Clinical trial NCT03512756
Conditions: Pancreatic Cancer
Keywords: Pancreatic cancer Pancreas cancer Pancreatic Pancreas cancer low toxicity chemotherapy metastatic SM-88 SM88 3rd line third line CMBT well tolerated MPS Racemetyrosine Methoxsalen Sirolimus Phenytoin
Sponsor: Tyme, Inc
Start date: 2018-03-27; Completion date: 2021-12-28
Enrollment: 130 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
A prospective, open-label phase 2/3 trial in metastatic pancreatic cancer participants who have failed two lines of prior systemic therapy. The trial is designed to evaluate the safety and efficacy of SM-88 used with MPS (methoxsalen, phenytoin and sirolimus) in pancreatic cancer and will measure multiple endpoints, including overall survival, progression free survival, relevant biomarkers, quality of life, safety, and overall response rate.

(Part 1 enrollment complete) In the initial stage of the trial (36 participants), two dose levels of SM-88's metyrosine-derivative was evaluated.

(Part 2 actively enrolling) The second part will consist of a subsequent expansion of the trial to further assess safety and efficacy of SM-88 used with MPS containing the selected SM-88 RP2D from Part 1. A total of 250 participants in the second part will be randomized 1:1 either to the SM-88 arm (125 participants) or Physician's Choice of therapy for the Control Arm (125 participants). Participants should have previously received two lines of prior systemic therapy.

Detailed description:
Please refer to Inclusion/Exclusion Criteria and Summary

Arms: arm 1: (Part 1 enrollment complete) SM-88 used with MPS (methoxsalen, phenytoin and sirolimus)

(Part 2 actively enrolling) SM-88 (920 mg per day) used with MPS (methoxsalen, phenytoin and sirolimus) will be administered to 125 evaluable participants until unacceptable toxicity, disease progression, or any of the treatment discontinuation criteria are met. arm 2: Physician's Choice therapy will be administered for a total of 125 evaluable participants until unacceptable toxicity, disease progression, or any of the treatment discontinuation criteria are met.
Interventions: intervention 1: SM-88 used with MPS (methoxsalen, phenytoin, sirolimus) intervention 2: Capecitabine, Gemcitabine, and 5-FU
Intervention descriptions: intervention 1: Daily oral therapy for cancer intervention 2: Investigator choice of the following therapies:

Capecitabine, Gemcitabine, and 5-FU

Protocol documents:
Prot_000.pdf: 
Tyme, Inc.  
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Page 1 of 131 
CONFIDENTIAL 
May 12, 2020 
Tyme, Inc. 
CLINICAL STUDY PROTOCOL 
Sponsor: 
Tyme, Inc. 
17 State St., 7th Floor 
New York, NY 10004 
IND No.:  
136891 
Clinical Trials.gov 
Identifier:  
NCT03512756 
Indication: 
Pancreas Cancer 
Protocol ID: 
Tyme-88-Panc 
Tyme, Inc. Medical 
Monitor: 
Name:  
 
Phone: 
 
Mobile: 
 
Clinical Research 
Organization (CRO) 
Medical Monitor: 
Name: IQVIA Biotech: 
 
Phone: 
 
Mobile:
 
Protocol Version/Date: 
May 12, 2020 (Version 8) 
CONFIDENTIALITY STATEMENT 
The information contained in this document, particularly unpublished data, is the property or under control of 
Tyme, Inc., and is provided to you in confidence as an investigator, potential investigator, or consultant, for 
review by you, your staff, and an applicable Institutional Review Board or Independent Ethics Committee.  The 
information is only to be used by you in connection with authorized clinical studies of the investigational drug 
described in the protocol.  You will not disclose any of the information to others without written authorization 
from Tyme, Inc., except to the extent necessary to obtain informed consent from those persons to whom the drug 
may be administered. 
PROTOCOL APPROVAL PAGE 
Study Title: 
A Randomized Phase 2/3 Multi-Center Study of SM-88 in Subjects 
with Pancreatic Cancer Whose Disease Has Progressed or Recurred 
Protocol Number: 
Tyme-88-Panc 
Original Protocol 
Date of Issue: 
February 15, 2018 


DocuSign Envelope ID: 0DCAD743-DB65-43E6-B0C7-D8EFA0C848A9 
Tyrne, Inc. 
SM-88; IND #136891 
PROTOCOL APPROVAL PAGE 
Confidential 
Page 2 of 131 
Study Title: 
A Randomized Phase 2/3 Multi-Center Study of SM-88 in Subjects with 
Pancreatic Cancer Whose Disease Has Progressed or Recurred 
Protocol Number: 
Tyme-88-Panc 
Original Protocol 
February 15, 2018 
Date of Issue: 
I, the undersigned, have read and approve this protocol and agree with its content. It is confirmed that the 
information and guidance given in this protocol complies with scientific principles, the guidelines of 
Good Clinical Practices, the Declaration of Helsinki in the latest relevant version, and the applicable legal 
and regulatory requirements. 
Sponsor 
Signature: 
CONFIDENTIAL 
6/15/2020 I 16:57:26 PDT 
(Date) 
May 12, 2020 


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CONFIDENTIAL 
 
May 12, 2020 
INVESTIGATOR PROTOCOL AGREEMENT 
Protocol Title: 
A Randomized Phase 2/3 Multi-Center Study of SM-88 in 
Subjects with Pancreatic Cancer Whose Disease Has Progressed 
or Recurred  
 
 
 
Protocol Number: 
Tyme-88-Panc 
Version:  May 12, 2020 
 
 
By my signature, I  
• Agree to comply with the conduct and terms of the study specified herein and with any 
other study procedures provided by the Sponsor, Tyme, Inc.   
• Agree to comply with US Food and Drug Administration (FDA) regulations, the 
International Conference on Harmonization (ICH) Good Clinical Practice (GCP) 
guidelines, the Declaration of Helsinki, and all applicable rules, regulations, and federal, 
state, and local laws relating to the conduct of clinical studies and the protection of 
human subjects.  
• Agree not to implement changes to the protocol without agreement from the Sponsor and 
prior written approval (where required) from the Institutional Review Board (IRB), 
except when necessary to eliminate an immediate hazard to the subjects.  
• Agree to onsite monitoring of the case report forms (CRFs) and source documents by 
Tyme, Inc. or designee and to audit by Tyme, Inc. or designee and appropriate regulatory 
authorities, including, but not limited to, the FDA and IRB inspectors. 
• Agree to supervise the conduct of the study and maintain responsibility for training and 
supervising all personnel who have been delegated responsibilities under my leadership.  
The protocol and other important study materials will be available to study staff 
throughout the conduct of the study. 
 
 
 
 
Investigator's Signature 
 
Date 
 
 
 
Print Name 
 
 


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Table 1: 
Content Updates (Version 7 to 8) 
Section 
Page 
Content Update 
Synopsis 
10-24 
No. of Centers: Changed to 10 to 15 
Objectives:  
Part 1: Safety objectives included  
Part 2: Primary, safety, secondary safety, and additional secondary objectives included; 
PK/Safety objectives included 
Duration of Treatment: Language added on patients with a compromised immune system 
Study Procedures/Frequency: Clarification on sampling schemes and addition of 12-lead 
ECG collections in triplicate language, ECGs (single) and PK sampling.  
Screening period: Added language on compliance with all Study related activities; 
clarification language on consenting patients 
Inclusion Criteria: Updated information for Part 2   
Added a sentence “A line of therapy is defined as either having prognosed on a line of 
treatment regimen or having received at least 2 months of a treatment regimen.” 
 
Modified sentence: Of the two prior lines, subjects must have been exposed to a 
gemcitabine-based regimen for a prior line and a 5-FU-based regimen as a prior line of 
therapy. Investigational therapies as part of a prior line regimen are permitted. 
 
1. Changed carcinoma to adenocarcinoma 
3. Changed to Radiographically measurable disease of at least one site by CT scan (or 
magnetic resonance imaging, MRI, or PET/CT if allergic to CT contrast media). Imaging for 
baseline results must be obtained at most 14 days prior to Randomization. 
 
Changed first dose to randomization throughout. 
 
8. Clarified language to at most 7 days prior to randomization 
 
8b(i). Added prior to the screening laboratory assessment 
 
8b(iii). Added or 24 hour urine-determined creatinine clearance ≥60 mL/min 
 
8 (b)(iv). Deleted within 28 days of starting study 
Exclusion Criteria:  Updated information for Part 2  
Changed baseline to randomization throughout 
 


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Section 
Page 
Content Update 
1. 6. Changed Radiation to all measurable target lesions within 12 
weeks of study baseline.  
2. 7. Changed to No measurable lesions. 
3. 8. Changed to “Current use, or any use within 14 days prior to 
Randomization, of a restricted medication (see Section 8.7), or 
subject requires any of these medications during treatment phase.” 
13/14. Added Note: testing is not required in the absence of clinical symptoms 
15. Deleted component of regimen 
4. 17. Subjects with a history of hypersensitivity to phenytoin, its 
inactive ingredients, or other hydantoins; or a history of prior acute 
hepatotoxicity attributable to phenytoin. 
Moved:  
5. 25. Subjects exhibiting idiosyncratic reactions to psoralen 
compounds.  
6. 26. Subjects with a hypersensitivity to sirolimus. 
7. 27. Changed to “Currently enrolled in, or have discontinued within 
30 days of Randomization, from a clinical trial involving an 
investigational product or non-approved use of a drug or device.” 
Modified: 
22. Changed to “The second weight measure should be captured prior to randomization.” 
8. 23. Subjects who have a variety of factors influencing their ability to 
ingest and absorb oral drugs (such as unable to swallow, nausea, 
vomiting, chronic diarrhea and intestinal obstruction, etc.). 
9. 24. Subjects with central nervous system metastasis, with the 
exception of subjects who have stable brain metastases as defined as 
off steroids and no CNS progression for 6 months after CNS 
treatment. 
10. 34. Screening prolongation of QT/QTc interval [e.g., > 480 
milliseconds (ms)] (CTCAE Grade 1) using Fredericia’s QT 
correction formula. 


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Section 
Page 
Content Update 
11. 37. Presence of symptomatic or clinically significant ascites or 
pleural effusion, defined as requiring clinical intervention in the 30 
days prior to consent. However, trace or small amount of physiologic 
fluid will not be excluded.   
Efficacy: Updated Secondary Endpoints:  
 
Clarified language on efficacy and capecitabine; added language on investigative site 
PK: Updated language on the timing of meals; added language on ECGs 
Sample Size Justification: Overall survival (OS added) 
 
Section 5.3 Additional Secondary Objectives of 
SM-88 vs the Control Arm  
39 
Language update:   
Section 6.2 Screening 
40 
Updated text and added a table to clarify screening 
Added language on Day 7 between randomization and start of first dose  
Table 3 
41 
Added table 
 
Section 6.3.1. Efficacy Assessment  
44 
• 
Efficacy: Updated Secondary Endpoints:  
 
Clarified language on efficacy and capecitabine; added language on investigative site 
Table 5 
47 
Table of events updated to include: 
 
• 
PK assessments in Day 1 cycle 1 and 2 (Part 2) 
• 
ECG language added Cycle 3 and 4 (Part 2) 
• 
ECG (triplicate) deleted 
• 
Food and drug diary added 
• 
Schedule of CTC collection and exploratory BM 
Footnotes c, g, h, j, k and o updated 
Table 6 
50 
Table of events updated to include: 


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Section 
Page 
Content Update 
 
• 
Collection of exploratory biomarker added 
• 
CT scans added 
Footnotes f, h, m updated 
Table 7 
53 
Table of events updated to include: 
• 
Collection of exploratory biomarker added 
• 
CT scans added 
Footnotes f, h, m updated 
Table 8 
 
55 
Sample collection updated: 
• 
CTC updated  
• 
CA19.9 updated  
Footnotes f, h, m updated 
Section 7.1 Inclusion Criteria 
 
59 
Inclusion Criteria: Updated information for Part 2   
Added a sentence “A line of therapy is defined as either having prognosed on a line of 
treatment regimen or having received at least 2 months of a treatment regimen.” 
 
Modified sentence: Of the two prior lines, subjects must have been exposed to a 
gemcitabine-based regimen for a prior line and a 5-FU-based regimen as a prior line of 
therapy. Investigational therapies as part of a prior line regimen are permitted. 
 
1. Changed carcinoma to adenocarcinoma 
3. Changed to Radiographically measurable disease of at least one site by CT scan (or 
magnetic resonance imaging, MRI, or PET/CT if allergic to CT contrast media). Imaging for 
baseline results must be obtained at most 14 days prior to Randomization. 
Changed first dose to randomization throughout. 
 
8. Clarified language to at most 7 days prior to randomization 
 
8b(i). Added prior to the screening laboratory assessment 
 
8(b)(iii). Added or 24 hour urine-determinied creatinine clearance ≥60 mL/min 


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Section 
Page 
Content Update 
 
8 (b)(iv). Deleted within 28 days of starting study 
Section 7.2 Exclusion Criteria 
61 
Exclusion Criteria:  Updated information for Part 2  
Changed baseline to randomization throughout 
12. 6. Changed Radiation to all measurable target lesions within 12 
weeks of study baseline.  
13. 7.  Changed to No measurable lesions. 
14. 8  Changed to “Current use, or any use within 14 days prior to 
Randomization, of a restricted medication (see Section 8.7), or 
subject requires any of these medications during treatment phase.” 
13/14:  Added Note: testing is not required in the absence of clinical symptoms 
15. Deleted component of regimen 
15. 17.  Subjects with a history of hypersensitivity to phenytoin, its 
inactive ingredients, or other hydantoins; or a history of prior acute 
hepatotoxicity attributable to phenytoin. 
Moved:  
16.  Subjects exhibiting idiosyncratic reactions to psoralen compounds.  
17.  Subjects with a hypersensitivity to sirolimus. 
18.  Changed to “Currently enrolled in, or have discontinued within 30 
days of Randomization, from a clinical trial involving an 
investigational product or non-approved use of a drug or device.” 
Modified: 
22. Changed to “The second weight measure should be captured prior to randomization.” 
19. 23.  Subjects who have a variety of factors influencing their ability to 
ingest and absorb oral drugs (such as unable to swallow, nausea, 
vomiting, chronic diarrhea and intestinal obstruction, etc.). 
20. 24.Subjects with central nervous system metastasis, with the 
exception of subjects who have stable brain metastases as defined as 
off steroids and no CNS progression for 6 months after CNS 
treatment. 


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Section 
Page 
Content Update 
21. 34. Screening prolongation of QT/QTc interval [e.g., > 480 
milliseconds (ms)] (CTCAE Grade 1) using Fredericia’s QT 
correction formula. 
37. Presence of symptomatic or clinically significant ascites or pleural effusion, defined as 
requiring clinical intervention in the 30 days prior to consent. However, trace or small 
amount of physiologic fluid will not be excluded.   
Section 8.7 Randomization and Blinding 
76 
22. Randomized language changed to balance 
Section 9 Assessment of Efficacy 
78 
Sections 9.1 and 9.2 updated  
Section 9.4 updated. 
Added PET/CT and clarified PK 
Section 10 Pharmacokinetic Assessment  
81 
Part 1 updated, and Part 2 added along with discussion of sampling schemes 
Section 11.1.4 Electrocardiogram  
83 
Language added to include ECGs will be performed at Screening, Day 1 of each cycle, pre-
dose, and at approximately 2 hours post-dose and at subjects’ Day 28 follow-up visit  
Section 11.2.2  Relationship to Investigational 
Product or Study Procedures 
87 
Added language on non-related 
Section 12 Statistics 
90 
Section 12.1 updated for Part 2.  
Section 12.2.1 added Evaluable 4-Cycle Population and updated Per-Protocol Population.  
Section 12.3.2 Part 2 primary objectives updated.  
 
Added sub-sections (Page 92): Key Secondary Objective, Additional Secondary Objectives, 
Exploratory Objectives. 
 
Section 12.3.3 Interim Analysis added. 
Misc 
-- 
Global:  Minor changes for formatting and consistency 
 
 


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1. 
SYNOPSIS  
Study Title  
A Randomized Phase 2/3 Multi-Center Study of SM-88 in Subjects with 
Pancreatic Cancer Whose Disease Has Progressed or Recurred  
Study Centers 
Planned 
Part 1 (completed): Approximately 36 study centers in N. America will 
participate in this study. 
Part 2: Approximately 10 to 15 study centers in N. America will participate 
in this study. 
Objectives 
Part 1: 
 
Primary Objectives: 
 
Secondary Objectives:  


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Safety Objectives: 
 
Part 2: 
 
Primary Objective 
To determine the OS of subjects treated with SM-88 used with methoxsalen, 
phenytoin, and sirolimus (MPS) versus the control arm (Physician’s 
Choice). 
Key Secondary Objective 
• To report Investigator-determined PFS. 
Additional Secondary Objectives 
Exploratory Objectives 
PK/Safety Objectives 


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Study Design 
This is a two part, open-label, prospective, randomized, multi-center, Phase 
2/3 trial in subjects with pancreatic cancer composed of the following parts: 
  
• Part 1: A total of 36 evaluable subjects will be randomized 1:1 
between two doses of SM-88 460 mg/day (230 mg b.i.d) or 920 
mg/day (460 mg b.i.d). The doses of the three conditioning agents - 
methoxsalen, phenytoin and sirolimus - will each maintain a 
consistent dose.  
• Part 2: The second part will consist of a subsequent expansion of 
the trial to further assess safety and efficacy of SM-88 containing the 
selected SM-88 RP2D from Part 1. A total of 250 subjects in the 
second part will be randomized 1:1 either to the SM-88 arm or 
Physician’s Choice of therapy for the control arm. 
Number of 
Subjects 
Planned 
Part 1: 
• There are 36 evaluable subjects planned for enrollment in the first 
part. 
 
Part 2: 
• The second part of this clinical trial will expand the use of the 
selected SM-88 dose from the first part for up to an additional 125 
subjects in addition to a Physician’s Choice control arm with 125 
subjects, for a maximum total trial size of 250 subjects.  
• For subjects who discontinue before they complete all planned study 
assessments, additional replacement subjects may be enrolled.   
Target 
Population 
Subjects will be ≥18 years of age with adequate organ function who have 
metastatic measurable pancreatic cancer. 
 
Part 1: 
• Subjects are eligible if they have histologically or cytologically 
confirmed adenocarcinoma of the pancreas with an ECOG score ≤ 2 
and with documented progression or recurrence and have failed at 
least one line of prior systemic therapy. (This will be second line or 
beyond treatment for these subjects). 
 
Part 2: 
• Subjects are eligible if they have histologically or cytologically 
confirmed adenocarcinoma of the pancreas with an ECOG score ≤ 2 
and have previously received two lines of prior systemic therapy. 
(This will be third line treatment for these subjects). 
Duration of 
Treatment 
For all subjects, treatment will continue until apparent PD (as defined in the 
protocol), unacceptable toxicity, or death. All subjects will be followed for 
OS until the end of this study, and possibly beyond their participation in the 
trial as approved by governing IRB. 
 


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It is hypothesized that subjects may show clinical benefit prior to 
demonstrating traditional RECIST-based responses.  
 
Some subjects, particularly those with active immune systems, may even 
have tumor site inflammation that is visible on computed tomography (CT) 
imaging (i.e., pseudo-progression) at the first follow-up scan. Subjects with 
radiographic evidence of PD (per RECIST 1.1 in Part 1; per the Investigator 
in Part 2), but without clinical deterioration, may be considered for repeat 
confirmation scans before clinically significant PD is defined and study 
therapy is withdrawn. This decision should be balanced against the potential 
toxicity associated with continued treatment and alternative treatment 
options and must be discussed with and approved by the Medical Monitor. 
Continuation should be evaluated at least every 4 weeks after initial 
response assessment or sooner if clinical deterioration occurs. 
 
For all subjects randomized to the Physician’s Choice control arm in Part 2, 
subjects will continue on study (with appropriate dose delay and/or 
modification if necessary) until disease progression, intolerable side effects 
or subject chooses to withdraw.  
 
Treatment interruptions: 
Any subject who experiences a DLT will have treatment discontinued until 
the toxicity is resolved to ≤ Grade 1 or returns to baseline level within 28 
days, unless the toxicity requires permanent discontinuation as described by 
the protocol.  
 
SM-88 used with MPS (Part 2 Only): 
If SM-88 is considered to be associated with a DLT, the dose of SM-88 will 
be reduced by one capsule at each dose period to a total daily dose of 460 
mg. If a subject has a second episode of any related or possibly drug-related 
DLT, SM-88 may be discontinued for up to 28 days while mitigating 
measures are attempted. If the DLT continues after restarting therapy, the 
subject will be removed from the study.   
 
If any of the methoxsalen, phenytoin, or sirolimus (MPS) is considered to be 
the component associated with a DLT, the individual component(s) may be 
discontinued for up to 28 days while mitigating measures are attempted 
(e.g., changing the timing of phenytoin to address phenytoin-related 
fatigue). This may be applied to any or all of the MPS components. If the 
DLT continues after restarting therapy, the subject will be removed from the 
study.   
 
Control Arm (Part 2 Only): 
In the case of Adverse Events or DLT in the control arm, refer to the 
prescribing information for dose modification or discontinuation. 


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Study 
Procedures/ 
Frequency 
Screening Period:   
During the Screening Period, subjects will be evaluated for their eligibility 
to participate in the study and ability to comply with all study specified 
activities.   
 
Subjects must be consented within 8 weeks after their last dose of 
chemotherapy (last dose is the day of the last drug administration). Study 
agents must be administered within 12 weeks of the last dose of 
chemotherapy. 
 
All previous cancer treatment should be discontinued prior to starting study 
medications. 
 


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Treatment Period:   
Subjects will visit the clinic on Day 1 of each treatment cycle. 
 
Treatment Cycles:   
 
Part 1 and Part 2 SM-88 Arm:  
Treatment cycles will begin on Day 1 and will be comprised of daily dosing 
with SM-88 used with MPS for 4 weeks with no break between treatment 
cycles for as long as there is no evidence of progression or safety concerns. 
 
Control (Physician’s Choice) Arm:  
 
Capecitabine treatment cycles will begin on Day 1 and will be comprised 
of 1000 mg/m2 orally twice a day, Days 1-14 on a 21-day cycle for as long 
as there is no evidence of progression. 
 
Gemcitabine treatment cycles will begin on Day 1 and will be comprised of 
1000 mg/m2 IV on Days 1, 8, and 15 on a 28-day cycle for as long as there 
is no evidence of progression. 
 
5-FU treatment cycles will begin on Day 1 and will be comprised of 2400 
mg/m2 continuous IV infusion over 46 hours on Days 1 and 15 on a 28-day 
cycle for as long as there is no evidence of progression. 
 
Safety Assessments:
Efficacy Assessments: 


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SM-88 used with MPS: 
Subjects in both parts of this study should be strongly encouraged to be on a 
low-carb diet. Inability to maintain a low-carb diet would not exclude 
subjects from participation in the trial.   
 
Control (Physician’s Choice) Arm:  
Physician’s Choice therapy will be administered for a total of 125 evaluable 
subjects until unacceptable toxicity, disease progression, or any of the 
treatment discontinuation criteria are met. 
 
Post-Study Follow-up Period: 
Twenty-eight (28) days after the last SM-88 dose or Physician’s Choice 
therapy dose, subjects will be evaluated for safety at a follow-up study visit. 
Subjects will continue to be followed at 3-month intervals via review of the 
medical records, public social media, phone or in person for survival data. 
Test Product, 
Dose, and 
Mode of 
Administration: 
 
SM-88 
Treatment Arm 
Part 1: 
• Subjects will be randomized to receive either 460 or 920 mg total 
daily dose of SM-88 used with MPS.   
• The low dose, SM-88(1) arm will receive: 
o SM-88 – one 230 mg capsule taken orally twice daily (460 
mg total). 
o Methoxsalen – one 10 mg capsule taken orally once daily. 
o Phenytoin – one 50 mg tablet taken orally once daily. 
o Sirolimus – one 0.5 mg tablet taken orally once daily. 
• The high dose, SM-88(2) arm will receive:  
o SM-88 – two 230 mg capsules taken orally twice daily (920 
mg daily). 
o Methoxsalen – one 10 mg capsule taken orally once daily. 


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o Phenytoin – one 50 mg tablet taken orally once daily. 
o Sirolimus – one 0.5 mg tablet taken orally once daily. 
 
Part 2: 
• Subjects will be randomized to either SM-88 used with MPS or 
Physician’s Choice.   
• All subjects enrolled into Part 2 of the trial who are randomized to 
SM-88 used with MPS will receive:  
o SM-88 – two 230 mg capsules taken orally twice daily (total 
920 mg daily). 
o Methoxsalen – one 10 mg capsule taken orally once daily. 
o Phenytoin – one 50 mg tablet taken orally once daily. 
o Sirolimus – one 0.5 mg tablet taken orally once daily. 
 
The four components of SM-88 used with MPS (SM-88, methoxsalen, 
phenytoin, and sirolimus) will be taken daily. It is best to take doses one 
hour before or two hours after meals, so as to ensure an empty stomach. 
They should be taken together consistently either in the morning or in the 
evening with a full glass of water – for example, before bedtime and upon 
waking up in the morning. 
 
A second dose of SM-88 will be taken 12 hours (+/- 4 hours) after the 
morning dose.  
 
Missed doses of any of the 4 agents will be omitted and skipped. Subjects 
who miss a dose of any of the 4 agents, for any reason, will omit that dose 
and take the next dose at the next regularly scheduled time point 12 hours 
(+/- 4 hours) after the missed dose was due. If the morning (AM) dose is 
missed, subjects will continue with the PM dose as scheduled and may take 
the adjunct medications (methoxsalen, phenytoin, and sirolimus) with their 
PM dose. If the PM dose is missed, subjects will skip that dose and resume 
dosing with the AM dose the following day.  
Reference 
Therapy, Dose, 
and Mode of 
Administration 
Part 2 Only: 
Investigator choice of the following therapies in the Control Arm: 
• Capecitabine (1000 mg/m2 orally twice a day, Days 1-14 on a 21- 
day cycle) 
• Gemcitabine (1000 mg/m2 IV on Days 1, 8, and 15 on a 28-day 
cycle) 
• 5-FU (2400 mg/m2 continuous IV infusion over 46 hours on Day 1 
and 15 on a 28-day cycle) 


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Inclusion 
Criteria 
Inclusion criteria include the following: 
 
Part 1: 
Biopsy-proven metastatic pancreatic adenocarcinoma with documented 
radiographic disease progression on or after one or more systemic therapies, 
including a gemcitabine-based chemotherapy regimen or any first line 
regimen as listed in PANC G National Comprehensive Cancer Network 
(NCCN) current guidelines. Chemotherapy given as part of prior chemo-
radiation in the setting of non-metastatic pancreatic cancer does not count as 
a line of therapy. Chemotherapy given for at least 4 months as adjuvant after 
CR is considered as a first line therapy. 
Part 2: 
Biopsy-proven metastatic pancreatic adenocarcinoma on or after two prior 
lines of systemic therapy. A line of therapy is defined as either: having 
progressed on a treatment regimen, or having received at least 2 months of a 
treatment regimen. Chemotherapy given as part of prior chemo-radiation in 
the setting of non-metastatic pancreatic cancer does not count as a line of 
therapy unless metastases develop within 6 months of completing the 
chemo-sensitization. Chemotherapy given for at least 4 months as adjuvant 
after a CR to any therapy (e.g., surgery or radiation therapy) is also 
considered a first line therapy. Of the two prior lines, subjects must have 
been exposed to a gemcitabine-based regimen for a prior line and a 5-FU-
based regimen as a prior line of therapy. Investigational therapies as part of 
a prior line regimen are permitted.   
1. Subjects have received two (2) and not more than two (2) previous 
systemic regimens for the treatment of pancreatic adenocarcinoma. 
2. Subjects must be eligible to receive one or more of the Physician’s 
Choice options. 
3. Radiographically measurable disease of at least one site by CT scan 
(or MRI or PET/CT, if allergic to CT contrast media). Imaging for 
baseline results must be obtained at most 14 days prior to 
Randomization. 
4. Subjects must have completed any investigational cancer therapy at 
least 30 days prior to Randomization. 
5. Subjects must have completed any other cancer therapy at least 14 
days prior to Randomization, and recovered from major side effects 
of prior therapies or procedures.  
6. ≥18 years of age. 
7. ECOG PS ≤2. 
8. Adequate organ function, defined as follows (lab results must be 
obtained at most 7 days prior to Randomization): 
a. All laboratory parameters ≤ Grade 2 NCI Common 
Terminology Criteria for Adverse Events (CTCAE) criteria. 
b. In addition:  


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i. Hematologic: Platelets ≥ 100 x 109 g/dL; Absolute 
Neutrophil Count ≥ 1.5 x 109/L (without platelet 
transfusion or growth factors within the 7 days prior 
to the screening laboratory assessment). 
ii. Hepatic: aspartate transaminase/alanine transaminase 
≤ 2.5 x upper limit of normal (ULN); total or 
conjugated bilirubin ≤ 1.5 x ULN, alkaline 
phosphatase (ALP) < 2.5 x ULN. 
iii. Renal: serum creatinine ≤ 1.5 x ULN and creatinine 
clearance ≥ 60 mL/min as calculated by the Cockroft-
Gault method, or 24 hour urine-determined creatinine 
clearance ≥60 mL/min. 
iv. Coagulation: international normalized ratio (INR) ≤ 
1.2. 
v. Albumin: ≥ 3.0 g/dL. 
9. All acute toxic effects of any prior antitumor therapy resolved to 
Grade ≤ 1 before Randomization, with the exception of alopecia and 
neurotoxicity (CTCAE Grade 1 or 2 permitted). 
10. Able and willing to provide written informed consent to participate 
in this study. 
11. Subject is willing and able to comply with the protocol for the 
duration of the study, including undergoing treatment and scheduled 
visits and examinations including follow-up.  
12. Subjects must be able to swallow whole capsules. 
13. Female subjects must either be of non-reproductive potential, not 
breast-feeding or must have a negative urine or serum pregnancy test 
within 28 days of Randomization, confirmed prior to treatment on 
Cycle 1 Day 1.  
14. Subjects of fertile potential who engage in heterosexual intercourse 
with partners of childbearing potential must attest to the use of 
highly effective contraception while enrolled in the study and for at 
least 6 months following the last dose of study drug. Highly 
effective birth control methods include the following (the subject 
should choose 2 to be used with their partner):   
a. Oral, injectable, or implanted hormonal contraceptives. 
b. Condom with a spermicidal foam, gel, film, cream, or 
suppository. 
c. Occlusive cap (diaphragm or cervical/vault cap) with a 
spermicidal foam, gel, film, cream, or suppository. 
Or any one of the following: 
a. Intrauterine device. 
b. Intrauterine system (for example, progestin-releasing coil). 
c. Vasectomized male (as determined by the Investigator). 
d. Tubal ligation/sterilization (female). 
 


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Exclusion 
Criteria 
Exclusion criteria are as follows: 
 
1. Any screening laboratory, ECG, or other findings that, in the opinion 
of the Investigator, Medical Monitor or the Sponsor, indicate an 
unacceptable risk for the subject’s participation in the study.   
2. History or evidence of any clinically significant disorder, condition, 
or disease that, in the opinion of the Investigator or Medical 
Monitor, would pose a risk to the subject’s safety or interfere with 
the study evaluations, procedures, or completion. Examples include: 
intercurrent illness such as active uncontrolled infection, active or 
chronic bleeding event within 28 days of Randomization, 
uncontrolled cardiac arrhythmia, or psychiatric illness/social 
situation that would limit compliance with study requirements.  
3. History of a concurrent or second malignancy, except for: 
adequately treated localized basal cell or squamous cell carcinoma of 
the skin, adequately treated superficial bladder cancer, adequately 
treated Stage 1 or 2 cancer currently in complete remission; or any 
other cancer that has been in complete remission for ≥ 5 years. 
4. Subjects with MSI-H pancreatic cancer who have not previously 
received pembrolizumab. 
5. Subjects with any known actionable mutation (e.g., BRCA mutation) 
who have not been treated with an approved drug for the mutation 
(the drug does not have to be approved for the indication). 
6. Radiation to all measurable lesions within 12 weeks of study 
baseline. 
7. No measurable lesions. 
8. Current use, or any use within 14 days prior to Randomization, of a 
restricted medication (see Section 8.7), or subject requires any of 
these medications during treatment phase. 
9. Major surgery, defined as any surgical procedure that involves 
general anesthesia and a significant incision (i.e., larger than that 
required for placement of central venous access, percutaneous 
feeding tube, or biopsy) within 28 days of the first dose of study 
drug. 
10. Minor surgical procedures within 7 days of Randomization, or not 
yet recovered from any prior surgery. 
11. Any dysphagia, odynophagia, esophageal dysmotility or stricture, 
known gastrointestinal (GI) malabsorption syndrome, or intractable 
diarrhea that may significantly alter the absorption of any of the 
components of SM-88 used with MPS, e.g., cirrhosis. 
12. Known human immunodeficiency (HIV) virus infection. Note: HIV 
testing is not required in the absence of clinical suspicion. 
13. Known hepatitis B surface antigen (HBsAg) positive. Note: testing 
is not required in the absence of clinical suspicion. 
14. Known hepatitis C (HCV) viral RNA present. Note: testing is not 
required in the absence of clinical suspicion. 


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15. Have previously been enrolled in this study or any other study 
investigating SM-88 or have previously received any SM-88, 
methoxsalen, phenytoin, or sirolimus in a clinical trial. 
16. History of any known drug allergies to any study medication. 
17. Subjects with a history of hypersensitivity to phenytoin, its inactive 
ingredients, or other hydantoins; or a history of prior acute 
hepatotoxicity attributable to phenytoin. 
18. Subjects exhibiting idiosyncratic reactions to psoralen compounds.  
19. Subjects with a hypersensitivity to sirolimus. 
20. Currently enrolled in, or have discontinued within 30 days of 
Randomization, from a clinical trial involving an investigational 
product or non-approved use of a drug or device. 
21. Subjects must not have any clinically significant and uncontrolled 
major medical condition(s) including, but not limited to: 
uncontrolled nausea/vomiting/diarrhea; active uncontrolled 
infection; symptomatic congestive heart failure (New York Heart 
Association [NYHA] class ≥ II); unstable angina pectoris or cardiac 
arrhythmia; psychiatric illness/social situation that would limit 
compliance with study requirements. 
22. >5% weight loss at any time during the 28 days prior to consent, or 
>5% change in weight from consent (Screening) to Randomization 
(must be at least 1 week apart). This second weight measure should 
be captured prior to Randomization. 
23. Subjects who have a variety of factors influencing their ability to 
ingest and absorb oral drugs (such as unable to swallow, nausea, 
vomiting, chronic diarrhea and intestinal obstruction, etc.). 
24. Subjects with central nervous system metastasis, with the exception 
of subjects who have stable brain metastases as defined as off 
steroids and no CNS progression for 6 months after CNS treatment. 
25. Pregnant or lactating women. 
26. Substance abuse that cannot be ended, or subjects with mental 
disorders that will prevent compliance or evaluation including 
uncontrolled schizophrenia, uncontrolled depression or other 
uncontrolled disorders. 
27. Subjects with a history of the light sensitive diseases for which 
methoxsalen would be contraindicated. Diseases associated with 
photosensitivity include: lupus erythematosus, porphyria cutanea 
tarda, erythropoietic protoporphyria, variegate porphyria, xeroderma 
pigmentosum, and albinism. 
28. Subjects treated, or anticipated to be treated, with delavirdine (due to 
potential for loss of virologic response and possible resistance to 
delavirdine or to the class of non-nucleoside reverse transcriptase 
inhibitors caused by phenytoin). 
29. Subjects with cutaneous melanoma or invasive squamous cell 
carcinomas or a history thereof, except for those in complete 


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remission for ≥5 years (due to contraindication for use of 
methoxsalen). 
30. Subjects with prior organ transplant or being treated, or anticipated 
to be treated, with cyclosporine (because long-term administration of 
the combination of cyclosporine and sirolimus is associated with 
deterioration of renal function). 
31. Subjects with a seizure disorder that is not well controlled or who 
have required a change in seizure medications within 60 days of 
Randomization. 
32. Subjects treated, or anticipated to be treated, with a calcineurin 
inhibitor (because concomitant use of sirolimus and a calcineurin 
inhibitor increases the risk of calcineurin inhibitor-induced 
hemolytic uremic syndrome/thrombotic thrombocytopenic 
purpura/thrombotic microangiopathy [HUS/TTP/TMA]). 
33. Subjects with interstitial lung disease (ILD) [including pneumonitis, 
bronchiolitis obliterans organizing pneumonia (BOOP), and 
pulmonary fibrosis]. 
34. Screening prolongation of QT/QTc interval [e.g., > 480 milliseconds 
(ms)] (CTCAE Grade 1) using Fredericia’s QT correction formula. 
35. A family history of Long QT Syndrome or Torsades de Pointes.  
36. Clinically significant cataracts or aphakia. 
37. Presence of symptomatic or clinically significant ascites or pleural 
effusion, defined as requiring clinical intervention in the 30 days 
prior to consent. However, trace or small amount of physiologic 
fluid will not be excluded. 
Criteria for 
Evaluation: 
 
Safety 
Safety will be evaluated by recording adverse events (AEs), clinical 
laboratory results, physical examinations, vital signs, and ECGs. 
Efficacy 
Part 1: 
Part 2: 
Efficacy of SM-88 used with MPS will be measured by OS; Investigator-
determined PFS; 
 


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PK 
Part 1: 
Part 2: 
Statistical 
Methods: 
Part 1: 
The trial will accrue 36 evaluable subjects during Part 1, in order to have 
sufficient subjects to determine which of the two doses will move forward 
into the expansion cohort of Part 2.  
 
Sample Size 
Justification 
The primary objective for Part 1 of this trial is to determine the ORR 
(between the included doses) based on the independent blinded third party 
review of radiologic imaging (i.e., diagnostic, contrast enhanced, CT) using 
RECIST 1.1 criteria as the endpoint. 
 
Part 2: 
Part 2 of the trial was amended to become a Phase 2/3, two-arm study with 
SM-88 used with MPS versus a Physician’s Choice control. Part 2 of the 
trial will accrue 250 subjects, with 125 in each arm. 
 
The primary endpoint is the time from Randomization to death from any 
cause (Overall Survival; OS). It is estimated that the control group will have 
a median survival time of 3 months, based on reports in the literature. The 
statistical plan developed assumes a hazard ratio of 0.667, which assumes a 
3-month median OS for the control arm and hence a 4.5-month median OS 
for the SM-88 arm. In order to have 80% power, using a two-sided log-rank 
test with a significance level 0.025, 125 subjects in each arm will be 
enrolled. An interim efficacy analysis is planned when 75% of events are 
reached. This could result in early stopping of the trial for efficacy.   
 
To account for dropouts of subjects who withdraw for reasons other than 
any of the outcomes (death, PD or toxicity), additional subjects may be 
enrolled to ensure an adequate number of subjects who have received at 
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cohort). The total number of subjects consented will depend on the number 
of subjects receiving study treatment.  
Safety 
All relevant safety data will be listed, summarized and reviewed after each 
subject completes each treatment cycle or after a subject has discontinued 
from the study. 
Efficacy 
• The efficacy of SM-88 used with MPS will be established using the 
primary endpoint of OS, compared by the log-rank test, stratified by 
randomization stratification factors (investigative site factors, 
Physician’s Choice and ECOG (0-1 vs. 2). A Kaplan-Meier plot, and 
quartile estimates with 2-sided 95% confidence intervals (CIs) will 
also be presented.   
• Disease progression will be assessed according to study-specified 
end points. The response rate will be estimated with 95% exact 2-
sided CIs. PFS will be summarized by using a log-rank test, Kaplan-
Meier plot, and quartile estimates with 2-sided 95% CIs.   
PK 
PK data will be summarized by treatment using descriptive statistics. 
 
This study will be conducted in accordance with the guidelines of Good Clinical Practices 
including archiving of essential documents.  
 


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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ...............................................................................................1 
PROTOCOL APPROVAL PAGE ...................................................................................................1 
INVESTIGATOR PROTOCOL AGREEMENT ............................................................................3 
1. 
SYNOPSIS .................................................................................................................10 
LIST OF TABLES .........................................................................................................................29 
2. 
LIST OF ABBREVIATIONS.....................................................................................30 
3. 
INTRODUCTION ......................................................................................................33 
3.1. 
SM-88 Background .....................................................................................................33 
3.2. 
Safety of SM-88 Used with MPS ...............................................................................35 
3.3. 
SM-88 Supportive Clinical Data ................................................................................36 
3.4. 
Effect of Food on SM-88 ............................................................................................37 
4. 
OBJECTIVES - PART 1 .............................................................................................38 
4.1. 
Primary Objective .......................................................................................................38 
4.2. 
Secondary Objectives .................................................................................................38 
4.3. 
Safety Objectives ........................................................................................................38 
5. 
OBJECTIVES - PART 2 .............................................................................................39 
5.1. 
Primary Objective .......................................................................................................39 
5.2. 
Key Secondary Objective ...........................................................................................39 
5.3. 
Additional Secondary Objectives ...............................................................................39 
5.4. 
Exploratory Objectives ...............................................................................................39 
5.5. 
PK/Safety Objectives ..................................................................................................39 
6. 
SUBJECT INVESTIGATIONAL PLAN ...................................................................40 
6.1. 
Overall Study Design ..................................................................................................40 
6.2. 
Screening Period (Part 1 and Part 2) ...........................................................................40 
6.3. 
Efficacy Assessments .................................................................................................44 
6.4. 
Safety Assessments .....................................................................................................45 
6.4.2. 
Post-Study Follow-up Period ......................................................................................46 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................62 
7.1. 
Inclusion Criteria ........................................................................................................62 


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7.2. 
Exclusion Criteria .......................................................................................................65 
7.3. 
Criteria for Subject Withdrawal ..................................................................................67 
7.4. 
Criteria for Study Site Discontinuation ......................................................................68 
7.5. 
Criteria for Study Discontinuation..............................................................................68 
8. 
TREATMENT ............................................................................................................69 
8.1. 
Treatments Administered ............................................................................................69 
8.2. 
SM-88 used with MPS ................................................................................................69 
8.2.1. 
Control Arm (Physician’s Choice) .............................................................................70 
8.3. 
Adverse Events ...........................................................................................................70 
8.3.1. 
SM-88 used with MPS ................................................................................................70 
8.3.2. 
Control Arm (Physician’s Choice) .............................................................................74 
8.4. 
Dose Interruption / Discontinuation of SM-88 used with MPS .................................74 
8.4.1. 
Permanent discontinuation of SM-88 used with MPS ................................................75 
8.4.2. 
Dose interruption of SM-88 and MPS from drug-related, or possibly related 
DLTs ...........................................................................................................................75 
8.4.3. 
Risk Mitigation/Discontinuation of MPS components of SM-88 used with 
MPS ............................................................................................................................77 
8.5. 
Dose Interruption / Discontinuation of Control Arm (Physician’s Choice) 
Therapy .......................................................................................................................78 
8.6. 
Description and Handling of Product .........................................................................78 
8.6.1. 
SM-88 used with MPS ................................................................................................78 
8.6.2. 
Part 2:  Control Arm (Physician’s Choice) .................................................................79 
8.7. 
Randomization and Blinding ......................................................................................80 
8.8. 
Concomitant Medications ...........................................................................................80 
8.9. 
Treatment Compliance ................................................................................................81 
9. 
ASSESSMENT OF EFFICACY ................................................................................82 
9.1. 
Overall Survival (OS) .................................................................................................82 
9.2. 
Progression-Free Survival (PFS) ................................................................................82 
10. 
PHARMACOKINETIC ASSESSMENT ...................................................................85 


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11. 
ASSESSMENT OF SAFETY .....................................................................................87 
11.1. 
Safety Parameters .......................................................................................................87 
11.1.1. 
Demographics and History .........................................................................................87 
11.1.2. 
Vital Signs ..................................................................................................................87 
11.1.3. 
Physical Examination .................................................................................................87 
11.1.4. 
Electrocardiogram .......................................................................................................87 
11.1.5. 
Safety Laboratory Assessments ..................................................................................87 
11.1.6. 
Ophthalmologic Exam (only required for those subjects enrolled in Part 1) .............88 
11.2. 
Adverse Events (AE) ..................................................................................................90 
11.2.1. 
Definition of Adverse Events .....................................................................................90 
11.2.2. 
Relationship to Investigational Product or Study Procedures ....................................91 
11.2.3. 
Assessment of Severity ...............................................................................................92 
11.2.4. 
Reporting Adverse Events ..........................................................................................92 
12. 
STATISTICS ..............................................................................................................94 
12.1. 
Hypotheses ..................................................................................................................94 
12.2. 
Analysis Considerations .............................................................................................96 
12.2.1. 
Analysis Populations ..................................................................................................96 
12.2.2. 
Exploratory Combined Population .............................................................................97 
12.2.3. 
Initial Analysis ............................................................................................................97 
12.3. 
Final Analysis .............................................................................................................98 
12.3.1. 
Safety Analysis ...........................................................................................................98 
12.3.2. 
Efficacy Analyses .......................................................................................................98 
12.3.3. 
Interim Analysis ........................................................................................................101 
12.3.4. 
Pharmacokinetic Analyses ........................................................................................102 
13. 
RESPONSIBILITIES ...............................................................................................103 
13.1. 
Investigator Responsibilities .....................................................................................103 
13.1.1. 
Good Clinical Practice ..............................................................................................103 
13.1.2. 
Institutional Review Board Approval .......................................................................103 
13.1.3. 
Informed Consent .....................................................................................................104 
13.1.4. 
Treatment Withdrawal ..............................................................................................104 
13.1.5. 
Withdrawal of Consent .............................................................................................104 
13.1.6. 
Confidentiality ..........................................................................................................105 


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13.1.7. 
Study Files and Retention of Records ......................................................................105 
13.1.8. 
Case Report Forms ...................................................................................................106 
13.1.9. 
Drug Accountability .................................................................................................106 
13.1.10. 
Audits and Inspections ..............................................................................................107 
13.1.11. 
Protocol Compliance ................................................................................................107 
13.2. 
Sponsor Responsibilities ...........................................................................................107 
13.2.1. 
Protocol Modifications .............................................................................................107 
13.2.2. 
Study Report, Presentations and Publications ..........................................................107 
13.2.3. 
Data and Safety Monitoring ......................................................................................108 
13.3. 
Joint Investigator/Sponsor Responsibilities ..............................................................108 
13.3.1. 
Access to Information for Monitoring ......................................................................108 
13.3.2. 
Access to Information for Auditing or Inspection ....................................................108 
13.3.3. 
Study Discontinuation ..............................................................................................108 
14. 
APPENDIX A: SM-88 MOA ...................................................................................109 
15. 
APPENDIX B: DETAILED DESCRIPTIONS OF ADVERSE EVENTS ..............112 
16. 
LIST OF REFERENCES ..........................................................................................123 
 
 


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LIST OF TABLES 
Table 1: 
Content Updates (Version 7 to 8) .................................................................................4 
Table 2: 
List of Abbreviations ..................................................................................................30 
Table 3. 
Activities Performed During Screening Period ..........................................................41 
Table 4: 
Recommended Dose Modifications for SM-88 in Part 2 ...........................................43 
Table 5: 
Part 1 - SM-88 used with MPS Time and Events Schedule .......................................47 
Table 6: 
Part 2 - SM-88 used with MPS Time and Events Schedule .......................................50 
Table 7: 
Control Arm - Capecitabine Time and Events Schedule ............................................53 
Table 8: 
Control Arm - 5-FU Time and Events Schedule ........................................................56 
Table 9: 
Control Arm - Gemcitabine Time and Events Schedule ............................................59 
Table 10: Adverse Events Possibly Associated with SM-88 ......................................................71 
Table 11: Adverse Events Associated with Sirolimus ................................................................72 
Table 12: Adverse Events Associated with Methoxsalen ...........................................................73 
Table 13: Adverse Events Associated with Phenytoin ...............................................................74 
Table 14: Permanent Discontinuation Criteria for SM-88 used with MPS ................................75 
Table 15: Dose-Limiting Toxicities Criteria for SM-88 used with MPS ...................................77 
Table 16: Drug Dispensing Guidelines .......................................................................................79 
Table 17: Safety Laboratory Analytes ........................................................................................89 
Table 18: Grading of Adverse Event Severity ............................................................................92 
 
 


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2. 
LIST OF ABBREVIATIONS 
Table 2: 
List of Abbreviations 
Abbreviation or Specialist 
Term 
Definition 
ACE 
Angiotensin-converting enzyme 
AE 
Adverse event 
AUC0-inf 
Area under the plasma concentration-time curve from time 0 
extrapolated to infinity 
AUC0-t 
Area under the plasma concentration-time curve from time 0 
up to time “t” 
AUCtau 
Area under the plasma concentration-time curve between 
dose administrations 
BICR 
Blinded independent central review 
b.i.d 
Bis in die (or dosing twice a day) 
BOOP 
Bronchiolitis obliterans organizing pneumonia 
CA-19.9 
Tumor marker used primarily in management of pancreatic 
cancer 
CBR 
Clinical Benefit Rate 
CI 
Confidence interval 
CL/F 
Oral clearance 
Cmax 
Maximum observed plasma concentration 
CNI 
Calcineurin Inhibitor 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTC 
Circulating tumor cell 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of response 
DRESS 
Drug reaction with eosinophilia and systemic symptoms 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 


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Abbreviation or Specialist 
Term 
Definition 
Evaluable subject 
A subject who has received at least 1 full cycle of therapies 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practices 
GI 
Gastrointestinal 
H 
Hypothesis 
ICH 
International Conference on Harmonization 
ILD 
Interstitial lung disease 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
LAT1 
L-type amino acid transporter 1 
LDH 
Lactate dehydrogenase 
MPS 
Methoxsalen, phenytoin, and sirolimus 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
mTOR 
Mammalian target of rapamycin 
NCCN 
National Comprehensive Cancer Network 
NLR 
Neutrophil:lymphocyte ratio 
NOAEL 
No-observed-adverse-effect-level 
O2 
Oxygen 
ORR 
Overall Response Rate 
OS 
Overall Survival 
OU 
Oculus uterque (both eyes) 
PABA 
p-Aminobenzoic acid 
PD 
Progressive disease 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PML 
Progressive multifocal leukoencephalopathy 
PR 
Partial response 
PRO 
Patient-reported outcome 


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Abbreviation or Specialist 
Term 
Definition 
PS 
Performance Status 
q.d. 
Quadue die (or dosing once a day) 
RD 
Recurrent disease 
RECIST 
Response Evaluation Criteria in Solid Tumors 
ROS 
Reactive oxygen species 
RP2D 
Recommended Phase II Dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SJS 
Stevens-Johnson Syndrome 
SM-88 
D,L-alpha-metyrosine (racemetyrosine) 
SM-88 used with MPS 
SM-88 (D,L-alpha-metyrosine), methoxsalen, phenytoin, 
and sirolimus 
SM-88 used with M2PS 
SM-88 (D,L-alpha-metyrosine), melanin and melanotan 2, 
phenytoin, and sirolimus 
SUV 
Standardized uptake value 
t½ 
Apparent terminal phase half-life 
Tmax 
Time to Cmax 
TEN 
Toxic epidermal necrolysis 
ULN 
Upper limit of normal 
UV 
Ultraviolet 
UVA 
Ultraviolet A 
Vz/F 
Apparent volume of distribution 
Kz 
Apparent terminal phase elimination rate constant 
 
 


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3. 
INTRODUCTION 
Approximately 53,070 people develop exocrine pancreatic cancer each year in the United States. 
Due to its typically aggressive growth profile and late-stage presentation of symptoms, one-year 
mortality is 80% (American Cancer Society) with few effective treatment alternatives. Surgical 
resection offers the best chance of cure. However, only 9% of subjects are diagnosed at the 
localized stage, causing the majority of pancreatic cancer cases to be unresectable (Siegel et al., 
2016).  
First-line systemic therapies are typically gemcitabine-based or fluorouracil/leucovorin-based 
combination regimens. Despite high toxicity levels, with the majority of subjects experiencing 
Grade 3 or greater adverse events, most progress within the first six months of treatment (Conroy 
et al., 2011; Von Hoff et al., 2013). The optimal second-line regimen has not been established.  
A limited amount of data suggests that second-line therapy may affect survival, and it is 
reasonable to consider further chemotherapy in subjects who maintain a good Performance 
Status (PS). A recently approved therapy using nanoliposomal irinotecan plus fluorouracil and 
folinic acid in the second-line setting demonstrated median OS of 6.1 months and only a 7.7% 
response rate (Wang-Gilliam et al., 2016), showing the need for additional therapeutic options.  
Equally distressing, the small increases in responses and progression-free survival (PFS) come 
with high levels of toxicity and loss of quality of life. 
In the past, cytotoxic chemotherapy agents were developed without cancer-specific targets.  
More recently, approved targeted agents with novel mechanisms of action, have been shown to 
provide clinical benefit, without the same dose-limiting toxicity associated with cytotoxic drugs.  
Unfortunately, by their very definition, these agents are useful only in small numbers of selected 
subjects. Thus, there is a need for more effective, less toxic, and broadly applicable anti-cancer 
agents (Gatenby et al., 2009; Kohner et al. 2015). 
3.1. 
SM-88 Background 
Many studies have affirmed the role of oxidative stress in carcinogenesis (Moriya et al., 2001; 
Wiseman and Halliwell, 1996). Cells are exposed to various exogenous to endogenous 
(intracellular) sources of oxidative stress primarily produced by reactive oxygen metabolism, 
immune responses, and inflammation. The outcome of these processes is the production of 
reactive oxygen/nitrogen species (reactive oxygen species [ROS]/reactive nitrogen species) 
interacting and damaging cellular DNA that can lead to mutations, genomic instability (pre-
cancerous state), and eventually to malignant transformations (cancerous state). These changes 
are also proposed as a therapeutic mechanism for targeted cell death (Kryston et al., 2011; 
Epstein et al., 2014; Akladios et al., 2015). 
Natural tyrosine undergoes rapid renal clearance and published literature highlights the 
preferential uptake by cancer cells in comparison to normal healthy cells (Fuchs and Bode, 
2005). The normal conversion of cellular phenylalanine to tyrosine and specific transport of 
tyrosine would suggest limited uptake of this product in environments where tumor cells are not 
present. One example of tyrosine’s selectivity is the radiolabeled tyrosine derivative, 18F-


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Fluoroethyl-L-Tyrosine, that has been extensively studied as a diagnostic agent in positron 
emission tomography (PET) imaging of cancer (Hutterer et al., 2017). 
SM-88 (D,L-alpha-metyrosine, racemetyrosine) is a novel dysfunctional modified amino acid.  
SM-88 is used with low doses (lower than doses used for approved indications) of three 
repurposed agents, methoxsalen, phenytoin, and sirolimus (hereafter, referred to as MPS). In 
2019, SM-88 was granted the USAN certified name of racemetyrosine. SM-88 used with MPS, 
leverages the known altered metabolism of cancer (also known as the Warburg effect) to enhance 
and target the delivery of its amino acid and oxidizing reactive lipid species to the cancer (Lynch 
et al., 2000; Shigemitsu et al., 1999; Hara et al., 1998; May and Buse, 1989; Mortimer et al., 
1987; Wiriyasermkul et al., 2012; Wei et al., 2016). SM-88 is believed to disrupt cancer cell 
protein synthesis processes and cause a breakdown of the cancer cells’ regulatory proteins. The 
MPS components are used to create an environment which: 1) increases absorption of SM-88 
into the tumor environment through increased cellular ketosis (sirolimus); sirolimus at these 
doses is reported to affect serum and intra-cellular glucose in the desired manner, i.e. increases 
the cancer cells’ dependency on amino acids and lipids for biomass and energy, 2) increase the 
production of reactive lipid species (phenytoin), and 3) enhance the effect of oxidative stress 
selectively inside the cancer cell (methoxsalen). Cancer cells exist in a highly oxidative 
intracellular environment due to the Warburg effect and related metabolic changes, and this 
combination of agents is intended to accentuate the intensity of that ROS stress leading to 
apoptosis. A further discussion of the mechanism of action for SM-88 used with MPS is included 
in APPENDIX A:  SM-88 MOA.   
The three repurposed agents, methoxsalen, phenytoin and sirolimus, are intended to adjust the 
tumor microenvironment for increased overall effectiveness of the denatured amino acid (SM-
88), rather than for their indicated/approved uses. Thus, these three agents are administered in 
lower doses than for their approved uses. The safety information for these three agents is taken 
from their respective Reference Listed Drug packaging inserts and prescribing information. 
Sirolimus is an approved immunomodulator used for prophylaxis of organ rejection in renal 
transplantation (Rapamune®; Package Insert, 2018). The current recommended dose of sirolimus 
is 2 to 5 mg/day with a 6 to 15 mg loading dose, higher than the 0.5 mg/day dose to be studied in 
this trial. Methoxsalen is approved for the treatment of psoriasis, eczema, vitiligo, and some 
cutaneous lymphomas when simultaneously exposing the skin to ultraviolet A (UVA) light 
(PUVA therapy) (Oxsorlan Ultra® Package Insert, 2015). The current recommended dose of 
methoxsalen for these indications is 20 to 70 mg/day, higher than the 10 mg/day dose to be 
studied in this trial. Phenytoin is currently approved as an anti-seizure medication (Dilantin® 
Package Insert, 2017). The current recommended dose of phenytoin in the management of 
seizure disorders is 300 to 600 mg/day, higher than the planned 50 mg/day dose to be studied in 
this trial.  
D,L-alpha-metyrosine (racemetyrosine, SM-88) is the racemic mixture of alpha-metyrosine. A 
related drug, L-alpha-metyrosine (Demser®), is approved for the treatment of 
pheochromocytoma (Demser® Package Insert, 2015). The approved dose of L-metyrosine is 
1000 to 4000 mg/day. 
 


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3.2. 
Safety of SM-88 Used with MPS  
In Part 1 of this study (Tyme-88-Panc), there have been two reported cases of possibly drug 
related/related serious adverse event (Grade ≥ 3), arthralgia and hypotension, both occurring in 
one subject. To date, SM-88 at doses of up to 920 mg/day has not been associated with a dose-
limiting toxicity. In pre-clinical toxicity studies, as reported at ESMO 2016, the no-observed-
adverse-effect-level (NOAEL) has been found to be at doses greater or equal to approximately 
ten times the human-equivalent doses of SM-88’s baseline dose in this clinical trial, i.e. 460 
mg/day (Sokol G et al., 2016).  
In an open-label, pilot study (Hoffman et al., 2013a; Hoffman et al., 2013b), a similar SM-88 
based therapy (referred to as SM-88 used with M2PS) was administered to subjects with 
progressive metastatic cancer. In this study, SM-88 used with M2PS was comprised of an oral 
regimen of 225 mg SM-88, 50 μg melanin, 15 mg phenytoin, and 0.2 mg sirolimus, and a 
subcutaneous regimen of 5 mg SM-88, and the other containing 10 μg melanotan II, 2 mg 
phenytoin, and 0.05 mg sirolimus. There were no drug-related Grade 3 or 4 AEs, and 17% (5/30) 
of subjects reported drug-related Grade 2 AEs. No subject was withdrawn from the study or 
discontinued from treatment due to an AE, and no subject had a dose reduction or interruption of 
study drug administration due to an AE. All subjects experienced hyperpigmentation (97% 
Grade 1), which was an expected event as hyperpigmentation is associated with the use of 
melanin. Thirteen percent (13%) of subjects (4/30) experienced a Grade 2 transient fatigue at the 
initiation of therapy, which generally resolved within the first two weeks, and 3% (1/30) 
experienced Grade 2 pain. There were no other Grade 2 or above AEs. In addition, average 
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) scores decreased from 
1.6 at baseline to 0.6 after six weeks of treatment. 
In another clinical trial (Tyme 2016b), SM-88 used with MPS was studied in an asymptomatic 
prostate cancer population, with SM-88 used with MPS administered daily over a six-month 
period (NCT02796898). Preliminary results showed no reported serious adverse events over 85 
months of cumulative subject experience as presented at ASCO GU in 2018 and elsewhere 
(Roach M et al., 2018; Del Priore et al., 2017a; Del Priore et al., 2017b; Del Priore et al., 2017c). 
SM-88 dosing in this ongoing study was also increased from the original pilot study referenced 
above during a dose ranging portion, from 230 mg/day (q.d. dosing) to 460 mg/day (230 mg 
b.i.d). Dosing of sirolimus (0.5 mg/day) and phenytoin (50 mg/day) was consistent between both 
studies. 10 mg/day of methoxsalen was substituted for currently unavailable same class 
components in the pilot study (melanin and melanotan II), without a change in observed 
tolerability or therapeutic effects. There were Grade 2 and 3 events that in the opinion of the 
Investigator were not drug related. In the same trial, one subject experienced a Grade 3 adverse 
event (hyperkalemia) and two subjects experienced Grade 2 adverse events (urinary tract 
infection, phimosis and gouty arthritis) that were reported as non-drug related (Del Priore et al., 
2017c).   
There were no ocular toxicities reported in the Tyme 2016b trial. In addition, as reported at the 
European Society of Medical Oncology in Barcelona in July 2019, no ocular toxicities have yet 
been documented in Part 1 of this Tyme-88-Panc trial. Therefore, although required for Part 1 of 
the trial, the requirements for ophthalmological exams has been removed from Part 2 of this trial.    


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3.3. 
SM-88 Supportive Clinical Data 
In the pilot study of SM-88 used with M2PS (see description above) in 30 subjects with a variety 
of progressive, metastatic cancer types, results were supportive of a therapeutic effect (Hoffman 
et al., 2013a; Hoffman et al., 2013b, Stega et al 2019). The median PFS overall was 14.7 months. 
The clinical benefit rate (CR + PR + stable disease [SD], as per Response Evaluation Criteria for 
Solid Tumors [RECIST] 1.1) was 90% (27/30), consisting of four complete responses (CRs), six 
PRs and 17 SDs (Stega et al 2019). In this trial, SM-88 used with M2PS was associated with a 
>2x increase (p<0.05) in PFS compared to the PFS immediately preceding the use of SM-88 
used with M2PS (penultimate PFS). As discussed above, there were no reported significant 
toxicities (Grade ≥ 3) associated with the drug regimen (Hoffman et al., 2013b; Hoffman et al., 
2014; Sokol et al., 2016). These clinical experiences have been updated, collated and published 
in conjunction with ASCO 2017 (Hoffman et al., 2017a; Hoffman et al., 2017b). In both of these 
updated reports, the safety and clinical results were consistent with the initial publications.  
Eleven subjects with pancreatic cancer were identified following a case review of subjects 
treated with SM-88 used with M2PS in the pilot study and compassionate use program 
(presented at ASCO GI 2018) (Hoffman et al., 2017b). The average age was 63.2 (44-81), 36.4% 
(4/11) were female. Prior treatment included surgery only (n = 3), chemo only (n = 4), multi-
modality therapy (n = 2), and unknown or none (n = 2). Duration of treatment ranged from 3-57 
weeks (mean = 28.5). Overall reduction in tumor size was seen in 27.3% (3/11) including one 
CR with PFS of at least 6 months duration, and 2 PRs with one known PFS of 15 weeks. 72.7% 
(8/11) maintained SD for 6-61 weeks. One subject had an OS of 23.3 months with no further 
treatment, and one had an OS of 43.2 months. All subjects developed hyperpigmentation during 
treatment. Overall, the tolerability of SM-88 used with M2PS appeared acceptable. No serious or 
unexpected adverse events related to SM-88 were reported. Additional benefits have been 
documented, including: 1-3 points improvement in ECOG PS, 1-5 point mean improvement on 
European Organization for Research and Treatment of Cancer (EORTC) questionnaire (scale 1-
7), weight gain (1-5 lbs.), and reduction in pain levels (1-9 points/10 scale) with cessation of all 
analgesics by the end of Cycle 1 in 36% (4/11). 
In 2018, Tyme reported additional clinical data regarding SM-88. There was no indication of 
cross-resistance based on prior treatments, metastatic site, or other poor prognosis indicators in 
subjects enrolled in a pilot study and Compassionate Use program (Zhu et al., 2018a). Further, 
SM-88 reported no Grade 3 or 4 AEs with a modified RECIST 1.1 response rate of 41% across a 
range of breast cancer subsets (Zhu et al., 2018b). In an update of SM-88 in non-metastatic 
prostate cancer (Phase 1b/2 results), subjects treated with SM-88 used with MPS continued to 
report no drug related Grade 2, 3, or 4 AEs, and 92% of subjects maintained radiographic PFS at 
a median of 12 months from PSA recurrence. This paralleled the reduction in subjects’ 
circulating tumor cells (CTCs) (Chen et al., 2018). Previously seen hyperpigmentation with SM-
88 used with M2PS was not observed in subjects treated with SM-88 used with MPS (the 
regimen used in the non-metastatic prostate cancer Phase 1b/2 study). The potential correlation 
of SM-88 efficacy with cutaneous biomarkers may be explored in the future. Lastly, a 
retrospective review of PET-based standardized uptake value (SUV) results appeared to be 
consistent with the hypothesized metabolic mechanism of action (Bonta et al., 2018).  


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Based on the preliminary clinical experience with SM-88 used with M2PS, together with the 
similarity to SM-88 used with MPS, the Sponsor is proposing a path forward to study SM-88 
used with MPS in clinical situations where optimal treatments have not been established, 
including late-stage, pancreatic cancer. Given the continued unmet medical need in subjects with 
pancreatic cancer, and the suggestion of possible benefit along with acceptable safety findings to 
date with SM-88, we believe the initiation of this larger, prospective, randomized clinical trial is 
justified. 
3.4. 
Effect of Food on SM-88 
An open-label study (Study Y101) was conducted in 16 healthy volunteers to assess the effect of 
food on the pharmacokinetic (PK) profile of SM-88 (administered as a single agent). In this 
study, subjects received a single 300 mg dose of SM-88 under fasting or fed (high-fat, high-
calorie breakfast) in a randomized crossover fashion. When administered in the presence of a 
high-fat, high-calorie diet, the Cmax and AUC of SM-88 increased by approximately 80%.  
Overall, SM-88 was safe and well tolerated in this study. To date, the safety profile of SM-88 has 
only been assessed in subjects treated under fasting conditions. In the present study, it is 
recommended that SM-88 doses be taken one hour before or two hours after meals, so as to 
ensure an empty stomach.   
 
 


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4. 
OBJECTIVES - PART 1 
4.1. 
Primary Objective 
4.2. 
Secondary Objectives 
4.3. 
Safety Objectives 
 


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5. 
OBJECTIVES - PART 2 
5.1. 
Primary Objective 
To determine the OS of subjects treated with SM-88 used with methoxsalen, phenytoin, and 
sirolimus (MPS) versus the control arm (Physician’s Choice). 
5.2. 
Key Secondary Objective 
• To report Investigator-determined PFS. 
5.3. 
Additional Secondary Objectives  
5.4. 
Exploratory Objectives 
5.5. 
PK/Safety Objectives 
 


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6. 
SUBJECT INVESTIGATIONAL PLAN 
6.1. 
 Overall Study Design 
This is a two part, open-label, prospective, randomized, multi-center trial of SM-88 used with 
MPS in subjects with pancreatic cancer. The first part will be used to determine which dose of 
SM-88 will be selected for further study (RP2D), and the second part will consist of an 
expansion cohort of subjects at this selected dose, randomized against Physician’s Choice 
therapies. For Part 1, subjects have completed therapy and RP2D has been determined. Follow 
up on OS of subjects enrolled in Part 1 is continuing.    
6.2. 
Screening Period (Part 1 and Part 2) 
During the screening period, subjects will be evaluated for their eligibility to participate in the 
study. Subjects must be consented within 8 weeks after their last dose of chemotherapy (last dose 
is the day of the last drug administration). Study agents must be administered within 12 weeks of 
the last dose of chemotherapy. A subject does not have to be within 12 weeks of the last dose of 
chemotherapy if they have had a CR on their immediately preceding systemic therapy; however, 
consent must occur within 8 weeks of their first detectable recurrence, and study agent must be 
administered within 12 weeks of their first detectable recurrence. For instance, if a patient 
subject has a CR after systemic therapy, but recurs 6 months later, they are eligible to start this 
trial.   
Whenever possible, Randomization and start of the first dose of study treatment (i.e., Cycle 1 
Day 1, C1D1) should occur on the same date. Planning for Physician’s Choice selection should 
begin at informed consent, so C1D1 can occur at Randomization to the assigned study arm. If 
needed, there may be, at most, 7 days between the date of Randomization and start of the first 
dose of study treatment (i.e., Cycle 1 Day 1).   
Imaging and lab results must be assessed, at most, 14 days prior to a subject’s first dose of study 
treatment (i.e., Cycle 1 Day 1). A subject’s weight change, as described in the Exclusion Criteria, 
should be assessed just before Randomization.  
All previous anti-neoplastic treatment should be discontinued for the experimental groups prior 
to starting study medications.   
Activities to be carried out during this screening period and their corresponding timeframes are 
summarized in the table below. Results of screening labs, images, and weight change measures 
should be gathered prior to Randomization, as detailed below.   


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Table 3. 
Activities Performed During Screening Period 
 
6.3 
Treatment Period (Part 1 and Part 2) 
Subjects will visit the clinic on Day 1 of each treatment cycle. Given the treatment period 
completion of Part 1, Part 2 is presented below.   
Treatment Cycles:  
• SM-88 used with MPS 
• Physician’s Choice 
Treatment cycles will begin on Day 1 and will be comprised of Physician’s Choice options, or 
daily dosing with SM-88 used with MPS for 4 weeks with no break between treatment cycles for 
as long as there is no evidence of clinical progression and/or dose limiting toxicity (DLT).  
Subjects will be enrolled in Part 2 of this trial as long as there are no DLTs or PDs, unacceptable 
toxicities, disease progressions, any treatment discontinuation criteria or death as defined in the 
protocol.  
 
 


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Dose Modifications (SM-88 used with MPS): 
Part 1: 
To support the study design, based on preclinical data and the Sponsor’s previous clinical 
experience, there is no clear dose limiting toxicity (DLT) or established maximum tolerated dose 
(MTD). The 2-dose design stage of this part of the trial may provide useful information on both 
DLT and maximum tolerated dose (MTD). However, in Part 1, until more data is available to 
make a more informed decision, our understanding of potential toxicity supports having the 
dosing be as simple as possible, hence the current study design. There is also precedent for 
similar dose adjustments. For instance, liposomal doxorubicin palmar plantar erythrodysesthesia 
is often treated with dose delay and not dose reduction. 
Additionally, based on past and ongoing clinical activity (Roach et al., 2018), persistent toxicity 
associated with SM-88 used with MPS is unexpected. The Part 1 randomized block design of 6 
(3 low dose, 3 high dose) ensures that no more than 3 subjects will be treated at the higher dose 
in any one block. From our preclinical profile, there was no NOAEL, and ongoing and previous 
clinical experience is also consistent with no DLT or MTD near the trial doses. Taking a 
treatment holiday and then restarting at the same dose may allow evaluation of whether observed 
AEs are drug-related or disease-related.  
For subjects experiencing a DLT in this trial, the dose of SM-88 will remain the same if 
treatment is reinitiated. For reinitiation in the SM-88(1) group (the lower dose cohort), SM-88 
will remain one capsule b.i.d. For SM-88(2) (the higher dose cohort), SM-88 will remain the 
same if treatment is reinitiated (two capsules in the AM and 2 capsules in the PM). If a subject 
has a second episode of any related or possibly drug-related DLT, the subject should be removed 
from the study (refer to Table 4).  
If any of the methoxsalen, phenytoin or sirolimus (MPS) is considered to be the component 
associated with a DLT and further administration of that component is contraindicated, it will be 
noted in the record and the subject removed from the trial after consultation with the Medical 
Monitor.   
Part 2: 
The RP2D of 920 mg/day administered as two 230 mg capsules, every 12 hours, allows for dose 
reduction. For subjects experiencing a DLT in Part 2 of the trial for the first time, the dose of 
SM-88 will be reduced by one capsule at each dose period to a total daily dose of 460 mg. If the 
subject has a second episode of any related or possibly drug-related DLT, SM-88 may be 
discontinued for up to 28 days while mitigating measures are attempted. If after restarting 
therapy the DLT continues, the subject will be removed from study (Table 4) (refer to Table 13).  
If any of the methoxsalen, phenytoin, or sirolimus is considered to be the component associated 
with a DLT, the individual component(s) may be discontinued for up to 28 days while mitigating 
measures are attempted (e.g., changing the timing of phenytoin to address phenytoin-related 
fatigue, if experienced). This may be applied to any or all of the MPS components. If the DLT 
continues for more than 28 days, the subject will be removed from the study.   


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Table 4: 
Recommended Dose Modifications for SM-88 in Part 2 
Dose Limiting Toxicity 
(DLT) 
Current 
Dose 
Dose Adjustment for Next Treatment  
1st DLT 
460 mg BID Decrease dose to 230 mg BID 
2nd DLT 
230 mg BID Discontinue study treatment for up to 28 days and 
attempt mitigation 
3rd DLT (after restarting 
therapy) 
230 mg BID Remove subject from study 
 
Dose Modifications (Control Arm: Physician’s Choice): 
Capecitabine  
The recommended dose of capecitabine is 1000 mg/m2 administered orally twice daily (morning 
and evening; equivalent to 2000 mg/m2 total daily dose). The recommended treatment schedule 
is as follows: 
• Dosing for 2 weeks followed by a 1-week rest period, given as 3-week cycles.  
Follow capecitabine package insert for dose modification guidelines. Dose modifications may be 
instituted at the start of treatment with capecitabine. Dose modifications must be noted in the 
EDC. 
 
Gemcitabine 
The recommended dosage of gemcitabine is 1000 mg/m2 intravenously over 30 minutes. The 
recommended treatment schedule is as follows:  
 
• Weekly dosing on Days 1, 8, and 15 of each 28-day cycle.  
 
Follow gemcitabine package insert for dose modification guidelines. Dose modifications may be 
instituted at the start of treatment with gemcitabine. Dose modifications must be noted in the 
EDC. 
5-FU 
The recommended dosage of 5-FU is 2400 mg/m2 continuous IV infusion over 46 hours. The 
recommended treatment schedule is as follows:   
 
• Dosing on Days 1 and 15 of a 28-day cycle. 
Follow 5-FU package insert for dose modification guidelines. Dose modifications may be 
instituted at the start of treatment with 5-FU. Dose modifications must be noted in the EDC. 


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6.3. 
Efficacy Assessments 
Part 1 
Efficacy Assessments: 
 
 
 
 
 
 
 
 
 
Magnetic resonance imaging 
(MRI) or PET/CT may also be used as adjunctive imaging where brain lesions are present, 
provided that requirements for the endpoints used to meet the objectives are also met, e.g., 
measurable lesions.   
Part 2 
Efficacy Assessments: 
 
 
 
 
 
 Although subjects 
randomized to capecitabine will be on a 21-day treatment cycle, imaging for these subjects will 
be performed on the same schedule, based on a 28-day cycle, as the other arms. CT is the 
preferred primary imaging modality. Preferred CT technique includes enhanced, diagnostic 
quality CT with oral and IV contrast. MRI or PET/CT may also be used as adjunctive imaging 
where brain lesions are present, provided that requirements for the endpoints used to meet the 
objectives are also met, e.g., measurable lesions.    
Some subjects, particularly those with active immune systems, may even have tumor site 
inflammation that is visible on CT imaging (i.e., pseudo-progression) at the first follow-up scan. 
Subjects with radiographic evidence of PD, but without clinical deterioration, may be considered 
for repeat confirmation scans before clinically significant PD is defined and study therapy is 
withdrawn. This decision should be balanced against the potential toxicity associated with 
continued treatment and alternative treatment options and must be discussed with and approved 
by the Medical Monitor. Continuation should be evaluated at least every 4 weeks after initial 
response assessment or sooner if clinical deterioration occurs. 
All subjects will be followed for PFS and OS until the end of this study, and possibly beyond 
their participation in the trial, as approved by the local Institutional Review Board (IRB). 


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Subjects will also participate in mobile device-controlled actigraphy monitoring.  
6.4. 
Safety Assessments 
Parts 1 and 2 
Safety Assessments: Routine safety evaluations, including clinical laboratory tests, physical 
examinations and vital signs will be conducted Day 1 of each treatment cycle, or more often if 
clinically indicated. ECGs will be performed at Screening, Day 1 of each cycle, pre-dose and at 
approximately 2 hours post-dose and at subjects’ Day 28 follow-up visit. In Part 1, 
ophthalmologic examinations (as described in Section 11.1.6) will be conducted yearly while on 
study, i.e., after 12 months of investigational agent (+/- 1 month); this is not a requirement for 
Part 2. In addition to PK measurements, SM-88, methoxsalen, phenytoin and sirolimus levels 
will be tested monthly in all subjects independent of renal and hepatic functional status. 
DLTs will be defined as an adverse event that meets the listed criteria and that is at least possibly 
related to any component of the study treatment (SM-88, methoxsalen, phenytoin, sirolimus or 
Physician’s Choice) (Table 15).  
In addition, there are certain serious adverse events related to specific components of SM-88 
used with MPS that must be assessed (See Section 11.2). In Part 1, if these adverse events are 
observed, the subject will permanently discontinue SM-88 used with MPS and be monitored 
accordingly. In Part 2, a dose reduction of SM-88 is allowed. 


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6.4.1.1. 
Cohort Expansion 
In Part 2, it is anticipated that a sufficient number of subjects will be enrolled to obtain 125 
evaluable subjects who have completed at least one cycle of therapy at the RP2D dose level of 
SM-88, and 125 subjects in the Physician’s Choice control group. However, should a biomarker 
indictor emerge, an additional cohort may be proposed. 
6.4.2. 
Post-Study Follow-up Period 
Twenty-eight (28) days after (at a follow-up study visit) the last SM-88 or Physician’s Choice 
therapy dose, subjects will be evaluated for safety and other outcome measures obtained in the 
course of usual clinical care. Subjects will continue to be followed at 3-month intervals via 
review of medical records, public social media, phone or in person contact for survival data. 
 


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Table 5: 
Part 1 - SM-88 used with MPS Time and Events Schedule 
Visit Description 
Screening 
Cycle 1 
Cycle 2 
 
Cycle 3 
 
Cycle 4 
 
Cycle 5 
 
Cycle 6 
 
Follow-Up  
Visit 
Annual 
Survival 
Follow- 
up 
Day  
(+ 2 days) 
-14 to -1 
Day 1  
Day 
28 
Day 1 
Day 
28 
Day 1 
Day 
28 
Day 1 
Day 
28 
 
Day 1 
 
Day 
28 
Day 1 
 
Day 
28 
28 Day post 
Discontinuation 
of Treatment  
(+ 2 days) 
(+) 30 
days) 
Every 3-
months  
(+7 
days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cancer history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology a 
Xa 
Xa 
 
Xa 
 
Xa 
 
Xa 
 
Xa 
 
Xa 
 
Xa 
 
 
Clinical chemistry b 
Xb 
Xb 
 
Xb 
 
Xb 
 
Xb 
 
Xb 
 
Xb 
 
Xb 
 
 
Urinalysis c 
Xc 
Xc 
 
Xc 
 
Xc 
 
Xc 
 
Xc 
 
Xc 
 
Xc 
 
 
Cholesterol and blood 
lipids d 
Xd 
Xd 
 
Xd 
 
Xd 
 
Xd 
 
Xd 
 
Xd 
 
Xd 
 
 
CTC count 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
PK’s e 
 
Xe 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
Phenytoin, and 
sirolimus levels f 
 
Xf 
 
Xf 
 
Xf 
 
Xf 
 
Xf 
 
Xf 
 
Xf 
 
 
SM-88 and 
methoxsalen levels g 
 
Xg 
 
Xg 
 
Xg 
 
Xg 
 
Xg 
 
Xg 
 
Xg 
 
 
Other laboratory tests 
h 
Xh 
Xh 
 
Xh 
 
Xh 
 
Xh 
 
Xh 
 
Xh 
 
 
 
 
PET/CT scans I   
Xi 
 
 
 
Xi 
 
 
 
Xi 
 
 
 
Xi 
 
 
 
Physical exam j 
Xj 
Xj 
 
Xj 
 
Xj 
 
Xj 
 
Xj 
 
Xj 
 
Xj 
 
 
Vital signs k 
Xk 
Xk 
 
Xk 
 
Xk 
 
Xk 
 
Xk 
 
Xk 
 
Xk 
 
 
ECG l 
Xl 
Xl 
 
Xl 
 
Xl 
 
Xl 
 
Xl 
 
Xl 
 
Xl 
 
 
Ophthalmologic 
examination m 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 
 
Concomitant meds 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
CA-19.9 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Other efficacy labs n 
Xn 
Xn 
 
Xn 
 
Xn 
 
Xn 
 
Xn 
 
Xn 
 
Xn 
 
 


Tyme, Inc.  
Confidential 
SM-88; IND #136891 
Page 48 of 131 
 
CONFIDENTIAL 
 
May 12, 2020 
Time and Events Schedules (Continued) Abbreviations:  CT = computed tomography; CTC = circulating tumor cell; ECG = electrocardiogram; ECOG = Eastern Cooperative 
Oncology Group Performance Status; 
 
 ET = early termination; eval = evaluation; LDH = lactate 
dehydrogenase; meds = medications; MRI = magnetic resonance imaging; NLR = neutrophil:lymphocyte ratio; PK = pharmacokinetic.  
a Hematology with differential- Erythrocyte count, Hematocrit, Absolute reticulocyte count, Mean cell volume, Mean cell hemoglobin, Mean cell hemoglobin concentration, 
Leukocytes, Neutrophils, Lymphocytes, Monocytes, Basophils, Eosinophils, Platelets 
b Chemistry - Sodium, Potassium, Chloride, Glucose, Blood urea nitrogen, Creatinine, Alanine aminotransferase, Aspartate aminotransferase, Total bilirubin, Total protein, 
Albumin, Calcium, Magnesium, Phosphate, Total cholesterol, LDL, HDL and triglycerides 
c Urinalysis - Color, Specific gravity, pH, Protein, Glucose, Ketones, Blood, Bilirubin, Leukocyte Esterase, Nitrites 
d Total Cholesterol, LDL, HDL, and triglycerides should be monitored in subjects on Day 1 of each cycle if not included in standard “Chemistry”. Subjects administered an HMG-
CoA reductase inhibitor and/or fibrate should be monitored for the possible development of rhabdomyolysis and other adverse effects, as described in the respective labeling for 
these agents.  
e Will be drawn on Day 1 of Cycle 1 and Cycle 2 (± 4 days) at Pre-Dose, 0.5, 1, 2, 4 and 6 hours Post-Dose.  All PK draws will have a window of ± 15 minutes. 
f In addition to the PK testing, measurements of phenytoin and sirolimus levels will be conducted on Day 1 of all cycles in all subjects. These samples will be assayed at the local 
lab for all cycles.  
g In addition to the PK testing, measurements of SM-88 and unbound methoxsalen levels will be conducted on Day 1 of all cycles in all subjects. These samples will be assayed at 
the central lab for all cycles. 
h  Other laboratory tests at screening include INR, HIV, Hep B, Hep C and Pregnancy Test.  
ECOG PS 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Adverse events o 
Xo 
Xo 
 
Xo 
 
Xo 
 
Xo 
 
Xo 
 
Xo 
 
Xo 
 
 
Dispense SM-88, 
methoxsalen, 
phenytoin and 
sirolimusp 
 
Xp 
 
Xp 
 
Xp 
 
Xp 
 
Xp 
 
Xp 
 
 
 
 
SM-88 pill count 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Survival Data q 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xq 


Tyme, Inc.  
Confidential 
SM-88; IND #136891 
Page 49 of 131 
 
CONFIDENTIAL 
 
May 12, 2020 
 i  CT Scans are required should be conducted on Day 28 every other cycle after Baseline/Screening, i.e. Day 28 of Cycles 2, 4, 6 (± 5 day window).  The elected imaging modality 
may be supplemented by alternative modalities as clinically indicated.  If regional MRI was used to determine local progression for eligibility, then CT must also be performed at 
baseline and every other cycle.  If results of a CT scan performed as a part of standard medical practice within 4 weeks of baseline are available, then an additional baseline scan 
will not be required.  Sites are to perform the Imaging according to the Tyme-88-Panc Imaging Manual. Diagnostic quality CT is for RECIST.   
j  A complete physical examination will be performed at screening and at the End of Treatment Visit.  An abbreviated physical examination to monitor for changes will be 
performed at all other visits indicated.  Body weight should be measured at each physical examination. Inquiry about suicidal thoughts or behavior and emergency or worsening 
depression or unusual changes of mood and behaviors should be assessed at each treatment visit. Height should be measured at screening. As part of a complete physical exam, 
dermatologic evaluation will be conducted at each visit for the development of rash and potential sign of Stevens Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN). 
Subjects with a history of basal cell carcinoma will be regularly observed for potential new lesions. 
k Vital signs will include blood pressure, respiratory rate, pulse, oxygen saturation, and temperature. 
l All scheduled ECGs will be performed before any blood draws scheduled for the same time point.  Subjects should be resting quietly and free of distraction for 10 minutes prior 
to ECG collection. The Investigator or a qualified designee will review all ECGs.  The time of the previous study drug administration will be recorded.  ECGs will be performed at 
Screening, Cycle 1 and Cycle 2 pre-dose and at approximately 2 hours post-dose and at subjects Day 28 Follow-up visit. 
m Window of ± 30 days for this annual ophthalmologic evaluation.  Data to be collected for the  Ophthalmology exam will include the following: Record oculus uterque (OU) at 
baseline and q 12 mo: 
a. Acuity best corrected 
b. Acuity Uncorrected 
c. Correction factor/RX 
d. Cataracts present? If subject has cataracts, they should be graded per clinician SOC, who must use the same methodology of grading for follow-up evaluations.   
e. Retina evaluation - normal, or not [if not, describe per clinician SOC; must use same for follow-up evaluation] 
n Other efficacy labs include CEA, LDH, total alkaline phosphatase, bone-specific alkaline phosphatase, urine N-telopeptide, hemoglobin, WBC, ANC, leptin, and NLR. 
o Screen for symptoms of progressive multifocal leukoencephalopathy (PML), hemiparesis, apathy, confusion, cognitive deficiencies and ataxia. Consult a neurologist as clinically 
indicated 
p SM-88 will be dispensed monthly for all cycles.  SM-88 should be taken twice daily at approximately the same time each day with approximately 240 mL water to minimize GI 
disturbance.  Doses are to be provided at least two-hours after meals and at least one-hour before.  Dosing should be 8-12 hours apart and planned to minimize food consumption 
after dosing periods.  
q Survival data to be collected every 3 months either by in person visits to the site or via telephone. 
 
 


Tyme, Inc.  
Confidential 
SM-88; IND #136891 
Page 50 of 131 
 
CONFIDENTIAL 
 
May 12, 2020 
Table 6: 
Part 2 - SM-88 used with MPS Time and Events Schedule 
Visit Description 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6+ 
Follow-Up 
Visit 
Survival 
Follow-
up 
Day 
(+ 2 days)  
 
-14 to -1 
days 
Day 1 
Day 
28 
Day 1 
Day 
28 
Day 1 
Day 
28  
Day 1 
Day 
28 
Day 1 
Day 
28 
Day 1 
Day 
28 
28 Day Post 
Discontinuation 
of Treatment  
(+ 2 days) 
Every 3-
months  
(+7 
days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cancer history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology a 
Xa 
Xa 
 
Xa 
 
Xa 
 
Xa 
 
Xa 
 
Xa 
 
Xa 
 
Clinical chemistry b 
Xb 
Xb 
 
Xb 
 
Xb 
 
Xb 
 
Xb 
 
Xb 
 
Xb 
 
Urinalysis c 
Xc 
Xc 
 
Xc 
 
Xc 
 
Xc 
 
Xc 
 
Xc 
 
Xc 
 
Cholesterol and blood lipids d 
Xd 
Xd 
 
Xd 
 
Xd 
 
Xd 
 
Xd 
 
Xd 
 
Xd 
 
CTC collection and 
exploratory biomarker 
analysis/sample banking 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Phenytoin and sirolimus levels 
e 
 
Xe 
 
Xe 
 
Xe 
 
Xe 
 
Xe 
 
Xe 
 
Xe 
 
SM-88 and methoxsalen levels 
f 
 
Xf 
 
Xf 
 
Xf 
 
Xf 
 
Xf 
 
Xf 
 
Xf 
 
Pharmacokinetics (PK) 
sampling 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Other laboratory tests g 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT scans h   
Xh 
 
 
 
Xh 
 
 
 
Xh 
 
 
 
Xh 
 
 
Physical exam i 
Xi 
Xi 
 
Xi 
 
Xi 
 
Xi 
 
Xi 
 
Xi 
 
Xi 
 
Vital signs j 
Xj 
Xj 
 
Xj 
 
Xj 
 
Xj 
 
Xj 
 
Xj 
 
Xj 
 
ECG - single k 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
ECG - triplicate k 
 
Xk 
 
Xk 
 
 
 
 
 
 
 
 
 
 
 
Concomitant meds 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
CA-19.9 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Other efficacy labs l 
Xl 
Xl 
 
Xl 
 
Xl 
 
Xl 
 
Xl 
 
Xl 
 
Xl 
 


Tyme, Inc.  
Confidential 
SM-88; IND #136891 
Page 51 of 131 
 
CONFIDENTIAL 
 
May 12, 2020 
Time and Events Schedules (Continued) Abbreviations: CT = computed tomography; CTC = circulating tumor cell; ECG = electrocardiogram; ECOG = Eastern Cooperative 
Oncology Group Performance Status; 
 
 ET = early termination; eval = evaluation; LDH = lactate 
dehydrogenase; meds = medications; MRI = magnetic resonance imaging; NLR = neutrophil:lymphocyte ratio; PK = pharmacokinetic.  
 
a Hematology with differential: Erythrocyte count, Hematocrit, Absolute reticulocyte count, Mean cell volume, Mean cell hemoglobin, Mean cell hemoglobin concentration, 
Leukocytes, Neutrophils, Lymphocytes, Monocytes, Basophils, Eosinophils, Platelets 
b Chemistry: Sodium, Potassium, Chloride, Glucose, Blood urea nitrogen, Creatinine, Alanine aminotransferase, Aspartate aminotransferase, Total bilirubin, Total protein, 
Albumin, Calcium, Magnesium, Phosphate, Total cholesterol, LDL, HDL and triglycerides 
c Urinalysis: Color, Specific gravity, pH, Protein, Glucose, Ketones, Blood, Bilirubin, Leukocyte Esterase, Nitrites 
d Total Cholesterol, LDL, HDL, and triglycerides should be monitored in subjects on Day 1 of each cycle if not included in standard “Chemistry.” Subjects administered an HMG-
CoA reductase inhibitor and/or fibrate should be monitored for the possible development of rhabdomyolysis and other adverse effects, as described in the respective labeling for 
these agents.  
e Measurements of phenytoin and sirolimus levels will be conducted on Day 1 of all cycles in all subjects. These samples will be assayed at the central lab for samples from Cycles 
1 and 2, and the local lab for all subsequent cycles. In addition to the PK testing, measurements of SM-88 and unbound methoxsalen levels will be conducted on Day 1 of all 
cycles in all subjects. These samples will be assayed at the central lab for all cycles. 
f In addition to the PK testing, measurements of SM-88 and unbound methoxsalen levels will be conducted on Day 1 of all cycles in all subjects. These samples will be assayed at 
the central lab for all cycles. 
g Other laboratory tests at screening include: serum cortisol, INR, HIV, Hep B, Hep C and Pregnancy Test. For HIV, Hep B and Hep C, testing is not required in the absence of 
clinical suspicion. 
h CT scans are required and should be conducted on Day 28 of every other (even-numbered) cycle after Baseline/Screening, i.e., Day 28 of Cycles 2, 4, 6 (± 5 day window). For all 
cycles beyond Cycle 6, this same measurement pattern should be continued (i.e., Day 28 of Cycles 8, 10, 12 (± 5 day window). The elected imaging modality may be 
supplemented by alternative modalities as clinically indicated. If regional MRI was used to determine local progression for eligibility, then CT (or PET/CT) must also be 
performed at baseline and every other cycle. If results of a CT scan performed as a part of standard medical practice within 14 days of Randomization are available, then an 
ECOG PS 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Wearable device (Fitbit) 
Continuous daily wear beginning C1D1 until completion of follow-up visit 
Adverse events m 
Xm 
Xm 
 
Xm 
 
Xm 
 
Xm 
 
Xm 
 
Xm 
 
Xm 
 
Dispense SM-88, methoxsalen, 
phenytoin and sirolimusn 
 
Xn 
 
Xn 
 
Xn 
 
Xn 
 
Xn 
 
Xn 
 
 
 
SM-88 pill count 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Survival data p 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xp 
Food and drug diary 
 
Daily documentation of study drug dose and meal times for SM-88 subjects, beginning on C1D1 


Tyme, Inc.  
Confidential 
SM-88; IND #136891 
Page 52 of 131 
 
CONFIDENTIAL 
 
May 12, 2020 
additional baseline scan will not be required. Sites are to perform the Imaging according to the Tyme-88-Panc Imaging Manual. Preferred CT technique includes enhanced, 
diagnostic quality CT with oral and IV contrast.  
i A complete physical examination will be performed at screening and at the end of treatment visits. An abbreviated physical examination to monitor for changes will be performed 
at all other visits indicated. Body weight should be measured at each physical examination. Inquiry about suicidal thoughts or behavior and emergency or worsening depression 
or unusual changes of mood and behaviors should be assessed at each treatment visit. Height should be measured at screening. As part of a complete physical exam, 
dermatologic evaluation will be conducted at each visit for the development of rash and potential sign of SJS/TEN. Subjects with a history of basal cell carcinoma will be 
regularly observed for potential new lesions. 
j Vital signs will include blood pressure, respiratory rate, pulse, oxygen saturation, weight and temperature. 
k For the SM-88 used with MPS arm, ECGs that are time-matched to PK sample collections (Day 1 of Cycles 1 and 2) will be collected in triplicate. ECGs will be performed 
before any blood draws scheduled for the same time point. Subjects should be resting quietly and free of distraction for 10 minutes prior to any ECG collection. The Investigator or 
a qualified designee will review all ECGs. The time of the previous study drug administration will be recorded. ECGs will be performed at Screening (single), Day 1 of Cycles 1 
and 2 (in triplicate, for time-matched to PK sample collection for subjects in SM-88 arm), and at subjects’ Day 28 follow-up visit (single).    
l Other efficacy labs include: CEA, LDH, total alkaline phosphatase, bone-specific alkaline phosphatase, hemoglobin, WBC, ANC, leptin, and NLR. 
m Screen for symptoms of PML, hemiparesis, apathy, confusion, cognitive deficiencies and ataxia. Consult a neurologist as clinically indicated. 
n SM-88 will be dispensed monthly for all cycles. SM-88 should be taken twice daily at approximately the same time each day with approximately 240 mL water to minimize GI 
disturbance. Doses are to be provided at least two-hours after meals and at least one-hour before. Dosing should be 8-16 hours apart and planned to minimize food consumption 
after dosing periods.  
o Survival data to be collected every 3 months by review of medical records, public social media, phone or in person contact. 
 


Tyme, Inc.  
Confidential 
SM-88; IND #136891 
Page 53 of 131 
 
CONFIDENTIAL 
 
May 12, 2020 
Table 7: 
Control Arm - Capecitabine Time and Events Schedule 
Visit Description 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6+ 
Follow-Up 
Visit 
Survival 
Follow-up 
Day 
(+ 2 days)  
 
-14 to -1 
days 
Day 1 
Day 21 
Day 1 
Day 21 
Day 1 
Day 21  
Day 1 
Day 21 
Day 1 
Day 21 
Day 1 
Day 21 
28 Day Post-
Discontinuati
on of 
Treatment  
(+ 2 days) 
Every 3-
months  
(+7 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cancer history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology a 
Xa 
Xa 
 
Xa 
 
Xa 
 
Xa 
 
Xa 
 
Xa 
 
Xa 
 
Clinical chemistry b 
Xb 
Xb 
 
Xb 
 
Xb 
 
Xb 
 
Xb 
 
Xb 
 
Xb 
 
Urinalysis c 
Xc 
Xc 
 
Xc 
 
Xc 
 
Xc 
 
Xc 
 
Xc 
 
Xc 
 
Cholesterol and blood 
lipids d 
Xd 
Xd 
 
Xd 
 
Xd 
 
Xd 
 
Xd 
 
Xd 
 
Xd 
 
CTC collection  and 
exploratory biomarker 
analysis/sample banking 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Other laboratory tests e 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT scans f 
Xf 
 
 
 
Xf (Day 
28) 
 
 
 
Xf (Day 
28) 
 
 
 
Xf (Day 
28) 
 
 
Physical exam g 
Xg 
Xg 
 
Xg 
 
Xg 
 
Xg 
 
Xg 
 
Xg 
 
Xg 
 
Vital signs h 
Xh 
Xh 
 
Xh 
 
Xh 
 
Xh 
 
Xh 
 
Xh 
 
Xh 
 
ECG - single i 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
Xi 
 
Concomitant meds 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
CA-19.9 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Other efficacy labs j 
Xj 
Xj 
 
Xj 
 
Xj 
 
Xj 
 
Xj 
 
Xj 
 
Xj 
 
Blood draw for 
exploratory biomarker 
analysis/sample banking 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 


Tyme, Inc.  
Confidential 
SM-88; IND #136891 
Page 54 of 131 
 
CONFIDENTIAL 
 
May 12, 2020 
Time and Events Schedules (Continued) Abbreviations: CT = computed tomography; CTC = circulating tumor cell; ECG = electrocardiogram; 
 
 
; ET = early termination; eval = evaluation; LDH = lactate 
dehydrogenase; meds = medications; MRI = magnetic resonance imaging; NLR = neutrophil:lymphocyte ratio; PK = pharmacokinetic.  
 
a Hematology with differential: Erythrocyte count, Hematocrit, Absolute reticulocyte count, Mean cell volume, Mean cell hemoglobin, Mean cell hemoglobin concentration, 
Leukocytes, Neutrophils, Lymphocytes, Monocytes, Basophils, Eosinophils, Platelets 
b Chemistry: Sodium, Potassium, Chloride, Glucose, Blood urea nitrogen, Creatinine, Alanine aminotransferase, Aspartate aminotransferase, Total bilirubin, Total protein, 
Albumin, Calcium, Magnesium, Phosphate, Total cholesterol, LDL, HDL and triglycerides 
c Urinalysis: Color, Specific gravity, pH, Protein, Glucose, Ketones, Blood, Bilirubin, Leukocyte Esterase, Nitrites 
d Total Cholesterol, LDL, HDL, and triglycerides should be monitored in subjects on Day 1 of each cycle if not included in standard “Chemistry”. Subjects administered an HMG-
CoA reductase inhibitor and/or fibrate should be monitored for the possible development of rhabdomyolysis and other adverse effects, as described in the respective labeling for 
these agents.  
e  Other laboratory tests at screening include cortisol, INR, HIV, Hep B, Hep C and Pregnancy Test. 
f CT scans are required and should be conducted on Day 28 of every other (even-numbered) cycle after Baseline/Screening, i.e., Day 28 of Cycles 2, 4, 6 (± 5 day window). For all 
cycles beyond Cycle 6, this same measurement pattern should be continued (i.e., Day 28 of Cycles 8, 10, 12 (± 5 day window). The elected imaging modality may be 
supplemented by alternative modalities as clinically indicated.  If regional MRI was used to determine local progression for eligibility, then CT (or PET/CT) must also be 
performed at baseline and every other cycle.  If results of a CT scan performed as a part of standard medical practice within 7 days of Randomization are available, then an 
additional baseline scan will not be required.  Sites are to perform the Imaging according to the Tyme-88-Panc Imaging Manual.  
g A complete physical examination will be performed at screening and at the End of Treatment Visit.  An abbreviated physical examination to monitor for changes will be 
performed at all other visits indicated.  Body weight should be measured at each physical examination. Inquiry about suicidal thoughts or behavior and emergency or worsening 
depression or unusual changes of mood and behaviors should be assessed at each treatment visit. Height should be measured at screening. As part of a complete physical exam, 
dermatologic evaluation will be conducted at each visit for the development of rash and potential sign of SJS/TEN. Subjects with a history of basal cell carcinoma will be 
regularly observed for potential new lesions. 
h Vital signs will include blood pressure, respiratory rate, pulse, oxygen saturation, weight and temperature. 
ECOG PS 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Wearable device (Fitbit) 
Continuous daily wear beginning C1D1 until completion of follow-up visit  
Adverse events k 
Xk 
Xk 
 
Xk 
 
Xk 
 
Xk 
 
Xk 
 
Xk 
 
Xk 
 
Dispense capecitabine l 
 
Xl 
 
Xl 
 
Xl 
 
Xl 
 
Xl 
 
Xl 
 
 
 
Survival data m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 


Tyme, Inc.  
Confidential 
SM-88; IND #136891 
Page 55 of 131 
 
CONFIDENTIAL 
 
May 12, 2020 
i All scheduled ECGs will be performed before any blood draws scheduled for the same time point.  Subjects should be resting quietly and free of distraction for 10 minutes prior to 
ECG collection. The Investigator or a qualified designee will review all ECGs.  ECGs will be performed only at baseline and follow-up visit. 
j Other efficacy labs include: CEA, LDH, total alkaline phosphatase, bone-specific alkaline phosphatase, hemoglobin, WBC, ANC, leptin, and NLR. 
k Screen for symptoms of PML, hemiparesis, apathy, confusion, cognitive deficiencies and ataxia. Consult a neurologist as clinically indicated. 
l Control arm treatment will be administered as follows: capecitabine (1000 mg/m2 orally twice a day, Days 1-14 on a 21-day cycle). 
m Survival data to be collected every 3 months by review of medical records, public social media, phone or in person contact. 
 
 


Tyme, Inc.  
Confidential 
SM-88; IND #136891 
Page 56 of 131 
 
CONFIDENTIAL 
 
May 12, 2020 
Table 8: 
Control Arm - 5-FU Time and Events Schedule 
Visit Description 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6+ 
Follow-Up  
Visit 
Survival 
Follow-up 
Day 
(+ 2 days)  
 
-14 to -1 days 
Day 1 
and 
Day 15 
Day 
28 
Day 1 
and 
Day 15 
Day 
28 
Day 1 
and 
Day 15 
Day 
28  
Day 1 
and 
Day 15 
Day 
28 
Day 1 
and 
Day 15 
Day 
28 
Day 1 
and 
Day 15 
Day 
28 
28 Day Post-
Discontinuation 
of Treatment  
(+ 2 days) 
Every 3-
months  
(+7 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cancer history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology a 
Xa 
Xa 
 
Xa 
 
Xa 
 
Xa 
 
Xa 
 
Xa 
 
Xa 
 
Clinical chemistry b 
Xb 
Xb 
 
Xb 
 
Xb 
 
Xb 
 
Xb 
 
Xb 
 
Xb 
 
Urinalysis c 
Xc 
Xc 
 
Xc 
 
Xc 
 
Xc 
 
Xc 
 
Xc 
 
Xc 
 
Cholesterol and blood 
lipids d 
Xd 
Xd 
 
Xd 
 
Xd 
 
Xd 
 
Xd 
 
Xd 
 
Xd 
 
CTC collection and 
exploratory biomarker 
analysis/sample banking 
 
X (Day 
1 only) 
 
X (Day 1 
only) 
 
X (Day 
1 only) 
 
X (Day 
1 only) 
 
X (Day 
1 only) 
 
X (Day 
1 only) 
 
X 
 
Other laboratory tests e 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT scans f 
Xf 
 
 
 
Xf 
 
 
 
Xf 
 
 
 
Xf 
 
 
Physical exam g 
Xg 
Xg 
 
Xg 
 
Xg 
 
Xg 
 
Xg 
 
Xg 
 
Xg 
 
Vital signs h 
Xh 
Xh 
 
Xh 
 
Xh 
 
Xh 
 
Xh 
 
Xh 
 
Xh 
 
ECG - single i 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
Xi 
 
Concomitant meds 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
CA-19.9 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Other efficacy labs j 
Xj 
Xj 
 
Xj 
 
Xj 
 
Xj 
 
Xj 
 
Xj 
 
Xj 
 
ECOG PS 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 


Tyme, Inc.  
Confidential 
SM-88; IND #136891 
Page 57 of 131 
 
CONFIDENTIAL 
 
May 12, 2020 
 
Time and Events Schedules (Continued) Abbreviations: CT = computed tomography; CTC = circulating tumor cell; ECG = electrocardiogram; ECOG = Eastern Cooperative 
Oncology Group Performance Status; 
 
; ET = early termination; eval = evaluation; LDH = lactate 
dehydrogenase; meds = medications; MRI = magnetic resonance imaging; NLR = neutrophil:lymphocyte ratio; PK = pharmacokinetic.  
 
a Hematology with differential: Erythrocyte count, Hematocrit, Absolute reticulocyte count, Mean cell volume, Mean cell hemoglobin, Mean cell hemoglobin concentration, 
Leukocytes, Neutrophils, Lymphocytes, Monocytes, Basophils, Eosinophils, Platelets 
b Chemistry: Sodium, Potassium, Chloride, Glucose, Blood urea nitrogen, Creatinine, Alanine aminotransferase, Aspartate aminotransferase, Total bilirubin, Total protein, 
Albumin, Calcium, Magnesium, Phosphate, Total cholesterol, LDL, HDL and triglycerides 
c Urinalysis: Color, Specific gravity, pH, Protein, Glucose, Ketones, Blood, Bilirubin, Leukocyte Esterase, Nitrites 
d Total Cholesterol, LDL, HDL, and triglycerides should be monitored in subjects on Day 1 of each cycle if not included in standard “Chemistry”. Subjects administered an HMG-
CoA reductase inhibitor and/or fibrate should be monitored for the possible development of rhabdomyolysis and other adverse effects, as described in the respective labeling for 
these agents.  
e Other laboratory tests at screening include cortisol, INR, HIV, Hep B, Hep C and Pregnancy Test. 
f CT scans are required and should be conducted on Day 28 of every other (even-numbered) cycle after Baseline/Screening, i.e., Day 28 of Cycles 2, 4, 6 (± 5 day window). For all 
cycles beyond Cycle 6, this same measurement pattern should be continued (i.e., Day 28 of Cycles 8, 10, 12 (± 5 day window). The elected imaging modality may be 
supplemented by alternative modalities as clinically indicated.  If regional MRI was used to determine local progression for eligibility, then CT  (or PET/CT) must also be 
performed at baseline and every other cycle.  If results of a CT scan performed as a part of standard medical practice within 7 days of Randomization are available, then an 
additional baseline scan will not be required.  Sites are to perform the Imaging according to the Tyme-88-Panc Imaging Manual.  
g A complete physical examination will be performed at screening and at the End of Treatment Visit.  An abbreviated physical examination to monitor for changes will be 
performed at all other visits indicated.  Body weight should be measured at each physical examination. Inquiry about suicidal thoughts or behavior and emergency or worsening 
depression or unusual changes of mood and behaviors should be assessed at each treatment visit. Height should be measured at screening. As part of a complete physical exam, 
dermatologic evaluation will be conducted at each visit for the development of rash and potential sign of SJS/TEN. Subjects with a history of basal cell carcinoma will be 
regularly observed for potential new lesions. 
h Vital signs will include blood pressure, respiratory rate, pulse, oxygen saturation, weight and temperature. 
Wearable device (Fitbit) 
Continuous daily wear beginning C1D1 until completion of follow-up visit  
Adverse events k 
Xk 
Xk 
 
Xk 
 
Xk 
 
Xk 
 
Xk 
 
Xk 
 
Xk 
 
Dispense 5-FU l 
 
Xl 
 
Xl 
 
Xl 
 
Xl 
 
Xl 
 
Xl 
 
 
 
Survival data m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 


Tyme, Inc.  
Confidential 
SM-88; IND #136891 
Page 58 of 131 
 
CONFIDENTIAL 
 
May 12, 2020 
i All scheduled ECGs will be performed before any blood draws scheduled for the same time point.  Subjects should be resting quietly and free of distraction for 10 minutes prior to 
ECG collection. The Investigator or a qualified designee will review all ECGs.  ECGs will be performed only at baseline and follow-up visit. 
j Other efficacy labs include: CEA, LDH, total alkaline phosphatase, bone-specific alkaline phosphatase, hemoglobin, WBC, ANC, leptin, and NLR. 
k Screen for symptoms of PML, hemiparesis, apathy, confusion, cognitive deficiencies and ataxia. Consult a neurologist as clinically indicated 
l Control arm treatment will be administered as follows: 5-FU (2400 mg/m2 continuous IV infusion over 46 hours on Days 1 and 15 on a 28-day cycle). 
m Survival data to be collected every 3 months by review of medical records, public social media, phone or in person contact. 
 


Tyme, Inc.  
Confidential 
SM-88; IND #136891 
Page 59 of 131 
 
CONFIDENTIAL 
 
May 12, 2020 
Table 9: 
Control Arm - Gemcitabine Time and Events Schedule 
Visit Description 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6+ 
Follow-Up  
Visit 
Survival 
Follow-up 
Day 
(+ 2 days)  
-14 to -1 
days 
Days 1, 
8 and 15  
Day 
28 
Days 
1, 8 
and 
15 
Day 
28 
Days 1, 
8 and 
15 
Day 
28  
Days 1, 
8 and 
15 
Day 
28 
Days 1, 
8 and 
15 
Day 
28 
Days 1, 
8 and 15 
Day 
28 
28 Day Post-
Discontinuation 
of Treatment  
(+ 2 days) 
Every 3-
months  
(+7 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cancer history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology a 
Xa 
Xa 
 
Xa 
 
Xa 
 
Xa 
 
Xa 
 
Xa 
 
Xa 
 
Clinical chemistry b 
Xb 
Xb 
 
Xb 
 
Xb 
 
Xb 
 
Xb 
 
Xb 
 
Xb 
 
Urinalysis c 
Xc 
Xc 
 
Xc 
 
Xc 
 
Xc 
 
Xc 
 
Xc 
 
Xc 
 
Cholesterol and blood lipids 
d 
Xd 
Xd 
 
Xd 
 
Xd 
 
Xd 
 
Xd 
 
Xd 
 
Xd 
 
CTC collection and 
exploratory biomarker 
analysis/sample banking 
 
X (Day 1 
only) 
 
X (Day 
1 only) 
 
X (Day 
1 only) 
 
X (Day 
1 only) 
 
X (Day 
1 only) 
 
X (Day 1 
only) 
 
X 
 
Other laboratory tests e 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT scans f 
Xf 
 
 
 
Xf 
 
 
 
Xf 
 
 
 
Xf 
 
 
Physical exam g 
Xg 
Xg 
 
Xg 
 
Xg 
 
Xg 
 
Xg 
 
Xg 
 
Xg 
 
Vital signs h 
Xh 
Xh 
 
Xh 
 
Xh 
 
Xh 
 
Xh 
 
Xh 
 
Xh 
 
ECG - single i 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
Xi 
 
Concomitant meds 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
CA-19.9 
X 
X (Day 1 
only) 
 
X (Day 
1 only) 
 
X (Day 
1 only) 
 
X (Day 
1 only) 
 
X (Day 
1 only) 
 
X (Day 1 
only) 
 
X 
 
Other efficacy labs j 
Xj 
Xj (CEA 
Day 1 
only) 
 
Xj (CEA 
Day 1 
only) 
 
Xj 
(CEA 
Day 1 
only) 
 
Xj 
(CEA 
Day 1 
only) 
 
Xj 
(CEA 
Day 1 
only) 
 
Xj (CEA 
Day 1 
only) 
 
Xj 
 
ECOG PS 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 


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Time and Events Schedules (Continued) Abbreviations: CT = computed tomography; CTC = circulating tumor cell; ECG = electrocardiogram; ECOG = Eastern Cooperative 
Oncology Group Performance Status; 
 
 ET = early termination; eval = evaluation; LDH = lactate 
dehydrogenase; meds = medications; MRI = magnetic resonance imaging; NLR = neutrophil:lymphocyte ratio; PK = pharmacokinetic. 
  
a Hematology with differential: Erythrocyte count, Hematocrit, Absolute reticulocyte count, Mean cell volume, Mean cell hemoglobin, Mean cell hemoglobin concentration, 
Leukocytes, Neutrophils, Lymphocytes, Monocytes, Basophils, Eosinophils, Platelets 
b Chemistry: Sodium, Potassium, Chloride, Glucose, Blood urea nitrogen, Creatinine, Alanine aminotransferase, Aspartate aminotransferase, Total bilirubin, Total protein, 
Albumin, Calcium, Magnesium, Phosphate, Total cholesterol, LDL, HDL and triglycerides 
c Urinalysis: Color, Specific gravity, pH, Protein, Glucose, Ketones, Blood, Bilirubin, Leukocyte Esterase, Nitrites 
d Total Cholesterol, LDL, HDL, and triglycerides should be monitored in subjects on Day 1 of each cycle if not included in standard “Chemistry”. Subjects administered an HMG-
CoA reductase inhibitor and/or fibrate should be monitored for the possible development of rhabdomyolysis and other adverse effects, as described in the respective labeling for 
these agents.  
e Other laboratory tests at screening include cortisol, INR, HIV, Hep B, Hep C and Pregnancy Test. 
f CT scans are required and should be conducted on Day 28 of every other (even-numbered) cycle after Baseline/Screening, i.e., Day 28 of Cycles 2, 4, 6 (± 5 day window). For all 
cycles beyond Cycle 6, this same measurement pattern should be continued (i.e., Day 28 of Cycles 8, 10, 12 (± 5 day window). The elected imaging modality may be 
supplemented by alternative modalities as clinically indicated.  If regional MRI was used to determine local progression for eligibility, then CT  (or PET/CT) must also be 
performed at baseline and every other cycle.  If results of a CT scan performed as a part of standard medical practice within 7 days of Randomization are available, then an 
additional baseline scan will not be required.  Sites are to perform the Imaging according to the Tyme-88-Panc Imaging Manual  
g A complete physical examination will be performed at screening and at the End of Treatment Visit.  An abbreviated physical examination to monitor for changes will be 
performed at all other visits indicated.  Body weight should be measured at each physical examination. Inquiry about suicidal thoughts or behavior and emergency or worsening 
depression or unusual changes of mood and behaviors should be assessed at each treatment visit. Height should be measured at screening. As part of a complete physical exam, 
dermatologic evaluation will be conducted at each visit for the development of rash and potential sign of SJS/TEN. Subjects with a history of basal cell carcinoma will be 
regularly observed for potential new lesions. 
h Vital signs will include blood pressure, respiratory rate, pulse, oxygen saturation, weight and temperature. 
Wearable device (Fitbit) 
Continuous daily wear beginning C1D1 until completion of follow-up visit 
Adverse events k 
Xk 
Xk 
 
Xk 
 
Xk 
 
Xk 
 
Xk 
 
Xk 
 
Xk 
 
Dispense gemcitabinel 
 
Xl 
 
Xl 
 
Xl 
 
Xl 
 
Xl 
 
Xl 
 
 
 
Survival data m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 


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i All scheduled ECGs will be performed before any blood draws scheduled for the same time point.  Subjects should be resting quietly and free of distraction for 10 minutes prior to 
ECG collection. The Investigator or a qualified designee will review all ECGs.  ECGs will be performed only at baseline and at follow-up visit. 
j Other efficacy labs include: CEA, LDH, total alkaline phosphatase, bone-specific alkaline phosphatase, hemoglobin, WBC, ANC, leptin, and NLR. 
k Screen for symptoms of PML, hemiparesis, apathy, confusion, cognitive deficiencies and ataxia. Consult a neurologist as clinically indicated. 
l Control arm treatment will be administered as follows: gemcitabine (1000 mg/m2 IV on Days 1, 8, and 15 on a 28-day cycle). 
m Survival data to be collected every 3 months by review of medical records, public social media, phone or in person contact. 
 
 
 


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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1. 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for participation in 
this study. Inclusion criteria include the following: 
1. 
Part 1: 
Biopsy-proven metastatic pancreatic adenocarcinoma with documented radiographic 
disease progression on or after one or more systemic therapies, including a gemcitabine-
based chemotherapy regimen or any first line regimen as listed in PANC G National 
Comprehensive Cancer Network (NCCN) current guidelines. Chemotherapy given as part 
of prior chemo-radiation in the setting of non-metastatic pancreatic cancer does not count 
as a line of therapy. Chemotherapy given for at least 4 months as adjuvant after CR is 
considered as a first line therapy. 
Part 2: 
Biopsy-proven metastatic pancreatic adenocarcinoma on or after two prior lines of 
systemic therapy. A line of therapy is defined as either: having progressed on a treatment 
regimen, or having received at least 2 months of a treatment regimen. Chemotherapy 
given as part of prior chemo-radiation in the setting of non-metastatic pancreatic cancer 
does not count as a line of therapy unless metastases develop within 6 months of 
completing the chemo-sensitization. Chemotherapy given for at least 4 months as 
adjuvant after a CR to any therapy (e.g., surgery or radiation therapy) is also considered a 
first line therapy. Of the two prior lines, subjects must have been exposed to a 
gemcitabine-based regimen for a prior line and a 5-FU-based regimen as a prior line of 
therapy. Investigational therapies as part of a prior line regimen are permitted.   
1. Subjects have received two (2) and not more than two (2) previous systemic regimens 
for the treatment of pancreatic adenocarcinoma. 
2. Subjects must be eligible to receive one or more of the Physician’s Choice options. 
3. Radiographically measurable disease of at least one site by CT scan (or MRI or 
PET/CT, if allergic to CT contrast media). Imaging for baseline results must be 
obtained at most 14 days prior to Randomization. 
4. Subjects must have completed any investigational cancer therapy at least 30 days 
prior to Randomization. 
5. Subjects must have completed any other cancer therapy at least 14 days prior to 
Randomization, and recovered from major side effects of prior therapies or 
procedures.  
6. ≥18 years of age. 
7. ECOG PS ≤2. 


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8. Adequate organ function, defined as follows (lab results must be obtained at most 
7 days prior to Randomization): 
a. All laboratory parameters ≤ Grade 2 NCI Common Terminology Criteria 
for Adverse Events (CTCAE) criteria. 
b. In addition:  
i. Hematologic: Platelets ≥ 100 x 109 g/dL; Absolute Neutrophil 
Count ≥ 1.5 x 109/L (without platelet transfusion or growth factors 
within the 7 days prior to the screening laboratory assessment). 
ii. Hepatic: aspartate transaminase/alanine transaminase ≤ 2.5 x upper 
limit of normal (ULN); total or conjugated bilirubin ≤ 1.5 x ULN, 
alkaline phosphatase (ALP) < 2.5 x ULN, or 24 hour urine-
determined creatinine clearance ≥60 mL/min 
iii. Renal: serum creatinine ≤ 1.5 x ULN and creatinine clearance ≥ 60 
mL/min as calculated by the Cockroft-Gault method, or 24 hour 
urine-determined creatinine clearance ≥ 60 mL/min. 
iv. Coagulation: international normalized ratio (INR) ≤ 1.2. 
v. Albumin: ≥ 3.0 g/dL. 
9. All acute toxic effects of any prior antitumor therapy resolved to Grade ≤ 1 before 
Randomization, with the exception of alopecia and neurotoxicity (CTCAE Grade 
1 or 2 permitted). 
10. Able and willing to provide written informed consent to participate in this study. 
11. Subject is willing and able to comply with the protocol for the duration of the 
study, including undergoing treatment and scheduled visits and examinations 
including follow-up.  
12. Subjects must be able to swallow whole capsules. 
13. Female subjects must either be of non-reproductive potential, not breast-feeding 
or must have a negative urine or serum pregnancy test within 28 days of 
Randomization, confirmed prior to treatment on Cycle 1 Day 1.  
14. Subjects of fertile potential who engage in heterosexual intercourse with partners 
of childbearing potential must attest to the use of highly effective contraception 
while enrolled in the study and for at least 6 months following the last dose of 
study drug. Highly effective birth control methods include the following (the 
subject should choose 2 to be used with their partner):   
a. Oral, injectable, or implanted hormonal contraceptives. 
b. Condom with a spermicidal foam, gel, film, cream, or suppository. 
c. Occlusive cap (diaphragm or cervical/vault cap) with a spermicidal foam, 
gel, film, cream, or suppository. 


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Or any one of the following: 
a. Intrauterine device. 
b. Intrauterine system (for example, progestin-releasing coil). 
c. Vasectomized male (as determined by the Investigator). 
d. Tubal ligation/sterilization (female). 


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7.2. 
Exclusion Criteria 
Exclusion criteria are as follows (subjects who meet any of the following exclusion 
criteria may not be enrolled in this study): 
1. Any screening laboratory, ECG, or other findings that, in the opinion of the 
Investigator, Medical Monitor or the Sponsor, indicate an unacceptable risk for 
the subject’s participation in the study.   
2. History or evidence of any clinically significant disorder, condition, or disease 
that, in the opinion of the Investigator or Medical Monitor would pose a risk to 
the subject’s safety or interfere with the study evaluations, procedures, or 
completion.  Examples include: intercurrent illness such as active uncontrolled 
infection, active or chronic bleeding event within 28 days of Randomization, 
uncontrolled cardiac arrhythmia, or psychiatric illness/social situation that would 
limit compliance with study requirements.  
3. History of a concurrent or second malignancy, except for: adequately treated 
localized basal cell or squamous cell carcinoma of the skin, adequately treated 
superficial bladder cancer, adequately treated Stage 1 or 2 cancer currently in 
complete remission; or any other cancer that has been in complete remission for ≥ 
5 years. 
4. Subjects with MSI-H pancreatic cancer who have not previously received 
pembrolizumab. 
5. Subjects with any known actionable mutation (e.g., BRCA mutation) who have 
not been treated with an approved drug for the mutation (the drug does not have 
to be approved for the indication). 
6. Radiation to all measurable lesions within 12 weeks of study baseline.  
7. No measurable lesions. 
8. Current use, or any use within 14 days prior to Randomization, of a restricted 
medication (see Section 8.7), or subject requires any of these medications during 
treatment phase. 
9. Major surgery, defined as any surgical procedure that involves general anesthesia 
and a significant incision (i.e., larger than that required for placement of central 
venous access, percutaneous feeding tube, or biopsy) within 28 days of the first 
dose of study drug. 
10. Minor surgical procedures within 7 days of Randomization, or not yet recovered 
from any prior surgery. 
11. Any dysphagia, odynophagia, esophageal dysmotility or stricture, known 
gastrointestinal (GI) malabsorption syndrome, or intractable diarrhea that may 
significantly alter the absorption of any of the components of SM-88 used with 
MPS, e.g., cirrhosis. 
12. Known human immunodeficiency (HIV) virus infection. Note: HIV testing is not 
required in the absence of clinical suspicion. 
13. Known hepatitis B surface antigen (HBsAg) positive. Note: testing is not required 
in the absence of clinical suspicion. 
14. Known hepatitis C (HCV) viral RNA present. Note: testing is not required in the 
absence of clinical suspicion. 
15. Have previously been enrolled in this study or any other study investigating SM-


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88 or have previously received any SM-88, methoxsalen, phenytoin, or sirolimus 
in a clinical trial. 
16. History of any known drug allergies to any study medication. 
17. Subjects with a history of hypersensitivity to phenytoin, its inactive ingredients, 
or other hydantoins; or a history of prior acute hepatotoxicity attributable to 
phenytoin. 
18. Subjects exhibiting idiosyncratic reactions to psoralen compounds.  
19. Subjects with a hypersensitivity to sirolimus. 
20. Currently enrolled in, or have discontinued within 30 days of Randomization, 
from a clinical trial involving an investigational product or non-approved use of a 
drug or device. 
21. Subjects must not have any clinically significant and uncontrolled major medical 
condition(s) including, but not limited to: uncontrolled nausea/vomiting/diarrhea; 
active uncontrolled infection; symptomatic congestive heart failure (New York 
Heart Association [NYHA] class ≥ II); unstable angina pectoris or cardiac 
arrhythmia; psychiatric illness/social situation that would limit compliance with 
study requirements. 
22. >5% weight loss at any time during the 28 days prior to consent, or >5% change 
in weight from consent (Screening) to Randomization (must be at least 1 week 
apart). This second weight measure should be captured prior to Randomization. 
23. Subjects who have a variety of factors influencing their ability to ingest and 
absorb oral drugs (such as unable to swallow, nausea, vomiting, chronic diarrhea 
and intestinal obstruction, etc.). 
24. Subjects with central nervous system metastasis, with the exception of subjects 
who have stable brain metastases as defined as off steroids and no CNS 
progression for 6 months after CNS treatment. 
25. Pregnant or lactating women. 
26. Substance abuse that cannot be ended, or subjects with mental disorders that will 
prevent compliance or evaluation including uncontrolled schizophrenia, 
uncontrolled depression or other uncontrolled disorders. 
27. Subjects with a history of the light sensitive diseases for which methoxsalen 
would be contraindicated. Diseases associated with photosensitivity include: 
lupus erythematosus, porphyria cutanea tarda, erythropoietic protoporphyria, 
variegate porphyria, xeroderma pigmentosum, and albinism. 
28. Subjects treated, or anticipated to be treated, with delavirdine (due to potential for 
loss of virologic response and possible resistance to delavirdine or to the class of 
non-nucleoside reverse transcriptase inhibitors caused by phenytoin). 
29. Subjects with cutaneous melanoma or invasive squamous cell carcinomas or 
history thereof, except for those in complete remission for ≥5 years (due to 
contraindication for use of methoxsalen). 
30. Subjects with prior organ transplant or being treated, or anticipated to be treated, 
with cyclosporine (because long-term administration of the combination of 
cyclosporine and sirolimus is associated with deterioration of renal function). 
31. Subjects with a seizure disorder that is not well controlled or who have required a 
change in seizure medications within 60 days of Randomization. 
32. Subjects treated, or anticipated to be treated, with a calcineurin inhibitor (because 


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concomitant use of sirolimus and a calcineurin inhibitor increases the risk of 
calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic 
thrombocytopenic purpura/thrombotic microangiopathy [HUS/TTP/TMA]). 
33. Subjects with interstitial lung disease (ILD) [including pneumonitis, bronchiolitis 
obliterans organizing pneumonia (BOOP), and pulmonary fibrosis]. 
34. Screening prolongation of QT/QTc interval [e.g., > 480 milliseconds (ms)] 
(CTCAE Grade 1) using Fredericia’s QT correction formula. 
35. A family history of Long QT Syndrome or Torsades de Pointes. 
36. Clinically significant cataracts or aphakia. 
37. Presence of symptomatic or clinically significant ascites or pleural effusion, 
defined as requiring clinical intervention in the 30 days prior to consent. 
However, trace or small amount of physiologic fluid will not be excluded.   
7.3. 
Criteria for Subject Withdrawal 
The criteria for enrollment must be followed explicitly. If a subject who does not meet 
enrollment criteria is inadvertently enrolled, the Investigator must contact the Tyme, Inc. 
Medical Monitor (see cover page) to discuss whether the subject should be discontinued 
from the study drug.  
Subjects may choose to discontinue study treatment or withdraw from the study for any 
reason at any time, and the reason for early withdrawal will be documented.   
In addition, subjects must be permanently discontinued from the study if any of the 
following occur: 
• Documented disease progression as detailed below 
• Occurrence of rare, but serious adverse events as listed in Section 8.2  
• Investigator decision for subject welfare  
• Medically necessary in the opinion of the Investigator or Sponsor 
• Uncontrolled intercurrent illness as defined by the Principal Investigator 
• Non-compliance 
It is hypothesized that subjects may show clinical benefit and reduced SUV prior to 
demonstrating traditional RECIST-based responses. Some subjects may even have tumor 
site inflammation that is visible on CT imaging (i.e., pseudo-progression) at the first 
follow-up scan.  
Subjects with radiographic evidence of PD, but without clinical deterioration, may be 
considered for repeat confirmation scans before clinically significant PD is defined and 
study therapy is withdrawn. This decision should be balanced against the potential 
toxicity associated with continued treatment and alternative treatment options and must 
be discussed with and approved by the Medical Monitor. Continuation should be 
evaluated at least every 4 weeks after initial response assessment or sooner if clinical 
deterioration occurs. 


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Subjects who discontinue the study early will have early termination procedures and 
follow-up performed as shown in the study Time and Events Schedule.  
7.4. 
Criteria for Study Site Discontinuation 
Study site participation may be discontinued if Tyme, Inc., the Investigator, or the IRB of 
the study site judges it necessary for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulations, and Good Clinical Practices (GCP).   
7.5. 
Criteria for Study Discontinuation 
This study will be discontinued if Tyme, Inc. judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable, laws, regulations, and GCP. At 
the end of Part 1 of this clinical trial, when 36 subjects have completed at least 1 cycle of 
the therapy and are evaluable for safety, if greater than one-third of enrolled subjects 
experience Grade 3-4 AEs at least possibly related to SM-88 used with MPS, enrollment 
may be paused, and the study data will be reviewed to determine whether alternate dose 
levels or treatment schedules should be evaluated. This assessment will take place again 
when all subjects have completed at least 1 cycle of therapy. Other assessments will be 
conducted by the Data Safety Monitoring Board (DSMB) according to its charter. 
 
 


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8. 
TREATMENT 
8.1. 
Treatments Administered 
In Part 1, subjects are treated with SM-88 used with MPS. In Part 2, subjects are 
randomized to either the SM-88 used with MPS or control arm (Physician’s Choice). 
8.2. 
SM-88 used with MPS 
The regimen consists of SM-88 and three conditioning agents:  
• SM-88 – 460 mg/day (230 mg b.i.d) or 920 mg/day (460mg b.i.d) as randomly 
assigned  
• Methoxsalen – 10 mg capsules q.d. 
• Phenytoin – 50 mg tablets q.d. 
• Sirolimus – 0.5 mg tablets q.d.  
SM-88 and MPS will be taken daily. It is best to take doses one hour before or two hours 
after meals, so as to ensure an empty stomach. They should be taken together consistently 
either in the morning or in the evening with a full glass of water – for example, before 
bedtime and upon waking up in the morning. 
A second dose of SM-88 will be taken 12 hours (+/- 4 hours) after the morning dose. 
Missed doses of any of the 4 agents will be omitted and skipped. Subjects who miss a 
dose of any of the 4 agents, for any reason, will omit that dose and take the next dose at 
the next regularly scheduled time point 12 hours (+/- 4 hours) after the missed dose was 
due. If the morning (AM) dose is missed, subjects will continue with the PM dose as 
scheduled and may take the adjunct medications (methoxsalen, phenytoin, and sirolimus) 
with their PM dose. If the PM dose is missed, subjects will skip that dose and resume 
dosing with the AM dose the following day.  
Part 1 
The low dose, SM-88(1) arm will receive:  
• SM-88 – one 230 mg capsules taken orally twice daily (460 mg total). 
• Methoxsalen – one 10 mg capsule taken orally once daily. 
• Phenytoin – one 50 mg tablet taken orally once daily. 
• Sirolimus – one 0.5 mg tablet taken orally once daily. 
The high dose, SM-88(2) arm will receive:  
• SM-88 – two 230 mg capsules taken orally twice daily (920 mg daily). 
• Methoxsalen – one 10 mg capsule taken orally once daily. 
• Phenytoin – one 50 mg tablet taken orally once daily. 
• Sirolimus – one 0.5 mg tablet taken orally once daily. 
 
 


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Part 2 
All subjects enrolled into Part 2 who are randomized to SM-88 used with MPS will 
receive:  
• SM-88 – two 230 mg capsules taken orally twice daily (total 920 mg daily). 
• Methoxsalen – one 10 mg capsule taken orally once daily. 
• Phenytoin – one 50 mg tablet taken orally once daily. 
• Sirolimus – one 0.5 mg tablet taken orally once daily. 
8.2.1. 
Control Arm (Physician’s Choice) 
All subjects enrolled into Part 2 who are randomized to the control arm (Physician’s 
Choice) will receive a choice of the following therapies: 
• Capecitabine (1000 mg/m2 orally twice a day, Days 1-14 on a 21-day cycle) 
• Gemcitabine (1000 mg/m2 IV on Days 1, 8, and 15 on a 28-day cycle) 
• 5-FU (2400 mg/m2 continuous IV infusion over 46 hours on Day 1 and 15 on a 
28-day cycle) 
8.3. 
Adverse Events 
8.3.1. 
SM-88 used with MPS 
There are known rare but potentially serious adverse events associated with SM-88 and 
MPS components. While doses of the approved drug components in this regimen are 
lower than their respective FDA-approved doses, the risks of these drugs when used 
together is not known and therefore, it is important that subjects are observed for these 
events. 
Below are warnings and common adverse events associated with SM-88 and MPS 
components that may be relevant to this trial’s enrollment criteria. Refer to APPENDIX 
B: DETAILED DESCRIPTIONS OF ADVERSE EVENTS for a more detailed 
description of these warnings. 
Please note, with respect to Table 10, the list of possible adverse events and risks of SM-
88 is based upon initial clinical testing of SM-88 used with MPS, as well as findings 
reported with the use of a similar product, DEMSER® (L-alpha-metyrosine). The 
mechanism of action of DEMSER® is believed to be similar to SM-88. 
 
 


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Table 10: 
Adverse Events Possibly Associated with SM-88 
D,L-Alpha-Metyrosine 
Severe Warnings 
(Black Box) 
Warning/Precautions*  
Most Common Adverse 
Reactions* 
(N/A) 
• Maintain Fluid Volume 
During and After Surgery 
• Life-threatening 
arrhythmias may occur 
during anesthesia and 
surgery and may require 
treatment with a beta-
blocker or lidocaine  
• Intraoperative Effects such 
as hypertensive crises or 
arrhythmias 
• Interaction with Alcohol 
and sedative effects of 
alcohol and other CNS 
depressants 
• Metyrosine Crystalluria 
• Caution engaging in 
activities requiring mental 
alertness and motor 
coordination 
• Hypotension 
• Arthralgia 
• Pregnancy Category C 
 
• Sedation can be 
moderate to severe, 
especially immediately 
after initiating therapy 
• Drooling 
• Speech Difficulty 
• Trismus 
• Frank Parkinsonism 
• Depression  
• Hallucination 
• Disorientation 
• Confusion 
• Bloating and flatulence 
• Loss of skin color 
• Hot flashes 
• Diarrhea  
*Based on USPI for L-alpha-metyrosine 
 
 


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Table 11: 
Adverse Events Associated with Sirolimus  
Severe Warnings (Black Box) Warning/Precautions  
Most Common Adverse 
Reactions 
• Increased susceptibility 
to infection and the 
possible development of 
lymphoma and other 
malignancies may result 
from immunosuppression 
• The safety and efficacy 
of Sirolimus as immune 
suppressive therapy have 
not been established in 
liver or lung transplant 
subjects, and therefore, 
such use is not 
recommended 
• Liver Transplantation – 
Excess mortality, graft 
loss, and hepatic artery 
thrombosis 
• Lung Transplantation – 
Bronchial anastomotic 
dehiscence 
 
• Increased susceptibility 
to infection and the 
possible development of 
lymphoma 
• Hypersensitivity 
Reactions 
• Angioedema 
• Fluid Accumulation and 
Impairment of Wound 
Healing 
• Hyperlipidemia 
• Decline in Renal 
Function 
• Proteinuria 
• Latent Viral Infections 
• Interstitial Lung 
Disease/Non-Infectious 
Pneumonitis 
• De Novo Use Without 
Cyclosporine 
• Increased Risk of 
Calcineurin Inhibitor-
Induced Hemolytic 
Uremic 
Syndrome/Thrombotic 
• Thrombocytopenic 
Purpura/Thrombotic 
Microangiopathy 
• Antimicrobial 
Prophylaxis 
• Embryo-Fetal Toxicity 
• Skin Cancer Events 
Interaction with Strong 
Inhibitors and Inducers 
of CYP3A4 and/or P-
glycoprotein 
 
• 
Sirolimus used in 
clinical studies for organ 
rejection prophylaxis 
and LAM: 
o Peripheral Edema 
o Hypertriglyceridemia 
o Hypertension 
o Hypercholesterolemia 
o Creatinine Increased 
o Constipation 
o Abdominal Pain 
o Diarrhea 
o Headache 
o Fever 
o Urinary Tract 
Infection 
o Anemia 
o Nausea 
o Arthralgia, Pain 
o Thrombocytopenia 
o Stomatitis 
o Nasopharyngitis 
o Acne 
o Chest Pain 
o Upper Respiratory 
Tract Infection 
o Dizziness 
o Myalgia 
 
 
 


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Table 12: 
Adverse Events Associated with Methoxsalen 
Methoxsalen 
Severe Warnings (Black Box) 
Warning/Precautions  
Most Common 
Adverse 
Reactions 
• Methoxsalen is a potent drug  
• Methoxsalen with UV 
radiation should be used only 
by physicians who have 
special competence in the 
diagnosis and treatment of 
psoriasis and who have 
special training and 
experience in 
photochemotherapy 
• Use of Psoralen and 
ultraviolent radiation therapy 
should be under constant 
supervision of such a 
physician  
• For the treatment of subjects 
with psoriasis, 
photochemotherapy should 
be restricted to subjects with 
severe, recalcitrant, disabling 
psoriasis which is not 
adequately responsive to 
other forms of therapy, and 
only when the diagnosis is 
certain  
• Possibilities of ocular 
damage, aging of the skin, 
and skin cancer (including 
melanoma); the subject 
should be fully informed by 
the physician of the risks 
inherent in this therapy 
 
• Skin Burning from UVA or 
sunlight can result if the 
recommended dosage of the 
drug is exceeded 
• Carcinogenicity in animal 
and human studies 
• Cataractogenicity  
• Actinic Degeneration 
• Basal Cell Carcinomas 
• Hepatic Diseases and drug 
exposure 
• Elderly Subjects with pre-
existing history of cataracts, 
kidney and/or liver 
dysfunction, or skin cancer 
• Risks with concomitant 
photosensitizing agents 
• Do not sunbathe during the 
24 hours prior to or after 
methoxsalen ingestion and 
wear UV exposure UVA-
absorbing wrap-around 
sunglasses for 24 hours after 
methoxsalen ingestion  
• Nausea 
• Pruritus 
• Erythema 
 
 
 
 


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Table 13: 
Adverse Events Associated with Phenytoin 
Phenytoin 
Severe Warnings (Black 
Box) 
Warning/Precautions  
Most Common 
Adverse Reactions 
(None in USPI) 
• Withdrawal Precipitated 
Seizure: May precipitate status 
epilepticus  
• Potential increase in suicidal 
behavior and Ideation  
• Serious Dermatological 
Reactions, including SJS/TEN 
• Drug Reaction with 
Eosinophilia and Systemic 
Symptoms 
(DRESS)/Multiorgan 
Hypersensitivity: phenytoin 
hypersensitivity 
• Hepatic Injury  
• Hematopoietic Complications 
• Nervous 
System 
Reactions: 
o Nystagmus 
o Ataxia 
o Slurred 
Speech 
o Decreased 
Coordination 
o Somnolence 
o Mental 
Confusion 
 
8.3.2. 
Control Arm (Physician’s Choice) 
There are known serious adverse events associated with each of the Physician’s Choice 
therapies. Refer to the prescribing information for a more detailed description of these 
warnings (APPENDIX B: DETAILED DESCRIPTIONS OF ADVERSE EVENTS). 
8.4. 
Dose Interruption / Discontinuation of SM-88 used with MPS 
SM-88 used with MPS consists of four drugs (see Section 8.1), three of which are FDA-
approved therapies which are dosed below their typically prescribed doses. There has 
only been one drug-related serious adverse event associated with SM-88 used with MPS 
in over 100 treated cancer subjects to date; the subject that experienced a drug-related 
SAE remains on treatment and has demonstrated response to therapy. However, the 
safety profile of SM-88 used with MPS has not been fully established. Rare, but 
potentially life-threatening adverse events have been associated with the other three 
approved drug components. Subjects enrolled in this clinical trial of SM-88 used with 
MPS will be observed for adverse events (outlined in Section 8.2) that are deemed at least 
possibly related to therapy. Below are instructions with regard to stopping SM-88 used 
with MPS in response to drug-related adverse events. If a subject has a dose interruption 
of greater than 28 days, they must be permanently discontinued from the study.   


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8.4.1. 
Permanent discontinuation of SM-88 used with MPS 
Subjects must permanently discontinue SM-88 used with MPS and be removed from the 
study if any of the adverse events described in Table 13 are observed and deemed related, 
or possibly related, to study therapy. Treatment with SM-88 cannot be continued without 
MPS. Subjects are to follow early termination procedures and follow-up must be 
performed as shown in the study Time and Events Schedule. 
Table 14: 
Permanent Discontinuation Criteria for SM-88 used with MPS 
General 
CTCAE Any possible drug-related Grade 4 event 
Immune system 
disorders 
CTCAE Grade ≥3 Allergic reaction (drug-related)  
Blood and lymphatic 
system disorders 
Drug Reaction with Eosinophilia and Systemic Symptoms 
(DRESS) / Eosinophilia, leukocytosis, Hepatobiliary 
disorders 
Skin and subcutaneous 
tissue disorders 
Stevens–Johnson syndrome (SJS) / Toxic epidermal 
necrolysis (TEN) 
CTCAE Grade ≥ 3 Erythema multiforme 
Psychiatric disorders 
Any increase in suicidal ideation from baseline 
8.4.2. 
Dose interruption of SM-88 and MPS from drug-related, or possibly 
related DLTs  
For Part 1: 
With the exception of the previously listed events in Table 13 that require permanent 
discontinuation of SM-88, for subjects who experience one of the following DLTs, the 
dosing of SM-88 must immediately be stopped until the toxicity has resolved to ≤ Grade 
1 or returns to baseline level within 28 days from the DLT event.  
• If the drug-related DLT is not resolved to ≤ Grade 1 within 28 days, the subject 
must permanently discontinue SM-88 and must be removed from study and to 
follow early termination procedures with follow-up performed as shown in the 
study schedule. 
• Re-initiation of SM-88 can only occur after consultation with the Medical 
Monitor.  
• Subjects are to receive all components of SM-88 used with MPS at the same 
doses as prior to withholding of treatment, as described in Section 8.1. 


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• If a subject has a second episode of a related or possibly drug-related DLT, the 
subject must permanently discontinue SM-88 and must be removed from study 
and to follow early termination procedures with follow-up performed as shown in 
the study schedule. 
• Supportive care should be implemented for all AE toxicities. 
DLTs will be defined as AEs at least possibly related to SM-88 used with MPS and are 
detailed in Table 15 below.  
For Part 2: 
For subjects who experience one of the following DLTs, the dosing of SM-88 must be 
stopped until the toxicity has resolved to ≤ Grade 1 or returns to baseline level within 
28 days from the DLT event.  
• If after the allowed dose reduction, or the temporary elimination of the related 
component(s) of MPS, the drug-related DLT is not resolved to ≤ Grade 1 within 
28 days, the subject must permanently discontinue SM-88 and must be removed 
from study, and follow early termination procedures with follow-up performed as 
shown in the study schedule. 
• Reinitiation of SM-88 can only occur after consultation with the Medical Monitor.  
• Subjects are to receive all components of MPS when given at the reduced dose of 
SM-88, as described in Section 8.1. 
• If a subject has a second episode of a related or possibly drug- related DLT, SM-
88 may be discontinued for 28 days while mitigating measures are attempted. 
• If after restarting therapy, the DLT continues, the subject will be removed from 
the study.   
• Supportive care should be implemented for all AE toxicities. 
Based on the preclinical profile (there was no NOAEL) and ongoing and previous 
experience, with no DLT or MTD yet detected, the protocol specifies a dose interruption 
for any DLTs. Further, there is precedent for no dose reduction and only a dose delay or 
termination for DLTs (for example, liposomal doxorubicin palmar plantar erythema is 
often treated with dose delay and not dose reduction). In Part 2, as detailed elsewhere, 
dose reductions of SM-88 are allowed.  
Persistent toxicity associated with SM-88 is unexpected based on the above. Utilizing a 
treatment holiday and then restarting at the same dose may allow clearer evaluation of 
whether observed AEs are drug-related or disease-related. The protocol also utilizes a 
Data Safety Monitoring Board (DSMB) that will be regularly monitoring the overall 
safety of the trial and evaluating any potentially serious safety signals. If the DSMB 
identifies any serious safety signals, the trial protocol will be amended to address 
concerns or pause enrollment until subject safety can be fully evaluated.   
 
 


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Table 15: 
Dose-Limiting Toxicities Criteria for SM-88 used with MPS 
Hematologic 
CTCAE Grade ≥3 Neutropenia or febrile neutropenia 
  
CTCAE Grade ≥3 Thrombocytopenia 
  
CTCAE Grade ≥3 Anemia (irrespective of its association 
with bleeding) 
Gastrointestinal 
CTCAE Grade ≥3 Nausea (of ≥72 hours duration with 
maximal supportive care) 
  
CTCAE Grade ≥3 Vomiting (of ≥72 hours duration with 
maximal supportive care) 
  
CTCAE Grade ≥3 Diarrhea (of ≥72 hours duration with 
maximal supportive care) 
Metabolism 
CTCAE Grade ≥3 Hypoalbuminemia (> 24-hour duration 
with repletion) 
  
CTCAE Grade ≥3 Hypocalcemia (> 24-hour duration with 
repletion) 
  
CTCAE Grade ≥3 Hypokalemia (> 24-hour duration with 
repletion) 
  
CTCAE Grade ≥3 Hypomagnesemia (> 24-hour duration 
with repletion) 
  
CTCAE Grade ≥3 Hyponatremia (> 24-hour duration with 
repletion) 
  
CTCAE Grade 3 Hypophosphatemia (> 24-hour duration 
with repletion) 
Cardiac disorders 
CTCAE Grade ≥3 Heart failure 
Hepatobiliary disorders CTCAE Grade ≥3 Hepatobiliary disorders 
  
CTCAE Grade ≥3 Hepatic failure 
Renal and urinary 
disorders 
CTCAE Grade ≥3 Acute kidney injury 
  
CTCAE Grade ≥3 Chronic kidney disease 
8.4.3. 
Risk Mitigation/Discontinuation of MPS components of SM-88 used with 
MPS 
For toxicity attributable to the MPS agents, a dose reduction adjustment of the individual 
components is not allowed in Part 1. In Part 2, if any of the methoxsalen, phenytoin, or 
sirolimus (MPS) components are considered to be associated with a DLT, the individual 
component(s) may be discontinued for up to 28 days while mitigating measures are 
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This may be applied to any or all of the MPS components. If after 28 days the DLT 
continues, the subject will be removed from the study.   
8.5. 
Dose Interruption / Discontinuation of Control Arm 
(Physician’s Choice) Therapy 
In the case of adverse events or DLT in the control arm, refer to the prescribing 
information for dose interruption, risk mitigation or discontinuation. 
8.6. 
Description and Handling of Product 
8.6.1. 
SM-88 used with MPS 
For Part 1 and for subjects randomized to SM-88 in Part 2: 
Tyme, Inc. designee ALMAC will provide: 
• SM-88 (D,L-alpha-metyrosine), in 230 mg capsules. 
• Methoxsalen, in 10 mg capsules. 
• Phenytoin, in 50 mg tablets. 
• Sirolimus, in 0.5 mg tablets. 
Investigational product will be dispensed to the subject at the study site. Adequate supply 
of investigational product will be dispensed to fulfill dosing requirements per cycle. 
Investigational product will be labeled according to applicable regulatory requirements.  
All investigational products will be stored, inventoried, reconciled, and destroyed 
according to applicable regulations.   
All components of SM-88 used with MPS should be kept in a secure area and stored as 
follows: 
• SM-88 should be stored at room temperature 15 to 25 degrees C (59° to 77°F) and 
protected from light and moisture (USP Controlled Room Temperature). 
• Methoxsalen capsules should be stored at 25 degrees C (77°F) (excursions 
permitted); temperatures between 15 to 30 degrees C (59° to 86° F) are 
acceptable, and protected from light and moisture (USP Controlled Room 
Temperature). Preserve in a tight, light-resistant container as defined in the USP. 
• Phenytoin should be stored at room temperature 20 to 25 degrees C (68° to 77°F) 
and protected from light and moisture (USP Controlled Room Temperature), 
dispensed in tight (USP), child-resistant containers. 
• Sirolimus should be stored at room temperature 20 to 25 degrees C (68° to 77° F) 
and protected from light and moisture (USP Controlled Room Temperature). 
Dispense in a tight, light-resistant container as defined in the USP.  


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8.6.1.1. 
 Drug returns from subjects 
Subjects will be asked to return all bottles, whether empty or not, to the site. Unused SM-
88, and MPS components, must be returned to pharmacy for counting and recording in 
the subject’s Drug Accountability Log.  
8.6.1.2. 
Drug destruction  
Returned, unused or expired drugs should be destroyed only once permission has been 
granted by the Sponsor, as per the following table:  
Table 16: 
Drug Dispensing Guidelines 
Expired drug  
 
Once authorized to do so by Sponsor, 
expired drug can be destroyed per local 
SOP or sent back to ALMAC if no such 
SOP exists 
Drug left unused/not dispensed 
 
Once authorized to do so by Sponsor, drug 
can be sent back to ALMAC  
Subject returns 
 
Upon receipt, number of capsules returned 
to be recorded on subject’s Drug 
Accountability Log. At the end of the 
study, once authorized to do so by the 
Sponsor, any unused drug should be 
destroyed by the site.  
Accountability for the IP returned is 
logged in to the visit in which the IP was 
dispensed.   
8.6.2. 
Part 2:  Control Arm (Physician’s Choice)  
All Physician’s Choice medication is to be sourced and funded locally. Drugs will be 
prescribed, tracked, and dispensed according to the local policy/SOPs for standard of care 
treatment.  
8.6.2.1. 
Drug returns from subjects 
Subjects randomized to capecitabine will be asked to return all bottles, whether empty or 
not, to the pharmacy for counting and recording in the subject’s Drug Accountability 
Log. 
8.6.2.2. 
Drug destruction 
Returned, unused or expired drugs should be destroyed only once permission has been 
granted by the Sponsor as per “Subject returns” in Table 15 above. 


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8.7. 
Randomization and Blinding 
This is a prospective, open-label, randomized Phase 2/3 trial design in pancreatic cancer 
subjects. The first part was a dose-selection study, examining at least 36 evaluable 
subjects who had failed at least one line of prior chemotherapy. Subjects were 
randomized between two doses of SM-88.   
The subjects in Part 2 will be randomized 1:1 between SM-88 used with MPS, or 
Physician’s Choice (from the treatment options noted in this protocol). The 
randomization will be balanced by investigative site, PS (ECOG 0-1 vs 2), and 
Physician’s Choice of control group treatment as identified before Randomization. That 
is, prior to Randomization, each physician will choose from among the treatment options 
for the control group, and this choice will then be implemented as a balancing factor for 
Randomization and a stratification factor in the analysis of the results.  
8.8. 
Concomitant Medications 
Subjects will be instructed to consult the Investigator or other appropriate study personnel 
before taking any new medications or supplements during the study.   
Concomitant medications taken within 30 days prior to baseline will be recorded. At each 
study visit, all concomitant medications taken since the previous visit, including 
prescription and non-prescription medications, vitamin and mineral supplements, herbal 
and naturopathic remedies, and supportive therapies, will be recorded.   
• Treatment with any other anticancer agents is not allowed.  
• Use of locally determined illegal drugs within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first 
dose of study medication and for the duration of the trial, including follow-up, 
will not be allowed. 
• Use of the following medications is discouraged: Medications that are clinically 
known to induce or inhibit metabolic enzymes or transporters, including 
CYP3A4, CYP2C9, CYP2C19, and p-glycoprotein (Pgp) must be used with 
caution or avoided. Known strong inhibitors or inducers of CYP3A4, CYP2C9 or 
CYP2C19, such as those listed below, are not allowed: 
o CYP2C9: 
• Strong inhibitors: fluconazole 
• Strong inducers: none known 
o CYP2C19: 
• Strong inhibitors: fluconazole, fluvoxamine, ticlopidine 
• Strong inducers: none known 
o CYP3A4: 
• Strong inhibitors: atazanavir, boceprevir, ciclosporin, 
clarithromycin, conivaptan, danazol, erythromycin, gemfibrozil, 
grapefruit juice, indinavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, 


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posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, 
voriconazole,  
• Strong inducers: avasimibe, carbamazepine, phenobarbital, 
rifabutin, rifampin, St. John’s Wort  
• Delavirdine 
• Cyclosporine 
• Calcineurin inhibitors 
• Medications that are clinically known to induce or inhibit metabolic enzymes or 
transporters, including CYP3A4, CYP2C9, CYP2C19 and Pgp must be used with 
caution or avoided.  
• Use of medications that are known to significantly prolong the QT interval is 
discouraged. 
• Cannabis or its products may not be used as a cancer therapy. Cannabis 
derivatives, including hemp, may be used by as supportive therapy, e.g., 
continued for nausea. 
• Initiation of any new medication intended as an anti-neoplastic is not permitted. 
8.9. 
Treatment Compliance 
Treatment compliance will be assessed at each study visit after Day 1 and up to the end 
of the treatment period. Treatment compliance will be measured by counting 
capsules/tablets/bottles of SM-88 used with MPS or Physician’s Choice components.  
Deviation from the prescribed dosage schedule will be recorded in the case report form 
(CRF).  
SM-88 used with MPS subjects should be encouraged to be on a low-carb diet. Inability 
to maintain a low-carb diet does not exclude subjects from participation in the trial. 
 
 


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9. 
ASSESSMENT OF EFFICACY 
Efficacy evaluations and endpoints will be performed at the times indicated in the Time 
and Events Schedule. 
For Part 2 of this study, a total of approximately 250 subjects will be enrolled to obtain 
125 subjects who have received one dose of SM-88 and 125 subjects in the control arm 
(Physician’s Choice) and are thus evaluable for the primary endpoint of OS. In addition, 
a per-protocol population will be assessed for efficacy using efficacy evaluations after 
4 full cycles of therapy (e.g., after confirmation of response per RECIST 1.1 in Part 1, 
and 2 full cycles in Part 2). 
9.1. 
Overall Survival (OS) 
The primary endpoint of OS is defined as the time from Randomization until death from 
any cause. OS will be censored at the date of the last follow-up visit or last survival 
assessment contact (whichever is later) for subjects who were still alive, or whose 
survival status is unknown at the time of the analysis.  
9.2. 
Progression-Free Survival (PFS) 
PFS is defined as the time from the subject’s date of Randomization to the date of first 
documentation of Progressive Disease (PD) or death due to any cause. PD can be defined 
clinically or radiographically, per Investigator assessment.   


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10. 
PHARMACOKINETIC ASSESSMENT 


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11. 
ASSESSMENT OF SAFETY 
11.1. 
Safety Parameters 
Safety evaluations will be performed at the times indicated in Table 5, Table 6, Table 7, 
Table 8, and Table 9 in all enrolled subjects. 
11.1.1. 
Demographics and History 
A complete medical history, including cancer history, will be obtained by the Investigator 
or qualified designee during screening. Cancer history will include data from the 
subject’s pathology reports, including tumor grade, histology, BRCA 1 and 2, MSI, PD-
L1, CDKN2A, SMAD4, KRAS, ATM, ATC, PALB2, HER-2, ERCC1, IGF-1, IDO, 
MEK, PTEN, and ARID1A, if available.  
Subject demographics will also be recorded at screening.   
11.1.2. 
Vital Signs 
Vital signs will include blood pressure, respiratory rate, pulse, oxygen saturation, weight 
and temperature. All scheduled vital signs will be measured before any blood draws 
scheduled for the same time point. Measurements should be taken per institutional 
guidelines. The time of the previous study drug administration will be recorded.   
11.1.3. 
Physical Examination 
The Investigator or qualified designee will perform complete physical examinations at 
screening and at the end of treatment visits. At all other study visits, an abbreviated 
physical examination will be performed to monitor for changes. Body weight should be 
measured at each physical examination. Height should be measured at screening.   
11.1.4. 
Electrocardiogram 
12-lead ECG reporting ventricular rate, PR, QRS, QT, and QTc intervals should be 
obtained at the visits indicated in the Time and Events Schedules. All scheduled ECGs 
will be collected in triplicate (for time-matched PK sampling) or single reports, and will 
be performed before any blood draws scheduled for the same time point. Subjects should 
be resting quietly and free of distraction for 10 minutes prior to ECG collection. The 
Investigator or a qualified designee will review all ECGs. The time of the previous study 
drug administration will be recorded. ECGs will be performed at Screening (single), Day 
1 of Cycles 1 and 2 (time-matched to PK sample collection for subjects in SM-88 arm 
only), and at subjects’ Day 28 follow-up visit (single).    
11.1.5. 
Safety Laboratory Assessments 
Laboratory samples for the appropriate analyses should be taken at the times indicated in 
the Time and Events Schedule tables. Local laboratories at each site will be responsible 


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for analysis of all safety laboratory samples. The date and time that each sample is 
collected should be recorded. All clinical laboratory results will be reviewed by the 
Investigator, or a qualified designee, for clinical significance.   
The laboratory analytes listed in Table 17 will be tested. White blood cell (WBC) 
differentials will be reported as absolute counts. Other safety and efficacy laboratory 
measures, as listed in Section 9.5, include CEA, LDH, total alkaline phosphatase, bone-
specific alkaline phosphatase, cortisol, hemoglobin, WBC, ANC, leptin, cholesterol, 
triglycerides, NLR and levels of SM-88, methoxsalen, phenytoin, and sirolimus. 
11.1.6. 
Ophthalmologic Exam (only required for those subjects enrolled in 
Part 1) 
Studies may require that Investigators arrange to obtain information critical to the study 
that cannot be obtained at the Investigator’s site. Since this study protocol requires testing 
with special equipment or expertise that may not be available at the Investigator’s site, 
the Investigator may make arrangements for an outside facility to perform the test. In this 
case, the results are usually provided directly to the Investigator, who then submits the 
information to the Sponsor. If the Investigator retains the services of a facility to perform 
study assessments, the Investigator should take steps to ensure that the facility is adequate 
(e.g., has the required certification or licenses). 
The Sponsor will allow providers licensed in the local regulatory consistent with the 
following guidance: 
• The exam can be performed by an individual whom the PI considers suitably 
trained. 
• This exam can be performed as part of the Standard of Care (SOC). 
• Further, although it is expected that an ophthalmologic exam, as part of the SOC, 
would have been performed recently within the protocol-specified window, if that 
is not the case, the Sponsor will reimburse the site for conducting an 
ophthalmologic exam as per local SOC, provided that it meets the minimum 
requested fields of the EDC. 
• Screening exam window is within 1 year of Randomization into the study.  
Data collected during the SOC visit will be entered in the EDC system. Data fields 
provided by Tyme, and to be collected for the Ophthalmology exam, will include the 
following: 
• Record OU at baseline (+30 days) for all subjects and q 12 mo (+30 days) for 
those subjects subsequently randomized to SM-88 used with MPS arm of 
treatment 
• Acuity best corrected 
• Acuity Uncorrected 
• Correction factor/RX 
• Cataracts present? – If subject has cataracts, they should be graded per clinician 
SOC, who must use the same methodology of grading for follow-up evaluations. 


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a) Retina evaluation - normal, or not [if not, describe per clinician SOC; must 
use same for follow-up evaluation] 
The PI will evaluate the subject at each visit for clinically significant changes in visual 
signs and symptoms. 
Table 17: 
Safety Laboratory Analytes 
Serum Chemistry 
Hematology 
Urinalysis 
Sodium 
Erythrocyte count 
Color 
Potassium 
Hematocrit 
Specific gravity (Part 2) 
Chloride 
Absolute reticulocyte count 
pH (Part 2) 
Glucose 
Mean cell volume 
Protein 
Blood urea nitrogen 
Mean cell hemoglobin 
Glucose 
Creatinine 
Mean cell hemoglobin 
concentration 
Ketones 
 
Leukocytes 
Blood  
Alanine aminotransferase 
Neutrophils 
Bilirubin 
Aspartate aminotransferase 
Lymphocytes 
Urine N-telopeptide 
Total bilirubin 
Monocytes 
Leukocyte esterase 
Total protein 
Basophils 
Nitrites 
Albumin 
Eosinophils 
 
Calcium 
Platelets 
 
Magnesium 
 
 
Phosphate 
 
Total Cholesterol 
HDL  
LDL 
Triglycerides 
 
 


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Other Laboratory Tests 
SM-88 
Phenytoin 
Methoxsalen 
Sirolimus 
Other Laboratory Tests for Screening Only 
Serum cortisol  
International normalized ratio (INR) 
Human immunodeficiency virus (HIV) 
Hepatitis B surface antigen 
Hepatitis C virus 
Pregnancy test (urine or serum)  
11.2. 
Adverse Events (AE) 
11.2.1. 
Definition of Adverse Events 
11.2.1.1. Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal product, whether or not considered drug-related. An AE can 
therefore be any favorable, unfavorable and/or unintended sign (including an abnormal 
clinical laboratory, ECG, or vital sign finding), symptom, or disease temporally 
associated with the use of a medicinal product. An AE can arise with any use of the drug 
(e.g., off-label use, use in combination with another drug) and with any route of 
administration, formulation, or dose, including an overdose.  
11.2.1.2. Serious Adverse Event (SAE) 
An AE is considered serious if, in the view of either Investigator or Sponsor, it results in 
any of the following outcomes: 
• Death, unless attributable to the cancer progression 
• A life-threatening AE 
An AE is considered “life-threatening” if, in the view of either the Investigator or 
Sponsor, its occurrence places the subject at immediate risk of death. It does not include 


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an AE that, had it occurred in a more severe form, might have caused death. The 
determination of whether an AE is life-threatening can be based on the opinion of either 
the Investigator or Sponsor. Thus, if either believes that it meets the definition of life-
threatening (possible examples listed below), it must be considered life-threatening for 
reporting purposes: 
• In subject hospitalization or prolongation of existing hospitalization, 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or 
• A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the subject or subject may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in in 
subject hospitalization, or the development of drug dependency or drug abuse. 
This definition of a serious adverse event (SAE) permits either the Sponsor or the 
Investigator to decide if an event is serious. Because SAEs are critically important for the 
identification of significant safety problems, the FDA believes taking into account both 
the Investigator’s and the Sponsor’s assessment is important. For example, the 
Investigator’s perspective may be informed by having actually observed the event, and 
the Sponsor is likely to have broader knowledge of the drug and its effects to inform its 
evaluation of the significance of the event. If either the Sponsor or Investigator believes 
that the event is serious, the event must be considered serious and evaluated by the 
Sponsor for possible expedited reporting. 
11.2.2. 
Relationship to Investigational Product or Study Procedures 
The Investigator or qualified Sub-Investigator is responsible for assessing the relationship 
to the investigational product using clinical judgment and the following considerations:  
• No (Not Related): Evidence exists that the AE has an etiology other than the 
investigational product. For SAEs, an alternative causality must be provided (e.g., 
pre-existing condition, underlying disease, intercurrent illness, or concomitant 
medication).  
• Yes (Related): There is reasonable possibility that the event may have been 
caused by the study drug.   
The relationship to study procedures (e.g., invasive procedures, such as venipuncture) 
should be assessed using the following considerations:   
• No (Not Related): Evidence exists that the AE has an etiology other than the 
investigational product.   
• Yes (Related): The AE occurred as a result of the protocol procedures (e.g., 
venipuncture). 


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11.2.3. 
Assessment of Severity 
The severity of AEs will be graded using CTCAE, version 4.03 (National Cancer 
Institute CTCAE web site). For each episode, the highest severity grade should be 
reported.   
If a CTCAE criterion does not exist, the Investigator should use the appropriate grade as 
shown in Table 18. 
Table 18: 
Grading of Adverse Event Severity 
Grade 
Adjective 
Description 
1 
Mild 
Sign or symptom is present, but it is easily 
tolerated, is not expected to have a clinically 
significant effect on the subject’s overall health 
and well-being, does not interfere with the 
subject’s usual function, and is not likely to 
require medical attention. 
2 
Moderate 
Sign or symptom causes interference with usual 
activity or affects clinical status and may require 
medical intervention. 
3 
Severe 
Sign or symptom is incapacitating or 
significantly affects clinical status and likely 
requires medical intervention or close follow-up. 
4 
Life-threatening 
Sign or symptom results in a potential threat to 
life. 
5 
Fatal 
Sign or symptom results in death. 
The distinction between the seriousness and the severity of an AE should be noted.  
Severity is a measure of intensity; thus, a severe reaction is not necessarily a serious 
reaction. For example, a headache may be severe in intensity, but would not be classified 
as serious unless it met one of the criteria for SAEs listed in Section 11.2.1.2. 
11.2.4. 
Reporting Adverse Events 
The occurrence and nature of each subject’s preexisting conditions will be recorded at 
screening, including clinically significant signs and symptoms of the disease under 
treatment. After the informed consent form is signed, any change in the conditions and 
the occurrence and nature of any AEs will be recorded, as described in the sections 
above. AEs occurring after a subject has taken the last dose of investigational product 
should be collected until 28 days after the last dose. All AEs should be followed up until 
resolution or until the AE is stable.   


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Cases of pregnancy that occur in the partner of a subject enrolled in this study, including 
fetal outcome, should be reported.   
Site personnel must inform the Tyme Medical Monitor or the Clinical Research 
Organization (CRO) Medical Monitor of any SAE within 24 hours of the Investigator’s 
awareness of the event. If the Medical Monitor is contacted by telephone, the site 
personnel must immediately follow-up with official notification on study-specific SAE 
forms.  


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12. 
STATISTICS 
A preliminary summary of the statistical analyses planned for this study is provided in the 
sections below. Additional analyses may be conducted as deemed appropriate and will be 
detailed in a Statistical Analysis Plan (SAP).   
Descriptive statistics will be employed to summarize the data. Summary statistics for 
continuous variables will include the mean, standard deviation, median, and range 
(minimum/maximum); categorical variables will be presented as frequency counts and 
percentages.  
Time-to-event analyses will be reported by Kaplan-Meier quartiles and curves. Data 
listings will be created to support each table and to present all data. 
12.1. 
Hypotheses  


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Part 1 Sample Size (Original Trial Design) 
The first 36 subjects enrolled in the study will be randomized to two different dose levels 
of SM-88 for PK assessments and dose-selection for continued testing (see treatment plan 
above). Randomization will be conducted by interactive web randomization system 
(IWRS). The sample size will provide PK results to ensure acceptably precise estimates 
of traditional parameters (e.g., Cmax, Tmax, t½ and AUC). To adequately estimate the t½, 
36 subjects are needed (n=ZP2PP2P/P2 P where Z=1.96;  is the standard deviation 
from Tyme’s previously reported PK, which is approximately 3 hours and the acceptable 
 is 1 hour). Similarly, to accurately estimate the OS at 6 months, assuming an OS of 
90% would be significant, with Z=1.96, β=0.9 and α=0.1, then the initial cohort at 36 
subjects for the PK portion of the trial will provide a 90% CI of OS ± 10%. 
The selected SM-88 dose will then be used for the expansion cohort for the additional 
subjects to reach 99 evaluable subjects who have completed at least two full cycles of 
therapy at a single dose level (i.e., 81 subjects in the expansion cohort) for an overall 
approximate 80% power to detect at least a 16% ORR by BICR using modified RECIST 
1.1 with a one sided α = 0.05.   
Part 2 Sample Size 
Part 2 of the trial was amended to become a Phase 2/3, two-arm study with SM-88 versus 
a Physician’s Choice control. The trial will accrue 250 subjects, with 125 in each arm. 
The primary objective for Part 2 of this trial is to determine the OS of SM-88 used with 
MPS vs. the control arm. The primary endpoint of Part 2 will be the time from 
Randomization to death from any cause.   
The primary endpoint is OS, and it was estimated that the control group would have a 
median survival time of approximately 3 months, based on reports in the literature, while 
the SM-88 group would have a median survival time of approximately 4.5 months (i.e., 
hazard ratio of 0.667). In order to have 80% power, using a two-sided log-rank test with a 
significance level of 0.025, a total of 234 events will be required. It is estimated that 
n=250 subjects (125 subjects in each arm) will need to be enrolled to achieve 234 events. 
To account for dropouts of subjects who withdraw for reasons other than any of the 
outcomes (death, PD, or toxicity), additional subjects may be enrolled to ensure adequate 
number of subjects who have received at least one dose of the study treatments (the 
primary study per protocol cohort). The total number of subjects consented will depend 
on the number of subjects receiving study treatment. 


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Randomization will be 1:1, balanced by investigative site, ECOG PS (0-1 vs. 2), and 
Physician’s Choice of control group treatment as identified before Randomization.  
12.2. 
Analysis Considerations 
12.2.1. 
Analysis Populations 
The following analysis populations will be used for the data reporting of the response and 
toxicity data. All results will be first described using simple descriptive statistics. 
Safety Population: All subjects enrolled in the study who receive at least one dose of 
study drug will be included in the safety population. This will be the population for the 
safety analyses and for summarization of baseline/demographic characteristics. 
Quarterly safety assessments of the entire cohort will be conducted depending on the 
number of subjects available for analysis. These quarterly assessments by the DSMB and 
Sponsor will begin no later than after the first 36 subjects have completed at least one 
cycle.  
Intent-to-Treat (ITT) Population: All subjects enrolled in the study and randomized to 
treatment will be included in the intent-to-treat population. This will be the population for 
the primary efficacy analyses.  
Modified Intent-to-Treat (mITT) Population: All subjects in the ITT population who 
receive at least one dose of study drug will be included in the modified intent-to-treat 
population.    
Evaluable Population: All subjects in the ITT population enrolled in the study who 
receive at least 1 cycle (28 days) of study drug will be included in the evaluable 
population. This same population will be used by the DSMB, PIs and Sponsor to 
determine the RP2D. 
Evaluable 4-Cycle Population: All subjects in the ITT population who received at least 4 
cycles (28 day cycles) of study drug and 2 imaging assessments past baseline will be 
included in the Evaluable 4-Cycle Population. This population will exclude those subjects 
who received treatment of less than 4 cycles or those who received less than 50% of the 
anticipated treatment during the first 16 weeks of the trial for reasons other than a DLT. 
Pharmacokinetic Population: The PK Population will include all subjects who undergo 
plasma/blood PK sampling and have at least one evaluable assay result. 
Per-Protocol (PP) Population: The per-protocol (PP) population will include subjects in 
the Evaluable population who did not have major protocol deviations.  A protocol 
deviation will be considered major it potentially has an impact on the assessment of 
efficacy for that patient.  The determination of major deviations will occur prior to 
database lock, and any such deviations will be presented in listings.   


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12.2.2. 
Exploratory Combined Population   
12.2.3. 
Initial Analysis 
For Part 1, a cohort of 36 subjects will be randomized one-to-one to the SM-88 
component at either 230 mg b.i.d or 460 mg b.i.d. Once the 36-subject cohort has 
completed 16 weeks (4 cycles, 2 scheduled imaging assessments) of treatment, an 
analysis of safety and efficacy will be conducted.  


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Note that the statistical tests in the above table will be used to inform the decision-
making process, but that clinical judgment (especially as related to the overall safety 
profile of the two dose groups) will be used to make the final dose selection decision 
based on the consensus of the clinical judgment of PIs, DSMB, and Sponsor.  
Acknowledging that the power will be very low for virtually any conditions, we will only 
use the formal statistical testing to help inform a decision. The selected dose will then be 
used for the expansion cohort. 
12.3. 
Final Analysis 
12.3.1. 
Safety Analysis 
Safety will be evaluated by assessment of clinical laboratory tests, physical examinations, 
ophthalmologic examinations (Part 1 only), vital signs measurements, ECG readings and 
drug levels at various time points during the study, and by the documentation of AEs. 
Dose-limiting toxicities will also be listed and summarized by dose cohort in the 
randomized portion of the Phase 2. 
AE verbatim text will be coded and classified by body system and preferred (coded) term 
using the Medical Dictionary for Regulatory Activities (MedDRA). All AEs, both serious 
and non-serious, will be listed. AE summaries by study part and treatment group, of the 
number and percent of subjects reporting each event at least once will be generated. 
Clinical chemistry and hematology data will be summarized at each scheduled 
assessment. Results will be flagged using toxicity grades, if available, or as normal or 
abnormal (high or low) with reference to standard reference ranges. 
ECOG Performance Status assessments will be listed and summarized by the originally 
assigned dose level for a given combination regimen. Vital signs will be recorded for 
each subject at all measured time points. A descriptive summary, including change from 
baseline pre-dose time points will also be presented.  
Other safety data will be summarized descriptively by treatment and assessment time. 
Details will be provided in the SAP. 
12.3.2. 
Efficacy Analyses 
Part 1 
Primary Objectives 


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Secondary Objectives  
PFS is defined as the time from the subject’s date of Randomization to the date of first 
documentation of PD, or clinical (radiographic or symptomatic per Investigator 
assessment) or death due to any cause, or RECIST by blinded independent radiology 
review. PFS will be summarized by using a Kaplan-Meier plot, quartile estimates, along 
with 2-sided 95% CIs. PFS will be censored at the date of the last follow-up visit for the 
subjects who were still alive and had no documented disease progression. 
OS is defined as the time from Randomization until death from any cause. Kaplan-Meier 
estimates and associated two-sided 90% CIs of OS at 6, 12 and 18 months will be 
presented along with median OS time. OS Kaplan-Meier curves will also be presented. 
OS will be censored at the date of the last follow-up visit for subjects who were still 
alive, or whose survival status is unknown at the time of the analysis. 


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Part 2 
Primary Objectives 
The primary objective of this part of the study is to determine the OS time to event 
characteristics of the SM-88 used with MPS vs. the control arm. 
The primary endpoint of OS is defined as the time from Randomization until death from 
any cause. OS will be censored at the date of the last follow-up visit or last survival 
assessment contact (whichever is later) for subjects who were still alive, or whose 
survival status is unknown at the time of the analysis. The efficacy of SM-88 used with 
MPS will be compared to Physician’s Choice for OS, using a log-rank test, stratified by 
the randomization stratification factors of investigative site, Physician’s Choice, and 
ECOG PS. The analysis will not be stratified by individual investigative site since there 
are a large number of sites and it is expected that many will have only a few subjects. 
However, aggregate site factors, such as distance traveled to the site or high vs. low 
accruing sites, will be included for analysis. An exploratory analysis by site may be 
conducted (e.g., early vs. late enrollment, high vs. low recruitment). A Kaplan-Meier 
plot, and quartile estimates with 2-sided 95% CIs will also be presented, along with 
Kaplan-Meier estimates and 95% confidence intervals for OS at 6, 12 and 18 months. 
 
Key Secondary Objective  
PFS is defined as the time from the subject’s date of Randomization to the date of first 
documentation of Progressive Disease (PD) or death due to any cause. PD can be defined 
clinically or radiographically, per Investigator assessment. PFS will be summarized by 
using Kaplan-Meier plot, quartile estimates, along with 2-sided 95% CIs. PFS will be 
censored at the date of the last follow-up visit for the subjects who were still alive and 
had no documented disease progression. The analysis of treatment differences in PFS will 
be conducted using the same methods as for the primary analysis of OS, described above. 
Additional Secondary Objectives 


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Exploratory Objectives 
12.3.3. 
Interim Analysis 
The statistical plan as described in the protocol was designed to conduct the final OS 
analysis when 234 total events have occurred, which is expected to happen approximately 
one (1) year after the last subject is enrolled. Given the poor prognosis of the control arm 
subjects, as reported in the literature, a planned interim efficacy analysis will be 
performed, allowing for the possibility of early stopping for efficacy. The planned interim 
efficacy analysis, with the chance for early stopping, will be conducted when 75% of the 
approximately 234 assumed total events have been reached. It is estimated that the 
planned interim efficacy analysis will occur at around 15-18 months into the trial.  
The primary endpoint is OS, and it was estimated that the control group would have a 
median survival time of approximately 3 months, based on reports in the literature, while 
the SM-88 group would have a median survival time of approximately 4.5 months (i.e., 
hazard ratio of 0.667). In order to have 80% power, using a two-sided log-rank test with a 
significance level of 0.025, a total of 234 events will be required. It is estimated that 
n=250 subjects (125 subjects in each arm) will need to be enrolled to achieve 234 events. 
It is estimated that 75% of the approximately 234 assumed total events would occur at 
around 15-18 months into the trial. The decision rule boundary for early stopping due to 
efficacy will be based on the O’Brien-Fleming method (O’Brien and Fleming 1979; Lan 
and DeMets 1983), using the actual information fraction at the time of the interim via the 
alpha spending approach of Lan and DeMets (1983). For illustration, if the interim 
occurred at precisely 75% information, it would then only stop for efficacy at that point 
(and declare the drug to be a success) if the p-value was less than 0.0079. This yields a 
probability of early stopping at the interim of 51%, based on a total sample size of n = 
250, i.e., the maximum sample size required in this design. 


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12.3.4. 
Pharmacokinetic Analyses 
12.3.4.1.  
Non-compartmental Pharmacokinetic Analyses 
Plasma/blood concentrations of SM-88 (both isomers), methoxsalen, phenytoin, and 
sirolimus (MPS) will be determined by validated assays. In Part 1, PK analysis of SM-88 
(both isomers), methoxsalen, phenytoin, and sirolimus concentration-time data will be 
conducted by non-compartmental methods. The following PK parameters will be 
determined if data permit:   
• Cmax 
• Tmax 
• AUC0-t, AUC0-inf, and/or AUCtau 
• 𝛌𝛌z 
• t½ 
• CL/F 
• Vz/F 
In Part 2, population PK analysis modeling will be employed. 


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13. 
RESPONSIBILITIES 
13.1. 
Investigator Responsibilities 
13.1.1. 
Good Clinical Practice 
The Investigator will ensure that this study is conducted in accordance with the principles 
of the Declaration of Helsinki on Ethical Principles for Medical Research Involving 
Human Subjects, adopted by the General Assembly of the World Medical Association 
(2013), International Conference on Harmonization (ICH) guidelines, or with the laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the study subject.   
The Investigator will ensure that the basic principles of Good Clinical Practice, as 
outlined in 21 Code of Federal Regulations (CFR) 312, subpart D, “Responsibilities of 
Sponsors and Investigators,” 21 CFR, part 50, 1998, and 21 CFR, part 56, 1998, are 
adhered to. These standards are consistent with the requirements of the European 
Community Directive 2001/20/EC, which shall be adhered to. 
Since this is a clinical trial conducted under IND oversight, the Investigator will ensure 
that 21 CFR, Part 54, 1998, is adhered to. A clinical trial conducted under IND oversight 
is any “study of a drug or device in humans submitted in a marketing application or 
reclassification petition subject to this part that the applicant or FDA relies on to establish 
that the product is effective (including studies that show equivalence to an effective 
product) or that make a significant contribution to the demonstration of safety.” This 
requires that Investigators and all Sub-Investigators must provide documentation of their 
financial interest or arrangements with Tyme, Inc. or proprietary interests in the drug 
being studied. This documentation must be provided before participation of the 
Investigator and any Sub-Investigator. The Investigator and Sub-Investigator agree to 
notify Tyme, Inc. of any change reportable interests during the study and for one year 
following completion of the study. Study completion is defined as the date that the last 
subject has completed the protocol-defined activities. 
13.1.2. 
Institutional Review Board Approval 
This protocol and any accompanying material to be provided to the subject (such as 
advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) will be submitted by the Investigator to an IRB. Approval from the 
IRB must be obtained before starting the study and should be documented in a letter to 
the Investigator specifying the protocol number, protocol version, protocol date, 
documents reviewed, and date on which the committee met and granted the approval. 
Any modifications made to the protocol or other documents described in the above 
paragraph after receipt of IRB approval must also be submitted to the IRB for approval 
before implementation. 


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13.1.3. 
Informed Consent 
The Investigator is responsible for obtaining written informed consent from each 
individual participating in this study after adequate explanation of the aims, methods, 
objectives, and potential hazards of the study and before undertaking any study-related 
procedures. The Investigator must utilize an IRB-approved consent form for documenting 
written informed consent. Each informed consent will be appropriately signed and dated 
by the subject or the subject’s legally authorized representative and the person obtaining 
consent.   
13.1.4. 
Treatment Withdrawal  
During the course of the trial, a subject may withdraw early from treatment. This may 
happen for a number of reasons, including:  
• Unacceptable toxicity, including but not limited to:  
o Life-threatening Grade 4 toxicity.  
o Repetition of non-life-threatening Grade 4 toxicity despite per protocol 
dose reduction.  
o Delay of a treatment cycle for more than 28 consecutive days beyond the 
due date  
• Objective evidence of PD as determined by CT scan and/or X-ray and/or 
ultrasound and/or clinical examination  
• Clinical decision by the Investigator that continued participation in the trial is 
contrary to the subject’s best interests  
• Patient decision to discontinue treatment (as opposed to continued participation in 
all other aspects of the study, e.g., following for OS). When a subject stops 
treatment early, an ‘End of Treatment’ Form should be completed, and any other 
relevant form (for example, a SAE Form). The reason for withdrawing from 
treatment early should be clearly documented in the medical records. An off-study 
visit assessment should be performed and the results of the evaluations and 
observations reported in the CRF.  
13.1.5. 
Withdrawal of Consent  
Withdrawal of consent represents that rare subject who has expressed a wish to withdraw 
from the study altogether. Under these circumstances, the site needs to document all 
relevant discussions in the subject notes and notify the Sponsor CRO. Under these 
conditions, ongoing SAEs require follow up until resolution. Some local IRBs may allow 
continued determination of OS based on publicly available data (e.g., social media). 


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13.1.6. 
Confidentiality 
The Investigator must assure that subjects’ personal health information will be strictly 
maintained and that their identities are protected from unauthorized parties. Only subject 
initials, date of birth, and an identification code (i.e., not names) should be recorded on 
any form or biological sample submitted to the Sponsor, IRB, or laboratory. NOTE: the 
Investigator must keep a screening log showing codes, names, and addresses for all 
subjects screened and for all subjects enrolled in the trial. 
The Investigator agrees that all information received from Tyme, Inc., including but not 
limited to the Investigator Brochure, this protocol, CRFs, the investigational product, and 
any other study information, remain the sole and exclusive property of Tyme, Inc. during 
the conduct of the study and thereafter. This information is not to be disclosed to any 
third party (except employees or agents directly involved in the conduct of the study or as 
required by law) without prior written consent from Tyme, Inc. The Investigator further 
agrees to take all reasonable precautions to prevent the disclosure by any employee or 
agent of the study site to any third party or otherwise into the public domain. 
13.1.7. 
Study Files and Retention of Records 
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented and the study data to be subsequently verified. These 
documents should be classified into at least the following two categories: the 
Investigator’s study file, and the subject clinical source documents. 
The Investigator’s study file will contain the protocol/amendments, CRF and query 
forms, IRB and governmental approval with correspondence, informed consent, drug 
records, staff curriculum vitae and authorization forms, and other appropriate documents 
and correspondence.  
The Investigator will keep records of laboratory tests, clinical notes, subject medical 
records, and any other appropriate documents in the subject files as original source 
documents for the study.   
All clinical study documents must be retained by the Investigator until at least 2 years 
after the last approval of a marketing application in an ICH region (i.e., United States, 
Europe, or Japan) and until there are no pending or contemplated marketing applications 
in an ICH region; or, if no application is filed or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer 
if required by applicable regulatory requirements, by local regulations, or by an 
agreement with Tyme, Inc. The Investigator must notify Tyme, Inc. before destroying 
any clinical study records. 
Should the Investigator wish to assign the study records to another party or move them to 
another location, Tyme, Inc. must be notified in advance. 


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If the Investigator cannot guarantee this archiving requirement at the study site for any or 
all of the documents, special arrangements must be made between the Investigator and 
Tyme, Inc. to store these in sealed containers outside of the site so that they can be 
returned sealed to the Investigator in case of a regulatory audit. When source documents 
are required for the continued care of the subject, appropriate copies should be made for 
storage outside of the site. 
Biological samples at the conclusion of this study may be retained in storage by the 
Sponsor for a period up to 2 years for purposes of this study. 
13.1.8. 
Case Report Forms 
As used in this protocol, the term CRF should be understood to refer to either a paper 
form or an electronic data record or both, depending on the data collection method used 
in this study.  
A CRF is required and should be completed for each subject within a reasonable time 
period after data collection. The completed original CRFs are the sole property of Tyme, 
Inc. and should not be made available in any form to third parties, except for authorized 
representatives of Tyme, Inc. or appropriate regulatory authorities, without written 
permission from Tyme, Inc.  
The Investigator has ultimate responsibility for the accuracy, authenticity, and timely 
collection and reporting of all data entered on the CRFs and any other data collection 
forms. The CRFs must be signed by the Investigator or by an authorized staff member to 
attest that the data contained on the CRFs is true. Any corrections to entries made in the 
CRFs, source documents must be dated, initialed and explained (if necessary) and should 
not obscure the original entry.  
In most cases, the source documents are the hospital's or the physician's subject chart. In 
these cases, data collected on the CRFs must match the data in those charts.  
13.1.9. 
Drug Accountability 
The Investigator or designee (i.e., pharmacist) is responsible for ensuring adequate 
accountability of all used and unused investigational product. This includes 
acknowledgment of receipt of each shipment of investigational product (quantity and 
condition), subject dispensing records, and returned or destroyed investigational product.  
Dispensing records will document quantities received from Tyme, Inc. and quantities 
dispensed to subjects, including lot number, date dispensed, subject identifier number, 
subject initials, and the initials of the person dispensing the investigational product. 
The Investigator or his/her designee will be responsible for maintaining accurate records 
of investigational product dispensing and collection and for returning all unused 
investigational product to Tyme, Inc. or its designee at the end of the study. Detailed 
instructions for return of investigational product will be provided upon request and when 
required.  


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All drug supplies and associated documentation will be periodically reviewed and 
verified by the study monitor over the course of the study. 
13.1.10. 
 Audits and Inspections 
The Investigator should understand that source documents for this trial should be made 
available to appropriately qualified personnel from Tyme, Inc. or its representatives, to 
IRBs, or to regulatory authority or health authority inspectors. 
13.1.11. 
 Protocol Compliance 
The Investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
13.2. 
Sponsor Responsibilities 
13.2.1. 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to study subjects, 
may be made only by Tyme Inc. All protocol modifications must be submitted to the IRB 
in accordance with local requirements. Approval must be obtained before changes can be 
implemented. 
13.2.2. 
Study Report, Presentations and Publications 
A clinical study report will be prepared and provided to the regulatory agency(ies).  
Tyme, Inc. will ensure that the report meets the standards set out in the ICH Guideline for 
Structure and Content of Clinical Study Reports (ICH E3). Note that an abbreviated 
report may be prepared in certain cases. 
After conclusion of the study, Investigators in this study may not share, communicate, 
orally present, or publish in any manner, including scientific journals or other scholarly 
media, without the explicit written approval of Tyme, Inc. No such communication, 
presentation, or publication will include Tyme, Inc. confidential information (see Section 
13.1.6). 
The Investigator will submit any proposed abstract, publication or presentation along 
with details of the respective scientific journal or presentation forum, at least 30 days 
before the publisher or meeting deadline for submission of the publication or 
presentation, respectively. The Investigator will comply with Tyme, Inc. request to delete 
references to its confidential information (other than the study results) in any paper or 
presentation and agrees to withhold publication or presentation for an additional 60 days 
in order to obtain patent protection if deemed necessary.  


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13.2.3. 
Data and Safety Monitoring  
There is a DSMB that will be in place to monitor the safety and progress of the trial, and 
to make the decision regarding early stopping for efficacy at the interim analysis in 
Part 2. 
13.3. 
Joint Investigator/Sponsor Responsibilities 
13.3.1. 
Access to Information for Monitoring 
In accordance with ICH GCP guidelines, the study monitor must have direct access to the 
Investigator’s source documentation in order to verify the data recorded in the CRFs for 
consistency. 
The monitor is responsible for routine review of the CRFs at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and 
accuracy of the data being entered on them. The monitor should have access to any 
subject records needed to verify the entries on the CRFs. The Investigator agrees to 
cooperate with the monitor to ensure that any problems detected in the course of these 
monitoring visits are resolved. 
13.3.2. 
Access to Information for Auditing or Inspection 
Representatives of regulatory authorities or of Tyme, Inc. may conduct inspections or 
audits of the clinical study. If the Investigator is notified of an inspection by a regulatory 
authority the Investigator agrees to notify the Tyme, Inc. Medical Monitor immediately.  
The Investigator agrees to provide to representatives of a regulatory agency or Tyme, Inc. 
access to records, facilities, and personnel for the effective conduct of any inspection or 
audit. 
13.3.3. 
Study Discontinuation 
The Sponsor reserves the right to terminate the study at any time. Should this be 
necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies) and IRBs. In terminating the study, Tyme, Inc. and the 
Investigator will assure that adequate consideration is given to the protection of the 
subjects’ interests. 
 
 


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14. 
APPENDIX A: SM-88 MOA  
The components of SM-88 used with MPS are thought to be effective in altering cancer 
cell metabolism and as antineoplastics (Liu et al., 2004; Enriquez-Navas et al., 2016; 
Joka et al., 2014).   
SM-88 used with MPS related agents have been previously described to possess 
characteristics now proposed by several groups as anticancer agents (Ruggiero et al., 
2012; Engel and Evens, 2006; Lordan et al., 2008; Vejux and Lizard, 2009; Leonarduzzi 
et al., 2007; Kasichavanula et al., 2014; Gibbons 2002; Imaoka et al., 2004; Hu et al., 
2005; Steffen et al., 2006; Trachootham et al., 2009) and have been used clinically in the 
treatment of other neoplastic conditions (Perry et al., 1990). Similarly, CYP3A4 inducers, 
including phenytoin, have been “repurposed” for other novel off-label uses (Fillekes et 
al., 2013). In some cases, repurposed, off-label uses of untraditional anti-neoplastic non-
cytotoxic drugs have been associated with an OS significantly longer than the standard of 
care (Watkins et al., 2015). When considering repurposing drugs approved for uses 
outside of cancer treatments for use in cancer therapies, the history of prior clinical use 
often provides support for safe use in cancer subjects, especially when approved uses 
require higher doses than proposed for use in cancer treatment (Perry et al., 1990; 
Bremner et al., 2003). 
Here we discuss possible mechanisms of action for the four components of SM-88 used 
with MPS. 
SM-88: 
Tyrosine isomers are employed in SM-88 to interfere with the cancer cell’s ability to 
create peptides, especially high turnover ones (Ruggiero et al., 2012; Hosios et al., 2016). 
Biopsies and other results suggest that there is increased inflammation associated with 
SM-88 activity (Personal communication, QRI JS, proprietary unpublished data) 
consistent with an attenuation of a barrier between tumors and the host immune system.  
It is interesting to note that in today’s research environment that mucin is a one such high 
turnover glycoprotein, important as a barrier against the host immune system, which is 
exploited by current immune-oncology therapies.  Equally interesting is that specific 
changes in dietary amino acid supplementation is also recognized as affecting mucin 
production (Faure et al., 2006).  It is encouraging that in 2016 and 2017, the FDA 
approved amino acids for imaging of cancers, and as therapy for a hematologic disorder, 
respectively: 
(https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm503920.htm ; 
https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm566097.htm?platfo
rm=hootsuite). 
Cancer’s altered glucose utilization, and preferred amino acid/lipid use as energy sources, 
may be considered similar to a ketotic state (Epstein et al., 2014).  Therefore, a 
preferential utilization of the tyrosine isomers and reactive lipid species may be further 
enhanced after a short fast just before administering SM-88 used with MPS, as specified 


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in the treatment protocol.  Current imaging makes use of a related mechanism and 
recommends fasting to enhance tyrosine-based and other PET imaging, e.g., ¹⁸F-fluoro-α-
methyl tyrosine (Wang et al., 2011; Suzuki et al., 2014).  FDG-PET, also demonstrates 
that mammalian target of rapamycin (mTOR) inhibitors are able to further reduce glucose 
uptake by cancer cells and would therefore also support the hypothesis that SM-88 
components increase alternative energy substrate utilization such as the substituted 
tyrosine and induced reactive oxygen lipid species (Chen et al., 2013; Boers-Sonderen et 
al., 2014). 
The sirolimus and SM-88 components of the regimen may also be acting through 
additional pathways.  For instance, induction of L-type amino acid transporter (LAT1) is 
important in the prognosis and potential treatment of numerous cancer types.  LAT1 also 
facilitates the intracellular delivery of amino acids including tyrosine (Stretton et al., 
2015; Yazawa et al., 2015; Ruggiero et al., 2012).  SM-88 used with MPS provides a 
mixture of non-nutritive tyrosine isomers that are unable to be used in cellular 
metabolism (Ruggiero et al., 2012). 
Phenytoin: 
Cytochrome P4503A4-inducing agents (e.g., phenytoin), stimulate the synthesis of 
reactive oxygen lipid species such as cholesterol, oxysterols, and related lipoproteins.  
These in turn are a source of high oxidizing potential molecules (Wang and Yi, 2008; 
Engel and Evens, 2006; Lordan et al., 2008; Lordan et al., 2009a; Lordan et al., 2009b; 
Vejux and Lizard, 2009; Leonarduzzi et al., 2007; Kasichayanula et al., 2014; Gibbons, 
2002; Imaoka et al., 2004; Pedruzzi et al., 2004; Hu et al., 2005; Steffen et al., 2006; 
Trachootham et al., 2009).  Elevated levels of cholesterol, and oxidized cholesterol 
(oxysterols) can have direct effects on the membrane to disaggregate portions and make 
them “leaky”, or to affect cholesterol rafts, thus disrupting cell signaling (Simons and 
Toomre, 2000; Janes et al., 1999; Gniadecki et al., 2002).  ROS, such as these lipids, also 
stimulate apoptosis (Gniadecki et al., 2001; Kim et al., 2006). 
Deprived of glucose and needing amino acids, cancer cells actively takes up lipids as 
fuel.  This increase uptake of lipids and shift to lipid metabolism, is routed to the 
mitochondria for oxidation (Gniadecki et al., 2001; Kim et al., 2006).  There, high levels 
of cholesterol and oxysterols in the presence of melanin, overwhelm the protective 
mechanisms that prevent free radical damage, inducing mitochondrial oxidation, 
depolarization, and apoptosis (Mostert et al., 2012; Gray-Schopfer et al., 2007).  The 
propensity for lipids to be spontaneously peroxidized and to stimulate oxidative stress 
provides another SM-88 mechanism for targeted cancer cell damage and death (Akladios 
et al., 2015).  
 


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Methoxsalen: 
Melanin contributes to the lethal interaction of cells with deleterious reactive oxygen 
species.  Melanin functions as an intracellular catalyst similar to platinum, but with less 
toxicity (McGinness, 1972; McGinness, 1974; Menter et al., 1990).  Melanin-inducing 
agents are utilized in clinical oncology to treat resistant cancers when combined with 
oxidizing agents (Edelson et al., 1987; Wozniak et al., 2009).  They are not cytotoxic 
unless used with an energy source (e.g., reactive lipid oxidative species). 
Sirolimus: 
Sirolimus, like other mTOR inhibitors, is an essential regulator of cellular lipids, protein 
synthesis, and proliferation (Shigemitsu et al., 1999; Hara et al., 1998; Lin et al., 1995; 
Hay and Sonenberg, 2004).  This is at least partly mediated by effects on insulin, 
serine/threonine protein kinase B (AKT) and insulin-like growth factor (IGF) (Patti et al., 
1998; Xiao et al., 2011; Cheng et al., 2010).  Even at low doses, these mechanisms may 
reduce the availability of typical extracellular nutrients, e.g. glucose, thus increasing the 
tumor cells’ already exaggerated metabolic demand to use alternative energy sources i.e., 
lipids and amino acids (again part of the Warburg effect) provided by the other 
components of SM-88 (Proud 2007; Vendelbo et al., 2014; Motzer et al., 2014; Joka et 
al., 2014; Gillies et al., 2015). 
 
 


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15. 
APPENDIX B: DETAILED DESCRIPTIONS OF ADVERSE 
EVENTS 
Related to Phenytoin 
Withdrawal Precipitated Seizure, Status Epilepticus 
Abrupt withdrawal of phenytoin in epileptic subjects may precipitate status epilepticus.  
When, in the judgment of the clinician, the need for dosage reduction, discontinuation, or 
substitution of alternative anticonvulsant medication arises, this should be done 
gradually.  However, in the event of an allergic or hypersensitivity reaction, more rapid 
substitution of alternative therapy may be necessary.  In this case, alternative therapy 
should be an anticonvulsant not belonging to the hydantoin chemical class. 
Suicidal Behavior and Ideation 
Phenytoin can increase the risk of suicidal thoughts or behavior in subjects.  Subjects 
should be monitored for the emergence or worsening of depression, suicidal thoughts or 
behavior, and/or any unusual changes in mood or behavior.  The increased risk of suicidal 
thoughts or behavior can occur as early as one week after starting treatment and persist 
for the duration of treatment.  Should suicidal thoughts and behavior emerge during 
treatment, Investigators need to consider whether the emergence of these symptoms in 
any given subject may be related to the disease being treated.  Subjects, their caregivers, 
and families should be informed that AEDs increase the risk of suicidal thoughts and 
behavior and should be advised of the need to be alert for the emergence of or worsening 
of the signs and symptoms of depression, any unusual changes in mood or behavior, the 
emergence of suicidal thoughts, behavior, or thoughts about self-harm.  Behaviors of 
concern should be reported immediately to healthcare providers. 
Serious Dermatologic Reactions 
Serious and sometimes fatal dermatologic reactions, including TEN and SJS, have been 
reported with phenytoin treatment.  The onset of symptoms is usually within 28 days but 
can occur later.  Phenytoin should be discontinued at the first sign of a rash, unless the 
rash is clearly deemed not drug-related.  If signs or symptoms suggest SJS/TEN, 
phenytoin should be discontinued and not re-administered.  If a rash occurs, the subject 
should be evaluated for signs and symptoms of Drug Reaction with Eosinophilia and 
Systemic Symptoms (DRESS) (see next paragraph). 
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan 
hypersensitivity 
DRESS, also known as Multiorgan hypersensitivity, has been reported in subjects taking 
phenytoin. Some of these events have been fatal or life-threatening.  DRESS typically, 
although not exclusively, presents with fever, rash, and/or lymphadenopathy, in 
association with other organ system involvement, such as hepatitis, nephritis, 
hematological abnormalities, myocarditis, or myositis sometimes resembling an acute 


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viral infection.  Eosinophilia is often present.  Because this disorder varies in its 
expression, other organ systems not noted here may be involved, and it is important to 
note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may 
be present even though rash is not evident.  If such signs or symptoms are present, the 
subject should be evaluated immediately.  Phenytoin should be discontinued and not re-
administered if an alternative etiology for the signs or symptoms cannot be established. 
Hypersensitivity 
Subjects with a history of hypersensitivity to phenytoin, its inactive ingredients, or other 
hydantoins; or a history of prior acute hepatotoxicity attributable to phenytoin, are 
excluded from this trial (see Exclusion Criteria).  If there is a history of hypersensitivity 
reactions to structurally similar drugs, such as carboxamides (e.g., carbamazepine), 
barbiturates, succinimides, and oxazolidinediones (e.g., trimethadione) in the subject or 
immediate family members, care must be taken to avoid potential subjects’ 
hypersensitivity to phenytoin.  Discontinue and do not re-administer phenytoin if subjects 
exhibit hypersensitivity to phenytoin during the study. 
Hepatic Injury 
Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have 
been reported with phenytoin.  These events may be part of the spectrum of DRESS or 
may occur in isolation.  Other common manifestations include jaundice, hepatomegaly, 
elevated serum transaminase levels, leukocytosis, and eosinophilia.  The clinical course 
of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal outcomes.  In 
these subjects with acute hepatotoxicity, Phenytoin should be immediately discontinued 
and not re-administered. 
Hematopoietic Complications 
Hematopoietic complications, some fatal, have occasionally been reported in association 
with Phenytoin.  These have included thrombocytopenia, leukopenia, granulocytopenia, 
agranulocytosis, and pancytopenia with or without bone marrow suppression.  There have 
been a number of reports suggesting a relationship between phenytoin and the 
development of lymphadenopathy (local or generalized) including benign lymph node 
hyperplasia, pseudolymphoma, lymphoma, and Hodgkin’s disease.  Although a cause and 
effect relationship has not been established, the occurrence of lymphadenopathy indicates 
the need to differentiate such a condition from other types of lymph node pathology.  
Lymph node involvement may occur with or without symptoms and signs of DRESS.  In 
all cases of lymphadenopathy, follow-up observation for an extended period is indicated. 
Effects on Vitamin D and Bone 
The chronic use of phenytoin in subjects with epilepsy has been associated with 
decreased bone mineral density (osteopenia, osteoporosis, and osteomalacia) and bone 
fractures.  Phenytoin induces hepatic metabolizing enzymes.  This may enhance the 
metabolism of vitamin D and decrease vitamin D levels, which may lead to vitamin D 


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deficiency, hypocalcemia, and hypophosphatemia.  Consideration should be given to 
screening with bone-related laboratory and radiological tests as appropriate and initiating 
treatment plans according to established guidelines. 
Renal or Hepatic Impairment or Hypoalbuminemia 
Because the fraction of unbound phenytoin is increased in subjects with renal or hepatic 
disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels 
should be based on the unbound fraction in those subjects. 
Exacerbation of Porphyria 
In view of isolated reports associating phenytoin with exacerbation of porphyria, caution 
should be exercised in using this medication in subjects with porphyria. 
Teratogenicity and Other Harm to the Newborn 
In this study, female subjects must either be of non-reproductive potential, not breast-
feeding or must have a negative urine or serum pregnancy test within 28 days of study 
treatment, confirmed prior to treatment on Day 1 (see Inclusion Criteria).  Subjects who 
are found pregnant during the study must discontinue treatment immediately. 
Phenytoin may cause fetal harm when administered to a pregnant woman.  Prenatal 
exposure to phenytoin may increase the risks for congenital malformations and other 
adverse development outcomes. 
Increased frequencies of major malformations (such as orofacial clefts and cardiac 
defects), and abnormalities characteristic of fetal hydantoin syndrome, including 
dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities 
(including microcephaly), and cognitive deficits, have been reported among children born 
to epileptic women who took phenytoin alone or in combination with other antiepileptic 
drugs during pregnancy. There have been several reported cases of malignancies, 
including neuroblastoma. 
The overall incidence of malformations for children of epileptic women treated with 
antiepileptic drugs, including phenytoin, during pregnancy is about 10%, or two-to three-
fold that in the general population. 
A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-
dependent clotting factors may occur in newborns exposed to phenytoin in utero. This 
drug-induced condition can be prevented with vitamin K administration to the mother 
before delivery and to the neonate after birth. 
Slow Metabolizers of Phenytoin 
A small percentage of individuals who have been treated with phenytoin have been 
shown to metabolize the drug slowly.  Slow metabolism may be caused by limited 


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enzyme availability and lack of induction, and it appears to be genetically determined.  If 
early signs of dose-related CNS toxicity develop, serum levels should be checked 
immediately. 
Hyperglycemia 
Hyperglycemia, resulting from the drug’s inhibitory effects on insulin release, has been 
reported.  Phenytoin may also raise the serum glucose level in diabetic subjects.  
Serum Phenytoin Levels above Therapeutic Range 
Serum levels of phenytoin sustained above the therapeutic range may produce 
confusional states referred to as “delirium,” “psychosis,” or “encephalopathy,” or rarely 
irreversible cerebellar dysfunction and/or cerebellar atrophy.  Accordingly, at the first 
sign of acute toxicity, serum levels should be immediately checked.  Since dose reduction 
of phenytoin is not applicable in this study due to the dose of phenytoin being one 50 mg 
tablet, dosing with phenytoin should be terminated. 
Overdosage 
The lethal dose in pediatric subjects is not known. The lethal dose in adults is estimated 
to be 2 to 5 grams.  The initial symptoms are nystagmus, ataxia, and dysarthria.  Other 
signs are tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and 
vomiting.  The subject may become comatose and hypotensive.  Death is caused by 
respiratory and circulatory depression. 
There are marked variations among individuals with respect to phenytoin serum levels 
where toxicity may occur.  Nystagmus, on lateral gaze, usually appears at 20 mcg/mL, 
ataxia at 30 mcg/mL; dysarthria and lethargy appear when the serum concentration is 
over 40 mcg/mL, but as high a concentration as 50 mcg/mL has been reported without 
evidence of toxicity.  As much as 25 times the therapeutic dose has been taken to result in 
a serum concentration over 100 mcg/mL with complete recovery.  Irreversible cerebellar 
dysfunction and atrophy have been reported. 
Treatment is nonspecific since there is no known antidote.  The adequacy of the 
respiratory and circulatory systems should be carefully observed, and appropriate 
supportive measures employed. Hemodialysis can be considered since phenytoin is not 
completely bound to plasma proteins. Total exchange transfusion has been used in the 
treatment of severe intoxication in pediatric subjects.  In acute overdosage, the possibility 
of other CNS depressants, including alcohol, should be borne in mind. 
Information for Subjects 
Advise subjects to read the FDA-approved subject labeling for phenytoin.  The 
counseling information included in the FDA-approved prescribing information is 
described below. 


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Administration Information 
Advise subjects taking phenytoin of the importance of adhering strictly to the prescribed 
dosage regimen, and of informing the physician of any clinical condition in which it is 
not possible to take the drug orally as prescribed, e.g., surgery, etc. 
Withdrawal of Phenytoin 
Advise subjects not to discontinue use of phenytoin without consulting with their 
healthcare provider.  Phenytoin should normally be gradually withdrawn to reduce the 
potential for increased seizure frequency and status epilepticus. 
Suicidal Ideation and Behavior 
Counsel subjects, their caregivers, and families that antiepileptic drugs, including 
phenytoin, may increase the risk of suicidal thoughts and behavior and advise them of the 
need to be alert for the emergence or worsening of symptoms of depression, any unusual 
changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or 
thoughts about self-harm.  Behaviors of concern should be reported immediately to 
healthcare providers. 
Potential Signs of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 
and Other Systemic Reactions 
Advise subjects of the early toxic signs and symptoms of potential hematologic, 
dermatologic, hypersensitivity, or hepatic reactions.  These symptoms may include, but 
are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, 
lymphadenopathy, facial swelling, and petechial or purpuric hemorrhage, and in the case 
of liver reactions, anorexia, nausea/vomiting, or jaundice. Advise the subject that, 
because these signs and symptoms may signal a serious reaction, that they must report 
any occurrence immediately to a physician. In addition, advise the subject that these signs 
and symptoms should be reported even if mild or when occurring after extended use. 
Effects of Alcohol Use and Other Drugs and Over-the-Counter Drug Interactions 
Caution subjects against the use of other drugs or alcoholic beverages without first 
seeking their physician’s advice. 
Inform subjects that certain over-the-counter medications (e.g., antacids, cimetidine, and 
omeprazole), vitamins (e.g., folic acid), and herbal supplements (e.g., St. John’s wort) 
can alter their phenytoin levels. 
Hyperglycemia 
Advise subjects that phenytoin may cause an increase in blood glucose levels 
 
 


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Gingival Hyperplasia 
Advise subjects of the importance of good dental hygiene in order to minimize the 
development of gingival hyperplasia and its complications. 
Neurologic Effects 
Counsel subjects that phenytoin may cause dizziness, gait disturbance, decreased 
coordination and somnolence. Advise subjects taking DILANTIN not to drive, operate 
complex machinery, or engage in other hazardous activities until they have become 
accustomed to any such effects associated with phenytoin. 
Use in Pregnancy 
In this study, female subjects must either be of non-reproductive potential, not breast-
feeding or must have a negative urine or serum pregnancy test within 28 days of study 
treatment, confirmed prior to treatment on Day 1 (see Inclusion Criteria).  Inform 
pregnant women and women of childbearing potential that use of phenytoin during 
pregnancy can cause fetal harm, including an increased risk for cleft lip and/or cleft 
palate (oral clefts), cardiac defects, dysmorphic skull and facial features, nail and digit 
hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits. 
Advise women of childbearing potential to use effective contraception during the study 
while using phenytoin, keeping in mind that there is a potential for decreased hormonal 
contraceptive efficacy. 
Instruct subjects to notify their physician if they become pregnant or intend to become 
pregnant during the study, and to notify their physician if they are breastfeeding or intend 
to breast feed during the study.  Encourage subjects to enroll in the North American 
Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry 
is collecting information about the safety of antiepileptic drugs during pregnancy. 
Related to Methoxsalen 
Protection from Ultraviolet A (UVA) on the Eye (Part 1 only) 
UVA-absorbing wrap-around sunglasses should be worn during daylight for 24 hours 
after methoxsalen ingestion. The protective eyewear must be designed to prevent entry of 
stray radiation to the eyes, including that which may enter from the sides of the eyewear. 
The protective eyewear is used to prevent the irreversible binding of methoxsalen to the 
proteins and DNA components of the lens. Cataracts form when enough of the binding 
occurs. Visual discrimination should be considered in choosing the eyewear, along with 
subject’s well-being and comfort. 
 
 


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Protection from UVA on the Skin 
Subjects must avoid sun exposure, even through window glass or cloud cover, for at least 
8 hours after methoxsalen ingestion. If sun exposure cannot be avoided, the subject 
should wear protective devices such as a hat and gloves, and/or apply sunscreens which 
contain ingredients that filter out UVA radiation (e.g., sunscreens containing 
benzophenone and/or p-aminobenzoic (PABA) esters which exhibit a sun protective 
factor equal to or greater than 15). These chemical sunscreens should be applied to all 
areas that might be exposed to the sun (including lips). Exposure to sunlight and/or 
ultraviolet radiation may result in “premature aging” of the skin. 
Laboratory Tests 
Subjects should have an ophthalmologic examination prior to start of therapy, and thence 
yearly (Part 1 only). Subjects should have routine laboratory tests prior to the start of 
therapy and at regular periods thereafter if subjects are on extended treatments. 
Overdosage 
In the event of methoxsalen overdosage, induce emesis and keep the subject in a 
darkened room for at least 24 hours. Emesis is most beneficial within the first 2 to 3 
hours after ingestion of methoxsalen, since maximum blood levels are reached by this 
time. 
Related to Sirolimus 
Increased Susceptibility to Infection and Possible Development of Lymphoma 
Increased susceptibility to infection and the possible development of lymphoma and other 
malignancies, particularly of the skin, may result from immunosuppression. 
Oversuppression of the immune system can also increase susceptibility to infection, 
including opportunistic infections such as tuberculosis, fatal infections, and sepsis. 
Subjects receiving the drug should be managed in facilities equipped and staffed with 
adequate laboratory and supportive medical resources. The physician responsible for 
maintenance therapy should have complete information requisite for the follow-up of the 
subject. 
Hypersensitivity Reactions  
Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, 
exfoliative dermatitis and hypersensitivity vasculitis, have been associated with the 
administration of sirolimus. Discontinue and do not re-administer sirolimus if subjects 
exhibit hypersensitivity during the study. 
 
 


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Angioedema  
Sirolimus has been associated with the development of angioedema. The concomitant use 
of sirolimus with other drugs known to cause angioedema, such as angiotensin-
converting enzyme (ACE) inhibitors, may increase the risk of developing angioedema. 
Elevated sirolimus levels (with/without concomitant ACE inhibitors) may also potentiate 
angioedema. In some cases, the angioedema has resolved upon discontinuation or dose 
reduction of sirolimus. Since dose reduction of sirolimus is not applicable in this study 
due to the dose of sirolimus being one 0.5 mg tablet, dosing with sirolimus should be 
terminated when angioedema occurs. 
Fluid Accumulation and Impairment of Wound Healing  
There have been reports of impaired or delayed wound healing in subjects receiving 
sirolimus, including lymphocele and wound dehiscence. mTOR inhibitors such as 
sirolimus have been shown in vitro to inhibit production of certain growth factors that 
may affect angiogenesis, fibroblast proliferation, and vascular permeability. Lymphocele, 
a known surgical complication of renal transplantation, occurred significantly more often 
in a dose-related fashion in subjects treated with sirolimus. Appropriate measures should 
be considered to minimize such complications. Subjects with a body mass index greater 
than 30 kg/Pm2P may be at increased risk of abnormal wound healing based on data from 
the medical literature. 
There have also been reports of fluid accumulation, including peripheral edema, 
lymphedema, pleural effusion, ascites, and pericardial effusions (including 
hemodynamically significant effusions and tamponade requiring intervention in children 
and adults), in subjects receiving sirolimus. Discontinue and do not re-administer 
sirolimus if subjects exhibit fluid accumulation. 
Hyperlipidemia  
Increased serum cholesterol and triglycerides requiring treatment occurred more 
frequently in subjects treated with sirolimus compared with azathioprine or placebo 
controls in clinical studies. There were increased incidences of hypercholesterolemia (43-
46%) and/or hypertriglyceridemia (45-57%) in subjects receiving sirolimus compared 
with placebo controls (each 23%). The risk/benefit should be carefully considered in 
subjects with established hyperlipidemia before initiating an immunosuppressive regimen 
including sirolimus. 
Any subject who is administered sirolimus should be monitored for hyperlipidemia. If 
detected, interventions such as diet, exercise, and lipid-lowering agents should be 
initiated as outlined by the National Cholesterol Education Program guidelines. 
In clinical trials of subjects receiving sirolimus plus cyclosporine or Sirolimus after 
cyclosporine withdrawal, up to 90% of subjects required treatment for hyperlipidemia 
and hypercholesterolemia with anti-lipid therapy (e.g., statins, fibrates). Despite anti-lipid 
management, up to 50% of subjects had fasting serum cholesterol levels >240 mg/dL and 


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triglycerides above recommended target levels. The concomitant administration of 
sirolimus and HMG-CoA reductase inhibitors resulted in adverse reactions such as CPK 
elevations (3%), myalgia (6.7%) and rhabdomyolysis (<1%). In these trials, the number 
of subjects was too small and duration of follow-up too short to evaluate the long-term 
impact of sirolimus on cardiovascular mortality. 
During sirolimus therapy with or without cyclosporine, subjects should be monitored for 
elevated lipids, and subjects administered an HMG-CoA reductase inhibitor and/or 
fibrate should be monitored for the possible development of rhabdomyolysis and other 
adverse effects, as described in the respective labeling for these agents. 
Decline in Renal Function 
In this study, subjects treated, or anticipated to be treated, with cyclosporine are excluded 
(see Exclusion Criteria) because long-term administration of the combination of 
cyclosporine and sirolimus is associated with deterioration of renal function. Subjects 
treated with cyclosporine and sirolimus were noted to have higher serum creatinine levels 
and lower glomerular filtration rates compared with subjects treated with cyclosporine 
and placebo or azathioprine controls. The rate of decline in renal function in these studies 
was greater in subjects receiving sirolimus and cyclosporine compared with control 
therapies. 
Appropriate adjustment of the immunosuppressive regimen, including discontinuation of 
sirolimus and/or cyclosporine, should be considered in subjects with elevated or 
increasing serum creatinine levels. In subjects at low- to moderate-immunologic risk, 
continuation of combination therapy with cyclosporine beyond 4 months following 
transplantation should only subjects. Caution should be exercised when using agents 
(e.g., aminoglycosides and amphotericin B) that are known to have a deleterious effect on 
renal function. In subjects with delayed graft function, sirolimus may delay recovery of 
renal function. 
Proteinuria 
Periodic quantitative monitoring of urinary protein excretion is recommended. In a study 
evaluating conversion from calcineurin inhibitors (CNI) to sirolimus in maintenance renal 
transplant subjects 6-120 months post-transplant, increased urinary protein excretion was 
commonly observed from 6 through 24 months after conversion to sirolimus compared 
with CNI continuation. Subjects with the greatest amount of urinary protein excretion 
prior to sirolimus conversion were those whose protein excretion increased the most after 
conversion. New onset nephrosis (nephrotic syndrome) was also reported as a treatment-
emergent adverse reaction in 2.2% of the sirolimus conversion group subjects in 
comparison to 0.4% in the CNI continuation group of subjects. Nephrotic range 
proteinuria (defined as urinary protein to creatinine ratio >3.5) was also reported in 9.2% 
in the sirolimus conversion group of subjects in comparison to 3.7% in the CNI 
continuation group of subjects. In some subjects, reduction in the degree of urinary 


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protein excretion was observed for individual subjects following discontinuation of 
sirolimus. 
The safety and efficacy of conversion from CNI to sirolimus in maintenance renal 
transplant subjects have not been established. 
Latent Viral Infections 
Immunosuppressed subjects are at increased risk for opportunistic infections, including 
activation of latent viral infections. These include BK virus-associated nephropathy, 
which has been observed in renal transplant subjects receiving immunosuppressants, 
including sirolimus. This infection may be associated with serious outcomes, including 
deteriorating renal function and renal graft loss. Subject monitoring may help detect 
subjects at risk for BK virus-associated nephropathy. Reduction in immunosuppression 
should be considered for subjects who develop evidence of BK virus-associated 
nephropathy. 
Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal have been 
reported in subjects treated with immunosuppressants, including sirolimus. PML 
commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies and 
ataxia. Risk factors for PML include treatment with immunosuppressant therapies and 
impairment of immune function. In immunosuppressed subjects, physicians should 
consider PML in the differential diagnosis in subjects reporting neurological symptoms 
and consultation with a neurologist should be considered as clinically indicated. 
Consideration should be given to reducing the amount of immunosuppression in subjects 
who develop PML. In transplant subjects, physicians should also consider the risk that 
reduced immunosuppression represents to the graft. 
Interstitial Lung Disease/Non-Infectious Pneumonitis 
Cases of ILD (including pneumonitis, BOOP, and pulmonary fibrosis), some fatal, with 
no identified infectious etiology have occurred in subjects receiving immunosuppressive 
regimens including sirolimus. In some cases, the ILD was reported with pulmonary 
hypertension (including pulmonary arterial hypertension) as a secondary event. In some 
cases, the ILD has resolved upon discontinuation or dose reduction of sirolimus. The risk 
may be increased as the trough sirolimus concentration increases. 
Increased Risk of Calcineurin Inhibitor-Induced Hemolytic Uremic 
Syndrome/Thrombotic Thrombocytopenic Purpura/Thrombotic Microangiopathy 
In this study, subjects treated, or anticipated to be treated, with a calcineurin inhibitor are 
excluded (see Exclusion Criteria). The concomitant use of sirolimus with a calcineurin 
inhibitor may increase the risk of calcineurin inhibitor-induced hemolytic uremic 
syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy 
(HUS/TTP/TMA). 


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Different Sirolimus Trough Concentration Reported between Chromatographic and 
Immunoassay Methodologies 
Currently in clinical practice, sirolimus whole blood concentrations are being measured 
by various chromatographic and immunoassay methodologies. Subject sample 
concentration values from different assays may not be interchangeable. 
Skin Cancer Events 
Subjects on immunosuppressive therapy are at increased risk for skin cancer. Exposure to 
sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and 
using a sunscreen with a high protection factor. 
Overdosage 
Reports of overdose with sirolimus have been received; however, experience has been 
limited. In general, the adverse effects of overdose are consistent with the adverse 
reactions section. 
General supportive measures should be followed in all cases of overdose. Based on the 
low aqueous solubility and high erythrocyte and plasma protein binding of sirolimus, it is 
anticipated that sirolimus is not dialyzable to any significant extent. In mice and rats, the 
acute oral LD50 was greater than 800 mg/kg. 
  
 
 
 
 


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16. 
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Randomized Phase 2/3 Multi-Center Study of SM-88 in Subjects with Pancreatic Cancer Whose 
Disease Has Progressed or Recurred 
 
 
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Table of Contents 
1 
Study Information ........................................................................................................................ 6 
1.1 
Background ............................................................................................................................ 6 
1.1.1 Study Design ...................................................................................................................... 6 
1.1.2 Number of Subjects ............................................................................................................ 6 
1.2 
Study Objectives..................................................................................................................... 7 
1.2.1 Part 1 .................................................................................................................................. 7 
1.2.2 Part 2 .................................................................................................................................. 8 
1.3 
Efficacy Endpoints ................................................................................................................. 9 
1.3.1.1 
Time-to-Event Efficacy Endpoints ................................................................................. 9 
1.4 
Pharmacokinetic Endpoints .................................................................................................. 11 
1.5 
Safety Endpoints .................................................................................................................. 11 
1.5.5 Ophthalmologic Exam (Part 1 only) ................................................................................ 12 
1.5.6 Adverse Events ................................................................................................................. 12 
2 
Statistical Methods ..................................................................................................................... 15 
2.1 
General Methods .................................................................................................................. 15 
2.1.1 Definition of Baseline ...................................................................................................... 15 
2.1.2 Programming Conventions ............................................................................................... 15 
2.1.3 Reporting Conventions ..................................................................................................... 15 
2.1.4 Handling of Missing Data ................................................................................................ 16 
2.2 
Analysis Populations ............................................................................................................ 16 
2.2.1 Safety Population ............................................................................................................. 16 
2.2.2 Intent-to-Treat (ITT) Population ...................................................................................... 16 
2.2.3 Evaluable Population ........................................................................................................ 16 
2.2.4 Pharmacokinetic (PK) Population .................................................................................... 17 


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2.3 
Study Subjects ...................................................................................................................... 17 
2.3.1 Subject Disposition .......................................................................................................... 17 
2.3.2 Protocol Deviations .......................................................................................................... 17 
2.3.3 Baseline and Demographic Characteristics ...................................................................... 17 
2.3.4 Cancer History ................................................................................................................. 17 
2.3.5 Non-Cancer Medical History ........................................................................................... 18 
2.3.6 Medications, and Procedures ............................................................................................ 18 
2.4 
Efficacy Analyses ................................................................................................................. 18 
2.4.1 Datasets Analyzed ............................................................................................................ 18 
2.4.2 Part 1 Efficacy Analyses .................................................................................................. 18 
2.4.3 Part 2 Efficacy Analyses .................................................................................................. 19 
2.4.4 Sensitivity Efficacy Analyses ........................................................................................... 20 
2.5 
Safety Analysis ..................................................................................................................... 21 
2.5.1 Adverse Events ................................................................................................................. 21 
2.5.2 Extent of Exposure ........................................................................................................... 22 
2.5.3 Other Safety Analyses ...................................................................................................... 22 
2.6 
Determination of Sample Size .............................................................................................. 22 
2.7 
Interim Analysis ................................................................................................................... 23 
2.8 
Pharmacokinetic Analyses ................................................................................................... 23 
2.9 
Changes in the Analysis Planned in the Protocol ................................................................. 24 
3 
Reference List ............................................................................................................................. 25 
4 
Schedule of Events...................................................................................................................... 26 


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1 
Study Information 
 
1.1 
Background 
This statistical analysis plan (SAP) is based on Protocol TYME-88-PANC Version 8 dated 12 May 
2020, and describes the analysis variables and statistical procedures that will be used to analyze and 
report the results of the trial using the latest available operational protocol. 
The SAP was written in accordance with the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 Guideline entitled “Guidance for Industry: Statistical 
Principles for Clinical Trials” and the ICH-E3 Guideline entitled “Guidance for Industry: Structure 
and Content of Clinical Study Reports”. 
This trial was originally designed to be in two parts. Part 1, whose goal was to evaluate the Overall 
Response Rate (ORR) via RECIST 1.1 and determine the Recommended Phase 2 Dose (RP2D) was 
completed in 2019. 
As this study was terminated early, this SAP represents an abbreviated analysis of what was 
originally planned for the study. 
 
1.1.1 Study Design 
This is a two part, open-label, prospective, randomized, multi-center, Phase 2/3 trial in subjects with 
pancreatic cancer composed of the following parts: 
Part 1: A total of 36 evaluable subjects will be randomized 1:1 between two doses of SM-88 
460 mg/day (230 mg b.i.d) or 920 mg/day (460 mg b.i.d). The doses of the three conditioning 
agents - methoxsalen, phenytoin and sirolimus - will each maintain a consistent dose. 
Part 2: An expansion of the trial to further assess safety and efficacy of SM-88 containing the 
selected SM-88 RP2D from Part 1. A total of 250 subjects in Part 2 will be randomized 1:1 
(open-label) either to the SM-88 arm or Physician’s Choice of therapy for the Control Arm, 
with a planned efficacy analysis to be performed when 75% of total events (assuming 234 
total events) are reached. This could result in early stopping for efficacy. 
For all subjects, treatment will continue until apparent PD (as defined in the protocol), unacceptable 
toxicity, death, or any of the treatment discontinuation criteria are met. All subjects will be followed 
for OS until the end of this study, and possibly beyond their participation in the trial as approved by 
governing IRB. 
For all subjects randomized to the Physician’s Choice control arm in Part 2, subjects will continue on 
study (with appropriate dose delay and/or modification if necessary) until disease progression, 
intolerable side effects or subject chooses to withdraw. 
The Physician’s Choice therapy must include exactly one of the following: 
• Capecitabine (1000 mg/m2 orally twice a day, Days 1-14 on a 21-day cycle) 
• Gemcitabine (1000 mg/m2 IV on Days 1, 8, and 15 on a 28-day cycle) 
• 5-FU (2400mg/m2 continuous IV infusion over 46 hours on Day 1 and 15 on a 28-day cycle) 
1.1.2 Number of Subjects 
Part 1: There are 36 evaluable subjects planned for enrollment in the first part. 
Part 2: The second part of this clinical trial will expand the use of the selected SM-88 dose from the 
first part for up to an additional 125 subjects in addition to a Physician’s Choice control arm with 


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125 subjects, for a maximum total trial size of 250 subjects. For subjects who discontinue before they 
complete all planned study assessments, additional replacement subjects may be enrolled. 
 
1.2 
Study Objectives 
 
The original objectives as stated in the protocol are as follows. Some objectives have been modified 
for this SAP, and are documented here with an SAP note. 
1.2.1 Part 1 
 
1.2.1.1 Primary Objective 
 
1.2.1.2 Secondary Objectives 
 
1.2.1.3 Safety Objectives 


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1.2.2 Part 2 
 
1.2.2.1 Primary Efficacy Objective 
The primary efficacy objective of this study is to determine the OS of subjects treated with SM-88 
used with methoxsalen, phenytoin, and sirolimus (MPS) vs the Control Arm (Physician’s Choice). 
 
1.2.2.2 Key Secondary Efficacy Objective 
• Evaluate investigator-determined PFS. 
 
1.2.2.3 Additional Secondary Efficacy Objectives 
 
1.2.2.4 Exploratory Objectives 
 
1.2.2.5 PK/Safety Objectives 


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1.3 
Efficacy Endpoints 
Efficacy evaluations and endpoints will be performed at the times indicated in the Time and Events 
Schedule. 
For Part 2 of this study, a total of approximately 250 subjects will be enrolled to obtain 125 subjects 
who have received one dose of SM-88 and 125 subjects in the control arm (Physician’s Choice) and 
are thus evaluable for the primary endpoint of OS. 
 
1.3.1.1 Time-to-Event Efficacy Endpoints 
Unless stated otherwise, the time-scale will be in weeks. 
 
1.3.1.2 Overall Survival (OS) 
The primary endpoint of OS is defined as the time from randomization until death from any cause. 
For subjects who were still alive, or whose survival status is unknown at the time of the analysis, OS 
will be censored at the date of the last follow-up visit or last survival assessment contact (whichever 
is later) where the subject is known to still be alive. 
 
1.3.1.3 Progression-Free Survival (PFS) 
PFS is defined as the time from the subject’s date of Randomization to the date of first 
documentation of Progressive Disease (PD) or death due to any cause. For Part 1, PD can only be 
determined radiographically (BICR). For Part 2, PD will be determined as per investigator 
assessment. 
For subjects who do not have a definitive date of death or disease progression, PFS will be censored 
at the date of the last follow-up visit which included a progression assessment for which they were 
still alive and without disease progression. This includes subjects who are either: 
• Still alive without documented PD at the time of analysis. 
• PFS status unknown at the time of the analysis. 
 
1.3.1.4 Time to subsequent therapy 
There will be no analyses on the time to subsequent therapy. 


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1.4 
Pharmacokinetic Endpoints 
PK assessments are outside the scope of this SAP. 
 
1.5 
Safety Endpoints 


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1.5.5 Ophthalmologic Exam (Part 1 only) 
Screening exam window is within 1 year of Randomization into the study. Data collected during the 
SOC visit will be entered in the EDC system. Data fields provided by Tyme, and to be collected for 
the Ophthalmology exam, will include the following: 
• Record OU at baseline (+30 days) for all subjects and q 12 mo (+30 days) for those subjects 
subsequently randomized to SM-88 used with MPS arm of treatment 
• Acuity best corrected 
• Acuity Uncorrected 
• Correction factor/RX 
• Cataracts present? – If subject has cataracts, they should be graded per clinician SOC, who 
must use the same methodology of grading for follow-up evaluations. 
o Retina evaluation - normal, or not [if not, describe per clinician SOC; must use same 
for follow-up evaluation] 
The PI will evaluate the subject at each visit for clinically significant changes in visual signs and 
symptoms. 
 
1.5.6 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical study subject administered a 
medicinal product, whether or not considered drug-related. An AE can therefore be any favorable, 
unfavorable and/or unintended sign (including an abnormal clinical laboratory, ECG, or vital sign 
finding), symptom, or disease temporally associated with the use of a medicinal product. An AE can 
arise with any use of the drug (e.g., off-label use, use in combination with another drug) and with any 
route of administration, formulation, or dose, including an overdose. 
 
1.5.6.1 Treatment-Emergent AEs 
An AE is said to be treatment-emergent (TE) if it occurs or worsen after the baseline visit. 


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1.5.6.2 Serious Adverse Event (SAE) 
An AE is considered serious if, in the view of either Investigator or Sponsor, it results in any of the 
following outcomes: 
• Death, unless attributable to the cancer progression 
• A life-threatening AE 
An AE is considered “life-threatening” if, in the view of either the Investigator or Sponsor, its 
occurrence places the subject at immediate risk of death. It does not include an AE that, had it 
occurred in a more severe form, might have caused death. The determination of whether an AE is 
life-threatening can be based on the opinion of either the Investigator or Sponsor. Thus, if either 
believes that it meets the definition of life-threatening (possible examples listed below), it must be 
considered life-threatening for reporting purposes: 
• In subject hospitalization or prolongation of existing hospitalization, 
• A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions, or 
• A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize the 
subject or subject may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition. Examples of such medical events include: allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in subject hospitalization, or the development of drug dependency or drug abuse. 
This definition of a serious adverse event (SAE) permits either the Sponsor or the Investigator to 
decide if an event is serious. Because SAEs are critically important for the identification of 
significant safety problems, the FDA believes taking into account both the Investigator’s and the 
Sponsor’s assessment is important. For example, the Investigator’s perspective may be informed by 
having actually observed the event, and the Sponsor is likely to have broader knowledge of the drug 
and its effects to inform its evaluation of the significance of the event. If either the Sponsor or 
Investigator believes that the event is serious, the event must be considered serious and evaluated by 
the Sponsor for possible expedited reporting. 
 
1.5.6.3 Relationship to Investigational Product or Study Procedures 
The Investigator or qualified Sub-Investigator is responsible for assessing the relationship to the 
investigational product using clinical judgment and the following considerations: 
• No (Not Related): Evidence exists that the AE has an etiology other than the investigational 
product. For SAEs, an alternative causality must be provided (e.g., pre-existing condition, 
underlying disease, intercurrent illness, or concomitant medication). 
• Yes (Related): There is reasonable possibility that the event may have been caused by the 
study drug. 
The relationship to study procedures (e.g., invasive procedures, such as venipuncture) should be 
assessed using the following considerations: 
• No (Not Related): Evidence exists that the AE has an etiology other than the investigational 
product. 


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• Yes (Related): The AE occurred as a result of the protocol procedures (e.g., venipuncture). 
 
1.5.6.4 Assessment of Severity 
The severity of AEs will be graded using CTCAE, version 4.03 (National Cancer Institute CTCAE 
web site). For each episode, the highest severity grade should be reported. 
If a CTCAE criterion does not exist, the Investigator should use the appropriate grade as shown 
below: 
 
Grade 
Adjective 
Description 
1 
Mild 
Sign or symptom is present, but it is easily 
tolerated, is not expected to have a clinically 
significant effect on the subject’s overall health 
and well-being, does not interfere with the 
subject’s usual function, and is not likely to 
require medical attention. 
2 
Moderate 
Sign or symptom causes interference with usual 
activity or affects clinical status and may require 
medical intervention. 
3 
Severe 
Sign or symptom is incapacitating or 
significantly affects clinical status and likely 
requires medical intervention or close follow-up. 
4 
Life-threatening 
Sign or symptom results in a potential threat to 
life. 
5 
Fatal 
Sign or symptom results in death. 


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2 
Statistical Methods 
 
2.1 
General Methods 
Any changes to the finalized SAP made prior to database lock will require a SAP amendment. Any 
changes to the planned analyses after database lock will be documented in the CSR. 
Some of the analyses detailed here may be more explicit or in some aspects different from those 
stated in the protocol. In case of differences, this SAP supersedes the statistical sections in the 
protocol. 
 
2.1.1 
Definition of Baseline 
The baseline visit is defined in the protocol as the day of initial dosing (Cycle 1 Day 1). Superseding 
this definition, in this SAP, the baseline visit will be defined as the last assessment made on or after 
the randomization date that is also before the first date of administration of any study drug (including 
Physician’s Choice, SM-88, methoxsalen, phenytoin, or sirolimus). If no such visit exists, the 
baseline visit will be the randomization date or screening date, whichever is later. Change from 
baseline will be calculated as the value at a given time point minus the baseline value. 
 
2.1.2 
Programming Conventions 
EMB Statistical Solutions will have responsibility for performing analyses. All computations for 
statistical analyses will be performed using SAS® software, Version 9.4 or later. All SAS programs 
used in the production of statistical summary outputs will be validated with independent 
programming prior to finalization. In addition, all program outputs will be independently reviewed. 
The validation process will be used to confirm that all data manipulations and calculations were 
accurately done. Once validation is complete, a senior statistical reviewer will perform a final review 
of the documents to ensure the accuracy and consistency with this plan and consistency within tables. 
Upon completion of validation and quality review procedures, all documentation will be collected 
and filed by the project statistician or designee. 
The eCRF data for all subjects will be provided in Standard Data Tabulation Model (SDTM) 
datasets. Analysis Data Model (ADaM) datasets will be developed from the SDTM datasets for use 
in table and figure production. 
 
2.1.3 
Reporting Conventions 
The formats for the tables, listings, and figures described in this SAP will be provided in a 
companion document. Changes to the formats of these reports that are decided after the finalization 
of the SAP will not require an amendment. In addition, any additional supportive or exploratory 
analyses requested after SAP approval will not require amendment of the SAP. These additional 
analyses will be described in the CSR. 
All study data from the eCRFs as well as derived variables will be provided in subject data listings. 
An indication of specific listings for each data type will not be indicated in the text of subsequent 
SAP sections. Data listings supplied as part of the CSR will be sorted by study center number 
concatenated with subject number, assessment dates, and/or time point. 
The following conventions will be applied to all data presentations and analyses: 
• Continuous variables will generally be summarized by the number of subjects, mean, 
standard deviation, median, minimum, and maximum. Unless otherwise specified, the 


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minimum and maximum values will be displayed to the same number of decimal places as 
the raw data, the mean and median will be presented to one extra decimal place compared to 
the raw data, and the standard deviation will be displayed to two extra decimal places 
compared to the raw data 
• Categorical variables will be summarized by the number and percentage of subjects within 
each category. Unless otherwise specified, the percentage will be presented in parentheses to 
one decimal place. Frequency and percentage values of 0 will be presented as ‘0’ rather than 
‘0 (0)’. 
• All summary tables will include the analysis population sample size (i.e. number of subjects) 
in each treatment group. 
• Date variables will be formatted as DDMMMYYYY for presentation. 
Unless stated otherwise, summaries for each part will be provided by randomization arm as 
appropriate. 
 
2.1.4 Handling of Missing Data 
The number of non-missing efficacy values will be reported. For response rates such as ORR, 
subjects who withdraw from the trial prior to a response (or whose response is unknown) will be 
included in the analysis as non-responders. 
If adverse event start dates are missing or incomplete, the following rules will apply for determining 
if an event is to be considered treatment emergent: if start date is completely missing, start date will 
be set as same day as start of treatment. If start date is incomplete, the date closest to start of 
treatment will be assumed, without compromising the incomplete data available for the start date. 
No additional imputation is planned for this study. 
 
2.2 
Analysis Populations 
The statistical analyses will be performed based on the following subject populations. 
 
2.2.1 Safety Population 
All subjects enrolled in the study who receive at least one dose of study drug will be included in the 
safety population, and assigned to the treatment they actually received. This will be the population 
for the safety analyses and for summarization of baseline/demographic characteristics. 
 
2.2.2 Intent-to-Treat (ITT) Population 
All subjects consented in the study and randomized to treatment will be included in the intent-to-treat 
population, and assigned to the treatment they were randomized to. This will be the population for 
the primary efficacy analyses. 
 
2.2.3 Evaluable Population 
All subjects in the ITT population who receive at least 1 cycle of study drug (21 days), as identified 
in the eCRF, will be included in the evaluable population. Note, if the ITT Population is equivalent 
to the Evaluable Population, the Evaluable Population will be used in place of the ITT Population for 
all tables, figures, and listings. 


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2.2.4 Pharmacokinetic (PK) Population 
The PK Population will include all subjects who undergo plasma/blood PK sampling and have at 
least one evaluable assay result. 
 
2.3 
Study Subjects 
For each Part, the following will be summarized: 
 
2.3.1 Subject Disposition 
The number of subjects who fail screening along with reasons for failure will be shown in total, 
using the number of screen failures as the denominator. The number of randomized subjects in each 
arm will be shown. 
Using the ITT population as the denominator , the number and percentage of subjects in the 
following categories will be summarized: 
• Analysis population (Safety, ITT, etc.) 
• Consented to survival follow-up 
• Discontinued study before day 21 (overall and by prior lines of therapy: 2 lines vs. 3+ lines, 
including primary reason for withdrawal for overall group) 
• Discontinued study (including primary reason for withdrawal). 
• Discontinued study drug (including primary reason) 
Subject disposition, including end-of-study status, will be included as a listing. Additionally, a 
separate listing of (1) subjects who withdrew between randomization and 1st dose and (2) subjects 
excluded from the Evaluable Population, will be provided, and will include any provided reason(s) 
for withdrawal (if applicable). 
 
2.3.2 Protocol Deviations 
The number of subjects with protocol deviations (and number of deviations) will be summarized 
(any deviation and major deviations only). Details of all protocol deviations will be included as a 
listing. 
 
2.3.3 Baseline and Demographic Characteristics 
Subject baseline and demographic data will be summarized for the Safety population. At the 
screening visit, demographic information including age, sex, race and ethnicity will be collected and 
recorded in the eCRF for each subject. 
 
2.3.4 Cancer History 
A complete medical history, including cancer history etc., will be obtained by the investigator or 
qualified designee during screening . A summary of pancreatic cancer history will be provided, and 
will include TNM staging, stage at initial diagnosis, years since diagnosis, disease type (recurrent or 
progressive), metastatic status, and family history. The number of anti-pancreatic cancer therapies 
will also be summarized. 
For Part 1 only, a listing containing each subject’s prior chemotherapies will be provided. 


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2.3.5 Non-Cancer Medical History 
A complete medical history will be collected as part of the screening assessment and include all 
clinically relevant past or coexisting medical conditions or surgeries. The medical history will be 
updated prior to treatment on Baseline/Day 1 should new findings be present since the screening 
visit. Findings will be recorded in the eCRF. 
Medical and surgical histories will be omitted from analyses. 
 
2.3.6 Medications, and Procedures 
Prior and concomitant medications will not be summarized. Concomitant medications will be 
provided as a listing only, along with new systemic therapies 
 
2.4 
Efficacy Analyses 
 
2.4.1 Datasets Analyzed 
All efficacy variables will be analyzed based on either the ITT or Evaluable Populations. Some 
analyses utilizing the ITT Population may be repeated on the Evaluable Population as sensitivity 
analyses. Response rates such as ORR, DCR, and SBR will impute subjects with missing responses 
as non-responders. Other summary statistics will be computed for each efficacy endpoint using the 
Observed Cases (OC) with no imputation for missing data. 
 
2.4.2 Part 1 Efficacy Analyses 
 
2.4.2.1 Primary Efficacy Analysis (ITT Population) 
 
2.4.2.2 Secondary Efficacy Analyses 


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2.4.3 Part 2 Efficacy Analyses 
Unless stated otherwise, analyses will be performed for both the ITT and Evaluable Populations. 
 
2.4.3.1 Primary Efficacy Analysis 
OS for SM-88 used with MPS will be compared to Physician’s Choice for OS, using the Log-Rank 
test, stratified by the randomization stratification factors (1) Physician’s Choice made pre- 
randomization and (2) baseline ECOG performance status (0-1 vs. 2). The p-value from the Log- 
Rank test will be reported. 
A Kaplan-Meier plot, and quartile estimates with 2-sided 95% CIs will also be presented, along with 
Kaplan-Meier estimates and 95% confidence intervals for OS at 6, 12 and 18 months. The plot will 
be produced for both ITT and Evaluable Populations. 
 
2.4.3.2 Key Secondary Efficacy Analysis 
The analysis of treatment differences in PFS will be conducted using the same methods as for the 
Part 2 primary analysis of OS, described above. The plot will be produced for the Evaluable 
Population only. 
 
2.4.3.3 Other Secondary Efficacy Analyses 
 


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2.4.4 Sensitivity Efficacy Analyses 
For select outcomes, additional sensitivity analysis summary tables will be provided. These analyses 
are as follows: 
 
 


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Part II 
OS 
X 
PFS 
X 
2.5 
Safety Analysis 
All safety data will be summarized descriptively by treatment group based on the safety population 
using the Observed Cases (OC). There are no planned inferential statistical analyses of safety 
endpoints. 
 
2.5.1 Adverse Events 
AE verbatim text will be coded and classified by body system and preferred (coded) term using the 
Medical Dictionary for Regulatory Activities (MedDRA) v20.1. All SAEs will be listed. AE 
summaries by treatment group, of the number and percent of subjects reporting each event at least 
once will be generated. Dose-limiting toxicities will also be listed and summarized by dose cohort. 
The severity of AEs will be graded using CTCAE, version 4.03 (National Cancer Institute CTCAE 
web site). For each episode, the highest severity grade should be reported. 
If a CTCAE criterion does not exist, the investigator should use the appropriate grade as shown in 
Table 17 of the protocol. 
An overall summary of AEs will be provided, and will include the number of AEs, and number (%) 
of subjects, for the following categories: 
• Any AE 
• Any TEAE 
o Any Treatment-Related TEAE 
o Any Dose Limiting Toxicity 
o Any Severe (Grade >=3) TEAE 
o Any TEAE resulting in treatment discontinuation 
o Any TEAE resulting in study discontinuation 
o 
• Any Serious AE 
o Any SAE resulting in death 
o Any SAE resulting in hospitalization 
o Any life-threatening SAE 
o Any SAE resulting in disability/incapacity 
o Any SAE resulting in congenital abnormality 
o Any Treatment-Related SAE 
The following summaries of AEs will be provided as individual summary tables. 
• TEAEs by System Organ Class and PT – related to study drug 
• TEAEs by System Organ Class and PT – by maximum severity where grade >=3 
• SAEs by System Organ Class and PT – related vs unrelated and grade >=3 vs <3 






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2.9 
Changes in the Analysis Planned in the Protocol 
No investigative or aggregate site factors, such as distance travelled to the study site, or accrual rate 
of site, will be included as covariate adjustments for any analyses. 
OS confidence intervals will be at the 95% level, rather than 90% level. 
The following analysis populations have been removed: Modified ITT population, Evaluable 4-Cycle 
population, Per-Protocol population. 
Only investigator-determined response was available for Part 2; only BICR RECIST will be used for 
PFS in Part 1. 
The following secondary efficacy objectives were not performed: 
As mentioned in ”Definition of Baseline”, the baseline visit is defined in the protocol as the day of 
initial dosing (Cycle 1 Day 1). Superseding this definition, in this SAP, the baseline visit will be 
defined as the last assessment made on or after the randomization date that is also before the first 
date of administration of anu study drug (including Physician’s Choice, SM-88, methoxsalen, 
phenytoin, or sirolimus). If no such visit exists, the baseline visit will be the randomization date or 
screening date, whichever is later. 


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3 
Reference List 
There are no other references beyond those that are included in the protocol 


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4 
Schedule of Events 
Please refer to Tables 5 through 8 in the protocol for treatment specific schedules of events.