Clinical trial NCT02936323
Conditions: Neuroendocrine Tumors Carcinoma, Small Cell Lung Neuroendocrine Carcinoma
Keywords: SCLC small cell lung cancer pancreatic neuroendocrine NET GI neuroendocrine NET
Sponsor: Tarveda Therapeutics
Start date: 2016-12-08; Completion date: 2021-02-25
Enrollment: 89 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Protocol PEN-221-001 is an open-label, multicenter Phase 1/2a study evaluating PEN-221 in patients with SSTR2 expressing advanced gastroenteropancreatic (GEP) or lung or thymus or other neuroendocrine tumors or small cell lung cancer or large cell neuroendocrine carcinoma of the lung.

Detailed description:
Protocol PEN-221-001 will first enroll patients into a dose escalation phase, where a Bayesian logistic regression model, guided by the escalation with overdose control principle and overseen by a safety review committee, will be used to make dose recommendations and estimate the maximum tolerated dose (MTD).

Once the MTD has been confirmed, remaining patients will be enrolled into a full expansion phase to assess PEN-221 efficacy in patients with gastrointestinal mid-gut neuroendocrine tumors or pancreatic neuroendocrine tumors or small cell lung cancer.

Arms: arm 1: Cohort 1 will consist of two (2) participants who will receive PEN-221 at the starting dose of 1.0 mg. The first participant will be followed for at least 7 days for safety and dose limiting toxicity (DLT). If PEN-221 is tolerated, the second participant will be enrolled into the cohort. The two (2) participants will be followed for safety and DLTs for at least a 4-week observation period. The Safety Review Committee (SRC) will determine the initiation of cohort 2.

Cohort 2 and each subsequent dose escalation cohort will consist of 3 to 6 participants who will be treated at each dose level of PEN-221 as determined by the SRC and will be followed for safety and DLTs for at least a 3-week observation period. Each dose escalation level and cohort initiation will be determined by the SRC.

Dose escalation will continue until the Maximum Tolerated Dose (MTD) of PEN-221 is determined and the Recommended Phase 2a Dose (RP2D) is established by the SRC. arm 2: Gastrointestinal mid-gut NET Cohort arm 3: Pancreatic NET Cohort arm 4: Small Cell Lung Cancer Cohort
Interventions: intervention 1: PEN-221 intervention 2: PEN-221
Intervention descriptions: intervention 1: PEN-221 administered IV over 1 hour on an every 3-week cycle (21 days +/- 2 days) starting dose of 1 mg with each subsequent cohort increased starting dose level until MTD is reached. intervention 2: PEN-221 administered IV over 1 hour on an every 3-week cycle (21 days +/- 2 days) starting dose at recommended Phase 2a dose established in Phase 1.

Protocol documents:
Prot_000.pdf: 
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Protocol PEN-221-001 
 
Version 8.0, 12 July 2019 
 
 
PEN-221 
 
PROTOCOL PEN-221-001 
 
A Phase 1/2a, open-label multicenter study to assess the 
safety, tolerability, pharmacokinetics, and preliminary 
antitumor activity of PEN-221 in patients with 
somatostatin receptor 2 expressing advanced cancers, 
including gastroenteropancreatic or lung or thymus or 
other neuroendocrine tumors or small cell lung cancer or 
large cell neuroendocrine carcinoma of the lung 
 
Protocol Version, Date: 
Version 8.0, 12 July 2019 
Includes Amendment 1, Amendment 2, Amendment 3, 
Amendment 4, Amendment 5, Amendment 6, and 
Amendment 7 
EudraCT Number 
2016-001468-12 
NCT number 
NCT02936323 
Table of Contents Link 
Sponsor: 
Tarveda Therapeutics, Inc. 
134 Coolidge Avenue 
Watertown, MA 02472 
 
USA 
Telephone: +1 (617) 923 4100 


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INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator Brochure for PEN-221. I have read Protocol PEN-
221-001 and agree to conduct the study as outlined. I agree to maintain the confidentiality of all 
information received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 






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Protocol PEN-221-001 
 
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1. 
SYNOPSIS  
 
Name of Sponsor/Company: 
Tarveda Therapeutics, Inc. 
Name of Investigational Product: 
PEN-221 
Name of Active Ingredient: 
PEN-221 
Title of Study: 
A Phase 1/2a, open-label multicenter study to assess the safety, tolerability, pharmacokinetics, and 
preliminary antitumor activity of PEN-221 in patients with somatostatin receptor 2 expressing 
advanced cancers, including gastroenteropancreatic or lung or thymus or other neuroendocrine 
tumors or small cell lung cancer or large cell neuroendocrine carcinoma of the lung 
Phase of development: 
1/2a 
Study Design: 
PEN-221 is a peptide-drug conjugate combining a somatostatin analog and mertansine (DM1), a 
thiol-containing maytansinoid, using a cleavable disulfide linker. The molecule is designed as a 
potent and selective anti-cancer agent to treat patients whose tumors express the somatostatin receptor 
SSTR2, namely, neuroendocrine tumors (NETs), small cell lung cancer (SCLC) and large cell 
neuroendocrine carcinoma (LCNEC) of the lung. In preclinical studies, PEN-221 demonstrated potent 
anti-tumor activity in multiple cancer models that express SSTR2. 
Protocol PEN-221-001 is an open-label, multi-center, first-in-human Phase 1/2a study evaluating 
PEN-221 in patients with SSTR2 expressing advanced gastroenteropancreatic (GEP) or lung or 
thymus or other NETs or SCLC or LCNEC of the lung. 
Pre-screening phase 
After provision of written informed consent for pre-screening, patients will have their cancers 
assessed for SSTR2 expression using an approved somatostatin analog radioisotope imaging (SARI) 
agent. 
Patients who have undergone recent SARI, i.e., within the preceding approximately 6 months, by 
Octreoscan or 68Ga-DOTATATE, 68Ga-DOTATOC, or 68Ga-DOTANOC, may have the results 
reviewed by the study Investigator for determination of tumor SSTR2 positivity in lieu of undergoing 
repeat imaging during the Pre-screening phase. Patients whose tumors are determined to be positive 
for SSTR2 expression by SARI are eligible to proceed to the Screening phase of the study. 
Screening phase 
After provision of written informed consent for the study, patients whose tumors were determined to 
be SSTR2 positive during the Pre-screening phase will proceed to the Screening phase of the study. 
Screening assessments include a careful review of the patient’s medical history, assessment of Eastern 
Cooperative Oncology Group (ECOG) performance status (PS), physical examination, neurological 
examination, electrocardiogram (ECG) and laboratory assessments, and computed tomography (CT) 
or magnetic resonance imaging (MRI) of all sites of disease. 
Screening assessments are to be performed within 14 days before the first study drug dose, with the 
exception of CT or MRI studies which may be performed within 28 days before the first study drug 
dose. 
Patients who are determined to be eligible based on Screening assessments will be enrolled in the 
study on Cycle 1 Day 1 (C1D1; baseline). 


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Treatment phase (Phase 1 and Phase 2a) 
Phase 1 will enroll patients with SSTR2 expressing advanced gastroenteropancreatic (GEP) or lung or 
thymus or other NETs or SCLC or LCNEC of the lung who have provided informed consent for the 
main study. 
Phase 2a will enroll patients with advanced or metastatic, well differentiated, low or intermediate 
grade gastrointestinal mid-gut NET, or with advanced or metastatic, well differentiated, low- 
intermediate grade pancreatic NET or  with advanced or metastatic SCLC. 
The safety, pharmacokinetics (PK), pharmacodynamics (PDc) and anti-tumor activity of PEN-221 
will be assessed. Safety will be assessed during the study by vital sign measurements, physical 
examinations, neurological examinations, ECOG PS, documentation of adverse events (AEs), clinical 
laboratory tests, and ECGs. 
Serial blood samples for pharmacokinetic (PK) and pharmacodynamic (PDc) assessments will be 
collected from all patients. 
Tumor response assessments will be performed using Response Evaluation Criteria in Solid Tumors 
(RECIST), version 1.1 (Eisenhauer 2009). Patients with advanced NETs will undergo tumor 
assessments every third cycle, and patients with advanced SCLC or LCNEC of the lung will undergo 
tumor assessments every other cycle. For patients who have a tumor (complete or partial RECIST) 
response, a repeat evaluation to confirm response will be performed approximately 6 weeks (but not 
less than 4 weeks) after the initial response. 
Patients may continue to receive PEN-221 as long as they are considered to show clinical benefit, as 
judged by the Investigator, and in the absence of discontinuation criteria. 
Phase 1 (Dose escalation) 
Phase 1 will employ an adaptive Bayesian logistic regression model (BLRM) with 2 parameters 
guided by the escalation with overdose control (EWOC) principle to make dose recommendations and 
estimate the maximum tolerated dose (MTD). 
To minimize the number of patients treated at potentially subtherapeutic dose levels, the first dose 
cohort will enroll 2 patients, whereas subsequent cohorts will enroll a minimum of 3 and up to 6 
patients. The initial patient in Cohort 1 will receive PEN-221 administered intravenously (IV) over 1 
hour at the starting dose of 1.0 mg on an every 3 week cycle. This patient will be followed for 7 days, 
including assessments during the scheduled visit on C1D8, prior to allowing additional patients to 
begin treatment with PEN-221. If PEN-221 is tolerated by the initial patient for at least 7 days, then 
the first cohort will be opened to treatment of 1 additional patient. The first 2 patients will be assessed 
for safety and dose limiting toxicity (DLT) for at least 4 weeks (including C2D1 and C2D8 
assessments) before enrollment in the second cohort may begin. 
In each dose escalation cohort following the first cohort, a minimum of 3 patients within a cohort are 
required to have completed C1 and have been assessed for safety and DLT for at least 3 weeks 
(including C2D1 pre-dose assessments) before enrollment of the next cohort may begin. 
The Safety Review Committee (SRC) will review the safety and tolerability of PEN-221 of each 
cohort to decide the next dose level to be tested. Statistical modeling will be performed using all 
safety data and will guide the SRC’s selection of dose levels to be tested. In addition, PK and PDc 
data may be used to inform dose selection. Dose escalation increments will be the decision of the 
SRC. Dose escalation will continue until the MTD is determined. 
During Phase 1, if a patient is tolerating PEN-221 without significant evidence of disease progression, 
the patient may, beginning with C3 or subsequent cycles, have the dose increased to a dose that has 
already been established as tolerable by the SRC, and with the agreement of the SRC. 
Phase 2a 
Phase 2a may begin, at the discretion of the Sponsor, once all patients treated in Phase 1 have been 
assessed for safety through and including C2D1, and the SRC has reviewed all safety data and 
recommends continuing with Phase 2a. 






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Phase 2a 
Approximately 75 patients will be enrolled as follows: gastrointestinal mid-gut NET (n=35, 25 
PRRT-naïve, 10  PRRT recurrent), pancreatic NET (n=20), SCLC (n=20). These cohort sample sizes 
are considered sufficient to obtain an early assessment of efficacy of PEN-221 in patients with 
distinct tumor types.  
 
Diagnosis and main criteria for inclusion: 
All patients must meet all of the following criteria to be eligible to participate: 
1. Provision and understanding of signed and dated, written informed consent prior to any 
mandatory study-specific procedures, sampling, analysis. 
2. Male or female aged ≥ 18 years. 
3. ECOG PS of 0 – 1. 
4. Adequate organ function within 14 days before C1D1, defined as follows: 
• 
Bone marrow: Absolute neutrophil count (ANC) ≥ 1.5×109/L, platelet count ≥ 
100×109/L, and hemoglobin ≥ 9 g/dl 
• 
Hepatic: total bilirubin ≤ 1.5× the upper limit of normal (ULN) and alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5× ULN 
• 
Renal: If serum creatinine concentration ≥ 1.5× ULN, then estimated creatinine 
clearance must be ≥ 50 mL/min (Cockroft-Gault formula). 
5. Serum potassium, calcium, magnesium and phosphorus within normal limits. If values 
are low on the initial screening assessment, supplements may be given and values 
repeated to confirm within normal limits. 
6. If a female of childbearing potential, negative serum pregnancy test within 3 days before 
C1D1, or in the event of a positive serum pregnancy test, exclusion of pregnancy as 
assessed by transvaginal ultrasound overseen by a health care professional with 
experience in investigating and diagnosing early pregnancy, as human chorionic 
gonadotropin (HCG) can be secreted by neuroendocrine tumor. A female of childbearing 
potential must agree to the use of highly reliable, physician-approved contraception from 
14 days before C1D1 through 3 months after the last study drug dose. Highly reliable 
contraception means 2 of the following: (1) established use of oral, injected, or implanted 
hormonal methods of contraception, (2) placement of an intrauterine device, (3) condom 
or occlusive cap (diaphragm or cervical vault cap with spermicidal gel, foam, film, 
cream, or vaginal suppository), (4) male sterilization with verified absence of sperm in 
ejaculate post-vasectomy. Alternatively, true abstinence is acceptable when it is the 
preferred and usual lifestyle of the individual. Calendar, symptothermal, post-ovulation, 
coitus interruptus, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. 
7. If male, is surgically sterile or agrees to use a condom from C1D1 through 3 months after 
the last study drug dose. Alternatively, true abstinence is acceptable when it is the 
preferred and usual lifestyle of the individual. 
8. SSTR2 positive tumor as assessed using a SARI agent and as defined as follows: 
• 
For SCLC patients, tumor uptake equal to or greater than liver uptake 
• 
For all other patients, tumor uptake greater than liver uptake.  
SARI performed during the Pre-screening phase must be an agent that is 
approved for use by the regional regulatory authority. Documented results of 
SARI performed as part of a patient’s routine diagnostic assessments prior to the 


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Pre-screening phase and within 180 days of C1D1 may be used in place of a Pre-
screening phase SARI assessment. 
9. Patients in Phase 1 must have a histologically- or cytologically-confirmed solid tumor in 
1 of the following categories: 
• 
Advanced SCLC or LCNEC of the lung having progressed after 1 or more prior 
lines of anticancer chemotherapy, or 
• 
Advanced low or intermediate grade GEP or lung or thymus NET, or NET of 
unknown primary, having progressed after 1 or more prior lines of anticancer 
therapy, unless no standard treatments are available or unless such treatments are 
deemed not appropriate, or 
• 
Advanced paraganglioma, pheochromocytoma, medullary thyroid carcinoma, 
Merkel cell carcinoma, or high grade extrapulmonary NEC, having progressed 
after 1 or more prior lines of anticancer therapy, unless no standard treatments 
are available or unless such treatments are deemed not appropriate. 
Anticancer therapies include liver-directed intra-arterial therapy, cytotoxic chemotherapy, 
everolimus, targeted inhibitors, metaiodobenzylguanidine (MIBG), and immunotherapies, but 
do not include somatostatin analogs. 
For patients who provide written informed consent to undergo an optional tumor biopsy during the 
Screening phase, such patients must meet the following additional criterion before undergoing a 
biopsy procedure: 
10. Patient must have at least 1 site of tumor that is accessible to biopsy and that is 
considered by the Investigator to be low risk and of sufficient size to undergo a biopsy 
procedure. 
Patients in Phase 2a must meet the following additional criteria: 
11. Measurable disease per RECIST 1.1 (i.e., at least 1 measurable lesion ≥ 20 mm by 
conventional techniques or ≥ 10 mm by spiral CT scan or MRI), with the last imaging 
performed within 28 days before C1D1 and documented radiographic disease 
progression. 
12. Patients in Phase 2a must have a histologically- or cytologically-confirmed, advanced or 
metastatic solid tumor, in 1 of the following categories: 
• 
Well differentiated, low or intermediate grade, gastrointestinal mid-gut (arising from 
the lower jejunum, ileum, appendix, cecum, and proximal colon) NET with 
documented disease progression within 6 months prior to start of study treatment (i.e. 
maximum of 24 weeks from documentation of progression until study entry) and 
evidence of radiographic disease progression based on scans performed not more 
than 15 months apart. Patients may have received 1 or more prior lines of anticancer 
therapy, such as somatostatin analogues, targeted agents, or liver-directed intra-
arterial therapy, but are NOT eligible if they have received prior systemic cytotoxic 
chemotherapy. 
• 
Well differentiated, low or intermediate, grade, pancreatic NET with documented 
disease progression within 6 months prior to start of study treatment (i.e. maximum 
of 24 weeks from documentation of progression until study entry), and evidence of 
radiographic disease progression based on scans performed not more than 15 months 
apart. Patients may have received 1 or more prior lines of anticancer therapy, such as 
somatostatin analogues, targeted agents, or liver-directed intra-arterial therapy, and 
up to 1 prior line of systemic cytotoxic chemotherapy, but are NOT eligible if they 
have received more than 1 prior line of systemic cytotoxic chemotherapy or if they 
have received prior peptide receptor radionuclide therapy (PRRT).  
• 
SCLC after having received up to three prior lines of anticancer therapy.  


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Patients meeting any of the following criteria are not eligible for study participation: 
1. Treatment with anticancer therapy (as defined in inclusion criterion 9 and 12) or an 
investigational drug or device within 3 weeks (6 weeks for mitomycin C and 
nitrosoureas) or 5 half-lives of the agent (whichever is shorter) before C1D1. In addition, 
any drug-related toxicity, with the exception of alopecia, must have recovered to ≤ Grade 
1. 
2. Any other malignancy known to be active or treated within 3 years of the start of 
screening, with the exception of treated cervical intra-epithelial neoplasia, superficial 
(non-invasive) bladder cancer, and non-melanoma skin cancer. 
3. One or more of the following cardiac criteria: 
• 
Unstable angina 
• 
Myocardial infarction within 6 months prior to screening 
• 
New York Heart Association Class II – IV heart failure 
• 
Corrected QT interval (QTc) > 470 msec obtained as the mean from 3 consecutive 
resting ECGs using the Fredericia formula 
• 
Clinically important abnormalities in rhythm, conduction, or morphology of resting 
ECG (e.g., complete left bundle branch block, third degree heart block) 
• 
Congenital long QT syndrome 
• 
Symptomatic orthostatic hypotension within 6 months prior to screening 
• 
Uncontrolled hypertension. 
4. Stroke or transient ischemic attack within 6 month prior to screening. 
5. Grade >1 peripheral neuropathy. 
6. Patient requires medication with a strong CYP3A4 inhibitor, e.g., ketoconazole, 
itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, 
saquinavir, telithromycin, and voriconazole. 
7. History of leptomeningeal disease or spinal cord compression. 
8. Brain metastases unless asymptomatic  on a stable low dose of steroids. 
• 
Patients with SCLC or LCNEC of the lung only: CT or MRI of the brain required 
during screening. If positive for brain metastases, patients must have undergone 
radiotherapy prior to initiating treatment with PEN-221. If whole brain radiotherapy 
is performed, a 14-day washout is required prior to treatment with PEN-221. If 
stereotactic radiosurgery or stereotactic radiotherapy is performed, a 7-day washout 
prior to treatment with PEN-221 is required. 
9. Major surgery within 28 days prior to C1D1. 
10. Female who is pregnant or breast-feeding. 
11. As judged by Investigator, evidence of severe or uncontrolled systemic disease, active 
bleeding diatheses, renal or liver transplant, or active infection including known hepatitis 
B, hepatitis C, or human immunodeficiency virus (HIV). 
12. Hypersensitivity or history of anaphylactic reaction to octreotide or other somatostatin 
analogs. 
13. Hypersensitivity or history of anaphylactic reaction to maytansinoids or their derivatives. 
14. Any medical, psychological, or social condition that would interfere with the patient’s 
participation in the study. 
Investigational product, dosage and mode of administration: 
PEN-221 Concentrate for Solution for Injection/Infusion is a 
 solution containing PEN-221, a 
DM1-peptide drug conjugate with affinity for the human SSTR2 receptor, 
 




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• 
The Full Analysis Set (Intention to Treat or ITT) set comprises all patients enrolled in the study 
who receive any amount of study drug. 
• 
The Safety Analysis set comprises all patients who receive any amount of study drug and have at 
least 1 post-baseline safety evaluation. 
• 
The efficacy analysis (EA) set comprises all patients who receive any amount of study drug and 
have at least 1 post-baseline efficacy assessment. 
• 
The Dose Determining set comprises all patients who receive any amount of study drug and either 
experienced a DLT or have been followed for the full DLT evaluation period. 
• 
The Pharmacokinetic Analysis set comprises all patients who receive any amount of study drug 
and provide adequate PK samples. Patients with major protocol violations will be assessed on a 
patient-by- patient basis for inclusion in the PK Analysis set. 
Phase 1  
It is estimated that 30 patients will be enrolled in Phase 1 Part A including at least 10 patients treated 
at MTD level. The actual number of patients will depend on the number of dose levels/cohorts that 
are tested. 
An adaptive BLR model guided by the escalation with overdose control (EWOC) principle (Babb 
1998; Neuenschwander 2008) will be employed to make dose recommendations and estimate the 
MTD. The MTD will be further evaluated for anti-tumor activity and overall tolerability during Phase 
2a. 
The MTD is defined as the highest dose for a given schedule that is not expected by the BLRM to 
cause DLTs in more than 33% of patients during the first cycle of treatment. The dose-toxicity (DLT) 
relationship will be described by a Bayesian 2-parameter logistic regression model. A vague bivariate 
normal prior for the model parameters will be used based on prior guesses (medians) from preclinical 
data and wide confidence intervals for the probabilities of a DLT at each dose. 
Dose recommendation 
After each cohort of patients has completed C1, the posterior distributions for the probabilities of 
DLT rates at different dose levels will be obtained and summarized in terms of the estimated 
probabilities that the true rate of DLT at each dose-level will have of lying in each of the following 
intervals: 
• 
[0, 0.16) under-dosing   
• 
[0.16, 0.33) targeted toxicity   
• 
[0.33, 1.00] excessive toxicity.   
Following the principle of EWOC, after each cohort of patients the recommended dose will be the 
one with the highest posterior probability of the DLT rate falling in the target interval [16%, 33%) 
among the doses fulfilling EWOC, i.e., it is unlikely (<25% posterior probability) that the DLT rate at 
the dose falls in the excessive toxicity interval. 
The recommended dose for the next cohort via this algorithm will not represent more than a doubling 
of the current dose. 
 
Phase 2a 
During Phase 2a, approximately 75 patients will be enrolled in the following cohorts: gastrointestinal 
mid-gut NET (n=35), pancreatic NET (n=20), and SCLC (n=20). Each of these cohorts will be 
enrolled in 2 stages, with approximately 10 patients enrolled per cohort in Stage 1, and  the remaining 
patients enrolled in Stage 2. Preliminary efficacy and safety will be assessed in approximately the first 
10 patients per cohort before deciding whether to proceed to the second stage of each cohort.  
If one or more DLTs are observed at any time up until 6 patients across any of the three cohorts have 
been treated for at least 1 cycle in Phase 2a, the BLRM will be run to re-evaluate the MTD. The SRC 
will convene to determine whether it is safe to proceed with dosing at the RP2D or whether an 
alternative lower dose is to be considered for subsequent patients. If an alternative lower dose is 


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selected, the SRC will reconvene after at least 6 patients have been treated at this new dose to review 
the data and confirm that subsequent patients be enrolled into the study at this new dose. 
In addition, at any time during Phase 2a, the BLRM may be re-run to confirm the estimated MTD and 
verify that the dose under study still satisfies the overdose criterion. If the dose fails to satisfy the 
criterion a change to the dose under study may be decided by the SRC, according to the Bayesian 
model recommendation, and after review of the clinical data. The SRC decision to change dose may 
also be spurred by other safety and tolerability considerations (e.g. frequency of lower grade AEs or 
events in later treatment cycles). Subsequent patients may then be enrolled at this new dose until at 
least 6 patients are treated at this new dose level and upon SRC review of the data the SRC will 
decide whether the new dose level is appropriate for continued study. 
After Phase 2a, the final recommended dose for future development will be based on considerations 
of the MTD estimated by the BLRM, and on an overall clinical assessment of all available safety, 
tolerability, PK, and PDc data from all cycles at all different dose levels tested, in both phases of the 
study. 
In the gastrointestinal mid-gut NET or PNET group, a CBR of approximately 75% or greater would 
be considered promising. For a group of 20 patients, if the observed proportion is 0.75 (clinical 
benefit observed in 15 out of 20 patients), there is 90.4% probability that the true underlying 
proportion exceeds 0.6, and 63.7% probability that the true underlying proportion exceeds 0.7. If the 
true underlying proportion is 0.75, there is 1.4% probability to observe a CBR of 50% or less.For a 
group of 35 patients, if the observed proportion is 0.74 (clinical benefit observed in 26 out of 35 
patients), there is 95.5% probability that the true underlying proportion exceeds 0.6, and 67.5% 
probability that the true underlying proportion exceeds 0.7. If the true underlying proportion is 0.75, 
there is 0.1% probability to observe a CBR of 50% or less. 
For the SCLC cohort, a response rate of 30% or greater would be considered promising. For a group 
of 20 patients, if the observed proportion is 0.3, there is 99.7% probability that the true underlying 
proportion exceeds 0.1, and 55% probability that the true underlying proportion exceeds 0.3. If the 
true underlying proportion is 0.3, there is 0.1% probability to observe 0 responses. 
 
Sample size calculations 
Based on the performance characteristics computed and described in the previous section, the sample 
sizes are adequate to address the study’s objectives. No formal statistical power calculations to 
determine sample size were performed. 
General statistical considerations 
As a general strategy, data will be analyzed by dose level for patients in Phase 1 and by cohort and 
dose group for patients in Phase 2a. 
Demographic and baseline characteristics will be summarized using data from all patients in the Full 
Analysis (ITT) set by cohort and/or dose group. Treatment exposure, including duration on treatment 
and extent of exposure to study drug, will be summarized by cohort and/or dose group. 
Safety analysis will include summaries by cohort and/or dose group of: AEs, laboratory measures, 
physical examinations, neurological examinations, ECG, and vital signs using data from patients in 
the Safety Analysis set. 
The incidence of DLTs will be summarized using data from the Dose Determining set. 
PK endpoints, including peak concentration, trough plasma concentration and area under the plasma 
concentration curve, will be tabulated for all patients in the PK Analysis set. 
Objective response rate and CBR will be reported with category counts, percentage and 95% 
confidence interval. Duration of response (DOR), progression-free survival (PFS) and overall survival 
(OS) will be evaluated using Kaplan-Meier estimates and curves will be generated based on these 
estimates. Primary efficacy analyses will be based on data from all patients in the efficacy analysis 
(EA) population. 


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Table 2: 
Schedule of Events-  Phase 1 
 
Evaluation/Procedure 
Treatment Period / Cycle / Day (Visit Window) 
Protocol 
Section 
Pre-
screening 
Screening 
C1 and C3 
C2, C4, and 
subsequent cycles 
EOT26 
Safety 
Follow-
Up 
(LDSD 
+28d) 
Pro-
gression 
Follow-
Up1 
D −180 to 
−1 
D −14 to 
−1 
D1 
D82 
D152 
D1 
D82 
D152 
Window 
– 
– 
– 
±2d 
±2d 
– 
±2d 
±2d 
±3d 
±3d 
±7d 
Baseline assessments 
  
  
  
  
  
  
  
  
  
  
  
  
Written informed consent 
X 
X 
  
  
  
  
  
  
  
  
  
7.2 
Approved SSTR tumor imaging 
X3 
  
  
  
  
  
  
  
  
  
  
9.2 
Height 
  
X 
  
  
  
  
  
  
  
  
  
9.3.3 
Medical history and demographics 
 
X  
  
  
  
  
  
  
  
  
  
9.1.1 
9.1.2 
Cancer diagnosis and history, including 
all prior systemic and radiation 
therapies and surgeries 
 
X  
  
  
  
  
  
  
  
  
  
9.1.2 
Review of entrance criteria 
 
X 
  
  
  
  
  
  
  
  
  
7.3, 7.4 
Safety Evaluations 
  
  
  
  
  
  
  
  
  
  
  
 
Physical examination: 
  
  
  
  
  
  
  
  
  
  
  
9.3.1 
 Complete 
  
X 
X4 
  
  
X 
  
  
X 
X 
  
9.3.1 
 Neurological 
  
X 
X4 
  
  
X 
  
  
X 
X 
  
9.3.1 
 Targeted (i.e., symptom-directed) 
  
  
  
X2 
X2 
  
X2 
X2 
  
  
  
9.3.1 
Vital signs5 
  
X 
X 
  
  
X 
  
  
X 
X 
  
9.3.2 
Weight 
  
X 
X 
  
  
X 
  
  
X 
X 
  
9.3.3 
Electrocardiogram6 
  
X 
X 
  
  
X 
  
  
X 
  
  
9.3.4 
ECOG performance status 
  
X 
X4 
  
  
X 
  
  
X 
X 
  
9.3.6 
Adverse events 
Adverse events (AEs) are to be documented from first consent through safety follow-up.  
 
9.3.7 
Concomitant medications 
All medications/procedures are to be documented from 30 days before first study drug dose on 
C1D1 through safety follow-up. 
 
9.3.8 
Safety Evaluations (Continued) 
  
  
  
  
  
  
  
  
  
  
  
  


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Protocol PEN-221-001 
 
Version 8.0, 12 July 2019 
Evaluation/Procedure 
Treatment Period / Cycle / Day (Visit Window) 
Protocol 
Section 
Pre-
screening 
Screening 
C1 and C3 
C2, C4, and 
subsequent cycles 
EOT26 
Safety 
Follow-
Up 
(LDSD 
+28d) 
Pro-
gression 
Follow-
Up1 
D −180 to 
−1 
D −14 to 
−1 
D1 
D82 
D152 
D1 
D82 
D152 
Window 
– 
– 
– 
±2d 
±2d 
– 
±2d 
±2d 
±3d 
±3d 
±7d 
Clinical laboratory tests: 
  
  
  
  
  
  
  
  
  
  
  
 
 Hematology7 
  
X 
X4 
X2 
X2 
X 
X2 
X2 
X 
X 
  
9.3.5.1  
 Clinical chemistries8 
  
X 
X4,9 
X2 
X2 
X9 
X2 
X2 
X 
X 
  
9.3.5.1 
 Estimated creatinine clearance 
  
X 
X 
  
  
X 
  
  
  
X 
  
9.3.5.1 
 Coagulation studies10 
  
X 
X4 
  
  
X 
  
  
  
X 
  
9.3.5.3  
 Urinalysis11 
  
X 
X4 
  
  
X  
  
  
X 
X 
  
9.3.5.2  
 Thyroid function12 
  
X 
 X4,13 
  
  
X13 
  
  
X 
  
  
9.3.5.1  
 Cholesterol and triglycerides (fasted) 
  
X 
X4,13 
  
  
X13 
  
  
X 
  
  
9.3.5.1 
 Cortisol 
 
 
X14 
 
 
X14 
 
 
 
 
 
9.3.5.1 
Peripheral blood anti-drug antibodies 
  
X 
X4,15 
  
  
X15 
  
  
X 
  
  
9.3.5.4  
Pregnancy testing16 
 X 
X 
X4 
  
  
X 
  
  
  
  
  
9.3.5.5  
Disease Activity Measurements 
  
  
  
  
  
  
  
  
  
  
  
 
Radiographic tumor assessments17 
  
X18 
 X19 
  
  
X19 
  
  
  
  
X1 
9.6  
Archival tumor sample 
  
X 
  
  
  
  
  
  
  
  
  
9.5.5  
Optional tumor biopsy23 
  
X23 
  
  
  
  
  
  
  
  
  
9.5.6  
Study Drug Administration 
  
  
  
  
  
  
  
  
  
  
  
  
PEN-221 drug administration 
  
  
X 
  
  
X 
  
  
  
  
  
8.6  
Pharmacokinetics 
  
  
  
  
  
  
  
  
  
  
  
  
Blood sample collection for PK 
  
  
X25 
  
  
  
  
  
  
  
  
9.4  
Survival 
 
 
 
 
 
 
 
 
 
 
X1 
5.1.4.3 


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Protocol PEN-221-001 
 
Version 8.0, 12 July 2019 
LDSD = Last Dose of Study Drug 
Note: PEN-221 dosing of each cycle should begin within 21±2 days of D1 of previous cycle unless PEN-221 is withheld for safety reasons. Visit windows may 
be lengthened for administrative reasons (e.g., holiday) after consultation with the Medical Monitor. 
1. If a patient discontinues treatment prior to objective disease progression, then the patient should continue to be followed until objective disease progression 
as defined by RECIST 1.1. For SCLC or LCNEC of the lung patients, approximately every 6 weeks from prior scan, or as clinically indicated. For all other 
patients, approximately every 9 weeks from prior scan, or as clinically indicated. After disease progression, patients should be followed approximately every 
3 months for survival. 
2. D8 and D15 evaluations are required for C1, C2, and for the first two cycles starting with a dose escalation . If no Grade 2 or higher abnormalities in clinical 
chemistries or hematology parameters during Cycles 1 and 2, or in the two cycles starting with a dose escalation (Section 8.11.1), then the D8 and D15 
evaluations may be eliminated in subsequent cycles, subject to Investigator discretion. If Grade 2 or higher abnormalities in clinical chemistries or 
hematology parameters are observed, the D8 and D15 evaluations are required for 2 additional cycles. If Grade 2 or higher abnormalities do not recur during 
the subsequent 2 cycles, the D8 and D15 evaluations may be eliminated in cycles thereafter, subject to Investigator discretion. 
3. Historical scans up to 180 d prior to C1D1 are permitted. 
4. If screening evaluation is done within 3 d before C1D1, it need not be repeated on C1D1. 
5. For any patients on concomitant beta blockers, blood pressure should be monitored carefully and doses of these medications should be adjusted if needed, as 
somatostatin analogs have been associated with bradycardia. 
6. Triplicate ECGs are to be collected approximately 5 minutes apart. On C1D1 and C3D1, ECGs are to be performed immediately prior to the start of study 
drug infusion, at 30 minutes after the start of the infusion, precisely at the end of infusion, and at all scheduled PK timepoints thereafter; the date and time of 
each ECG start and stop are to be documented. On all other dosing days, ECGs should be performed prior to infusion and at end of infusion. 
7. Hematology parameters include hemoglobin, red blood cell (RBC) count, platelet count, and white blood cell (WBC) count with differential. Samples may 
be collected up to 48 hours prior to scheduled clinic visits. On study drug administration days, results must be available and reviewed before study drug 
administration and must continue to qualify patients as defined in the study eligibility (inclusion/exclusion) criteria. 
8. Clinical chemistries include chloride, bicarbonate, sodium, potassium, calcium, magnesium, phosphorus, blood urea nitrogen, creatinine, glucose, total 
protein, albumin, alkaline phosphatase (ALP), AST, ALT, total and direct bilirubin, amylase, and lipase. Samples may be collected up to 48 hours prior to 
scheduled clinic visits. On study drug administration days, results must be reviewed by the Investigator prior to study drug administration and must continue 
to qualify patients as defined in the study eligibility (inclusion/exclusion) criteria. 
9. On C1D1, glucose will be monitored along with PK samples: pre-dose, at 0.5 hours (±5 minutes) after the start of study drug infusion; precisely at the end of 
infusion  (±1 minute); and 1.5 hours (±10 minutes), 2 hours (±10 minutes), 4 hours (±10 minutes), 6 hours (±10 minutes), 8 hours (±30 minutes), and 10 
hours (±60 minutes) after the start of study drug infusion. If the 10 hour time point requires an inpatient admission at the center, the 10 hour time point will 
not be collected. If the patient experiences symptomatic hypoglycemia or hyperglycemia, or if any glucose level falls below 55 mg/dL (or below 3.0 
mmol/L) or above 250 mg/dL (or above 13.9 mmol/L) at any timepoint on C1D1, this intense sampling will be repeated (regardless of whether PK samples 
are collected) on D1 of each subsequent cycle until the above criteria are no longer met throughout an entire treatment day.  
For any patients on concomitant anti-hyperglycemic medications, glucose should be monitored carefully and doses of these medications should be adjusted 
if needed, as somatostatin analogs have been associated with changes in blood glucose levels and regulation. 
10. Coagulation studies include prothrombin time (PT)  and activated partial thromboplastin time (aPTT).  For patients on Coumadin or warfarin only, international 
normalized ratio should also be included. 
11. Urinalysis includes specific gravity, pH, blood, glucose, protein, ketones, and microscopic examination of sediment. 
12. Thyroid function to be monitored as free T4 and thyroid-stimulating hormone (TSH). 




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Page 19 of 132 
Protocol PEN-221-001 
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Table 3: 
 
Schedule of Events Phase 2a  
Evaluation/Procedure 
Treatment Period / Cycle / Day (Visit Window) 
Protocol 
Section 
Pre-screening 
Screening 
C1  
C2 and subsequent 
cycles 
EOT26 
Safety 
Follow-Up 
LDSD+28d 
Pro-
gression 
Follow-
Up1 
D −180 to −1 
D −14 to −1 
D1   
D2 
D82 
D152 
D1 
D82 
D152 
Window 
– 
– 
– 
– 
±2d 
±2d 
– 
±2d 
±2d 
±3d 
±3d 
±7d 
Baseline assessments 
  
  
  
 
  
  
  
  
  
  
  
  
  
Written informed consent 
X 
X 
  
 
  
  
  
  
  
  
  
  
7.2 
Approved SSTR tumor imaging 
X3 
  
  
 
  
  
  
  
  
  
  
  
9.2 
Height 
  
X 
  
 
  
  
  
  
  
  
  
  
9.3.3 
Medical history and demographics 
 
X  
  
 
  
  
  
  
  
  
  
  
9.1.1 
9.1.2 
Cancer diagnosis and history, including all 
prior systemic and radiation therapies and 
surgeries 
 
X  
  
 
  
  
  
  
  
  
  
  
9.1.2 
Review of entrance criteria 
 
X 
  
 
  
  
  
  
  
  
  
  
7.3, 7.4 
Safety Evaluations 
  
  
  
 
  
  
  
  
  
  
  
  
 
Physical examination: 
  
  
  
 
  
  
  
  
  
  
  
  
9.3.1 
 Complete 
  
X 
X4 
 
  
  
X27 
  
  
X 
X 
  
9.3.1 
 Neurological 
  
X 
X4 
 
  
  
X27 
  
  
X 
X 
  
9.3.1 
 Targeted (i.e., symptom-directed) 
  
  
  
 
X2 
X2 
  
X2 
X2 
  
  
  
9.3.1 
Vital signs5 
  
X 
X 
 
 
  
X 
  
  
X 
X 
  
9.3.2 
Weight 
  
X 
X 
 
 
  
X27 
  
  
X 
X 
  
9.3.3 
Electrocardiogram6 
  
X 
X 
 
 
  
X 
  
  
X 
  
  
9.3.4 
ECOG performance status 
  
X 
X4 
 
  
  
X27 
  
  
X 
X 
  
9.3.6 
Adverse events 
 
Adverse events (AEs) are to be documented from first consent through safety follow-up.  
 
9.3.7 
Concomitant medications 
 
All medications/procedures are to be documented from 30 days before first study drug dose on 
C1D1 through safety follow-up. 
 
9.3.8 
Clinical laboratory tests: 
  
  
  
 
  
  
  
  
  
  
  
  
 
 Hematology7 
  
X 
X4 
 
X2 
X2 
X 
X2 
X2 
X 
X 
  
9.3.5.1  
 Clinical chemistries8 
  
X 
X4,9 
 
X2 
X2 
X9 
X2 
X2 
X 
X 
  
9.3.5.1 
 Estimated creatinine clearance 
  
X 
X 
 
  
  
X27 
  
  
  
X 
  
9.3.5.1 


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Protocol PEN-221-001 
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Evaluation/Procedure 
Treatment Period / Cycle / Day (Visit Window) 
Protocol 
Section 
Pre-screening 
Screening 
C1 
C2 and subsequent 
cycles 
EOT26
Safety 
Follow-Up 
LDSD+28d 
Pro-
gression 
Follow-
Up1 
D −180 to −1 
D −14 to −1 
D1  
D2 
D82 
D152 
D1
D82
D152 
Window 
– 
– 
– 
–
±2d
±2d 
– 
±2d 
±2d 
±3d 
±3d 
±7d 
Clinical laboratory tests continued: 
 Coagulation studies10 
X 
X4 
X27 
X 
9.3.5.3 
 Urinalysis11 
X 
X4 
X27 
X 
X 
9.3.5.2 
 Thyroid function12 
X 
 X4,13 
X13, 27 
X 
9.3.5.1 
 Cholesterol and triglycerides (fasted) 
X 
X4,13 
X13, 27 
X 
9.3.5.1 
 Cortisol 
X14 
X14 
9.3.5.1 
Peripheral blood anti-drug antibodies 
X 
X15,27 
X 
9.3.5.4 
Pregnancy testing16 
 X 
X 
X4 
X27 
9.3.5.5 
Disease Activity Measurements 
Radiographic tumor assessments17 
X18 
X19 
X1 
9.6 
Archival tumor sample 
X 
9.5.5 
Optional tumor biopsy23 
X23 
9.5.6 
Study Drug Administration 
PEN-221 drug administration 
X 
- 
X 
8.6 
Pharmacokinetics 
Blood sample collection for PK 
X25 
X25 
X25 
9.4 
Survival Status 
X1 
 5.1.4.3 
LDSD = Last Dose of Study Drug 
Note: PEN-221 dosing of each cycle should begin within 21±2 days of D1 of previous cycle unless PEN-221 is withheld for safety reasons. Visit windows may be lengthened for 
administrative reasons (e.g., holiday) after consultation with the Medical Monitor. 
1.
If a patient discontinues treatment prior to objective disease progression, then the patient should continue to be followed until objective disease
progression as defined by RECIST 1.1. For SCLC, approximately every 6 weeks from prior scan, or as clinically indicated. For all other patients, 
approximately every 9 weeks from prior scan, or as clinically indicated. After disease progression, patients should be followed approximately every 3 
months for survival. 


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Protocol PEN-221-001 
 Version 8.0, 12 July 2019 
2. D8 and D15 evaluations are required for C1. If no Grade 2 or higher abnormalities in clinical chemistries or hematology parameters are observed during 
C1, then D8 and D15 evaluations are not required for C2 and subsequent cycles. If Grade 2 or higher abnormalities in clinical chemistries or hematology 
parameters (excluding hyperglycemia in diabetic patients) are observed during C1, the D8 and D15 evaluations are required for C2 and C3. If Grade 2 
or higher abnormalities do not recur during C2 and C3, the D8 and D15 evaluations may be eliminated in cycles thereafter, subject to Investigator 
discretion. If Grade 2 or higher abnormalities occur after C3, evaluations may be performed at a schedule determined by the Investigator, based on the 
patient’s clinical status. 
3. Historical scans up to 180 d prior to C1D1 are permitted. 
4. If screening evaluation is done within 3 d before C1D1, it need not be repeated on C1D1. 
5. For any patients on concomitant beta blockers, blood pressure should be monitored carefully and doses of these medications should be adjusted if 
needed, as somatostatin analogs have been associated with bradycardia. 
6. Triplicate ECGs are to be collected approximately 5 minutes apart. On C1D1 ECGs are to be performed immediately prior to the start of study drug 
infusion, at 30 minutes after the start of the infusion (±5 minutes), at the end of infusion (±5 minutes), and at all scheduled PK timepoints thereafter on 
C1D1; the date and time of each ECG start and stop are to be documented. On all other dosing days, ECGs should be performed prior to infusion and at 
end of infusion (±5 minutes). When multiple study assessments are scheduled at the same time, ECGs should be performed after the PK blood draw and 
glucose monitoring. 
7. Hematology parameters include hemoglobin, red blood cell (RBC) count, platelet count, and white blood cell (WBC) count with differential. Samples 
may be collected up to 48 hours prior to scheduled clinic visits. On study drug administration days, results must be available and reviewed before study 
drug administration and must continue to qualify patients as defined in the study eligibility (inclusion/exclusion) criteria. 
8. Clinical chemistries include chloride, bicarbonate, sodium, potassium, calcium, magnesium, phosphorus, blood urea nitrogen, creatinine, glucose, total 
protein, albumin, alkaline phosphatase (ALP), AST, ALT, total and direct bilirubin, amylase, and lipase. Samples may be collected up to 48 hours prior 
to scheduled clinic visits. On study drug administration days, results must be reviewed by the Investigator prior to study drug administration and must 
continue to qualify patients as defined in the study eligibility (inclusion/exclusion) criteria.  
9. On C1D1, glucose will be monitored pre-dose and at the end of infusion (±3 minute); and 2 hours (±10 minutes), 4 hours (±10 minutes), 6 hours (±10 
minutes), and 8 hours (±30 minutes) after the start of study drug infusion. When multiple study assessments are scheduled at the same time, glucose 
monitoring should be done after PK blood draws and prior to ECGs. If the patient experiences symptomatic hypoglycemia or hyperglycemia, or if any 
glucose level falls below 55 mg/dL (or below 3.0 mmol/L) or above 250 mg/dL (or above 13.9 mmol/L) at any timepoint on C1D1 additional 
monitoring may be required per Investigator discretion. For any patients on concomitant anti-hyperglycemic medications, glucose should be monitored 
carefully and doses of these medications should be adjusted if needed, as somatostatin analogs have been associated with changes in blood glucose 
levels and regulation. 
10. Coagulation studies include prothrombin time (PT) and activated partial thromboplastin time (aPTT). For patients on Coumadin or warfarin only 
international normalized ratio should also be included. 
11. Urinalysis includes specific gravity, pH, blood, glucose, protein, ketones, and microscopic examination of sediment. 
12. Thyroid function to be monitored as free T4 and thyroid-stimulating hormone (TSH). 
13. Every third cycle beginning with C3 (C3, C6, C9, etc.). 
14. C1D1 and C2D1 only, to be collected in the morning pre-dose. 
15. Every odd cycle only beginning on C3. 
16. Pregnancy testing, either urine or serum, is required only for females of childbearing potential. Pregnancy testing is to be repeated on-study any time 
pregnancy is suspected. If pregnancy test is positive, pregnancy should be assessed by transvaginal ultrasound overseen by a health care professional 
with experience in investigating and diagnosing early pregnancy. 




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Protocol PEN-221-001 
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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
INVESTIGATOR’S AGREEMENT ...............................................................................................2 
SIGNATURE PAGE .......................................................................................................................3 
PROCEDURES IN CASE OF EMERGENCY ...............................................................................4 
1. 
SYNOPSIS ...................................................................................................................5 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............23 
3. 
LIST OF ABBREVIATIONS.....................................................................................32 
4. 
INTRODUCTION ......................................................................................................36 
4.1. 
Investigational Agent ..................................................................................................36 
4.2. 
Neuroendocrine Tumors .............................................................................................36 
4.3. 
Small Cell Lung Cancer and Large Cell Neuroendocrine Carcinoma of the 
Lung ............................................................................................................................38 
4.4. 
Somatostatin Receptor Expression in Cancers of Neuroendocrine Origin .................39 
4.5. 
Rationale for the Study ...............................................................................................40 
4.6. 
Nonclinical Pharmacology Studies .............................................................................40 
4.7. 
Nonclinical Pharmacokinetics and Drug Metabolism ................................................41 
4.8. 
Nonclinical Toxicology Studies .................................................................................41 
5. 
INVESTIGATIONAL PLAN .....................................................................................47 
5.1. 
Overall Study Design ..................................................................................................47 
5.1.1. 
Pre-screening ..............................................................................................................47 
5.1.2. 
Screening ....................................................................................................................48 
5.1.3. 
Main Study..................................................................................................................48 
5.1.3.1. 
Treatment Period ........................................................................................................48 
5.1.3.2. 
End of Treatment ........................................................................................................49 
5.1.4. 
Follow-up Period ........................................................................................................49 
5.1.4.1. 
Safety Follow-Up ........................................................................................................49 
5.1.4.2. 
Progression Follow-Up ...............................................................................................49 
5.1.4.3. 
Survival Follow-Up ....................................................................................................49 
5.1.5. 
Starting dose ...............................................................................................................49 
5.1.6. 
Phase 1 (Dose escalation) ...........................................................................................50 


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Protocol PEN-221-001 
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5.1.7. 
Phase 2a ......................................................................................................................52 
5.2. 
Justification for the Study Design ...............................................................................53 
5.3. 
Criteria for Study Termination ...................................................................................53 
5.4. 
Benefit/Risk Assessment ............................................................................................54 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................56 
6.1. 
Phase 1 ........................................................................................................................56 
6.1.1. 
Primary Objective .......................................................................................................56 
6.1.2. 
Secondary Objectives .................................................................................................56 
6.1.3. 
Exploratory Objectives ...............................................................................................56 
6.2. 
Phase 2a ......................................................................................................................57 
6.2.1. 
Primary Objective .......................................................................................................57 
6.2.2. 
Secondary Objectives .................................................................................................57 
6.2.3. 
Exploratory Objectives ...............................................................................................57 
7. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................59 
7.1. 
Number of Patients .....................................................................................................59 
7.1.1. 
Phase 1 ........................................................................................................................59 
7.1.2. 
Phase 2a ......................................................................................................................59 
7.2. 
Consent .......................................................................................................................59 
7.3. 
Patient Inclusion Criteria ............................................................................................59 
7.4. 
Patient Exclusion Criteria ...........................................................................................61 
7.5. 
Patient Restrictions During Treatment .......................................................................63 
7.6. 
Source of Patients .......................................................................................................63 
7.7. 
Patient Identification and Enrollment .........................................................................63 
7.8. 
Patient Withdrawal Criteria ........................................................................................64 
7.9. 
Withdrawal of Consent for Use of Donated Samples .................................................64 
7.10. 
Incorrectly Enrolled Patients ......................................................................................65 
7.11. 
Safety Review Committee ..........................................................................................65 
7.12. 
Investigator Compliance .............................................................................................66 
7.13. 
Patient Adherence to Protocol Schedule.....................................................................66 
8. 
TREATMENT OF PATIENTS ..................................................................................67 
8.1. 
Study Drug Supply .....................................................................................................67 
8.2. 
Study Drug Packaging and Labeling ..........................................................................67 
8.3. 
Study Drug Storage .....................................................................................................67 


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Protocol PEN-221-001 
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8.4. 
Study Drug Accountability .........................................................................................67 
8.5. 
Study Drug Dose Preparation .....................................................................................68 
8.6. 
Study Drug Administration.........................................................................................68 
8.6.1. 
Phase 1 ........................................................................................................................68 
8.6.1.1. 
Starting Dose and Dose Escalation Levels .................................................................68 
8.6.1.2. 
Dose Escalation Process (Phase 1) .............................................................................68 
8.6.1.3. 
Dose Selection Process ...............................................................................................69 
8.6.2. 
Phase 2a ......................................................................................................................70 
8.7. 
Definition of Dose-Limiting Toxicity ........................................................................70 
8.8. 
Definition and Estimation of Maximum Tolerated Dose ...........................................71 
8.9. 
Definition of Evaluable Patient ..................................................................................71 
8.10. 
Definition of Recommended Phase 2 Dose ................................................................71 
8.11. 
Dose Modifications .....................................................................................................71 
8.11.1. 
Intra-patient Dose Escalation ......................................................................................72 
8.11.2. 
Dose Modifications for Hematological Toxicities .....................................................72 
8.11.3. 
Dose modification for Non-hematologic Toxicities ...................................................73 
8.11.3.1. 
Hepatic Toxicity .........................................................................................................73 
8.11.3.2. 
Gastrointestinal Effects ...............................................................................................74 
8.11.3.2.1. Nausea and Vomiting .................................................................................................74 
8.11.3.2.2. Constipation ................................................................................................................74 
8.11.3.2.3. Diarrhea ......................................................................................................................74 
8.11.3.3. 
Peripheral Neuropathy ................................................................................................75 
8.11.3.4. 
QTc Prolongation ........................................................................................................75 
8.11.3.5. 
Infusion-related Reactions, Hypersensitivity Reactions .............................................75 
8.11.3.6. 
Other Non-hematologic Toxicities .............................................................................75 
8.12. 
Concomitant Medications ...........................................................................................75 
8.12.1. 
Prohibited Medications ...............................................................................................76 
8.12.2. 
Medications to be Used with Caution .........................................................................76 
8.12.3. 
Permitted Medications ................................................................................................77 
9. 
ASSESSMENT OF PATIENTS .................................................................................78 
9.1. 
Demographics and Medical History ...........................................................................78 
9.1.1. 
Demographics .............................................................................................................78 
9.1.2. 
Medical History, Including Cancer History ................................................................78 


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Protocol PEN-221-001 
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9.2. 
Somatostatin Analog Radioisotope Imaging ..............................................................78 
9.2.1. 
Indium-labeled SARI ..................................................................................................78 
9.2.2. 
Gallium-labeled SARI ................................................................................................80 
9.3. 
Safety Assessments .....................................................................................................80 
9.3.1. 
Physical Examination .................................................................................................80 
9.3.2. 
Vital Signs ..................................................................................................................81 
9.3.3. 
Weight and Height ......................................................................................................82 
9.3.4. 
Electrocardiogram .......................................................................................................82 
9.3.5. 
Laboratory Assessments .............................................................................................82 
9.3.5.1. 
Hematology and Clinical Chemistries ........................................................................82 
9.3.5.2. 
Urinalysis ....................................................................................................................83 
9.3.5.3. 
Coagulation Studies ....................................................................................................84 
9.3.5.4. 
Peripheral Blood Anti-drug Antibodies ......................................................................84 
9.3.5.5. 
Pregnancy Testing ......................................................................................................84 
9.3.6. 
ECOG Performance Status .........................................................................................85 
9.3.7. 
Adverse Events ...........................................................................................................85 
9.3.8. 
Concomitant Medications ...........................................................................................85 
9.3.9. 
Evaluation of Safety Information Collected at Each Visit .........................................86 
9.4. 
Pharmacokinetic Assessments ....................................................................................86 
9.5. 
Biomarker and Pharmacodynamic Assessments ........................................................86 
9.5.1. 
Rationale for Biomarker and Pharmacodynamic Assessments ..................................86 
 
 
 
 
 
 
9.5.5. 
Archival Tumor Sample .............................................................................................88 
9.5.6. 
Optional Tumor Biopsy ..............................................................................................88 
 
 
 
 
9.6. 
Efficacy Assessments .................................................................................................89 
10. 
ADVERSE EVENT DEFINITIONS, RECORDING, AND REPORTING ..............92 
10.1. 
Definition of Adverse Events .....................................................................................92 
10.1.1. 
Adverse Events ...........................................................................................................92 
10.1.2. 
Unexpected Adverse Event .........................................................................................92 


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10.1.3. 
Serious Adverse Event ................................................................................................92 
10.2. 
Adverse Event Assessment .........................................................................................93 
10.2.1. 
Intensity ......................................................................................................................93 
10.2.2. 
Relationship to Study Drug ........................................................................................93 
10.2.2.1. 
Adverse Events Based on Signs and Symptoms.........................................................93 
10.2.2.2. 
Adverse Events Based on Examinations and Tests ....................................................94 
10.2.2.3. 
Hy’s Law ....................................................................................................................94 
10.2.2.4. 
Disease Progression ....................................................................................................95 
10.2.2.5. 
New Cancers ...............................................................................................................95 
10.2.2.6. 
Deaths .........................................................................................................................95 
10.3. 
Recording Adverse Events .........................................................................................95 
10.3.1. 
Time Period for Collection of Adverse Events ...........................................................96 
10.3.2. 
Follow-Up of Unresolved Adverse Events .................................................................96 
10.3.3. 
Variables .....................................................................................................................96 
10.3.4. 
Reporting Serious Adverse Events .............................................................................97 
10.4. 
Pregnancy ...................................................................................................................97 
10.5. 
Overdose .....................................................................................................................98 
10.6. 
Protocol Deviations ....................................................................................................98 
11. 
DATA REVIEW AND MANAGEMENT .................................................................99 
11.1. 
Study Monitoring ........................................................................................................99 
11.2. 
Case Report Form Completion ...................................................................................99 
11.3. 
Computerized Systems / Medical Records as Source Data ......................................100 
12. 
STATISTICAL METHODS AND DATA ANALYSIS ..........................................101 
12.1. 
General Statistical Considerations ............................................................................101 
12.2. 
Populations for Analysis ...........................................................................................101 
12.3. 
Patient Disposition ....................................................................................................101 
12.4. 
Demographics and Baseline Characteristics .............................................................102 
12.5. 
Treatments and Concomitant Medications ...............................................................102 
12.6. 
Primary Objective .....................................................................................................102 
12.6.1. 
Phase 1 ......................................................................................................................103 
12.6.1.1. 
Definition of MTD and the Primary Variable ..........................................................103 
12.6.1.2. 
Statistical Hypothesis, Model, and Method of Analysis ...........................................103 
12.6.1.3. 
Prior Specification ....................................................................................................103 


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12.6.1.4. 
Dose Recommendation .............................................................................................104 
12.6.1.5. 
Stopping Rules ..........................................................................................................105 
12.6.2. 
Phase 2a ....................................................................................................................105 
12.6.2.1. 
Clinical Benefit Rate for gastrointestinal mid-gut NET and pancreatic NET ..........105 
12.6.2.2. 
Objective Response Rate for SCLC .........................................................................106 
12.6.2.3. 
Duration of Response for SCLC ...............................................................................106 
12.7. 
Secondary Objectives ...............................................................................................106 
12.7.1. 
Safety Analysis .........................................................................................................106 
12.7.1.1. 
Adverse Events .........................................................................................................106 
12.7.1.2. 
Laboratory Anomalies ..............................................................................................107 
12.7.1.3. 
Vital Signs, ECG, and Other Safety Data .................................................................107 
12.7.1.4. 
Tolerability ...............................................................................................................107 
12.7.2. 
Pharmacokinetic Analysis ........................................................................................107 
12.7.3. 
Efficacy Analysis ......................................................................................................108 
12.7.3.1. 
Progression-free Survival .........................................................................................108 
12.7.3.2. 
Overall Survival ........................................................................................................108 
12.7.3.3. 
Objective Response Rate for gastrointestinal mid-gut NET and pancreatic 
NET ...........................................................................................................................108 
12.7.3.4. 
Duration of Response for gastrointestinal mid-gut NET and pancreatic NET .........109 
12.8. 
Interim Analyses .......................................................................................................109 
12.9. 
Sample Size Calculation ...........................................................................................109 
12.9.1. 
Phase 1 ......................................................................................................................109 
12.9.2. 
Phase 2a ....................................................................................................................109 
12.9.3. 
Primary Analysis Cutoff ...........................................................................................112 
12.10. 
Replacement of Patients ...........................................................................................112 
12.11. 
Changes to the Planned Statistical Methods .............................................................112 
13. 
ETHICS ....................................................................................................................113 
13.1. 
Good Clinical Practice Compliance..........................................................................113 
13.2. 
Institutional Review Board or Ethics Committee .....................................................113 
13.3. 
Ethical Conduct of the Study ....................................................................................113 
13.4. 
Written Informed Consent ........................................................................................114 
13.5. 
Patient Confidentiality ..............................................................................................114 
14. 
ADMINISTRATIVE REQUIREMENTS ................................................................115 


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14.1. 
Retention of Records ................................................................................................115 
14.2. 
Audits and Inspections ..............................................................................................115 
14.3. 
Publication Policy .....................................................................................................115 
15. 
APPENDIX: PRIOR CALIBRATION AND OPERATING 
CHARACTERISTIS OF THE BAYESIAN LOGISTIC REGRESSION 
MODEL ....................................................................................................................116 
15.1. 
Introduction ...............................................................................................................116 
15.2. 
Operating Characteristics for Simulation .................................................................116 
15.2.1. 
Dose Levels ..............................................................................................................116 
15.2.2. 
Statistical Model .......................................................................................................116 
15.2.3. 
Prior Specification ....................................................................................................116 
15.2.4. 
Dose Escalation Rules for Simulation ......................................................................120 
15.2.5. 
Hypothetical Dose-Toxicity Relationships for Simulation.......................................120 
15.2.6. 
Simulation Results ....................................................................................................122 
15.3. 
Dose Escalation Scenarios in Early Cohorts ............................................................123 
15.4. 
Dose Recommendation .............................................................................................124 
15.5. 
Discussion .................................................................................................................125 
16. 
LIST OF REFERENCES ..........................................................................................126 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Schedule of Events-  Phase 1 ......................................................................................15 
Table 3: 
 Schedule of Events Phase 2a .....................................................................................19 
Table 4: 
Human Starting Dose Calculation ..............................................................................50 
Table 5: 
HNSTD in Dog for Comparison to Rat STD10 ...........................................................50 
Table 6: 
Planned PEN-221 Dose Levels ...................................................................................51 
Table 7: 
Dose Modifications and Management of Neutropenia, Febrile Neutropenia, 
Infection, Thrombocytopenia, and Anemia ................................................................73 
Table 8: 
Octreoscan SSTR2 Scoring ........................................................................................79 
Table 9: 
Affinity Profiles (Half-maximal Inhibitory Concentrations) for Various 
Somatostatin Analogs .................................................................................................80 
Table 10: Eastern Cooperative Oncology Group Performance Status Scale ..............................85 
Table 11 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Guidelines for 
Tumor Response .........................................................................................................90 
Table 12 
Overall Response Criteria ...........................................................................................91 
Table 13: Prior parameter values for the bivariate normal distribution of the model 
parameters .................................................................................................................103 
Table 14: Prior probability of excessive toxicity (DLT rate > 0.33) ........................................104 
Table 15: Posterior probability of true ORR based on observed number of responses ............111 
Table 16:    Posterior probability of true CBR based on observed number of patients with 
clinical benefit ..........................................................................................................111 
Table 17: Prior parameter values for the bivariate normal distribution of model 
parameters .................................................................................................................117 
Table 18: Prior probability of excessive toxicity (DLT rate > 0.33) ........................................117 
Table 19: Hypothetical DLT rates at each dose under 5 different scenarios for 
simulation .................................................................................................................121 
Table 20: Operating characteristics of the BLRM design. The toxicity of a dose is 
classified by its DLT rate as follows: [0,0.16) under dosing; [0.16, 0.33) 
targeted toxicity; [0.33, 1] excessive toxicity. ..........................................................122 
Table 21:   Probability that each dose is selected as MTD in scenario g ......................................122 
Table 22:   Probability that each dose is selected as MTD in scenario g using a 3+3 design.......123 
Table 23: Possible scenarios up to the 3rd cohort .....................................................................123 


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LIST OF FIGURES 
Figure 1: 
Protocol PEN-221-001 Study Design .........................................................................47 
Figure 2: 
Prior DLT rates and 95% confidence intervals .........................................................104 
Figure 3: 
Prior median DLT rates and 95% confidence intervals at dose levels used for 
simulations ................................................................................................................117 
Figure 4: 
Prior probability of excessive toxicity at each dose and posterior 
probabilities of excessive toxicity upon observing the first DLT in cohort 1, 
2, or 3 ........................................................................................................................118 
Figure 5: 
Hypothetical dose toxicity curves under 5 different scenarios for simulation .........121 
 


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3. 
LIST OF ABBREVIATIONS 
Abbreviation 
Explanation 
 
 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AJCC 
American Joint Committee on Cancer 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC0-t 
Area under the plasma concentration time curve from time 
zero to time of the last measurable concentration 
AUC0-36h 
Area under the concentration time curve from time zero to 
36h 
AUC∞ 
Area under the concentration time curve from time zero to 
infinity 
BLRM 
Bayesian logistic regression model 
BMI 
Body mass index 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
C 
Cycle (as in C1D1 for Cycle 1 Day 1) 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
 
 
CI 
Confidence intervals 
CL 
Clearance 
Cmax 
Maximum plasma concentration 
CR 
Complete response 
CRA 
Clinical research associate 
CSR 
Clinical study report 
CT 
Computed tomography 
 
 
CTCAE 
Common Terminology Criteria for Adverse Events 
D 
Day (as in C1D1 for Cycle 1 Day 1) 
DD 
Dose-determining 


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Abbreviation 
Explanation 
DDS 
Dose-determining set 
DLL3 
Delta-like 3 
DLT 
Dose-limiting toxicity 
DM1 
Mertansine 
DOR 
Duration of Response 
EA 
Efficacy analysis 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
ED 
Extensive disease 
ELISA 
Enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
EOT 
End of treatment 
EWOC 
Escalation with overdose control 
FDA 
Food and Drug Administration 
FFPE 
Formalin-fixed paraffin-embedded 
FOB 
Functional observational battery 
FOCBP 
Females of childbearing potential 
GCP 
Good Clinical Practice 
GEP 
Gastroenteropancreatic 
GI 
Gastrointestinal 
HCG 
Human chorionic gonadotropin 
HIV 
Human immunodeficiency virus 
HNSTD 
Highest non-severely toxic dose 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IHC 
Immunohistochemistry 
IP 
Investigational product 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IV 
Intravenous or intravenously 
LCNEC 
Large cell neuroendocrine carcinoma 


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Abbreviation 
Explanation 
LD 
Longest diameter (when used with RECIST and tumor 
measurements) or limited disease (when used with SCLC 
cancer staging) 
MCC 
Merkel cell carcinoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEN 
Multiple endocrine neoplasia 
MIBG 
Metaiodobenzylguanidine  
MRI 
Magnetic resonance imaging 
MTC 
Medullary thyroid carcinoma 
mTOR 
Mammalian target of rapamycin 
NCCN 
National Cooperative Cancer Network 
NCI 
National Cancer Institute 
NET 
Neuroendocrine tumor 
 
 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PDc 
Pharmacodynamic 
PFS 
Progression-free survival 
PK 
Pharmacokinetic or pharmacokinetics 
PNET 
Pancreatic neuroendocrine tumor 
PP 
Per-protocol 
PR 
Partial response 
PRRT 
Peptide receptor radionuclide therapy 
PS 
Performance status 
PT 
Prothrombin time 
RBC 
Red blood cells 
RECIST 
Response Evaluation Criteria in Solid Tumors v1.1 
(Eisenhauer 2009) 
RET 
Ret proto-oncogene 
RP2D 
Recommended phase 2 dose 
SA 
Safety analysis 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 


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Abbreviation 
Explanation 
SARI 
Somatostatin analog radioisotope imaging 
SCLC 
Small cell lung cancer 
SD 
Stable disease 
SRC 
Safety Review Committee 
SSTR 
Somatostatin receptor 
t½  
Elimination half-life 
TEAE 
Treatment-emergent adverse event 
TGI 
Tumor growth inhibition 
Tmax 
Time to maximum plasma concentration 
TKI 
Tyrosine kinase inhibitor 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
V 
Volume of distribution 
Vss 
Volume of distribution at steady state 
VEGFR 
Vascular endothelial growth factor receptor 
WBC 
White blood cells 
 


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4. 
INTRODUCTION 
4.1. 
Investigational Agent 
PEN-221 is a novel peptide-drug conjugate that is being developed as a targeted anticancer agent 
for the treatment of patients with neuroendocrine tumors or other tumors of neuroendocrine 
origin or small cell lung cancer (SCLC) whose tumors overexpress the somatostatin receptor 2 
(SSTR2). PEN-221 contains a somatostatin analog with high potency and selectivity for SSTR2 
conjugated to DM1 (mertansine), a thiol-containing maytansinoid, using a cleavable disulfide 
linker. The linker is designed to be preferentially cleaved in the reducing environment of the 
tumor, thereby selectively releasing DM1 in tumor cells where it acts by disrupting microtubule 
networks and intracellular trafficking, resulting in apoptosis and mitotic catastrophe (Barok 
2014). Significant antitumor activity has been seen in multiple SSTR2 positive xenograft models. 
Higher levels of anti-tumor activity, including complete regressions, were observed with either 
repeat dosing at a relatively low dose or with a single relatively high dose. These observations 
suggest potential for activity in patients with SSTR2-expressing tumors. 
4.2. 
Neuroendocrine Tumors 
Neuroendocrine tumors (NETs) are a relatively rare, biologically and clinically heterogeneous 
group of malignant neoplasms that arise from neuroendocrine cells throughout the body and are 
most commonly formed in the gastrointestinal (GI) tract, pancreas, or lung. Other less common 
neuroendocrine tumors include those arising in the parathyroid, thyroid, adrenal and pituitary 
glands. These tumors are characterized by their ability to produce peptides that may or may not 
produce symptoms related to oversecretion. They are often associated with characteristic 
symptoms such as flushing and diarrhea. Epidemiological studies indicate that the incidence of 
NET is rising in the US and Europe (NCCN 2016). 
NETs are generally classified by site of origin, histological characteristics, stage, and grade. 
Histological classification is based on tumor differentiation (well or poorly differentiated). NETs 
are staged according to the American Joint Committee on Cancer (AJCC) TNM staging system. 
Tumor grade (Grades 1 – 3) is generally defined by mitotic count and/or Ki-67 index. 
Functioning vs. non-functioning tumors are part of the clinical diagnosis based on whether or not 
tumors are associated with symptoms of hormone hypersecretion. The National Cancer Institute 
(NCI at http://cancer.gov/) separates its detailed information on background, staging, and 
treatment of NETs into 4 main groups: gastrointestinal carcinoids (well-differentiated NETs or 
carcinomas of the gastrointestinal tract); pancreatic NETs; small cell lung cancer (SCLC); and 
typical and atypical lung carcinoid tumors and large cell neuroendocrine carcinoma of the lung 
as types of non-small cell lung cancer. The National Comprehensive Cancer Network (NCCN at 
http://nccn.org) practice guidelines group NETs into 9 distinct tumors: neuroendocrine tumors of 
the GI tract, lung and thymus (carcinoids), pancreatic NETs (PNETs), NETs with an unknown 
primary, adrenal gland tumors, pheochromocytomas and paragangliomas, poorly differentiated 
neuroendocrine carcinoma or large or small cell carcinoma other than lung, multiple endocrine 
neoplasia type 1 (MEN1), MEN type 2 (MEN2), and Merkel cell carcinoma. 
Surgical resection is the only curative treatment and is generally recommended for patients with 
localized disease or those whose primary and metastatic sites that are amenable to a complete 
resection. If the tumor is not resectable, standard of care varies depending on the anatomical site 


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of the primary tumor as well as tumor grade. Somatostatin analogs are prescribed to palliate 
symptoms of functional tumors and to slow tumor growth. Liver-directed therapies such as 
radiofrequency ablation or hepatic regional therapy may be considered for patients with 
unresectable, liver-predominant metastatic disease. In addition, everolimus, interferon alfa-2b, or 
cytotoxic chemotherapy may be indicated for clinically significant progressive disease; sunitinib 
may be an option for PNETs (NCCN 2016). 
Somatostatin analogs are used routinely to control symptoms related to hormone hypersecretion 
in patients with neuroendocrine tumors (Chan 2016). In addition, randomized controlled trials 
have established that somatostatin analogs delay tumor growth in patients with advanced, well-
differentiated or moderately-differentiated enteropancreatic tumors. In the randomized, double-
blind PROMID trial (Rinke 2009), eighty-five patients with locally inoperable or metastatic 
well-differentiated, functioning or nonfunctioning intestinal NETs were randomized to receive 
treatment with either long-acting octreotide (Octreotide LAR) or placebo. There was a 
statistically significant prolongation in time to progression, compared to placebo (median 14.3 
versus 6.0 months). In the randomized, double-blind CLARINET trial (Caplin 2014), 204 
patients with advanced well- or moderately-differentiated, non-functioning, enteropancreatic 
NETs, patients were randomized to receive treatment with either an extended release aqueous-
gel formulation of lanreotide (n=101) or placebo (n=103). Lanreotide, as compared to placebo, 
was associated with significantly prolonged progression-free survival (median not reached vs. 
median 18.0 months). 
Molecularly targeted therapies have been proven to be effective for patients with advanced, low 
or intermediate grade NETs. The mTOR inhibitor everolimus showed a significant improvement 
in progression-free survival in advanced pancreatic (Yao 2011) and advanced gastrointestinal or 
lung NETs (Yao 2016), but was associated with RECIST tumor response rates of only 2 to 5%. 
For patients with advanced pancreatic NET, sunitinib is approved based on the results of a 
randomized Phase 3 study that demonstrated improved progression-free survival compared to 
placebo (Raymond 2011). 
Cytotoxic chemotherapy can lead to objective tumor responses in patients with pancreatic NETs, 
and is recommended for patients with well differentiated NETs who have bulky, rapidly 
progressive disease; however, no prospective clinical trials have observed benefits in progression 
free or overall survival (Kunz 2015). 
The concept of targeting somatostatin receptor with somatostatin analogs linked to an anti-cancer 
payload has been demonstrated in the clinic. Peptide receptor radionuclide therapy (PRRT) 
delivers yttrium-90 or lutetium-177 coupled to DOTATATE, an amide of the acid DOTA, which 
acts as a chelator for a radionuclide, and (Tyr3)-octreotate, a derivative of the somatostatin 
analog octreotide. The latter binds to somatostatin receptors, which are found on the cell surfaces 
of a number of NETs and direct the radioactivity into the tumor. PRRT has resulted in tumor 
response rates of approximately 15 to 35% in patients with advanced GEP NETs in 
nonrandomized studies (van der Zwan 2015). A recent Phase 3 study randomized 230 patients 
with advanced mid-gut NETs to receive 4 doses of 177Lu-DOTATATE (4 × 7.4 GBq every 8 
weeks) plus symptom control treatment with 30 mg long-acting octreotide (Octreotide LAR) 
compared to high dose (60 mg) Octreotide LAR every 4 weeks (Strosberg 2015). There was a 
statistically significant improvement in progression-free survival in the 177Lu-DOTATATE plus 
30 mg Octreotide LAR group; the median PFS was not reached for 177Lu-DOTATATE plus 30 


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mg Octreotide LAR and was 8.4 months with 60 mg Octreotide LAR (hazard ratio 0.21 [95% CI: 
0.13-0.34], p<0.0001) Objective response rates were 19% in the patients randomized to 177Lu-
DOTATATE plus 30 mg Octreotide LAR vs. 3% in patients randomized to 60 mg octreotide 
LAR. 
Pheochromocytomas and paragangliomas are catecholamine-secreting neuroendocrine tumors 
that arise from chromaffin cells of the adrenal medulla (pheochromocytomas) and the extra-
adrenal autonomic paraganglia (paragangliomas). Approximately 10 percent of 
pheochromocytomas, 20 to 25% of extra-adrenal abdominal and mediastinal paragangliomas, 
and 2 to 19% of skull base and neck paragangliomas are metastatic; 5-year survival rates are 
generally less than 50% (Chan 2016; McGranahan 2016). For patients with meta-
iodobenzylguanidine (MIBG)-positive tumors with unresectable, symptomatic progressive 
disease, 131I-MIBG is a first-line treatment approach. For patients with rapidly progressive, 
MIBG-negative disease or disease that is predominantly localized to the skeleton, chemotherapy 
such as combination therapy with cyclophosphamide, vincristine, and dacarbazine is an option. 
Clinical trials of sunitinib in patients with advanced/malignant 
pheochromocytoma/paraganglioma are ongoing (Chan 2016; McGranahan 2016). 
As reviewed by Duprat (2011), Merkel cell carcinomas (MCCs) are very rare but very aggressive 
skin cancers likely arising from cutaneous mechanoreceptor cells (Merkel cells) in the epidermis 
basal layer. They mostly occur as red or bluish nodules, growing on the head, neck, extremities, 
or trunk, and are associated with sun exposure, immunocompromise, and a polyomavirus. 
Disease that is not treatable by resection or local radiotherapy is treated with cisplatin or 
carboplatin, combined with either etoposide or doxorubicin. Response rates as high as 40% have 
been observed, but are rarely sustained. Recurrent disease has been treated with radiation or 
chemotherapy but results have been poor. Nghiem (2016) describe a phase 2 study of 
pembrolizumab (an anti-PD-1 agent) where 56% overall response and 16% complete response 
was observed in 25 evaluable MCC patients. 
Medulary thyroid carcinomas (MTCs) arise from calcitonin-producing C-cells (Hadoux 2016). 
Distant metastases are the main cause of death. Vandetanib, an inhibitor of kinases of the 
vascular endothelial growth factor rectptors (VEGFRs) 2 and 3, Ret proto-oncogene (RET), and 
epidermal growth factor, is approved in both the US and EU for treatment of MTC. A placebo-
controlled phase 3 trial with 331 patients showed significant prolongation of PFS with a 65% 
relative reduction of risk of disease progression, and 44% partial response rate (Wells 2012). (No 
complete responses were observed.) Cabozantinib, an inhibitor of RET, VEGFR2, and 
hepatocyte growth factor receptor, produced partial response in 28% of patients (Elisei 2013). In 
contrast, chemotherapy with single or multiple agents has only yielded response rates of less than 
20% (Hadoux 2016). 
4.3. 
Small Cell Lung Cancer and Large Cell Neuroendocrine Carcinoma 
of the Lung 
SCLC represents 15 – 20% of all lung cancers. Little progress has been made over the last 30 
years in identifying effective new treatments and median overall survival is only about 12 
months (Morabito 2014). The traditional staging system classifies SCLC into 2 stages, according 
to the extent of disease (Mountain 2000). Limited disease (LD), diagnosed in about 1/3 of 
patients, is confined to the hemithorax with regional lymph node metastasis and can be treated 


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within a single field of radiation. Extensive disease (ED), diagnosed in approximately 2/3 of 
patients, extends beyond a single radiation field (National Cancer Institute 2016). 
Patients with LD can be treated with surgery, radiotherapy, or both, and also may be candidates 
for chemotherapy, especially if Ki-67 score is greater than 50% (National Cancer Institute 2016). 
Patients with ED do not typically benefit from resection or radiotherapy; chemotherapy with 
platinum and etoposide is first-line standard of care. Upon relapse, topotecan is approved for 
second-line therapy, and paclitaxel, docetaxel, irinotecan, temozolomide, gemcitabine, or 
ifosfamide may be used for subsequent therapy (National Cancer Institute 2016). A variety of 
agents, including tyrosine kinase inhibitors (TKIs), mammalian target of rapamycin (mTOR) 
inhbitors, and other targeted agents have been tested unsuccessfully as SCLC treatments. DNA 
repair and cellular developmental pathway inhibitors, antibody-drug conjugates, 
immunomodulators, immune checkpoint inhibitors, and anti-SCLC vaccines are in studies 
(Mamdani 2015). Recent testing of an antibody-drug conjugate targeting delta-like 3 (DLL3) has 
shown promise, with a cohort of 29 DLL3+ patients demonstrating 34% partial response and 
31% disease stabilization, and durable response of more than 178 days. 
Large cell neuroendocrine carcinoma (LCNEC) of the lung is a biologically aggressive, high 
grade cancer that accounts for approximately 3% of all lung cancers. Due to the lack of 
controlled clinical trials, there are no standard treatment regimens. Retrospective analyses of 
clinical outcomes in small series of patients with advanced or metastatic disease suggest that 
response rates to platinum based doublet chemotherapy in the first-line, advanced disease setting 
are similar to those achieved in patients with SCLC; overall survival is poor, with median OS 
ranging from 8 to 16 months depending on the study (Fasano 2015). In the second-line or later 
setting, data are sparse; a retrospective analysis of 18 LCNEC of the lung treated with amrubicin 
as a single agent, all of whom were previously treated with platinum based doublet 
chemotherapy, resulted in an objective response rate of 27.7% (Yoshida 2011). 
4.4. 
Somatostatin Receptor Expression in Cancers of Neuroendocrine 
Origin 
Somatostatin is a small cyclic peptide. As described by Hofland (2001), it is widely expressed in 
the body, predominantly in the central nervous system and peripheral tissues. In brain, it can be 
both stimulatory and inhibitory, but in peripheral tissue it mostly inhibits secretion processes. 
Somatostatin acts through binding to five different high-affinity G-protein coupled membrane 
SSTRs. All five receptors are expressed in brain and islets; all but SSTR4 are expressed in the 
pituitary gland. Tumors originating from somatostatin target tissues often express a high density 
of various receptors. 
Overexpression of these receptors on tumors provides a potential target for direct delivery of 
anti-cancer agents. Cancers of neuroendocrine origin including NETs of pancreatic, 
gastrointestinal, lung or other tissue origin, SCLC (Barbieri 2013; O'Byrne 1994; Reubi 2001), 
medullary thyroid cancers, and others (Barbieri 2013; de Herder 2003; Hofland 2001) have often 
been found to overexpress SSTR and are drug development targets for SSTR-drug treatment. 
Reubi (2001) describe expression of SSTRs in both normal and various neoplastic tissues using 
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4.5. 
Rationale for the Study 
As described in Section 4.2 and Section 4.3, treatment options for patients with tumors of 
neuroendocrine origin are limited. New, effective therapies are urgently needed to improve the 
clinical outcome for patients with these cancers. PEN-221 is designed specifically to target tumor 
cells that express SSTR2 such that the delivery of the DM1 payload is directed to the SSTR2 
expressing tumors to drive efficacy, while minimizing the uptake of the conjugate in other 
tissues. A series of nonclinical studies have been performed to evaluate the pharmacology of 
PEN-221 to support and guide its clinical evaluation. 
4.6. 
Nonclinical Pharmacology Studies 
PEN-221 is designed to bind to the somatostatin receptor SSTR2 and be internalized into cancer 
cells overexpressing this receptor to deliver a cytotoxic payload. In vitro radioligand competitive 
binding assays comparing PEN-221 affinity to the 5 somatostatin receptor family members 
(SSTR1-5) demonstrated PEN-221 selectively binds SSTR2. In vitro, PEN-221, like the SSTR2 
natural ligand, was shown to stimulate SSTR2 internalization. PEN-221 receptor dependent, 
functional and mechanistic cellular activity was also demonstrated in vitro. Incubation of PEN-
221 with the NCI-H524, an SSTR2 positive cell line, induced dose-dependent increases in 
mitotic arrest (as measured by phosphohistone H3, or PHH3) and decreases in cellular 
proliferation. These effects were shown to be dependent upon PEN-221 specific binding to 
SSTR2. These in vitro data demonstrate that PEN-221 affects cancer viability via selective 
SSTR2 binding, stimulation of receptor internalization, induction of cell cycle (mitotic) arrest 
and apoptosis. 
The mechanism of action of PEN-221 was explored in vivo in a study that examined the PDc 
effects in tumors after PEN-221 dosing of mice. Rapid SSTR2 internalization by NCI-H524 
SCLC tumor cells was demonstrated, with measurement of high levels of internalized SSTR2 
following a single dose of PEN-221 to tumor xenograft-bearing mice. Additional in vivo PDc 
studies were carried out to measure the biological effects of a single dose of PEN-221 treatment 
on a second SSTR2 expressing SCLC xenograft model, NCI-H69. Using either an 
immunohistochemistry (IHC) or an enzyme-linked immunosorbent assay (ELISA) based 
approach, significant increases in the apoptotic marker, cleaved caspase 3 and the mitosis 
marker, PHH3, were observed in tumors in response to administration of PEN-221at doses as 
low as 0.5 mg/kg to mice. The PEN-221 effects on the tumor cells were time- and dose-
dependent. These results demonstrate active targeting of the receptor in vivo leading to mitotic 
arrest and apoptosis of tumor cells and support the mechanism of antitumor efficacy with tumor 
regressions seen in the xenograft models described below. 
Significant anti-tumor activity, including complete regressions with some treatment regimens, 
was demonstrated in 3 SSTR2-positive SCLC models (NCI-H69, MCI-H524 MD, HCC-33 NCI-
H82) and 1 neuroblastoma model (IMR-32). Doses tested ranged from 0.25 to 2.5 mg/kg with 
complete regressions seen following a single dose as low as 1.0 mg/kg in the NCI-H69 model. In 
the HCC-33 model, with a dose as low as 0.33 mg/kg administered once a week for 4 weeks. 
Tumor growth inhibition (TGI) of 83% was observed. Additionally, superior efficacy was 
observed with a single dose of PEN-221 compared to a single cycle of standard of care 
treatment, cisplatin plus etoposide, in the NCI-H69 model. 


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In summary, these data collectively support the hypothesis that active targeting of tumors 
through PEN-221 specific binding to SSTR2 drives the antitumor efficacy observed in multiple 
SSTR2 expressing xenograft models. Higher levels of antitumor activity, including complete 
tumor control with regressions, were observed with either repeat dosing at a relatively low dose 
or with a single relatively high dose. These observations suggest potential for activity in patients 
with SSTR2-expressing tumors. 
4.7. 
Nonclinical Pharmacokinetics and Drug Metabolism 
PEN-221 is a peptide-drug conjugate consisting of a somatostatin analog attached to the 
cytotoxin DM1, a thiol-containing maytansinoid, using a disulfide linker. The somatostatin 
analog provides tumor targeting, while DM1 provides antitumor activity. A series of nonclinical 
studies were conducted to characterize the pharmacokinetic properties of PEN-221. 
A single bolus IV administration of PEN-221 resulted in the similar plasma pharmacokinetics for 
NCr nude mice, Sprague-Dawley rats, and beagle dogs. The pharmacokinetic curves showed bi-
phasic profiles, with low clearances (CL) and low to moderate steady state volumes of 
distribution (Vss) resulting in the average PEN-221 plasma half-lives (t1/2) of 12.2 h, 8.07 h and 
4.88 h for mice, rats and dogs respectively. Allometric scaling showed a strong relationship 
among the 3 nonclinical species and was used to predict human pharmacokinetics. The low 
plasma PEN-221 clearance rate with the low volume of distribution were projected for humans 
resulting in a predicted half-life for PEN-221 of 2.4 hours. 
The membrane permeability of PEN-221 was shown to be very low in a Caco-2 cell monolayer 
assay indicating low passive permeability across cell membranes. The reversible binding in 
plasma of PEN-221 was studied in mouse, rat, dog, and human plasma. The unbound fraction of 
PEN-221 was similar across species (3.3% –10.6%) and was not dependent on the concentration. 
Since PEN-221 is designed to deliver the toxin DM1 into the cells, measurement of total DM1 in 
the tumors and tissues was used to evaluate PEN-221 distribution. Following administration of a 
single dose of PEN-221 to mice bearing NCI-H69 xenograft tumors expressing high levels of 
SSTR2, the maximum DM1 levels in tumors were seen between 2 and 8 hours after the dosing. 
The total DM1 levels in tumors showed a significantly longer half-life than PEN-221 in plasma. 
Decreases in DM1 tumor levels of less than 50% were seen between day 1 and day 5. In a tissue 
distribution study in Sprague-Dawley rats, the highest total DM1 levels were seen in the kidneys 
followed by other highly perfused organs in the order kidneys > lungs > spleen > liver > rough 
pituitary > pancreas. Very low levels of total DM1 were detected in the skeletal muscle and the 
bone marrow. 
PEN-221 excretion after a single IV dose was evaluated in Sprague-Dawley rats. Over a 24 hour 
period, 8.48% of the PEN-221 dose was excreted in an unchanged form, with a majority of the 
intact PEN-221 excreted in urine. 
4.8. 
Nonclinical Toxicology Studies 
PEN-221 toxicity was evaluated in 6 exploratory/dose range finding studies and 2 repeat dose IV 
GLP toxicology studies. Both rat and dog are relevant species for assessment of toxicity, based 
on sequence conservation of the PEN-221 targeting moiety (somatostatin) and the somatostatin 
receptor (SSTR2) across species (Creutzfeldt 1987; Flyvbjerg 1992; Hatzoglou 1995; Kaupmann 


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1995; Liapakis 1996; Misumi 1988; Robben 1997; Waser 2009; Zhang 1995) and the known 
toxicities of maytansinoid compounds in humans, dogs and rats (Leighton 2013; Poon 2013; 
Thake 1975). Dose-range finding studies in rat and dog, established the dose levels and timing of 
measurements and endpoints for GLP repeat-dose studies in both species. Findings showed rat to 
be the more PEN-221 sensitive species and therefore the STD10 in rat has been used to justify the 
Phase 1 starting dose as noted in Section 5.1.3.1. 
The non-GLP studies were designed as exploratory or dose-range finding studies to assist in the 
dose selection for the GLP repeat dose toxicity studies in rats and dogs and for the GLP 
cardiovascular safety pharmacology study in dogs. The highest dose in the rat GLP study was set 
at 1.0 mg/kg while the highest dose in the dog GLP study was set at 0.24 mg/kg. 
Repeat-dose GLP toxicology studies in rat and dog were designed to evaluate PEN-221 safety 
and to characterize the toxic effects with respect to target organs, dose-dependence, relationship 
to exposure progression, or delayed appearance of any changes and reversibility. In the repeat-
dose GLP studies, PEN-221 was administered on Days 1 and 21 to mimic the intended clinical 
regimen. Studies were designed to examine early effects after the first dose through blood 
sampling at multiple time points and histopathology and to evaluate the consequences and 
recovery from repeat dosing. Dose levels tested in the rat repeat dose GLP study were 0.55 
mg/kg, 0.76 mg/kg, and 1.0 mg/kg. In dogs, the dose levels for the GLP study were 0.16 mg/kg, 
0.20 mg/kg, and 0.24 mg/kg. Terminal groups of animals were euthanized on Day 8 while 
recovery groups were euthanized on Day 42. Assessment of toxicity was based on mortality, 
clinical observations, body weight, food consumption, ophthalmoscopic examinations, and 
clinical and anatomic pathology. Safety pharmacology endpoints including a functional 
operational battery (FOB) of tests were conducted and clinical observations were monitored that 
included assessment of CNS (e.g. tremors, convulsion, unusual/abnormal behaviors or motor 
movements, sensorimotor responses), respiratory (rate and ease), and cardiovascular safety 
pharmacology parameters. 
Toxicokinetic assessments and collections for immunogenicity assessments were included in 
both rat and dog GLP studies. Blood sampling for determination of plasma concentrations of 
PEN-221, total DM1, and peptide ligand (BT-979) was conducted for 36 hours starting on Days 
1 and 21. In rats the mean plasma C0 and mean area under the plasma concentration time curve 
from zero to 36 hours (AUC0-36h) values of PEN-221, total DM1, and BT-979 increase in an 
approximately dose proportional manner on Days 1 and 21. AUC0-36h did not change 
significantly following repeat administration. A moderate sex difference was observed in rats 
with a 1.5 – 1.9-fold higher PEN-221 AUC0-36h in males and a 1.5 – 2.2-fold higher total DM1 
AUC0-36h in females. These differences in AUC0-36h values resulted in differences in the ratio of 
DM1 to PEN-221. In females, ratios > 8 were observed and in males the ratio remained ≤ 2.4. 
The net result was a higher AUC0-36h for DM1 in female rats. In dogs the mean C0 and mean 
AUC0-36h values of PEN-221, total DM1, and BT-979 increased in an approximately dose 
proportional manner on Days 1 and 21. AUC0-36h to PEN-221, total DM1, and BT-979 did not 
change following repeat administration. There was no difference in the toxicokinetics of PEN-
221, DM1, or BT-979 in male and female dogs. The DM1 AUC0-36h was on average 1.37-fold 
higher than the PEN-221 AUC0-36h. 
In the rat study, a single female administered 1 mg/kg PEN-221 was found dead on Day 29. This 
animal was noted with decreased body weight and clinical observations of thin appearance, red 


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material around the nose, and forefeet discolored red. Histopathology findings were lymphoid 
depletion in thymus, decreased hematopoietic cells in the bone marrow of the femur and 
sternum, bilateral severe hemorrhage in the adrenal glands, Kupffer cell hypertrophy, and 
cytoplasmic alteration of hepatocytes including increased mitotic figures. The cause of death was 
considered treatment related. In the repeat dose GLP study in dogs, there were no mortalities. 
Weight loss and decreases in food consumption were observed in rats after dosing with reversal 
and weight gains seen during the study. Overall, by the end of the recovery period, the mean 
body weight for high-dose males and females were reduced by 4.9% and 12.4%, respectively, 
when compared to control values. Notable clinical observations in the GLP rat study were 
decreased activity, thin, unkempt appearance in a few animals at the higher doses. In dogs, 
minimal, transient decreases in body weight were noted in all PEN-221 treated groups following 
the first dose which correlated with transiently decreased food consumption in the high PEN-221 
dose group. Similarly, a minimal, transient decrease in body weight was noted in high dose 
group male and female dogs following the second administration of PEN-221. These changes in 
the dogs exhibited complete resolution. 
There were no treatment-related effects noted in ophthalmic exams in the rat or dog GLP studies. 
In rats, hematology and coagulation changes at the terminal necropsy were decreased red cell 
mass in both sexes at all PEN-221 dose levels with decreased reticulocyte counts (females, mid- 
and high dose groups) and decreased total leukocyte, neutrophil, and lymphocyte counts (males, 
mid- and high-dose groups and all female groups). Due to the severity of the changes, decreases 
in red cell mass, reticulocyte and neutrophil counts were considered adverse in high dose group 
males and mid-and high-dose female animals. The noted differences may be due to the higher 
DM1 exposure in the female rats. Also noted was an increase in platelet counts in PEN-221 
treated males. Following the second dose, at the recovery necropsy, increased reticulocyte counts 
in mid-dose males and high-dose females were noted that correlated with resolution of red cell 
mass changes (noted following the first PEN 221 dose). The clinical pathology changes observed 
in dogs were decreases in reticulocyte counts and platelet counts in both sexes in mid- and high-
dose PEN-221 dose groups. Transient decreases in lymphocyte counts in both sexes at the high 
dose were noted on Days 4 and 24 that resolved 7 days following administration. 
Decreased activated partial thromboplastin time (aPTT) and prolonged prothrombin time (PT) 
were observed in high dose group female rats and increased fibrinogen was noted in females at 
the mid and high PEN-221 dose levels. In the GLP study in dogs, there were no PEN-221 related 
effects noted for coagulation. 
Urinalysis evaluation on Day 42 revealed absence of sperm in the urine of male rats in the high 
dose PEN-221 group. There were no notable urinalysis findings in dogs. 
In rats, clinical chemistry findings on Day 4 indicated hepatocellular and hepatobiliary effects in 
both sexes at all dose levels with observations of increased aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), and alkaline phosphatase (ALP) activities, and increased total 
bilirubin concentration that was primarily attributable to direct bilirubin. Despite the changes in 
AST, ALT, ALP, and total bilirubin levels, these changes were transient and were not associated 
with correlative microscopic liver changes at either terminal or recovery necropsies. Erythrocyte 
hemolysis may have contributed to the elevations in AST and ALT activities and total bilirubin 
concentration, as well. However, no significant hemolysis was observed ex vivo with PEN-221 


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in whole blood from rat at 10 µM, compared to the 5.6 µM maximum concentration achieved in 
the toxicokinetic analysis. In addition, no significant hemolysis was observed ex vivo in human 
or dog whole blood at 5 µM. The maximum concentration of PEN-221 achieved in the dog 
toxicokinetic analysis was 1.6 µM. Using PEN-221 pharmacokinetic parameters and allometric 
scaling, the proposed starting dose for humans predicts a maximum PEN-221 concentration in 
humans of 0.08 µM, 62-fold less than the concentration tested in the human whole blood 
hemolysis assay. Albumin was decreased in PEN-221 treated rats and cholesterol concentration 
was increased in high dose group males and in all PEN-221 treated females. ALT and AST 
increases were resolved by Day 8 and cholesterol and albumin changes were partially or fully 
resolved on Day 8. Bilirubin and ALP changes were resolved by Day 15. Following the second 
dose on Day 21, similar effects were noted 3 days post dose albeit to a lesser degree which 
resolved by the end of the recovery period. The magnitude of these clinical chemistry changes 
was generally higher after both dosing days in the female compared to male rats which may be 
due to the higher DM1 exposure in the female rats. In dogs, no PEN-221-related effects were 
noted in clinical chemistry parameters. 
Postmortem findings in the rat GLP study were macroscopic findings of small thymus in males 
and females in the mid- and high-dose PEN-221 groups at the terminal necropsy. Small testes 
were noted in males in the mid- and high-dose PEN-221 groups at the recovery necropsy. In the 
dog GLP study, decreased thymus weights were observed in high dose PEN-221-treated animals. 
Microscopically, in rats at the terminal necropsy, dose-dependent lymphoid depletion was 
present in the thymus in males and females at all PEN-221 dose levels. This depletion was 
characterized by varying degrees of cortical and medullary lymphocyte loss. In severe cases, 
only the remaining thymus stroma was present. At the recovery necropsy, lymphoid depletion 
was noted in the thymus in some animals in all dose groups in both sexes and severe lymphoid 
depletion was present in the 1 female at the high dose, which was found dead on Day 29. In the 
testes, there was seminiferous tubule degeneration/atrophy at the high dose and minimal germ 
cell degeneration at the mid- and high-PEN-221 doses, at the terminal necropsy. Testes findings 
had progressed at the recovery necropsy compared to the terminal necropsy in males at mid and 
high doses. In the kidney, single cell necrosis and/or tubular regeneration was observed in male 
rats at all dose levels and female rats at the mid and high doses at the terminal necropsy, but not 
the recovery necropsy. The rat kidney findings were minimal and reversible and, therefore, 
considered non-adverse. Bone findings (femur and sternum) were predominantly noted in 
females at the terminal necropsy and were characterized as increased endosteal osteoid 
deposition at the mid and high doses. Bone findings had progressed at the recovery necropsy 
compared to the terminal necropsy in female rats at mid and high doses. At the recovery 
necropsy, decreased cellularity of the bone marrow was present in the femur and/or sternum of 
male and female rats at all PEN-221 dose levels, and increased cellularity was present in the 
bone marrow of the sternum in 1 male at the mid-dose. Also noted was extramedullary 
hematopoiesis in the liver of females at the mid and high doses and 1 male at the high dose, and 
in the spleen extramedullary hematopoiesis was observed in males and females at the high dose 
at the recovery necropsy. The noted microscopic differences that are more marked in the female 
rats may be due to the higher DM1 exposure. In dogs, microscopic findings were observed in the 
kidneys (single cell necrosis, tubular degeneration/necrosis, increased mitotic figures, and/or 
tubular regeneration) in males and females at all PEN-221 dose levels. Most of the findings were 
graded minimal and were completely reversible and were, therefore, considered non adverse. 


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Lymphoid depletion was seen in the thymus of mid and high dose PEN-221 treated male animals 
and in high dose PEN-221 treated females that resolved by the end of the recovery period. 
Local tolerance of PEN-221 following IV administration was assessed in the repeat dose GLP 
studies. There were no macroscopic findings. Microscopic findings were generally minimal. 
A dedicated dog telemetry study was conducted to evaluate the potential cardiovascular and 
respiratory effects of the test article, PEN-221, in conscious freely moving beagle dogs. Dose 
levels tested were identical to those used in the dog GLP study. PEN-221, administered as a 
single IV infusion over 6 minutes to male beagle dogs at dose levels of 0.16, 0.20, and 0.24 
mg/kg, was generally well tolerated and did not produce any clinical observations or mortality. 
There were no test article-related effects on the QRS duration, electrocardiogram (ECG) 
morphology, or tidal volume at any dose level tested. At a dose level of 0.24 mg/kg, from the 
time of dosing through 1.5 to 2 hours following dosing, PEN-221 induced statistically significant 
increases in blood pressure, heart rate, and respiratory rate with  (Leighton 2013; Poon 2013) 
decreases (reflective of the heart rate changes) in the RR, PR, and QT intervals, as well as 
increases in body temperature that did not reach statistical significance. From 7 to 24 hours post 
dose, slight increases in respiratory rate and minute volume were observed at 0.24 mg/kg. From 
2 to 17 hours post dose, non-dose-dependent increases in blood pressure were observed for all 
test article treatments. Decreases in the PR and QT intervals were observed beginning at 5 or 12 
hours, respectively, following the 0.24 mg/kg treatment, lasting through the 24 hour monitoring 
period. Given the transient nature of the immediate effects observed at 0.24 mg/kg and the 
relatively small magnitude of the sustained effects observed at all dose levels, these changes are 
not considered to be adverse; intravenous (IV) administration of PEN-221 produced no adverse 
effects on cardiovascular or respiratory function in male beagle dogs at doses up to and including 
0.24 mg/kg. 
The findings in the PEN-221 studies identified target organ toxicities consistent with those 
identified in toxicology studies with DM1 or the DM1-containing antibody drug conjugate ado-
trastuzumab emtansine in rats, with maytansine in dogs (Thake 1975), and with ado-trastuzumab 
emtansine in cynomolgus monkeys (Leighton 2013; Poon 2013). Notable microscopic findings 
in Sprague-Dawley rats dosed with ado-trastuzumab emtansine were seen in the liver, thymus, 
kidney, testis, spleen, mesenteric lymph node, femur marrow and sternum marrow (Poon 2013). 
In rats dosed with DM1, hematologic changes included decreased platelet, reticulocyte and 
lymphocyte counts. DM1 and ado-trastuzumab emtansine related decreases in platelets have 
been observed in preclinical safety studies in rats and monkeys and thrombocytopenia is an 
adverse reaction to ado-trastuzumab emtansine in humans (KADCYLA® (ado-trastuzumab 
emtansine) [Package Insert]). Changes in serum chemistry with DM1 dosing in rats reflected 
adverse effects on the liver: increases in ALT, AST, and total bilirubin (ado-trastuzumab 
emtansine). In monkeys, ado-trastuzumab emtansine induced changes observed in blood and 
target organs were as noted in rats (Poon 2013). Increases in aPTT, fibrinogen, and cholesterol 
were observed in monkeys following dosing with ado-trastuzumab emtansine (Leighton 2013). 
Observations were noted in the testes of rats dosed with ado-trastuzumab emtansine. 
Bone marrow to induce ectopic calcification has been observed with potent tubulin-binding 
drugs in rats (Tamura 1986). Large doses of vinblastine or colchicine (potent microtubule 
poisons) produced ectopic calcified tissue in the rat bone marrow cavity. Vinblastine sulfate is an 
effective single agent treatment for patients with Hodgkin’s disease and is indicated for the 


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palliative treatment of several malignancies. No data included in the product label suggest 
potential for adverse effects on bone in humans (VinBLAStine Sulfate for Injection USP 
[package insert]). 
In the PEN-221 toxicology studies, effects were demonstrated to be dose-dependent and 
generally reversible and readily monitored, with rats being the more sensitive species. The 
microscopic changes were reflected in hematology or clinical chemistry changes in animals, 
providing guidance for clinical safety monitoring in humans. 


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5. 
INVESTIGATIONAL PLAN 
5.1. 
Overall Study Design 
Protocol PEN-221-001 is a first-in-human, open-label, Phase 1/2a study evaluating the safety, 
PK, pharmacodynamics, and anti-tumor activity of PEN-221 in patients with SSTR2 expressing 
advanced GEP or lung or thymus or other NETs or SCLC or LCNEC of the lung. The study will 
be carried out in 2 stages: Phase 1 (dose escalation), and Phase 2a (disease-specific cohort 
expansion). 
The overall study design is presented in Figure 1. 
Figure 1: 
Protocol PEN-221-001 Study Design 
Phase 1 
Dose Escalation 
Phase 2a 
Expansion 
Number of dose cohorts dependent on toxicity 
results as determined by Bayesian logistic 
regression model (BLRM) with overdose 
control (EWOC) 
Patients with advanced or metastatic, well-
differentiated, low or intermediate grade 
gastrointestinal mid-gut NET  
n=35  
 
Patients with advanced or metastatic, well-
differentiated, low or intermediate grade 
pancreatic NET  
n=20 
Patients with advanced or metastatic, small 
cell lung cancer 
n=20 
 
 
5.1.1. 
Pre-screening 
Each patient must demonstrate a tumor that is positive for expression of SSTR2, by historical or 
study-related somatostatin analog radioimaging (SARI). Patients who do not have historical 
positive SARI will, after provision of written informed consent for the pre-screening assessment, 
receive SARI. Patients with a historical positive SARI and patients whose pre-screening 
assessment SARI is positive will enter screening assessments after provision of written informed 
consent. Patients whose pre-screening assessment SARI is negative will not undergo any further 
protocol assessments and are not eligible to continue in the study. 
Investigators should maintain a log of patients who are consented for pre-screening, including 
histological type of tumor, stage and grade, anatomical location(s) (primary and metastatic) of 
tumor, type of SARI used (Octreoscan or 68Ga imaging), and results of screening. 
Cohort 1 
n=2 
Cohort 2 
n=3-6 
Cohort 3 
n=3-6 
Cohort 4 
n=3-6 
etc. 


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5.1.2. 
Screening 
After provision of written informed consent for the study, patients will be screened for study 
eligibility within 14 days [and within 28 days for tumor assessments by computed tomography 
(CT) or magnetic resonance imaging (MRI)] before the first study drug dose. 
Investigators should maintain a log of patients who are consented for screening but do not meet 
eligibility criteria, including histological type of tumor, stage and grade, anatomical location(s) 
(primary and metastatic) of tumor, and reason for screen failure. 
5.1.3. 
Main Study 
5.1.3.1. 
Treatment Period 
Patients who are determined to be eligible, based on screening assessments, and who have 
provided written informed consent for the study, will begin treatment in the study on Cycle 1 
Day 1 (C1D1; baseline). A treatment cycle is 3 weeks in length. All patients will receive 
PEN-221 administered IV on Day 1 every 3 weeks; the PEN-221 dose received is dependent on 
the cohort/phase in which the patient is enrolled. During treatment, patients will attend study 
center visits and have study evaluations performed on D1 of each treatment cycle. D8 and D15 
visits will also occur, except that, if after initial dosing or an intra-patient dose escalation, if two 
cycles are completed with no Grade 2 or higher abnormalities in clinical chemistries or 
hematology parameters, these visits may be eliminated in subsequent cycles, subject to 
Investigator discretion (see 9.3.5.1) (Except for C1D1, visits during treatment cycles have a 2-
day window.) All study visits are anticipated to be conducted on an out-patient basis, but may be 
conducted on an in-patient basis per institutional policy. 
Safety will be assessed during the study by documentation of adverse events (AEs), clinical 
laboratory tests, physical examination, neurological examination, vital sign measurements, 
ECGs, and Eastern Cooperative Oncology Group (ECOG) performance status (PS). 
Pharmacodynamic (PDc) and serial blood samples for PK will be collected from all patients. 
All sites of disease will be assessed by CT. If the anatomic region cannot be adequately imaged 
by CT, MRI may be used instead. For SCLC and LCNEC of the lung patients, tumor 
measurements are to be repeated within 7 days prior to the first study drug dose in every other 
cycle, starting in C3, and at the Progression Follow-up visits. For all other patients, tumor 
measurements are to be repeated within 7 days prior to the first study drug dose in every third 
cycle, starting in C4, and at the Progression Follow-up visits. Repeat assessments should use the 
same radiographic methods as used at baseline. Disease response is to be assessed by the 
Investigator using RECIST guidelines, version 1.1 (Eisenhauer 2009). Patients who achieve a 
partial response (PR) or complete response (CR) by RECIST are to have repeat assessments 
performed approximately 6 weeks later (and no sooner than 4 weeks from the prior assessment) 
to confirm the response. Following the confirmatory assessment, the response assessment 
schedule will resume at intervals of every other cycle for SCLC and LCNEC patients, and every 
third cycle for all other patients.  


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5.1.3.2. 
End of Treatment 
Patients who discontinue treatment for any reason (see Section 7.8) should have an EOT visit. 
The EOT visit should occur within 3 days from the event resulting in treatment discontinuation 
(i.e. disease progression, AE, withdraw consent).  
5.1.4. 
Follow-up Period 
5.1.4.1. 
Safety Follow-Up 
All patients discontinuing treatment or withdrawing from the study will have physical 
examination, laboratory, AE, and concomitant medication assessments performed as part of a 
safety follow-up visit 28 days (±3 days) after their last dose of study drug. 
5.1.4.2. 
Progression Follow-Up 
For patients that discontinue treatment for reasons other than radiographic progression of 
disease, tumor assessments should be performed approximately every 6 weeks from previous 
scan for SCLC and LCNEC of the lung patients and every 9 weeks from previous scan for all 
other patients, or as clinically indicated, until radiographic progression of disease is observed.  
5.1.4.3. 
Survival Follow-Up 
Upon disease progression, all patients will be followed approximately every 3 months to assess 
survival status and the date and cause of death (if known) will be recorded for patients who died. 
Survival follow-up will occur every 3 months until death, lost to follow-up or consent 
withdrawal. 
5.1.5. 
Starting dose 
The PEN-221 selected starting dose of 1.0 mg IV every 3 weeks is based upon international 
guidance for starting dose selection for agents in cancer patients (ICH S9 2010 Guidance for 
Industry). ICH S9 recommends that a starting clinical dose for a first-in-human study should be 
either 1/10th of the severely toxic dose (STD10) in rodent toxicity studies or 1/6th of the highest 
non-severely toxic dose (HNSTD) in non-rodent toxicity studies. 
Based on the findings in the 6-week rat repeat dose IV toxicity (PEN-221-TX-006), the STD10 
for PEN-221 following single or repeat dose administration to rats was determined to be 
1.00 mg/kg. Based on these data, the dose of one-tenth the rat STD10 gives a Human Equivalent 
Dose (HED) of 0.016 mg/kg informing the PEN-221 first-in-human starting dose (Table 4 ). The 
calculation based on the dog HNSTD (PEN-221-TX-007) is shown in Table 5 and results in a 
higher HED of 0.022 mg/kg substantiating that rat is the more sensitive species. The human 
starting dose of 0.016 mg/kg is equivalent to 0.60 mg/m2 (Table 5 ). Assuming an average 
weight of 60 kg in human, the starting dose translates to 0.96 mg or using an average body 
surface area of 1.7 m2, the starting dose calculates as 1.02 mg. Hence, we have selected a starting 
dose of 1.0 mg IV every 3 weeks. 
Based on tumor bearing mouse xenograft studies (PEN-221-PHARM-023), the minimum 
biologic effective dose in mice is 0.33 mg/kg. Applying the mouse to human conversion factor of 
12.3 and assuming an average human weight of 60 kg, the human equivalent minimum effective 
dose is estimated to be 1.6 mg. 


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Table 4: 
Human Starting Dose Calculation 
Rat STD10 
mg/kg 
1/10 Rat STD10 
mg/kg 
Rat 1/10 STD10 
mg/m2 
Calculation of Human Starting Dose 
HED 
mg/kg 
HED 
mg/m2 
1.0 
0.10a 
0.6b 
0.016c 
0.60c 
a As the rodent is the most sensitive species, starting dose was calculated as 1/10 the Severely Toxic Dose in 10% of 
the animals (STD10) in rodents. (ICH Topic S9 Nonclinical Evaluation for Anticancer Pharmaceuticals, March 
2010). 
b BSA (Body Surface Area, m2) = mg/kg dose in rat multiplied by 6 to calculate mg/m2 dose in rat. (FDA Guidance 
for Industry, Estimating Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, July 
2005). 
c The human equivalent dose (HED = animal dose in mg/kg × (animal weight in kg/human weight in kg)0 33) or 
alternatively this can be calculated, for HED for rat dose, divide the rat dose in mg/kg by 6.2, assumes 60 kg 
human. Starting dose HED using 1/10 the STD10, as rat is most sensitive species. To convert the human mg/kg 
dose to the BSA (mg/m2) dose, multiply the mg/kg human dose by 37 = human mg/m2. (FDA Guidance for 
Industry, Estimating Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, July 
2005). 
 
Table 5: 
HNSTD in Dog for Comparison to Rat STD10 
Dog HNSTD 
mg/kg 
1/6 Dog HNSTD 
mg/kg 
Dog 1/6 HNSTD 
mg/m2 
 
Human Equivalent Dose 
HED 
mg/kg 
HED 
mg/m2 
0.24 
0.04a 
0.8b 
0.022c 
0.82c 
a Highest Non- Severely Toxic Dose (HNSTD). If the non-rodent is the most sensitive species then 1/6 the Highest 
Non- Severely Toxic Dose (HNSTD) is considered an appropriate start dose. (ICH Topic S9 Nonclinical 
Evaluation for Anticancer Pharmaceuticals, December 2008). 
b BSA (Body Surface Area, m2) = mg/kg dose in dog multiplied by 20 to calculate mg/m2 dose in dog. (FDA 
Guidance for Industry, Estimating Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy 
Volunteers, July 2005). 
c The human equivalent dose (HED = animal dose in mg/kg × (animal weight in kg/human weight in kg)0 33) or 
alternatively this can be calculated by dividing the dog dose in mg/kg by 1.8, assumes 60 kg human. To convert 
the human mg/kg dose to the human BSA (mg/m2) dose, multiply the mg/kg dose by 37 = human mg/m2. (FDA 
Guidance for Industry, Estimating Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy 
Volunteers, July 2005). 
5.1.6. 
Phase 1 (Dose escalation) 
Phase 1 will employ an adaptive Bayesian logistic regression model (BLRM) with 2 parameters 
guided by the EWOC principle to make dose recommendations and estimate the MTD. 
To minimize the number of patients treated at potentially subtherapeutic dose levels, the first 
dose cohort will enroll 2 patients, whereas subsequent cohorts will enroll a minimum of 3 and up 
to 6 patients. The initial patient in Cohort 1 will receive PEN-221 administered IV over 1 hour at 
the starting dose of 1.0 mg on an every 3 week cycle. This patient will be followed for 7 days, 
including assessments during the scheduled visit on C1D8, prior to allowing additional patients 
to begin treatment with PEN-221. If PEN-221 is tolerated by the initial patient for at least 7 days, 


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then the first cohort will be opened to treatment of 1 additional patient. The first 2 patients will 
be assessed for safety and dose limiting toxicity (DLT) for at least 4 weeks (including C2D1 and 
C2D8 assessments) before enrollment in the second cohort may begin. 
The SRC will convene to review all data from the first 2 patients in Cohort 1 through C2D8. 
Providing there are no safety concerns after completion of the first cohort, subsequent cohorts of 
patients will be dosed as suitable patients are identified. However, the SRC may choose to 
stagger dosing in the second cohort and likewise for subsequent cohorts. 
In each dose escalation cohort following the first cohort, a minimum of 3 patients within a cohort 
are required to have completed C1 and have been assessed for safety and DLT for at least 3 
weeks (including C2D1 pre-dose assessments) before enrollment of the next cohort may begin. 
The Safety Review Committee (SRC) will review the safety and tolerability of PEN-221 of each 
cohort to decide the next dose level to be tested. Statistical modeling will be performed using all 
safety data and will guide the SRC’s selection of dose levels to be tested. In addition, 
pharmacokinetic (PK) and pharmacodynamics (PDc) data may be used to inform dose selection. 
Dose escalation increments will be the decision of the SRC. PEN-221 dose cohorts will be 
enrolled sequentially after the SRC reviews safety data collected during C1 (and through C2D8 
for Cohort 1) from the patients enrolled in the current dose level. Dose escalation will continue 
until the MTD is determined. 
During Phase 1, if a patient is tolerating PEN-221 without significant evidence of disease 
progression, the patient may, beginning with C3 or subsequent cycles, have the dose increased to 
a dose that has already been established as tolerable by the SRC, and with the agreement of the 
SRC. 
The starting dose of PEN-221 is 1.0 mg. The planned dose levels are summarized in Table 6 . 
Table 6: 
Planned PEN-221 Dose Levels 
Dose Level 
% Increment from 
Prior Dose Level 
PEN-221 Dose (mg) 
−1 
(50% decrease) 
0.5 
1 
Starting dose 
1 
2 
100% 
2 
3 
100% 
4 
4 
67% 
6.7 
5 
50% 
10 
6 
33% 
13.3 
7 
25% 
16.6 
8 
25% 
20.8 
*Actual dose increments will be the decision of the SRC but will not exceed a doubling of dose from the 
prior dose level. The doses assigned will be the decision of the SRC and will be guided by the updated 
results of BLRM. 


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In cohort 1, each patient must have received PEN-221 in C1 and C2 and completed follow-up 
safety evaluations through C2D8 to be evaluable for the assessment of DLT. In all subsequent 
cohorts, each patient in a dose cohort must have received PEN-221 in C1 and completed follow-
up safety evaluations through C2D1 to be evaluable for the assessment of DLT. Patients who 
discontinue from the study for reasons other than DLT before completing C1 are to be replaced. 
See Section 8.9 for definition of evaluable patient. 
If a DLT necessitates enrollment of additional patients into a cohort, the SRC will review all 
safety data for that cohort after all patients have received PEN-221 in C1 and completed follow-
up safety evaluations through the end of C1. Based on the interim evaluation of the safety and 
tolerability data of the previous dose level, it may also be decided that accrual will take place at 
an intermediate dose level. The SRC may be convened earlier at the discretion of the Sponsor if 
important safety issues arise requiring the attention of the committee. 
Toxicities are to be graded by the Investigator using the National Cancer Institute (NCI) 
Common Terminology for Cancer Adverse Events (CTCAE), version 4.03. 
Although decisions regarding dose escalation will be made based on review of data from C1, 
safety data will also be collected from all patients continuing treatment and this will be reviewed 
periodically by the SRC. Any detected cumulative toxicity may require later dose reductions or 
other action as appropriate, including further refinement of the RP2D. 
5.1.7. 
Phase 2a 
In Phase 2a, PEN-221 will be evaluated using the recommended Phase 2 dose (RP2D) identified 
by the SRC. 
Phase 2a may begin once a RP2D is identified in Phase 1 of the study. The RP2D will be the 
decision of the SRC and will be based on the findings of the safety, tolerability, PK, and PDc 
profile of PEN-221 during Phase 1. The recommended Phase 2 dose may be the same as the 
MTD, or may be below the MTD. In the event that the MTD is higher than the dose determined 
by the SRC to have an acceptable safety and tolerability profile after multiple cycles of 
administration, the SRC may select a RP2D that is below the MTD. 
Phase 2a may, at the discretion of the Sponsor, begin once all patients have been enrolled in 
Phase 1 and have been assessed for safety through and including C2D1, and the SRC has 
reviewed all safety data and recommends continuing with Phase 2a. 
If one or more DLTs are observed at any time up until 6 patients across any of the three cohorts 
have been treated for at least 1 cycle in Phase 2a, the BLRM may be re-run to confirm the 
estimated MTD. The SRC will convene to determine whether it is safe to proceed with dosing at 
the  RP2D or whether an alternative lower dose is to be considered for subsequent patients. If an 
alternative lower dose is selected, the SRC will reconvene after at least 6 patients have been 
treated at this new dose to review the data and confirm whether subsequent patients be enrolled 
into the study at this new dose.  
In addition, at any time during Phase 2a, the BLRM may be re-run to confirm the estimated 
MTD and verify that the dose under study still satisfies the overdose criterion. If the dose fails to 
satisfy the criterion a change to the dose under study may be decided by the SRC, guided by the 
Bayesian model recommendation, after review of the clinical data. The SRC decision to change 
dose may also be spurred by other safety and tolerability considerations (e.g. frequency of lower 


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grade AEs or events in later treatment cycles). Subsequent patients may then be enrolled at this 
new dose until at least 6 patients are treated at this new dose level and upon SRC review of the 
data, the SRC will decide whether the new dose level is appropriate for continued study. 
5.2. 
Justification for the Study Design 
Goals of Phase 1 oncology studies include estimation of the MTD and initial assessment of 
safety and tolerability of a study drug, determination of a recommended range of doses for 
evaluation in future clinical studies (Ahn 1998; Dillman 1992; Gatsonis 1992; International 
Conference on Harmonization 1997), and an initial characterization of the PK profile in humans. 
The objectives of the current study are consistent with those typical of Phase 1 oncology studies. 
This first-in-human study is designed as a Phase 1 dose escalation and a Phase 2a expansion 
phase once the MTD and RP2D have been defined. 
The primary objective of the dose escalation phase of the study is to determine the MTD. Dose 
escalation will be guided by an adaptive BLRM following the EWOC principle. The use of 
BLRMs for Phase 1 studies has been advocated by the European Medicines Agency (EMA) and 
by (Rogatko 2007). This design uses all accumulating toxicity data to assign enrolling patients to 
escalating doses of study drug, while controlling the risk of excessive toxicity. 
Once the MTD and RP2D has been determined, the study will proceed in to Phase 2.  
The primary objective of Phase 2a is to evaluate the potential anti-tumor activity of PEN-221. 
The activity of PEN-221 at the MTD or RP2D, as identified in Phase 1, will be evaluated in 
Phase 2a in patients with specific tumor types to determine whether the activity seen is 
sufficiently promising to evaluate PEN-221 in patients with those particular tumor types in future 
clinical studies. 
5.3. 
Criteria for Study Termination 
The Sponsor reserves the right to terminate the study or particular study center at any time. If the 
Sponsor or Investigator discovers conditions arising during the study that suggest the study 
should be halted, then study termination can occur only after appropriate consultation between 
the Sponsor and Investigators. Conditions that may warrant study or study center termination 
include, but are not limited to: 
• The discovery of any unexpected, significant, or unacceptable risk to the patients 
enrolled in the study. 
• Failure of the Investigator to enter patients at an acceptable rate. 
• Insufficient adherence to the protocol requirements. 
• A decision on the part of the Sponsor to suspend or discontinue development of study 
drug. 
Should the study be closed prematurely, all study materials (study drug, etc.) must be returned to 
the Sponsor or designee (or disposed of after consultation with the Sponsor or designee, as 
directed by the Sponsor or designee). 


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5.4. 
Benefit/Risk Assessment 
PEN-221 is a novel peptide-drug conjugate that is specifically designed as a targeted anticancer 
agent for patients with advanced cancers that overexpress SSTR2. Significant antitumor activity 
has been seen in multiple SSTR2 positive xenograft models, including complete regressions. 
PEN-221 in this first in human study is being tested in the patient population who is considered 
most likely to benefit from the study medication, namely, those with advanced cancers that 
overexpress SSTR2. These cancers include gastroenteropancreatic and lung and thymus NETs, 
NETs of unknown primary, SCLC and LCNEC of the lung, and other tumors of neuroendocrine 
origin, namely, paraganglioma, pheochromocytoma, medullary thyroid carcinoma, Merkel cell 
carcinoma, and high grade extrapulmonary neuroendocrine carcinoma (NEC). The somatostatin 
receptor is known to be overexpressed in the majority of NETs, and approximately 40% of 
SCLC (Hofland 2001; Lehman 2015; Mato 1998; O'Byrne 1994; Pisarek 2009; Wangberg 1997). 
Effective treatment options for patients with these cancers in the advanced setting are extremely 
limited and new therapies are urgently needed. To improve the possibility that patients enrolled 
in this Phase 1/2a study might benefit from PEN-221, patients must meet eligibility criteria that 
include tumor expression of SSTR2 as assessed by a noninvasive, approved imaging modality. 
The primary objective of the Phase 1 dose escalation portion of this Phase 1/2a study is to 
investigate the safety and tolerability and determine the maximum tolerated dose (MTD) of 
PEN-221. The nonclinical toxicology studies have not identified any risks that would preclude 
investigation of PEN-221 in the advanced cancer setting, although at high exposures, significant 
toxicities known to be associated with DM1, antibody-drug conjugates that contain DM1, and 
other microtubule disrupting agents were observed. Based on the identified and potential risks 
associated with PEN-221 treatment, this clinical study protocol incorporates mandatory and 
thorough safety monitoring procedures and additional guidance documents to assist with early 
diagnosis and rapid management of potential treatment related toxicities. The safety monitoring 
plan takes into consideration the results of PEN-221 GLP toxicology studies as well as published 
reports of other targeted conjugates that contain DM1 including ado-trastuzumab emtansine, an 
approved agent for the treatment of women with previously treated, HER2-positive, metastatic 
breast cancer (Poon 2013; Verma 2012) and other antibody-drug conjugates in early phase 
development (Amiri-Kordestani 2014; Galsky 2008; Rodon 2008; Shah 2016). 
The Phase 1 dose escalation portion of the study is designed to maximize safety while 
minimizing the number of patients treated at subtherapeutic dose levels. The starting dose cohort 
will enroll only 2 patients, whereas subsequent cohorts will enroll a minimum of 3 and up to 6 
patients. The first patient treated with PEN-221 in the first cohort will be observed for 7 days 
prior to allowing additional patients to begin treatment with PEN-221. If PEN-221 is tolerated 
for at least 7 days by the first patient, then the first cohort will be opened to treatment of 1 
additional patient. After the first 2 patients have been assessed for safety and dose limiting 
toxicity (DLT) for at least 4 weeks (up until C2D8), enrollment in the second cohort may begin. 
Dose escalation will be guided by an adaptive BLRM following the EWOC principle. The use of 
BLRMs for Phase 1 studies has been advocated by the European Medicines Agency (EMA) 
(Committee for Medicinal Products for Human Use (CHMP) 2006) and by Rogatko (2007). This 
design uses all accumulating toxicity data to assign enrolling patients to doses that have a higher 
chance of targeted toxicity (close to the MTD), while controlling the risk of excessive toxicity. 


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During Phase 1, if a patient is tolerating PEN-221 without significant evidence of disease 
progression, the patient may, starting on D1 of C3 or subsequent cycles, have the dose increased 
to a dose that has already been established as tolerable by the SRC, and with the agreement of 
the SRC. This intra-patient dose escalation may allow patients a greater possibility of benefit 
from treatment with PEN-221 than might be achieved at the starting dose in his/her assigned 
dose cohort. 
Risks specific to patients who have provided written informed consent to undergo an optional 
tumor biopsy during screening include pain and tenderness at the tumor biopsy site and potential 
bleeding complications, which will be minimized by inclusion of patients who have at least 1 site 
of tumor that is accessible to biopsy and that is considered by the Investigator to be low risk and 
of sufficient size to undergo a biopsy procedure, and monitoring per institutional practice. 
No reproductive toxicology, genotoxicity, or carcinogenicity studies have been conducted with 
PEN-221 to date. Both women and men should be fully informed of the lack of reproductive 
toxicology testing. Women of childbearing potential and men must agree to use highly effective 
contraception (as defined in inclusion criterion 6) prior to study entry and for the duration of 
study participation. Women must have a negative pregnancy test prior to enrollment. It is 
unknown whether the drug is excreted in human milk, and women who are breast feeding are 
excluded from the study. 
The study design for this first in human Phase 1/2a dose escalation/expansion study of PEN-221 
aims to minimize potential risks and offer the potential to benefit patients whose tumors 
overexpress the SSTR2 target of this anticancer agent. Although the potential benefits to patients 
are unknown at this time, nonclinical data demonstrate evidence of potent anti-tumor activity in 
tumor models that overexpress SSTR2. The benefit/risk assessment for this Phase 1 study 
appears acceptable based on the lack of effective alternative treatments, the limited life 
expectancy of the patient population, and the strength of the nonclinical data in support of potent 
antitumor activity. 








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7. 
SELECTION AND WITHDRAWAL OF PATIENTS 
7.1. 
Number of Patients 
A total of approximately 105 patients are planned to be enrolled in the study. 
7.1.1. 
Phase 1 
It is estimated that approximately 30 patients will be enrolled in Phase 1. After 2 patients are 
treated in the starting dose cohort, a cohort size of 3 to 6 patients will be treated at each dose 
level. An adaptive BLRM guided by the EWOC principle will be employed to make dose 
recommendations and estimate the MTD. Approximately 4 to 6 dose escalation cohorts are 
anticipated. The total number of patients to be enrolled is dependent upon the observed safety 
profile as well as the number of dose escalation cohorts required to achieve the MTD and 
establish the RP2D of PEN-221. 
Each patient will participate in only 1 dose cohort with respect to assignment of starting dose. At 
least 6 patients will be treated at the MTD. 
7.1.2. 
Phase 2a 
Approximately 75 patients will be enrolled as follows: gastrointestional mid-gut NET (n=35, 25 
PRRT-naïve, 10  PRRT recurrent), pancreatic NET (n=20), and SCLC (n=20). These cohort 
sample sizes are considered sufficient to obtain an early assessment of efficacy of PEN-221 in 
patients with distinct tumor types. 
7.2. 
Consent 
Patients who undergo any study-related assessment or study-related modification of medical care 
must, of their free will, give fully considered, written informed consent to those assessments or 
modifications. Consent is not considered given simply by the patient signing an approved form. 
The patient’s medical record must also clearly indicate that the Investigator, or a qualified health 
care provider under the direction and designation of the Investigator, had a comprehensive 
discussion with the patient about the risks, benefits, and responsibilities of participation, ensuring 
the patient understood the contents of the informed consent form (ICF), and offering the patient 
sufficient time to consider details and discuss with others if they desire. 
In the event that the partner of a patient becomes pregnant, the partner must provide voluntary, 
fully considered, written informed consent to the use of any information collected about them, 
the fetus, or any resulting birth before such information can be collected or used in the study. 
7.3. 
Patient Inclusion Criteria 
All patients must meet all of the following criteria to be eligible to participate: 
1. Provision and understanding of signed and dated, written informed consent prior to any 
mandatory study-specific procedures, sampling, analysis. 
2. Male or female aged ≥ 18 years. 
3. ECOG PS of 0 – 1. 
4. Adequate organ function within 14 days before C1D1, defined as follows: 


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• Bone marrow: Absolute neutrophil count (ANC) ≥ 1.5×109/L, platelet count ≥ 
100×109/L, and hemoglobin ≥ 9 g/dl. 
• Hepatic: total bilirubin ≤ 1.5× the upper limit of normal (ULN) and alanine ALT and 
AST ≤ 2.5× ULN. 
• Renal: If serum creatinine concentration ≥ 1.5× ULN, then estimated creatinine 
clearance must be ≥ 50 mL/min (Cockroft-Gault formula) 
5. Serum potassium, calcium, magnesium and phosphorus within normal limits. If values 
are low on the initial screening assessment, supplements may be given and values 
repeated to confirm within normal limits. 
6. If a female of childbearing potential, negative serum pregnancy test within 3 days before 
C1D1, or in the event of a positive serum pregnancy test, exclusion of pregnancy as 
assessed by transvaginal ultrasound overseen by a health care professional with 
experience in investigating and diagnosing early pregnancy, as human chorionic 
gonadotropin (HCG) can be secreted by neuroendocrine tumor. A female of childbearing 
potential must agree to the use of highly reliable, physician-approved contraception from 
14 days before C1D1 through 3 months after the last study drug dose. Highly reliable 
contraception means 2 of the following: (1) established use of oral, injected, or implanted 
hormonal methods of contraception, (2) placement of an intrauterine device, (3) condom 
or occlusive cap (diaphragm or cervical vault cap with spermicidal gel, foam, film, 
cream, or vaginal suppository), (4) male sterilization with verified absence of sperm in 
ejaculate post-vasectomy. Alternatively, true abstinence is acceptable when it is the 
preferred and usual lifestyle of the individual. Calendar, symptothermal, post-ovulation, 
coitus interruptus, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. 
7. If male, is surgically sterile or agrees to use a condom from C1D1 through 3 months after 
the last study drug dose. Alternatively, true abstinence is acceptable when it is the 
preferred and usual lifestyle of the individual. 
8. SSTR2 positive tumor as assessed using a SARI agent and as defined as follows:  
• For SCLC patients, tumor uptake equal to or greater than liver update 
• For all other patients, tumor uptake greater than liver uptake.  
SARI performed during the Pre-screening phase must be obtained using an agent that is 
approved for use by the regional regulatory authority. Documented results of SARI 
performed as part of a patient’s routine diagnostic assessments prior to the Pre-screening 
Phase and within 180 days of C1D1 may be used in place of a Pre-screening phase SARI 
assessment. 
9. Patients in Phase 1 must have a histologically- or cytologically-confirmed solid tumor in 1 of 
the following categories: 
• Advanced SCLC or LCNEC of the lung having progressed after 1 or more prior lines 
of anticancer chemotherapy, or 
• Advanced low or intermediate grade GEP or lung or thymus NET, or NET of 
unknown primary, having progressed after 1 or more prior lines of anticancer 
therapy, unless no standard treatments are available or unless such treatments are 
deemed not appropriate, or 


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• Advanced paraganglioma, pheochromocytoma, medullary thyroid carcinoma, Merkel 
cell carcinoma, or high grade extrapulmonary NEC having progressed after 1 or more 
prior lines of anticancer therapy, unless no standard treatments are available or unless 
such treatments are deemed not appropriate. 
Anticancer therapies include liver-directed intra-arterial therapy, cytotoxic 
chemotherapy, everolimus, targeted inhibitors, MIBG, and immunotherapies, but does 
not include somatostatin analogs. 
For patients who provide written informed consent to undergo an optional tumor biopsy during 
the Screening phase, such patients must meet the following additional criterion before 
undergoing a biopsy procedure: 
10. Patient must have at least 1 site of tumor that is accessible to biopsy and that is 
considered by the Investigator to be low risk and of sufficient size to undergo a biopsy 
procedure. 
Patients in Phase 2a must meet the following additional criteria: 
11. Measurable disease per RECIST 1.1 (i.e., at least 1 measurable lesion ≥ 20 mm by 
conventional techniques or ≥ 10 mm by spiral CT scan or MRI), with the last imaging 
performed within 28 days before C1D1 and documented radiographic disease 
progression. 
12. Patients in Phase 2a must have  a histologically- or cytologically-confirmed, advanced or 
metastatic solid tumor, in 1 of the following categories:  
• Well differentiated, low or intermediate grade, gastrointestinal mid-gut (arising 
from the lower jejunum, ileum, appendix, cecum, and proximal colon) NET with 
documented disease progression within 6 months prior to start of study treatment 
(i.e. maximum of 24 weeks from documentation of progression until study entry) 
and evidence of radiographic disease progression based on scans performed not 
more than 15 months apart. Patients may have received 1 or more prior lines of 
anticancer therapy, such as somatostatin analogues, targeted agents, or liver-
directed intra-arterial therapy, but are NOT eligible if they have received prior 
systemic cytotoxic chemotherapy. 
• Well differentiated, low or intermediate grade, pancreatic NET with documented 
disease progression within 6 months prior to start of study treatment (i.e. 
maximum of 24 weeks from documentation of progression until study entry), and 
evidence of radiographic disease progression based on scans performed not more 
than 15 months apart. Patients may have received 1 or more prior lines of 
anticancer therapy, such as somatostatin analogues, targeted agents, or liver-
directed intra-arterial therapy, and up to 1 prior line of systemic cytotoxic 
chemotherapy, but are NOT eligible if they have received more than 1 prior line 
of systemic cytotoxic chemotherapy or if they have received prior peptide 
receptor radionuclide therapy (PRRT). 
• SCLC after having received up to three prior lines of anticancer therapy. 
7.4. 
Patient Exclusion Criteria 
Patients meeting any of the following criteria are not eligible for study participation  


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1. Treatment with anticancer therapy (as defined in inclusion criterion 9 and 12 ) or an 
investigational drug or device within 3 weeks (6 weeks for mitomycin C and 
nitrosoureas) or 5 half-lives of the agent (whichever is shorter) before C1D1.  In addition, 
any drug-related toxicity, with the exception of alopecia, must have recovered to ≤ Grade 
1. 
2. Any other malignancy known to be active or treated within 3 years of the start of 
screening, with the exception of cervical intra-epithelial neoplasia, superficial (non-
invasive) bladder cancer, and non-melanoma skin cancer. 
3. One or more of the following cardiac criteria: 
• Unstable angina 
• Myocardial infarction within 6 months prior to screening 
• New York Heart Association Class II – IV heart failure 
• Corrected QT interval (QTc) >470 msec obtained as the mean from 3 consecutive 
resting ECGs using the Fredericia formula 
• Clinically important abnormalities in rhythm, conduction, or morphology of 
resting ECG (e.g., complete left bundle branch block, third degree heart block) 
• Congenital long QT syndrome 
• Symptomatic orthostatic hypotension within 6 months prior to screening 
• Uncontrolled hypertension.  
4. Stroke or transient ischemic attack within 6 months prior to screening 
5. Grade >1 peripheral neuropathy 
6. Patient requires medication with a strong CYP3A4 inhibitor, e.g., ketoconazole, 
itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, 
saquinavir, telithromycin, and voriconazole. 
7. History of leptomeningeal disease or spinal cord compression. 
8. Brain metastases unless asymptomatic on a stable low dose of steroids. 
• Patients with SCLC or LCNEC of the lung only: CT or MRI of the brain required 
during screening. If positive for brain metastases, patients must have undergone 
radiotherapy prior to initiating treatment with PEN-221. If whole brain 
radiotherapy is performed, a 14-day washout is required prior to treatment with 
PEN-221. If stereotactic radiosurgery or stereotactic radiotherapy is performed, a 
7-day washout prior to treatment with PEN-221 is required. 
9. Major surgery within 28 days prior to C1D1. 
10. Female who is pregnant or breast-feeding. 
11. As judged by Investigator, evidence of severe or uncontrolled systemic disease, active 
bleeding diatheses, renal or liver transplant, or active infection including known hepatitis 
B, hepatitis C, or human immunodeficiency virus (HIV). 
12. Hypersensitivity or history of anaphylactic reaction to octreotide or other somatostatin 
analogs. 
13. Hypersensitivity or history of anaphylactic reaction to maytansinoids or their derivatives. 


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14. Any medical, psychological, or social condition that would interfere with the patient’s 
participation in the study. 
7.5. 
Patient Restrictions During Treatment 
From the first dose of PEN-221, C1D1, patients must adhere to the following restrictions: 
• Male patients must not donate sperm for 3 months after the last study drug dose, and 
those who have not been sterilized with verified absence of sperm in ejaculate post-
vasectomy must use a condom from C1D1 through 3 months after the last study drug 
dose. Alternatively, true abstinence is acceptable when it is the preferred and usual 
lifestyle of the individual. 
• Female patients of childbearing potential must practice the use of highly reliable, 
physician-approved contraception from 14 days before C1D1 through 3 months after 
the last study drug dose. Highly reliable contraception means 2 of the following: (1) 
established use of oral, injected, or implanted hormonal methods of contraception, (2) 
placement of an intrauterine device (3) condom or occlusive cap (diaphragm or 
cervical vault cap with spermicidal gel, foam, film, cream, or vaginal suppository), 
(4) male sterilization with verified absence of sperm in ejaculate post-vasectomy. 
Alternatively, true abstinence is acceptable when it is the preferred and usual lifestyle 
of the individual. Calendar, symptothermal, post-ovulation, coitus interruptus, 
spermicides only, and lactational amenorrhea are not acceptable methods of 
contraception. 
• All patients must follow concomitant medication provisions in Section 8.12.1. 
• Patient hematology and blood chemistries must continue to meet Inclusion Criteria 4 
and 5 for patients to continue receiving PEN-221. 
7.6. 
Source of Patients 
This will be a multi-center study. Each study center is required to obtain Institutional Review 
Board (IRB) or Ethics Committee (EC) approval to conduct the study before enrollment of 
patients may begin. Patients meeting the entry criteria will be eligible for enrollment. 
7.7. 
Patient Identification and Enrollment 
To ensure accurate and timely monitoring of patient enrollment, the following procedures will be 
implemented: 
• Patients who are candidates for enrollment into the study will be assigned a sequential 
and unique patient number by the Investigator after the patient has provided written 
informed consent into the Screening phase. Once a patient number has been assigned, 
it cannot be reused. 
• Patients who have provided written informed consent will be evaluated for eligibility 
by the Investigator to ensure that the entry criteria (see Section 7.2 and Section 7.4) 
have been satisfied and that the patient is eligible for participation in this clinical 
study. 


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• The Investigator or the Investigator’s research staff will provide eligibility 
information to the Medical Monitor. 
• Patients who are enrolled but not treated will be replaced. Furthermore, during Phase 
1, patients who discontinue from the study before completing C1 for reasons other 
than DLT will be replaced. 
• Investigators will be notified by the Sponsor when enrollment in a given dose cohort / 
study phase is closed and enrollment into the next dose cohort / study phase can 
begin. Investigators will be consulted in all dose escalation decisions. 
• Investigators will be notified by the Sponsor if the study is placed on administrative 
hold, when it is completed, or is closed to further patient enrollment. 
7.8. 
Patient Withdrawal Criteria 
Patients may withdraw from the study at any time for any reason, without prejudice to their 
medical care. The Investigator also has the right to discontinue treatment with PEN-221 or  
withdraw patients from the study for any of the following reasons: 
• Progression of disease 
• AE 
• Life threatening or other unacceptable toxicity 
• PEN-221 cycle delay for > 3 weeks due to study drug-related toxicity 
• Patient requires use of a prohibited concomitant medication or therapy 
• General or specific changes in the patient’s condition unacceptable for further 
treatment within the study parameters, in the Investigator’s opinion 
• Severe non-compliance 
• Lost to follow-up 
• Patient withdrawal of consent 
• A decision to modify or discontinue development of the drug 
The EOT visit is to be completed within 3 days from the event resulting in treatment 
discontinuation (e.g., disease progression, AE, consent withdrawal, etc.). A Safety Follow up 
visit is to be completed 28 days after the last study drug dose. End of study (EOS) occurs when 
the patient is no longer being followed up for progression or survival (i.e. death, lost to follow-
up, withdrawal of consent). The primary reason for a patient’s discontinuation from treatment 
and withdrawal from the study is to be recorded in the electronic case report form (eCRF).  
7.9. 
Withdrawal of Consent for Use of Donated Samples 
Patients may withdraw consent for use of any tissue, fluid, or other biological samples they 
provide, without prejudice to their medical care, and without necessarily having to withdraw 
from the whole study. 


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If patients withdraw consent for use of donated samples, the Investigator must immediately 
notify the Sponsor or designee and ensure that any samples stored at the study site are disposed 
of or destroyed in a manner consistent with institutional policy, as promptly as possible, and such 
actions are recorded. The Sponsor or designee will, as promptly as possible, ensure that any 
samples stored outside of the study site are similarly disposed of or destroyed, document this 
action, and provide a copy of that documentation to the study site. 
7.10. 
Incorrectly Enrolled Patients 
If it is determined that any patient does not meet all inclusion criteria, or that any patient meets 
any exclusion criteria, or both, the patient should NOT receive any study drug, and should not 
receive any study assessments from that point on aside from those used to ensure patient safety. 
If an ineligible patient has entered the study but has not yet received any study drug, the patient 
is to be withdrawn from the study, and may be replaced. 
If an ineligible patient has entered the study and has received any amount of study drug, the 
Medical Monitor must be notified by the Investigator immediately. The SRC will convene to 
assess the specific patient risks and benefits of the case. The patient must be withdrawn from the 
study if the SRC determines it is in the patient’s best interest. 
7.11. 
Safety Review Committee 
The SRC will consist of the Medical Monitor, who will chair the committee, and the Principal 
Investigator or delegate from each active study center. The study statistician will participate in 
the SRC during Phase 1. Ad hoc participants such as the clinical pharmacology scientist, and 
clinical operations leader may be invited as appropriate. Additional experts may be consulted by 
the SRC as needed. The SRC Charter for this study will define the exact membership and who 
should be present for decisions to be made. 
The SRC has the responsibility for monitoring the clinical study’s progress and the safety of the 
participating patients. After there are at least 2 evaluable patients for the first cohort and 3 
evaluable patients for subsequent cohorts at each dose level during Phase 1 of the study, the SRC 
will review and assess all available safety data from the cohort together with available PK data 
and recommendations from the BLRM to make a decision on the dose for the next cohort of 
patients. The decision may be to: 
• Proceed with dose escalation 
• Expand the cohort to a maximum of 6 evaluable patients 
• De-escalate the dose to a lower dose level (up to a maximum of 6 evaluable patients) 
or to an intermediate lower dose level 
• Stop the dose escalation 
When there are other patients that are ongoing at the time of this review, the SRC may decide to 
defer their decision until these further patients become evaluable. 
Any patient started on treatment in error, i.e., he or she failed to comply with all of the selection 
criteria but meets the criteria of an evaluable patient, will be reviewed on a case by case basis by 


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the SRC to determine if the patient should be included or excluded in the decision for dose 
escalation. 
The decisions and decision-making of the SRC on the next dose level will be documented by the 
Sponsor or designee and provided to the Investigators before dosing any new patients. 
After identification of the MTD, the SRC will periodically review all safety data and available 
PK data to confirm that no unexpected, significant, or unacceptable risk to patients enrolled in 
the study has been discovered. 
7.12. 
Investigator Compliance 
Study centers that deviate significantly from the protocol without prior approval from the 
Sponsor and regulatory authorities may be discontinued from the study. The Investigator at each 
study center is responsible for ensuring the accuracy and completeness of all research records, 
the accountability of study drug, and the conduct of clinical and laboratory evaluations as 
outlined in the protocol. 
7.13. 
Patient Adherence to Protocol Schedule 
All patients are required to adhere to the protocol-specified visit schedule. 
Permissible visit windows are specified in Table 2 and Table 3. Visit windows may be 
lengthened for administrative reasons (e.g., holidays) after consultation with the Medical 
Monitor. 
On D1 of each cycle (i.e., study drug administration days), patients are to present to the study 
center, ideally within approximately 2 hours before study drug administration for pre-treatment 
assessments. 
Additional study center visits may be scheduled, as deemed necessary based on the patient’s 
clinical status. 
An EOT visit should be conducted within 3 days of the event resulting in treatment 
discontinuation. A Safety Follow-up visit should be conducted 28 days (±3 days) after the last 
dose of study drug. Progression follow-up visits will occur until objective disease progression. 
Following disease progression, survival follow-up will occur every 3 months until death, lost to 
follow-up or consent withdrawal. 
Failure to attend scheduled study visits within the protocol-specified windows may result in 
discontinuation from the study. 






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If 2 patients in a cohort experience a DLT, further enrollment to the study will be 
suspended and the Bayesian model will be updated with this new information. If the 
Bayesian model supports enrolling the next cohort at the same dose level, or at a higher 
dose level, the relevant data and rationale will be discussed and agreed upon at the SRC. 
If the SRC agrees that it is medically appropriate to enroll an additional cohort at the 
same dose level, or at a higher dose level, the data and rationale supporting this decision 
will be provided to regulatory agencies, IRBs and ECs for their review and approval 
before proceeding with enrollment at the same or higher dose level. 
4. Following the principle of EWOC, after each cohort of patients the recommended dose is 
the 1 with the highest posterior probability of the DLT rate falling in the target toxicity 
interval [0.16, 0.33) among the doses fulfilling the EWOC criteria. Per EWOC it should 
be unlikely (<25% posterior probability) that the DLT rate at the dose will exceed 0.33. 
5. After repeating the preceding steps, the MTD is declared when at least 6 patients have 
been evaluated at the dose level recommended by the BLRM, and either of the following 
conditions is met: 
a. The posterior probability of targeted toxicity is at least 60% for this, or 
b. A minimum of 18 patients have already been treated in the study. 
8.6.1.3. 
Dose Selection Process 
At the end of each treatment cohort, the SRC will convene for a dose escalation teleconference. 
The clinical course for each patient in the current dose cohort will be presented and discussed in 
detail. Updated safety data on other ongoing patients, including data in later cycles, will be 
discussed as well. 
All available toxicity information, PK, PDc, and anti-tumor activity information, as well as 
recommendations from the BLRM will be evaluated by the SRC in order to make a determine 
the dose regimen for the next cohort. The SRC must reach a consensus on whether to declare 
MTD, escalate the dose any further, or whether to de-escalate and/or expand recruitment into 
particular cohorts. 
Dose levels presented in Table 6  are provisional. Dose decisions during escalation are however 
not limited to these doses. Based on the recommendation of the BLRM regarding the highest 
dose that is not to be exceeded at any decision point and the maximum increase in dose allowed 
by the protocol, intermediate doses may be administered to subsequent cohorts of patients. 
Dose escalation may be terminated at any time based on emerging safety concerns without 
establishing the MTD. 
The Sponsor or designee will prepare minutes from these meetings and circulate them to each 
Investigator for comment prior to finalization. Drug administration at the next dose level may not 
proceed until the Investigator receives written confirmation from the Sponsor or designee that 
the results of the previous dose level were evaluated and the higher dose level is estimated not to 
have exceeded the MTD. 


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8.6.2. 
Phase 2a 
The RP2D will be the decision of the SRC and will be based on the findings of the safety, 
tolerability, PK, and PDc profile of PEN-221 during Phase 1. The RP2D may be re-evaluated by 
the SRC at any time based on emerging safety concerns but may not exceed the MTD established 
in Phase 1. See section 8.10.  
8.7. 
Definition of Dose-Limiting Toxicity 
A dose-limiting toxicity (DLT) is defined as any toxicity occurring within the first four weeks 
(i.e., up until C2D8) for patients in Cohort 1 and within the first three weeks (i.e., up until C2D1) 
for patients in subsequent cohorts that is not related to the underlying disease, disease 
progression, intercurrent illness, or concomitant medications, and that meets any of the following 
criteria: 
1. Hematological toxicity: 
Grade 4 neutropenia (ANC < 500 cells/mm3) lasting longer than 4 consecutive days 
Grade 3 neutropenia (ANC ≥ 500 to < 1000 cells/mm3) of any duration associated with 
fever ≥ 38.5°C or systemic infection 
Grade 4 thrombocytopenia (< 25,000/mm3) or Grade 3 thromobcytopenia (25,000 to 
<50,000/mm3) associated with bleeding 
2. Non-hematological toxicity ≥ CTCAE Grade 3 including: 
QTc prolongation (> 500 msec) 
Grade 3 increase in total bilirubin, ALT, AST or ALP 
ALT or AST ≥ 3× ULN and concomitant total bilirubin ≥ 2× ULN 
Refer to Section 10.2.2.3, for more detailed information about the review, assessment and 
reporting of cases that meet the criteria for potential Hy’s Law. 
3. Any other toxicity that: 
Is greater than that at baseline, is clinically significant and/or unacceptable, does not 
respond to supportive care, results in a disruption of PEN-221 dosing schedule of more 
than 2 weeks and/or is judged to be a DLT by the SRC 
A DLT excludes: 
1. Isolated laboratory changes of any grade without clinical sequelae or clinical significance 
with the exception of those laboratory changes outlined above 
2. Grade 3 nausea, vomiting, diarrhea or dehydration that resolves to < Grade 3 within 48 
hours of initiating supportive care treatment specified in Section 8.11.3.2 
3. Grade 3 fever (in the absence of neutropenia), or fatigue that resolves to < Grade 3 within 
72 hours. 


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8.8. 
Definition and Estimation of Maximum Tolerated Dose 
The maximum tolerated dose (MTD) is the highest drug dosage not expected to cause dose-
limiting toxicity (DLT) in more than 33% of the treated patients in the first 3 weeks of PEN-221 
treatment (or in the first 4 weeks of PEN-221 treatment for Cohort 1 only). 
A 2-parameter (BLRM) in conjunction with EWOC (Babb 1998; Neuenschwander 2008) will be 
used during the escalation phase to guide the selection of doses to investigate and for estimation 
of the MTD. 
The general plan is that cohorts of patients will receive escalating doses of PEN-221 until the 
MTD is reached. Each cohort will consist of newly enrolled patients. 
Estimation of the MTD will be based upon the estimation of the probability of DLT in C1 in 
patients in the dose-determining set (DDS). Details are described in Section 15. 
8.9. 
Definition of Evaluable Patient 
An evaluable patient is defined as a patient that has received PEN-221 and either: 
• has completed minimum safety evaluation requirements during the first 21-day cycle, 
or 
• has experienced a DLT during the first 21 day cycle. 
8.10. 
Definition of Recommended Phase 2 Dose 
The RP2D may be equal to or below the MTD. The RP2D will be determined by the SRC and 
will take into consideration the safety data from the patients treated in Phase 1, and, if 
appropriate, the early experience in Phase 2a. Additionally, observations related to PK, and any 
cumulative toxicity observed after multiple cycles may be included in the rationale supporting 
the RP2D. 
8.11. 
Dose Modifications 
All patients will receive PEN-221 at the prescribed dose in C1. After C1, if, in the Investigator’s 
judgment, a patient experiences a clinical significant and/or unacceptable toxicity including a 
DLT not attributable to the disease or disease-related processes under investigation, dosing will 
be delayed and/or the subsequent dose will be reduced, and supportive therapy will be 
administered as required. Dose adjustments will be based on the organ system exhibiting the 
greatest degree of toxicity. 
For individual patients, treatment for each new cycle will be delayed if the scheduled off-drug 
periods are not adequate to allow for recovery to ≤ Grade 1 or the baseline status of the patient; 
with the exception of fatigue, anorexia, and ALT and/or AST elevation that must have recovered 
to ≤ Grade 2 and be considered tolerable. Alopecia of any grade or duration will not lead to dose 
modification or treatment delay. 
In Phase 1, patients who are at the lowest possible dose, i.e., in Cohort 1 or who have had their 
dose previously reduced to the Cohort 1 dose and who have demonstrated an acceptable response 
to dose interruption may re-start at either the provisional Cohort −1 dose level or the Cohort 1 
dose level, at the discretion of the Investigator. 


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Any patient requiring a toxicity-related dose delay of more than 3 weeks from the intended day 
of the next scheduled dose must be discontinued from study treatment unless there is approval 
from the Medical Monitor for the patient to continue. Patients who discontinue from treatment 
should be observed until resolution of the toxicity. 
Patients in Phase 1 and Phase 2a can have a maximum of 1 dose modification of study therapy 
throughout the course of the study for toxicities. Dose-re-escalation is not permitted. Patients 
who require more than 1 dose modification will be discontinued from the study. 
8.11.1. 
Intra-patient Dose Escalation 
During the Dose escalation phase only, if a patient is tolerating PEN-221 without evidence of 
PD, the patient may have the dose increased, starting on D1 of C3 or subsequent cycles, to a dose 
that has already been established as safe and tolerable by the SRC, with the agreement of the 
Medical Monitor. Patients who undergo intra-patient dose escalation will follow the schedule of 
safety assessments as outlined in C1 and C2, including PK assessments as outlined in C1D1, for 
the first 2 cycles of PEN-221 administered at the higher dose level. 
Dose modification for toxicity will proceed according to guidelines detailed in Section 8.11.2 
and Section 8.11.3. 
8.11.2. 
Dose Modifications for Hematological Toxicities 
Complete blood counts (CBC) will be monitored prior to treatment of each dose of PEN-221 and 
at regular intervals throughout the study (see Section 9.3.5.1). If hematological toxicity occurs, 
treatment should be held, and ANC, platelets and hemoglobin should be monitored at least 
weekly until recovery. 
Hematological toxicities are to be treated as medically indicated. In addition, the measures listed 
in Table 7 are recommended. 


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Table 7: 
Dose Modifications and Management of Neutropenia, Febrile Neutropenia, 
Infection, Thrombocytopenia, and Anemia 
AE 
Action to be Taken 
Grade 3/4 neutropenia lasting < 5 days 
• 
Resume treatment at 100% dose, on schedule, with 
prophylactic granulocyte-colony stimulating factor 
(G-CSF) for subsequent treatment. 
Grade 3/4 neutropenia lasting for ≥ 5 days 
• 
Delay treatment for up to 3 weeks (i.e., up to 
6 weeks after the previous study drug dose) until 
ANC is ≥ 1.5×109/L (and until infection has 
resolved completely). Once ANC returns to ≥ 
1.5×109/L, resume study drug at the next lowest 
dose level with prophylactic G-CSF for subsequent 
treatment. 
• 
If G3/4 neutropenia recurs on the reduced dose or if 
ANC recovery to ≥ 1.5×109/L does not occur within 
6 weeks of the previous study drug dose, then study 
drug is to be discontinued. 
Grade 3/4 neutropenia with oral temperature ≥ 38.5°C 
Infection (documented with Grade 3/4 neutropenia) 
Grade 3/4 thrombocytopenia 
• 
Delay treatment for up to 3 weeks until platelet 
count is ≥ 100×109/L. Once platelet count returns to 
≥ 100×109/L, re-start study drug at the next lowest 
dose level. 
• 
If platelet count does not return to ≥ 100×109/L 
after delaying treatment for up to 3 weeks 
(i.e., within 6 weeks after the previous study drug 
dose), then study drug is to be discontinued. 
Grade 2/3 anemia 
• 
Delay treatment up to 3 weeks (i.e., within 6 weeks 
after the previous study drug dose) until 
hemoglobin returns to ≥ 9 g/dl. Once hemoglobin 
returns to ≥ 9 g/dl, re-start study drug at the next 
lowest dose level. 
• 
If hemoglobin does not return to ≥ 9 g/dl after 
delaying treatment for up to 3 weeks (i.e., within 
6 weeks after the previous study drug dose), then 
study drug is to be discontinued. 
Grade 4 anemia 
• 
Discontinue study drug. 
8.11.3. 
Dose modification for Non-hematologic Toxicities 
8.11.3.1. Hepatic Toxicity 
Serum transaminases and total and direct bilirubin will be monitored prior to treatment of each 
dose of PEN-221 and at regular intervals throughout the study (see Section 9.3.5.1). If elevations 
of transaminases or total and direct bilirubin are observed, PEN-221 dose delay, dose reduction 
or treatment discontinuation may be required as per guidelines below. 
For ALT or AST > 2.5× ULN to ≤ 5× ULN delay treatment until recovers to ≤ 2.5× ULN and 
then treat at same dose level. 


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For ALT or AST > 5× ULN to ≤ 20× ULN (Grade 3) with or without concomitant elevation of 
bilirubin >1.5 × and < 2 × ULN, delay treatment until ALT/AST recovers to ≤ 2.5× ULN or 
baseline and bilirubin has returned to baseline, and then reduce 1 dose level. 
For ALT or AST or ALP >20× ULN (Grade 4), discontinue treatment. 
For total bilirubin > 1.5 to ≤ 3× ULN (Grade 2), delay treatment until recovers to Grade ≤ 1 and 
then treat at same dose level. 
For total bilirubin > 3 to ≤ 10× ULN (Grade 3), and ALT or AST <3 × ULN, delay treatment 
until recovers to Grade ≤ 1 and then reduce 1 dose level. 
For total bilirubin > 10× ULN (Grade 4), discontinue treatment. 
For ALT or AST ≥ 3× ULN and total bilirubin ≥ 2× ULN (Hy’s Law), discontinue treatment. 
Refer to Section 10.2.2.3, for more detailed information about the review, assessment and 
reporting of cases that meet the criteria for potential Hy’s Law. 
8.11.3.2. Gastrointestinal Effects 
8.11.3.2.1. Nausea and Vomiting 
For ≤ Grade 2 nausea and vomiting, manage symptomatically and re-treat with no reduction of 
PEN-221 dose, on schedule. Refer to Section 8.12.3 for permitted medications. 
For ≥ Grade 3 nausea and vomiting, manage symptomatically and delay treatment for up to 
3 weeks until resolution to ≤ Grade 2 or baseline. Thereafter, re-start study drug at the next 
lowest dose level. If nausea and vomiting do not resolve to ≤ Grade 2 after a delay of up to 3 
weeks (i.e., 6 weeks after the previous study drug dose), then study drug is to be discontinued. 
8.11.3.2.2. Constipation 
For ≤ Grade 2 constipation, manage symptomatically and re-treat with no reduction of PEN-221 
dose, on schedule. Refer to Section 8.12.3 for permitted medications. 
For ≥ Grade 3 constipation, manage symptomatically and delay treatment for up to 3 weeks until 
resolution to ≤ Grade 2 or baseline. Thereafter, re-start study drug at the next lowest dose level. 
If constipation does not resolve to ≤ Grade 2 after a delay of up to 3 weeks (i.e., 6 weeks after the 
previous study drug dose), then study drug is to be discontinued. 
8.11.3.2.3. Diarrhea 
For ≤ Grade 2 diarrhea, manage symptomatically and re-treat with no reduction of PEN-221 
dose, on schedule. Refer to Section 8.12.3 for permitted medications. 
For ≥ Grade 3 diarrhea, manage symptomatically and delay treatment for up to 3 weeks until 
resolution to ≤ Grade 2 or baseline. Thereafter, re-start study drug at the next lowest dose level. 
If diarrhea does not resolve to ≤ Grade 2 after a delay of up to 3 weeks (i.e., 6 weeks after the 
previous study drug dose), then study drug is to be discontinued. 


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8.11.3.3. Peripheral Neuropathy 
For ≥ Grade 2 peripheral neuropathy, delay treatment for up to 3 weeks until resolution to ≤ 
Grade 1. Re-start study drug at the next lowest dose level. 
If peripheral neuropathy does not resolve to ≤ Grade 1 after delaying treatment for up to 3 weeks 
(i.e., within 6 weeks after the previous study drug dose), then study drug is to be discontinued. 
8.11.3.4. QTc Prolongation 
For QTcF > 470 to ≤ 500 msec on the average of 3 consecutive readings taken pre-dose on any 
dosing day, delay treatment for up to 2 weeks and repeat QTcF testing on a subsequent day. If ≤ 
470msec upon repeat testing on a subsequent day, resume treatment at the same dose level. If 
QTcF > 470 to ≤ 500 upon repeat testing, discontinue treatment. 
If QTcF > 500 msec on the average of 3 consecutive readings taken at any time point during 
study, discontinue treatment. 
8.11.3.5. Infusion-related Reactions, Hypersensitivity Reactions 
Mild to moderate infusion-related reactions (i.e., NCI CTCAE Grades 1 and 2 and infusion 
reactions that do not involve symptoms of anaphylaxis) should be managed with temporary 
interruption of the infusion and medical management of symptoms, as per institutional 
guidelines. After all symptoms have resolved, re-challenge with a reduced infusion rate and 
additional premedication is permitted. 
Severe infusion-related reactions (NCI CTCAE Grade 3 or higher) or reactions with any features 
of anaphylaxis require immediate discontinuation of the study drug infusion, immediate 
treatment with epinephrine and antihistamines and additional management per institutional 
guidelines. Following a severe infusion-related reaction or suspected anaphylaxis, re-challenge 
with PEN-221 is not permitted; therefore, the patient must permanently discontinue study 
treatment. 
8.11.3.6. Other Non-hematologic Toxicities 
For all other Grade 3 – 4 toxicities other than those described above, delay treatment with PEN-
221 (max up to 3 weeks) until resolved to ≤ Grade 1 or baseline, and resume at next lowest dose 
level. 
If Grade 3 – 4 toxicity recurs, permanently discontinue treatment. 
For all other Grade <3 toxicity, decision to delay PEN-221 for a maximum of 3 weeks is at the 
Investigator’s discretion. PEN-221 will resume at the same dose or at the next lowest dose level 
prior to interruption, at the Investigator’s discretion. 
8.12. 
Concomitant Medications 
All prescription and non-prescription medications and therapies, including pharmacologic doses 
of vitamins, herbal medicines, or other non-traditional medicines, taken from 30 days prior to the 
first dose of PEN-221 through the EOT visit must be recorded in the eCRF. On PK sample 
collection days, both the date and time of concomitant medications and therapies must be 
recorded. 


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8.12.1. 
Prohibited Medications 
The following medications and treatments are prohibited during study participation. 
• Concomitant use of strong CYP3A4 inhibitors (such as ketoconazole, itraconazole, 
clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, 
telithromycin, and voriconazole). DM1, the cytotoxic component of PEN-221, is 
metabolized in vitro mainly by CYP3A4 and to a lesser extent by CYP3A5 
[(KADCYLA® (ado-trastuzumab emtansine) package insert, Genentech, Inc., South 
San Francisco, CA]. Therefore, concomitant use of strong CYP3A4 inhibitors is 
prohibited due to the potential for an increase in DM1 exposure and toxicity. The use 
of aprepitant (EMEND®), a substrate, moderate inhibitor and inducer of CYP3A4, is 
NOT permitted. 
• Any investigational agent or device other than PEN-221, including agents that are 
commercially available for indications other than the patient’s solid tumor that are 
under investigation for the treatment of solid tumors. 
• Any radiotherapy, chemotherapy, anti-neoplastic treatments or investigational agents 
other than study drug. Radiation for palliation at focal sites may be permitted after 
discussion between the Investigator and Medical Monitor. 
• Live virus and bacterial vaccines should not be administered, e.g., yellow fever, 
measles, influenza, rubella, mumps, typhoid, mycobacterium tuberculosis (BCG), 
Yersinia pestis (EV). An increased risk of infection by the administration of these 
vaccines has been observed with conventional chemotherapy and the effects with 
PEN-221 are unknown. The administration of killed vaccines is allowed. Examples of 
killed vaccines are cholera, bubonic plague, polio vaccine, hepatitis A and rabies. 
Other medications, other than those described above, which are considered necessary for the 
patient’s safety and well-being, may be given at the discretion of the Investigator and recorded in 
the appropriate sections of the eCRF. 
8.12.2. 
Medications to be Used with Caution 
The following medications should be used with caution during study participation: 
• Anti-hyperglycemic medications: Somatostatin analogs inhibit the secretion of 
insulin and glucagon, which may result in hypoglycemia or hyperglycemia. Due to 
the similarity between somatostatin and the peptide component of PEN-221, dose 
adjustments of concomitant antihyperglycemic medications may be necessary in 
patients being treated with PEN-221. 
• Bradycardia-inducing drugs: Concomitant administration of bradycardia-inducing 
drugs (e.g., beta-blockers) may have an additive effect on the reduction of heart rate 
associated with somatostatin analogs. Due to the similarity between somatostatin and 
the peptide component of PEN-221, dose adjustments of concomitant bradycardia-
inducing drugs may be necessary in patients being treated with PEN-221. 
• Orally administered medications: Somatostatin analogs may reduce the intestinal 
absorption of concomitant medications. Due to the similarity between somatostatin 


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and the peptide component of PEN-221, there is a possibility that PEN-221 may 
reduce the intestinal absorption of concomitant medications. 
8.12.3. 
Permitted Medications 
Patients are permitted to receive appropriate supportive care measures as deemed necessary by 
the treating physician including but not limited to the items outlined below: 
• Nausea/vomiting: Anti-emetic treatment such as with 5-HT3 receptor antagonists is 
to be administered according to the guidelines of the study centers. Patients should be 
strongly encouraged to maintain liberal oral fluid intake. Strong consideration should 
be given to the administration of prophylactic anti-emetic therapy according to 
standard institutional practice, after the first cycle of PEN-221. The use of aprepitant 
(EMEND®), a substrate, moderate inhibitor and inducer of CYP3A4, is NOT 
permitted. 
• Diarrhea: Diarrhea should be treated promptly with appropriate supportive care, 
including administration of an anti-diarrheal agent according to standard practice 
guidelines. Anti-diarrheal agents should not be taken prophylactically. Patients should 
be instructed to begin taking anti-diarrheal medication at the first sign of: 1) poorly 
formed or loose stool, 2) occurrence of more bowel movements than usual in 1 day, 
or 3) unusually high volume of stool. Anti-diarrheal agents should be deferred if 
blood or mucus is present in the stool or if diarrhea is accompanied by fever. In this 
setting, appropriate diagnostic microbiologic specimens should be obtained to 
exclude an infectious etiology. Patients should also be advised to drink liberal 
quantities of clear fluids to help prevent dehydration. 
• Constipation: Contipation may be treated with stool softeners or lubricants. Use of 
osmotics is allowed with careful monitoring of electrolytes. 
• Anemia: Transfusions and/or erythropoietin may be used as clinically indicated for 
the treatment of anemia, but should be clearly noted as concomitant medications. 
Patients already receiving erythropoietin at the time of screening for the study may 
continue it providing they have been receiving it for more than 1 month at the time 
study treatment is started. Prophylactic erythropoietin should not be started during C1 
of the study, but may be started during C2 and thereafter. 
• Neutropenia: Patients who experience Grade 4 neutropenia lasting for ≥ 5 days; 
Grade 3/4 neutropenia with oral temperature ≥ 38.5°C; or infection with Grade 3/4 
neutropenia may receive treatment with colony-stimulating factors as described in 
Section 8.11.2. Prophylactic use of colony-stimulating factors including G-CSF, 
pegylated G-CSF or GM-CSF may be used according to institutional standards after 
the first cycle of PEN-221 therapy. 
• Somatostatin analogs: Agents such as octreotide, lanreotide, pasireotide, and other 
somatostatin analogs are permitted if their use is providing benefit in controlling 
carcinoid symptoms. 
Medications and treatments other than those specified in Section 8.12.1, including palliative and 
supportive care for disease-related symptoms, are permitted during the study, as appropriate. 


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9. 
ASSESSMENT OF PATIENTS 
9.1. 
Demographics and Medical History 
9.1.1. 
Demographics 
Patient demographics, including age, sex, race, and ethnicity, are to be documented during 
screening. 
9.1.2. 
Medical History, Including Cancer History 
A complete medical history is to be documented during screening and updated at baseline, prior 
to administration of the first PEN-221 dose. 
The medical history is to include cancer history, including the patient’s primary tumor type, 
current disease stage, date of and disease stage at diagnosis, method of diagnosis, and all 
previous treatments, including systemic therapy, radiation therapy, and surgeries, as well as 
response to such treatments. 
Each patient’s history of somatostatin analog treatment (start and stop dates, agents, doses), and 
results of any somatostatin analog imaging will be collected. 
As part of the patient’s cancer history, study centers are to submit a local histology or cytology 
report obtained prior to enrollment, if available. Furthermore, paraffin blocks (preferred) or a 
minimum of 10 unstained slides of available archival tumor tissue are to be requested from the 
patient’s local institution and collected, if available. 
9.2. 
Somatostatin Analog Radioisotope Imaging 
Those patients who do not have documented results of a historically positive SARI obtained 
within 180 days of C1D1 will be prescreened by SARI in this study to ensure their 
neuroendocrine tumors express somatostatin receptor prior to entering screening and prior to 
receiving PEN-221. This pre-screening must be performed using only SARI with regional 
marketing authorization to be used for detection and localization of somatostatin-receptor-
positive tumors. If multiple kits with marketing authorization are available, any method may be 
used at the discretion of the Investigator. Patients with documentation of a historically positive 
SARI (by 111In, 68Ga, 99mTc, or other radioisotope linked to a somatostatin analog) within 180 
days of C1D1 to be considered positive for SSTR2 expression, and will not be required to 
receive SARI during pre-screening in this study. 
The current state of neuroendocrine tumor imaging has recently been reviewed by Brabander 
(2015). 
9.2.1. 
Indium-labeled SARI 
Octreoscan™ Kit for the Preparation of Indium In 111 Pentetreotide (pentetreotide scanning) 
(Mallinckrodt Nuclear Medicine LLC, Maryland Heights MO USA) comprises 2 parts: a 10 ml 
reaction vial and a 10 ml vial of 111In chloride (Mallinckrodt 2015). The imaging agent is 
prepared within 6 h prior to use by combining the two components according to package 
directions to produce 111In pentetreotide. At time of calibration, the kit contains 111 MBq/ml (3.0 
mCi/ml) 111In, with a half-life of 2.8 d. 


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The scan should be performed according to institutional guidelines and manufacturer 
instructions. FOCBP should be tested for pregnancy and excluded if pregnant. Additional 
practice guidelines should also be reviewed (Balon 2011). Immediately prior to use, labeling 
yield must be determined according to package directions. The evening prior to 111In 
pentetreotide administration, a mild laxative such as bisacodyl or lactulose should be given and 
continued for 48 h. Both prior to and after administration, patients should be well hydrated, and 
should be encouraged to drink fluids liberally to reduce radiation dose by flushing out unbound 
agent through the kidneys as well as to ensure proper bowel cleansing. Although imaging can be 
performed by both planar and single-photon emission computed tomography (SPECT) cameras, 
only SPECT imaging should be used for scans performed in this study due to its 3-dimensional 
capabilities, superior sensitivity, and ability to more precisely allow tumor localization for 
possible comparision with CT or MRI scans. The recommended radiation dose for SPECT 
imaging is 222 MBq (6.0) mCi of 111In pentetreotide, and the expected effective dose equivalent 
is 26 mSv. 
Typically, imaging is performed 4 h and 24 h after administration of 111In pentetreotide. In some 
cases, images taken after 48 h are also useful to aid interpretation. Investigators and designees 
should follow standard practice for imaging time points. 
Scans are to be scored in relation to non-diseased areas of liver as described by Kwekkeboom 
(2005) and listed in Table 8 . 
Table 8: 
Octreoscan SSTR2 Scoring 
Score 
Description 
1 
111In pentetreotide uptake lower than normal liver tissue 
2 
111In pentetreotide uptake equal to normal liver tissue 
3 
111In pentetreotide uptake greater than normal liver tissue 
4 
111In pentetreotide uptake greater than normal spleen or kidney uptake 
SCLC patients are considered to have a positive Octreoscan if their score from Table 8  is 2, 3, or 
4. All other patients are considered to have a positive Octreoscan if their score from Table 8  is 3 
or 4. 
According to the manufacturer (Mallinckrodt 2015), the hormonal effect of 111In pentetreotide is 
1/10 that of octreotide. Since imaging doses are less than therapeutic doses of somatostatin 
analogs, the agent is not expected to exert clinically significant somatostatin effects in most 
cases, although severe hypoglycemia can occur in patients with insulinomas. An IV glucose 
solution should be administered just before and during administration in patients suspected of 
having an insulinoma. 
In a clinical study, 83 of 87 patients (95%) who received octreotide therapy within 72 h of 111In 
pentetreotide were successfully imaged. Nevertheless, imaging sensitivity may be reduced in 
patients concurrently receiving therapeutic doses of short-acting somatostatin therapy, so this 
should be considered in timing 111In pentetreotide administration. 
As 111In pentetreotide is eliminated primarily by the kidneys, use in patients with renal 
impairment should be considered carefully. 


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Adverse reactions associated with 111In pentetreotide (<1% in clinical trials of 538 patients) 
included dizziness, fever, flush, headache, hypotension, changes in liver enzymes, joint pain, 
nausea, sweating, weakness, a single case of bradycardia, and a single case of decreased 
hemoglobin and hematocrit. 
9.2.2. 
Gallium-labeled SARI 
SARI with 68Ga derivatives of somatostatin analogs has been practiced since at least 2001 
(Hofmann 2001). 68Ga-DOTATATE and 68Ga-DOTATOC are commonly used. Compared with 
PEN-221, they have the following affinity profiles (half-maximal inhibitory concentrations) to 
various human somatostatin receptors (Table 9): 
Table 9: 
Affinity Profiles (Half-maximal Inhibitory Concentrations) for Various 
Somatostatin Analogs 
 
SSTR1 
SSTR2 
SSTR3 
SSTR4 
SSTR5 
111In pentetreotidea 
>10 000 
22 
182 
>1 000 
237 
68Ga-DOTATATEa 
>10 000 
0.2 
>1 000 
300 
377 
68Ga-DOTATOCa 
>10 000 
2.5 
613 
>1 000 
73 
PEN-221b 
380 
0.042 
58 
>1 000 
24 
a Data from (Reubi 2000) 
b Data from internal Tarveda report PEN-221-PHARM-026 
68Ga is produced from a cyclotron, or collected from a Ge-Ga generator. It is then combined with 
somatostatin analogs, for example, as described by Mukherjee (2014). The resulting imaging 
agent is administered to patients and, almost immediately thereafter, imaged using concurrent 
positron emission tomography (PET) and CT. 
Lesions can be assigned standardized uptake values; however, a patient can be classified as 
positive overall using the scheme outlined in Table 8 . 
9.3. 
Safety Assessments 
9.3.1. 
Physical Examination 
Complete physical examinations are to be performed at the time points designated in Table 2 and 
Table 3. Complete physical examinations include assessment of the following: 
• General appearance 
• Head, eyes, ears, nose, and throat 
• Cardiovascular system 
• Respiratory system 
• Chest 
• Gastrointestinal system (abdomen) 


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• Lymphatic system 
• Musculoskeletal system 
• Skin 
• Psychiatric 
• Neurological: 
A thorough neurological assessment must be performed as part of the complete 
physical exam at the time points designated in Table 2 and Table 3  as microtubule 
disrupting agents including DM1 may be associated with sensory and/or motor 
peripheral neuropathies and these effects may be cumulative with dose. 
Neurological assessments should include questioning regarding whether the patient is 
experiencing any numbness, tingling, burning, or pain, or any sensation of weakness 
or difficulty performing daily activities. Exam to include light touch, sharp touch 
[skin prick], temperature, proprioception, and vibration sensation testing, as well as 
testing of deep tendon reflexes. Additional neurological assessments are to be 
performed as appropriate for the patient’s condition, at the Investigator’s discretion. 
Symptom-directed (i.e., abbreviated) physical examinations are to be conducted at all other study 
visits. 
On dosing days, physical examinations should be completed prior to infusion. Abnormal 
physical examination findings that are considered by the Investigator to be clinically significant 
for a particular patient during screening and before dosing on C1D1 are to be reported as part of 
the patient’s medical history. Abnormal, clinically significant examination findings following 
initiation of dosing on C1D1 are to be reported as an AE, if the finding represents a change from 
baseline. 
9.3.2. 
Vital Signs 
Vital signs, including blood pressure, pulse, respiration rate, and body temperature, are to be 
measured at the time points designated in Table 2 and Table 3. 
During screening, pulse rate and blood pressure will be measured across 3 positions: supine, 
sitting and standing, after at least 10 minutes rest. 
On C1D1 and D1 of subsequent cycles (dosing days), vital signs are to be measured prior to the 
start of study drug infusion and at 15 minute intervals throughout the infusion and for 1 hour 
after end of infusion. Pulse rate and blood pressure immediately prior to dosing will be measured 
across 3 positions: supine, sitting and standing. Other timepoints may be collected in 1 position 
only. If no notable changes in vital signs are observed, no additional vital sign measurements 
will be performed subsequent to 1 hour post end of infusion. If notable changes are observed, 
vital signs will be taken every hour for the next 6 hours, or longer if changes persist. 
For any patients on concomitant beta blockers, blood pressure should be monitored carefully and 
doses of these medications should be adjusted if needed, as somatostatin analogs have been 
associated with bradycardia. 
Abnormal, clinically significant vital signs results are to be reported as AEs, if the finding 
represents a change from baseline. 


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9.3.3. 
Weight and Height 
Height is to be measured for all patients during screening. 
Body weight is to be measured at the time points designated in Table 2 and Table 3 and at any 
time the Investigator suspects the patient has experienced a notable change in weight (±10%). 
9.3.4. 
Electrocardiogram 
A 12-lead ECG, measuring rhythm, QT, QRS, PR, and R-R intervals, is to be collected with the 
patient lying face-up at the time points designated in Table 2 and Table 3. Triplicate ECGs are to 
be collected approximately 5 minutes apart at all time points. On C1D1 (and during Phase 1 
only, also on C3D1), ECGs are to be performed immediately prior to the start of study drug 
infusion, at 30 minutes after the start of the infusion, (±5 minutes),  at the end of infusion (±5 
minutes), and at all scheduled PK time points thereafter; the date and time of each ECG start and 
stop are to be documented. On all other dosing days, ECGs should be performed immediately 
prior to infusion and at end of infusion (±5 minutes).  ECGs should be performed after the PK 
and glucose monitoring. 
The Investigator or designated physician will review all ECGs and see that any significant 
abnormalities are under appropriate management. 
9.3.5. 
Laboratory Assessments 
Laboratory assessments for hematology, clinical chemistries, coagulation studies, urinalysis and 
pregnancy testing will be performed by the local laboratory. 
Abnormal, clinically significant laboratory abnormalities are to be reported as AEs, if the 
findings represent a change from baseline. 
9.3.5.1. 
Hematology and Clinical Chemistries 
Blood samples for hematology and clinical chemistries are to be collected at the time points 
designated in Table 2 and Table 3. If the screening sample is collected within 3 days before 
C1D1, a sample need not be collected on C1D1. After C1D1, samples may be collected up to 48 
hours before scheduled study center visits. Hematology and clinical chemistry results must be 
reviewed by the Investigator prior to study drug administration. If any clinically relevant 
hematology or clinical chemistry abnormalities are identified after the patient leaves the study 
center, the patient is to be contacted and appropriate follow-up performed. 
On C1D1, glucose will be monitored pre-dose and at the end of infusion (±3 minute); and 2 
hours (±10 minutes), 4 hours (±10 minutes), 6 hours (±10 minutes), and 8 hours (±30 minutes) 
after the start of study drug infusion and for Phase 1 only at 10 hours (±30 minutes) after the start 
of study drug infusion (Table 2 and Table 3). If the patient experiences symptomatic 
hypoglycemia or hyperglycemia, or if any glucose level falls below 55 mg/dL (or below 3.0 
mmol/L) or above 250 mg/dL (or above 13.9 mmol/L) at any timepoint on C1D1, additional 
monitoring may be required per Investigator discretion. When multiple study assessments are 
scheduled at the same time, glucose monitoring should be done after PK blood collection and 
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For any patients on concomitant anti-hyperglycemic medications, glucose should be monitored 
carefully and doses of these medications should be adjusted if needed, as somatostatin analogs 
have been associated with changes in blood glucose levels and regulation. 
The following clinical laboratory parameters are to be measured: 
Hematology 
RBC count 
Platelet count 
Hemoglobin 
White blood cell count with differential 
Chemistry 
Chloride 
Bicarbonate  
Sodium 
Potassium 
Calcium 
Phosphorus 
Blood urea nitrogen (BUN) 
Magnesium 
Glucose 
Creatinine (with calculated creatinine clearance)* 
ALP 
Albumin 
ALT 
AST 
Total protein 
Total and direct bilirubin 
Cholesterol and triglycerides (fasting) 
Thyroid function (TSH and free T4) 
Amylase 
Lipase 
Cortisol 
 
*Creatinine clearance is to be estimated using the Cockcroft-Gault formula 
For Phase 2a, D8 and D15 evaluations are required for C1. If no Grade 2 or higher abnormalities 
in clinical chemistries or hematology parameters are observed during C1, then D8 and D15 
evaluations are not required for C2 and subsequent cycles. If Grade 2 or higher abnormalities in 
clinical chemistries or hematology parameters (excluding hyperglycemia in diabetic patients) are 
observed during C1, the D8 and D15 evaluations are required for C2 and C3. If Grade 2 or 
higher abnormalities do not recur during C2 and C3, the D8 and D15 evaluations may be 
eliminated in cycles thereafter, subject to Investigator discretion. If Grade 2 or higher 
abnormalities occur after C3, evaluations may be performed at a schedule determined by the 
Investigator, based on the patient’s clinical status. 
9.3.5.2. 
Urinalysis 
Urine for urinalysis is to be collected at the time points designated in Table 2 and Table 3.  If the 
screening sample is collected within 3 days before C1D1, a sample need not be collected on 
C1D1. 
The following urinalysis parameters are to be determined: 


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Urinalysis 
Specific gravity 
Protein 
pH 
Ketones 
Blood 
Microscopic examination of sediment 
Glucose 
 
 
9.3.5.3. 
Coagulation Studies 
Blood samples for coagulations studies, including PT and aPTT, along with international 
normalized ratio for patients on Coumadin or warfarin only, are to be collected at the time points 
designated in Table 2 and Table 3.  If the screening sample is collected within 3 days before 
C1D1, a sample need not be collected on C1D1. 
9.3.5.4. 
Peripheral Blood Anti-drug Antibodies 
Blood samples for anti-drug antibody assay are to be collected at the time points designated in 
Table 2 and Table 3.  
9.3.5.5. 
Pregnancy Testing 
Serum samples for HCG pregnancy testing are to be collected from females of childbearing 
potential (FOCBP) at the time points designated in Table 2. and Table 3.  If the screening sample 
is collected within 3 days before C1D1, a sample need not be collected on C1D1. Alternatively, 
urine dip stick testing can be performed instead, at the discretion of the Investigator and 
institutional policy. 
As HCG can be secreted by neuroendocrine tumors, in the event of a positive pregnancy test, 
pregnancy is to be assessed by transvaginal ultrasound overseen by a health care professional 
with experience in investigating and diagnosing early pregnancy. 
Pregnancy testing is to be repeated any time pregnancy is suspected. 
A FOCBP is defined as any female who has experienced menarche and who has not undergone 
successful surgical sterilization (hysterectomy, bilateral oophorectomy, bilateral salpingectomy 
but not tubal ligaton) or is not postmenopausal (defined as age ≥ 50 years and amenorrheic ≥ 12 
consecutive months; or amenorrheic ≥ 12 consecutive months and serum follicle-stimulating 
hormone, luteinizing hormone and plasma estradiol levels in the postmenopausal range for the 
institution). Women who are using oral, implanted, or injectable contraceptive hormones or 
mechanical products, such as an intrauterine device or barrier methods (diaphragm, condoms, 
spermicides) to prevent pregnancy, are practicing abstinence, or whose partner is sterile (e.g., 
vasectomy), are considered to be of childbearing potential. 
Prior to study enrollment, FOCBP must be advised of the importance of avoiding pregnancy 
during study participation and the potential risk factors for an unintentional pregnancy. This 
information will be included in the ICF that must be signed by the patient. In addition, all 
FOCBP or fertile men with partners of childbearing potential should be instructed to contact the 
Investigator immediately if they suspect they or their partner might be pregnant (e.g., missed or 
late menstrual period) at any time during study participation. 


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Accordingly, the patient must agree to highly effective contraception (as defined in inclusion 
criterion 6) from 14 days before C1D1 through 3 months after the last study drug dose. 
Patients with a positive pregnancy test result during screening or on C1D1 are not eligible for 
study participation, unless pregnancy is ruled out by transvaginal ultrasound. Patients with 
positive results any time after the start of study drug administration are to have a transvaginal 
ultrasound overseen by a health care professional with experience in investigating and 
diagnosing early pregnancy to confirm or rule out pregnancy, and if positive, study drug is to be 
permanently discontinued. Refer to Section 10.4 for details regarding management of any 
pregnancies during the study. 
9.3.6. 
ECOG Performance Status 
ECOG performance status is to be determined at the time points designated in Table 2 and 
Table 3. 
The ECOG performance status scale is presented in Table 10. 
Table 10: 
Eastern Cooperative Oncology Group Performance Status Scale 
ECOG (Oken 1982) 
Score 
Criterion 
0 
Fully active, able to carry out all pre-disease activities without restrictions 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature eg, light housework, office work 
2 
Ambulatory and capable of self-care, but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled, cannot carry on self-care, totally confined to bed or chair 
 
9.3.7. 
Adverse Events 
Each patient must be carefully monitored for the development of any AEs. This information 
should be obtained in the form of non-leading questions (e.g., “How are you feeling?”) and from 
signs and symptoms detected during each examination, observations of study personnel, and 
spontaneous reports from patients. 
Refer to Section 10 for details regarding AE definitions, recording, and reporting. 
9.3.8. 
Concomitant Medications 
Patients should be asked at each clinic about the medications they are taking, including any new 
medications they have started or stopped as well as any missed doses. In addition, the patient’s 
medical record and records of any hospitalizations should be reviewed to ensure all drugs the 
patient is taking are listed. 
Medications include prescription and over-the-counter medicines, herbal supplements, and 
vitamin and mineral supplements (excludes once-daily multivitamins). 








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9.6. 
Efficacy Assessments 
Tumor measurements and disease response assessments are to be performed for all patients. 
Tumor evaluation studies are to be performed during screening within 28 days before C1D1. For 
patients with SCLC or LCNEC of the lung, disease response assessments are to be performed 
within 7 days of the first study drug dose in every other cycle, starting before C3. For all other 
patients, disease response assessments are to be performed within 7 days of the first study drug 
dose in every 3rd cycle, starting before C4. All patients that discontinue treatment for reasons 
other than radiographic progression of disease will be followed for disease progression 
(Progression follow-up). SCLC and LCNEC of the lung patients will be followed approximately 
every 6 weeks from their last tumor assessment, or as clinically indicated. Other patients will be 
followed approximately every 9 weeks from their last tumor assessment, or as clinically 
indicated. Upon disease progression, all patients will be followed approximately every 3 months 
from the date of progression to assess survival status and the date and cause of death (if known) 
will be recorded for patients who died. 
All sites of disease should be imaged by CT or MRI. Subsequent assessments should use the 
same radiographic methods as used during screening. Anatomical measurements (summed across 
target lesions) will be documented during screening and each subsequent evaluation. When 
possible, the same qualified physician will interpret results to reduce variability. Radiographic 
images will be maintained at the study center and test results and Investigator’s findings will be 
filed in the patient’s source documents. 
Patients in Phase 1 are not required to have measurable disease. Patients in Phase 2a are required 
to have measurable disease. De-identified results of radiographic tumor evaluations performed 
prior to study entry and/or during study, such as radiologists’ reports or electronic copies of CT 
and MRI scans may be requested by the Sponsor for independent review of tumor response.  
During screening, tumor lesions are to be categorized as measurable versus non-measurable and 
target versus non-target, as follows. 
Measurable versus non-measurable 
• Measurable: lesions that could accurately be measured in at least 1 dimension as 
≥10 mm by CT scan or caliper measurement by clinical examination or ≥20 mm by 
chest X-ray; the longest diameter is to be recorded. For malignant lymph nodes, a 
node must be ≥15 mm in short axis by CT scan 
• Non-measurable: all other lesions, including small lesions (longest diameter <10 mm 
or pathological lymph nodes with ≥ 10 to < 15 mm short axis) and truly non-
measurable lesions. 
Target versus non-target 
• Target: all measurable lesions up to a maximum of 2 lesions per organ and 5 lesions 
in total, representative of all involved organs, are to be identified as target lesions and 
measured and recorded at screening. Target lesions are to be selected on the basis of 
their size (i.e., those with the longest diameter) and suitability for accurate repeated 
measurement. The sum of the longest diameter for all target lesions is to be calculated 
and recorded in the eCRF as the baseline sum longest diameter. 


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• Non-target: all other lesions not classified as target lesions (or sites of disease) are to 
be identified as non-target lesions and are to be recorded in the eCRF. Measurement 
of non-target lesions is not required. 
Disease response in target and non-target lesions will be assessed by the Investigator using 
RECIST 1.1, according to the categories and criteria described in Table 11. The best overall 
response for each patient will be reported as the best response documented over the sequence of 
objective statuses recorded using the categories and criteria in Table 12. 
Table 11 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Guidelines for 
Tumor Response 
Disease Response Criteria for Target and Nontarget Lesions 
Evaluation of Target lesions 
Complete Response (CR): 
Disappearance of all target lesions. 
Partial Response (PR): 
At least a 30% decrease in the sum of the LD of target lesions, 
taking as reference the baseline sum LD. 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum LD since the treatment started. 
Progressive Disease (PD): 
At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum LD recorded since the 
treatment started or the appearance of 1 or more new lesions. 
Evaluation of Nontarget lesions 
Complete Response (CR): 
Disappearance of all nontarget lesions and normalization of 
tumor marker level. 
Incomplete Response/ Stable Disease 
(SD): 
Persistence of 1 or more nontarget lesion(s) or/and 
maintenance of tumor marker level above the normal limits. 
Progressive Disease (PD): 
Appearance of 1 or more new lesions and/or unequivocal 
progression of existing nontarget lesions. 
Source: (Eisenhauer 2009) Available at: http://www.eortc.be/recist/documents/RECISTGuidelines.pdf 
Key: LD = longest diameter. 


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Table 12 
Overall Response Criteria 
Patients with Target and Nontarget Lesions 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR / Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
Patients with Nontarget Lesions Only 
Non-Target Lesions 
New Lesions 
Overall 
Response 
CR 
No 
CR 
Non-CR / Non-PD 
No 
Non-CR / 
Non-PD 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Source: (Eisenhauer 2009) Available at: http://www.eortc.be/recist/documents/RECISTGuidelines.pdf 
Key: CR = complete response; NE = inevaluable; PD = progressive disease. 
Any patient with a PR or CR by RECIST 1.1 is to have repeat assessments performed 
approximately 6 weeks later (and no sooner than 4 weeks from the prior assessment) to confirm 
the response. Following the confirmatory assessment, the response assessment schedule will 
resume at intervals of every other cycle for SCLC or LCNEC of the lung patients, and every 
third cycle for all other patients. 


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10. 
ADVERSE EVENT DEFINITIONS, RECORDING, AND 
REPORTING 
10.1. 
Definition of Adverse Events 
10.1.1. 
Adverse Events 
Adverse event (AE) means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug-related. An AE can therefore be any unfavorable and 
unintended sign (including abnormal laboratory findings), symptom, or disease temporally 
associated with the use of an investigational product, and does not imply any judgment about 
causality. 
For the purposes of this study, death and disease progression (i.e., PD) are not considered AEs 
and should not be reported as such. Death is considered an outcome of 1 or more primary AEs, 
and PD is considered a worsening of underlying disease and is a criterion for study drug 
discontinuation. Events that are unequivocally due to disease progression should not be 
reported as AEs during the study. 
10.1.2. 
Unexpected Adverse Event 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the current 
Investigator Brochure or is not listed at the specificity or severity that has been observed. 
"Unexpected" also refers to AEs or suspected adverse reactions that are mentioned in the 
Investigator Brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 
10.1.3. 
Serious Adverse Event 
An AE or suspected adverse reaction is considered serious if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes: 
• Death. 
• A life-threatening AE. Life-threatening means that, in the view of either the 
Investigator or the Sponsor, its occurrence places the patient 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. 
• In-patient hospitalization or prolongation of existing hospitalization. Hospitalization 
admissions and/or surgical operations scheduled to occur during the study period, but 
planned prior to study entry are not considered AEs if the illness or disease existed 
before the patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected manner during the study (e.g., surgery performed earlier than planned). 
Additional exclusions to serious adverse event (SAE) reporting include 
hospitalizations for: 
o Elective procedures. 
o Social/administrative reasons in the absence of an AE. 


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o Expected deterioration caused by PD. 
• A persistent or significant disruption of a person’s ability to conduct normal life 
functions. 
• A congenital anomaly/birth defect. 
• An important medical event that may not result in death, be life-threatening, or 
require hospitalization but may be considered serious when, based upon appropriate 
medical judgment, it may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this for SAEs. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in in-
patient hospitalization, or the development of drug dependency or drug abuse. 
All SAEs that occur after signing of study-related informed consent, whether or not the SAEs are 
related to the study drug, must be reported. (As stated in Section 10.1.1, only PD with an 
outcome of death is to be reported as an SAE.) 
If an Investigator learns of any SAEs, including death, at any time after a patient has completed 
the study and he/she considers there is a reasonable possibility that the event is related to PEN-
221, the Investigator should notify the Sponsor. 
10.2. 
Adverse Event Assessment 
10.2.1. 
Intensity 
The intensity of each AE is to be assessed by the Investigator according to the NCI CTCAE, 
Version 4.03 (see http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf). 
10.2.2. 
Relationship to Study Drug 
The Investigator will assess causal relationship between PEN-221 and each AE, and answer ‘yes’ 
or ‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event may 
have been caused by the investigational product?’ 
For SAEs causal relationship will also be assessed for other medication and study procedures For 
SAEs that could be associated with any study procedure, the causal relationship is implied as 
‘yes’. 
10.2.2.1. Adverse Events Based on Signs and Symptoms 
All AEs spontaneously reported by the patient or reported in response to the open question from 
the study personnel or revealed by observation will be collected and recorded in the eCRF. When 
collecting AEs, the recording of a diagnosis is preferred (when possible) to the recording of a list 
of signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately. 


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10.2.2.2. Adverse Events Based on Examinations and Tests 
 
Abnormal, clinically significant laboratory results are to be reported as an AE and must be 
recorded in the patient’s source documents and in the eCRF if the findings represent a change 
from baseline. If deterioration in a laboratory value/vital sign is associated with clinical signs and 
symptoms, the sign or symptom will be reported as an AE and the associated laboratory 
result/vital sign will be considered as additional information. Wherever possible the reporting 
Investigator uses the clinical rather than the laboratory term (e.g. anemia versus low hemoglobin 
value). In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AEs. 
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination as 
compared with the baseline assessment will be reported as an AE. 
10.2.2.3. Hy’s Law 
The Investigator is responsible for determining whether a patient meets potential Hy’s Law 
criteria at any time during the study. Potential Hy’s Law criteria are defined as AST or ALT ≥ 3× 
upper limit of normal (ULN) together with total bilirubin ≥ 2× ULN, irrespective of an increase 
in ALP, at any point during the study following the start of study medication. 
When a case meeting potential Hy’s Law is identified, the Investigator will notify the Medical 
Monitor. The Investigator will also request a new blood draw to repeat the test immediately and 
will review all previous laboratory data to determine whether potential Hy’s Law criteria were 
met at any study visit prior to or after starting study treatment. 
The Investigator will review the case with the Medical Monitor and agree on the approach for the 
patients’ follow-up assessments, which include monitoring the patient until liver chemistry tests 
and clinical signs and symptoms return to normal or baseline levels, and investigating the 
etiology of the event including diagnostic tests, as appropriate. The SRC and other subject matter 
experts may also be involved in the case review and assessment, as needed. Within 3 weeks of 
detection of the initial laboratory abnormality the Investigator and Medical Monitor will review 
all available data and agree upon whether there is an alternative explanation for meeting potential 
Hy’s Law criteria other than drug induced liver injury caused by the study drug. 
Hy’s Law is defined AST or ALT ≥ 3× ULN together with total bilirubin ≥ 2× ULN, where no 
explanation can be found other than drug induced liver injury caused by the study drug. For 
potential Hy’s Law and Hy’s Law, the elevation in transaminases precedes or is concurrent with 
the elevation in total bilirubin, but there is no specified timeframe within which the elevations in 
transaminases and total bilirubin occur (FDA 2009). 
Standard safety reporting procedures will be followed for reporting AEs and SAEs according to 
the outcome of the review and assessment. If it is agreed that there is no alternative explanation 
that would explain the ALT or AST and total bilirubin elevations other than the study drug, then 
the Investigator is required to report an SAE with the term Hy’s Law and the causality 
assessment of related. 


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If there is a delay of over 3 weeks in obtaining the information needed to assess whether the case 
meets Hy’s Law criteria then the event should be reported as an SAE with the report term 
potential Hy’s Law and the causality assessment of related, until such time as a reassessment and 
informed decision is made and the SAE report updated accordingly. 
10.2.2.4. Disease Progression 
Disease progression can be considered as a worsening of a patient’s condition attributable to the 
disease for which the IP is being studied. It may be an increase in the severity of the disease 
under study and/or increases in the symptoms of the disease. The development of new, or 
progression of existing metastasis to the primary cancer under study should be considered as 
disease progression and not an AE. Events that are unequivocally due to disease progression 
should not be reported as AEs during the study. 
10.2.2.5. New Cancers 
The development of a new cancer should be regarded as an AE and will generally meet at least 1 
of the serious criteria desribed in Section 10.1.3. New cancers are those that are not the primary 
reason for the administration of the study treatment and have been identified after the patient’s 
inclusion in this study. They do not include metastases of the original cancer. 
10.2.2.6. Deaths 
All deaths that occur during the study, or within the follow-up period after the administration of 
the last dose of investigational product, should be reported as follows: 
• Death, which is unequivocally due to disease progression, should be communicated to 
the study monitor at the next monitoring visit and should be documented in the CRF 
module, but should not be reported as a SAE during the study 
• Where death is not clearly due to disease progression of the disease under study, the 
AE causing the death should be reported as an SAE within 24 hours. The report 
should contain a comment regarding the co-involvement of progression of disease, if 
appropriate, and should assign a single primary cause of death together with any 
contributory causes 
Deaths with an unknown cause should always be reported as a SAE but every effort should be 
made to establish a cause of death. An autopsy may be helpful in the assessment of the cause of 
death, and if performed a copy of the autopsy results should be reported in an expedited fashion 
to the Sponsor. 
10.3. 
Recording Adverse Events 
All AEs (serious and non-serious) will be documented in the patient’s source documents and 
recorded in the eCRF.  
The AE term should be reported in standard medical terminology when possible. Also when 
possible, signs and symptoms indicating a common underlying pathology should be noted as 1 
comprehensive event. For each AE, the Investigator will evaluate and report the onset, 
resolution, intensity, causality, action taken, serious outcome (if applicable), and whether or not 
it caused the patient to discontinue the study. 


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10.3.1. 
Time Period for Collection of Adverse Events 
AEs will be collected from the time of signature on pre-screening (if applicable) or screening 
ICFs throughout the treatment period and including the safety follow-up period. The safety 
follow-up period is defined as 28±3 days after last dose of study drug. For each AE, the 
Investigator will evaluate and report the onset, resolution, intensity, causality, action taken, 
serious outcome (if applicable), and whether or not it caused the patient to discontinue the study. 
The change in CTCAE v4.03 grade for each event will be recorded in the eCRF.  
10.3.2. 
Follow-Up of Unresolved Adverse Events 
Any AEs that are unresolved at the patient’s follow-up visit are to be followed up by the 
Investigator for as long as medically indicated. Additional information for any patient with an 
ongoing AE at the end of the follow-up period may be requested by the Sponsor, as needed. 
If an Investigator learns of any SAEs, including death, at any time after a patient has completed 
the study and he/she considers there is a reasonable possibility that the event is related to PEN-
221, the Investigator should follow the reporting process for SAEs as outlined in Section 10.3.4. 
10.3.3. 
Variables 
The following variables will be collected for each AE: 
• Adverse event term 
• Date when the AE started 
• Date when the AE stopped 
• CTCAE v4.03 grade and changes in grade during the course of the AE 
• Whether the AE is serious or not 
• Causality assessment in relation to PEN-221 (yes or no) 
• Action taken with regard to PEN-221 
• Outcome 
In addition, the following variables will be collected for SAEs, if they pertain: 
• Date AE met criteria for serious AE 
• Date Investigator became aware of serious AE 
• Reason AE is serious 
• Date of hospitalization 
• Date of discharge 
• Probable cause of death 
• Date of death 
• Autopsy performed 
• Causality assessment in relation to study procedure(s) 




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If the outcome of the pregnancy meets the criteria for immediate classification as an SAE (i.e., 
spontaneous abortion [any congenital anomaly detected in an aborted fetus is to be documented], 
stillbirth, neonatal death, or congenital anomaly), then the Investigator should report it as such. 
All neonatal deaths that occur within 30 days of birth should be reported, without regard to 
causality, as SAEs. Any infant death after 30 days that the Investigator suspects is related to the 
in utero exposure to the study drug should also be reported. 
10.5. 
Overdose 
Signs and symptoms of an overdose should be reported as AEs. Overdoses will not be considered 
SAEs unless the outcome of the overdose meets seriousness criteria (see Section 10.1.3). 
However, any overdose must be reported to the Medical Monitor or designee immediately. 
The Medical Monitor, in conjunction with the Investigator, will decide whether the patient 
should continue to participate in the study. All protocol deviations and reasons for such 
deviations must be documented in the patient’s source records. 
Any patient receiving a higher dose than intended should be monitored carefully and managed 
with appropriate supportive care measures. 
10.6. 
Protocol Deviations 
Protocol deviations, including protocol waivers (i.e., prospective deviations), are not acceptable. 
Any protocol deviations and reasons for such deviations must be documented in the patient’s 
source records. The Sponsor will review any protocol deviations and provide additional training 
to ensure that deviations are not repeated, and, if required, amend the protocol. The Sponsor will 
notify regulatory authorities of any non-compliance considered a serious breach of GCP or the 
protocol. 


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11. 
DATA REVIEW AND MANAGEMENT 
11.1. 
Study Monitoring 
Monitoring and auditing procedures developed by the Sponsor or designee will be followed, in 
order to comply with good clinical practices (GCP) guidelines. 
Before a study center can enter a patient into the study, a representative of the Sponsor or 
designee will visit the study center to: 
• Determine the adequacy of the facilities. 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard 
to protocol adherence, and the responsibilities of the Sponsor or its representatives. 
This will be documented in a Clinical Study Agreement between the Sponsor and the 
Investigator. 
During the study, a monitor from the Sponsor or designee will have regular contacts with the 
study center, for the following: 
• Provide information and support to the Investigator(s). 
• Confirm that facilities remain acceptable. 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the source documents and eCRFs, and that investigational 
product accountability checks are being performed. 
• Perform source data verification. This includes a comparison of the data in the eCRFs 
with the patient’s medical records at the hospital or practice, and other records 
relevant to the study. This will require direct access to all original records for each 
patient (e.g., clinic charts). 
• Record and report any protocol deviations not previously sent to the Sponsor or 
designee. 
• Confirm AEs and SAEs have been properly documented in the eCRFs and confirm 
any SAEs have been forwarded to the Sponsor or designee, and those SAEs that met 
criteria for reporting have been forwarded to the IRB or EC. 
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
11.2. 
Case Report Form Completion 
The Sponsor or designee will provide the study centers with eCRFs. 
eCRFs will be completed for each study patient. It is the Investigator’s responsibility to ensure 
the accuracy, completeness, and timeliness of the data reported in the patient’s eCRF. Source 
documentation supporting the eCRF data should indicate the patient’s participation in the study 
and should document the dates and details of study procedures, AEs, and patient status. 
The Investigator, or designated representative, should complete the eCRF as soon as possible 
after information is collected, preferably on the same day that a patient is seen for an 


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examination, treatment, or any other study procedure. Any outstanding entries must be 
completed immediately after the final examination. An explanation should be given for all 
missing data. 
The Investigator must electronically sign and date the Investigator’s Statement at the end of the 
eCRF to endorse the recorded data. 
11.3. 
Computerized Systems / Medical Records as Source Data 
All study data recorded on source documents are to be transcribed into the eCRFs. Any 
electronic study data are to be entered into a secure, validated data processing system and a 
backup maintained. Any changes to electronic study data will be documented. 


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12. 
STATISTICAL METHODS AND DATA ANALYSIS 
12.1. 
General Statistical Considerations 
Protocol PEN-221-001 is an open-label, Phase 1/2a study evaluating PEN-221 in patients with 
advanced solid tumors expressing somatostatin receptor 2. The study has 2 phases: Phase 1 
comprising dose escalation  to establish the MTD,  and Phase 2a comprising expansion of 3 
cohorts, each with distinct, tumor-specific arms. The study objectives and endpoints are listed in 
Section 6. 
Data will be summarized using descriptive statistics (continuous data) and/or contingency tables 
(categorical data) for demographic and baseline characteristics, efficacy measurements, safety 
measurements, and all relevant pharmacokinetic and pharmacodynamics measurements. 
All data will be summarized by study phase (Phase 1, Phase 2a), cancer indication, and PEN-221 
dose received. All data collected will also be presented in patient listings. 
Details of the statistical analysis and data reporting will be provided in the SAP document 
finalized prior to database lock. 
12.2. 
Populations for Analysis 
The following patient populations will be evaluated and used for presentation and analysis of the 
data: 
• The Full Analysis Set (intent-to-treat [ITT] population) comprises all patients enrolled 
into the study and who receive any amount of study drug 
• The efficacy analysis (EA) population comprises all patients who receive any amount 
of study drug and have at least 1 post-baseline efficacy assessment 
• The safety analysis (SA) population comprises all patients who receive any amount of 
study drug and have at least 1 post-baseline safety evaluation 
• The per-protocol (PP) population comprises all patients who receive at least 1 cycle 
of treatment, have at least 1 post-baseline efficacy assessment, and have no major 
protocol violations, as defined by the Medical Monitor 
• The dose-determining (DD) population comprises all patients who receive any 
amount of study drug and either experienced a DLT or have been followed for the full 
DLT evaluation period 
• The pharmacokinetic (PK) population comprises all patients who receive any amount 
of study drug and provide adequate PK samples for analysis. Patients with major 
protocol violations will be assessed on a patient-by-patient basis for inclusion in the 
PK population. 
12.3. 
Patient Disposition 
A tabulation of patient disposition, including the number screened, the number enrolled at each 
dose of study drug, the number in each patient population for analysis (safety and efficacy), the 


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number of protocol violations, the number that withdrew prior to completing the study, and 
reasons for withdrawal. 
A by-patient listing of study completion information, including the reason for premature study 
withdrawal, if applicable, will be presented. 
The ITT population will be used. 
12.4. 
Demographics and Baseline Characteristics 
Demographic and other baseline data, including age, sex, race, ethnicity, height, weight, baseline 
ECOG PS, primary diagnosis, disease stage at diagnosis and baseline, prior therapies (including 
systemic therapies, radiation, and surgeries, etc. will be listed individually by patient and 
summarized by treatment group using descriptive statistics (continuous data) or contingency 
tables (categorical data) in the CSR. 
The ITT population will be used. 
12.5. 
Treatments and Concomitant Medications 
The actual dose and duration in days of PEN-221, as well as the dose intensity (computed as the 
ratio of actual dose received and actual duration) and the relative dose intensity (computed as the 
ratio of dose intensity and planned dose received/planned duration) will be listed and 
summarized by treatment group using descriptive statistics in the CSR. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study drug will be listed by patient, and summarized by anatomical therapeutic chemical term 
and treatment group by means of contingency tables. 
The ITT population will be used. 
12.6. 
Primary Objective 
The primary objective of Phase 1 is to determine the MTD of PEN-221 when administered IV on 
a 3 week schedule. The corresponding primary analysis is based on an adaptive BLRM in 
conjunction with EWOC, as described in detail in Section 12.6.1. 
The DD population will be used. 
At the conclusion of Phase 1, the final recommended dose for future development will be based 
on considerations of the MTD estimated by the BLRM, and on an overall clinical assessment of 
all available safety, tolerability, PK and PDc data from all cycles at all different dose levels 
tested, in both phases of the study. This dose, which may be lower than the MTD estimated from 
the BLRM, will be referred to as the recommended phase 2 dose (RP2D). 
The primary objective of Phase 2a is to assess the efficacy of PEN-221 with gastrointestinal mid-
gut NET and pancreatic NET using CBR as defined as the proportion of patients with the best 
overall response of CR, PR, or SD using RECIST, version 1.1. For the SCLC cohort, efficacy 
will be assessed using ORR as defined as the proportion of patients with best overall response of 
CR or PR using tumor response criteria defined by RECIST, version 1.1,  along with duration of 
response.  
The EA population will be used. 


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12.6.1. 
Phase 1  
12.6.1.1. Definition of MTD and the Primary Variable 
The MTD is defined as the highest dose for a given schedule that is not expected by the BLRM 
to cause DLTs in more than 33% of patients. Estimation of the MTD during the dose escalation 
phase of the study will be based upon the posterior distribution of the incidence of DLT in C1 in 
patients in the dose-determining set. 
The primary variable is the frequency of DLTs associated with continuous daily administration 
of PEN-221 during the first cycle of treatment. 
12.6.1.2. Statistical Hypothesis, Model, and Method of Analysis 
An adaptive BLRM with 2 parameters, guided by EWOC (Babb 1998; Neuenschwander 2008), 
will be used to make dose recommendations and estimate the MTD during the dose-escalation 
phase of the study. 
The dose-toxicity relationship is modeled by the BLRM: 
logit൫𝜋𝜋(𝑑𝑑)൯= log(𝛼𝛼) + 𝛽𝛽log(𝑑𝑑𝑑𝑑∗
⁄
) , 𝛼𝛼> 0, 𝛽𝛽> 0 
where logit൫𝜋𝜋(𝑑𝑑)൯= log (𝜋𝜋(𝑑𝑑) (1 −𝜋𝜋(𝑑𝑑))
⁄
). Doses are rescaled as d/d* with reference dose 
d*=20.8 mg of PEN-221. The model parameters 𝛼𝛼 and 𝛽𝛽 have the following interpretation: 
• 𝛼𝛼 equals the odds of toxicity at the reference dose d*. 
• Doubling the dose results in an increase in odds of toxicity by a factor of 2𝛽𝛽. 
For a dose equal to zero, the probability of toxicity is zero. 
12.6.1.3. Prior Specification 
The model parameters (log(𝛼𝛼) , log(𝛽𝛽)) are given a weakly informative bivariate normal prior 
distribution that is guided by guesses from preclinical data and that ensures wide confidence 
intervals for the DLT rates at each dose, and allows efficient escalation toward the MTD. To tune 
the prior distribution for the model, a priori it is assumed that doses higher than 13.3 mg exceed 
the EWOC threshold (i.e., greater than 25% probability of excessive toxicity), while doses at or 
below 16 mg are considered admissible for dose escalation. Such a prior distribution would 
facilitate initial escalation toward the 6.7 – 13.3 mg range, which includes the predicted MTD of 
9 mg based on allometric scaling. Prior parameter values for the bivariate normal distribution of 
the model parameters are presented in Table 13, and the resulting prior distribution of DLT rates 
is illustrated in Figure 2. Prior probabilities of excessive toxicity at each dose are shown in 
Table 14. 
Table 13: 
Prior parameter values for the bivariate normal distribution of the model 
parameters 
Parameters 
Means 
Standard deviations 
Correlation 
(log(𝛼𝛼) , log (𝛽𝛽)) 
(−1.099, 0.693) 
(2, 1) 
0 


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Table 14: 
Prior probability of excessive toxicity (DLT rate > 0.33) 
Dose (mg) 
0.5 
1 
2 
4 
6.7 
10 
13.3 
16.6 
20.8 
Probability 
of excessive 
toxicity 
0.029 
0.039 
0.056 
0.085 
0.124 
0.175 
0.235 
0.305 
0.422 
 
Figure 2: 
Prior DLT rates and 95% confidence intervals 
 
12.6.1.4. Dose Recommendation 
After each cohort of patients, the posterior distribution for the probabilities of DLT rates at 
different dose levels are obtained. The results of this analysis are summarized in terms of the 
estimated probabilities that the true rate of DLT at each dose level will have of lying in each of 
the following intervals: 
• [0, 0.16) under-dosing 
• [0.16, 0.33) targeted toxicity 
• [0.33, 1] excessive toxicity 
The escalation with overdose control (EWOC) criteria is used to guide dose recommendations 
for each cohort. A dose is not considered admissible for the next cohort unless, given the current 


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data, there is a small chance (posterior probability < 25%) that this dose is excessively toxic 
(DLT rate > 33%). 
Within the constraints of the EWOC criteria, dose recommendations are based on maximizing 
the posterior probability that the DLT rate is in the targeted toxicity interval. 
The dose recommended for the next cohort is the 1 which has maximum probability of being in 
the targeted toxicity region (16% – 33% DLT rate), provided it satisfies the EWOC criteria and 
does not represent more than a doubling (≤ 100% increase) of the current dose. 
If the recommended dose satisfying the EWOC criteria is > 100% increase in dose, then 
escalation will proceed to the highest dose level which is ≤ 100% increase from current dose. 
The dose recommended by the BLRM may be regarded as guidance and information to be 
integrated with a clinical assessment of the toxicity profiles observed at the time of analysis in 
determining the next dose level to be investigated. 
Details of the criteria for dose escalation and determination of the MTD are provided in 
Section 12.6.1. 
12.6.1.5. Stopping Rules 
The dose-escalation phase may be stopped in 1 of the following circumstances: 
• Stop to declare MTD: The study stops with a determination of MTD at dose 𝑑𝑑̃ if the 
model’s recommended dose for the next cohort is 𝑑𝑑̃ and the following conditions are 
met: 
1. At least 6 patients have already been evaluated at dose 𝑑𝑑̃. 
2. One of the following conditions is satisfied: 
a. The probability of 𝑑𝑑̃ being in the targeted toxicity region is at least 0.6. 
b. At least 18 patients have been evaluated in the study. 
• Stop for over-dosing: The study stops with a declaration that the MTD is below the 
lowest dose if there are no doses available that satisfy the EWOC criteria. 
12.6.2. 
Phase 2a 
  
12.6.2.1. Clinical Benefit Rate for gastrointestinal mid-gut NET and pancreatic NET 
Clinical benefit rate (CBR) is defined as the proportion of patients with a best overall CR, PR, or 
SD as defined by RECIST 1.1. 
For each NET cohort, CBR will be estimated and presented with 95% confidence intervals 
(CIs)based on the exact binomial distribution.  
In addition, a Bayesian approach will be used to estimate the CBR and its 95% credible interval 
based on the posterior distribution. A vague beta prior distribution with parameters a=1 and b=1 
will be used. This translates to a prior mean of 50% with wide uncertainty. 


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At completion of the study, the prior distribution will be updated with all data available from the 
evaluable patients at the MTD/RP2D to obtain the posterior distribution of the true CBR. For 
each NET cohort, the posterior probability that the true CBR is greater than 75% will be 
reported. 
12.6.2.2. Objective Response Rate for SCLC 
Objective response rate (ORR) is defined as the proportion of patients with a best overall CR or 
PR as defined by RECIST 1.1. 
ORR will be estimated and presented with 95% confidence intervals (CIs) based on the exact 
binomial distribution. 
In addition, a Bayesian approach will be used to estimate the ORR and its 95% credible interval 
based on the posterior distribution. A vague beta prior distribution with parameters a=1 and b=1 
will be used. This translates to a prior mean of 50% with wide uncertainty. 
At completion of the study, the prior distribution will be updated with all data available from the 
evaluable patients at the MTD/RP2D to obtain the posterior distribution of the true ORR. For the 
SCLC, the posterior probability that the true ORR is greater than 30% will be reported. 
12.6.2.3. Duration of Response for SCLC 
Duration of response (DOR) is defined as the time from first documented response (CR or PR) to 
the date of first documented disease progression or death due to underlying cancer. If a patient 
has not progressed or died before the analysis cutoff date, DOR will be censored at the date of 
last adequate tumor assessment. 
DOR will be analyzed and presented using the Kaplan-Meier method, along with the estimated 
median (in months) with 95% CIs, 25th and 75th percentiles. 
12.7. 
Secondary Objectives 
12.7.1. 
Safety Analysis 
An objective of all phases of the study is to further characterize the safety and tolerability of 
PEN-221, including acute and chronic toxicities. This will be based on a comprehensive review 
of all safety data, including all observed AEs . Data from patients of all study phases will be 
pooled for analysis according to dose received. All patients who receive any amount of PEN-221 
will be included in the final summaries and listings of safety data. 
For all safety analyses, the SA population will be used. All listings and tables will be presented 
by treatment group (dose level) and tumor-specific cohort group. 
12.7.1.1. Adverse Events 
Summary tables will present the number of patients observed with treatment-emergent adverse 
events (TEAEs) and corresponding percentages, where treatment-emergent is defined as any AE 
that occurs after administration of the first dose of study drug and through 28 days after the last 
dose of study drug, any event that is considered study drug-related regardless of the start date of 
the event, or any event that is present at baseline but worsens in intensity or is subsequently 
considered study drug-related by the Investigator. 


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The denominator used to calculate incidence percentages consists of patients receiving any 
amount of PEN-221. Within each summary table, the AEs will be categorized according to the 
Medical Dictionary for Regulatory Activities (MedDRA) system organ class and preferred term. 
Additional subcategories will be based on event intensity (severity graded according to CTCAE, 
version 4.03) and relationship to study drug. 
Deaths, SAEs, and TEAEs leading to study drug discontinuation will be tabulated on a per-
patient basis, as warranted by the data. 
For Phase 1, the DLTs, MTD, and RP2D will be identified. 
12.7.1.2. Laboratory Anomalies 
Change from baseline in clinical laboratory parameters will be summarized across time on study. 
Furthermore, the frequency of laboratory abnormalities by maximum post-baseline CTCAE 
grade will be tabulated by cycle and overall for selected laboratory parameters to include at least 
hemoglobin, white blood cell count, ANC, lymphocytes, platelet count, AST, ALT, total and 
direct bilirubin, creatinine, ALP, and electrolytes. Shift tables also may be produced for these 
parameters based on the baseline CTCAE grade and the maximum CTCAE grade by cycle and 
overall. 
12.7.1.3. Vital Signs, ECG, and Other Safety Data 
Changes in vital sign parameters (including systolic and diastolic blood pressure and heart rate) 
and body weight will be summarized over time, and any abnormal values will be tabulated. 
The proportions of patients with treatment-emergent clinically significant ECG abnormalities 
will be tabulated, and changes in ECG findings will be presented in data listing format. 
ECOG performance status will be summarized by cycle and worst status overall; ECOG 
performance status will be presented in data listing format. 
Additional safety analyses may be determined at any time without prejudice, in order to most 
clearly enumerate rates of toxicities and to define further the safety profile of PEN-221. 
12.7.1.4. Tolerability 
Tolerability will be comprehensively examined based on safety data. 
12.7.2. 
Pharmacokinetic Analysis 
All patients who have at least 1 blood sample providing evaluable PK data for PEN-221 will be 
included in the PK population. The PK population will be used for analysis. 
Actual sampling times will be used for the pharmacokinetic analysis of the plasma concentration 
data for PEN-221, DM1, and peptide from PEN-221. PK parameters will be derived using 
standard non-compartmental methods. For Phase 2a, additional PK timepoints will be collected 
on C1D2 and C1D8 to better characterize PEN-221, DM1 and peptide from PEN-221. PK 
samples on C3D1 are not required for Phase 2a.  
The following PK parameters will be calculated: the maximum plasma concentration (Cmax), time 
to Cmax (tmax), area under the plasma concentration time curve from zero to the time of the last 
measurable concentration (AUC(0-t)) and from zero to infinity (AUC∞), CL, and the apparent 


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volume of distribution (Vss; Vz), terminal rate constant (λz), and t½. The dependency of the 
pharmacokinetics on multiple dosing will be assessed by the calculation of the ratio of AUC(0-t) 
C3D1 and C1D1. 
This protocol uses fixed doses. The relationship between CL of PEN-221 and body size, as 
measured by weight and body mass index (BMI), will be examined as data accrues. If the 
analysis indicates that CL is dependent on body size, then dosing will be modified to a body-size 
basis by Safety Review Committee agreement. 
The PK may also be characterized by fitting an appropriate compartmental model to aid in 
evaluation of drug exposure-PDc response relationships and population covariates. The model to 
be used will be determined from the data and will be parameterized in terms of CL and Vss. 
12.7.3. 
Efficacy Analysis 
Evidence of preliminary anti-tumor activity will be assessed by the objective response, as 
defined by RECIST 1.1. This will be used to summarize the objective response rate (CR+PR), as 
well as the rates for the individual categories of response, (i.e., CR, PR, SD, and PD). 
12.7.3.1. Progression-free Survival 
Progression-free survival (PFS) is defined as the time from the date of first dose of PEN-221 to 
the date of first documented disease progression per RECIST 1.1, or death due to any cause. If a 
patient has not progressed or died before the analysis cutoff date, PFS will be censored at the 
date of last adequate tumor assessment. 
PFS will be analyzed and presented using the Kaplan-Meier method, along with the estimated 
median (in months) with 95% CIs, 25th and 75th percentiles. 
12.7.3.2. Overall Survival 
Overall survival (OS) is defined as the time from the date of first dose of PEN-221 to the date of 
death due to any cause. If a patient has not died before the analysis cutoff date, OS will be 
censored at the date of last contact. 
OS will be analyzed and presented using the Kaplan-Meier method, along with the estimated 
median (in months) with 95% CIs, 25th and 75th percentiles. 
12.7.3.3. Objective Response Rate for gastrointestinal mid-gut NET and pancreatic NET 
For gastrointestinal mid-gut-NET and pancreatic NET, objective response rate (ORR) is defined 
as the proportion of patients with a best overall CR or PR as defined by RECIST 1.1. 
ORR will be estimated and presented with 95% confidence intervals (CIs) based on the exact 
binomial distribution. 
In addition, a Bayesian approach will be used to estimate the ORR and its 95% credible interval 
based on the posterior distribution. A vague beta prior distribution with parameters a=1 and b=1 
will be used. This translates to a prior mean of 50% with wide uncertainty. 
At completion of the study, the prior distribution will be updated with all data available from the 
evaluable patients at the MTD/RP2D to obtain the posterior distribution of the true ORR. The 
posterior probability that the true ORR is greater than 20% will be reported. 


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12.7.3.4. Duration of Response for gastrointestinal mid-gut NET and pancreatic NET 
For gastrointestional mid-gut NET and pancreatic NET, duration of response (DOR) is defined 
as the time from first documented response (CR or PR) to the date of first documented disease 
progression or death due to underlying cancer. If a patient has not progressed or died before the 
analysis cutoff date, DOR will be censored at the date of last adequate tumor assessment. 
DOR will be analyzed and presented using the Kaplan-Meier method, along with the estimated 
median (in months) with 95% CIs, 25th and 75th percentiles. 
12.8. 
Interim Analyses 
No formal interim analyses are planned in Phase 1. However, the dose-escalation design is 
adaptive by nature, basing ongoing decisions about dose assignment on observed data. Details of 
this procedure and the process for communication with Investigators are provided in 
Section 8.6.1.In Phase 2a, no formal interim analysis are planned. However, preliminary efficacy 
and safety will be assessed in approximately the first 10 patients per cohort before deciding 
whether to proceed to the second stage of each cohort. 
12.9. 
Sample Size Calculation 
No formal statistical power calculations to determined sample size were performed for this study. 
However, based on the performance characteristics computed and described hereafter, the 
sample sizes in each phase are adequate to address the study’s objectives. 
12.9.1. 
Phase 1 
No formal sample size calculations were performed for Phase 1. It is estimated that 30 patients 
will be enrolled in the dose-escalation phase including at least 6 patients treated at the MTD 
level. The actual number of patients will depend on the number of dose levels/cohorts that are 
tested. Based on the simulation study undertaken with the East 6.4 software to evaluate operating 
characteristics of the BLRM (see Section 15.2) at least 18 patients are expected to be treated in 
the dose-escalation phase for the model to have reasonable operating characteristics relating to 
its MTD recommendation. 
12.9.2. 
Phase 2a 
No formal sample size calculations were performed for Phase 2a. A total of approximately 75 
patients will be enrolled in Phase 2a. This includes the following Phase 2a cohorts: GI mid-gut 
NETs (n=35), pancreatic NETs (n=20), and advanced or metastatic SCLC (n=20).  
For patients with advanced pancreatic NET, approved drugs (beyond somatostatin analogs) 
include sunitinib and everolimus, both of which improved PFS but are associated with clinical 
benefit rates of approximately 72% for sunitinib and 78% for everolimus (Raymond 2011; Yao 
2011). In the pancreatic NET group, an observed clinical benefit  rate of 75% or greater would 
be considered promising. Given a sample size of 20 patients, if clinical benefit is observed in 15 
patients (observed rate of 75%), the posterior probability of the true rate being <65% is 0.20, 
with the 95% credible interval around the true rate being (52.8%, 88.7%). If only 14 responses 
are seen (observed clinical benefit rate of 70%), the probability of the true clinical benefit rate 
being at least 75% is 0.26, while seeing only 13 responses (observed clinical benefit rate of 65%) 


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would result in that probability being only 0.13. If the true underlying clinical benefit rate is 
75%, there is 0.38 probability to observe fewer than 15 patients achieve clinical benefit. This 
probability drops to 0.20 if the true underlying rate is 80%. 
For patients with advanced gastrointestinal NETs, approved drugs (beyond somatostatin analogs) 
include everolimus, which has been shown to improve PFS but is associated with a clinical 
benefit rate of 83% (Yao 2016). In a randomized Phase 3 study,177Lu-DOTATATE plus 
Octreotide LAR  in patients with advanced GI mid-gut NETs was shown to improve PFS and is 
associated with a clinical benefit rate of 82% (Strosberg 2017; Strosberg 2016 [4th Theranostics 
World Congress 2016])). In the gastrointestinal mid-gut NET group, an observed clinical benefit 
rate of approximately 75% or greater would be considered promising. In a sample 35 patients, if 
clinical benefit is observed in 26 patients (observed rate of 74%), the posterior probability of the 
true rate being <65% is 0.14, with the 95% credible interval around the true rate being (57.8%, 
85.8%). If only 25 responses are seen (observed clinical benefit rate of 71%), the probability of 
the true clinical benefit rate being at least 75% is 0.27, while seeing only 24 responses (observed 
clinical benefit rate of 69%) would result in that probability being only 0.17. If the true 
underlying clinical benefit rate is 75%, there is 0.37 probability to observe fewer than 26 patients 
achieve clinical benefit. This probability drops to 0.15 if the true underlying rate is 80%. 
Approximately 25 of the 35 patients in the gastrointestinal mid-gut NET group are expected to 
be treated at the current RP2D (15mg), and among these patients, approximately 20 are expected 
to have not received prior PRRT. These two subgroups will be summarized separately. For the 
subgroup of approximately 20 patients without prior PRRT and who are treated at the current 
RP2D, the performance characteristics based on a target CBR of 75% (15 patients with clinical 
benefit out of 20) are the same as those presented in the previous paragraph for the pancreatic 
NET cohort.  
For patients with advanced SCLC, approved drugs in the second-line include topotecan, which 
has been shown in a randomized Phase 3 study (von Pawel 1999) compared to 
cyclophosphamide-doxorubicin-vincristine (CAV) to achieve similar time to progression, 
survival, and response rates (topotecan 24% vs. CAV 18%) in patients who relapsed >90 days 
after completion of their first line platinum containing chemotherapy regimen, and similar 
though somewhat lower response rates in the subset of patients who relapsed within 60 to 90 
days after completion of the first-line chemotherapy (topotecan 13.6% vs. CAV 4.8%). In the 
platinum-sensitive SCLC group, a tumor response rate of 30% or greater would be considered 
very promising. Given a sample size of 20 patients, if 6 responses are seen (observed ORR of 
30%), the posterior probability of the true ORR being < 10% is 0.5% and being ≥ 30% is 55%, 
with the 95% credible interval about the true ORR being (14.6%, 52.2%). For a cohort of 20 
patients, if the observed proportion is 0.3, there is 100% probability that the true underlying 
proportion exceeds 0.05, and 55.0% probability that the true underlying proportion exceeds 0.3. 
If the true underlying proportion is 0.3, there is 0.1% probability to observe 0 responses. If only 
4 responses are seen (observed ORR of 20%) the probability of the true ORR being ≥ 30% drops 
to 19.8%, while seeing only 2 responses (observed ORR of 10%) would result in that probability 
being only 2.7%. If the true underlying proportion is 0.3, there is 0.1% probability to observe 0 
responses. 
 




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12.9.3. 
Primary Analysis Cutoff 
For the GI mid-gut NET,  pancreatic NET and SCLC groups, the cutoff date for the primary 
analysis will occur after all  patients received the first dose of PEN-221 at least 21 weeks (7 
cycles) prior to the analysis cutoff date. 
12.10. 
Replacement of Patients 
Patients may only be replaced in 2 instances: 
•
Patients who are discontinued from the study prior to receiving study drug PEN-221 may
be replaced (i.e. lost to follow-up, withdraw consent).
•
Patients in the dose-escalation phase who withdraw before completing C1 assessments
for reasons other than experiencing a DLT may be replaced.
12.11. 
Changes to the Planned Statistical Methods 
Planned statistical analyses will be documented in a formal Statistical Analysis Plan before 
database lock. Any changes to the planned statistical methods will be documented in the CSR. 


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13.
ETHICS
13.1. 
Good Clinical Practice Compliance 
The Sponsor, Investigators, and any third party to whom aspects of the study management or 
monitoring have been delegated will undertake their assigned roles for this study in compliance 
with US 21 Code of Federal Regulations (CFR) 11, 21 CFR 50, 21 CFR 54, 21 CFR 56, and 
21 CFR 312, all applicable local industry regulations, and International Conference on 
Harmonisation (ICH) Good Clinical Practice (GCP) Guideline E6. 
ICH GCP Guideline E6 is available at: 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/good-clinical-
practice.html 
13.2. 
Institutional Review Board or Ethics Committee 
The IRB or EC will review all appropriate study documentation in order to safeguard the rights, 
safety, and well-being of the patients. The study will only be conducted at study centers where 
IRB or EC approval has been obtained. The protocol, Investigator Brochure, informed consent, 
advertisements (if applicable), written information given to the patients (including diary cards), 
safety updates, annual progress reports, and any revisions to these documents will be provided to 
the IRB or EC by the Investigator. 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or EC, as appropriate. Written IRB or EC approval must 
be received by the Sponsor or designee before a study center can enroll any patient into the 
study. 
The Investigator is responsible for informing the IRB or EC of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB or EC must approve all advertising used 
to recruit patients for the study. The protocol (and other amended study documents) must be re-
approved by the IRB or EC upon receipt of amendments and annually, as local regulations 
require. The Investigator is also responsible for providing the IRB or EC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product. The Sponsor or designee will provide this information to the Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or EC according to local regulations and guidelines. 
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor or 
designee may conduct a quality assurance audit. Please see Section 14.2 for more details 
regarding the audit process. 
13.3. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH GCP, and applicable regulatory 
requirements. 


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13.4. 
Written Informed Consent 
The Investigator at each center will ensure that the patient is given full and adequate oral and 
written information about the nature, purpose, possible risk, and benefit of the study. Patients 
must also be notified that they are free to discontinue from the study at any time. The patient 
should be given the opportunity to ask questions and allowed time to consider the information 
provided. This process should be recorded in the patient’s source documentation. 
The patient’s signed and dated ICF must be obtained before conducting any study procedures. 
Documentation of the consenting process must be recorded in the patient’s source documents. 
The Investigator must maintain the original, signed ICF. A copy of the signed ICF must be given 
to the patient, and this must be documented in the patient’s source documents. 
13.5. 
Patient Confidentiality 
In order to maintain patient privacy, all eCRFs, study drug accountability records, study reports, 
and communications will identify the patient by initials (as allowed by local regulations) and the 
assigned patient number. The Investigator will grant monitor(s) and auditor(s) from the Sponsor 
or designee and regulatory authority(ies) access to the patient’s original medical records for 
verification of data gathered on the eCRFs and to audit the data collection process. The patient’s 
confidentiality will be maintained and will not be made publicly available to the extent permitted 
by the applicable laws and regulations. 


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14.
ADMINISTRATIVE REQUIREMENTS
14.1. 
Retention of Records 
The Investigator will maintain all study records according to ICH GCP and applicable regulatory 
requirement(s). Records will be retained for at least 2 years after the last marketing application 
approval or 2 years after formal discontinuation of the clinical development of the investigational 
product or according to applicable regulatory requirement(s). If the Investigator withdraws from 
the responsibility of keeping the study records, custody must be transferred to a person willing to 
accept the responsibility. The Sponsor or designee must be notified immediately by telephone or 
email and the notification confirmed in writing if a custodial change occurs. 
14.2. 
Audits and Inspections 
Authorized representatives of the Sponsor, or designee, a regulatory authority, IRB, or EC may 
visit the study center to perform audits or inspections, including source data verification. The 
purpose of a Sponsor audit or inspection is to systematically and independently examine all 
study-related activities and documents to determine whether these activities were conducted, and 
data were recorded, analyzed, and accurately reported according to the protocol, ICH GCP, and 
any applicable regulatory requirements. 
The Investigator should contact the Sponsor immediately if contacted by a regulatory agency 
about an inspection. 
14.3. 
Publication Policy 
All information regarding PEN-221 supplied by the Sponsor to the Investigator or generated as a 
result of any clinical studies is privileged and confidential information belonging to the Sponsor. 
The Investigator agrees to use Sponsor’s confidential information solely to accomplish the study 
and will not use such information for any other purposes without the prior written consent of the 
Sponsor. It is understood that there is an obligation to provide the Sponsor with complete and 
accurate data obtained during the study. The information obtained from the clinical study will be 
used towards the development of PEN-221 and may be disclosed by the Sponsor to regulatory 
authority(ies), other Investigators, corporate partners, or consultants as required. 
It is anticipated that the results of this study may be presented at scientific meetings and/or 
published in a peer reviewed scientific or medical journal. A Publications Committee, comprised 
of Investigators participating in the study and representatives from the Sponsor, as appropriate, 
will be formed to oversee any publication or presentation of the study results, which will reflect 
the experience of all participating study centers. All publications and presentations must be 
approved in advance by the Sponsor at its sole discretion. Subsequently, individual Investigators 
may publish results from the study in compliance with their agreement with the Sponsor. 
A pre-publication manuscript is to be provided to the Sponsor at least 30 days prior to the 
submission of the manuscript to a publisher. Similarly, the Sponsor will provide any company-
prepared manuscript to the Investigators for review at least 30 days prior to submission to a 
publisher. All publications and presentations must be approved in writing by the Sponsor before 
public disclosure. 


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15.
APPENDIX: PRIOR CALIBRATION AND OPERATING
CHARACTERISTIS OF THE BAYESIAN LOGISTIC
REGRESSION MODEL
15.1. 
Introduction 
This appendix evaluates the performance of the proposed adaptive BLRM with EWOC via 
computer simulations. The detailed dose escalation procedure is described in Section 8.6.1 of the 
study protocol. In brief, the EWOC criteria is used to guide dose recommendations for each 
cohort. A dose is not considered admissible for the next cohort unless, given the current data, 
there is a small chance (posterior probability < 25%) that this dose is excessively toxic (DLT rate 
> 33%). Within the constraints of the EWOC criteria, dose recommendations are based on 
maximizing the posterior probability that the DLT rate is in the targeted toxicity interval of 16% 
– 33%.
15.2. 
Operating Characteristics for Simulation 
15.2.1. 
Dose Levels 
The dose levels for simulation are given as 0.5, 1, 2, 4, 6.7, 10, 13.3, 16.6, and 20.8 mg. The 
starting dose for simulations is 1.0 mg, but a lower dose of 0.5 mg is provided in case a dose 
reduction from the starting dose is necessary. 
15.2.2. 
Statistical Model 
For a dose 𝑑𝑑, let 𝜋𝜋(𝑑𝑑) denote the probability of dose limiting toxicity (DLT) at dose 𝑑𝑑. For a 
cohort of size 𝑛𝑛 evaluated at dose 𝑑𝑑, the number of patients, 𝑦𝑦, with a DLT is assumed to follow 
a binomial distribution: 
𝑦𝑦 | 𝜋𝜋(𝑑𝑑) ~ Binomial(𝑛𝑛, 𝜋𝜋(𝑑𝑑)) 
The relationship between doses and DLT rates is modeled by the logistic curve 
logit൫𝜋𝜋(𝑑𝑑)൯= log(𝛼𝛼) + 𝛽𝛽log(𝑑𝑑𝑑𝑑∗
⁄
) , 𝛼𝛼> 0, 𝛽𝛽> 0 
where logit൫𝜋𝜋(𝑑𝑑)൯= log (𝜋𝜋(𝑑𝑑) (1 −𝜋𝜋(𝑑𝑑))
⁄
). Doses are rescaled as d/d* with reference dose 
d*=20.8 mg of PEN-221. The model parameters 𝛼𝛼 and 𝛽𝛽 have the following interpretation: 
•
𝛼𝛼 equals the odds of toxicity at the reference dose d*.
•
Doubling the dose results in an increase in odds of toxicity by a factor of 2𝛽𝛽.
For a dose equal to zero, the probability of toxicity is zero. 
15.2.3. 
Prior Specification 
The model parameters (log(𝛼𝛼) , log(𝛽𝛽)) are given a weakly informative bivariate normal prior 
distribution that is guided by guesses from preclinical data and that ensures wide confidence 
intervals for the DLT rates at each dose, and allows efficient escalation towards the MTD. To 
tune the prior distribution for the model, a priori it is assumed that doses higher than 13.3 mg 
exceed the EWOC threshold (i.e., greater than 25% probability of excessive toxicity), while 


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doses at or below 13.3 mg are considered admissible for dose escalation. Such a prior 
distribution would facilitate initial escalation toward the 6.7 – 13.3 mg range, which includes the 
predicted MTD of 9 mg based on allometric scaling. The prior parameter values to be used in 
this study are given in Table 17, and the resulting prior distribution of DLT rates is illustrated 
inFigure 3.Prior probabilities of excessive toxicity at each dose are shown in Table 18. 
Table 17: 
Prior parameter values for the bivariate normal distribution of model 
parameters 
Parameters 
Means 
Standard deviations 
Correlation 
(log(𝛼𝛼) , log (𝛽𝛽)) 
(−1.099, 0.693) 
(2, 1) 
0 
Table 18: 
Prior probability of excessive toxicity (DLT rate > 0.33) 
Dose (mg) 
0.5 
1 
2 
4 
6.7 
10 
13.3 
16.6 
20.8 
Probability of 
excessive 
toxicity 
0.029 
0.039 
0.056 
0.085 
0.124 
0.175 
0.235 
0.305 
0.422 
Figure 3: 
Prior median DLT rates and 95% confidence intervals at dose levels used for 
simulations 
A consideration in tuning the prior parameter values is to produce a model that adapts well to 
emerging data. To illustrate the proposed model’s response to DLTs in early cohorts, Figure 4 
shows the prior probabilities of excessive toxicity for each dose along with the posterior 
probabilities of excessive toxicity after observing a single DLT in cohort 1, 2 or 3. Prior to 






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15.2.4. 
Dose Escalation Rules for Simulation 
The principle of escalation with overdose control (EWOC) prohibits recommending a particular 
dose for the next cohort unless, given the current data, there is a small chance (posterior 
probability < 25%) that this dose is excessively toxic (DLT rate > 33%). 
Within the constraints of the EWOC criteria, dose recommendations are based on maximizing 
the posterior probability that the DLT rate is in the targeted toxicity interval. For simulations, 
dose escalation proceeds according to the following rules: 
• Each cohort has 3 patients. 
• The dose recommended for the next cohort is the 1 that has maximum probability of 
being in the targeted toxicity region (16% – 33% DLT rate), provided it satisfies the 
EWOC criteria and is does not skip an untried dose. 
• If the recommended dose satisfying the EWOC criteria is higher than the next higher 
dose, then escalate only to the next higher dose. 
• Stop to declare MTD: The study stops with a determination of MTD at dose 𝑑𝑑̃ if the 
model’s recommended dose for the next cohort is 𝑑𝑑̃ and the following conditions are 
met: 
1. At least 6 patients have already been evaluated at dose 𝑑𝑑̃. 
2. One of the following conditions is satisfied: 
a. The probability of 𝑑𝑑̃ being in the targeted toxicity region is at least 0.6. 
b. At least 18 patients have been evaluated in the study. 
• Stop for over-dosing: The study stops with a declaration that the MTD is below the 
lowest dose if there are no doses available that satisfy the EWOC criteria. 
15.2.5. 
Hypothetical Dose-Toxicity Relationships for Simulation 
Simulations were performed considering 5 hypothetical dose toxicity curves (Table 19  and 
Figure 5) which capture a range of potential true underlying dose toxicity relationships. 
a. Steep dose toxicity curve and MTD is in the early range of dose levels 
b. Steep dose toxicity curve and MTD is in the middle range of dose levels 
c. Steep dose toxicity curve and MTD is in the upper range of dose levels 
d. Flat dose toxicity curve and MTD is in the middle range of dose levels 
e. Flat dose toxicity curve and MTD is in the late range of dose levels 
f. Steep dose toxicity curve and all doses are excessively toxic 
g. Flat dose toxicity curve and all doses are excessively toxic 




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15.2.6. 
Simulation Results 
To evaluate the operating characteristics of the BLRM method with the specified prior 
distribution, simulations were performed in East 6.4 under each of 5 true dose-toxicity scenarios. 
Results based on 1000 simulated studies per scenario are summarized in Table 20. 
Table 20: 
Operating characteristics of the BLRM design. The toxicity of a dose is 
classified by its DLT rate as follows: [0,0.16) under dosing; [0.16, 0.33) 
targeted toxicity; [0.33, 1] excessive toxicity. 
Sce-
nari
o 
% simulations selecting MTD in 
interval 
Average % of 
patients receiving 
a dose with 
Average 
number 
of DLTs 
Ave 
Sample 
size 
Ave % of 
patients 
experiencin
g DLT 
targeted 
toxicity 
excessive 
toxicity 
under 
dosing 
below 
lowest 
dose 
targeted 
toxicity 
excessive 
toxicity 
a 
77.6 
10.9 
8.3 
3.2 
58.8 
12.4 
4.2 
18.7 
23.5 
b 
79.3 
7.5 
13.2 
0 
41.1 
8.1 
3.4 
21.0 
16.3 
c 
62.5 
6.5 
31.0 
0 
26.2 
3.7 
3.1 
25.0 
12.3 
d 
72.9 
9.7 
16.6 
0.8 
50.6 
5.3 
3.6 
20.7 
18.1 
e 
67.6 
- 
32.4 
0 
23.3 
- 
2.3 
26.4 
8.7 
f 
- 
6.7 
- 
93.3 
- 
100 
3.5 
7.1 
60.3 
g 
- 
35.8 
- 
64.2 
- 
100 
4.1 
11.5 
46.0 
In scenarios a – e, there is a high chance (62% – 80% probability) that the BLRM method 
recommends a dose with DLT rate in the target range of 0.16 – 0.33. Across all of these 
scenarios, there is a low chance of recommending an excessively toxic dose (<11% probability), 
of assigning a patient to an excessively toxic dose (<13% probability), and of a patient in the 
study experiencing a DLT (<24% probability). In scenario f, which assumes all doses are highly 
toxic with DLT rates of at least 50%, it is very unlikely (7% probability) that any dose is 
recommended. Instead, the MTD would be declared to be below the lowest dose (93% 
probability). Scenario g also assumes all doses are in the excessive toxicity region, but the early 
doses are only slightly above the cutoff for excessive toxicity. Table 21 shows the probability of 
selecting each dose as MTD in scenario g. When a dose is selected as MTD, there is a high 
probability (95%) that the selected dose is one of 0.5, 1, 2, or 4, all of which have DLT rates 
33% – 40%, just above the cutoff for excessive toxicity. 
Table 21:        Probability that each dose is selected as MTD in scenario g 
Dose (mg) 
0.5 
1 
2 
4 
6.7 
10 
13.3 
16.6 
20.8 
Probability 
of selecting 
dose as MTD 
4.6% 
13.9% 
11.2% 
4.3% 
1.5% 
0.1% 
0.2% 
0% 
0% 
For comparison, simulations of the standard 3+3 design were also performed for scenario g. 
These show worse performance overall as illustrated in Table 22. The MTD was only declared 
below the lowest dose 17.9% of the time. 


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Table 22:      Probability that each dose is selected as MTD in scenario g using a 3+3 design 
Dose (mg) 
Below 
lowest 
dose 
0.5 
1 
2 
4 
6.7 
10 
13.3 
16.6 
20.8 
Probability 
of selecting 
dose as 
MTD 
17.9% 21.7% 38.4% 14.1% 6.2% 
1.3% 
0.3% 
0.1% 
0% 
0% 
15.3. 
Dose Escalation Scenarios in Early Cohorts 
Table 23 presents dose escalation scenarios to illustrate dose levels recommended by BLRM via 
EWOC up to the first 3 cohorts, following the rules described in the previous section. The 
BLRM performs reasonably in these hypothetical scenarios. The actual dose selected for each 
cohort will be guided also by medical review of all available clinical data. Notably, if a toxicity 
is observed in the first cohort, the choice of dose level for the next cohort would largely rely on 
clinical judgment as the available statistical information would be relatively weak. 
Table 23: 
Possible scenarios up to the 3rd cohort 
Scenario 
Cohort 
Dose 
assigned 
(mg) 
Number of 
patients 
Number of 
DLTs 
Next 
provisional 
dose 
recom-
mended 
(mg) 
Highest 
acceptable 
next dose 
(mg) 
1 
1 
2 
3 
1 
2 
4 
2 
3 
3 
0 
0 
0 
2 
4 
6.7 
2 
4 
8 
2 
1 
2 
3 
1 
2 
4 
2 
3 
3 
0 
0 
1 
2 
4 
6.7 
2 
4 
6.9 
3 
1 
2 
3 
1 
2 
4 
2 
3 
3 
0 
0 
2 
2 
4 
2 
2 
4 
3.3 
4 
1 
2 
3 
1 
2 
2 
2 
3 
3 
0 
1 
0 
2 
2 
4 
2 
3.3 
4 
5 
1 
2 
3 
1 
2 
2 
2 
3 
3 
0 
1 
1 
2 
2 
2 
2 
3.3 
2.3 


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Scenario 
Cohort 
Dose 
assigned 
(mg) 
Number of 
patients 
Number of 
DLTs 
Next 
provisional 
dose 
recom-
mended 
(mg) 
Highest 
acceptable 
next dose 
(mg) 
6 
1 
2 
3 
1 
2 
2 
2 
3 
3 
0 
1 
2 
2 
2 
1 
2 
3.3 
1.2 
7 
1 
2 
3 
1 
2 
0.5 
2 
3 
3 
0 
2 
0 
2 
0.5 
1 
2 
0.9 
1 
8 
1 
2 
3 
1 
2 
0.5 
2 
3 
3 
0 
2 
1 
2 
0.5 
0.5 
2 
0.9 
0.6 
9 
1 
2 
3 
1 
2 
0.5 
2 
3 
3 
0 
2 
2 
2 
0.5 
NA* 
2 
0.9 
<0.5 
10 
1 
2 
3 
1 
0.5 
1 
2 
3 
3 
1 
0 
0 
0.5 
1 
2 
0.6 
1 
2 
11 
1 
2 
3 
1 
0.5 
1 
2 
3 
3 
1 
0 
1 
0.5 
1 
1 
0.6 
1 
1.2 
12 
1 
2 
3 
1 
0.5 
1 
2 
3 
3 
1 
0 
2 
0.5 
1 
NA* 
0.6 
1 
<0.5 
13 
1 
2 
1 
0.5 
2 
3 
1 
1 
0.5 
NA* 
0.6 
<0.5 
*No available doses satisfying the EWOC criteria 
15.4. 
Dose Recommendation 
After at least 3 patients in a cohort become evaluable, the posterior distribution for the 
probabilities of DLT rates at different dose levels will be obtained. The results of this analysis 
will be summarized in terms of the estimated probabilities that the true rate of DLT at each dose-
level has of lying in each of the following intervals: 
• [0, 0.16) under-dosing 
• [0.16, 0.33) targeted toxicity 
• [0.33, 1] excessive toxicity 


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The escalation with overdose control (EWOC) criteria will be used to guide dose 
recommendations for each cohort. A dose will not be considered admissible for the next cohort 
unless, given the current data, there is a small chance (posterior probability < 25%) that this dose 
is excessively toxic (DLT rate > 33%). 
Within the constraints of the EWOC criteria, dose recommendations will be based on 
maximizing the posterior probability that the DLT rate is in the targeted toxicity interval. 
The dose recommended for the next cohort will be the 1 that has maximum probability of being 
in the targeted toxicity region (16% – 33% DLT rate), provided it satisfies the EWOC criteria 
and does not represent more than a doubling (≤ 100% increase) of the current dose. 
If the recommended dose satisfying the EWOC criteria is > 100% increase in dose, then 
escalation will proceed to the highest dose level which is ≤ 100% increase from current dose. 
The dose recommended by the BLRM may be regarded as guidance and information to be 
integrated with a clinical assessment of the toxicity profiles observed at the time of analysis in 
determining the next dose level to be investigated. 
Details of the criteria for dose escalation and determination of the MTD are provided in 
Section 8.6.1. 
15.5. 
Discussion 
The BLRM with EWOC for the dose-escalation phase of the study enables the use of all safety 
data in the study when making dose-escalation recommendations. 
The metrics provided in this section demonstrate that the model is robust to different scenarios of 
the truth, selecting the MTD with high probability. In general, the model is conservative due to 
the overdose control criterion. In all scenarios, the probabilities of recommending a dose with 
excessive toxicity (probability of DLT greater than 33%) are much smaller than the probabilities 
of recommending a dose with targeted toxicity (probability of DLT between 16% and 33%) as 
the MTD. In addition, the average proportion of patients receiving a dose with excessive toxicity 
(probability of DLT greater than 33%) is less than 13%. 
On-study recommendation based on the model are consistent with the clinical decision-making 
process, and should be considered in conjunction with other available clinical information by the 
SRC in making dose recommendations for purposes of estimating the MTD. 


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16. 
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SAP_001.pdf: 
A Phase 1/2a, open-label multicenter study to assess the safety, 
tolerability, pharmacokinetics, and preliminary antitumor activity 
of PEN-221 in patients with somatostatin receptor 2 expressing 
advanced cancers, including gastroenteropancreatic or lung or 
thymus or other neuroendocrine tumors or small cell lung cancer or 
large cell neuroendocrine carcinoma of the lung 
 
 
Statistical Analysis Plan 
 
Protocol Number 
PEN-221-001 
NCT Number 
NCT02936323 
Date of SAP 
21-Jul-2020 
 


 
 
This document is confidential. 
SAP Version: 3.0 
 
Page 1 of 83 
Filing requirement: TMF 
Statistical Analysis Plan for Phase I/II Oncology Studies 
 
Sponsor Name: Tarveda Therapeutics, Inc. 
 
Protocol Number: PEN-221-001. 
 
Protocol Title: A Phase 1/2a, open-label multicenter study to assess the safety, tolerability, 
pharmacokinetics, and preliminary antitumor activity of PEN-221 in patients with somatostatin 
receptor 2 expressing advanced cancers, including gastroenteropancreatic or lung or thymus or 
other neuroendocrine tumors or small cell lung cancer or large cell neuroendocrine carcinoma 
of the lung. 
 
Protocol Version and Date: Version 8.0 (12-Jul-2019). Includes Amendment 1 (21-Jun-2016), 
Amendment 2 (16-Dec-2016), Amendment 3 (02-Mar-2017), Amendment 4 (11-Dec-2017), 
Amendment 5 (03-Aug-2018), Amendment 6 (08-Jan-2019), and Amendment 7 (12-Jul-2019) 
 
 
 
Author(s): 
, Senior Biostatistician, 
, Senior Pharmacokineticist Early Phase 
 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Tarveda Therapeutics Inc. 
Acceptance of this document constitutes agreement by the recipient that no information contained 
herein will be published or disclosed without prior written authorization from an official of Tarveda 
Therapeutics, Inc. However, this document may be disclosed to appropriate Institutional Review Board 
and Ethics Committees or duly authorized representatives of a national regulatory authority under the 
condition that they are requested to keep it confidential. In the event of an actual or suspected breach 
of this obligation, 
 should be notified promptly. 
 






Statistical Analysis Plan for Phase I/II Oncology I Studies 
Sponsor: Tarveda; Protocol No.: PEN-221-001 
 
 
This document is confidential. 
SAP Version: 3.0 
 
Page 4 of 83 
Filing requirement: TMF 
Table of Contents 
Approvals .................................................................................................................................. 3 
1. 
List of Abbreviations and Definition of Terms ...................................................................... 8 
2. 
Introduction ...................................................................................................................... 13 
3. 
Study Objectives .............................................................................................................. 14 
3.1. 
Phase 1 (Dose Escalation) ................................................................................... 14 
3.1.1. 
Primary ................................................................................................................. 14 
3.1.2. 
Secondary ............................................................................................................ 14 
3.1.3. 
Exploratory ........................................................................................................... 14 
3.2. 
Phase 2a (Dose Expansion) ................................................................................. 15 
3.2.1. 
Primary ................................................................................................................. 15 
3.2.2. 
Secondary ............................................................................................................ 15 
3.2.3. 
Exploratory ........................................................................................................... 16 
4. 
Study Design .................................................................................................................... 17 
4.1. 
Pre-screening Phase ............................................................................................ 17 
4.2. 
Screening Phase .................................................................................................. 17 
4.3. 
Treatment Phase (Phase 1 and Phase 2a) ........................................................... 18 
4.3.1. 
Phase 1 ................................................................................................................ 18 
4.3.2. 
Phase 2a .............................................................................................................. 19 
4.4. 
Patient Selection ................................................................................................... 20 
4.4.1. 
Inclusion Criteria .................................................................................................. 20 
4.4.2. 
Exclusion Criteria ................................................................................................. 20 
4.5. 
Treatment Assignment & Blinding ......................................................................... 20 
4.6. 
Administration of Study Medication ....................................................................... 20 
4.7. 
Timing of Analyses ............................................................................................... 21 
4.7.1. 
Interim Analysis (end of Phase 1): ....................................................................... 21 
4.7.2. 
Interim Analysis (Phase 2a): ................................................................................ 21 
4.7.3. 
Final Analysis (end of Phase 2a): ........................................................................ 21 
4.7.4. 
Schedule of Assessments .................................................................................... 21 
4.7.5. 
Progression Follow-Up ......................................................................................... 22 
4.7.6. 
Survival Follow-Up ............................................................................................... 22 
5. 
Analysis Populations ........................................................................................................ 23 
5.1. 
The Full Analysis Set (FAS) .................................................................................. 23 
5.2. 
The Efficacy Analysis (EA) Population .................................................................. 23 


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5.3. 
The Safety Analysis (SA) Population .................................................................... 23 
5.4. 
The Per-protocol (PP) Population ......................................................................... 23 
5.5. 
The Dose-determining (DD) Population ................................................................ 23 
5.6. 
The Pharmacokinetic (PK) Population .................................................................. 23 
5.7. 
The Pharmacodynamic (PDc) Population ............................................................. 24 
5.8. 
Protocol Deviations ............................................................................................... 24 
6. 
Statistical Methodology..................................................................................................... 25 
6.1. 
General Methods .................................................................................................. 25 
6.2. 
Visit Windows ....................................................................................................... 27 
6.3. 
Handling of Dropouts and Missing Data ................................................................ 27 
6.4. 
Pooling of Investigative Sites ................................................................................ 27 
6.5. 
Subgroups ............................................................................................................ 27 
6.6. 
Determination of Sample Size ............................................................................... 27 
6.6.1. 
Phase 1 ................................................................................................................ 27 
6.6.2. 
Phase 2a .............................................................................................................. 27 
7. 
Patient Characteristics...................................................................................................... 31 
7.1. 
Patient Disposition ................................................................................................ 31 
7.2. 
Background and Demographic Characteristics ..................................................... 31 
7.3. 
Treatment Exposure and Compliance ................................................................... 31 
7.4. 
Prior and Concomitant Medications and Therapies ............................................... 32 
7.4.1. 
Prior Medication ................................................................................................... 32 
7.4.2. 
Concomitant Medication ...................................................................................... 33 
7.4.3. 
Other Therapies ................................................................................................... 33 
7.5. 
Medical Histories .................................................................................................. 33 
7.5.1. 
Cancer-Related Medical History .......................................................................... 33 
8. 
Efficacy ............................................................................................................................ 35 
8.1. 
Primary Efficacy Endpoint and Analysis ................................................................ 35 
8.1.1. 
Primary Analysis of the Primary Efficacy Endpoints ............................................ 35 
8.1.2. 
Secondary Analysis of the Primary Efficacy Endpoints ....................................... 37 
8.2. 
Secondary Efficacy Endpoint(s) and Analyses ...................................................... 37 
8.2.1. 
Tumor Response and Duration of Response for Phase 1 ................................... 37 
8.2.2. 
Progression Free Survival (PFS) ......................................................................... 37 
8.2.3. 
Overall Survival (OS) ........................................................................................... 37 
8.2.4. 
Objective Response Rate for Gastrointestinal Mid-gut NET and Pancreatic 
NET 
38 
















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2. 
INTRODUCTION 
 
PEN-221 is a peptide-drug conjugate combining a somatostatin analog and mertansine (DM1), a thiol-
containing maytansinoid, using a cleavable disulfide linker. The molecule is designed as a potent and 
selective anti-cancer agent to treat patients whose tumors express the somatostatin receptor SSTR2, 
namely, neuroendocrine tumors (NETs), small cell lung cancer (SCLC) and large cell neuroendocrine 
carcinoma (LCNEC) of the lung. In preclinical studies, PEN-221 demonstrated potent anti-tumor activity 
in multiple cancer models that express SSTR2. 
Study PEN-221-001 is an open-label, multi-center, first-in-human Phase 1/2a study evaluating PEN-221 
in patients with SSTR2 expressing advanced gastroenteropancreatic (GEP) or lung or thymus or other 
NETs or SCLC or LCNEC of the lung. 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary tables and 
figures which will be produced, and the statistical methodologies that will be used, are complete and 
appropriate to allow valid conclusions regarding the study objectives.   
 will perform the statistical analyses and are responsible for the production and quality 
control of all tables, listings and figures (TLFs) including the Bayesian approach to efficacy endpoints.  
Development, use, and reporting results of an adaptive Bayesian logistic regression model (BLRM) 
guided by the escalation with overdose control (EWOC) principle to make dose recommendations and 
estimate the maximum tolerated dose (MTD) and will be carried out by a 3rd party vendor chosen by 
Tarveda Other results will be produced by 
. 
 


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3. 
STUDY OBJECTIVES 
 
3.1. 
Phase 1 (Dose Escalation) 
3.1.1. 
Primary 
The primary objective of Phase 1 is to: 
Investigate the safety and tolerability, determine the MTD, and recommended phase 2 dose (RP2D) of 
PEN-221 when administered intravenously (IV) on an every 3 week schedule in patients with SSTR2 
expressing advanced cancers, including gastroenteropancreaticor lung or thymus or other NETs or SCLC 
or large cell neuroendocrine carcinomaof the lung. 
 
3.1.2. 
Secondary 
The secondary objectives of Phase 1 are to: 
• 
Characterize the safety and tolerability of PEN-221, including both acute and chronic toxicities. 
• 
Characterize the pharmacokinetics (PK) of PEN-221, DM1, and peptide from PEN-221, when 
administered IV in patients with SSTR2 expressing advanced cancers including GEP or lung or 
thymus or other NETs or SCLC or LCNEC of the lung. 
• 
Assess the potential of PEN-221 to induce anti-PEN-221 antibodies in the serum when 
administered IV in patients with SSTR2 expressing advanced cancers including GEP or lung or 
thymus or other NETs or SCLC or LCNEC of the lung. 
• 
Assess preliminary anti-tumor activity of PEN-221 in patients with SSTR2 expressing advanced 
cancers including GEP or lung or thymus or other NETs or SCLC or LCNEC of the lung, using 
tumor response criteria as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, 
and duration of response (DOR). 
 
3.1.3. 
Exploratory 
 
 
 
 
 
 
 
 
 
 
 


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3.2. 
Phase 2a (Dose Expansion) 
 
3.2.1. 
Primary 
The primary objective of Phase 2a is to: 
Assess the efficacy of PEN-221 as a single-agent when administered IV using clinical benefit rate (CBR) as 
defined as the proportion of patients with the best overall response of complete response (CR), partial 
response (PR), or stable disease (SD) using tumor response criteria as defined by RECIST 1.1 in the 
following tumor-specific cohorts: 
• 
Patients with advanced or metastatic, well-differentiated, low or intermediate grade 
gastrointestinal (GI) mid-gut NETs.  
• 
Patients with advanced or metastatic, well-differentiated, low or intermediate grade pancreatic 
NETs. 
Assess the efficacy of PEN-221 as a single-agent when administered IV using objective response rate 
(ORR) defined as the proportion of patients with best overall response of CR or PR using tumor response 
criteria defined by RECIST 1.1 along with DOR in the following tumor-specific cohort of patients: 
• 
Patients with advanced or metastatic SCLC.  
 
3.2.2. 
Secondary 
The secondary objectives of Phase 2a are to: 
 
• 
Confirm the MTD identified during the dose-escalation phase, and further investigate the safety 
and tolerability of the RP2D and schedule of PEN-221 when administered IV in patients with 
SSTR2 expressing advanced GEP NETs or SCLC. 
• 
Evaluate PFS and OS in the above tumor-specific cohorts of patients whose tumors express 
SSTR2. 
• 
Evaluate ORR and DOR for gastrointestinal mid-gut NET and pancreatic NET. 
• 
Evaluate the safety and tolerability of PEN-221 administration in the above tumor-specific 
cohorts of patients whose tumors express SSTR2. 
• 
Characterize the PK of PEN-221, DM1, and peptide from PEN-221 in the above tumor-specific 
cohorts of patients whose tumors express SSTR2. 
 
 
 


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3.2.3. 
Exploratory 
 
 
 
 
 
 
 
 
 


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4. 
STUDY DESIGN 
Study PEN-221-001 is a first-in-human, open-label, Phase 1/2a study evaluating the safety, PK, PDc, and 
anti-tumor activity of PEN-221 in patients with SSTR2 expressing advanced GEP or lung or thymus or 
other NETs or SCLC or LCNEC of the lung. The study will be carried out in 2 stages: Phase 1 (dose 
escalation) and Phase 2a (disease-specific cohort expansion). 
The overall study design is presented in Figure 1. 
Figure 1: 
Protocol PEN-221-001 Study Design 
Phase 1 
Dose Escalation 
Phase 2a 
Expansion 
Number of dose cohorts dependent on toxicity 
results as determined by Bayesian logistic 
regression model with overdose control 
Patients with advanced or metastatic, well-
differentiated, low- or intermediate grade 
gastrointestinal mid-gut NET  
n=3535  
 
Patients with advanced or metastatic, well-
differentiated, low-, or intermediate grade 
pancreatic NET  
n=20 
Patients with advanced or metastatic small cell 
lung cancer 
n=20 
 
4.1. 
Pre-screening Phase 
Each patient must demonstrate a tumor that is positive for expression of SSTR2 using an approved SARI 
agent within 180 days of Cycle 1 Day 1 (C1D1). If historical data is not available and after provision of 
written informed consent for pre-screening, patients will have their cancers assessed for SSTR2 
expression using an approved SARI agent. 
 
4.2. 
Screening Phase 
After provision of written informed consent for the study and successful demonstration that tumor 
uptake of SSTR2 analogs is sufficient per inclusion criteria, patients will proceed to the Screening phase 
of the study.  Screening assessments are to be performed within 14 days before the first study drug 
dose, with the exception of CT (computed tomography) or MRI (magnetic resonance imaging) studies 
which may be performed within 28 days before the first study drug dose. 
Cohort 1 
n=2 
Cohort 2 
n=3-6 
Cohort 3 
n=3-6 
Cohort 4 
n=3-6 
Etc. 


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Patients who are determined to be eligible based on Screening assessments will be enrolled in the study 
on C1D1  (baseline). 
 
4.3. 
Treatment Phase (Phase 1 and Phase 2a) 
The study will enroll patients with SSTR2 expressing advanced GEP or lung or thymus or other NETs or 
SCLC or LCNEC of the lung who have provided informed consent for the main study. 
The safety, PK, PDc, and anti-tumor activity of PEN-221 will be assessed. 
 
4.3.1. 
Phase 1 
Phase 1 will employ an adaptive BLRM with 2 parameters guided by the EWOC principle to make dose 
recommendations and estimate the MTD. 
To minimize the number of patients treated at potentially sub-therapeutic dose levels, the first dose 
cohort will enroll 2 patients, whereas subsequent cohorts will enroll a minimum of 3 and up to 6 
patients. The initial patient in Cohort 1 will receive PEN-221 administered IV over 1 hour at the starting 
dose of 1.0 mg on an every 3 week cycle. This patient will be followed for 7 days, including assessments 
during the scheduled visit on C1D8, prior to allowing additional patients to begin treatment with PEN-
221. If PEN-221 is tolerated by the initial patient for at least 7 days, then the first cohort will be opened 
to treatment of 1 additional patient. The first 2 patients will be assessed for safety and dose-limiting 
toxicity (DLT) for at least 4 weeks (including C2D1 and C2D8 assessments) before enrollment in the 
second cohort may begin. 
In each dose escalation cohort following the first cohort, a minimum of 3 patients within a cohort are 
required to have completed C1 and have been assessed for safety and DLT for at least 3 weeks 
(including C2D1 pre-dose assessments) before enrollment of the next cohort may begin. 
The Safety Review Committee (SRC) will review the safety and tolerability of PEN-221 of each cohort to 
decide the next dose level to be tested. Statistical modeling will be performed using all safety data and 
will guide the SRC’s selection of dose levels to be tested. In addition, PK and PDc data may be used to 
inform dose selection. Dose escalation increments will be the decision of the SRC. Dose escalation will 
continue until the MTD is determined. 
During Phase 1, if a patient is tolerating PEN-221 without significant evidence of disease progression, the 
patient may, beginning with C3 or subsequent cycles, have the dose increased to a dose that has already 
been established as tolerable by the SRC, and with the agreement of the SRC. 
 
 
 


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4.3.2. 
Phase 2a 
 
Phase 2a may begin, at the discretion of the Sponsor, once all patients treated in Phase 1 have been 
assessed for safety through and including C2D1, and the SRC has reviewed all safety data and 
recommends continuing with Phase 2a. 
PEN-221 will be evaluated using the RP2D defined by the SRC at the conclusion of Phase 1. The RP2D will 
be the decision of the SRC and will be based on the findings of the safety, tolerability, PK, and PDc 
profile of PEN-221 during Phase 1. The RP2D may be the same as the MTD,  or may be below the MTD. 
In the event that the MTD is higher than the dose determined by the SRC to have an acceptable safety 
and tolerability profile after multiple cycles of administration, the SRC may select a RP2D that is below 
the MTD. 
If one or more DLTs are observed at any time up until 6 patients across any of the three cohorts have 
been treated for at least 1 cycle in Phase 2a, the BLRM will be run to re-evaluate the MTD. The SRC will 
convene to determine whether it is safe to proceed with dosing at the RP2D or whether an alternative 
lower dose is to be considered for subsequent patients. If an alternative lower dose is selected, the SRC 
will reconvene after at least 6 patients have been treated at this new dose to review the data and 
confirm that subsequent patients be enrolled into the study at this new dose. 
In addition, at any time during Phase 2a, the BLRM may be re-run to confirm the estimated MTD and 
verify that the dose under study still satisfies the overdose criterion. If the dose fails to satisfy the 
criterion a change to the dose under study may be decided by the SRC, according to the Bayesian model 
recommendation, and after review of the clinical data. The SRC decision to change dose may also be 
spurred by other safety and tolerability considerations (e.g. frequency of lower grade adverse events 
(AEs) or events in later treatment cycles). Subsequent patients may then be enrolled at this new dose 
until at least 6 patients are treated at this new dose level and upon SRC review of the data the SRC will 
decide whether the new dose level is appropriate for continued study. 
During Phase 2a, approximately 75 patients will be enrolled in the following cohorts: gastrointestinal 
mid-gut NET (n=35, 25 PRRT-naïve, 10  PRRT-recurrent), pancreatic NET (n=20), and SCLC (n=20). Each of 
these cohorts will be enrolled in 2 stages, with approximately 10 patients enrolled per cohort in Stage 1, 
and the remaining patients enrolled in Stage 2. Preliminary efficacy and safety will be assessed in 
approximately the first 10 patients per cohort before deciding whether to proceed to the second stage 
of each cohort.  
Patients in both phases may receive PEN-221 as long as they continue to show clinical benefit, as judged 
by the Investigator, or until disease progression or other treatment discontinuation criteria are met.  
Patients may withdraw from the study or at any time for any reason, without prejudice to their medical 
care. The Investigator also has the right to discontinue treatment with PEN-221 and withdraw patients 
from the study for reasons detailed in Protocol Section 7.8 
The number of centers is to be determined. 
 
 


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Patients may only be replaced in 2 instances: 
• 
Patients who are discontinued from the study prior to receiving study drug PEN-221 may be 
replaced (i.e. lost to follow-up, withdraw consent). 
• 
Patients in the dose-escalation phase who withdraw before completing C1 assessments for 
reasons other than experiencing a DLT may be replaced. 
 
4.4. 
Patient Selection 
4.4.1. 
Inclusion Criteria 
See Protocol Section 7.3 for details. 
4.4.2. 
Exclusion Criteria 
See Protocol Section 7.4 for details. 
 
4.5. 
Treatment Assignment & Blinding 
This is an open-label study and blinding is not applicable for this study. 
 
4.6. 
Administration of Study Medication 
PEN-221 Concentrate for Solution for Injection is a 
 solution containing PEN-221, a DM1-peptide 
drug conjugate with affinity for the human SSTR2 receptor, 
 
 
Patients will receive PEN-221 administered IV over 
 on D1 every 3 weeks. Patients may be 
premedicated with an H1 antagonist and/or an IV corticosteroid per institutional policy if infusion-
related reactions are experienced. 
In Phase 1, the starting dose of PEN-221 is 1.0 mg. Dose escalation will employ an adaptive BLRM design 
following the EWOC principle. 
If a patient is tolerating PEN-221 without significant evidence of disease progression, the patient may, 
beginning with C3 or subsequent cycles, have the dose increased to a dose that has already been 
established as tolerable by the SRC, at the discretion of the Investigator and with the agreement of the 
Medical Monitor. Note if a patient does change dose, their data will be summarized under the starting 
dose. 
In Phase 2a, PEN-221 will be administered at the RP2D as established in Phase 1. If one or more DLTs are 
observed at any time up until 6 patients across any of the above three cohorts have been treated and 


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evaluated for safety for at least 1 cycle, the BLRM will be run and the SRC will review all available safety 
data to determine whether the RP2D remains an appropriate dose to be continued for Phase 2a, or 
whether an alternative dose should be selected. 
 
4.7. 
Timing of Analyses 
4.7.1. 
Interim Analysis (end of Phase 1): 
The dose-escalation design is adaptive by nature, basing ongoing decisions about dose assignment on 
observed data. Details of this procedure and the process for communication with Investigators are 
provided in Protocol Section 8.6.1.  
An informal analysis of safety, efficacy, and certain PK and PDc endpoints occurred after all patients 
enrolled in Phase I had discontinued treatment.  
4.7.2. 
Interim Analysis (Phase 2a): 
In Phase 2a, no formal interim analysis is planned. However, preliminary efficacy and safety was 
assessed in approximately the first 10 patients per cohort before deciding whether to proceed to the 
second stage of each cohort.  
4.7.3. 
Final Analysis (end of Phase 2a): 
In April 2020, the SRC concluded that the trial had achieved its objectives and enrollment could be 
closed. Database lock is planned for Q3 2020 and final analysis will occur after lock. 
 
4.7.4. 
Schedule of Assessments 
Full details can be found in Protocol Table 2 (Phase 1) and Table 3 (Phase 2a). 
Scheduled visits are Pre-screening, Screening, treatment cycles – D1, D8 and D15, End of Treatment 
(EOT), Safety Follow-up (last dose of study drug + 28 Days) and a Progression Follow up. 
Day 8 and D15 evaluations are required for C1, C2, and for the first two cycles starting with a dose 
escalation. If no Grade 2 or higher abnormalities in clinical chemistries or hematology parameters during 
Cycles 1 and 2, or in the two cycles starting with a dose escalation, then the D8 and D15 evaluations may 
be eliminated in subsequent cycles, subject to Investigator discretion. If Grade 2 or higher abnormalities 
in clinical chemistries or hematology parameters are observed, the D8 and D15 evaluations are required 
for 2 additional cycles. If Grade 2 or higher abnormalities do not recur during the subsequent 2 cycles, 
the D8 and D15 evaluations may be eliminated in cycles thereafter, subject to Investigator discretion. 
 
The EOT visit is to be completed within 3 days from the event resulting in treatment discontinuation 
(e.g., disease progression, AE, consent withdrawal, etc.). A Safety Follow up visit is to be completed 
28 days after the last study drug dose. The primary reason for a patient’s discontinuation from 
treatment and withdrawal from the study is to be recorded in the electronic case report form (eCRF). 


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End of study (EOS) occurs when the patient is no longer being followed up for progression or survival 
(i.e. death, lost to follow-up, withdrawal of consent). 
4.7.5. 
Progression Follow-Up 
For patients that discontinue treatment for reasons other than radiographic progression of disease, 
tumor assessments should be performed approximately every 6 weeks from previous scan for SCLC and 
LCNEC of the lung patients and every 9 weeks from previous scan for all other patients, or as clinically 
indicated, until radiographic progression of disease is observed.  
4.7.6. 
Survival Follow-Up 
Upon disease progression, all patients will be followed approximately every 3 months to assess survival 
status and the date and cause of death (if known) will be recorded for patients who died. Survival 
follow-up will occur every 3 months until death, lost to follow-up or consent withdrawal. 
 
 


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5. 
ANALYSIS POPULATIONS 
The patient populations will be summarized in the disposition table. The following patient populations 
will be evaluated and used for presentation and analysis of the data: 
5.1. 
The Full Analysis Set (FAS) 
The FAS (intent-to-treat (ITT)) population comprises all patients enrolled into the study and who receive 
any amount of study drug. Patients will be analyzed according to treatment received. Unless specified 
otherwise, this population will be used for summaries of patient disposition, demographics and baseline 
characteristics, efficacy endpoints PFS and OS, PEN-221 exposure, medications and significant non-drug 
therapies and patient listings. 
5.2. 
The Efficacy Analysis (EA) Population  
The efficacy analysis (EA) population comprises all enrolled patients who receive any amount of study 
drug and have at least 1 post-baseline efficacy assessment (RECIST 1.1). Patients will be analyzed 
according to treatment received. Unless specified otherwise, this population will be used for summaries 
of efficacy endpoints ORR and DOR. This is the primary efficacy analysis population.  
5.3. 
The Safety Analysis (SA) Population  
The safety analysis (SA) population comprises all enrolled patients who receive any amount of study 
drug and have at least 1 post-baseline safety evaluation (AE, clinical laboratory assessments, vital signs, 
ECG (electrocardiogram), ECOG (Eastern Cooperative Oncology Group) scores, physical examination). 
Patients will be analyzed according to treatment received.  The SA will be used for all analyses of safety 
endpoints. 
5.4. 
The Per-protocol (PP) Population  
The per-protocol (PP) population comprises all enrolled patients who receive at least 1 cycle of study 
drug, have at least 1 post-baseline efficacy assessment, and have no major protocol violations, as 
defined by the medical monitor and sponsor (see SAP Section 5.8). Patients will be analyzed according to 
treatment received.  The PP population will be used for all analyses of ORR and DOR. This is the 
secondary efficacy analysis population. 
5.5. 
The Dose-determining (DD) Population 
The dose-determining (DD) population comprises all enrolled patients who receive any amount of study 
drug in Phase 1 and either experienced a DLT or have been followed for the full DLT evaluation period 
and has at least 1 post-baseline safety evaluation. The DD population will be used to determine the MTD 
of PEN-221. 
5.6. 
The Pharmacokinetic (PK) Population  
The PK population comprises all enrolled patients who receive any amount of study drug and have at 
least one measured post-dose concentration for at least one of the PEN-221 relevant analytes as 
described in the Section 9 of the SAP. Patients with major protocol violations will be assessed on a 


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patient-by-patient basis for inclusion in the PK population. The PK population will be used for all 
analyses of PK endpoints. 
5.7. 
The Pharmacodynamic (PDc) Population  
The PDc population comprises all patients who have at least one measured PDc biomarker value at 
either screening or post-dose. Patients with major protocol violations will be assessed on a patient-by-
patient basis for inclusion of the post-dose data in the PDc population. The PDc population will be used 
for all analyses of PD endpoints. 
5.8. 
Protocol Deviations 
Deviations will be managed as detailed in Protocol Deviation and Non-compliance Management Plan. 
Deviations are entered directly into the eCRF and categorized as follows:  
• 
Inclusion/exclusion criteria violation. 
• 
Discontinuation criteria violation. 
• 
Study drug administration. 
• 
Use of prohibited concomitant medication(s). 
• 
Non-compliance. 
• 
Safety evaluation(s) not done. 
• 
Efficacy evaluation(s) not done. 
• 
Procedural deviation. 
All protocol deviations will be classified as major or minor by the medical monitor and sponsor prior to 
the final analysis as detailed in Protocol Deviation and Non-compliance Management Plan.  
All protocol deviations will be provided in a by-patient listing.  
 
 


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6. 
STATISTICAL METHODOLOGY 
See SAP Section 16 for general programming considerations. 
6.1. 
General Methods 
 will be responsible for reporting the demographic, safety, efficacy and PK/PDc data 
including the development, use and reporting results of a Bayesian model to calculate CBR and ORR. A 
3rd party vendor will be responsible for the development, use and reporting of the Phase 1 primary 
objective (determining MTD and RP2D) based on the adaptive BLRM in conjunction with EWOC.  
SAS version 9.4 or later will be used. 
Phoenix WinNonLin version 6.4 or higher will be used for PK parameters derivation. 
Categorical variables will be summarized using number of observations (n), frequency, and percentages 
of patients, unless stated otherwise.  Unless stated otherwise, the calculation of percentages will be 
based on the total number of patients in the population of interest.  Thus counts of missing observations 
will be included in the denominator and presented as a separate category. 
Continuous variables will be summarized using the number of observations (n), mean, standard 
deviation, median, minimum, and maximum, unless stated otherwise.   
In cases where n≤1 patient, no summary table/figure will be produced but the data for this patient will 
be listed.  
Time to event data (DOR, PFS and OS) will be analyzed using Kaplan-Meier survival estimates. Summary 
statistics will include median, 25th, and 75th percentile survival times and corresponding 95% 
confidence intervals.  
Unless otherwise specified, all disposition, demography, baseline characteristics and safety summaries 
will be presented by total and study phase as follows: 
• 
‘Study Total’ (Phase 1 and Phase 2a combined).). 
• 
‘xx.x mg’ (dose 1, dose 2 etc - a column for each dose level in Phase 1). 
• 
For Phase 2a, tumor types will be summarized on separate pages by the following by-lines (sub-
headings): ‘Overall’, ‘GINET (PRRT Naive)’, ‘GINET (PRRT Recurrent)’, ‘GINET (Total)’, ‘PNET’ and 
‘SCLC’ 
o ‘< 8.8 mg/m sq’  
o ‘8.8 mg/m sq’ 
o ‘> 8.8 mg/m sq’ 
o ‘Total’ 
Efficacy tables will be as described above but without the ‘Study Total’ column.  
 
 


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For Phase 2a, dose level in mg/m sq is determined using the first dose of PEN-221 in mg received on 
C1D1. Body surface area (BSA) will be determined using the Du Bois formula: 
BSA (m sq) = 0.007184 x (patient height in cm)0.725 x (patient weight in kg at C1 D1)0.425 
The total number of patients in the dose level (for Phase 1), or by tumor-specific cohorts/dose level (for 
Phase 2a) (N) will be used as the denominator for percentage calculations, unless stated otherwise in 
the table shell.  
Listings will also be provided for Phase 1 and Phase 2a combined. In general, the listings will be sorted 
by phase (C1D1 dose level within Phase 1 and Phase 2a combined), patient number and assessment date 
(and time), if applicable. The listings will be presented as follows (see shells for further details): 
Example for Phase 1, ‘Phase 1  xx.x mg’. 
Example for Phase 2a, ‘Phase 2a PNET 8.8 mg/m sq’ 
Missing records will be omitted from the listings, and missing data within a record will be left blank. 
Reasons why scheduled visits were not completed will be listed when known.  
Multiple assessments at a given time point (planned, repeat) will not be included in summary tables 
unless specified otherwise, but will be included in the listings.  If there are multiple results at a given 
visit, eg a repeated laboratory test within a visit, the earliest value will be used in the tables.  
In general, unscheduled visit data will be listed but not included in the summary tables by time point. 
Unscheduled data will be included to identify the worst case post first PEN-221 dose for safety shift 
tables.  
The study day is the day relative to the date of first dose of PEN-221 study medication, where Day 1 is 
the day of first dose of PEN-221 study medication. 
The first dose date is defined as the first non-missing date where a non-zero dose of PEN-221 study 
medication was recorded. 
The last dose date is defined as the last non-missing date where a non-zero dose of PEN-221 study 
medication was recorded.  For patients ongoing at time of analysis, last dose date will be considered the 
date of the most recent study visit in the database for that patient where a non-zero dose of PEN-221 
study medication was recorded. 
Unless otherwise specified, baseline is the last non-missing observation before the start of PEN-221 
study drug medication, which is expected to be Day 1 of Cycle 1 (pre-dose), or screening if the Day 1 
data are not available. 
 
 
 
 


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6.2. 
Visit Windows 
There are no plans to derive visit windows; visits will be used in the analyses as reported on the 
electronic Case Report Form (eCRF).  
6.3. 
Handling of Dropouts and Missing Data 
There will be no imputation of missing data except partial diagnosis dates (see SAP Section 7.5). Missing 
data will be treated as missing except for AEs where toxicity and relationship to study drug are missing 
(see SAP Section 12.1).  SAP Section 7.4.2 describes how to determine if a medication is concomitant if 
partial dates exist. Similarly, SAP Section 12.1 describes how to determine if an adverse event is 
treatment emergent where partial dates exist.    
6.4. 
Pooling of Investigative Sites 
As it is anticipated that accrual will be spread thinly across centers and summaries of data by center 
would be unlikely to be informative, data from all participating centers will be pooled prior to analysis. 
6.5. 
Subgroups 
There are no plans for any subgroup analysis for the efficacy and safety endpoints. SAP Sections 9 and 
10 detail subgroup analysis of the PK and PDc endpoints. 
6.6. 
Determination of Sample Size 
No formal statistical power calculations to determined sample size were performed for this study. 
However, based on the performance characteristics computed and described hereafter, the sample sizes 
in each phase are adequate to address the study’s objectives. 
6.6.1. 
Phase 1  
No formal sample size calculations were performed for Phase 1. It is estimated that 30 patients will be 
enrolled in the dose-escalation phase including at least 6 patients treated at the MTD level. The actual 
number of patients will depend on the number of dose levels/cohorts that are tested. Based on the 
simulation study undertaken with the East 6.4 software to evaluate operating characteristics of the 
BLRM (see Protocol Section 15) at least 18 patients are expected to be treated in the dose-escalation 
phase for the model to have reasonable operating characteristics relating to its MTD recommendation. 
6.6.2. 
Phase 2a 
No formal sample size calculations were performed for Phase 2a. A total of approximately 75 patients 
will be enrolled in Phase 2a. This includes the following Phase 2a cohorts: GI mid-gut NETs (n=35), 
pancreatic NETs (n=20), and advanced or metastatic SCLC (n=20).  
For patients with advanced pancreatic NET, approved drugs (beyond somatostatin analogs) include 
sunitinib and everolimus, both of which improved PFS but are associated with clinical benefit rates of 
approximately 72% for sunitinib and 78% for everolimus (Raymond 2011; Yao 2011). In the pancreatic 
NET group, an observed clinical benefit rate of 75% or greater would be considered promising. Given a 
sample size of 20 patients, if clinical benefit is observed in 15 patients (observed rate of 75%), the 
posterior probability of the true rate being <65% is 0.20, with the 95% credible interval around the true 
rate being (52.8%, 88.7%). If only 14 responses are seen (observed clinical benefit rate of 70%), the 


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probability of the true clinical benefit rate being at least 75% is 0.26, while seeing only 13 responses 
(observed clinical benefit rate of 65%) would result in that probability being only 0.13. If the true 
underlying clinical benefit rate is 75%, there is 0.38 probability to observe fewer than 15 patients 
achieve clinical benefit. This probability drops to 0.20 if the true underlying rate is 80%. 
For patients with advanced gastrointestinal NETs, approved drugs (beyond somatostatin analogs) 
include everolimus, which has been shown to improve PFS but is associated with a clinical benefit rate of 
83% (Yao 2016). In a randomized Phase 3 study,177Lu-DOTATATE plus Octreotide LAR  in patients with 
advanced GI mid-gut NETs was shown to improve PFS and is associated with a clinical benefit rate of 
82% (Strosberg 2017; Strosberg 2016 [4th Theranostics World Congress 2016])). In the gastrointestinal 
mid-gut NET group, an observed clinical benefit rate of approximately 75% or greater would be 
considered promising. In a sample 35 patients, if clinical benefit is observed in 26 patients (observed 
rate of 74%), the posterior probability of the true rate being <65% is 0.14, with the 95% credible interval 
around the true rate being (57.8%, 85.8%). If only 25 responses are seen (observed clinical benefit rate 
of 71%), the probability of the true clinical benefit rate being at least 75% is 0.27, while seeing only 24 
responses (observed clinical benefit rate of 69%) would result in that probability being only 0.17. If the 
true underlying clinical benefit rate is 75%, there is 0.37 probability to observe fewer than 26 patients 
achieve clinical benefit. This probability drops to 0.15 if the true underlying rate is 80%. Approximately 
25 of the 35 patients in the gastrointestinal mid-gut NET group are expected to be treated at the current 
RP2D (15mg), and among these patients, approximately 20 are expected to have not received prior 
PRRT. These two subgroups will be summarized separately. For the subgroup of approximately 20 
patients without prior PRRT and who are treated at the current RP2D, the performance characteristics 
based on a target CBR of 75% (15 patients with clinical benefit out of 20) are the same as those 
presented in the previous paragraph for the pancreatic NET cohort.  
For patients with advanced SCLC, approved drugs in the second-line include topotecan, which has been 
shown in a randomized Phase 3 study (von Pawel 1999) compared to cyclophosphamide-doxorubicin-
vincristine (CAV) to achieve similar time to progression, survival, and response rates (topotecan 24% vs. 
CAV 18%) in patients who relapsed >90 days after completion of their first line platinum containing 
chemotherapy regimen, and similar though somewhat lower response rates in the subset of patients 
who relapsed within 60 to 90 days after completion of the first-line chemotherapy (topotecan 13.6% vs. 
CAV 4.8%). In the platinum-sensitive SCLC group, a tumor response rate of 30% or greater would be 
considered very promising. Given a sample size of 20 patients, if 6 responses are seen (observed ORR of 
30%), the posterior probability of the true ORR being < 10% is 0.5% and being ≥ 30% is 55%, with the 
95% credible interval about the true ORR being (14.6%, 52.2%). For a cohort of 20 patients, if the 
observed proportion is 0.3, there is 100% probability that the true underlying proportion exceeds 0.05, 
and 55.0% probability that the true underlying proportion exceeds 0.3. If the true underlying proportion 
is 0.3, there is 0.1% probability to observe 0 responses. If only 4 responses are seen (observed ORR of 
20%) the probability of the true ORR being ≥ 30% drops to 19.8%, while seeing only 2 responses 
(observed ORR of 10%) would result in that probability being only 2.7%. If the true underlying 
proportion is 0.3, there is 0.1% probability to observe 0 responses. 
 
Table 1  provides more probability statements about the true ORR based on number of responses 
observed in 20 patients, and Table 2 provides probability statements about the true CBR based on the 
number of patients with clinical benefit observed in 20 patients 


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Table 1: Posterior probability of true ORR based on observed number of responses 
Number of 
Responses out 
of 20 Patients 
Observed ORR 
Prob (True 
ORR>5%) 
Prob (True 
ORR>10%) 
Prob (True 
ORR>20%) 
Prob (True 
ORR>30%) 
0 
0% 
34.1% 
10.9% 
<1% 
<0.1% 
1 
5% 
71.7% 
36.5% 
5.8% 
0.6% 
2 
10% 
91.5% 
64.8% 
17.9% 
2.7% 
3 
15% 
98.1% 
84.8% 
37.0% 
8.6% 
4 
20% 
99.7% 
94.8% 
58.6% 
19.8% 
5 
25% 
100.0% 
98.6% 
76.9% 
36.3% 
6 
30% 
100% 
99.7% 
89.1% 
55.1% 
7 
35% 
100% 
99.9% 
95.7% 
72.3% 
Twenty patients will result in 88% and 64% probability of detecting at least one response with a true 
rate of 10% and 5%, respectively. 
 
Table 2 Posterior probability of true CBR based on observed number of patients with clinical benefit 
Number of 
Patients with 
Clinical Benefit 
out of 20 Patients 
Observed 
CBR 
Prob (True 
CBR>60%) 
Prob (True 
CBR>65%) 
Prob (True 
CBR>70%) 
Prob (True 
CBR>75%) 
10 
50% 
17.4% 
7.7% 
2.6% 
0.6% 
11 
55% 
30.9% 
16.2% 
6.8% 
2.1% 
12 
60% 
47.6% 
29.4% 
14.8% 
5.6% 
13 
65% 
65.0% 
46.4% 
27.7% 
13.0% 
14 
70% 
80.0% 
64.3% 
44.9% 
25.6% 
15 
75% 
90.4% 
79.9% 
63.7% 
43.3% 
16 
80% 
96.3% 
90.8% 
80.2% 
63.3% 
17 
85% 
98.9% 
96.7% 
91.4% 
80.8% 


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Based on the performance characteristics above, the sample sizes are adequate to address Phase 2a 
objectives.  
Note at the time of the SRC decision to close the trial to enrollment, the number of patients enrolled in 
the GINET cohort was 31, (25 PRRT naïve, 6 PRRT recurrent).  For the PNET cohort 15, and for the SCLC 
cohort 17. 
 
 
 


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7. 
PATIENT CHARACTERISTICS 
 
7.1. 
Patient Disposition 
A tabulation of patient disposition, including the number of patients enrolled in each patient population 
and the number of protocol violations. The table will also include the number that withdrew prior to 
completing the study, and the primary reasons for withdrawal. The number of patients completing 
treatment, and the primary reasons for treatment discontinuation will also be summarized.  A patient 
listing of study/treatment completion information, including the reason for premature study 
withdrawal/treatment discontinuation, if applicable, will be presented. The FAS will be used for the 
summary tables. 
A listing of protocol deviations will be provided including category of deviation as recorded on the eCRF 
and whether the deviation was considered major or minor as determined by the medical monitor. 
A listing of analysis populations will be provided. 
Eligibility criteria will be listed including patient consent data. 
 
7.2. 
Background and Demographic Characteristics 
Demographic and other baseline data, including age, sex, race, ethnicity, height (cm), weight (kg) and 
baseline ECOG performance status will be listed individually by patient and summarized. The FAS will be 
used. 
The following derivations will be used: 
• 
Age at C1D1 = (C1D1 visit date - date of birth + 1) / 365.25 and truncated to complete years. 
• 
Height (in cm) = height (in inches) * 2.54 
• 
Weight (in kg) = weight (in lbs) * 0.4536 
Demographic data and baseline characteristics will be listed for all enrolled patients. 
 
7.3. 
Treatment Exposure and Compliance 
Patients will receive PEN-221 administered IV over 60 minutes on Day 1 every 3 weeks.  
The extent of exposure will be examined by summarizing the variables below: 
• 
Actual dose (mg) (‘Dose Administered (mg)’ on eCRF) and BSA dose (mg/m sq) of PEN-221 
administered overall and in each cycle. 
• 
PEN-221 dosage interrupted or not in each cycle. 
• 
Duration of exposure (weeks (wk)) for PEN-221.  This is calculated as: (Last administration date – 
first administration date) + 1 / 7 


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• 
Number of cycles started (where a non-null value for ‘Dose administered (mg)’ is captured on 
Day 1.  Presented as a categorical and continuous variable. Categories are ‘1 – 2 Cycles’, ‘2 – 4 
Cycles’, ‘> 4 Cycles’.  
• 
Dose intensity (mg/wk) overall and in each cycle. Computed as the ratio of actual dose received 
and actual cycle duration. Cycle duration (wk) is calculated as: 
(Administration date of Cx+1)  – (administration date of Cx) + 1 / 7 
The last cycle duration will be set to 3 weeks. 
• 
Relative dose intensity (%) overall and in each cycle. Computed as the ratio of dose intensity and 
planned dose received (BSA Dose mg/m sq)/planned duration (3 weeks): 100 * dose intensity 
(mg/wk) / planned dose intensity (mg/wk).  
A relative dose intensity of 100% indicates that the drug was administered at the correct dose within 
the planned timeframe (e.g. every 21 days). 
All study drug administration data captured on the eCRF will be listed.  
 
7.4. 
Prior and Concomitant Medications and Therapies 
All medications will be documented from 30 days before first study drug dose on C1D1 through to the 
Safety Follow-up visit. Medications will be presented in tabular form using Anatomical Therapeutic 
Chemical (ATC) level 2 (therapeutic main group) and ATC level 4 (chemical subgroup) via the latest 
World Health Organization Drug classification Dictionary (WhoDRUG).  All medications will be sorted by 
descending order of occurrence in the study total group for ATC level 2, then ATC level 4 terms.  The 
number and percentage of patients who took at least 1 drug within each specific ATC level 4 will be 
presented.  Patients will only be counted once if they are taking more than 1 medication or take the 
same medication more than once.  
All prior and concomitant medications will be listed including the derived study day (for both start and 
stop dates) and a flag for prior medications. 
 
7.4.1. 
Prior Medication 
A medication is considered prior if the medication stop date is before treatment start date. Prior 
medications will be summarized. The FAS will be used. 
Prior medications will be listed with the concomitant medications for all enrolled patients. Prior 
medications will be flagged in the listing.  
 
 
 


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7.4.2. 
Concomitant Medication 
All medications will be considered concomitant unless the medication stop date is before treatment 
start date.  
Medications with incomplete start dates will be considered concomitant if the: 
• 
Day and month are missing and the year is equal to or after the year of the first dose date;  
• 
Day is missing and the year is after the year of the first dose;  
• 
Day is missing and the year is equal to the year of the first dose date and the month is equal to 
or after the month of the first dose date; 
• 
Year is missing; or 
• 
Complete date is missing. 
Concomitant medications will be summarized. The FAS will be used.  
Concomitant medications will be listed with the prior medications for all enrolled patients.  
 
7.4.3. 
Other Therapies  
Prior therapies (including systemic therapies, radiation and surgeries) will be summarized using the FAS 
and listed for all enrolled patients.  
Concomitant procedures will be listed for all enrolled patients. 
 
7.5. 
Medical Histories 
Medical histories/active symptoms will be coded using the latest Medical Dictionary for Regulatory 
Activities (MedDRA), and coded system organ class (SOC) and preferred terms (PTs) will be used for the 
summary table.  All medical histories will be sorted by decreasing order of occurrence in the study total 
group for SOC and decreasing order of occurrence of PT within the SOC. The FAS will be used. 
Medical history conditions/active symptoms will be listed for all enrolled patients. 
 
7.5.1. 
Cancer-Related Medical History 
Cancer diagnosis and history and SSTR tumor imaging will be summarized. Length of time since diagnosis 
(months) will be derived as follows: 
Time since diagnosis at C1D1 = (C1D1 visit date - date of initial diagnosis + 1) / 30.5. 
If partial dates exist for initial diagnosis date, the date will be imputed to the 15th of the month (for 
missing day) or 01JUL (for missing day and month). 
The FAS will be used. 


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8. 
EFFICACY  
Unless otherwise specified, the EA population will be used for the efficacy analyses except PFS and OS 
where the FAS will be used. 
 
8.1. 
Primary Efficacy Endpoint and Analysis 
Tumor measurements and disease response assessments are to be performed for all patients. Tumor 
evaluations are to be performed during screening within 28 days before C1D1. For patients with SCLC or 
LCNEC of the lung, disease response assessments are to be performed within 7 days of the first study 
drug dose in every other cycle, starting before C3. For all other patients, disease response assessments 
are to be performed within 7 days of the first study drug dose in every 3rd cycle, starting before C4. 
Note for efficacy endpoints based on RECIST 1.1, patients in Phase 1 are not required to have 
measurable disease. Patients in Phase 2a are required to have measurable disease. De-identified results 
of radiographic tumor evaluations performed prior to study entry and/or during study, such as 
radiologists’ reports or electronic copies of CT and MRI scans may be requested by the Sponsor for 
independent review of tumor response.  
 
8.1.1. 
Primary Analysis of the Primary Efficacy Endpoints 
Note for Phase 1, the primary endpoint is the frequency of DLTs associated with a single administration 
of PEN-221 during the first cycle of treatment. The MTD is the highest drug dosage not expected to 
cause dose-limiting toxicity DLT in more than 33% of the treated patients in the first 3 weeks of PEN-221 
treatment (or in the first 4 weeks of PEN-221 treatment for Cohort 1 only). This is determined based on 
an adaptive BLRM in conjunction with EWOC as described in Protocol Section 12.6.1 and will be 
reported separately by a 3rd party vendor. The DD population will be used.  
For Phase 2a, the primary endpoint for gastrointestinal mid-gut NET and pancreatic NET is CBR defined 
as the proportion of patients with the best overall response of CR, PR, or SD using RECIST, version 1.1. 
For the SCLC cohort, the primary endpoint is ORR defined as the proportion of patients with best overall 
response of CR or PR using tumor response criteria defined by RECIST, version 1.1, along with duration 
of response.  
 
8.1.1.1. 
Clinical Benefit Rate for Gastrointestinal Mid-gut NET and Pancreatic NET 
 
Clinical benefit rate is defined as the proportion of patients with a best overall CR, PR, or SD as defined 
by RECIST 1.1. 
For each NET cohort, CBR will be estimated and presented with 95% confidence intervals (CIs) based on 
the exact binomial distribution.  


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In addition, a Bayesian approach will be used to estimate the CBR and its 95% credible interval based on 
the posterior distribution. A vague beta prior distribution with parameters a=1 and b=1 will be used. This 
translates to a prior mean of 50% with wide uncertainty. 
At completion of the study, the prior distribution will be updated with all data available from the 
evaluable patients at the RP2D to obtain the posterior distribution of the true CBR. For each NET cohort, 
the posterior probability that the true CBR is greater than 75% will be reported. 
 
8.1.1.2. 
Objective Response Rate (ORR) for SCLC 
Objective response rate is defined as the proportion of patients with a best overall CR or PR as defined 
by RECIST 1.1 using the investigator assessment captured on the eCRF. Both tumor responses without 
confirmation as well as confirmed tumor responses (by second assessment at least 4 weeks after first 
assessment) will be used for efficacy evaluation.  
ORR will be estimated and presented with 95% confidence intervals (CIs) based on the exact binomial 
distribution. Confirmed responses and a row including all responses (confirmed and unconfirmed) will 
be presented in the summary table. Similarly, rates of individual categories of response (i.e. CR, PR, SD 
and progressive disease (PD)) will be presented. The best overall response per patient will be presented 
(order from best to worst is CR, PR, SD, PD). Confirmed best response and all responses (confirmed and 
unconfirmed) will be summarized separately. All response, target lesion, non-target lesion and new 
lesion data will be listed. 
Additionally, a waterfall plot for best percentage change from baseline in the sum of target lesion 
longest diameters will be provided. The Y axis will be percent change from baseline and patient number 
on the X axis. A positive result indicates an increase in tumor size; a negative result indicates a decrease 
(shrinkage). 
In addition, for each tumor-specific cohort, a Bayesian approach will be used to estimate the ORR and its 
95% credible interval based on the posterior distribution. An equal tailed 95 % credible interval will be 
calculated.  A vague beta prior distribution with parameters a=1 and b=1 will be used. This translates to 
a prior mean of 50% with wide uncertainty. 
At completion of the study, the prior distribution will be updated with all data available from the 
evaluable patients at the MTD/RP2D to obtain the posterior distribution of the true ORR. For the SCLC, 
the posterior probability that the true ORR is greater than 30% will be reported. This analysis will be 
completed for confirmed responders and all responders (confirmed and unconfirmed responses) 
separately.  
 
8.1.1.3. 
Duration of Response (DOR) for SCLC 
Duration of response is defined as the time from first documented response (CR or PR), as assessed by 
the investigator, to the date of first documented disease progression or death due to underlying cancer. 
If a patient has not progressed or died before the analysis cutoff date, DOR will be censored at the date 
of last adequate tumor assessment. 


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DOR (months) = ([Date of progression/death due to underlying cancer – date of first response] + 1) / 
30.5 
DOR analyses will be performed using investigator lesion assessments (for RECIST v1.1 criteria) collected 
in the eCRF.  
DOR will be analyzed and presented using the Kaplan-Meier method, along with the estimated median 
(in months) with 95% CIs, 25th and 75th percentiles.  
 
8.1.2. 
Secondary Analysis of the Primary Efficacy Endpoints 
The analysis will be repeated using the PP population (with the exception of the Bayes analysis which 
will be based on the EA population only). The analysis using the EA population will be considered the 
primary analysis. 
 
8.2. 
Secondary Efficacy Endpoint(s) and Analyses 
8.2.1. 
Tumor Response and Duration of Response for Phase 1 
Objective response rate, best overall response and DOR will be analyzed as for the primary analysis for 
Phase 1 using dose level with the exception that the Bayesian approach will not be used. 
 
8.2.2. 
Progression Free Survival (PFS) 
PFS (months) = ([Date of progression / death – date of first dose] + 1) / 30.5 
PFS analyses will be performed using investigator lesion assessments (for RECIST v1.1 criteria) collected 
in the eCRF.  
PFS will be analyzed and presented using the Kaplan-Meier method, along with the estimated median 
(in months) with 95% CIs, 25th and 75th percentiles. Separate curves will be produced for Phase 1; 
Phase 2a will be presented on a separate page from Phase 1 and separate curves will be produced for 
‘GINET (PRRT Naive)’, ‘GINET (PRRT Recurrent)’, ‘GINET (Total)’, ‘PNET’ and ‘SCLC’. The FAS will be used. 
Data collected at the Survival and Progression Follow-up visits (i.e. patient status (dead, alive, lost to 
follow up), new anticancer treatments) will be listed. 
  
8.2.3. 
Overall Survival (OS) 
Overall survival is defined as the time from the date of first dose of PEN-221 to the date of death due to 
any cause. If a patient has not died before the analysis cutoff date, OS will be censored at the date of 
last contact. 


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OS (months) = ([Date of death – date of first dose] + 1) / 30.5 
OS will be analyzed and presented using the Kaplan-Meier method, along with the estimated median (in 
months) with 95% CIs, 25th and 75th percentiles. Separate curves will be produced for ‘Phase 1’; Phase 
2a will be presented on a separate page and separate curves will be produced for ‘GINET (PRRT Naive)’, 
‘GINET (PRRT Recurrent)’, ‘GINET (Total)’, ‘PNET’ and ‘SCLC’. The FAS will be used. 
 
8.2.4. 
Objective Response Rate for Gastrointestinal Mid-gut NET and Pancreatic NET 
For gastrointestinal mid-gut-NET and pancreatic NET, objective response rate (ORR) is defined as the 
proportion of patients with a best overall CR or PR as defined by RECIST 1.1. 
ORR will be estimated and presented with 95% CIs based on the exact binomial distribution. 
In addition, a Bayesian approach will be used to estimate the ORR and its 95% credible interval based on 
the posterior distribution. A vague beta prior distribution with parameters a=1 and b=1 will be used. This 
translates to a prior mean of 50% with wide uncertainty. 
At completion of the study, the prior distribution will be updated with all data available from the 
evaluable patients at the RP2D to obtain the posterior distribution of the true ORR. The posterior 
probability that the true ORR is greater than 20% will be reported. 
 
8.2.5. 
Duration of Response for Gastrointestinal Mid-gut NET and Pancreatic NET 
Duration of response for GINET and PNET will be analyzed as described in SAP Section 8.1.1.3 for SCLC.  
 
 
 


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9. 
ANALYSIS OF PHARMACOKINETICS 
PK analysis will be done for PK population. PK parameters will be derived using Phoenix WinNonLin 
version 6.4 or higher. The TLFs including inferential analyses will be done in SAS 9.3. The PK 
concentrations and parameters will be available for:  
• 
PEN-221.  
• 
Total DM1 (unconjugated from PEN-221 plus DM1 that is still a part of the PEN-221). 
• 
Total peptide (unconjugated from PEN-221 plus peptide that is still a part of the PEN-221). 
• 
Free sulfhydryl DM1 (DM1, that has been unconjugated from PEN-221, but hasn’t reacted with 
anything else); 
• 
Measured Unconjugated DM1 (DM1 that has been unconjugated from PEN-221 and reacted 
with other thiols in plasma plus free sulfhydryl DM1) 
• 
Calculated Unconjugated DM1. (Calculated Unconjugated DM1 concentration will be estimated 
by the difference between the total DM1 and PEN-221 to estimate the amount of DM1 not 
associated with PEN-221 and will be listed and summarized together with other analytes). 
 
9.1. 
PK Sampling Schedule  
The PK samples for PEN-221 related analytes will be collected on Cycle 1 Day 1 and Cycle 3 Day 1 (C3D1 
for Phase 1 only) pre-dose (time zero) and at 0.5 hours (±5 minutes) after the start of study drug 
infusion, precisely at the end of infusion (±1 minute); and 1.5 hours (±10 minutes), 2 hours (±10 
minutes), 4 hours (±10 minutes), 6 hours (±10 minutes), 8 hours (±30 minutes), and 10 hours (±60 
minutes) after the start of study drug infusion (the 10 hour timepoint applies to Phase 1 only). If 
collection of the 10 hour time point would require an inpatient admission, the 10 hour time point is not 
to be collected. If the study drug infusion is interrupted and re-started for any reason, then the time of 
interruption and re-start of infusion should be recorded, a second pre-dose (time zero) time point 
should be collected just prior to re-start of the infusion, and subsequent sampling time points should 
then be adjusted to follow the above schedule in relation to the time of the re-start of the infusion. 
The allowable time windows for samples after start of infusion very between ±1 minute to ±10 minutes 
depending upon the planned time of sample collection. For Phase 2a serial blood samples are to be 
collected on Day 1 of Cycle 1 pre-dose (time zero) and at 0.5 hours (±5 minutes) after the start of study 
drug infusion, precisely at the end of infusion (±1 minute); and 1.5 hours (±10 minutes), 2 hours (±10 
minutes), 4 hours (±10 minutes), 6 hours (±10 minutes), 8 hours (±30 minutes) after the start of study 
drug infusion. On Day 2 of C1 a single 24 hours (±120 minutes) sample will be collected. On C1D8 a 
single sample will be collected. If the study drug infusion is interrupted and re-started for any reason, 
then the time of interruption and re-start of infusion should be recorded, a second pre-dose (time zero) 
time point should be collected just prior to re-start of the infusion, and subsequent sampling time points 
should then be adjusted to follow the above schedule in relation to the time of the re-start of the 
infusion.  
The ‘allowable time windows’ for samples collection after start of infusion vary between ±1 minute to 
±10 minutes depending upon the planned time of sample collection. Additional unscheduled PK 
sampling will be performed for the intra-patient dose escalation (Phase 1 only). The treatment of these 
data is described in the Section 9.3.2 and other relevant SAP Sections. 


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9.2. 
Plasma PK Endpoint 
Following PK parameters will be derived using non-compartmental analysis (NCA) for all analytes 
(including calculated unconjugated DM1) for Cycle 1 Day 1 Phase 1 and 2a and Cycle 3 Day 1 (C3 D1 
Phase 1 only) where possible: 
• 
Cmax - the maximum plasma concentration, (ng/mL). 
• 
Cmax/D – dose normalized Cmax 
• 
tmax - time to Cmax, (h). 
• 
AUCt - area under the plasma concentration time curve from zero to the time of the last 
measurable concentration (ng/mL*h).   
• 
Clast – last quantifiable concentration for dosing interval (ng/mL) 
• 
Tlast – time of last quantifiable concentration for dosing interval ) (h) 
• 
AUC8h – partial area under curve from time 0 to 8 hours post-dose, may require extrapolation 
(ng/mL*h). 
• 
AUCtau - area under the plasma concentration time curve from zero to the end of dosing 
interval, may need extrapolation (ng/mL*h).   
• 
AUC∞ - area under the plasma concentration time curve from zero to infinity, (ng/mL*h).  
• 
AUCt/D- dose normalized AUCt 
• 
CL – plasma clearance (PEN-221 only) (L/h). 
• 
Vz the apparent volume of distribution (PEN-221 only) (L). 
• 
CLss at steady state (PEN-221 only) (L/h). 
• 
Vss – volume of distribution at steady state (PEN-221 only) (L). 
• 
λz - terminal rate constant (1/h). 
• 
t½ - terminal elimination half-life (h). 
• 
RCmax, RAUCtau and RAUCt – accumulation ratio assessed as the ratio of Cmax, AUCtau or AUCt 
C3D1 and C1D1. 
Some parameters such as Cmax and AUCt will be also presented as dose normalized for statistical 
comparisons across the dose levels. 
 
9.3. 
Presentation of Concentration Data 
 
9.3.1. 
Handling of Missing Data  
 
Missing concentration data for all patients who are administered scheduled study treatments will be 
considered as non-informative missing and will not be imputed. No concentration estimates will be 
provided for missing sample values. All enrolled subjects excluded from the PK analysis population or 
the PK analysis subset will be described in the PK Report, including reason for exclusion.  
For the derivation of PK parameters and for the plasma concentration versus time curves and summary 
statistics, the following rules will apply: 


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• 
Concentration values below the assay’s lower limit of quantification (BLQ) in pre-dose samples 
and in samples taken before the time of the first quantifiable concentration will be treated as 
zero; 
• 
The sampling time of pre-dose samples relative to dosing will also be treated as zero; 
• 
Post-dose BLQ values after the first quantifiable time point will be set to missing. 
• 
If the actual time of sampling is missing, the samples should be excluded from the NCA and 
concentration summary statistics. 
• 
Samples taken outside the sampling windows will be used for NCA analysis. 
  
9.3.2. 
Listing and Presentation of Individual Concentration Data 
 
The actual sampling time of PK blood sample collection will be listed for each patient and will include 
the deviation in time from the protocol scheduled time, if applicable. 
All concentrations will be presented in original units as reported by Bioanalytical lab- nM and 
recalculated in weight by volume units eg ng/mL using molecular weight (MW) for all analytes: 
PEN-221 – 1786.55 g/mol 
Total DM1, Measured Unconjugated DM1, Calculated Unconjugated DM1, sulfhydryl DM1 – 738.29 
g/mol 
Total peptide – 1048.26 g/mol 
The formula for calculation 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 ቀ
𝑛𝑛𝑛𝑛
𝑚𝑚𝑚𝑚ቁ= 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐(𝑛𝑛𝑛𝑛) ∗𝐹𝐹𝐹𝐹(
𝑔𝑔
𝑚𝑚𝑚𝑚𝑚𝑚)/1000 
Individual patient plasma concentration data for PEN-221, Total DM1, Total peptide, Free sulfhydryl 
DM1, Measured Unconjugated DM1 and Calculated Unconjugated DM1 will be listed by patient, time 
point and will be summarized at each time point by cohort.  
% ratio of Free sulfhydryl DM1, Measured Unconjugated DM1 and Calculated Unconjugated DM1 to 
PEN-221 and Total DM1 will be also presented calculated from concentrations in nM units. 
The following figures will be produced for individual data for PEN-221: 
Individual concentration-time profiles will be presented, for each cohort with all patients in the same 
figure on linear and log-linear scales vs. actual time for Cycle 1 and Cycle 3 (Phase 1 only) for each 
analyte separately. Profiles for patients within the same cohort will be combined.  
Individual concentration-time profiles will be presented, for each cohort with all analytes in the same 
figure on linear and log-linear scales vs. actual time for Cycle 1 and Cycle 3 (Phase 1 only) for each 
patient separately.  


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Intra-patient dose escalation was performed for some patients after completing planned PK sampling for 
Cycle 3. The timing of the dose escalation was different for different patients. The intense PK samples 
were taken at the cycle and day when the dose escalation was implemented. These data will be included 
in the PK concentration listing and presented as individual profiles with a flag for the additional 
unscheduled visit and information about dose escalation – original dose and escalated dose.  
 
9.3.3. 
Summary of Concentration Data  
PK concentration data for both types of units (nM and ng/mL) and % molar ratios will be summarized by 
treatment using the following descriptive statistics: n, number and % BLQ, arithmetic mean, SD, CV%, 
minimum, median and maximum. 
Concentrations for samples on day 8 of cycle 1 will be summarized.  
Mean concentrations for PEN-221, Total DM1, Total peptide, Free sulfhydryl DM1, Measured 
Unconjugated DM1 and Calculated Unconjugated DM1 will not be presented if 50% or more of the 
actual values at any one time point in the terminal phase are BLQ or missing. 
Samples after start of infusion taken more than 10 minutes outside the ’allowable time windows’ will be  
excluded from by-time point concentration summary statistics and mean concentration-time plots The 
exclusions will be decided based on the review of protocol deviation log and communicated to the 
sponsor prior to implementation. 
Mean ± standard deviation concentration-time profiles and % molar ratio-time profiles will be 
presented, combining the curves for all dose levels within the same figure, on linear and log-linear scales 
vs. nominal time separately for each analyte. 
Additionally mean ± standard deviation concentration-time profiles and % molar ratio-time profiles will 
be presented, combining the curves for all analytes within the same figure, on linear and log-linear 
scales vs. nominal time separately for each dose level. 
For the patients with escalated dose levels the trough concentrations, if measured after dose escalation, 
will not be summarized with the patients from the same cohort. The summaries for intense PK sampling 
after dose will not be provided unless more than 2 patients had the same dose escalation implemented 
at the same time relative to start of treatment. For these patients their PK concentrations may be 
summarized and presented in a separate table and mean plots. 
9.4. 
PK parameters derivation 
The PK parameters for PEN-221, Total DM1, Total peptide, Free sulfhydryl DM1, Measured 
Unconjugated DM1 and Calculated Unconjugated DM1 will be estimated using concentrations in ng/ml 
units as follows: 
The apparent Cmax and the corresponding tmax will be read directly from the concentration-time plot 
(observed data). 
Cmax/D will be derived dividing individual values by corresponding dose 
AUCt will be calculated using the log-linear trapezoidal interpolation rule for intravenous model. 


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AUCtau will be calculated using the log-linear trapezoidal interpolation rule for intravenous model with 
the possible extrapolation to the end of dosing interval if needed. 
AUC8h will be calculated using the log-linear trapezoidal interpolation rule for intravenous model with 
the possible extrapolation to the 8h post-dose if needed. Terminal elimination parameters will be 
derived if sufficient data are available. 
AUC/D will be derived dividing individual values by corresponding dose 
The terminal elimination rate constant (λz) will be determined by log linear regression obtained on at 
least the 3 last quantifiable concentrations and will not include Cmax;t1/2 is calculated by the program 
as ln2/λz; 
The AUC∞ will be calculated by the program as: 
AUC∞ = AUCt + AUCextrap where last is the sampling time point of the last measurable concentration 
(tlast). AUCextrap is calculated by the program as: Clast/λz, where Clast is the observed concentration at 
time tlast and λz is the elimination rate constant during the apparent terminal elimination phase; AUC∞ 
will only be presented for patients with a reliable λz; 
CL/CLss will be calculated by program as (dose/AUC∞ or dose/AUC0-tau) 
VZ will be calculated by the program as (dose/AUC∞)/λz.  
Vss will be calculated by program as (MRTinf/CLss) where MRTinf is mean residence time; 
RCmax, RAUCtau and RAUCt will be calculated as ratios of the parameters on Cycle 3 day 1 to Cycle 1 
day 1 for Phase 1 patients. 
The following PK acceptance criteria will be applied to assess the reliability of elimination parameters: 
- 
Number of points to calculate λz is greater than or equal to 3 excluding Cmax point; 
- 
Interval for calculation of λz is longer than half-life; 
- 
The adjusted square of the correlation coefficient (Rsquare adjusted) for the goodness of fit of 
the regression line through the data points must be ≥0.85; 
- 
AUCextrap ≤30%. 
Individual patient PK parameters will be listed for the PK population in a table by patient and will be 
summarized, by treatment group/cohort. Unreliable PK parameters will be listed but flagged and 
excluded from summary. 
9.4.1. 
PK Parameters Summarization 
 
Table 2. PK Summary Statistics 


Statistical Analysis Plan for Phase I/II Oncology I Studies 
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Variable 
Summarized with: 
AUC, Cmax, CL and Vz , t1/2, 
and λZ 
n, arithmetic mean, SD, CV%, minimum, median, maximum, 
geometric mean and geometric CV%  
Tmax (actual time) 
n, minimum, Q1 (25% percentile), median, Q3 (75% 
percentile) and maximum 
 
The following conventions will be used for the presentation of the descriptive statistics of PK parameters 
and of plasma concentrations: 
Table 3. PK Reporting Precision 
Statistics 
Degree of Precision 
Minimum, Maximum 
3 significant digits or as needed based on actual 
measured values (for example PK 
concentrations) 
Mean (arithmetic and geometric), 
Median 
4 significant digits 
Standard deviation 
5 significant digits 
CV and Geometric CV 
1 decimal point 
 
For the patients with dose escalation at later cycles the additional unscheduled PK parameters will be 
calculated and listed with actual dose for the unscheduled visits. The parameters will not be summarized 
if less than 3 patients will have the same starting and escalated doses at the same time. 
 
9.5. 
Assessment of Dose Proportionality for PEN-221 Related Analytes 
Exploratory dose proportionality for PEN-221 and related analytes will be analyzed with the method 
originally described by Gough et al. (1995) and modified as described by Smith et al. (2000) and further 
adapted by Hummel et al. (2009) for Phase 1. Hereby the general model log (Cmax, Cmin, AUCt and 
AUC∞ for cycles 1 and 3) = µ+ ß log (dose) will be used to investigate the null hypothesis (H0: ß=1). 
Dose-proportionality will be rejected if the 90% confidence interval (CI) of the estimated slope falls 
outside the critical interval. 
The critical interval will be calculated as follows:  


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First the ratio (r) of the highest dose level to the lowest dose level will be calculated. 
The lower limit of the critical interval will be calculated as: Log (0.5)/log(r) + 1. 
The upper limit of the critical interval will be calculated as: Log (2.0)/log(r) + 1. 
The r value is based on the ratio between planned highest and lower dose levels of PEN-221 and equals 
to 20.8 / 1 mg = 20.8 
Thus critical interval to declare dose linearity will be 0.77 to 1.23 for 90% confidence interval of the 
slope estimate for the current dose escalation and will be updated based on actual data. Only cohorts 
with sufficient number of patients per dose level (n>2) will be included in this analysis.  
Additionally PK parameters Cmax, AUCt and AUC∞ for all analytes for Cycles 1 and 3 (C3 Phase 1 only) 
with total dose, body surface area and body weight adjusted types of dose will be investigated using 
Pearson correlation analysis to estimate which type of dosing has an effect on pharmacokinetics of PEN-
221 and related analytes. Body weight and body surface area adjusted doses will be calculated from 
demographics data and total dose administered. Body surface area (BSA) will be determined using the 
Du Bois formula: 
BSA (m sq) = 0.007184 x (patient height in cm)0.725 x (patient weight in kg at C1 D1)0.425 
The FISHER option in the PROC CORR statement will be used to estimate confidence limits and p-values 
for Pearson correlation coefficients based on Fisher’s z transformation. Alpha value and a null 
hypothesis value will be specified for 95% two-sided confidence interval. 
Formula for sample Pearson product-moment correlation is  
𝑟𝑟𝑥𝑥𝑥𝑥=
∑(𝑥𝑥𝑖𝑖−𝑥𝑥̅)(𝑦𝑦𝑖𝑖−𝑦𝑦)
തതത
𝑖𝑖
ඥ∑(𝑥𝑥𝑖𝑖−𝑥𝑥̅)2
𝑖𝑖
∑(𝑦𝑦𝑖𝑖−𝑦𝑦ത)2
𝑖𝑖
 
Fisher z transformation is calculated as 𝑧𝑧= 0.5𝑙𝑙𝑙𝑙𝑙𝑙𝑒𝑒ቀ
1+𝑟𝑟
1−𝑟𝑟ቁ 
 
Confidence intervals in addition to p-value will be calculated to demonstrate the validity of correlation.  
Dose proportionality will also be explored graphically with plots of Cmax, AUCt and AUC∞ vs. body 
weight adjusted dose (mg/kg), BSA adjusted dose (mg/m sq) and total dose (mg). 
Dose proportionality plots will be presented for PEN-221 and all related analytes PK parameters Cmax, 
AUCt and AUC∞. Regression/scatter plot in log-log and linear scales of PK parameters vs. dose levels 
including body weight normalized and total dose will be presented. 
The parameters for unscheduled visits obtained as a result in intra-patient dose escalation will not be 
included. 
 




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9.8. 
Assessment of the Effect of Concomitant Medications on PK of PEN-
221 
Concomitant medications will be summarized by type of inhibitory or inducing properties for metabolic 
enzymes such as CYP450 or UGT. Patients with concomitant medications may be included in more than 
one group. The information about concomitant medications will be reviewed at the end of the study to 
make a decision on possible grouping if sufficient information available. The comparison of CL and CLss 
of PEN-221 between different groups of concomitant medications will be done using ANOVA model for 
log(e) transformed PK parameters. Dose normalized AUCt parameters for C1D1 and C3D1 (C3 Phase 1 
only) will be also used for PEN-221 related analytes. SSTR2 expression information may be included in 
the model as covariates where available.   
 
9.9. 
Interim Analyses 
Informal interim PK data review will be performed by Tarveda for the dosing and safety decisions. This 
analysis is not within the scope of the SAP. 
 
9.10. 
Deviation from Analyses Planned in Protocol 
Additional PK parameters were added or clarified such as CLss, Vss, AUC/D, Cmax/D and accumulation 
ratio. 
The treatment of the data from unscheduled visits for PK and PD including those arising from intra-
patient dose escalation are described.  












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11. 
ANALYSIS OF IMMUNOGENICITY 
 
Blood samples for anti-PEN-221 antibodies are collected at pre-dose on day 1, pre-dose for Cycle 2 and 
every odd number Cycle starting from Cycle 3 and end of treatment visit. Note from Cycle 2 onwards, 
collection can be within 48 hours prior to the scheduled clinic visit. 
Immunogenicity sampling times and results will be listed for the Safety population. 
Immunogenicity endpoints include occurrence of anti-PEN-221 specific antibodies, frequency of 
occurrence of antibodies by visit and overall by cohort, time of onset immunogenicity and time of 
resolution of immunogenicity. Time of onset is defined as 1st time point with a positive anti-drug 
antibody (ADA) result; time of resolution is defined as the 1st time point when previously observed 
positive ADA result returns to baseline. 
Patients developing an antibody response will be listed. The effect of possible antibody responses on PK 
parameters will be evaluated (only if required i.e., meaningful reports of immunogenic response) by 
comparison of: 
1. Phase 1: CL and dose normalized trough concentration Cmin/D for the Cycle 3 where available 
for patients with and without ADA.  
2. For Phase 2a: AUCt and Cmax where available for patients with and without ADA. 
The effect will be analyzed graphically and statistically if sufficient data are available.  
Tables summarizing the frequency of the occurrence of ADAs by dose and by time point with overall 
summary per treatment will be produced. The time of onset of immunogenicity, duration and number of 
resolved ADA cases will be summarized. 
Immunogenicity results will be compared descriptively between treatments using frequency of each 
type of ADA as main parameter as well as the time of onset of immunogenicity. 
Note that the neutralizing antibody assay may not need to be developed given the preliminary results. 
See associated shells for details. 
 


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12. 
SAFETY ANALYSIS 
 
12.1. 
Adverse Events / Adverse Drug Reactions 
AEs will be collected from the time of signature on pre-screening (if applicable) or screening ICFs 
throughout the treatment period and including the safety follow-up period. The safety follow-up period 
is defined as 28±3 days after last dose of study drug. 
Adverse events will be summarized by the SOC and PT based on the latest MedDRA dictionary (the most 
current available MedDRA version at database lock should be used).   
The CTCAE grades will be summarized by SOC and PT, using the NCI CTCAE version 4.03. 
Treatment-emergent adverse events (TEAEs) are defined as any AE that occurs after administration of 
the first dose of study drug and through 28 days after the last dose of study drug, any event that is 
considered study drug-related regardless of the start date of the event, or any event that is present at 
baseline but worsens in intensity or is subsequently considered study drug-related by the Investigator. 
Adverse events with incomplete start dates will be considered to be TEAEs if: 
Day and month are missing, and the year is equal to or after the year of the first dose date;  
Day is missing and the year is after the year of the first dose;  
Day is missing and the year is equal to the year of the first dose date and the month is equal to or after 
the month of the first dose date; 
Year is missing; or 
Complete date is missing. 
If the relationship to study drug is missing, then the relationship will be counted as related to PEN-221 
for the summary tables.  Similarly, missing severity will be counted as Grade 3 (severe).  
The summary tables will include the number of patients and number of events. For summaries by SOC 
and PT, a patient is counted once at the SOC level and once at each PT within the SOC level. For 
summaries by SOC, PT, and maximum intensity, a patient is counted once at the highest intensity level 
for which the event occurred at the SOC level and the highest intensity level for each unique PT within 
that SOC level. Therefore, patients may only contribute once to each PT and once to each SOC level.  
The summaries presenting frequency of AEs by SOC and PT will be ordered by overall descending 
frequency of SOC and then, within a SOC, by overall descending frequency of PT. All AE tables will be 
ordered by descending frequency for the study in total in each SOC. 
 
 
 


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The following AE tables will be provided: 
 
• 
An overall summary of the number and percentage of patients reporting TEAEs, serious TEAEs, 
treatment-related TEAEs, TEAEs leading to discontinuation of study drug and TEAEs leading to 
death.   
• 
TEAEs overall and by system organ class and preferred term. 
• 
Study-treatment-related TEAEs overall and by system organ class and preferred term 
• 
TEAEs by maximum intensity, overall and by system organ class and preferred term. 
• 
Serious TEAEs, overall and by system organ class and preferred term. 
• 
Study-treatment related TEAEs by maximum intensity, overall and by system organ class and 
preferred term. 
• 
TEAEs leading to discontinuation of study drug, overall and by system organ class and preferred 
term.  
• 
TEAEs leading to DLTs, overall and by system organ class and preferred term. 
• 
TEAEs leading to death, overall and by system organ class and preferred term.  
• 
TEAEs by preferred term. 
 
Only the TEAEs will be included in the summary tables; however, all AEs will be included in the AE listing.  
Note pre-screening adverse events will be listed separately.  
Additional listings will be provided for:  
• 
AEs with an outcome of death.  
• 
Serious TEAEs. 
• 
TEAEs leading to discontinuation of study drug. 
• 
TEAS leading to DLTs (Phase 1 only). 
 
The primary cause of death, death date and any autopsy results as recorded on the eCRF ‘Death’ will be 
listed.   
12.2. 
Laboratory Evaluations 
 
Protocol Tables 2 and 3 indicates when clinical laboratory assessments are scheduled. Local laboratories 
will be used. 
For Phase 2a, D8 and D15 evaluations are required for C1. If no Grade 2 or higher abnormalities in 
clinical chemistries or hematology parameters are observed during C1, then D8 and D15 evaluations are 
not required for C2 and subsequent cycles. If Grade 2 or higher abnormalities in clinical chemistries or 
hematology parameters (excluding hyperglycemia in diabetic patients) are observed during C1, the D8 
and D15 evaluations are required for C2 and C3. If Grade 2 or higher abnormalities do not recur during 
C2 and C3, the D8 and D15 evaluations may be eliminated in cycles thereafter, subject to Investigator 


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discretion. If Grade 2 or higher abnormalities occur after C3, evaluations may be performed at a 
schedule determined by the Investigator, based on the patient’s clinical status. 
Parameters include: 
Hematology 
White blood cell (WBC) count (with differential blood count – 
neutrophils (bands), lymphocytes, monocytes, eosinophils, 
basophils), red blood cell (RBC) count, hemoglobin, platelet 
count 
Chemistry 
Sodium, potassium, chloride, bicarbonate, blood urea nitrogen 
(BUN), creatinine, creatinine clearance, glucose, glucose 
monitoring, albumin, total protein, calcium, alkaline 
phosphatase (ALP), magnesium, phosphorus, total bilirubin, 
aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), amylase, and lipase  
Coagulation 
parameters 
Prothrombin time (PT), activated partial thromboplastin time 
(aPTT), and International Normalized Ratio (INR) 
Urinalysis 
specific gravity, pH, blood, glucose, protein, ketones, and 
microscopic examination: WBC, RBC, epithelial, casts, and 
crystals 
Thyroid function 
Free T4, thyroid stimulating hormone (TSH) 
Cholesterol and 
triglycerides 
Total cholesterol, and triglycerides 
Cortisol levels 
Cortisol 
Pregnancy Test 
Serum samples for HCG (human chorionic gonadotropin) 
pregnancy testing are to be collected from females of 
childbearing potential (FOCBP). If the screening sample is 
collected within 3 days before C1D1, a sample need not be 
collected on C1D1. Alternatively, urine dip stick testing may be 
performed instead 
 


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All summaries will be based on results in the International System of Units (SI units); conversion will be 
performed prior to the transfer to INC Biostatistics.  High/low classifications will be derived relative to 
the result and normal range in SI units where normal ranges exist.  
Toxicity grading following the NCI CTCAE grades version 4.03 will be summarized for gradable 
parameters. The frequency of laboratory abnormalities by maximum post-baseline CTCAE grade will be 
tabulated by cycle and overall. Unscheduled data will be included in overall summaries which will 
capture a maximum (worst) case across all scheduled and unscheduled visits after the first dose of study 
treatment. This means that if there are CTCAE grades derived from both unscheduled and scheduled 
visits data per test per patient then the highest grade will be summarized.  
Shift tables also will be produced for these parameters based on the baseline CTCAE grade and the 
maximum CTCAE grade by cycle and overall. Patients with both a non-missing baseline and at least 
1 non-missing post baseline grade will be included in the shift tables.  
The following parameters are gradable: 
Parameter 
NCI-CTCAE Term 
WBC 
Leukocytosis 
WBC 
White blood cell decreased 
Hemoglobin 
Anemia 
Hemoglobin 
Hemoglobin increased 
Platelets 
Platelet count decreased 
Lymphocytes* 
Lymphocyte count decreased 
Neutrophils# 
Neutrophil count decreased 
Sodium 
Hypernatremia 
Sodium 
Hyponatremia 
Potassium 
Hyperkalemia 
Potassium 
Hypokalemia 
Creatinine 
Creatinine increased 
Glucose 
Hyperglycemia 
Glucose 
Hypoglycemia 
Albumin 
Albuminuria 
Calcium (corrected for albumin) 
Hypercalcemia 


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Calcium (corrected for albumin) 
Hypocalcemia 
ALP 
Alkaline phosphatase increased 
Magnesium 
Hypermagnesemia 
Magnesium 
Hypomagnesemia 
Total bilirubin (note that direct bilirubin 
appear on the eCRF but it is only the Total 
bilirubin that is gradable) 
Blood bilirubin increased 
AST 
Aspartate aminotransferase increased 
ALT 
Alanine aminotransferase increased 
Amylase 
Serum amylase increased 
Lipase 
Lipase increased 
aPTT 
Activated partial thromboplastin time 
prolonged 
Cholesterol 
Cholesterol high 
Triglycerides 
Hypertriglyceridemia 
* Lymphocytes are collected as a relative value on the eCRF. Absolute values are derived using the 
absolute value for WBC as follows: (WBC count/100) * relative lymphocyte count.  
# Relative neutrophils (bands) are currently being collected. Relative values for total neutrophils will be 
collected, an absolute value will be derived as described for lymphocytes and a CTCAE grade assigned. 
This change is described in SAP Section 14.  
For non-CTCAE gradable tests, a shift table will be provided relative to the normal ranges.  This summary 
of normal range category changes illustrates the number and percentage of patients who fall into 
specified categories (Decrease to Low, Change to Normal or No Change, Increase to High) by comparing 
the baseline normal range category to the planned time normal range category and the worst-case on-
therapy normal range category.  The worst-case post-baseline will be used to summarize the patients’ 
overall worst-case normal range category change during the on-therapy period.  The determination of 
the worst-case during the on-therapy period takes into account both planned and unscheduled 
assessments.  Only laboratory tests which cannot be graded per protocol specified criteria will be 
included.  Patients with missing baseline value are to be assumed to have a normal baseline value.  
Worst-case can be either High or Low.  If a patient has a Decrease to Low and an Increase to High during 
the same time interval, then the patient is counted in both the ‘Decrease to Low’ and ‘Increase to High’ 
categories.  If a patient was High at baseline and Decreases to Low during the time interval, then the 
patient is counted in the ‘Decrease to Low’ category.  Likewise, if a patient was Low at baseline and 
Increases to High during the time interval, then the patient is counted in the ‘Increase to High’ category.  
Patients are only counted in the ‘Change to Normal or No Change’ category if they are: 


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• 
Normal at baseline and have no values changing to outside the normal range  
• 
High at baseline and do not change to Low during the time interval 
• 
Low at baseline and do not change to High during the time interval   
In all cases, patients are only counted once in the total column. 
The following parameters are non-CTCAE gradable: 
RBC count 
Monocytes 
Eosinophils 
Basophils 
Chloride 
Bicarbonate 
BUN 
Creatinine clearance 
Total protein 
Phosphorous 
Direct bilirubin 
PT 
INR 
Free T4 
TSH 
Cortisol 
 
All worst-case post-baseline summaries will be summarized in a separate table from the by-visit 
summaries. 
All laboratory results in original and SI units will be included in data listings.  Reported units and ranges 
will be included in the data listings. Tests will be summarized and listed in eCRF order.  
 


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12.3. 
Vital Signs  
Vital signs will include measurements of heart rate (beats per minute [bpm]), systolic and diastolic blood 
pressure (mmHg), body temperature (centigrade) and body weight (kg). 
All vital signs data will be listed.  
12.3.1. 
Vital Sign Values of Potential Clinical Importance  
The Potential Clinical Importance (PCI) ranges are given in the table below for vital sign results. The 
values outside these ranges will be flagged on the listings as either ‘Low’ or ‘High’ relative to the PCI 
ranges.  
Vital Signs Parameter 
PCI Range 
Unit 
Systolic Blood Pressure 
<85 (L) and >160 (H) 
mmHg 
Diastolic Blood Pressure 
<45 (L) and >100 (H) 
mmHg 
 
The change from baseline values will be compared to the ranges in the tables below and be flagged on 
the listings if outside of these PCI ranges. 
 
Vital Signs Parameter 
PCI Range 
Unit 
Systolic Blood Pressure 
(Change from Baseline) 
Increase ≥20 and ≥40 
mmHg 
Decrease ≥20 and ≥40 
Diastolic Blood 
Pressure  (Change from 
Baseline) 
Increase ≥10 and ≥20 
mmHg 
Decrease ≥10 and ≥20 
 
12.3.2. 
Summary of Changes in Heart Rate from Baseline 
A summary of changes in heart rate comparing the baseline value to the worst-case post baseline value 
will be provided.   
For heart rate, both an increase and decrease in value are of clinical concern.  The worst-case post 
baseline summary is used to summarize the patients’ overall worst-case shifts post baseline.  The 
determination of the worst-case post baseline will take into account both planned and unscheduled 
assessments.      
Patients with missing baseline value are to be assumed to have a normal baseline value.  The 
percentages are based on the number of patients with heart rate data at the specified planned time.   
The oncology standard categories of clinical concern are: 


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Heart Rate (bpm): ‘Decrease to <60’, ‘Increase to >100’   
Worst-case can be either High (ie >100) or Low (ie <60).  If a patient has a Decrease to Low and an 
Increase to High during the same time interval, then the patient is counted in both the “Decrease to 
<60” category and the “Increase to >100” category.  If a patient was High at baseline and decreases to 
Low during the time interval, then the patient is counted in the ‘Decrease to <60’ category.  Likewise, if a 
patient was Low at baseline and increases to High during the time interval, then the patient is counted 
in the ‘Increase to >100’ category.   
Patients are only counted in the ‘Change to Normal or No Change’ category if they are: 
• 
Normal at baseline and have no normal range High and no normal range Low values during the 
time interval 
• 
High at baseline and do not change to Low during the time interval 
• 
Low at baseline and do not change to High during the time interval    
 
12.3.3. 
Summary of Increases in Blood Pressure from Baseline 
A summary of increases in blood pressure parameters comparing the baseline value to each planned 
time and to the worst-case post baseline value will be provided.  The worst-case post baseline will be 
summarized separately from the by-visit summaries. These summaries apply to blood pressure 
parameters where increases in value are of clinical concern.  The worst-case post baseline summary is 
used to summarize the patients’ overall worst-case shifts post baseline.  The determination of the worst-
case post baseline takes into account both planned and unscheduled assessments.   
Patients with missing baseline values are assumed to have baseline value below the lowest threshold.  
The percentages are based on the number of patients in the treatment group with data for the vital sign 
parameter at the specified planned time.   
The oncology standard categories for Systolic Blood Pressure in mmHg are: 
• 
‘Any Grade Increase’ 
• 
‘Increase to Grade 2 (140-159)’  
• 
‘Increase to Grade 3 (≥160)’ 
Note: ‘Any Grade Increase’ will be footnoted as Grade 0 (<120), Grade 1 (120-139), Grade 2 (140-159), 
or Grade 3 (≥160). 
The oncology standard categories for Diastolic Blood Pressure in mmHg are: 
• 
‘Any Grade Increase’ 
• 
‘Increase to Grade 2 (90-99)’  
• 
‘Increase to Grade 3 (≥100)’ 
 
Note: ‘Any Grade Increase’ will be footnoted as Grade 0 (<80), Grade 1 (80-89), Grade 2 (90-99), or 
Grade 3 (≥100). 


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Note:  Whole numbers are expected for systolic and diastolic blood pressure in mmHg.  For values with 
decimal places in the data the following cut-offs will be used for programming of the oncology standard 
categories.  For systolic blood pressure:  Any Increase to ≥120, Increase to ≥140-<160, and Increase to 
≥160.  For diastolic blood pressure:  Any Increase to ≥80, Increase to ≥90-<100, and Increase to ≥100. 
An increase is defined as an increase in grade (eg, for diastolic blood pressure, if a patient had Grade 1 
hypertension [84 mmHg] at baseline and at week 4 had an increase to 85 mmHg [still Grade 1], this is 
NOT counted as an increase).  However, if the patient had an increase to 101 mmHg (Grade 3) this is 
counted as an increase and the patient will be counted in the ‘Any Grade Increase’ and the ‘Increase to 
Grade 3 (≥100)’ categories). 
For body temperature and weight, summary tables by visit and change from baseline to visit will be 
provided. Summaries will include data from scheduled assessments only, and all data will be reported 
according to the nominal visit date for which it was recorded (ie, no visit windows will be applied). If 
there are multiple results at a given visit, eg a repeated vital signs test within a visit, the earliest value 
will be used in the tables (see SAP Section 6.1). 
 
12.4. 
Triplicate 12-lead ECG  
At C1D1, C3D1 (Phase 1 only), and at visits with dose escalation, ECG assessments are conducted prior to 
infusion, 30 minutes post infusion (+/- 5 minutes) and at infusion end (+/- 5 minutes), then 1.5, 2, 4, 6, 8 
and 10 hours post infusion (Phase 1 only). At other D1 visits, ECG assessments are conducted prior to 
infusion and end of infusion. A summary table of pulse rate (bpm), RR interval (msec), QRS interval 
(msec), QT Interval (msec), QTcF Interval (msec) and QTcB interval (msec) by visit/timepoint and change 
from baseline to visit/timepoint will be provided. Prior to summary, the mean of the 3 results will be 
determined per patient per visit/timepoint. Summaries will include data from scheduled assessments 
only, and all data will be reported according to the nominal visit date and timepoint for which it was 
recorded (ie, no visit windows will be applied). If there are multiple results at a given visit/timepoint, eg 
a repeated ECG test within a visit/timepoint, the earliest value will be used in the tables (see SAP Section 
6.1).  
Central tendency analysis: the change from baseline in QTcF, RR, QRS, QTcB, and pulse rate will be 
summarized by visit/time point using descriptive statistics including SD and 90% confidence intervals.  
A shift from baseline summary table of QTcF CTCAE grade to the worst (highest) value on study (based 
on individual assessment, not and aggregation of the triplicate readings). The determination of the 
worst-case post baseline takes into account both planned and unscheduled assessments.  Patients with 
missing baseline values are assumed to have baseline value below the lowest threshold (i.e. less than 
450 msec).   
A shift from baseline summary table of overall ECG interpretation to each scheduled visit/timepoint will 
be provided. Prior to summary, the worst of the 3 results will be determined per patient per 
visit/timepoint.  For multiple assessments at the same visit/timepoint, the worst value will be 
summarized. Order from best to worse is ‘Normal’, ‘Abnormal NCS’, ‘Abnormal CS’. The percentages are 
based on the number of patients in the treatment group with data at the specified visit/timepoint.  A 
worst-case post baseline summary will also be included. The determination of the worst-case post 
baseline takes into account both planned and unscheduled assessments.   


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A summary table of the following will be presented by visit/timepoint: 
• 
QTcF values > 450 msec and ≤ 480 msec; > 480 msec and < 500 msec; and ≥ 500 msec 
• 
QTcF increase from baseline values ≥ 30 and <60 msec; and ≥ 60 msec 
• 
QRS change from baseline > 25% resulting in QRS > 120 msec 
• 
RR interval change from baseline >25% reaching a value >220 msec 
• 
Pulse rate change from baseline > 25% decrease resulting in a pulse rate < 50 bpm; and pulse 
rate change from baseline > 25% increase resulting in a heart rate > 100 bpm 
The percentages are based on the number of patients in the treatment group with data at the specified 
visit/timepoint.   
Note SAP Section 10.3.3 describes the drug concentration-ECG correlation analysis.  
 
12.5. 
Physical Examination 
 
Physical examination body system results data will be listed in eCRF order. 
 
12.6. 
Other Safety 
 
12.6.1. 
Eastern Cooperative Oncology Group Performance Status  
 
Eastern Cooperative Oncology Group (ECOG) performance status data will be listed.  A summary table 
will be provided with the number and percentage of patients with each ECOG score (0 to 4) by visit. 
Summaries will include data from scheduled assessments only, and all data will be reported according to 
the nominal visit date for which it was recorded (ie, no visit windows will be applied). If there are 
multiple results at a given visit, the earliest value will be used in the tables (see SAP Section 6.1). A 
summary will also be included summarizing the worst (highest) post-baseline value per patient.  An 
additional summary table will also include the number and percentage of patients with change from 
baseline, ‘Improved’, ‘No Change’ and ‘Deteriorated’, by visit.  The percentages are based on the 
number of patients in the treatment group with data at the specified visit.  An additional summary will 
also be included summarizing the worst change post-baseline per patient. The determination of the 
worst-case post baseline takes into account both planned and unscheduled assessments.   
 
 
 


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13. 
INTERIM ANALYSIS 
The dose-escalation design is adaptive by nature, basing ongoing decisions about dose assignment on 
observed data. Details of this procedure and the process for communication with Investigators are 
provided in Protocol Section 8.6.1.  
Note for Phase 1, the SRC will review the safety and tolerability of PEN-221 of each cohort to decide the 
next dose level to be tested. Statistical modeling (provided by a 3rd party vendor) will be performed 
using all safety data and will guide the SRC’s selection of dose levels to be tested. In addition, PK and 
PDc data may be used to inform dose selection. Dose escalation increments will be the decision of the 
SRC. 
Interim Analysis (end of Phase 1) and for Phase 2a is described in SAP Section 4.7.1 and 4.7.2 
respectively. 
 
 
 
 


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14. 
CHANGES TO METHODS PLANNED IN THE PROTOCOL  
 
1. The laboratory parameter relative neutrophil bands are currently collected. Relative total 
neutrophils will be collected so a CTCAE grade can be assigned. 
 
2. Section 12.9.3 of the protocol states the following: For the gastrointestinal (GI) mid-gut 
neuroendocrine tumor (NET),  pancreatic NET (PNET) and small cell lung cancer groups (SCLC) 
groups, the cutoff date for the primary analysis will occur after all 20 patients received the first 
dose of PEN-221 at least 21 weeks (7 cycles) prior to the analysis cutoff date. The timing of 
analysis will occur as described in SAP Section 4.7.3. 
 
























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16. 
PROGRAMMING GUIDELINES 
 
All tables, data listings, figures (TLFs), and statistical analyses will be generated using SAS® for Windows, 
Release 9.3 (SAS® Institute Inc., Cary, NC, USA). Computer-generated table, listing and figure output will 
adhere to the following specifications.   
Phoenix WinNonLin version 6.4 or higher will be used for PK parameters derivation. 
 
16.1. 
General Considerations 
A separate SAS program will be created for each output. 
Each output will be stored in a separate file. 
Output files will be delivered in Word format (rtf). 
Numbering of TLFs will follow ICH E3 guidance. 
 
16.2. 
Table, Listing and Figure Format 
16.2.1. 
General 
All TLFs will be produced in landscape format on American letter size, unless otherwise specified. 
All TLFs will be produced using the Courier New font, size 8  
The data displays for all TLFs will have a minimum 2.5 cm blank margin on all 4 sides. 
Headers and footers for figures will be in Courier New font, size 8. 
Legends will be used for all figures with more than 1 variable, group, or item displayed. 
TLFs will be in black and white (no color), unless otherwise specified. 
Specialized text styles, such as bolding, italics, borders, shading, and superscripted and subscripted text, 
will not be used in the TLFs. On some occasions, superscripts 1, 2, or 3 may be used (see below). 
Only standard keyboard characters will be used in the TLFs. Special characters, such as non-printable 
control characters, printer-specific, or font-specific characters, will not be used. Hexadecimal-derived 
characters will be used, where possible, if they are appropriate to help display math symbols (e.g., μ). 
Certain subscripts and superscripts (e.g., cm2, Cmax) will be employed on a case-by-case basis. 
Mixed case will be used for all titles, footnotes, column headers and programmer-supplied formats, as 
appropriate. 
 


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16.2.2. 
Headers 
All output should have the following header at the top left of each page: 
Tarveda Therapeutics, Inc. Protocol PEN-221-001(
)      
          
Draft/Final Run ddMMMyyyy 
All output should have Page n of N at the top or bottom right corner of each page. TLFs should be 
internally paginated in relation to the total length (i.e., the page number should appear sequentially as 
page n of N, where N is the total number of pages in the table). 
 
16.2.3. 
Display Titles 
Each TLF should be identified by the designation and a numeral. (i.e., Table 14.1.1). ICH E3 numbering 
will be used. A decimal system (x.y and x.y.z) should be used to identify TLFs with related contents. The 
title is centered. The analysis population should be identified on the line immediately following the title. 
The title and table designation are single spaced. A solid line spanning the margins will separate the 
display titles from the 
 Column headers. There will be 1 blank line between the last title and the solid line. 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
FAS 
 
16.2.4. 
Column Headers 
Column headings should be displayed immediately below the solid line described above in initial upper-
case characters.  
In the case of efficacy tables, the variable (or characteristic) column will be on the far left followed by 
the treatment group columns and total column (if applicable). P-values may be presented under the 
total column or in separate p-value column (if applicable). Within-treatment comparisons may have p-
values presented in a row beneath the summary statistics for that treatment. 
For numeric variables, include “unit” in column or row heading when appropriate. 
Analysis population sizes will be presented for each treatment group in the column heading as (N=xx) (or 
in the row headings if applicable). This is distinct from the ‘n’ used for the descriptive statistics 
representing the number of patients in the analysis population. 
 
 


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16.2.5. 
Body of the Data Display 
General Conventions 
Data in columns of a table or listing should be formatted as follows: 
alphanumeric values are left-justified; 
whole numbers (e.g., counts) are right-justified; and 
numbers containing fractional portions are decimal aligned. 
 
Table Conventions 
Units will be included where available 
If the categories of a parameter are ordered, then all categories between the maximum and minimum 
category should be presented in the table, even if n=0 for all treatment groups in a given category that is 
between the minimum and maximum level for that parameter. For example, the frequency distribution 
for symptom severity would appear as: 
Severity Rating N 
Severe 
0 
Moderate 
8 
Mild 
3 
 
Where percentages are presented in these tables, zero percentages will not be presented and so any 
counts of 0 will be presented as 0 and not as 0 (0%). 
If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation from the Study, 
etc.), then only those categories for which there is at least 1 patient represented in 1 or more groups 
should be included. 
An Unknown or Missing category should be added to any parameter for which information is not 
available for 1 or more patients.  
Unless otherwise specified, the estimated mean and median for a set of values should be printed out to 
1 more significant digit than the original values, and standard deviations should be printed out to 2 more 
significant digits than the original values. The minimum and maximum should report the same 
significant digits as the original values. For example, for systolic blood pressure: 
N 
  XX 
Mean 
XXX.X 


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Std Dev 
     X.XX 
Median 
XXX.X 
Minimum 
XXX 
Maximum 
XXX 
P-values should be output in the format: “0.xxx”, where xxx is the value rounded to 3 decimal places. 
Any p-value less than 0.001 will be presented as <0.001. If the p-value should be less than 0.0001 then 
present as <0.0001. If the p-value is returned as >0.999 then present as >0.999 
Percentage values should be printed to one decimal place, in parentheses with no spaces, one space 
after the count (e.g., 7 (12.8), 13 (5.4)). Pre-determine how to display values that round down to 0.0.  A 
common convention is to display as '<0.1', or as appropriate with additional decimal places. Unless 
otherwise noted, for all percentages, the number of patients in the analysis set for the treatment group 
who have an observation will be the denominator. Percentages after zero counts should not be 
displayed and percentages equating to 100% should be presented as 100, without any decimal places.  
Tabular display of data for medical history, prior / concomitant medications, and all tabular displays of 
adverse event data should be presented by the body system, treatment class, or SOC with the highest 
occurrence in the study total group in decreasing order, assuming all terms are coded. Within the body 
system, drug class and SOC, medical history (by preferred term), drugs (by ATC2 code), and adverse 
events (by preferred term) should be displayed in decreasing order. If incidence for more than 1 term is 
identical, they should then be sorted alphabetically. Missing descriptive statistics or p-values which 
cannot be estimated should be reported as “-”. 
The percentage of patients is normally calculated as a proportion of the number of patients assessed in 
the relevant treatment group (or overall) for the analysis population presented. However, careful 
consideration is required in many instances due to the complicated nature of selecting the denominator, 
usually the appropriate number of patients exposed. Describe details of this in footnotes or 
programming notes. 
For categorical summaries (number and percentage of patients) where a patient can be included in 
more than one category, describe in a footnote or programming note if the patient should be included 
in the summary statistics for all relevant categories or just 1 category and the criteria for selecting the 
criteria. 
Where a category with a subheading (such as system organ class) has to be split over more than one 
page, output the subheading followed by “(cont)” at the top of each subsequent page.  The overall 
summary statistics for the subheading should only be output on the first relevant page. 
 
Listing Conventions 
Listings will be sorted for presentation by phase and part then patient number, visit/collection day, and 
visit/collection time. 


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Missing data should be represented on patient listings as either a hyphen (“-”) with a corresponding 
footnote (“- = unknown or not evaluated”), or as “N/A”, with the footnote “N/A = not applicable”, 
whichever is appropriate. 
Dates should be printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing portions of dates 
should be represented on patient listings as dashes (--JUL2000). Dates that are missing because they are 
not applicable for the patient are output as “N/A”, unless otherwise specified. 
All observed time values must be presented using a 24-hour clock HH:MM or HH:MM:SS format (e.g., 
11:26:45, or 11:26). Time will only be reported if it was measured as part of the study. 
Units will be included where available 
 
Figure Conventions 
Unless otherwise specified, for all figures, study visits will be displayed on the X-axis and endpoint (e.g., 
treatment mean change from Baseline) values will be displayed on the Y-axis. 
 
16.2.6. 
Footnotes 
A solid line spanning the margins will separate the body of the data display from the footnotes.  
All footnotes will be left justified with single-line spacing immediately below the solid line underneath 
the data display. 
Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, etc. if a reference 
footnote. Each new footnote should start on a new line where possible. 
PatientPatient specific footnotes should be avoided, where possible. 
Footnotes will be used sparingly and must add value to the table, figure, or data listing. If more than six 
lines of footnotes are planned, then a cover page may be used to display footnotes, and only those 
essential to comprehension of the data will be repeated on each page.  
The penultimate line of the footnote section will be a standard source line that indicates the listing 
source (i.e., ‘Listing Source: 16.x.y.z’). 
The last line of the footnote section will be a standard line that indicates the date output was generated 
(i.e., ‘Listing Generation: ddmmmyyyy hh:mm). 
The program name will appear as a footer on each page. 


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17. 
REFERENCES 
 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47. 
Fasano M, Della Corte CM, Papaccio F, Ciardiello F, Morgillo F. Pulmonary Large-Cell Neuroendocrine 
Carcinoma: From Epidemiology to Therapy. J Thorac Oncol 2015;10:1133-41. 
Gough K, Hutchinson M, Keene O, Byrom B, Ellis S, Lacey L, McKellar J. Assessment of Dose 
Proportionality: Report from the Statisticians in The Pharmaceutical Industry/Pharmacokinetics UK joint 
working party. Drug Inf J. 1995; 29:1039-1048. 
Hummel J, McKendrick S, Brindley C and French, R. Exploratory assessment of dose proportionality: 
review of current approaches and proposal for a practical criterion. Pharmaceut. Statist. 2009; 8: 38-49. 
Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine 
tumors. N Engl J Med 2011;364:501-13. 
Smith BP, Vandenhende FR, DeSante KA, Farid NA, Welch PA, Callaghan JT, Forgue ST. Confidence 
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Statistical Analysis Plan for Phase I/II Oncology I Studies 
Sponsor: Tarveda; Protocol No.: PEN-221-001 
 
 
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18. 
APPENDICES 
18.1. 
Table Mock-Ups 
See attachment  
 
18.2. 
Figure Mock-Ups 
See attachment  
 
18.3. 
Listing Mock-Ups 
See attachment