants who have had major surgery within 4 weeks prior to the first dose of study 
medication.


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3.2.7
Participants with known brain metastases should be excluded from this clinical trial 
because of their poor prognosis and because they often develop progressive neurologic 
dysfunction that would confound the evaluation of neurologic and other adverse events.
3.2.8
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to LY3214996 or HCQ.
3.2.9
Individuals with a history of a different malignancy are ineligible with the following 
exceptions: individuals who have been treated and are disease-free for a minimum of 3 
years prior to study enrollment, or individuals who are deemed by the treating 
investigator to be at low risk for disease recurrence. Additionally, individuals with the 
following cancers are eligible if diagnosed and curatively treated within the past 3 years: 
basal or squamous cell carcinomas of the skin, and breast or cervical carcinomas in situ.
3.2.10 Uncontrolled intercurrent illness including, but not limited to: ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with study 
requirements.
3.2.11 Pregnant women are excluded from this study because LY3214996 and HCQ are agents 
with the potential for teratogenic or abortifacient effects.  Because there is an unknown 
but potential risk for adverse events in nursing infants secondary to treatment of the 
mother with LY3214996 or HCQ, breastfeeding should be discontinued if the mother is 
treated with LY3214996 or HCQ. A negative serum pregnancy test is required for women 
of childbearing potential prior to the first dose of study medication.
3.2.12 Participants who are known to be seropositive for human immunodeficiency virus (HIV) 
or hepatitis B or C. 
3.2.13 Participants with a history or findings of central or branch retinal artery or venous 
occlusion with significant vision loss, or other retinal diseases causing visual impairment 
or would likely cause visual impairment over the time period of the study, as assessed by 
an ophthalmologist.
3.2.14 Participants with a known personal or family history of long QT syndrome.
3.2.15 Participants with known glucose-6-phosphate dehydrogenase (G6PD) deficiency.
3.2.16 Participants who are known at the time of trial enrollment to require concomitant 
treatment with strong CYP3A4 inhibitors or inducers. Because the lists of these agents 
are constantly changing, it is important to regularly consult a frequently updated medical 
reference.
3.3
Inclusion of Women and Minorities


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Both men and women of all races and ethnic groups are eligible for this trial.
4.
REGISTRATION PROCEDURES 
4.1
General Guidelines for DF/HCC Institutions
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of any protocol-specific therapy or 
intervention. Any participant not registered to the protocol before protocol-specific therapy or 
intervention begins will be considered ineligible and registration will be denied.
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist.
Following registration, participants may begin protocol-specific therapy and/or intervention. 
Issues that would cause treatment delays should be discussed with the Overall Principal 
Investigator (PI). If the subject does not receive protocol therapy following registration, the 
subject must be taken off-study in the CTMS (OnCore) with an appropriate date and reason 
entered.  
4.1.1
For Enrollment to Arm 1 or Arm 2 (Randomized Trial Arms)
The eligibility checklist(s) and all pages of the consent form(s) will be faxed to the ODQ at 617-
632-2295. The ODQ will (a) review the eligibility checklist, (b) register the participant on the 
protocol, and (c) randomize the participant.
Randomization can only occur during ODQ business hours (8:30 am – 5 pm Eastern Time, 
Monday through Friday excluding holidays).
An email confirmation of the registration and/or randomization will be sent to the Overall PI, 
study coordinator(s) from the Lead Site, treating investigator and registering person immediately 
following the registration and/or randomization.
4.2
Registration Process for DF/HCC Institutions
Applicable DF/HCC policy (REGIST-101) must be followed.  
4.3
General Guidelines for Non-DF/HCC Investigative Sites
Eligible participants will be entered on study centrally at the Dana-Farber Cancer Institute by the 
Project Manager or Study Coordinator.  The required forms can be found in Section 4.4.
Following registration, participants should begin protocol therapy within 7 days. Issues that 
would cause treatment delays should be discussed with the Overall PI.  If the subject does not 


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receive protocol therapy following registration, the subject must be taken off-study in the CTMS 
(OnCore) with an appropriate date and reason entered.  
4.4
Registration Process for Non-DF/HCC Investigative Sites
To register a participant, the following documents should be completed by the participating site 
and faxed or e-mailed to the Study Coordinator/Project Manager:

Signed participant consent form

HIPAA authorization form

Eligibility checklist

Screening provider note including the medical/surgical history, ECOG performance 
status, vital signs, and physical exam findings

Pathology report confirming adenocarcinoma or poorly differentiated carcinoma of 
the pancreas

Laboratory reports including:
o
CBC with differential
o
Chemistry panel
o
Pregnancy test (if applicable)

Screening imaging report (CT and/or MRI scans)

Screening ophthalmic exam report

Screening EKG
To complete the registration process, the Project Manager or Study Coordinator will follow 
DF/HCC policy (REGIST-101) and register the participant on the protocol.  The registering party 
will fax or email the participant study number and assigned arm or dose treatment level to the 
participating site.
NOTE: Registration can only be conducted during the regular business hours of 8:30 AM 
to 4:30 PM Eastern Standard Time Monday through Friday, holidays excluded. Same day 
treatment registrations will only be accepted with prior notice and discussion with the DF/HCC 
Project Manager or Study Coordinator.
5.
TREATMENT PLAN
5.1
Treatment Regimen
A treatment cycle will be defined as 28 consecutive days. Treatment will be administered on an 
outpatient basis.  Reported adverse events and potential risks are described in Section 7.  
Appropriate dose modifications are described in Section 6.  
5.1.1
Safety Lead-in Cohort
To confirm the safety of the LY3214996 and HCQ combination, a lead-in cohort will be 
conducted. The first six participants will enroll to Dose Level 0, as depicted in the table below. 
Enrollment to the dose level can occur in parallel with no observation period or delay between 


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the start of therapy for each enrolled participant. 
Table 2: Safety Lead-in Cohort Dose Plan
Dose Level
LY3214996 Dose 
(mg PO QD)
Hydroxychloroquine (HCQ) Dose 
(mg PO BID)
-1 (Fallback Dose)
400*
200*
0
400
400
*: At the discretion of the overall principal investigator, the fallback dose of LY3214996 may 
be reduced to 200 mg PO QD instead of or in addition to a reduction of the HCQ dose level. 
The principal investigator determined dose level -1 to be LY3214996 200 mg PO QD and 
HCQ 400 mg PO BID
Participants will be observed during the first cycle of therapy for toxicity consistent with a dose-
limiting toxicity (DLT) definition, defined in Section 5.1.2. If ≤ 1 DLT is observed among the 
six participants, the randomized two arm portion of the trial will begin with enrollment to Arms 
1 and 2 (see Section 5.1.3). 
If Dose Level 0 is found intolerable (with ≥ 2 participants experiencing a DLT), Dose Level -1 
will be evaluated. If Dose Level -1 is also not tolerable, the cohort will be closed with no further 
combination treatment enrollment and the trial will proceed as a single arm evaluation of 
LY3214996 as monotherapy.
Table 3: Dose Escalation Decision Criteria for Safety Lead-in Cohort
Number of 
Participants with 
DLT at a Given Dose 
Level
Escalation Decision Rule
≤ 1 
Proceed with enrollment to the randomized two arm portion of the 
trial.
≥ 2
Enrollment to the dose level will be stopped.  This dose level will be 
declared the MAD (highest dose administered).  Proceed with 
enrollment of six participants to the fallback dose level if at Dose 
Level 0. If at Dose Level -1, enrollment to combination treatment 
will be stopped.
Participants enrolled to the safety lead-in portion of the trial will be required to have received at 
least 75 percent of their assigned doses of LY3214996 and HCQ during the first cycle to be 
considered evaluable for DLT purposes. Participants will be replaced if they do not meet these 
parameters during cycle 1 for reasons other than toxicity (e.g. withdrawal of consent for 
participation, or rapid disease progression and subsequent removal from the trial).
 
5.1.2
Dose-Limiting Toxicities (Applicable for Safety Lead-in Cohort Only)
DLTs will be defined as toxicities experienced by participants enrolled in the safety lead-in that 
are considered at least possibly related to the treatment regimen, occur during the first cycle of 
treatment, and fit at least one of the following criteria:


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
Grade 4 absolute neutrophil count (ANC) decrease of greater than 7 days duration, or 
ANC decrease that necessitates the use of growth factor support

Febrile neutropenia 

Grade 3 thrombocytopenia with clinically significant bleeding, or that requires 
transfusion support

Grade 4 thrombocytopenia

Grade 4 anemia

Intolerable Grade 2 nausea or vomiting that is unresponsive to maximal medical 
management (see Section 5.4 for anti-emetic regimen information). 

Any ≥ Grade 3 non-hematologic toxicity, with the following exceptions:
o
Grade 3 gastrointestinal toxicities (nausea, vomiting, diarrhea, or constipation) 
that were not optimally managed. Grade 3 gastrointestinal toxicities will only be 
considered dose-limiting if refractory to treatment, defined as a failure to resolve 
to ≤ Grade 2 or baseline within 48 hours of instituting appropriate supportive care. 
o
Grade 3 rash that resolves to ≤ Grade 2 within 7 days and remains tolerable may 
not be considered a DLT if agreed upon with the overall principal investigator.
o
Grade 3 asymptomatic electrolyte abnormalities that resolve to ≤ Grade 2 or 
baseline within 48 hours of repletion/clinical intervention. 

Any death not clearly due to underlying disease or extraneous causes.

Any toxicity that results in the participant receiving < 75% of the assigned doses of 
LY3214996 or HCQ during cycle 1. 
Management and dose modifications associated with the above adverse events are outlined in 
Section 6.  
5.1.3
Arm 1 and Arm 2
If combination dosing with LY3214996 and HCQ is found tolerable (≤ 1 DLT among 6 
participants enrolled to the dose level), the randomized two arm portion of the trial will 
commence. Participants will be randomized 1:1 to enroll to either Arm 1 or Arm 2. 
5.1.3.1 Arm 1 Treatment: LY3214996 + HCQ
If Dose Level 0 was found tolerable, enrollment to Arm 1 will initiate with LY3214996 at a dose 
of 400 mg PO daily and HCQ at 600 mg PO BID. Following accrual of six evaluable participants 
to Arm 1, enrollment to Arm 1 will be paused for an assessment of safety of the increased dose 
of HCQ.
The safety assessment will occur after all six participants on Arm 1 have completed at least one 
cycle of dosing with the combination. Participants must have received at least 75% of their 
assigned doses of LY3214996 and HCQ to be considered evaluable for this safety analysis, 
unless dosing was held or reduced due to toxicity. If one or more of the first six participants 
enrolled does not meet this parameter for a reason other than toxicity (e.g. rapid disease 
progression and subsequent removal), Arm 1 will continue to accrue as many participants as 
needed to have six evaluable participants for safety assessment. Participants will be replaced in 


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the randomized portion of the trial if they withdraw consent for participation before initiating 
protocol therapy or rapid disease progression limits their ability to receive any therapy per 
protocol. All participants accrued to the arm who start protocol treatment will be considered 
evaluable for efficacy endpoints, regardless of whether they meet criteria to be considered 
evaluable for assessment of safety of the increased dose of HCQ.
The overall principal investigator will review applicable adverse event data and determine if 
enrollment should continue with HCQ at the 600 mg dose level. At the discretion of the overall 
principal investigator, the dose level may be reduced for all participants remaining to be accrued 
to the arm. 
If Dose Level 0 was not tolerable, but Dose Level -1 was tolerable, enrollment to Arm 1 will be 
initiated with LY3214996 200 mg PO QD and HCQ600 mg PO BID. An interim safety 
assessment will still occur in this scenario. If Dose Level -1 was also not tolerable, Arm 1 will 
not move forward. The trial will proceed with enrollment to Arm 2 only, evaluating LY3214996 
as monotherapy.
At the conclusion of the safety lead-in cohort, on March 26, 2021 findings demonstrated 
that Dose Level 0 was not tolerable, but Dose Level -1 was tolerable. Therefore, patients 
enrolling to the randomized two arm portion of the trial will receive:
Arm 1 LY3214996 200 mg QD and 600 mg HCQ BID and 
Arm 2 LY3214996 400 mg QD
5.1.3.2 Arm 2 Treatment: LY3214996 
Participants enrolled to Arm 2 will receive treatment with LY3214996 at the recommended 
phase II dose of 400 mg PO once daily. 
5.1.4
Treatment Cross-Over
Participants who are enrolled to Arm 2 who experience radiologic disease progression on 
monotherapy will have the option to cross-over to receive treatment with the combination. Cross-
over will occur at the treating investigator’s discretion following consultation and approval from 
the overall principal investigator. Participants who cross-over must meet all of the following 
criteria:
1. The participant does not meet any other investigational product discontinuation criteria 
(see Section 5.5).
2. ECOG performance status is ≤ 1.
3. Absence of rapid disease progression or threat to vital organs/critical anatomical sites 
(e.g. spinal cord compression) requiring urgent alternative medical intervention.
4. The participant must have a tumor imaging assessment and EKG prior to initiating cross-
over treatment (within 28 days of the start of combination dosing). All subsequent 
assessments will continue with the same frequency defined in the Study Calendar and 
Section 11.


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5. Participants must re-consent prior to treatment cross-over.
The treating investigator should ensure that patients do not have any significant, unacceptable, or 
irreversible toxicities indicating that continuing treatment will not benefit the patient. 
Participants should be made aware of the potential risks of initiating combination therapy by the 
treating investigator and must provide re-consent prior to the beginning of cross-over therapy.
Participants who cross-over will receive LY3214996 and HCQ at the dose being administered to 
Arm 1 participants.  Under no circumstances may a participant crossing-over receive treatment 
with HCQ at a dose level higher than what is being evaluated on Arm 1. Participants enrolled to 
Arm 2 who cross-over will not be considered one of the six required participants for the safety 
analysis of Arm 1 (see Section 5.1.3.1). In the event combination dosing was not found tolerable 
during the safety lead-in, no treatment with HCQ will be permitted.
5.2
Pre-Treatment Criteria
5.2.1
Cycle 1, Day 1
If screening laboratory assessments were completed ≤ 7 days prior to cycle 1 day 1, laboratory 
tests do not need to be repeated on cycle 1 day 1 and the screening laboratory values can be used 
as the cycle 1 day 1 values. If cycle 1 day 1 laboratories are performed, the values do not need to 
re-meet eligibility criteria, participants will be allowed to initiate treatment at the treating 
investigator’s discretion.
5.2.2
Subsequent Cycles 
Management guidelines for toxicities associated with study treatment are located in Section 6.
5.3
Agent Administration
Table 4: Treatment Regimen Description
Study 
Arm
Agent
Precautions
Dose
Route
Schedule
Cycle 
Length
Safety 
Lead-in,  
Arm 1 & 
Cross-
Over
LY3214996
Participants should fast for 
1 hour prior to each dose, 
and continue fasting for 1 
hour following each dose
Refer to Section 5.4 for 
anti-emetic regimen 
information
Variable
Oral
Once 
Daily
28 
Days 
(4 
weeks)


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Table 4: Treatment Regimen Description
Study 
Arm
Agent
Precautions
Dose
Route
Schedule
Cycle 
Length
Hydroxychloroquine 
(HCQ)
Participants should take 
HCQ with a meal (or 
within 30 minutes of 
eating) or a glass of milk
Oral
Twice 
Daily
Arm 2
LY3214996
Participants should fast for 
1 hour prior to each dose, 
and continue fasting for 1 
hour following each dose
Refer to Section 5.4 for 
anti-emetic regimen 
information
400 mg
Oral
Once 
Daily
5.3.1
LY3214996 Administration
Instructions for administration of LY3214996: 

LY3214996 will be administered by mouth once daily continuously throughout each 
treatment cycle. 

Participants should be advised to take their dose at approximately the same time each 
day, a ± 4 hour dosing window is allowed. Doses that would occur outside of this time 
frame should be considered missed and should not be administered. 

Participants should be advised to fast for at least 1 hour prior to each dose, and to 
continue fasting for at least 1 hour after each dose. Water is permitted during the fasting 
period. 

If a participant vomits following a dose, the dose should not be re-taken. The participant 
should be advised to continue with their next regularly scheduled dose as clinically 
appropriate. 

LY3214996 should be swallowed whole, capsules should not be opened, chewed, or 
crushed.   

Refer to Section 5.4 for anti-emetic regimen information.
5.3.2
Hydroxychloroquine (HCQ) Administration
Only participants enrolled to the Safety Lead-in Cohort, Arm 1, or who cross-over on Arm 2 
will receive treatment with HCQ. Instructions for administration of HCQ: 

HCQ will be administered by mouth twice daily continuously throughout each treatment 
cycle. 

Participants should be advised to take their doses approximately 12 hours apart, a ± 4 
hour dosing window is allowed. Doses that would occur outside of this time frame should 
be considered missed and should not be administered. 

Participants should be advised to take each dose with a meal (or within 30 minutes of 


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eating) or with a glass of milk. 

If a participant vomits following a dose, the dose should not be re-taken. The participant 
should be advised to continue with their next regularly scheduled dose as clinically 
appropriate. 

HCQ should be swallowed whole, tablets should not be dissolved, chewed, or crushed.  

Order of administration of HCQ and LY3214996 does not matter but note the different 
administration requirements regarding food. It may be easier for participants to take their 
dose of LY3214996 in the morning prior to taking HCQ, and to take HCQ with breakfast 
after the 1 hour fasting period for LY3214996 is completed. 
5.4
General Concomitant Medication and Supportive Care Guidelines
No investigational or commercial agents or therapies other than LY3214996 or HCQ may be 
administered with the intent to treat the participant's malignancy, with the exception of palliative 
radiation treatment with the overall principal investigator’s agreement. Study treatment should be 
held for the duration of the radiation therapy and may be resumed when adverse events 
associated with the radiation treatment have resolved to ≤ Grade 1 or baseline. Bisphosphonate 
use is permitted.
Investigators should use appropriate supportive medications to address toxicities that arise
during the study, including but not limited to anti-emetics (see Section 5.4.8 below), anti-
diarrheals, and blood product transfusion.
5.4.1
Granulocyte Colony-Stimulating Factor
Growth factor support may be initiated per ASCO or local institutional guidelines at the treating 
investigator’s discretion during or following the first occurrence of neutropenia or neutropenic 
fever.
5.4.2
Participants Receiving HCQ: Hypoglycemia
HCQ has been shown to cause hypoglycemia including loss of consciousness that could be life 
threatening in patients treated with or without antidiabetic medications. Patients treated with 
HCQ should be warned about the risk of hypoglycemia and the associated clinical signs and 
symptoms. Patients presenting with clinical symptoms suggestive of hypoglycemia (e.g. 
shakiness, palor, anxiety, sweating, an irregular heart rhythm, confusion, etc.) during treatment 
with HCQ should have their blood glucose checked and treatment reviewed as necessary. Please 
also refer to Section 6.3.
5.4.3
Participants Receiving HCQ: Medications Known or Suspected to Cause Prolonged QTc Intervals or 
Torsades de Pointes 
HCQ may prolong the QT interval. Ventricular arrhythmias and Torsades de Pointes have been 
reported in patients taking HCQ. Patients should avoid taking concomitant medications that are 
known or suspected to cause prolonged QTc or Torsades de Pointes (see Appendix B). If 
possible, alternative agents should be considered. 


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5.4.4
Participants Receiving HCQ: Other Concomitant Medication Guidelines 
Please also refer to the FDA package insert for complete information:

Digoxin: Concomitant HCQ and digoxin therapy may result in increased serum digoxin 
levels. Serum digoxin levels should be closely monitored in patients receiving combined 
therapy.

Insulin or antidiabetic drugs: As HCQ may enhance the effects of a hypoglycemic 
treatment, a decrease in doses of insulin or antidiabetic drugs may be required.

Mefloquine and other drugs known to lower the convulsive threshold: HCQ can lower the 
convulsive threshold. Co-administration of HCQ with other antimalarials known to lower 
the convulsion threshold (e.g., mefloquine) may increase the risk of convulsions.

Antiepileptics: The activity of antiepileptic drugs might be impaired if co-administered 
with HCQ.

Cyclosporin: An increased plasma cyclosporin level was reported when cyclosporin and 
HCQ were co-administered.
5.4.5
LY3214996: Drug-Drug Interactions (DDIs)
Investigators should avoid the use of concomitant therapy with sensitive substrates of CYP3A4 
(e.g. simvastatin, lovastatin, buspirone, etc.) and drugs cleared by CYP3A4 that have a narrow 
therapeutic range when clinically feasible. LY3214996 is a time-dependent inhibitor of CYP3A4 
metabolism. Assuming this is due to mechanism-based inhibition, LY3214996 appears to be a 
less efficient inhibitor than erythromycin, a known moderate in vivo time-dependent inhibitor of 
CYP3A. The clinical relevance of this apparent mechanism-based inhibition is currently 
unknown.
Caution should be used when using concomitant therapy with CYP2D6 and CYP3A5
substrates as the metabolism of such drugs may be induced. In vitro, LY3214996 was an inducer 
of CYP2D6 and CYP3A5 messenger ribonucleic acid. The clinical relevance of the in vitro 
induction of CYP2D6 and CYP3A5 by LY3214996 is currently unknown. Use caution with 
drugs metabolized by CYP2C9 because LY3214996 is a reversible CYP2C9 inhibitor.
Participants should avoid any concomitant medications that are moderate or strong inhibitors 
(e.g.  grapefruit juice, ketoconazole, etc.) or inducers of CYP3A4 when clinically feasible. In 
vitro data indicates that the major cytochrome P450 involved in the clearance of LY3214996 is 
CYP3A (~88%).
5.4.6
Prohibited Foods
The consumption of grapefruit or grapefruit juice is prohibited while receiving LY3214996 
therapy.
5.4.7
Rash Management Guidelines
Both LY3214996 and HCQ have been associated with rash or dermatologic reactions. Please 


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refer to Appendix C for rash management guidelines.
5.4.8
LY3214996 Anti-Emetics
Approximately 90% of patients have experienced nausea and/or vomiting due to LY3214996 
when dosed at 600 mg daily (which is above the maximum dose evaluated in this study). In a 
limited number of cases this has led to more severe adverse events (i.e., dehydration, acute 
kidney injury). Anti-emetic treatment for participants receiving LY3214996 will be at the 
discretion of the treating investigator.
Anti-emetic medication will be prescribed and administered according to local standards. 
Recommended anti-emetic treatment follows the National Comprehensive Cancer Network 2018 
(v. 3) guidelines. Anti-emetic treatment consists of a 5-HT3 receptor antagonist and should be 
given 30 – 60 minutes prior to the LY3214996 dose as needed:

Ondansetron 16 mg (total dose) by mouth once. Repeat 8 mg every 8 hours as needed for 
nausea. Do not exceed more than 24 mg daily.  
In the event use of ondansetron is contraindicated in a participant, an alternative agent may be 
used. Breakthrough or additional treatment may also be given by adding an agent from a 
different drug class to the current regimen (e.g., olanzapine 5 – 10 mg by mouth daily, 
dexamethasone 12 mg by mouth or IV daily).
5.4.9
LY3214996 Dehydration
Patients must be instructed to maintain adequate oral hydration at home, in order to prevent 
dehydration secondary to vomiting or diarrhea. During clinic visits, patients should be evaluated 
for signs and symptoms of dehydration and, if necessary, intravenous hydration should be 
implemented at the discretion of the treating investigator.
5.5
Criteria for Taking a Participant Off Protocol Therapy
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue 
until one of the following criteria applies:

Disease progression (except in the case of participants on Arm 2 LY3214996 
monotherapy who are going to cross-over to combination treatment)

Intercurrent illness that prevents further administration of treatment

Unacceptable adverse event(s)

Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements

Participant decides to withdraw from the protocol therapy


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
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant.
When a participant is removed from protocol therapy and/or is off of the study, the participant’s 
status must be updated in OnCore in accordance with REGIST-OP-1.
5.6
Duration of Follow Up
Participants will be followed for 30 days after removal from protocol therapy or until death for 
serious adverse events, whichever occurs first.  Participants removed from protocol therapy for 
unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse 
event. After completion of the 30 day follow up period, participants will continue to be followed 
for 6 months after removal from protocol therapy or until death for survival status only.
5.7
Criteria for Taking a Participant Off Study
Participants will be removed from study when any of the following criteria apply:

Lost to follow-up

Completion of the survival follow up period

Withdrawal of consent for data submission

Death
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). In addition, the study team will ensure the 
participant’s status is updated in OnCore in accordance with REGIST-OP-1.
6.
DOSING DELAYS/DOSE MODIFICATIONS
Dose delays and modifications will be made as indicated in the following table(s). The 
descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
6.1
Dosing Delays
The study agents may be held for a maximum of 28 days to allow for recovery of toxicity. 
Participants requiring a longer delay should be removed from protocol therapy. Participants who 
are deriving clinical benefit who require a longer hold may be allowed to continue treatment 


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following discussion and agreement with the overall principal investigator.
If attribution of the toxicity is known, study medications may be held independently of each 
other. For example, a participant may continue dosing with LY3214996 while holding HCQ at 
the treating investigator’s discretion. If attribution of the toxicity is unknown or the combination 
of study agents may be contributing to the toxicity, both study agents must be held.
In the event of a dose hold due to toxicity, the counting of cycle days and protocol assessment 
schedule will continue without interruption. For example, a participant who holds dosing of 
LY3214996 on Cycle 4 Day 15 to Cycle 4 Day 18 for toxicity will resume dosing on Cycle 4 
Day 19 and proceed with their next scheduled clinic visit as previously planned (Cycle 5 Day 1). 
Interim visits may be conducted as clinically necessary to manage toxicity; however, the cycle 
will not restart and doses will not be “made up” in the event of dosing delays. 
6.2
Dose Modifications
Dose reductions may be made in accordance with the tables below. Once a participant’s dose of 
HCQ or LY3214996 has been reduced, it may be re-escalated to the previous dose level if the 
toxicity has resolved to baseline or ≤ Grade 1 with agreement from the overall principal 
investigator. If the toxicity recurs necessitating another dose reduction, the dose may not be re-
escalated. 
Table 5: HCQ Dose Reductions
Original HCQ Dose (PO BID)
HCQ Dose Reduction (PO BID)
1st Reduction: 400 mg
2nd Reduction: 200 mg
600 mg
3rd Reduction: Discontinue
1st Reduction: 200 mg
400 mg
2nd Reduction: Discontinue
200 mg
Discontinue
Table 6: LY3214996 Dose Reductions
Original LY3214996 Dose (PO Daily)
LY3214996 Dose Reduction (PO Daily)
1st Reduction: 200 mg
2nd Reduction: 100 mg
400 mg
3rd Reduction: Discontinue
1st Reduction: 100 mg
200 mg
2nd Reduction: Discontinue
If attribution of the toxicity is known, dose reductions may occur independently of each other. 
For example, the dose of HCQ may be reduced while maintaining the dose of LY3214996. If 
toxicity attribution is unknown or the combination of study agents may contribute to the toxicity, 


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both agents must be dose reduced.
If attribution of the toxicity is known, discontinuation of study medications may also occur 
independently of each other with agreement from the overall principal investigator. For example, 
participants who cannot tolerate HCQ may be allowed to continue to receive LY3214996 if the 
overall principal investigator agrees. If toxicity attribution is unknown or the combination of 
study agents may contribute to the toxicity, the participant should be removed from protocol 
therapy.
6.3
Toxicity Management Guidelines
Management of toxicity considered at least possibly related to HCQ and/or LY3214996 is 
detailed in the tables below.
Table 7: Hematologic Toxicity Management
Event Terms
CTCAE 
Grade
Management Guidelines
Neutrophil count 
decreased
≥ Grade 3
Hold study agent(s) until recovery to ≤ Grade 2, resume with one 
dose level reduction.
Febrile neutropenia
≥ Grade 3
Hold study agent(s) until resolution, resume with one dose level 
reduction.
Platelet count 
decreased
≥ Grade 3
Hold study agent(s) until recovery to ≤ Grade 2, resume with one 
dose level reduction.
Table 8: Non-Hematologic Toxicity Management
Event Terms
CTCAE 
Grade
Management Guidelines
Ocular Toxicity
≤ Grade 2
Ocular toxicity is associated with HCQ, and blurred vision has been 
observed in patients receiving LY3214996.
Participants experiencing new or worsening visual disturbances or 
suspected ocular toxicity of any grade while receiving study treatment 
should be referred for ophthalmic examination. 
In the case of mild or moderate ocular toxicity (i.e. CTCAE Grade 1 or 
Grade 2), the treating investigator may hold and/or dose reduce the study 
agent(s) at their discretion.
Ocular Toxicity 
≥ Grade 3
Ocular toxicity is associated with HCQ, and blurred vision has been 
observed in patients receiving LY3214996.
Participants experiencing new or worsening visual disturbances or 
suspected ocular toxicity of any grade while receiving study treatment 
should be referred for ophthalmic examination. 
Hold study agent dosing until resolution to ≤ Grade 2 or baseline. Resume 
with one dose level reduction. 


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Table 8: Non-Hematologic Toxicity Management
Event Terms
CTCAE 
Grade
Management Guidelines
Hypoglycemia
≥ Grade 3
-OR-
Symptomatic 
(ANY 
GRADE)
HCQ has been shown to cause severe hypoglycemia that has included loss 
of consciousness and can be life-threatening.
 
Implement appropriate supportive care. Hold dosing until resolution to ≤ 
Grade 2 or baseline, AND participant is asymptomatic. Resume with one 
dose level reduction. 
Skin Rash
≤ Grade 21
Dermatologic reactions have been associated with both LY3214996 and 
HCQ. 
No change in dosing. Implement supportive care as appropriate (e.g. 
topical steroids, antibiotics).3 
Skin Rash
Grade 3
Dermatologic reactions have been associated with both LY3214996 and 
HCQ. Hold dosing until resolution to ≤ Grade 2 or baseline. Implement 
appropriate supportive care (e.g. topical steroids, antibiotics).3 
With first occurrence, if there is resolution to ≤ Grade 2 or baseline in ≤ 
7 days, study agent(s) may be resumed at the same dose level.2 If toxicity 
does not improve in ≤ 7 days, upon resolution reduce dose by one dose 
level. 
If toxicity recurs despite appropriate supportive care (e.g. topical steroids, 
antibiotics), upon resolution to ≤ Grade 2 or baseline reduce dose of by 
one dose level.
Skin Rash
Grade 4
Dermatologic reactions have been associated with both LY3214996 and 
HCQ. Hold dosing and implement appropriate supportive care.3 
Permanently discontinue protocol therapy.
Any other non-
hematologic 
toxicity
≤ Grade 21
No change in dosing.
Implement supportive care as appropriate.
Any other non-
hematologic 
toxicity
≥ Grade 3
Hold dosing until resolution to ≤ Grade 2 or baseline. Upon resolution, 
resume with one dose level reduction. Exceptions:

Grade 3 nausea, vomiting, diarrhea, or constipation that was not 
medically managed: appropriate medical management should be 
initiated, and study medication should be held until resolution to ≤ 
Grade 2 or baseline. Upon resolution, study medication may be 
resumed at the same dose level or with one dose level reduction at 
the treating investigator’s discretion.

Asymptomatic laboratory abnormalities that resolve to ≤ Grade 2 
or baseline within 48 hours of repletion or treatment: study 
medication should be held until resolution to Grade 2 and may be 
resumed at the same dose level or with one dose level reduction at 
the treating investigator’s discretion. Treatment and resumption of 
study medication dosing may occur on the same day.

Asymptomatic laboratory abnormalities considered non-clinically 
significant: participants may continue dosing at the treating 
investigator’s discretion.
1.
At the treating investigator’s discretion, participants experiencing intolerable grade 2 toxicities may hold 
and/or dose reduce LY3214996 and/or HCQ.
2.
At the treating investigator’s discretion, dose of LY3214996 and/or HCQ may be reduced by one dose 
level.
3.
Please refer to Appendix C for rash management guidelines. 


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6.4
Overdose
There is currently no specific treatment in the event of overdose with LY3214996 and possible 
symptoms of overdose are not established. In the event of an overdose, the participant should be 
monitored and adverse reactions associated with the overdose should be treated symptomatically. 
In the event of overdosage of HCQ, management should be in accordance with institutional 
standards of practice and the FDA package insert. Please refer to Section 7 for adverse event 
reporting requirements.
7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2 and 7.3) will determine whether the event requires expedited reporting 
in addition to routine reporting.
7.1
Expected Toxicities
7.1.1
Expected Toxicities for HCQ
The table below summarizes treatment-emergent adverse events considered expected for HCQ 
serious adverse reaction reporting. Please refer to the FDA package insert for detailed 
information.
Table 9: HCQ Toxicities Considered Expected
System Organ Class
Event Preferred Term
Leukopenia (including white blood cell decreased)
Thrombocytopenia (including platelet count decreased)
Anemia (including hemoglobin and hematocrit decreased)
Bone marrow failure
Aplastic anemia
Blood and lymphatic 
system disorders
Agranulocytosis
Cardiac disorders
Cardiomyopathy
Vertigo
Tinnitus
Nystagmus
Nerve deafness
Ear and labyrinth 
disorders
Deafness (including hearing impaired)
Irreversible retinopathy with retinal pigmentation changes 
(includes retinopathy)
Eye disorders
Visual field defects, paracentral scotomas


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Table 9: HCQ Toxicities Considered Expected
System Organ Class
Event Preferred Term
Visual disturbances (includes vision decreased)
Maculopathies, macular degeneration
Decreased dark adaptation
Color vision abnormalities
Corneal changes, corneal edema, corneal opacities, corneal 
deposition of drug with or without symptoms (halo around 
lights, photophobia, blurred vision)
Nausea
Vomiting
Diarrhea
Gastrointestinal disorders
Abdominal pain
General disorders and 
administration site 
conditions
Fatigue
Hepatobiliary disorders
Hepatic failure 
Electrocardiogram QT corrected interval prolonged
Liver function tests abnormal (includes aspartate 
aminotransferase increased, alanine aminotransferase 
increased, blood bilirubin increased)
Investigations
Weight decreased (includes weight loss)
Angioedema
Bronchospasm
Immune system disorders
Urticaria
Decreased appetite (includes anorexia)
Hypoglycemia
Metabolism and nutrition 
disorders
Porphyria
Abnormal nerve conduction
Depression of tendon reflexes
Sensorimotor disorder
Musculoskeletal and 
connective tissue disorders
Skeletal muscle myopathy or neuromyopathy leading to 
progressive weakness and atrophy of proximal muscle groups
Ataxia
Dizziness
Extrapyramidal disorders such as dystonia, dyskinesia, and 
tremor
Headache
Nervous system disorders
Seizure
Affect/emotional lability
Irritability
Nervousness (includes anxiety)
Nightmares
Psychosis
Psychiatric disorders
Suicidal behavior


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Table 9: HCQ Toxicities Considered Expected
System Organ Class
Event Preferred Term
Rash
Pruritis
Pigmentation disorders in skin and mucous membranes
Hair color changes
Alopecia
Dermatitis bullous eruptions including erythema multiforme, 
Stevens-Johnson syndrome, and toxic epidermal necrolysis
Drug reaction with eosinophilia and systemic symptoms 
(DRESS syndrome)
Photosensitivity
Dermatitis exfoliative
Acute generalized exanthematous pustulosis (AGEP)
Skin and subcutaneous 
tissue disorders
Psoriasis
7.1.2
Expected Toxicities for LY3214996
Please refer to the most recent LY3214996 IB for detailed information. Recently identified 
expected serious adverse drug reactions (SADRs) for LY3214996 include the following:

Nausea

Vomiting

Diarrhea

Renal failure
One patient experienced itching of hands and feet, swelling of lips and tongue, and itching in ear, 
followed by a hive-like rash on the upper legs and lower abdomen two days later. The symptoms 
were believed to be secondary to an allergic reaction. As this has not been described in any other 
patient who has received this drug, it remains a possible though not yet expected toxicity.
Any fatal or life-threatening events (i.e. events posing an immediate risk of dying) will always be 
considered unexpected for the purposes of suspected unexpected serious adverse reaction 
(SUSAR) reporting.
7.2
Adverse Event Characteristics

CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.

For expedited reporting purposes only:  
-
AEs for the agent(s) that are listed above should be reported only if the adverse event 


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varies in nature, intensity or frequency from the expected toxicity information which 
is provided.

Attribution of the AE:
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.
-
Possible – The AE may be related to the study treatment.
-
Unlikely – The AE is doubtfully related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.
7.3
Serious Adverse Events
A serious adverse event (SAE) is any adverse event that occurs after the initial dose of study 
treatment, during treatment, or within 30 days of the last dose of treatment that results in one of 
the following outcomes:

Death

Hospitalization for greater than 24 hours

Prolonging an existing inpatient hospitalization

A life-threatening experience (that is, immediate risk of dying)

Persistent or significant disability/incapacity

Congenital anomaly/birth defect

Considered significant by the investigator for any other reason
Previously planned (prior to signing the informed consent form) surgeries, and non-disease 
related elective surgeries planned during the course of the study, should not be reported as SAEs 
unless the underlying medical condition has worsened or appeared during the course of the 
study. Events that occur prior to the first administration of study medication should not be 
reported as SAEs.
Preplanned hospitalizations or procedures for pre-existing conditions that are already recorded in 
the patient’s medical history at the time of study enrollment should not be considered SAEs. 
Hospitalization or prolongation of hospitalization without a precipitating clinical AE (e.g., for 
the administration of study therapy or other protocol-required procedure) should not be 
considered SAEs.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.
Death due to disease progression should not be reported as an SAE unless the investigator deems 
it to be related to the use of study drug.
Study site personnel must alert Eli Lilly of any SAE as soon as possible and no later than 1 


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business day of the investigator receiving notification of the SAE experienced by a patient 
participating in the study. The SAE reports should be on a standard reporting form (e.g. CIOMS, 
local institutional SAE form, MedWatch 3500a, or similar) and are to be sent to Eli Lilly via 
email: MAILINDATA_GSMTINDY@LILLY.COM.
7.4
Adverse Event Reporting 
7.4.1
In the event of an unanticipated problem or life-threatening complications treating 
investigators must immediately notify the Overall PI.
7.4.2
Investigators must report to the Overall PI any adverse event (AE) that occurs after the 
initial dose of study treatment, during treatment, or within 30 days of the last dose of 
treatment on the local institutional SAE form. 
7.4.3
For Multi-Center Trials where a DF/HCC investigator is serving as the Sponsor, each 
participating institution must abide by the reporting requirements set by the DF/HCC. 
This applies to any medical event equivalent to an unexpected grade 2 or 3 with a 
possible, probable or definite attribution, unexpected grade 4 toxicities, and grade 5 
(death) regardless of study phase or attribution.
7.4.4
DF/HCC Adverse Event Reporting Guidelines
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for 
Human Research Studies (OHRS) per the DFCI IRB reporting policy. 
Other investigative sites will report AEs to their respective IRB according to the local 
IRB’s policies and procedures in reporting adverse events. A copy of the submitted 
institutional AE form should be forwarded to the Overall PI within the timeframes 
detailed in the table below.  
DF/HCC Reportable Adverse Events(AEs)
Attribution
Gr. 2, 3, & 4 AE
Expected#
Gr. 2 & 3 AE 
Unexpected
Gr. 4 AE
Unexpected
Gr. 5 AE Expected or 
Unexpected
Unrelated
Unlikely
Not required
Not required
5 calendar days
24 hours*
Possible
Probable
Definite
Not required
5 calendar days
5 calendar days
24 hours*
# Please note, an event that presents at a higher severity than what is currently listed within the protocol and/or 
current consent as expected would be considered unexpected and reportable.
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last 
intervention, the AE should be reported within 1 business day of learning of the event.
The Overall PI will submit AE reports from outside institutions to the DFCI OHRS 
according to DFCI IRB policies and procedures in reporting adverse events. 


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7.5
Reporting to the Food and Drug Administration (FDA)
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA.
7.6
Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any participant 
safety reports, sentinel events or unanticipated problems that require reporting per institutional 
policy. 
7.7
Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions.
8.
PHARMACEUTICAL INFORMATION
A list of the adverse events and potential risks associated with the investigational administered in 
this study can be found in Section 7.1.
8.1
LY3214996
Chemical Name: 4H-Thieno[2,3-c]pyrrol-4-one, 5,6-dihydro-6,6-dimethyl-2-[2-[(1-
methyl-1H-pyrazol-5-yl)amino]-4-pyrimidinyl]-5-[2-(4-morpholinyl)ethyl]- 
Chemical Structure:
Molecular Weight: 453.57


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Molecular Formula: C22H27N7O2S
Description: White to light brown powder
Solubility: Water: 0.06 mg/mL; Methanol: 7.8 mg/mL
8.1.1
Form
The drug product is supplied as capsules. Each capsule contains LY3214996 equivalent 
to 25 mg or 100 mg of the base compound, with no inactive ingredients.
8.1.2
Storage and Stability
The drug product should be stored at room temperature (10˚C to 30˚C).
8.1.3
Handling
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the chemotherapeutic agent in a self-contained and protective environment. 
8.1.4
Availability
LY3214996 is an investigational agent that will be supplied by Eli Lilly and Company.
8.1.5
Administration
LY3214996 administration instructions: 

LY3214996 will be administered by mouth once daily continuously throughout 
each treatment cycle. 

Participants should be advised to take their dose at approximately the same time 
each day, a ± 4 hour dosing window is allowed. Doses that would occur outside of 
this time frame should be considered missed and should not be administered. 

Participants should be advised to fast for at least 1 hour prior to each dose, and to 
continue fasting for at least 1 hour after each dose. Water is permitted during the 
fasting period. 

If a participant vomits following a dose, the dose should not be re-taken. The 
participant should be advised to continue with their next regularly scheduled dose 
as clinically appropriate. 

LY3214996 should be swallowed whole, capsules should not be opened, chewed, 
or crushed.   

Refer to Section 5.4 for anti-emetic regimen information.
8.1.6
Ordering


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LY3214996 will be ordered by site pharmacy personnel from Eli Lilly and Company.
8.1.7
Accountability
The investigator, or a responsible party designated by the investigator, should maintain a 
careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form.  
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.)
8.1.8
Destruction and Return
Expired, returned, or unused supplies of LY3214996 should be destroyed according to 
local institutional policies. Destruction will be documented in the Drug Accountability 
Record Form. 
8.2
Hydroxychloroquine Sulfate (HCQ, Plaquenil®)
Chemical Name: 2-[[4-[(7-Chloro-4-quinolyl) amino]pentyl] ethylamino]ethanol sulfate (1:1)
Chemical Structure:
Molecular Weight: 433.95
Molecular Formula: C18H26ClN3O.H2SO4
Description: White or practically white, crystalline powder
Solubility: Freely soluble in water, practically insoluble in alcohol, chloroform, and in ether
8.2.1
Form
Please refer to the FDA package insert. HCQ tablets contain 200 mg hydroxychloroquine 
sulfate, equivalent to 155 mg base, and are for oral administration. Inactive Ingredients: 
Dibasic calcium phosphate USP, hypromellose USP, magnesium stearate NF, 
polyethylene glycol 400 NF, polysorbate 80 NF, corn starch, titanium dioxide USP, 
carnauba wax NF, shellac NF, black iron oxide NF.
8.2.2
Storage and Stability
Please refer to the FDA package insert.
8.2.3
Handling


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Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the agent in a self-contained and protective environment in accordance with 
local institutional standards of practice. 
8.2.4
Availability
HCQ is an FDA approved drug that is commercially available.
8.2.5
Administration
Only participants enrolled to the Safety Lead-in Cohort, Arm 1, or who cross-over on 
Arm 2 will receive treatment with HCQ. Instructions for administration of HCQ: 

HCQ will be administered by mouth twice daily continuously throughout each 
treatment cycle. 

Participants should be advised to take their doses approximately 12 hours apart, a 
± 4 hour dosing window is allowed. Doses that would occur outside of this time 
frame should be considered missed and should not be administered. 

Participants should be advised to take each dose with a meal (or within 30 
minutes of eating) or with a glass of milk. 

If a participant vomits following a dose, the dose should not be re-taken. The 
participant should be advised to continue with their next regularly scheduled dose 
as clinically appropriate. 

HCQ should be swallowed whole, tablets should not be dissolved, chewed, or 
crushed.   
8.2.6
Ordering
HCQ is an FDA approved commercially available agent that should be ordered by site 
pharmacy personnel per local institutional standards of practice. The cost of HCQ will be 
covered by the research trial, it will not be billed to patient insurance.
8.2.7
Accountability
HCQ accountability will be handled in accordance with local institutional standards of 
practice.
8.2.8
Destruction and Return
Expired, returned, or unused supplies of HCQ should be destroyed according to local 
institutional policies.
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES


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9.1
Tumor Biopsy Collection
Core needle, incisional, or excisional biopsies may be obtained for analysis at the time points 
indicated below. Biopsy procedures will be performed following standard institutional 
procedures. The tissue collection goal is 3 – 6 core biopsy samples collected using an 18 - 20 
gauge needle. Less than the goal amount of tissue is acceptable and should be based upon the 
clinical judgment of the treating investigator and the clinician performing the procedure. In the 
event tissue is insufficient for analysis it will not be considered a protocol violation. 

Biopsy #1 (Pre-Treatment): A mandatory fresh tumor tissue biopsy will be obtained pre-
treatment from all participants. 
o
The pre-treatment fresh tumor biopsy may be obtained any time before the 
participant’s Cycle 1 Day 1 visit.

Biopsy #2: An additional optional biopsy at the time of disease progression will be 
offered to all participants. 
o
The time of progression biopsy should be obtained prior to the initiation of 
another anti-cancer therapy when possible. In the event this is not feasible, the 
time of progression biopsy may be obtained up to 30 days after the date that 
disease progression was determined. The date of progression may be considered 
either the date the radiological scan was performed, or the date the treating 
investigator judged the participant to have progressed. 
o
In the event a participant enrolled to Arm 2 crosses-over to combination 
treatment, the time of progression biopsy may be collected prior to cross-over 
and/or upon progression on combination treatment. A tumor biopsy is not 
required prior to the initiation of cross-over treatment.
Please refer to the protocol laboratory manual for specific handling and shipping 
instructions.
9.2
Pharmacodynamic Marker Collection
Serial blood sampling will be performed for pharmacodynamic assessments on all patients. A 
total of 30 - 40 mL of blood will be collected at the following time points:

Cycle 1 Day 1 prior to dosing with the study agent(s)

Cycle 1 Day 15 at any time during the study visit

Day 1 of all subsequent cycles at any time during the study visit

At the off treatment visit
Please refer to the protocol laboratory manual for specific collection and handling 
instructions.
9.3
Pharmacokinetic (PK) Sample Collection
Limited PK blood sampling will be performed on participants enrolled to the Safety Lead-in 
Cohort and the first 6 evaluable participants enrolled to Arm 1. The PK sampling will serve to 


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evaluate the plasma concentration-time profiles of LY3214996 when combined with HCQ. Refer 
to the table below.
Please refer to the protocol laboratory manual for specific collection and handling 
instructions.
Table 10: Pharmacokinetic Blood Sample Collection1,2
Visit Day
Time
Sample Number
Cycle 1 Day 1
Any time prior to first doses 
of LY3214996 and HCQ
PK-00
Cycle 1 Day 1
1 hour post-LY3214996 
dosing (± 15 minutes)
PK-01
Cycle 1 Day 1
2 hours post-LY3214996 
dosing (± 15 minutes)
PK-02
Cycle 1 Day 1
4 hours post-LY3214996 
dosing (± 15 minutes)
PK-03
Cycle 1 Day 1
8 hours post-LY3214996 
dosing (± 30 minutes)
PK-04
Cycle 1 Day 2
Any time on Cycle 1 Day 2 
prior to the Cycle 1 Day 2 
doses of LY3214996 and 
HCQ
PK-05
Cycle 2 Day 1
Any time prior to the Cycle 2 
Day 1 doses of LY3214996 
and HCQ
PK-06
Cycle 2 Day 1
2 hours post-LY3214996 
dosing (± 15 minutes)
PK-07
1. Approximately 3 – 4 mL of blood will be collected at each time point. Refer to the 
protocol laboratory manual for specific collection and handling instructions.
2. Applicable only to participants enrolled to the Safety Lead-in Cohort or the first 6 
evaluable participants enrolled to Arm 1.
10. STUDY CALENDAR
Screening evaluations are to be conducted within 14 days prior to the start of protocol therapy, 
with the exception of obtaining the informed consent, imaging, and ophthalmic exam, which may 
be obtained up to 28 days prior to the start of protocol therapy. Assessments must be performed 
prior to administration of the study agent.


Page 51
Table 11: Study Calendar for the Safety Lead-in Cohort, Arm 1, and Cross-Over Participants
Screening∞
Cycle 1 Day 
1a
Cycle 1 Day 
2
Cycle 1 Day 
8b
Cycle 1 Day 
15b
Cycle 1 Day 
22b
Cycle 2+ Day 
1c
Cycle 2 Day 
15b
Off Treatmentd
Every Month 
Following Treatment 
Discontinuation
EDC Timepoints¥
Informed 
consent
X
N/A
Demographics
X
Screening
Medical 
history
X
Screening
Physical exam
X
X
X
X
X
X
X
X
N/A
Vital signse
X
X
X
X
X
X
X
X
N/A
Height
X
N/A
Weight
X
X
X
X
X
X
X
X
N/A
ECOG 
performance 
status
X
X
X
X
Screening, Day 1 of every cycle, 
Off Treatment
CBC w/diff, 
plts
X
X
X
X
X
X
X
X
N/A
Serum 
chemistryf
X
X
X
X
X
X
X
X
N/A
Serum β-
HCGg
X
N/A
EKGh
X
X
X
X
X
N/A
Adverse event 
evaluation
X----------------------------------------------------------------------X
X
All Visits
Radiologic 
evaluationi
X
Radiologic measurements should be performed every 8 weeks (± 7 day scheduling window)
X
Screening, Every 8 weeks, Off 
Treatment
Tumor 
Biopsyj
X
X
Screening, Off Treatment
PD Markerk
X
X
X
X
Screening, Day 1 of all cycles, 
C1D15, Off Treatment
Standard 
ophthalmic 
examl
X
X
N/A


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Table 11: Study Calendar for the Safety Lead-in Cohort, Arm 1, and Cross-Over Participants
Screening∞
Cycle 1 Day 
1a
Cycle 1 Day 
2
Cycle 1 Day 
8b
Cycle 1 Day 
15b
Cycle 1 Day 
22b
Cycle 2+ Day 
1c
Cycle 2 Day 
15b
Off Treatmentd
Every Month 
Following Treatment 
Discontinuation
EDC Timepoints¥
PK 
Collectionm
X
X
X
C1D1, C2D1
LY3214996n
As described in Section 5.3
Day 1 of every cycle
HCQn
As described in Section 5.3
Day 1 of every cycle
Telephone or 
Care Provider 
Contacto
X
Every month following treatment 
discontinuation × 6 months
∞: Cross-over participants do not need to re-screen but must provide re-consent prior to initiating cross-over treatment. First day of combination treatment will be considered C1D1 of cross-over. 
See Section 5.1.4.
¥: Note: column relevant only for CRF builders.
a.
Please refer to Section 5.2.1.
b.
A ± 3 day scheduling window is allowable to account for holidays, adverse weather, vacations, or any other scheduling issues.
c.
A ± 7 day scheduling window is allowable to account for holidays, adverse weather, vacations, or any other scheduling issues.
d.
Off treatment evaluation. Note: for IND trials, follow up visits or other contact are required in order to identify SAEs during the 30 days following the end of study treatment. 
e.
Heart rate, respiratory rate, temperature, blood pressure, and oxygen saturation; to be performed prior to study agent dosing.
f.
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT [AST], SGPT [ALT], sodium, phosphorus, 
creatinine phosphokinase (CPK).
g.
Serum pregnancy test only required for women of childbearing potential. Childbearing potential defined as any female who has experienced menarche and who has not undergone 
successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea >12 consecutive months; or women with 
a documented plasma follicle-stimulating hormone level >35µlU/mL).
h.
EKG to be collected during screening, C1D8, on C1D15, C1D22, C2D1, and C3D1 at any time during the study visit, and as clinically indicated. Single EKG to be collected at each time 
point. QTc to be calculated using Bazett’s formula. 
i.
Radiologic imaging of any disease-involved site. 
j.
A tumor biopsy is mandatory at baseline for all participants, and optional at the time of disease progression for all participants. Tumor biopsies to be collected as per Section 9.1. A repeat 
screening tumor biopsy is not required for cross-over participants (i.e. participants are not required to have a biopsy prior to crossing-over).
k.
Blood samples to be collected as per Section 9.2.
l.
To be performed by an ophthalmologist. Exam required during screening and on Cycle 3 Day 1 (± 7 day window). In addition, exam required if participant experiences new or worsening 
visual disturbances or suspected ocular toxicity while receiving trial treatment.
m.
PK sample collection only required on participants enrolled to the Safety Lead-in Cohort and the first six evaluable participants enrolled to Arm 1. Refer to Section 9.3 for details.
n.
Adequate supply of the study agents should be dispensed to account for any pre-planned scheduling delays.
o.
Following treatment discontinuation, participants will continue to be followed for survival status only for 6 months or until death, whichever occurs first. Survival status may be verified via 
medical record review, contact with care providers, or telephone contact with the patient. A ±14 day window is allowed for survival status verifications.


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Table 12: Study Calendar for Arm 2 Participants
Screening
Cycle 1 
Day 1a
Cycle 1 Day 
8b
Cycle 1 Day 15b
Cycle 1 Day 
22b
Cycle 2+ 
Day 1c
Cycle 2 Day 
15b
Off Treatmentd
Every Month Following 
Treatment 
Discontinuation
EDC Timepoints¥
Informed 
consent
X
N/A
Demographics
X
Screening
Medical 
history
X
Screening
Physical exam
X
X
X
X
X
X
X
X
N/A
Vital signse
X
X
X
X
X
X
X
X
N/A
Height
X
N/A
Weight
X
X
X
X
X
X
X
X
N/A
ECOG 
performance 
status
X
X
X
X
Screening, Day 1 of 
every cycle, Off 
Treatment
CBC w/diff, 
plts
X
X
X
X
X
X
X
X
N/A
Serum 
chemistryf
X
X
X
X
X
X
X
X
N/A
Serum β-
HCGg
X
N/A
EKGh
X
As clinically indicated
N/A
Adverse event 
evaluation
X----------------------------------------------------------------------X
X
All Visits
Radiologic 
evaluationi
X
Radiologic measurements should be performed every 8 weeks (± 7 day scheduling window)
X
Screening, Every 8 
weeks, Off Treatment
Tumor 
Biopsyj
X
X
Screening, Off 
Treatment
PD Markerk
X
X
X
X
Screening, Day 1 of all 
cycles, C1D15, Off 
Treatment


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Table 12: Study Calendar for Arm 2 Participants
Screening
Cycle 1 
Day 1a
Cycle 1 Day 
8b
Cycle 1 Day 15b
Cycle 1 Day 
22b
Cycle 2+ 
Day 1c
Cycle 2 Day 
15b
Off Treatmentd
Every Month Following 
Treatment 
Discontinuation
EDC Timepoints¥
Standard 
ophthalmic 
examl
X
As clinically indicated
N/A
LY3214996m
As described in Section 5.3
Day 1 of every cycle
Telephone or 
Care Provider 
Contactn
X
Every month following 
treatment discontinuation 
× 6 months
¥: Note: column relevant only for CRF builders.
a.
Please refer to Section 5.2.1.
b.
A ± 3 day scheduling window is allowable to account for holidays, adverse weather, vacations, or any other scheduling issues.
c.
A ± 7 day scheduling window is allowable to account for holidays, adverse weather, vacations, or any other scheduling issues.
d.
Off treatment evaluation. Note: for IND trials, follow up visits or other contact are required in order to identify SAEs during the 30 days following the end of study treatment. 
e.
Heart rate, respiratory rate, temperature, blood pressure, and oxygen saturation; to be performed prior to study agent dosing.
f.
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT [AST], SGPT [ALT], sodium, phosphorus, 
creatinine phosphokinase (CPK).
g.
Serum pregnancy test only required for women of childbearing potential. Childbearing potential defined as any female who has experienced menarche and who has not undergone 
successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea >12 consecutive months; or women with 
a documented plasma follicle-stimulating hormone level >35µlU/mL).
h.
Single EKG to be collected during the screening period. QTc to be calculated using Bazett’s formula. 
i.
Radiologic imaging of any disease-involved site. 
j.
A tumor biopsy is mandatory at baseline for all participants, and optional at the time of disease progression for all participants. Tumor biopsies to be collected as per Section 9.1.
k.
Blood samples to be collected as per Section 9.2.
l.
To be performed by an ophthalmologist. Repeat exam required if participant experiences new or worsening visual disturbances or suspected ocular toxicity while receiving trial treatment.
m.
Adequate supply of the study agent should be dispensed to account for any pre-planned scheduling delays.
n.
Following treatment discontinuation, participants will continue to be followed for survival status only for 6 months or until death, whichever occurs first. Survival status may be verified via 
medical record review, contact with care providers, or telephone contact with the patient. A ±14 day window is allowed for survival status verifications.


Page 55
11. MEASUREMENT OF EFFECT
11.1
Antitumor Effect – Solid Tumors
For the purposes of this study, participants should be re-evaluated for response every 8 weeks (± 
7 day scheduling window).  In addition to a baseline scan, confirmatory scans should also be 
obtained not less than 4 weeks following initial documentation of objective response.
For patients who discontinue protocol treatment prior to disease progression, they will continue 
to undergo restaging scans every 8 weeks ± 7 days or earlier if clinically indicated, until the 
documentation of disease progression.
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) 
[Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional measurement) of 
the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria.
11.1.1 Definitions
Evaluable for Target Disease response.  Only those participants who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for target disease response.  These 
participants will have their response classified according to the definitions stated below.  
(Note:  Participants who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaluable.)
Evaluable Non-Target Disease Response.  Participants who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, have 
received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for non-target disease.  The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions. 
11.1.2 Disease Parameters
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm by 
chest x-ray or ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters).
Note: Tumor lesions that are situated in a previously irradiated area will not be 
considered measurable unless there has been demonstrated progression in the lesion. 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 


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thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed.
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all considered 
non-measurable.
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same participant, these are preferred for selection as 
target lesions.
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease. 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow up. 
11.1.3 Methods for Evaluation of Disease
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a digital measurement tool.  All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before the beginning 
of the treatment.


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The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm in diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended. 
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. 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT thickness is 5mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size of a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans).  
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible.
FDG-PET. While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm: 
a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion.
b) No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT, additional follow-up CT  scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD.


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c) FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and 
biopsy resolution/sensitivity.
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image.
PET-CT. At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.  
MIBG (meta-iodobenzylguanidine).The following is recommended, to assure high 
quality images are obtained. 
Patient preparation: Iodides, usually SSKI (saturated solution of potassium iodide), are 
administered to reduce thyroidal accumulation of free radioiodine, preferably beginning 
the day prior to injection and continuing for 3 additional days (4 days total). For infants 
and children, one drop t.i.d. is sufficient, for adolescents 2 drops t.i.d., and for adults 3 
drops t.i.d. Participants and/or parents are asked about exposure to potential interfering 
agents. If none is noted, an indwelling intravenous line is established. The dose of MIBG 
is administered by slow intravenous injection over 90 seconds. 
Images from the head to the distal lower extremities should be obtained. 
I-123MIBG scintigraphy is performed to obtain both planar and tomographic images. 
Planar: Anterior and posterior views from the top of the head to the proximal lower 
extremities are obtained for 10 minutes at 24 hours and occasionally at 48 hours 
following injection of 10 mCi/1.7 square meters of body surface area (~150 μCi/kg, 
maximum 10 mCi). Anterior views of the distal lower extremities are adequate. A large 
field of view dual head gamma camera with low energy collimators is preferred. 
SPECT: Most participants receiving I-123 MIBG also undergo SPECT at 24 hours, using 
a single or multi-headed camera with a low energy collimator. The camera is rotated 
through 360 degrees, 120 projections at 25 seconds per stop. Data are reconstructed using 
filtered back projections with a Butterworth filter and a cut off frequency of 0.2-0.5. 
SPECT/CT may be performed at institutions with this capacity.


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Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later data and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised. If there is concern about radiation exposure 
from CT, MRI may be used instead of CT in selected instances. 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint.
Tumor markers. Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a participant to be 
considered in complete clinical response.  Specific guidelines for both CA-125 response 
(in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have been 
published [JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 
26:1148-1159, 2008].  In addition, the Gynecologic Cancer Intergroup has developed 
CA-125 progression criteria which are to be integrated with objective tumor assessment 
for use in first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000].
Cytology, Histology. These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease.
11.1.4 Evaluation of Target Lesions
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm.
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters.
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study).  In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm.  (Note:  the appearance of one or 
more new lesions is also considered progressions).


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Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on study.
11.1.5 Evaluation of Non-Target Lesions
Complete Response (CR):  Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm short 
axis).
Note:  If tumor markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response.
Non-CR/Non-PD:  Persistence 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 unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally 
trump target lesion status.  It must be representative of overall disease status change, not 
a single lesion increase.    
Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or Principal Investigator).
11.1.6 Evaluation of New Lesions
The finding of a new lesion should be unequivocal (i.e. not due to difference in scanning 
technique, imaging modality, or findings thought to represent something other than tumor 
(for example, some ‘new’ bone lesions may be simply healing or flare of pre-existing 
lesions). However, a lesion identified on a follow-up scan in an anatomical location that 
was not scanned at baseline is considered new and will indicate PD. If a new lesion is 
equivocal (because of small size etc.), follow-up evaluation will clarify if it truly 
represents new disease and if PD is confirmed, progression should be declared using the 
date of the initial scan on which the lesion was discovered.
11.1.7 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.


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Table 13: For Participants with Measurable Disease (i.e., Target Disease)
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
CR
CR
No
CR
>4 wks Confirmation**
CR
Non-CR/Non-
PD
No
PR
CR
Not evaluated
No
PR
PR
Non-CR/Non-
PD/not 
evaluated
No
PR
>4 wks Confirmation**
SD
Non-CR/Non-
PD/not 
evaluated
No
SD
Documented at least once >4 
wks from baseline**
PD
Any
Yes or No
PD
Any
PD***
Yes or No
PD
Any
Any
Yes
PD
no prior SD, PR or CR

See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.
**        Only for non-randomized trials with response as primary endpoint.
***      In exceptional circumstances, unequivocal progression in non-target lesions may be
            accepted as disease progression.
Note:  Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment.
Table 14: For Participants with Non-Measurable Disease (i.e., Non-Target Disease)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD

‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised
11.1.8 Duration of Response
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, or 
death due to any cause. Participants without events reported are censored at the last 
disease evaluation).


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Duration of overall complete response: The duration of overall CR is measured from the 
time measurement criteria are first met for CR until the first date that progressive disease 
is objectively documented, or death due to any cause. Participants without events 
reported are censored at the last disease evaluation.
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, including the baseline measurements. 
11.1.9 Progression-Free Survival
Overall Survival: Overall Survival (OS) is defined as the time from randomization (or 
registration) to death due to any cause, or censored at date last known alive.
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
randomization (or registration) to the earlier of progression or death due to any cause. 
Participants alive without disease progression are censored at date of last disease 
evaluation.
Time to Progression: Time to Progression (TTP) is defined as the time from 
randomization (or registration) to progression, or censored at date of last disease 
evaluation for those without progression reported.
11.1.10
 Response Review
Confirmation of scan results will be done centrally using the Tumor Imaging Metrics 
Core (TIMC) at DF/HCC, however treatment decisions may be made based on local scan 
interpretation. 
12. DATA REPORTING / REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements).
12.1
Data Reporting
12.1.1 Method
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on 
the data for this study.
12.1.2 Responsibility for Data Submission
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the Office of Data Quality (ODQ) in accordance with DF/HCC policies.


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12.2
Data Safety Monitoring
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of medical oncologists, research 
nurses, pharmacists and biostatisticians with direct experience in cancer clinical research.  
Information that raises any questions about participant safety will be addressed with the Overall 
PI and study team.
The DSMC will review each protocol up to four times a year with the frequency determined by 
the outcome of previous reviews. Information to be provided to the committee may include: up-
to-date participant accrual; current dose level information; DLT information; all grade 2 or 
higher unexpected adverse events that have been reported; summary of all deaths occurring 
within 30 days of intervention for Phase I or II protocols; for gene therapy protocols, summary of 
all deaths while being treated and during active follow-up; any response information; audit 
results, and a summary provided by the study team. Other information (e.g. scans, laboratory 
values) will be provided upon request. 
12.3
Multi-Center Guidelines
This protocol will adhere to DF/HCC Policy MULTI-100 and the requirements of the DF/HCC 
Multi-Center Data and Safety Monitoring Plan. The specific responsibilities of the Overall PI, 
Coordinating Center, and Participating Institutions and the procedures for auditing are presented 
in Appendix D.
13. STATISTICAL CONSIDERATIONS
13.1
Study Design/Endpoints
This is an open label, randomized, two arm, phase II study evaluating LY3214996 alone and in 
combination with HCQ in participants with advanced pancreatic cancer. Following completion 
of a brief combination treatment safety lead-in cohort (N=6 patients), participants will be 
randomized 1:1 for enrollment to one of two treatment arms: 

Arm 1: receiving combination treatment with LY3214996 and HCQ

Arm 2: receiving monotherapy treatment with LY3214996
13.2
Sample Size, Accrual Rate and Study Duration
The safety lead-in cohort will enroll a maximum of 12 patients. For the randomized component 
of the trial, a total of 20 patients will be enrolled to each treatment arm of the trial, for an overall 
maximum total of 52 patients. Participants will be replaced in the randomized portion of the trial 
if they withdraw consent for participation before receiving any protocol treatment or rapid 
disease progression limits their ability to receive any therapy per protocol. We will enroll up to 
54 subjects in order to obtain 52 evaluable cases. We expect to complete trial enrollment within 
24 months. An additional 4 months will be required to observe the response of the last 


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participant accrued, for a total length of approximately 28 months for determination of the 
primary endpoint of DCR. OS is a secondary endpoint of the trial, and participants will continue 
to be followed for survival status for 6 months following treatment discontinuation or until death. 
13.3
Analysis of Primary Endpoint
13.3.1 Safety Lead-in Cohort
The probability to escalate dose in the safety lead-in phase is presented in the table below. The 
randomized portion of the trial will proceed if there are < 2 DLTs observed among participants 
accrued to Dose Level 0. If Dose Level 0 is found intolerable (with ≥ 2 participants experiencing 
a DLT), Dose Level -1 will be evaluated. If Dose Level -1 is also not tolerable, the cohort will be 
closed with no further combination treatment enrollment and the trial will proceed as a single 
arm evaluation of LY3214996 as monotherapy.
Table 15: Safety Lead-in Probability Table
True Toxicity Rate
Probability for Dose Escalation in the Safety Lead-in Phase
0.01
>0.99
0.05
0.97
0.1
0.89
0.2
0.66
0.4
0.23
13.3.2 Randomized Arms
The randomized arms will be treated independently, not directly compared. Anti-tumor activity 
will be measured via disease control rate (DCR), which will be defined as the proportion of 
patients with complete response (CR), partial response (PR) or stable disease (SD) that persists 
for ≥ 4 months. Radiologic response will be assessed using RECIST v1.1 criteria. With 20 
subjects in each treatment arm, there is 79% power using a one-sided alpha of 0.1 to differentiate 
between an unacceptable DCR of 5% and a desirable DCR of 20%. Observing at least 3 patients 
with disease control in a treatment arm will be sufficient for the rejection of the null hypothesis 
in favor of the desirable DCR of 20% and suggesting that further evaluation of this treatment arm 
is warranted.
While treatment cross-over will be permitted (see Section 5.1.4), participants who cross-over 
will not be considered in the primary endpoint analysis of combination treatment.  
13.4
Analysis of Secondary Endpoints
Point estimates and exact binomial 90% confidence intervals will be provided for binary 
secondary endpoints such as ORR.  The method of Kaplan and Meier will be used to estimate 
overall survival in all patients; and duration of response in those that achieve OR.


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13.5
Analysis of Exploratory Endpoints
All participants will have a mandatory pre-treatment biopsy, and an optional time of progression 
biopsy will be offered to all participants. Non-parametric paired analysis will be conducted to 
assess the significance of changes between pre-treatment and time of progression samples.
Concordance of drug sensitivity and WTS results will be analyzed. The percentage of pre-
treatment biopsies with that are above a 66% sensitivity threshold for organoid sensitivity will be 
determined. With a sample size of 20 per arm, we will obtain a 95% confidence interval of 
(36.1%, 80.9%) if we observe 60% (or 12) of the pre-treatment biopsies that are above the 
threshold.
Agreement between the two biopsies will be analyzed using the Kappa statistics.
13.6
Reporting and Exclusions
13.6.1 Evaluation of Toxicity
All patients will be evaluable for evaluation of toxicity from the time of their first dose of 
study medication.
13.6.2 Evaluation of the Primary Efficacy Endpoint
All eligible patients included in the study who receive study medication will be assessed 
for response, even if there are major protocol therapy deviations. Patients who are 
replaced due to not receiving any protocol therapy will not be included in efficacy 
analyses. 
14. PUBLICATION PLAN
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study. 


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Ahronian LG, Sennott EM, Van Allen EM, et al. Clinical acquired resistance to RAF 
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Wagle N, Emery C, Berger MF, et al. Dissecting Therapeutic Resistance to RAF 
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Villanueva J, Vultur A, Lee JT, et al. Acquired resistance to BRAF inhibitors mediated 
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Aguirre AJ, Nowak JA, Camarda ND, et al. Real-time genomic characterization of 
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APPENDIX A
PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease.
0
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of disease.
80
Normal activity with effort; some 
signs or symptoms of disease.
1
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active work.
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs.
2
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours.
50
Requires considerable assistance and 
frequent medical care.
40
Disabled, requires special care and 
assistance.
3
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, hospitalization 
indicated.  Death not imminent.
20
Very sick, hospitalization indicated. 
Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.


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APPENDIX B
LIST OF DRUGS KNOWN TO PREDISPOSE TO TORSADE DE POINTES


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APPENDIX C
RASH MANAGEMENT GUIDELINES
Rash is a common on target toxicity associated with the treatment of MAPK inhibitors including 
ERK inhibitors and is also commonly observed with HCQ treatment. Grade 3 rash lasting for > 7 
days has been observed in ongoing sponsored trials of LY3214996. The following guidelines are 
suggested to help mitigate rash.
Once a patient starts on the trial, patients should be instructed to initiate the use of a moisturizer 
with no scents added. In addition, patients should be directed to limit sun exposure or to apply 
sunscreen protection before going outdoors (PABA-free, SPF 15 or higher) if appropriate.
A prescription for topical antimicrobials and steroidal agents based on institutional practice or 
guidelines should be provided by appropriate medical staff to the patient. The patient should be 
instructed to immediately fill the prescription for the topical agents and to start it immediately at 
the first onset of a grade 1 rash. If the rash escalates further, then the patient should be instructed 
to call the study investigator(s) / nurse(s) and additional interventions per institutional practice or 
guidelines for oral steroids, oral antimicrobials or dose reductions per investigator discretion may 
be implemented.
Suggested Topical and oral agents for use (additional or alternate agents may be used as based on 
availability, investigator discretion, and institutional standards of practice):
i.
clindamycin 1% solution or lotion
ii.
hydrocortisone valerate 0.2% or hydrocortisone cream 1%
iii.
Moisturizer (e.g. Cetaphil or Lubriderm) with no scents added
iv.
Steroids (e.g. Medrol dose pack or pulses of prednisone 40 mg BID for 5 – 7 days if non-
responsive).


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APPENDIX D
DF/HCC MULTI-CENTER DATA AND SAFETY MONITORING PLAN
DFCI IRB Protocol #: TBD
APPENDIX D
Dana-Farber/Harvard Cancer Center
Multi-Center Data and Safety Monitoring Plan
 


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15. INTRODUCTION
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan (DF/HCC 
DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research protocol. The 
DF/HCC DSMP serves as a reference for any sites external to DF/HCC that are participating in a 
DF/HCC clinical trial. 
15.1
Purpose
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-Center 
protocol will comply with Federal Regulations, Health Insurance Portability and Accountability 
Act (HIPAA) requirements and applicable DF/HCC Standard Operating Procedures.      
15.2
Multi-Center Data and Safety Monitoring Plan Definitions
DF/HCC Multi-Center Protocol:  A research protocol in which one  or more outside 
institutions are collaborating with Dana-Farber/Harvard Cancer Center where  a DF/HCC 
investigator is the sponsor. DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) 
Network Clinical Trial Affiliates. 
Lead Institution:  One of the Dana-Farber/Harvard Cancer Center consortium members (Dana-
Farber Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth Israel Deaconess 
Medical Center (BIDMC), Boston Children’s Hospital (BCH), Brigham and Women’s Hospital 
(BWH) responsible for the coordination, development, submission, and approval of a protocol as 
well as its subsequent amendments per the DFCI IRB and applicable regulatory guidelines 
(CTEP, Food and Drug Administration (FDA), Office of Biotechnology Activities (OBA) etc.).  
The Lead Institution is typically the home of the DF/HCC Sponsor. The Lead Institution also 
typically serves as the Coordinating Center for the DF/HCC Multi-Center Protocol.  
DF/HCC Sponsor:  The person sponsoring the submitted Multi-Center protocol who takes 
responsibility for initiation, management and conduct of the protocol at all research locations. In 
applicable protocols, the DF/HCC Sponsor will serve as the single liaison with any regulatory 
agencies (i.e. FDA). The DF/HCC Sponsor has ultimate authority over the protocol and is 
responsible for the conduct of the study at DF/HCC and all Participating Institutions. In most 
cases the DF/HCC Sponsor is the same person as the DF/HCC Overall Principal Investigator; 
however, both roles can be filled by two different people. 
Participating Institution:  An institution that is outside the DF/HCC and DF/PCC consortium 
that is collaborating with DF/HCC on a protocol where the sponsor is a DF/HCC Investigator.  
The Participating Institution acknowledges the DF/HCC Sponsor as having the ultimate authority 
and responsibility for the overall conduct of the study.   
Coordinating Center: The entity (i.e. Lead Institution, Medical Monitor, Contract Research 
Organization (CRO), etc.) that provides administrative support to the DF/HCC Sponsor in order 
that he/she may fulfill the responsibilities outlined in the protocol document and DSMP, and as 
specified in applicable regulatory guidelines (i.e. CTEP Multi-Center Guidelines). In general, the 
Lead Institution is the Coordinating Center for the DF/HCC Multi-Center Protocol. 


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DF/HCC Office of Data Quality (ODQ): A group within DF/HCC responsible ensuring high-
quality standards are used for data collection and the ongoing management of clinical trials, 
auditing, and data and safety monitoring. ODQ also coordinates quality assurance efforts related 
to multi-center clinical research.
DF/HCC Research Informatics for Operations (RIO): A group within DF/HCC responsible 
for providing a comprehensive data management platform for managing clinical trial data.
16. GENERAL ROLES AND RESPONSIBILITIES
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and the 
Participating Institutions are expected to adhere to the following general responsibilities: 
16.1
DF/HCC Sponsor
The DF/HCC Sponsor, Brian Wolpin, MD, will accept responsibility for all aspects of 
conducting a DF/HCC Multi-Center protocol which includes but is not limited to: 

Oversee the coordination, development, submission, and approval of the protocol as well 
as subsequent amendments. 

Ensure that the investigators, study team members, and Participating Institutions are 
qualified and appropriately resourced to conduct the protocol.  

Include the Multi-Center Data and Safety Monitoring Plan as an appendix to the protocol.

Ensure all Participating Institutions are using the correct version of the protocol.

Ensure that each participating investigator and study team member receives adequate 
protocol training (and/or a Site Initiation Visit prior to enrolling participants) and 
throughout trial’s conduct as needed.

Monitor progress and overall conduct of the study at all Participating Institutions. 

Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable (i.e. 
FDA) reporting requirements are met. 

Review data and maintain timely submission of data for study analysis. 

Act as the single liaison with the FDA, as applicable.

Ensure compliance with all requirements as set forth in the Code of Federal Regulations, 
applicable DF/HCC requirements, HIPAA requirements, and the approved protocol.

Commit to the provision that the protocol will not be rewritten or modified by anyone 
other than the DF/HCC Sponsor.

Identify and qualify Participating Institutions and obtain accrual commitments prior to 
extending the protocol to that site.

Monitor accrual and address Participating Institutions that are not meeting their accrual 
requirements. 
16.2
Coordinating Center 
The general responsibilities of the Coordinating Center may include but are not limited to:

Assist in protocol development. 

Maintain FDA correspondence, as applicable.


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
Review registration materials for eligibility and register participants from Participating 
Institutions in the DF/HCC clinical trial management system (CTMS).

Distribute protocol and informed consent document updates to Participating 
Institutions as needed.

Oversee the data collection process from Participating Institutions.

Maintain documentation of Serious Adverse Event (SAE) reports and 
deviations/violation submitted by Participating Institutions and provide to the DF/HCC 
Sponsor for timely review and submission to the DFCI IRB, as necessary. 

Distribute serious adverse events reported to the DF/HCC Sponsor that fall under the 
DFCI IRB Adverse Event Reporting pPolicy to all Participating Institutions.

Provide Participating Institutions with information regarding DF/HCC requirements 
that they will be expected to comply with.

Carry out plan to monitor Participating Institutions either by on-site or remote 
monitoring. 

Maintain Regulatory documents of all Participating Institutions which includes but is 
not limited to the following: local IRB approvals/notifications from all Participating 
Institutions, confirmation of Federalwide Assurances (FWAs) for all sites,  all SAE 
submissions, Screening Logs for all sites, IRB approved consents for all sites

Conduct regular communications with all Participating Institutions (conference calls, 
emails, etc.) and maintain documentation all relevant communications.
16.3
Participating Institution
Each Participating Institution is expected to comply with all applicable federal regulations and 
DF/HCC requirements, the protocol and HIPAA requirements. 
The general responsibilities for each Participating Institution may include but are not limited to:

Document the delegation of research specific activities to study personnel.

Commit to the accrual of participants to the protocol.

Submit protocol and/or amendments to their local IRB of record.

Maintain regulatory files as per sponsor requirements.

Provide the Coordinating Center with regulatory documents or source documents as 
requested.

Participate in protocol training prior to enrolling participants and throughout the trial as 
required (i.e. teleconferences).

Update Coordinating Center with research staff changes on a timely basis.

Register participants through the Coordinating Center prior to beginning research related 
activities. 

Submit Serious Adverse Event (SAE) reports to local IRB per institutional requirements 
and to the Coordinating Center, in accordance with DF/HCC requirements.

Submit protocol deviations and violations to local IRB per institutional requirements and 
to the DF/HCC Sponsor in accordance with DF/HCC requirements.

Order, store and dispense investigational agents and/or other protocol mandated drugs per 
federal guidelines and protocol requirements.

Have office space, office equipment, and internet access that meet HIPAA standards.


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
Participate in any quality assurance activities and meet with monitors or auditors at the 
conclusion of a visit to review findings.

Promptly provide follow-up and/or corrective action plans for any monitoring queries or 
audit findings.
17. DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS
The following section will clarify DF/HCC Requirements and further detail the expectations for 
participating in a DF/HCC Multi-Center protocol. 
17.1
Protocol Distribution
The Coordinating Center will distribute the final DFCI IRB approved protocol and any 
subsequent amended protocols to all Participating Institutions.   
17.2
Protocol Revisions and Closures
The Participating Institutions will receive notification of protocol revisions and closures from the 
Coordinating Center.  It is the individual Participating Institution’s responsibility to notify its 
IRB of these revisions.

Non life-threatening revisions: Participating Institutions will receive written notification 
of protocol revisions regarding non life-threatening events from the Coordinating Center. 
Non-life-threatening protocol revisions must be IRB approved and implemented within 
90 days from receipt of the notification.

Revisions for life-threatening causes: Participating Institutions will receive immediate 
notification from the Coordinating Center concerning protocol revisions required to 
protect lives with follow-up by fax, mail, e-mail, etc.  Life-threatening protocol revisions 
will be implemented immediately followed by IRB request for approval.

Protocol closures and temporary holds: Participating Institutions will receive 
notification of protocol closures and temporary holds from the Coordinating Center. 
Closures and holds will be effective immediately.  In addition, the Coordinating Center, 
will update the Participating Institutions on an ongoing basis about protocol accrual data 
so that they will be aware of imminent protocol closures.
17.3
Informed Consent Requirements
The DF/HCC approved informed consent document will serve as a template for the informed 
consent for Participating Institutions. The Participating Institution consent form must follow the 
consent template as closely as possible and should adhere to specifications outlined in the 
DF/HCC Guidance Document on Model Consent Language for Investigator-Sponsored Multi-
Center Trials. This document will be provided separately to each Participating Institution upon 
request.


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Participating Institutions are to send their version of the informed consent document and HIPAA 
authorization, if a separate document, to the Coordinating Center for review and approval prior 
to submission to their local IRB. The approved consent form must also be submitted to the 
Coordinating Center after approval by the local IRB for all consent versions.
The Principal Investigator (PI) at each Participating Institution will identify the physician 
members of the study team who will be obtaining consent and signing the consent form for 
therapeutic protocols. Participating institutions must follow the DF/HCC requirement that for all 
interventional drug, biologic, or device research, only attending physicians may obtain initial 
informed consent and any re-consent that requires a full revised consent form.  
17.4
IRB Documentation
The following must be on file with the Coordinating Center:

Initial approval letter of the Participating Institution's IRB. 

Copy of the Informed Consent Form(s) approved by the Participating Institution’s IRB. 

Participating Institution’s IRB approval for all amendments.

Annual approval letters by the Participating Institution's IRB.
17.5
IRB Re-Approval
Verification of IRB re-approval from the Participating Institutions is required in order to 
continue research activities.  There is no grace period for continuing approvals.
The Coordinating Center will not register participants if a re-approval letter is not received from 
the Participating Institution on or before the anniversary of the previous approval date.  
17.6
Participant Confidentiality and Authorization Statement
In 1996, congress passed the first federal law covering the privacy of health information known as 
the Health Insurance Portability and Accountability Act (HIPPA). Any information, related to the 
physical or mental health of an individual is called Protected Health Information (PHI). HIPAA 
outlines how and under what circumstances PHI can be used or disclosed. 
In order for covered entities to use or disclose protected health information during the course of a 
study, the study participant must sign an authorization statement.  This authorization statement 
may or may not be separate from the informed consent document.  The Coordinating Center, with 
the approval from the DFCI IRB, will provide a consent template, with information regarding 
authorization for the disclosure of protected health information. 
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in its trials. 
However, because of the nature of these trials, certain protected health information must be 
collected. DF/HCC has chosen to use authorizations, signed by the participant in the trial, rather 
than limited data sets with data use agreements.


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17.6.1  DF/HCC Multi-Center Protocol Confidentiality
All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center 
should be de-identified. It is recommended that the assigned protocol case number (as 
described below) be used for all participant specific documents. Participant initials may be 
included or retained for cross verification of identification. 
17.7
DF/HCC Multi-Center Protocol Registration Policy
17.7.1  Participant Registration and Randomization 
Please refer to Protocol Section 4.4.
17.7.2  Initiation of Therapy
Participants must be registered with the DF/HCC CTMS before the initiation of treatment 
or other protocol-specific interventions. Treatment and other protocol-specific 
interventions may not be initiated until the Participating Institution receives confirmation 
of the participant’s registration from the Coordinating Center. The DF/HCC Sponsor and 
DFCI IRB must be notified of any violations to this policy.
17.7.3  Eligibility Exceptions
No exceptions to the eligibility requirements for a protocol without DFCI IRB approval 
will be permitted. All Participating Institutions are required to fully comply with this 
requirement. 
17.8
DF/HCC Protocol Case Number
At the time of registration, the following identifiers are required for all subjects: initials, date of 
birth, gender, race and ethnicity. Once eligibility has been established and the participant 
successfully registered, the participant is assigned a unique protocol case number.  Participating 
Institutions should submit all de-identified subsequent communication and documents to the 
Coordinating Center, using this case number to identify the subject.  
17.8.1 Protocol Deviations, Exceptions and Violations
Federal Regulations require an IRB to review proposed changes in a research activity to 
ensure that researchers do not initiate changes in approved research without IRB review 
and approval, except when necessary to eliminate apparent immediate hazards to the 
participant. DF/HCC requires all departures from the defined procedures set forth in the 
IRB approved protocol to be reported to the DF/HCC Sponsor, who in turn is responsible 
for reporting to the DFCI IRB.
For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and “exception” 
to describe departures from a protocol. All Participating Institutions must adhere to these 


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requirements for reporting to the DF/HCC Sponsor and will follow their institutional 
policy for reporting to their local IRB.
17.8.2  Definitions
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-
approved protocol which is prospectively approved prior to its implementation.
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g.
enrollment of a participant who does not meet all inclusion/exclusion criteria.
Protocol Violation: Any protocol departure that was not prospectively approved by the 
IRB prior to its initiation or implementation. 
17.8.3  Reporting Procedures
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the 
medical record and/or regulatory documents to describe all protocol exceptions, deviations 
and violations. The DF/HCC Sponsor will also be responsible for ensuring that all 
protocol violations/deviations are promptly reported per DFCI IRB guidelines. 
Participating Institutions: Protocol deviations require prospective approval from the DFCI 
IRB. The Participating Institution must submit the deviation request to the Coordinating 
Center who will then submit the deviation request to the DFCI IRB. Upon DFCI IRB 
approval the deviation is submitted to the Participating Institution IRB, per institutional 
policy. A copy of the Participating Institution’s IRB report and determination will be 
forwarded to the Coordinating Center within 10 business days after the original 
submission.  The deviation may not be implemented without all required approvals.
All protocol violations must be sent to the Coordinating Center in a timely manner. The 
Coordinating Center will provide training for the requirements for the reporting of 
violations. 
Coordinating Center:  Upon receipt of the violation/deviation report from the Participating 
Institution, the Coordinating Center will submit the report to the DF/HCC Sponsor for 
review. Subsequently, the Participating Institution’s IRB violation/deviation report will be 
submitted to the DFCI IRB for review per DFCI IRB reporting guidelines. 
17.9
Safety Assessments and Toxicity Monitoring
The study teams at all participating institutions are responsible for protecting the safety, rights and 
well-being of study participants. Recording and reporting of adverse events that occur during the 
course of a study help ensure the continuing safety of study participants. 
All participants receiving investigational agents and/or other protocol mandated therapy will be 
evaluated for safety. The safety parameters include all laboratory tests and hematological 
abnormalities, physical examination findings, and spontaneous reports of adverse events reported 


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by participants.  All toxicities encountered during the study will be evaluated according to the 
NCI criteria specified in the protocol. Life-threatening toxicities must be reported immediately to 
the DF/HCC Sponsor via the Coordinating Center. 
Additional safety assessments and toxicity monitoring will be outlined in the protocol.
17.9.1 Guidelines for Reporting Serious Adverse Events 
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are 
detailed in Protocol Section 7.
Participating Institutions must report the SAEs to the DF/HCC Sponsor and the 
Coordinating Center following the DFCI IRB Adverse Event Reporting Policy. 
The Coordinating Center will maintain documentation of all Participating Institution 
Adverse Event reports and be responsible for communicating to all participating 
investigators, any observations reportable under the DFCI IRB Reporting Requirements.  
Participating Institutions will review and submit to their IRB according to their 
institutional policies and procedures
17.9.2 Guidelines for Processing IND Safety Reports 
The DF/HCC Sponsor will review all IND Safety Reports and ensure that all IND Safety 
Reports are distributed to the Participating Institutions. Participating Institutions will 
review/submit to the IRB according to their institutional policies and procedures.
17.10
Data Management
DF/HCC RIO develops case report forms (CRF/eCRFs), for use with the protocol.  These forms 
are designed to collect data for each study. DF/HCC RIO provides a web based training for all 
eCRF users.
  
17.10.1 Data Forms Review
Data submissions are monitored for timeliness and completeness of submission. If study 
forms are received with missing or questionable data, the submitting institution will receive 
a written or electronic query from the DF/HCC Office of Data Quality, Coordinating Center, 
or designee. 
Responses to all queries should be completed and submitted within 14 calendar days.  
Responses may be returned on the written query or on an amended paper case report form, 
or in the case of electronic queries, within the electronic data capture (eDC) system. In the 
case of a written query for data submitted on a paper case report form, the query must be 
attached to the specific data being re-submitted in response.  


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If study forms are not submitted on schedule, the Participating Institution will periodically 
receive a Missing Form Report from the Coordinating Center noting the missing forms. 
18. REQUISITIONING INVESTIGATIONAL DRUG
The ordering of the investigational agents is specified in the Protocol Section 8. 
Participating Institutions should order their own agent regardless of the supplier (i.e., 
pharmaceutical company or commercial supply).
If the agent is commercially available, check with the local Director of Pharmacy and/or the 
Research Pharmacy to ensure that the agent is in stock. If the agent is not stocked, ensure that the 
agent can be ordered once the protocol is approved by the local IRB. 
If the agent is investigational, ensure that the pharmacy will be able to receive and store the agent 
according to state and federal requirements. The local IRB should be kept informed of who will 
supply the agent (i.e., pharmaceutical company) so that any regulatory responsibilities can be 
met in a timely fashion. 
19. MONITORING: QUALITY CONTROL
The quality control process for a clinical trial requires verification of protocol compliance and 
data accuracy. The Coordinating Center, with the aid of the DF/HCC Office of Data Quality, 
provides quality control oversight for the protocol.
19.1
Ongoing Monitoring of Protocol Compliance
The Participating Institutions may be required to submit participant source documents to the 
Coordinating Center for monitoring. Participating Institution may also be subject to on-site 
monitoring conducted by the Coordinating Center. 
The Coordinating Center will implement ongoing monitoring activities to ensure that 
Participating Institutions are complying with regulatory and protocol requirements, data quality, 
and participant safety. Monitoring practices may include but are not limited to source data 
verification, review and analysis of eligibility requirements, informed consent procedures, 
adverse events and all associated documentation, review of study drug administration/treatment, 
regulatory files, protocol departures reporting, pharmacy records, response assessments, and data 
management. 
Participating institutions will be required to participate in monthly Coordinating Center initiated 
teleconferences. Frequency of teleconferences may be increased or decreased based on research 
needs and patient accrual but will not occur less than quarterly. “Newsletters” highlighting 
overall protocol progress and important announcements will be distributed regularly.
Remote Monitoring: The Coordinating Center will request source documentation from 
Participating Institutions as needed to complete monitoring activities. Participating Institutions 


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will be required to forward de-identified copies of participants’ medical record and source 
documents to the Coordinating Center to aid in source documentation verification.
On-Site Monitoring: On-site monitoring will occur on an as-needed basis. Participating 
Institutions will be required to provide access to participant’s complete medical record and 
source documents for source documentation verification (SDV) during the on-site visit. In 
addition, upon request from a monitor or auditor, Participating Institutions should provide access 
to regulatory documents, pharmacy records, local policies related to the conduct of research, and 
any other trial-related documentation maintained by the participating site. If there are concerns 
for protocol compliance, issues that impact subject safety or the integrity of the study are found, 
or trends identified based on areas of need, additional monitoring visits may be scheduled. On 
site monitoring visits can be supplemented with virtual monitoring assessments, provided that 
the minimum monitoring frequencies are adhered to.
19.2
Monitoring Reports
The DF/HCC Sponsor will review all monitoring reports to ensure protocol compliance. The 
DF/HCC Sponsor may increase the monitoring activities at Participating Institutions that are 
unable to comply with the protocol, DF/HCC Sponsor requirements or federal and local 
regulations. 
19.3
Accrual Monitoring
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish accrual 
requirements for each participating institution. Accrual will be monitored for each participating 
institution by the DF/HCC Sponsor or designee. Sites that are not meeting their accrual 
expectations may be subject to termination.
A minimum of 3 patients per site annually is expected.
20. AUDITING: QUALITY ASSURANCE
Auditing is a method of Quality Assurance and involves the systematic and independent 
examination of all trial related activities and documents.  Audits determine if evaluated activities 
were appropriately conducted and whether data was generated, recorded and analyzed, and 
accurately reported per the protocol, applicable Policies, and the Code of Federal Regulations 
(CFR).
20.1
DF/HCC Internal Audits
 
All Participating Institutions are subject to audit by the DF/HCC Office of Data Quality (ODQ). 
Typically, approximately 3-4 participants would be audited at the site over a 2-day period. If 
violations which impact participant safety or the integrity of the study are found, more 
participant records may be audited. 


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20.2
Audit Notifications
It is the Participating Institution’s responsibility to notify the Coordinating Center of all external 
audits or inspections (e.g., FDA) that involve this protocol. All institutions will forward a copy of 
final audit and/or re-audit reports and corrective action plans (if applicable) to the Coordinating 
Center, within 12 weeks after the audit date. 
20.3
Audit Reports 
The DF/HCC Sponsor will review all final audit reports and corrective action plans, if applicable. 
The Coordinating Center must forward any reports to the DF/HCC ODQ per DF/HCC policy for 
review by the DF/HCC Audit Committee. For unacceptable audits, the DF/HCC Audit Committee 
would forward the final audit report and corrective action plan to the DFCI IRB as applicable.
20.4
Participating Institution Performance
The DF/HCC Sponsor and the IRB of record are charged with considering the totality of an 
institution’s performance in considering institutional participation in the protocol.
Participating Institutions that fail to meet the performance goals of accrual, submission of timely 
and accurate data, adherence to protocol requirements, and compliance with state and federal 
regulations, may be recommended for a six-month probation period. Such institutions must 
respond with a corrective action plan and must demonstrate during the probation period that 
deficiencies have been corrected, as evidenced by the improved performance measures. 
Participating Institutions that fail to demonstrate significant improvement will be considered by 
the DF/HCC Sponsor for revocation of participation. A DF/HCC Sponsor and/or the DFCI IRB 
may terminate a site’s participation if it is determined that a site is not fulfilling its 
responsibilities as described above.