A Phase II Trial of the Superenhancer Inhibitor Minnelide in Advanced Refractory Adenosquamous Carcinoma of the Pancreas (ASCP)
Phase: PHASE2
Conditions: Adenosquamous Carcinoma of the Pancreas
Sponsor: National Cancer Institute (NCI)



Abbreviated Title: Minnelide for ASCP 
 
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PRÉCIS  
Background: 
• Adenosquamous carcinoma of the pancreas (ASCP) is a highly aggressive variant of 
pancreatic ductal adenocarcinoma (PDA), the most common type of pancreas cancer.  
• ASCP is estimated to account for 0.5-4% of the 55,000 people who are diagnosed with 
pancreatic cancer in the U.S. each year, making it a very rare tumor type.  
• No prospective clinical trials specific to ASCP have ever been performed. 
• Preclinical data in ASCP models indicate that an activated superenhancer network drives 
epigenetic changes which cause the prognostically unfavorable squamous differentiation. 
• Genomic analysis of ASCP tumors identifies frequent amplification of MYC. 
• Minnelide is a small molecule anti-superenhancer drug that inhibits MYC. 
• The recommended dose of Minnelide has previously been established through clinical 
testing for other indications. 
Primary Objective: 
• To determine the single agent antitumor activity (disease control rate) of the anti-
superenhancer agent Minnelide in participants with advanced, previously treated ASCP  
Eligibility: 
• Age ≥ 18 years 
• Histologically confirmed ASCP or high suspicion for ASCP based on histologic analysis 
for squamous markers 
• Participants with metastatic or locally advanced unresectable disease and progression on 
at least 1 prior treatment regimen 
Design: 
• This is a phase II single cohort clinical trial with one arm. 
• The number of evaluable participants needed for the primary endpoint is 25; maximum 
accrual set at 55 participants (accounting for screen failures and inevaluable participants).   
• Initial participants will receive Minnelide at 2 mg/day PO on Days 1-21 of a 28 day cycle. 
Later participants will receive a higher dose of 2.5 mg/day PO on the same schedule. 
• Treatment will be continued for up to 12 cycles (1 year) in the absence of disease 
progression or unacceptable toxicity. 
• Treatment response will be assessed by imaging every 2 cycles (8 weeks).   
• Optional tumor biopsies will be requested mid-cycle 1 and at time of progression. 
• A disease control rate of ≥ 40% in this highly refractory population would constitute a 
positive study. Up to 12 participants will treated be initially. If 3 of the 12 participants have 
a response, then up to 13 additional participants will be entered to determine the true 
response rate. 
 

Abbreviated Title: Minnelide for ASCP 
 
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TABLE OF CONTENTS  
PRÉCIS .......................................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ 3 
STATEMENT OF COMPLIANCE ................................................................................................ 6 
1 
INTRODUCTION .................................................................................................................. 6 
1.1 
Study Objectives .............................................................................................................. 6 
1.2 
Background and Rationale ............................................................................................... 6 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ....................................................... 14 
2.1 
Eligibility Criteria .......................................................................................................... 14 
2.2 
Recruitment Strategies ................................................................................................... 17 
2.3 
Screening Evaluation ...................................................................................................... 17 
2.4 
Participant Registration and Status Update Procedures ................................................. 18 
3 
STUDY IMPLEMENTATION ............................................................................................ 19 
3.1 
Study Design .................................................................................................................. 19 
3.2 
Drug Administration ...................................................................................................... 19 
3.3 
Dose Modifications ........................................................................................................ 20 
3.4 
On Treatment Evaluations .............................................................................................. 22 
3.5 
End of Treatment Assessments ...................................................................................... 24 
3.6 
Follow-Up Period ........................................................................................................... 24 
3.7 
Study Calendar ............................................................................................................... 25 
3.8 
Cost and Compensation .................................................................................................. 27 
3.9 
Criteria for Removal from Protocol Therapy and Off Study Criteria ............................ 27 
4 
CONCOMITANT MEDICATIONS/MEASURES .............................................................. 28 
5 
CORRELATIVE STUDIES FOR RESEARCH ................................................................... 28 
5.1 
Biospecimen Collection ................................................................................................. 28 
5.2 
Specimen Collection Table ............................................................................................ 31 
5.3 
Sample Storage, Tracking and Disposition .................................................................... 33 
5.4 
Samples for Genetic/Genomic Analysis ........................................................................ 34 
6 
DATA COLLECTION AND EVALUATION ..................................................................... 35 
6.1 
Data Collection ............................................................................................................... 35 
6.2 
Data Sharing Plans ......................................................................................................... 36 
6.3 
Response Criteria ........................................................................................................... 37 
6.4 
Toxicity Criteria ............................................................................................................. 42 

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7 
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN .. 43 
7.1 
Definitions ...................................................................................................................... 43 
7.2 
OHSRP Office of Compliance and Training / IRB Reporting ....................................... 43 
7.3 
NCI Clinical Director Reporting .................................................................................... 43 
7.4 
NIH Required Data and Safety Monitoring Plan ........................................................... 43 
8 
SPONSOR PROTOCOL/SAFETY REPORTING ............................................................... 44 
8.1 
Definitions ...................................................................................................................... 44 
8.2 
Assessment of Safety Events .......................................................................................... 45 
8.3 
Reporting of Serious Adverse Events ............................................................................ 45 
8.4 
Waiver of expedited reporting to Sponsor (CCR) .......................................................... 46 
8.5 
Safety Reporting Criteria to the Pharmaceutical Collaborators ..................................... 46 
8.6 
Reporting Pregnancy ...................................................................................................... 46 
8.7 
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND .................. 46 
8.8 
Sponsor Protocol Deviation Reporting .......................................................................... 47 
9 
CLINICAL MONITORING ................................................................................................. 47 
10 STATISTICAL CONSIDERATIONS.................................................................................. 48 
10.1 Objectives and Endpoints ............................................................................................... 48 
10.2 Statistical Hypothesis ..................................................................................................... 50 
10.3 Sample Size Determination ............................................................................................ 50 
10.4 Populations for Analyses ................................................................................................ 50 
10.5 Statistical Analyses ........................................................................................................ 51 
11 COLLABORATIVE AGREEMENTS ................................................................................. 52 
11.1 Agreement Type ............................................................................................................. 52 
12 HUMAN SUBJECTS PROTECTIONS ............................................................................... 52 
12.1 Rationale For Subject Selection ..................................................................................... 52 
12.2 Participation of Children ................................................................................................ 52 
12.3 Risk/Benefit Assessment ................................................................................................ 52 
12.4 Consent Process and Documentation ............................................................................. 54 
13 REGULATORY AND OPERATIONAL CONSIDERATIONS ......................................... 54 
13.1 Study Discontinuation and Closure ................................................................................ 54 
13.2 Quality Assurance and Quality Control ......................................................................... 55 
13.3 Conflict of Interest Policy .............................................................................................. 55 
13.4 Confidentiality and Privacy ............................................................................................ 55 

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14 PHARMACEUTICAL INFORMATION ............................................................................. 56 
14.1 Minnelide – IND # 155631 ............................................................................................ 56 
15 LIST OF ABBREVIATIONS ............................................................................................... 62 
16 REFERENCES ..................................................................................................................... 65 
17 APPENDICES ...................................................................................................................... 66 
17.1 Appendix A: Performance Status Criteria ...................................................................... 66 
17.2 Appendix B: Participant Medication Diary .................................................................... 68 
 
 
 

Abbreviated Title: Minnelide for ASCP 
 
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creatinine 
     OR 
measured or calculated bcreatinine 
clearance (GFR can also be used in 
place of creatinine or CrCl) 
≤1.5 × ULN 
     OR 
≥ 45 mL/min for participant with creatinine 
levels >1.5 × institutional ULN 
total bilirubin 
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels >1.5 
× ULN 
AST (SGOT) and ALT (SGPT) 
≤2.5 × ULN (≤5 × ULN for participants 
with liver metastases) 
International normalized ratio (INR)      
     OR  
− prothrombin time (PT)  
− activated partial thromboplastin time 
(aPTT) 
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or PTT 
is within therapeutic range of intended use 
of anticoagulants 
ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT) = 
aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR = glomerular filtration 
rate; ULN=upper limit of normal. 
a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks. 
b Creatinine clearance (CrCl) should be calculated per institutional standard. 
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory 
value requirements should be adapted according to local regulations and guidelines for the 
administration of specific chemotherapies. 
2.1.1.9 The effects of Minnelide on the developing human fetus are unknown. For this reason, 
women of child-bearing potential (WOCBP) and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to study 
entry, for the duration of study participation, and for 6 months (women) and 3 months 
(men) after the last dose of trial treatment. Male participants must also refrain from 
donating sperm during this period.  Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should inform her 
treating physician immediately. 
2.1.2 Exclusion Criteria  
2.1.2.1 Has uncontrolled vomiting or medical condition which inhibits oral ingestion or digestion 
because the study treatment is administered orally. 
2.1.2.2 Pregnant and/or women who are breast feeding are excluded from this study because there 
is an unknown but potential risk for adverse events in nursing infants secondary to 
treatment of the mother with Minnelide. 
2.1.2.3 Is currently participating and receiving trial therapy, or has participated in a trial of an 
investigational agent/therapy  or used an investigational device within 3 weeks of the first 
planned treatment on this study. 

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2.1.2.4 Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 
2 weeks prior to Cycle 1/Day 1  
2.1.2.5 Requires use of ondansetron or another prohibited medication (see Section 4). Note that 
other 5-HT3 inhibitors are NOT prohibited. 
2.1.2.6 Has received major surgery within the last 4 weeks, minor endoscopic procedure such as 
biliary stenting within the last 2 weeks, or percutaneous procedure such as hepatic biopsy 
or celiac plexus block within 24 hours of planned treatment start date. Note: participant 
must have recovered adequately from the toxicity and/or complications from the 
intervention prior to starting therapy. 
2.1.2.7 Has a known additional malignancy that is progressing or requires active treatment. 
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the 
skin that has undergone potentially curative therapy or in situ cervical cancer. 
2.1.2.8 Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Participants with previously treated brain metastases may participate if: 
a) follow-up brain imaging after central nervous system (CNS)-directed therapy shows 
no evidence of progression at ≥ 4 weeks since treatment, AND b) participant has stability 
of baseline neurologic symptoms without receiving immunosuppressive-doses of 
systemic corticosteroid (physiologic replacement doses are permitted) x7 days or 
increases in other supportive medications that treat neurologic symptoms such as anti-
epileptics x14 days. Participants with carcinomatous meningitis are excluded regardless 
of clinical stability. 
2.1.2.9 Has an active infection requiring systemic therapy. 
2.1.2.10 Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the participant’s participation 
for the full duration of the trial, or is not in the best interest of the participant to participate, 
in the opinion of the treating investigator. 
2.1.2.11 Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
2.1.2.12 Has known uncontrolled or poorly controlled human immunodeficiency virus (HIV) 
infection. HIV is considered uncontrolled or poorly controlled if an HIV-infected 
individual is not taking highly active anti-retroviral therapy or has a detectable viral load 
within the previous 6 months. 
2.1.2.13 Has active HBV or HCV or is currently under treatment for HBV or HCV.  Active HBV 
or HCV does not include previously cleared HBV or HCV or successfully cured HBV or 
HCV through treatment 
2.1.2.14 Has received a live vaccine within 30 days of planned start of trial therapy. 
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and 
are allowed; however intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated 
vaccines, and are not allowed. 

Abbreviated Title: Minnelide for ASCP 
 
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2.1.2.15 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to Minnelide   
2.2 
RECRUITMENT STRATEGIES 
This protocol may be abstracted into a plain language announcement posted on NIH websites and 
on NIH social media platforms.   
2.3 
SCREENING EVALUATION 
2.3.1 Screening activities performed prior to obtaining informed consent 
Minimal risk activities that may be performed before the participant has signed a consent include 
the following:  
• Email, written, in person or telephone communications with prospective participants 
• Review of existing medical records to include H&P, laboratory studies, etc.  
• Review of existing  MRI, x-ray, or CT images 
• Review of existing photographs or videos 
• Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes 
2.3.2 Screening activities performed after a consent for screening has been signed 
The following activities will be performed only after the participant has signed the consent for 
screening on this study. Assessments performed at outside facilities or on another NIH protocol 
within the timeframes below may also be used to determine eligibility once a participant has signed 
the 000254 consent for screening. 
Screening of potential participants must be performed within 21 days prior to first dose of trial 
medication (unless otherwise noted below).  All necessary laboratory values and assessment 
reports must be available and reviewed prior to signing study consent for treatment.  
The following will be completed as part of the screening visit: 
2.3.2.1 Confirmation of diagnosis:  Obtain archival tumor specimen (primary or metastatic site) 
for all participants for review by NCI Laboratory of Pathology; may be performed at any 
time prior to eligibility determination (no time limit). If archival tumor specimen is 
unavailable for confirmation of diagnosis, then fresh tumor biopsy will be performed. If 
fresh biopsy is done for diagnosis, sufficient tissue for baseline research biopsy may be 
obtained at the same time; refer to Section 5.1.3. 
2.3.2.2 Medical history: review of concurrent baseline conditions (using NCI CTCAE version 
5.0), prior cancer therapy (including documentation of prior surgery, adjuvant or 
neoadjuvant chemotherapy and radiotherapy). 
2.3.2.3 Physical examination, including vital signs, height (cm) and weight (kg): review of organ 
systems, weight, and vital signs (i.e., temperature, pulse, respirations, blood pressure). 
Height is at screening only.  
2.3.2.4 Performance status (ECOG):  an assessment of activities of daily living; see Appendix 
A: Performance Status Criteria 
2.3.2.5 Clinical laboratories 

Abbreviated Title: Minnelide for ASCP 
 
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Arms 
Number 
Name 
Description 
1 
Minnelide  
Treat with Minnelide  PO daily, Days 1-21 of each 28 day 
cycle 
Arm Assignment 
Participants in Cohort 1 will be directly assigned to Arm 1.  
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STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
This is a Phase II single arm, single cohort study that will enroll up to 25 evaluable participants 
with advanced ASCP that has been previously treated. In order to account for screen failures and 
inevaluable patients (i.e., participants who are not evaluable for the primary endpoint of response), 
the accrual ceiling will be set at 55 participants.  
Accrual may continue up to 15 treated participants while the primary objective is being determined 
but no new participants may be accrued once it is known that this criteria has not been met (see 
Sections 10.3 and 10.5.6).   
Initial participants will self-administer Minnelide at 2 mg PO daily on Days 1-21 of each 28 days 
cycle. Those joining the study after modification dated 3/10/23 will receive Minnelide at 2.5 mg 
PO daily on Days 1-21 of each 28 days cycle. Participants initially enrolled at the 2 mg dose may 
be increased to the 2.5 mg dose at the discretion of the study team if they have been tolerating the 
lower dose (i.e., intrapatient dose escalation is permitted). Treatment will continue for up to 12 
cycles (1 year) in the absence of disease progression or unacceptable toxicity. After initiation of 
treatment, restaging scans will be conducted approximately every 2 cycles or 8 weeks. Optional 
biopsies will be requested mid-cycle 1 and at time of progression. 
3.2 
DRUG ADMINISTRATION 
3.2.1 Minnelide 
• Study participants will be provided Minnelide capsules (0.5 mg) (see Appendix B: 
Participant Medication Diary). Quantity of each container will be sufficient for 1 cycle; 
resupplies will be provided as necessary at the beginning of each cycle.  Any remaining 
capsules and containers will be returned to the investigational pharmacy for accountability. 
• Containers will be white opaque, round HDPE bottle (120 cc, 38mm screw neck (Heavy 
Weight), induction sealed with a 38mm child-resistant white polypropylene cap with liner.  
• Capsules will be Size 2 White/White opaque capsules are filled with 150 mg blended 
powder that contains 0.50 mg Minnelide ™ free acid. 
• Medication will be stored at controlled cold temperature (2–8°C, excursions permitted  
0–15°C) in the site investigational pharmacy. 
• Medication will be provided to participants by the site investigational pharmacy on receipt 
of a prescription from the investigator. The medication will be provided in a bag with ice 
packs for the transfer home and participants will be instructed to store the medication in a 
refrigerator at home. 

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• Doses will be self-administered at home daily for 21 days and then 7 days without dose for 
each treatment cycle.  The maximum number of cycles will be 12. 
• The daily dose will be 2 mg (four capsules) or 2.5 mg (five capsules). Participants will be 
instructed to take the dose after fasting for at least 30 minutes prior to Minnelide 
administration, with a recommended 90-minute fast post dose. If needed, 60-minute fast 
post dose is acceptable. Capsules may be taken with 240 mL of water. 
• If the medication dose is more than 6 hours late then it should be skipped. 
• Any missed doses will be reported during the study visits.  Do not try to make up missed 
doses or continue taking past the 21 allotted days for that cycle. 
• NOTE:  Upon return of each supply, the study staff will record in the source documents 
(e.g., medical record) the number of capsules returned at each visit.   
3.2.2 Supportive Medications for risk of nausea and emesis 
• Participants with baseline nausea and/ or emesis will be continued on their home 
medication regimen. If this contains ondansetron (a prohibited medication), then 
ondansetron will be transitioned to an acceptable alternative such as granisetron. 
• Participants who do not have a prescribed anti-emetic regimen at baseline or those whose 
current anti-emetic regimen is deemed insufficient will be prescribed sufficient supply of 
oral granisetron (1 mg, PRN) to use until first return visit (at 14 days) in case increased 
nausea/ emesis occurs while taking Minnelide. An alternative anti-emetic may be 
prescribed in case of participant allergy, intolerance or preference. Refills will be 
prescribed as needed at subsequent visits. 
3.3 
DOSE MODIFICATIONS 
Two dose-reductions per participant (see Table 2 below) will be permitted in response to either 
hematologic or non-hematologic toxicities for criteria as defined in the sub-sections below. 
Table 2: Minnelide Dose Reduction  
Minnelide Dose Reductions 
Minnelide Dose 
(Low) 
Minnelide Dose 
(High) 
Full-dose 
2 mg/ day 
2.5 mg/ day 
1st occurrence of AE requiring dose 
reduction 
1.5 mg/ day (75%) 
2.0 mg/day (80%) 
2nd occurrence of AE requiring dose 
reduction 
1.0 mg /day (50%) 
1.5 mg/day (60%) 
3rd  occurrence of AE requiring dose 
reduction 
No further Minnelide 
given 
No further 
Minnelide given 
A new cycle of Minnelide should not be started if the participant’s laboratory values, clinical status 
or medical conditions no longer meet initial study eligibility criteria as per the assessments to be 
completed prior to each cycle (see Study Calendar, Section 3.7) with Minnelide held until these 
values reach eligibility criteria unless otherwise described below (i.e., Section 3.3.1 to 3.3.4).  
If treatment is delayed for > 2 weeks due to any drug-related toxicity, the participant must be 1) 
dose-reduced (as defined above) or 2) discontinued from treatment with Minnelide capsules and 

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followed for safety. Cycles of Minnelide are never skipped. If participants are delayed receiving 
the next cycle of Minnelide for > 2 weeks due to complications of disease, co-morbid conditions, 
scheduling problems or any reason other than drug-related toxicity, Minnelide should be continued 
at previously administered dose when these issues have resolved to meet requirements of study 
eligibility criteria. In such cases where a new cycle of Minnelide is delayed, the duration of the 
current cycle lengthens to >28 days. A new cycle does not start until a participant takes the first 
dose of Minnelide for that next cycle. 
As defined below, individual doses of Minnelide may be held in response to lab abnormalities or 
or clinical issues. If Minnelide treatment must be paused in this way, these missed doses are not 
administered later. Minnelide treatment for the cycle will still finish on Day 21. 
3.3.1 Neutropenia and Febrile Neutropenia 
Minnelide should be halted and growth factor should be given to all participants experiencing 
grade ≥ 3 neutropenia until ANC exceeds 1500/ mm3. After recovery of ANC, dose reduction (see 
Section 3.3) to next lowest level of Minnelide is required to continue therapy, except if grade ≥ 3 
neutropenia occurs within first 1-2 weeks of cycle 1. Transient grade ≥3 neutropenia has been 
observed during the first 1-2 weeks of cycle 1 in some participants on prior study of oral Minnelide. 
In this situation, Minnelide should be held until ANC recovers to Grade 1 or better, but can 
subsequently be resumed at the previous dose. Any subsequent neutropenia events will require 
dose reduction as specified in Section 3.3.  
Febrile neutropenia should always be treated as a medical emergency; Grade 5 sepsis has been 
observed in patients receiving Minnelide treatment. Minnelide treatment should be halted 
immediately and growth factor administered to all participants experiencing febrile neutropenia 
until ANC exceeds 1500/ mm3. Pan-cultures should be taken as per standard of care and 
appropriate empiric antibiotic treatment should be promptly initiated. In addition, Minnelide 
should be held and no new cycle started until ANC exceeds 1500/ mm3 AND prescribed antibiotic 
course has been completed. Upon resumption of Minnelide, dose reduction is required for each 
episode of febrile neutropenia as per Section 3.3. 
3.3.2 Thrombocytopenia 
Minnelide should be held for grade 4 platelet count decrease or for grade ≥ 3 platelet count decrease 
that is accompanied by new clinically significant bleeding. The current cycle of Minnelide may be 
resumed at a decreased dose when platelet count exceeds 50,000/ mm3. Dose reductions should be 
made as specified in Section 3.3. To start next cycle, platelets must recover to that specified by 
eligibility criteria and Minnelide should be administered at the decreased dose. Any subsequent 
grade 4 thrombocytopenia events or grade 3 events associated with clinically significant bleeding 
will require dose reduction as specified in Table 2. 
3.3.3 Anemia 
Minnelide should be held for grade ≥3 anemia. The current cycle may be resumed when Hgb 
exceeds 8.0 g/dL. Transfusion may be given to increase Hgb. Minnelide should be dose-reduced 
if participant requires transfusion 2 or more times due to drug-related anemia or if Hgb has not 
recovered to at least 8.0 g/dL by the scheduled start of the next cycle. Dose reductions should be 
made as specified in Section 3.3. Any subsequent occurrences of anemia requiring transfusion or 
failure of Hgb to recover to at least 8.0 g/dL by the scheduled start the next cycle will require 
further dose reduction as specified in Section 3.3. 

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3.3.4 Non-hematologic toxicity 
Minnelide should be held for any clinically significant grade ≥ 3 non-hematologic toxicity. The 
present cycle of Minnelide may be resumed when toxicity resolves to at least grade 1 (or to baseline 
in participants with liver metastases and elevated transaminases). If the clinically significant 
toxicity is attributable to study drug, then Minnelide should be dose-reduced when resumed. If the 
adverse event is judged to be unrelated or unlikely to be related to Minnelide, then Minnelide may 
be resumed at the previous dose. 
Asymptomatic grade ≥ 3 electrolyte abnormalities than can be rapidly corrected with 
supplementation are not considered clinically significant. 
Nausea, vomiting or diarrhea that resolve within 48 hrs of initiating appropriate supportive 
medications are not considered clinically significant. NOTE: See contraindication for concomitant 
use of ondansetron in Section 4. 
3.4 
ON TREATMENT EVALUATIONS 
The following describes all tests and procedures to be conducted during treatment.  Refer to Study 
Calendar (Section 3.7) for timing and applicable windows.   
For each time period, consider the following order of assessments: 
• Baseline/Cycle 1:  The results of all assessments, with the exception of tumor markers, 
must be available and reviewed prior to initiation of Minnelide administration to ensure 
results still meet standards defined in eligibility criteria. The cycle should be delayed if 
these criteria are not met (refer to Dose Modifications, Section 3.3). 
• Subsequent Cycles:  The results of all assessments, with the exception of tumor markers, 
must be available and reviewed prior to initiation of Minnelide administration in a new 
cycle to confirm eligibility for ongoing treatment administration.   
• Mid-cycle – Cycle 1/Subsequent Cycles:  There is no specific order of events for these 
days. The study team must review results of laboratory studies within 2 calendar days of 
the blood draw. 
• Unscheduled Visits:  In the event of an unscheduled/unplanned visit (e.g., additional 
clinical assessment(s) due to toxicity), the investigator should use best clinical judgement 
as to the necessary assessments.  In the event that the decision is made to continue 
treatment, all tests/assessments as required by the next visit on the Study Calendar (Section 
3.7) should still be conducted (or repeated) within the applicable windows.  If a decision is 
made to discontinue treatment, the participant should move to the End of Treatment visit 
(Section 3.5), with tests/assessments completed (or repeated) within the applicable 
windows.   
If a physical exam and vital signs are required by the study calendar, then an in-person clinic visit 
is required. If only symptom assessment is required, a telehealth visit may be conducted so that 
participants need not travel to the NIH Clinical Center for evaluation unless preferred by the 
participant or felt to be clinically indicated by the provider. Given the standard nature of the 
planned clinical laboratories, interlaboratory variability is not a concern and participants may have 
clinical labs drawn locally, with results sent to the NIH study team (e.g., via fax); in these cases, 
an appropriate member of the study team will follow-up remotely to discuss any symptoms and to 
make recommendations/adjustments, as necessary. 

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The following is a description of all procedures: 
• Symptom assessment: verbal review of participant’s current symptoms  
• Physical exam, including vital signs and weight:  review of organ systems, weight (kg), 
and vital signs (i.e., temperature, pulse, respirations, blood pressure). After initiation of 
study drug, symptom-directed physical examinations will be performed as clinically 
indicated in the investigator’s judgment. 
• Performance status (ECOG):  an assessment of activities of daily living; see Appendix A: 
Performance Status Criteria 
• Clinical laboratories:   
o CBC with differential: includes Neutrophils, Lymphocytes, Monocytes, 
Eosinophils, Basophils, WBC, RBC, Hemoglobin, Hematocrit, MCV, RDW, 
Platelet 
o Serum Chemistries: Sodium (NA), Potassium (K), Chloride (CL) Total CO2 
(Bicarbonate), Creatinine, Glucose, Urea nitrogen, Alkaline Phosphatase, 
ALT/GPT, AST/GOT, Total Bilirubin, Direct Bilirubin,  Albumin, Calcium, 
Magnesium, Phosphorus  
o Urinalysis:  protein, specific gravity, glucose, and blood 
o Pregnancy test:  Serum β-HCG for women of child-bearing potential 
o Serum tumor markers:  CA19-9 and CEA (or CA-125 if not a secretor of CA19-9 
and CEA) 
• Imaging scans:  CT scans or MRI as required for evaluation (including chest, abdomen, 
pelvis, and other regions as clinically indicated); may be adjusted to assess additional 
known sites of disease, as needed. Performed up to 3 days prior to start of every other cycle 
(typically odd numbered cycles). If radiologic response to treatment is observed (see 
Section 6.3), confirmatory scans may be performed at 4 week interval (e.g., start of next 
cycle), and in this case subsequent scans should continue prior to every other cycle 
thereafter (i.e., prior to even numbered cycles). 
• Adverse events and Concomitant medication review:  Adverse events (assessed using the 
NCI CTCAE v5.0) and concomitant medication will be continuously monitored throughout 
the study until 30 days from last dose of Minnelide or start of new anticancer treatment, 
whichever comes first. Adverse events that occur beyond 30 days after the last 
administration will be recorded as noted in Section 6.1. 
• Minnelide administration, including dispensing and adherence review:  Study drug will be 
dispensed at each cycle and instructed to be self-administered by participants per schedule- 
see Section 3.2. Participants will be given a dosing diary (see Appendix B: Participant 
Medication Diary); to be reviewed at each noted visit for drug adherence/accountability. 
• Contraception review:  Review of contraception use for men and women of childbearing 
potential.  See Section 2.1.1.9. 
• Correlative research samples:  Refer to Section 5. 
• NIH Advance Directives Form:  All participants will be offered the opportunity to complete 
an NIH advance directives form. This should be done preferably at baseline but can be 
done at any time during the study as long as the capacity to do so is retained. The 
completion of the form is strongly recommended, but is not required. 

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3.5 
END OF TREATMENT ASSESSMENTS 
The participant will continue on study drug until there is evidence of tumor progression, intolerable 
toxicities, completion of 12 cycles, or withdraws from treatment (refer to Section 3.9.1). The “End 
of Treatment” assessments (Section 3.7) will be performed 7-35 days after completing the last 
dose of study drug or before the initiation of a new anti-cancer treatment, whichever comes first.  
If the participant cannot return to the study center for this visit, the participant may complete 
assessments locally, including seeing a local physician for a physical exam and local clinical 
laboratories, and the study team will follow-up with the participant remotely. Imaging scans need 
only be performed at end of treatment, if not performed within the last 4 weeks. 
3.6 
FOLLOW-UP PERIOD 
3.6.1 30-day Follow-up Visit 
The mandatory Safety Follow- up visit should be conducted approximately 30 (+ 5 days) after the 
last dose of study drug and before initiation of a new anti-cancer treatment, whichever comes first 
(see assessments, Section 3.7).  In addition, the study team will confirm contact information for 
participant and a designated family member, and remind participant of follow-up contact that will 
be conducted for survival status. 
3.6.2 Survival Follow-up 
Overall survival will be collected until 1 year post-last dose of Minnelide.  Participants will be 
contacted remotely (e.g., phone or email) approximately every 90 days.  If participants are still 
being seen at the NIH, this information may be obtained from the medical records.   

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3.8 
COST AND COMPENSATION  
3.8.1 Costs 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center. If some tests and procedures are 
performed outside the NIH Clinical Center, participants may have to pay for these costs if they are 
not covered by an insurance company.  Medicines that are not part of the study treatment will not 
be provided or paid for by the NIH Clinical Center.   
3.8.2 Compensation 
Participants will not be compensated on this study.  
3.8.3 Reimbursement  
The NCI will cover the costs of some expenses associated with protocol participation.  Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate.  The amount and form of these payments are determined by 
the NCI Travel and Lodging Reimbursement Policy.  
No reimbursement is provided to participants enrolled at sites other than NIH Clinical Center.  
3.9 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
Prior to removal from study, effort must be made to have all participants complete a safety visit 
(See Study Calendar). 
3.9.1 Criteria for removal from protocol therapy 
A participant must be discontinued from the protocol therapy for any of the following reasons: 
• Completed 12 cycles of trial treatment 
• Confirmed disease progression 
• Participants request to be withdrawn from active therapy 
• Unacceptable adverse experiences as described in Section 3.3 
• Inter-current illness that prevents further administration of treatment 
• Investigator Discretion 
• The participant has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
3.9.2 Off-Study Criteria 
A participant who meets one of the following criteria will be considered Off Study: 
• Participant requests to be withdrawn from study 
• Death 
• Screen failure 
3.9.3 Lost to Follow-up 
A participant will be considered lost to follow-up if he or she fails to return for three scheduled 
visits and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
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• The site will attempt to contact the participant and reschedule the missed visit within three 
business days and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain if the participant wishes to and/or should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, an IRB-approved certified letter to the participant’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record or study file.  
• Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
4 
CONCOMITANT MEDICATIONS/MEASURES 
Necessary supportive measures for optimal medical care may be given throughout the study, 
including IV antibiotics to treat infections, blood components, and antiemetics. Additional care 
will be administered as indicated by the treating physician and the participant’s medical need. 
No concomitant cytotoxic therapy, whether conventional or investigational, will be allowed during 
this study. All concomitant medications and supportive therapy must be recorded on the 
appropriate CRF.  
Palliative radiotherapy may be permitted at the discretion of the PI while the participant is 
undergoing treatment.  
All concomitant medications received within 30 days before the first dose of trial treatment and at 
the 30 day (+ 5 days) follow-up visit should be recorded.   
In vitro studies suggest that Minnelide has a low potential for CYP450 related drug-drug 
interactions. 
Minnelide  is a substrate for but not an inhibitor of P-glycoprotein. Co-administration with 
inhibitors of glycoprotein is permitted with caution. 
Ondansetron may not be given with Minnelide. It was noted in the Phase 1 study that 
participants receiving ondansetron in conjunction with Minnelide had higher serum Minnelide 
concentrations. Follow-up of this observation in murine models confirmed that co-administration 
of ondansetron with Minnelide increased Minnelide exposures. The mechanism for this interaction 
is unknown. Other 5-HT3 receptor antagonists did not produce this interaction and are 
acceptable. 
5 
CORRELATIVE STUDIES FOR RESEARCH  
Note: Platforms and procedures for analysis may be adjusted based upon current technology 
and/or collaborations in place at the time of actual analyses. 
5.1 
BIOSPECIMEN COLLECTION  
Please note that details for collection, processing, storing and shipping will be described in the 
Trial Lab Manual. 

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5.1.1 Blood Sample  
Blood samples will be collected for all enrolled participants at the time points described in the 
Specimen Collection Table (Section 5.2).   
5.1.1.1 Cytokine and immune cell profiling 
Peripheral immune cell profiling and cytokine analysis will be performed to determine the effect 
of  Minnelide on the systemic immune environment in ASCP participants. Peripheral immune cells 
will be analyzed by multiparameter flow cytometry to identify potential changes in 10 classic 
subsets (CD4 and CD8 T cells, B cells, NK cells, NK-T cells, conventional and plasmacytoid 
dendritic cells, T regulatory cells, MDSCs, and monocytes) and 121 refined subsets relating to 
their maturation and function.  
5.1.1.2 CTCs and circulating tumor DNA (ctDNA) 
Analysis of CTCs and ctDNA will be performed to identify potential early biomarkers of response 
to Minnelide therapy. CTCs will be enumerated and characterized. If CTCs are sufficient, they 
will be enriched and analyzed for gene expression and mutation. Mutational status of genes in 
ctDNA including, but not necessarily limited to, KRAS will be evaluated as well as copy number 
variation of MYC and potentially other genes of interest will be assessed.  
5.1.2 Archival Tumor Tissue 
All participants will be asked to provide an archival tumor tissue specimen to identify overall 
mutational landscape of tumor or results of prior tumor mutational analysis by an FDA approved 
platform (e.g., Foundation One).    
If information from genomic mutational analysis previously performed on a participant’s tumor 
sample using another CLIA-certified platform is not available, tissue will be analyzed by NCI 
Laboratory of Pathology (LP) COMPASS program. Results will be returned to participants. Whole 
exome sequencing (WES) or whole genome sequencing (WGS) may be performed on selected 
samples. 
A minimum of 10-unstained slides will be requested for TruSight analysis by NCI LP.  
5.1.3 Fresh Tumor Tissue/ recent archival tumor tissue 
Participants may elect to provide tissue for additional research studies designed to better 
understand the treatment effect of Minnelide on their tumor. Participants will be provided with the 
following options to provide tumor tissue for the analyses described below: 
1. Participants who have had recent core or excisional biopsy of a tumor lesion (within 90 
days prior to Cycle 1/Day 1 and since completion of last anti-cancer therapy) may consent 
to use this tissue for baseline analysis for the purposes of this study even if it was collected 
for another reason.  
2. Participants lacking a recent core or excisional biopsy of a tumor lesion may consent to 
undergo new biopsy of a tumor lesion for research purposes unless tumor is considered 
inaccessible or biopsy is otherwise considered not in the participant’s best interest.  
3. Participants on study will be asked to consent to biopsy after the completion of 2 weeks of 
treatment (~Cycle 1 Day 15), and at the time of disease progression unless tumor is 
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interest. 
Consent for biopsy will be obtained by the interventionalist at the time of the procedure. If the 
participant refuses the optional biopsy, the refusal will be documented in the medical record. 
Each tumor biopsy will consist of approximately 5 passes, and will be processed, stored and 
shipped as per the Trial Lab Manual. In case of insufficient tissue to complete all assays described 
below, priority will be given to completing the analyses listed first in the Specimen Collection 
Table.  
5.1.3.1 IHC Studies 
IHC analysis will be performed by collaborators at TGen to determine the expression of MYC and 
other super-enhancer regulated genes such as HSP70 and COL1A2 in samples from Minnelide 
treated participants. 
5.1.3.2 Assay for Transposase Accessible Chromatin using sequencing (ATAC-seq) 
ATAC-seq analysis will be performed by collaborators at TGen in samples from Minnelide treated 
participants to determine effects of Minnelide treatment on chromatin accessibility. 
5.1.3.3 Multiplex IHC for immune cells 
Changes in the profile of immune cells infiltrating the tumor following Minnelide treatment will 
be assessed by the Gulley/ Sader lab(s). Tumor biopsies will also be analyzed by multiplexed, 
multispectral IHC and assessed for immune subsets, include including MDSCs, Tregs, CD4+ or 
CD8+ T cells, and M1/M2 tumor-associated macrophages (TAMs). If there are sufficient samples, 
functional markers such as PD1, PDL1, Tim3, CTLA4 and CD40 may also be included. 
5.1.3.4 Digital Spatial Genomics  
Digital spatial genomics will be performed at TGen on selected samples to determine the effects 
of Minnelide treatment on the localization of different cell populations within the tumor 
microenvironment.  
5.1.3.5 Single cell RNA-seq 
Single cell RNA-seq will be performed by collaborators at TGen on selected samples to determine 
changes in cell population composition and cell state within the ASCP tumor microenvironment 
upon Minnelide  treatment. 
5.1.3.6 Establishment of participant-derived xenograft (PDX) and organoid models 
PDX/Organoid models will be established by collaborators at TGen if residual tissue remains after 
other analyses are completed. Those models will be used to study the biology of ASCP and test 
new therapeutic regimens for ASCP and may also be used to help understand mechanisms of 
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study will remain open so long as sample or data analysis continues. Samples from consenting 
participants will be stored until they are no longer of scientific value or if a participant withdraws 
consent for their continued use, at which time they will be destroyed. If, at any time, a participant 
withdraws consent, the participants data will be excluded from future distributions, but data that 
have already been distributed for approved research use will not be able to be retrieved. The PI 
will record any loss or unanticipated destruction of samples as a deviation. Reporting will be per 
the requirements of Section 7.2. 
Sample barcodes are linked to participant demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
Labmatrix. It is critical that the sample remains linked to participant information such as race, age, 
dates of diagnosis and death, and histological information about the tumor, in order to correlate 
genotype with these variables. 
Note: All other CCR lab systems/databases at which samples will be stored/analyzed are as noted 
in the Specimen Collection Table (e.g., Labmatrix; Section 5.2).  
5.3.2 Specimen Labeling, Storage 
All specimens (blood and tissue) collected during the course of this study will follow storage, 
handling and labeling procedures that ensure security, confidentiality, and sample integrity are 
maintained.  All samples are tracked by distinct identification labels that include a unique 
participants identifier and data of specimen collection.  Thus, samples will be de-identified of 
personal data, with access to personal data restricted to the study investigators. 
All cryopreserved samples are tracked for freezer location and storage criteria in the Investigators 
designated laboratory at specified temperature with alarm systems in place, and as per the Trial 
Lab Manual.     
5.3.3 Protocol Completion/Sample Destruction 
All specimens obtained in the protocol are used as defined in the protocol. Any specimens that are 
remaining at the completion of the protocol will be stored in the conditions described below. The 
study will remain open so long as sample or data analysis continues. Samples from consenting 
participants will be stored until they are no longer of scientific value or if a participant withdraws 
consent for their continued use, at which time they will be destroyed.  Once primary research 
objectives for the protocol are achieved, intramural researchers can request access to remaining 
samples, provided they have an IRB-approved protocol and participant consent or an exemption 
form OHSRP.  
The PI will record any loss or unanticipated destruction of samples as a deviation. Reporting will 
be per the requirements of Section 7.2 
5.4 
SAMPLES FOR GENETIC/GENOMIC ANALYSIS 
5.4.1 Description of the scope of genetic/genomic analysis 
Tumor tissue may undergo somatic Whole Exome Sequencing (WES), Whole Genome 
Sequencing (WGS) and single cell RNA sequencing to look for the molecular basis of the 
participant’s cancer as described in Sections 5.1.2 and 5.1.3. 
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specimens will be maximized 
Every effort will be made to keep participants’ personal information, biospecimens and resultant 
data confidential. 
Precautions will be taken to protect the privacy of participants. The Clinical Investigator or a 
member of the study staff will maintain a master enrollment log containing participant names and 
their assigned study-specific numbers and the consent forms. All of these documents will be stored 
in locked cabinet(s) at the Clinical Site. Only the study Clinical Investigators or the study 
coordinator(s) will have routine access to the master enrollment log and participant identifiable 
information. The informed consent form discloses the limits of confidentiality and the fact that 
participants may be requested to disclose such information by a third party. This is a risk of 
participation in the study and the participants will be informed of this risk. Given the uniqueness 
of one's genetic information, we cannot guarantee that participant's genetic information will never 
be able to be linked back to them.  
Samples will be stored at TGen or NCI CC. Samples will not be stored with any participant 
identifiers. Research laboratory staff will not see any identifying participant information that could 
be linked to the sample. Research staff will receive only de-identified and coded information.  
Data from the study may be published in scientific journals and/or public data sharing databases 
(such as dbGaP). All data published or shared will not include any participant identifiers. 
Participants samples and data will be covered by a certificate of confidentiality, providing 
additional protections to study participants. 
5.4.3 Management of Results 
Participants will be contacted if a clinically actionable gene variant is discovered. Clinically 
actionable findings for the purpose of this study are defined as disorders appearing in the American 
College of Medical Genetics and Genomics recommendations for the return of incidental findings 
that is current at the time of primary analysis. Participants will be contacted at this time with a 
request to provide a sample to be sent to a CLIA certified laboratory. If the research findings are 
verified in the CLIA certified lab, the participant will be offered the opportunity to come to NIH 
(at our expense) to have genetic education and counseling to explain this result. If the participant 
does not want to come to NIH, a referral to a local genetic healthcare provider will be provided (at 
their expense). 
This is the only time during the course of the study that incidental findings will be returned. No 
interrogations regarding clinically actionable findings will be made after the primary analysis. 
6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
The PI will be responsible for overseeing entry of data into a 21 CFR Part 11-compliant data 
capture system provided by the NCI CCR and ensuring data accuracy, consistency and timeliness. 
The principal investigator, associate investigators/research nurses and/or a contracted data 
manager will assist with the data management efforts.   Primary and final analyzed data will have 
identifiers so that research data can be attributed to an individual human subject participant. 
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
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Document AEs from the first study intervention, Study Day 1, through 30 (+5) days following the 
last dose of study medication, whichever occurs later.   Beyond 30 days after the last intervention, 
only adverse events which are serious and related to the study intervention need to be recorded.  
SAE assessment after the 30 days will be documented by a licensed physician listed on the 1572 
in the source documents. 
All adverse events related to study intervention will be recorded in the study database, regardless 
of grade. Abnormal grade 1 or grade 2 laboratory values not considered related to study 
intervention will be recorded in the database as an AE only if the laboratory abnormality is 
characterized by any of the following: 
• Results in discontinuation from the study 
• Is associated with clinical signs or symptoms  
• Requires treatment or any other therapeutic intervention 
• Is associated with death or another serious adverse event, including hospitalization.  
• Is judged by the Investigator to be of significant clinical impact. AE’s related to changes 
in creatinine, AST, ALT and bilirubin are always considered clinically significant. 
• If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the 
participant’s outcome. 
The PI (or PI designee) evaluation of each AE not captured in the clinical database determining 
that it meets the criteria above will be documented in the source documents. Note: the investigator 
performing the assessment must be a licensed clinician listed on the FDA form1572. 
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable.  
6.2 
DATA SHARING PLANS 
6.2.1 Human Data Sharing Plan 
What data will be shared? 
I will share human data generated in this research for future research as follows: 
_X_ Coded, linked data in an NIH-funded or approved public repository. 
___ Coded, linked data in another public repository. 
_X_ Coded, linked data in BTRIS (automatic for activities in the Clinical Center) 
_X_  Identified or coded, linked data with approved outside collaborators under appropriate 
agreements. 
___ I will not share human data generated in this research for future research. If checked, explain: 
How and where will the data be shared?  
Data will be shared through  
_X_   An NIH-funded or approved public repository. Insert name or names:clinicaltrials.gov. 
___ Another public repository. Insert name or names: ____________________________. 

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_X_  BTRIS (automatic for activities in the Clinical Center) 
_X_   Approved outside collaborators under appropriate individual agreements. 
_X_  Publication and/or public presentations. 
When will the data be shared?  
_X_  Before publication. 
_X_  At the time of publication or shortly thereafter. 
6.2.2 Genomic Data Sharing Plan 
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy. 
6.3 
RESPONSE CRITERIA 
For the purposes of this study, participants should be re-evaluated for response every 8 weeks. In 
addition to a baseline scan, confirmatory scans should also be obtained 4-8 weeks (not less than 4) 
weeks following initial documentation of objective response.  
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
version 1.1 (22). Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria. 
6.3.1 Disease Parameters 
Measurable disease:  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as:  
• By chest x-ray: >20 mm;  
• By CT scan:  
o Scan slice thickness 5 mm or under: as >10 mm 
o Scan slice thickness >5 mm: double the slice thickness  
• With calipers on clinical exam: >10 mm.   
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. If the investigator thinks it appropriate to include them, the conditions 
under which such lesions should be considered must be defined in the protocol. 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph node 
must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed. 
Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
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effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same participant, these are preferred for selection as target lesions. 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then 
only the short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the disease. 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or 
in rare cases unequivocal progression of each should be noted throughout follow-up.  
6.3.2 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers 
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable.  
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is 
also acceptable in certain situations (e.g. for body scans). 
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however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable 
globally. As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, 
as with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the 
RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans. Body scans should be performed 
with breath-hold scanning techniques, if possible. 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the 
site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to 
a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces 
additional data which may bias an investigator if it is not routinely or serially performed. 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances. 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, such techniques may be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
Tumor markers: Tumor markers alone cannot be used to assess response. If markers are initially 
above the upper normal limit, they must normalize for a participant to be considered in complete 
clinical response. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and 
PSA response (in recurrent prostate cancer) have been published.(23-25) In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer.(26) 
Cytology, Histology: These techniques can be used to differentiate between partial responses (PR) 
and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell 
tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes 
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of progression (particularly possible 'new' disease). New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not 
PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described 
in the protocol and supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
6.3.3 Response Criteria 
6.3.3.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum of diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest 
on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered 
progressions). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study. 
6.3.3.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
Note: If tumor markers are initially above the upper normal limit, they must normalize for a 
participant to be considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression 

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of existing non-target lesions. Unequivocal progression should not normally trump target lesion 
status. It must be representative of overall disease status change, not a single lesion increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at 
a later time by the review panel (or Principal Investigator). 
6.3.3.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The participant's best response assignment will depend on 
the achievement of both measurement and confirmation criteria. 
For Participants with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 

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8 
SPONSOR PROTOCOL/SAFETY REPORTING 
8.1 
DEFINITIONS 
8.1.1 Adverse Event  
Any untoward medical occurrence in a participant or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (ICH E6 (R2)) 
8.1.2 Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• 
Death, 
• 
A life-threatening adverse event (see Section 8.1.3) 
• 
Inpatient hospitalization or prolongation of existing hospitalization  
o A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event. 
o A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient or subject convenience) is not considered a serious adverse 
event.  
o Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria. 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
• 
A congenital anomaly/birth defect 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the participant or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
8.1.3 Life-threatening  
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the participant or subject at immediate risk 
of death. It does not include an adverse event or suspected adverse reaction that, had it occurred in 
a more severe form, might have caused death. (21CFR312.32) 

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8.8 
SPONSOR PROTOCOL DEVIATION REPORTING 
A Protocol Deviation is defined as any non-compliance with the clinical trial Protocol, Manual of 
Operational Procedures (MOP) and other Sponsor approved study related documents, GCP, or 
protocol-specific procedural requirements on the part of the participant, the Investigator, or the 
study site staff inclusive of site personnel performing procedures or providing services in support 
of the clinical trial. 
It is the responsibility of the study Staff to document any protocol deviation identified by the Staff 
or the site Monitor in the CCR Protocol Deviation Tracking System (PDTS) online application. 
The entries into the PDTS online application should be timely, complete, and maintained per CCR 
PDTS user requirements.  
In addition, any deviation to the protocol should be documented in the participant’s source records 
and reported to the reviewing IRB per their guidelines. OSRO required protocol deviation 
reporting is consistent with E6(R2) GCP: Integrated Addendum to ICH E6(R1): 4.5 Compliance 
with Protocol; 5.18.3 (a), and 5.20 Noncompliance; and ICH E3 16.2.2 Protocol deviations. 
9 
CLINICAL MONITORING  
Clinical site monitoring is conducted to ensure: 
• that the rights of the participants are protected;  
• that the study is implemented per the approved protocol, Good Clinical Practice and 
standard operating procedures; and,  
• the quality and integrity of study data and data collection methods are maintained.   
Monitoring for this study will be performed by NCI CCR Office of Sponsor and Regulatory 
Oversight (OSRO) Sponsor and Regulatory Oversight Support (SROS) Services contractor. 
Clinical site monitoring activities will be based on OSRO standards, FDA Guidance E6(R2) Good 
Clinical Practice: Integrated Addendum to ICH E6(R1) March 2018, and applicable regulatory 
requirements. 
Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) 
developed by OSRO. CMPs will be protocol-specific, risk-based and tailored to address human 
subject protections and integrity of the study data. OSRO will determine the intensity and 
frequency of monitoring based on several factors, including study type, phase, risk, complexity, 
expected enrollment rate, and any unique attributes of the study and the site. The Sponsor will 
conduct a periodic review of the CMP to confirm the plan's continued appropriateness. A change 
to the protocol, significant or pervasive non-compliance with GCP, or the protocol may trigger 
CMP updates. 
OSRO SROS Monitoring visits and related activities will be conducted throughout the life cycle 
of each protocol. The first activity is before the study starts to conduct a Site Assessment Visit 
(SAV) (as warranted), followed by a Site Initiation Visit (SIV), Interim Monitoring Visit(s) 
(IMVs), and a study Close-Out Visit (COV). 
Some monitoring activities may be performed remotely, while others will occur at the study site(s). 
Monitoring visit reports will describe visit activities, observations, and associated action items or 
follow-up required for resolution of any issues, discrepancies, or deviations. Monitoring reports 

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10.4.1 Evaluable for toxicity  
All participants will be evaluable for toxicity from the time of their first treatment with Minnelide. 
10.4.2 Evaluable for objective response:  
Only those participants who have measurable disease present at baseline, have received at least 
one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for 
objective response.  These participants will have their response classified according to the 
definitions stated below. (Note: Participants who exhibit objective disease progression prior to the 
end of cycle 1 will also be considered evaluable.) 
10.4.3 Evaluable Non-Target Disease Response:   
Participants who have lesions present at baseline that are evaluable but do not meet the definitions 
of measurable disease, have received at least one cycle of therapy, and have had their disease re-
evaluated will be considered evaluable for non-target disease.  The response assessment is based 
on the presence, absence, or unequivocal progression of the lesions.  
10.5 STATISTICAL ANALYSES 
10.5.1 General Approach 
The fraction of all evaluable participants who experience clinical benefit (CR+PR +SD>16 weeks) 
will be reported along with a confidence interval. 
10.5.2 Analysis of the Primary Endpoint 
The fraction of evaluable participants who experience clinical benefit will be reported along with 
a 95% two-sided confidence interval. 
10.5.3 Analysis of the Secondary Endpoints 
PFS and OS will be determined using the Kaplan-Meier method and will be reported along with a 
95% confidence interval for the median.   
Objective response rate (ORR) will be calculated as the percentage of patients with CR or PR as 
defined by RECIST 1.1 criteria. 
Analysis of safety is as described in the Section 10.5.4. 
10.5.4 Safety Analyses 
The fraction of participants who experience a toxicity, by grade and type of toxicity, will be 
tabulated.  
10.5.5 Baseline Descriptive Statistics 
Baseline demographic characteristics will be reported. 
10.5.6 Planned Interim Analyses 
As indicated in the two-stage design, the number of responses after 12 evaluable participants have 
been treated will be noted and will be used to determine if enrollment to the second stage of accrual 
may continue. 
10.5.7 Sub-Group Analyses 
None. 

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10.5.8 Tabulation of individual Participant Data 
None. 
10.5.9 Exploratory Analyses 
The following are the planned exploratory analyses:  
• Utilize participant blood and biopsy tissue acquired on this protocol to identify factors that 
may be important in determining participant response to treatment (techniques involved 
immune phenotyping analysis, whole genome sequencing, ATAC-seq, Digital Spatial 
Profiling (Nanostring GeoM) and effect of the study drug on tumor a circulating cell 
populations. 
• Evaluate ctDNA as a marker of response in ASCP 
The exploratory objectives are intended to collect data for use in planning future scientific 
investigations or clinical research. These analyses are expected to be performed first using 
descriptive techniques, reporting descriptive statistics including confidence intervals when 
appropriate. Any statistical tests performed for evaluation of exploratory objectives will be done 
without formal adjustment for multiple comparisons, but in the context of the number of tests 
performed.  
11 COLLABORATIVE AGREEMENTS  
11.1 AGREEMENT TYPE 
Clinical trial agreement (CTA # 01208-21) with Minneamrita is executed. 
12 HUMAN SUBJECTS PROTECTIONS  
12.1 RATIONALE FOR SUBJECT SELECTION 
All participants meeting the criteria listed in Section 2.1 are eligible for enrollment regardless of 
race, ethnicity, sex, nationality, or English-language ability. 
Participants with ASCP are specifically being recruited to this study because the preclinical 
evidence supports efficacy of the trial intervention in this participant population. 
12.2 PARTICIPATION OF CHILDREN 
ASCP is typically a disease of adults. Because ASCP does not typically occur in children and no 
dosing or adverse event data are currently available on the use of Minnelide in participants <18 
years of age, children are excluded from this study. 
12.3 RISK/BENEFIT ASSESSMENT 
12.3.1 Known Potential Risks 
12.3.1.1 Minnelide   
Minnelide given in oral form is still under investigation. At this stage, the major treatment-related 
toxicities appear to be related to myelosuppression, including neutropenia, febrile neutropenia and 
neutropenic sepsis. At least one death due to sepsis attributed to Minnelide  has been reported on 
studies of IV and oral Minnelide.  

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12.3.1.2 Blood Collection 
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting. Up to 
60.5 mL of research blood may be collected at any visit but no more than 178 ml in an 8 week 
period. 
12.3.1.3 Urine Collection 
No physical risks are associated with urine collection. 
12.3.1.4 Electrocardiogram 
Some skin irritation can occur where the ECG/EKG electrodes are placed. The test is completely 
painless, and generally takes less than a minute to perform. 
12.3.1.5 Imaging 
In addition to the radiation risks discussed below, CT scans may include the risks of an allergic 
reaction to the contrast. Participants might experience hives, itching, headache, difficulty 
breathing, increased heartrate and swelling. Furthermore, the IV catheter used to administer the 
contrast may cause bleeding, infection or inflammation of the skin and vein with pain and swelling. 
Participants undergoing gadolinium enhanced MRIs may also be at risk for kidney damage. MRIs 
include the additional risk of damage to hearing. 
12.3.1.6 Biopsy Collection 
The risks of the optional research biopsies include pain, bleeding and infection at the biopsy site. 
In addition, as the biopsies may be collected under CT guidance, participants in this study may be 
exposed to radiation as discussed below. 
12.3.1.7 Risks from Radiation Exposure 
On this study, patients will receive up to 3 CT-guided biopsies and up to 5 CT scans. The total 
radiation dose for research purposes will be approximately 8.9 rem. The risk of getting cancer from 
the radiation exposure in this study is 0.9% and of getting a fatal cancer is 0.4%. 
12.3.2 Known Potential Benefits 
Pre-clinical studies of Minnelide in ASCP models support our hypothesis that participant tumors 
will be sensitive to this drug. Better control of ASCP provided by Minnelide may improve tumor-
related symptoms such as pain and fatigue and may slow disease progression. Treatment with these 
drugs have the potential to provide direct benefit to participants.  
12.3.3 Assessment of Potential Risks and Benefits 
Advanced ASCP that has progressed after previous treatment has a grim prognosis with median 
survival of no more than 3 months. There are no standard treatments for this disease. Available 
research suggests that Minnelide may be effective against ASCP. These potential benefits are 
balanced against the risk of drug toxicity. While Minnelide can cause serious toxicities, these 
toxicities have been successfully managed with supportive measures and dose reduction in other 
clinical studies. In addition, the frequent clinical and laboratory assessments that have been built 
into this protocol will further minimize risk to participants.  

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will provide the reason(s) for the termination or suspension.  Study participants will be contacted, 
as applicable, and be informed of changes to study visit schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping    
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA). 
13.2 QUALITY ASSURANCE AND QUALITY CONTROL 
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion. An individualized quality management plan 
will be developed to describe a site’s quality management. 
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical 
trial is conducted and data are generated and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Council for Harmonisation 
Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory 
Practices (GLP), Good Manufacturing Practices (GMP)).  
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
13.3 CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial. The study leadership in conjunction with the NIH has established policies and 
procedures for all study group members to disclose all conflicts of interest and will establish a 
mechanism for the management of all reported dualities of interest. 
13.4 CONFIDENTIALITY AND PRIVACY 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. Therefore, 
the study protocol, documentation, data, and all other information generated will be held in strict 

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confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical 
study site will permit access to such records. 
The study participant’s contact information will be securely stored at the/each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored at the NCI CCR. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems used 
by the clinical site(s) and by NCI CCR research staff will be secured and password protected. At 
the end of the study, all study databases will be archived at the NIH. 
To further protect the privacy of study participants, a Certificate of Confidentiality has been issued 
by the National Institutes of Health (NIH). This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any civil, 
criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local 
level. By protecting researchers and institutions from being compelled to disclose information that 
would identify research participants, Certificates of Confidentiality help achieve the research 
objectives and promote participation in studies by helping assure confidentiality and privacy to 
participants. 
14 PHARMACEUTICAL INFORMATION 
14.1 MINNELIDE – IND # 155631 
14.1.1 Source/Acquisition and Accountability  
14.1.1.1 Supplier  
Minneamrita Therapeutics, LLC, 17939 Cachet Isle Drive, Tampa, FL 33647 
Aizant Drug Research Solutions Pvt. Ltd. (“Aizant”) manufactures and packages Minnelide ™ 
Capsules under cGMP for clinical trial material (CTM).  
14.1.1.2 Receipt of Minnelide ™ Supplies. 
Minnelide ™ will be received by the pharmacy department. The pharmacy department should 
review and confirm receipt of the IMP is as per the paperwork received with the drug. Pharmacy 
must ensure that ordering and delivery records for the IMP are retained in the Pharmacy Site File. 
Drug accountability will be recorded on a study-specific IMP accountability log. Shipments of 
IMP received at pharmacy will be logged on the accountability log, which will be kept in the 

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Pharmacy Site File.  
14.1.1.3 Minnelide ™ Accountability 
The Investigator or a delegated individual (e.g. pharmacist), must ensure that the study drug is 
dispensed in accordance with hospital standard operating procedures and applicable regulatory 
requirements. Full drug accountability records must be maintained for Minnelide ™.  
The Minnelide ™ provided for this study is for use only as directed in the study protocol. IMP 
related documentation will be provided to the site in a pharmacy pack. It is the Investigator’s 
responsibility to establish a system for handling the IMP to endure that: 
• 
Deliveries of IMPs by Minneamrita Therapeutics LLP are correctly received by a 
responsible person (e.g. pharmacist or suitable pharmacy designee) and are handled and 
stored correctly and safely. 
• 
Minnelide ™ is dispensed only to study participants, and in accordance with the 
protocol 
• 
A dispensing record (which will include the identification of the participant to whom 
the IMP was dispensed, the date of dispensing, the quantity of IMP dispensed, and the 
date and quantity of any unused IMP returned to pharmacy) is accurately maintained. 
Any discrepancies must be accounted for on the appropriate form.  
In the case that any study drug is damaged, the NCI CCR coordinating team must be contacted for 
reconciliation and replacement.  
14.1.1.4 Dispensing of Minnelide ™ 
Minnelide ™ will be dispensed by the pharmacy in accordance with a trial-specific prescription. 
A prescription template will be provided in the pharmacy file, although site will be permitted to 
use their own clinical trial template prescription if suitable. Prior approval of the final prescription 
template by Minneamrita Therapeutics is required. Minnelide ™ will be dispensed on the day of 
administration i.e. days 1-21 of each cycle.  
14.1.1.5 Return or Destruction of IMP 
At study termination or at the request of Minneamrita Therapeutics any quantities of IMP that have 
expired or remain unused must be destroyed according to the site’s local standard operating 
procedures and only following permission by OSRO.  OSRO will seek approval from Minneamrita 
Therapeutics, as required, per the study agreement. Minneamrita Therapeutics will not carry out 
IMP destruction. Certificates of destruction must be provided by the site and copies must be 
retained in the Pharmacy Site File.  
14.1.2 Toxicity 
Results from nonclinical pharmacological, pharmacokinetic, and toxicological studies evaluating 
Minnelide ™ given intravenously or orally support the rationale for evaluation of Minnelide ™ in 
cancer participants. Plasma concentrations of Minnelide ™ and triptolide associated with key 
responses and exposure margins calculated against these key responses which reflect toxicological 
findings considered relevant or possibly relevant to human risk.  
In definitive 28-day repeat dose toxicity studies, a no-observed adverse-effect level (NOAEL) for 
Minnelide ™ in female dogs was identified to be 0.05 mg/kg/day and considered the highest non-

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severely toxic dose (HNSTD); the NOAEL for Minnelide ™ in rats or male dogs could not be 
determined. Target organ toxicities indicated reproductive organ accumulation. 
In humans, 42 participants with advanced GI tumors were given Minnelide ™ intravenously in a 
phase 1 open-label dose-escalation safety, pharmacokinetic and pharmacodynamic study. Doses 
were given daily for 21 days followed by 7 days off or each day for 5 days with two days off for 
three weeks followed by a 7 day rest period. The primary reason for the discontinuation of 
treatment was disease progression. There were 6 deaths in the study, but these occurred after the 
study drug had ended and were within the 30-day follow-up period. The deaths that occurred 
during the study were found to be not related to the study drug, and were found to be related to 
progression of the participant’s disease (pancreatic/gastric cancer). There was one participant who 
died from respiratory failure, and this was also found to be not related to use of the study drug. 
There were 3 participant who discontinued the study drug due to a treatment emergent adverse 
events (TEAEs). All instances were considered Grade 3, and two of these TEAEs were considered 
to be probably related to use of the study drug. These two cases were also considered (DLTs). 
These events included:  cerebellar toxicity, embolism, and cerebellar dysfunction.  A total of 28 
Serious Adverse Events occurred in 17 participants and six were found to be related to the study 
drug.   
Overall, the most commonly reported TEAE (> 20%) regardless of causality included: 
hypoalbuminaemia, 
anemia, 
hypoproteinemia, 
fatigue, 
neutropenia, 
leukopenia, 
thrombocytopenia, nausea, hypocalcemia, diarrhea, hyperphosphatemia, constipation, vomiting, 
hyponatremia, lymphopenia, abdominal pain, dehydration, hyperglycemia, peripheral edema, 
hypophosphatemia, and headache. 
32 participants had at least 1 AE that was considered related to the study drug. Adverse events of 
neutropenia grade 3 and 4 of short durations have been observed at all dose levels and were 
determined to be drug related. The neutropenia resolved within a couple of days of not receiving 
treatment. Neutropenic fever and neutropenic infection were observed in three participants and 
determined to be drug related. Anemia and thrombocytopenia grade 3 and 4 were observed in 22% 
of the participants and determined to be drug related. Other side effects of any grade that were 
possibly related to the drug included nausea, vomiting, diarrhea, constipation, anorexia, stomatitis, 
cerebellar toxicity, embolism and dyspnea, which occurred in ≤ 3% of the participants. 
In an ongoing phase 1 multi-center, open-label, dose-escalation, safety, pharmacokinetic and 
pharmacodynamic study of Minnelide ™ capsules were given alone or in combination with 
Protein-Bound Paclitaxel to participants with Advanced Solid Tumors. This study is still ongoing. 
To date, there have been a total of 67 participants enrolled and dosed in the Phase 1 study, 43 in 
the monotherapy regimen, and 24 in the combination regimen. The primary reason for 
discontinuation of treatment has been disease progression. There have been 6 deaths on the study, 
5 of which were assessed as not related to Minnelide  and were after discontinuation of the study 
drug. One participant on the 1.25mg monotherapy regimen passed away from G5 related sepsis. 
One participant on the combination regimen at 0.25mg of Minnelide TM  plus protein bound 
paclitaxel passed away from G5 sepsis, which after investigation and review of pharmacokinetic 
data, was found to be unrelated to Minnelide TM. There have been 6 participants that have 
discontinued the study drug due to a treatment emergent adverse event (TEAE). Four instances 
were considered Grade 5, one was Grade 3, one was Grade 2. Only one of these TEAE’s were 
considered to be probably related to use of the study drug three possibly related (Two Grade 5 

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sepsis, one Grade 3 hypokalemia, one Grade 2 neutrophil count decrease), and the other two not 
related (Grade 5 disease progression). A total of 56 Serious Adverse Events have occurred in 33 
patients and 11 were found to be related to the investigational product. The 11 related SAE’s, two 
grade five sepsis, a grade four sepsis, a grade three nausea, a grade three polymicrobial bacteremia, 
a grade three intractable nausea, a grade three hypokalemia event, a grade three worsening 
leukocytosis, a grade three blood infection, and a grade two enteritis were on the monotherapy 
regimen. A grade five sepsis and a grade two esophagitis were on the combination therapy 
regimen..  
Overall, the most commonly reported TEAE (> 20%) regardless of grade or causality have 
included: anemia, abdominal pain, anorexia, vomiting, diarrhea, nausea, fatigue, hypokalemia, and 
hypoalbuminemia. 43 participants had at least 1 AE that was considered definitely, probably, or 
possibly related to the study drug.  
Grade 3 Adverse Events: Abdominal Pain 10%, Anemia 15%, Alkaline Phosphatase Increased 
4%, Dehydration 3%, Diarrhea 6%, Hypoalbuminemia 6%, Hypokalemia 10%, Hyponatremia 6%, 
Nausea 3%, Neutrophil Counts Decreased 13%, Thrombocytopenia 3%, Urinary Tract Infection 
3%, Vomiting 3%, Weight decreased 3%, White Blood Cell Count Decreased 3%. 
Grade 4 Adverse Events: Leukopenia 3%, Neutropenia 7%, Sepsis 3%. 
Grade 5 Adverse Event: Sepsis Disease Progression 9%. 
14.1.3 Formulation and Preparation  
The oral dosage form of product, Minnelide ™ Capsules, is Minnelide TM drug substance blended 
with excipients, filled in hard gelatin capsules.  
Compendial grade excipients include Avicel PH101 (filler: microcrystalline cellulose, MCC), 
Colloidal silicon dioxide (glidant: Aerosil 200), magnesium oxide DC (diluent: granular) and 
magnesium stearate (lubricant). Minnelide ™ API powder (<1 wt %) is blended with the excipients 
(>99 wt % total). The bulk powder blend is filled in capsules: 
• Size 2 White/White opaque capsules are filled with 150 mg blended powder that contains  
0.50 mg Minnelide ™ free acid. 
Aizant Drug Research Solutions Pvt. Ltd. (“Aizant”) manufactures and packages Minnelide ™ 
Capsules under cGMP for clinical trial material (CTM).  
14.1.4 Stability and Storage  
The finished product is stored at Controlled Cold Temperature (2–8° C, excursions permitted  
0–15° C). Participants will be provided cooler bags to transport medication home and instructed 
to store the medication in their refrigerator at home. 
14.1.5 Administration Procedures 
The oral dosage form of product, Minnelide ™ Capsules, is Minnelide TM drug substance blended 
with excipients, filled in hard gelatin capsules.  
Minnelide ™ Capsules for this study are white, opaque, hard gelatin size 2 capsules containing 
0.5mg free acid Minnelide TM for oral administration.  

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C21H25O10P·2Na (disodium salt) 
C21H27PO10 (free acid) 
 
14.1.7.3 Mechanism of Action 
Minnelide ™ is a prodrug that was designed to rapidly release the antitumor molecule, triptolide, 
through the action of phosphatases in the bloodstream.  Triptolide is a diterpenoid triepoxide found 
in the Chinese plant Tripterygium wilfordii, which has widely been used as a natural medicine in 
China for hundreds of years, particularly in the treatment of autoimmune and inflammatory 
diseases. Triptolide has been shown to inhibit proliferation and induce apoptosis in tumor cell lines 
in vitro and in animal models of cancer. However, triptolide has undesirable physicochemical 
properties that limit its usage as a therapeutic product and Minnelide ™ was designed to overcome 
these issues.  Based on current evidence Minnelide is believed to act as an antisuperenhancer 
through its interaction with the transcription factor TFIIH with evidence that this interaction down 
regulates Myc.  
 
 

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17 APPENDICES 
17.1 APPENDIX A: PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 

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to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated. Death 
not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 

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Participant’s Signature: ___________________________________  Date: ____________________ 
Staff Signature: _______________________________________Date: ____________________