PEN-221 in Somatostatin Receptor 2 Expressing Advanced Cancers Including Neuroendocrine and Small Cell Lung Cancers

• Sponsor: Tarveda Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02936323
• Collaborator: (none)
• Enrollment: 89
• Locations: 13
• Arms: 4
• Actual Duration (Months): 50.6
• Patients Per Site: 6.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Neuroendocrine Tumors; Carcinoma, Small Cell Lung; Neuroendocrine Carcinoma	Drug: PEN-221; Drug: PEN-221	Phase 1/Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 89 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official 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
• Actual Study Start Date: Dec 8, 2016
• Actual Primary Completion Date: Jul 31, 2020
• Actual Study Completion Date: Feb 25, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 1: Dose Escalation 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.	Drug: PEN-221; 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.
Experimental: Phase 2a: Dose Expansion (GI mid-gut NET) Gastrointestinal mid-gut NET Cohort	Drug: PEN-221; 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.
Experimental: Phase 2a: Dose Expansion (PNET) Pancreatic NET Cohort	Drug: PEN-221; 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.
Experimental: Phase 2a: Dose Expansion (SCLC) Small Cell Lung Cancer Cohort	Drug: PEN-221; 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.

Outcome Measures

Primary Outcome Measures

1. Phase 1: Maximum Tolerated Dose of PEN-221 and Recommended Phase 2a Dose (RP2D) [Up to 4 weeks in the first cohort and up to 3 weeks for each subsequent cohort]

   MTD was determined by testing increasing doses up to 25 mg flat dose IV over 1 hour on an every 3 week cycle on dose escalation cohorts 1 to 7 with 2 participants in cohort 1 and 3-6 participants each in cohorts 2-7. The MTD was defined as the highest drug dosage not causing a Dose Limiting Toxicity (DLT) in > 33% of the treated participants during the first cycle of treatment. DLTs were defined as any Grade 3 or 4 adverse event (AE) using the Common Terminology Criteria for Adverse Events Version 4.03 occurring within the first 4 weeks for cohort 1 and within 3 weeks for each subsequent cohort that was not related to underlying disease, disease progression, intercurrent illness, or concomitant medications. The RP2D was established by achieving the Maximum Tolerated Dose (MTD). The RP2D may be equal to or below the MTD.

2. Phase 1: Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) [Up to 4 weeks in the first cohort and up to 3 weeks for each subsequent cohort]

   DLTs were defined as any Grade 3 or 4 adverse event (AE) using the Common Terminology Criteria for Adverse Events Version 4.03 occurring within the first 4 weeks for cohort 1 and within 3 weeks for each subsequent cohort that was not related to underlying disease, disease progression, intercurrent illness, or concomitant medications. Grade 3 is a severe AE and Grade 4 is a life-threatening or disabling AE. DLTs were collected to determine the Maximum-Tolerated Dose (MTD), which is defined as the dose level below the dose at which > 33% of participants experienced a DLT during the first cycle of treatment.

3. Phase 2a: Percentage of Gastrointestinal Mid-gut NETs and Pancreatic NETs Participants Who Achieved Clinical Benefit as Determined by RECIST 1.1 [Baseline and every 9 weeks up to time of disease progression (per RECIST 1.1) or death, up to data cut-off (31 Jul 2020).]

   Efficacy of PEN-221 in gastrointestinal mid-gut NETs and pancreatic NETs using clinical benefit rate (CBR) defined as the best overall response of complete response (CR), partial response (PR), or stable disease (SD) according to RECIST 1.1 using the investigator assessment.

4. Phase 2a: Number of Small Cell Lung Cancer (SCLC) Participants Who Achieved an Objective Response of Complete Response (CR) or Partial Response (PR) as Defined by RECIST 1.1. [Baseline and every 6 weeks up to time of disease progression (per RECIST 1.1) or death, up to data cut-off (31 Jul 2020).]

   Efficacy of PEN-221 in Small Cell Lung Cancer (SCLC) using objective response rate (ORR) as defined as the best overall response of CR or PR using tumor response criteria defined by RECIST 1.1.

5. Phase 2a: Duration of Response (DOR) for Small Cell Lung Cancer (SCLC) [From the date of first treatment through the date of first documented progression, assessed up to data cut-off (31 Jul 2020).]

   Duration of Response (DOR) is defined as the time from the 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 patient did not progress or die before the data cutoff date (31-July-2020), DOR was censored at the date of last adequate tumor assessment.

Secondary Outcome Measures

1. Number of Study Participants Who Experienced Treatment-Emergent Adverse Events [From date of first treatment/trial entry until 28 days after last treatment for each participant, up to data cut-off (31 Jul 2020).]

   Phase 1 and Phase 2a participants who experienced any Treatment-Emergent Adverse Event (TEAE) to determine the safety and tolerability of PEN-221. TEAEs are any AE that occurred after first dose of study drug through 28 days after the last dose of study drug, any event considered study drug related regardless of start date of the event, or any event that was present at baseline but worsened in intensity or was subsequently considered study drug related by the Investigator. Phase 2a TEAEs were collected for reporting in the BSA dosing format only.

2. Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide [Phase 1: Day 1 of Cycles 1 and 3 pre-start of infusion (SOI), at 0.5, 1, 1.5, 2, 4, 6, 8, 10 hours post-start of infusion. Phase 2a: Day 1 Cycle 1 pre-start of infusion, at 0.5,1, 1.5, 2, 4, 6, 8, 24 hours post-SOI; once at Day 8 Cycle 1.]

   Blood samples were obtained and plasma concentrations were determined using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. Phase 2a data were collected for reporting in the BSA dosing format only.

3. Area Under the Curve (AUC) of PEN-221, DM1, and Peptide [Phase 1: Day 1 of Cycles 1 and 3 pre-start of infusion (SOI), at 0.5, 1, 1.5, 2, 4, 6, 8, 10 hours post-start of infusion. Phase 2a: Day 1 Cycle 1 pre-start of infusion, at 0.5,1, 1.5, 2, 4, 6, 8, 24 hours post-SOI; once at Day 8 Cycle 1.]

   Blood samples were obtained and plasma concentrations were determined using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. Phase 2a data were collected for reporting in the BSA dosing format only.

4. Half-life (t1/2) of PEN-221, DM1, and Peptide [Phase 1: Day 1 of Cycles 1 and 3 pre-start of infusion (SOI), at 0.5, 1, 1.5, 2, 4, 6, 8, 10 hours post-start of infusion. Phase 2a: Day 1 Cycle 1 pre-start of infusion, at 0.5,1, 1.5, 2, 4, 6, 8, 24 hours post-SOI; once at Day 8 Cycle 1.]

   Blood samples were obtained and plasma concentrations were determined using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. Phase 2a data collected for reporting in the BSA dosing format only.

5. Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. [Baseline, every 6 or 9 weeks depending on the tumor type, up to time of disease progression (per RECIST 1.1) or death, up to data cut-off (31 Jul 2020).]

   Assess the potential of preliminary anti-tumor activity of PEN-221 using tumor response criteria as defined by RECIST 1.1.

6. Phase 2a: Maximum Tolerated Dose (MTD) and Recommended Phase 2a Dose (RP2D) Based on Body Surface Area [From date of first treatment/trial entry until 28 days after last treatment for each Phase 2a participant, up to data cut-off (31 Jul 2020)]

   Confirm the MTD identified during the dose-escalation phase and further investigate the safety and tolerability of the RP2D and schedule of PEN-221. Initial Phase 2a PEN-221 start dose at Phase 1 MTD and RP2D was determined at 18 mg flat dose. The MTD was defined as the highest drug dosage not causing a Dose Limiting Toxicity (DLT) in > 33% of the treated participants during the first cycle of treatment. DLTs were defined as any Grade 3 or 4 adverse event (AE) using the Common Terminology Criteria for Adverse Events Version 4.03 occurring within the first 4 weeks for cohort 1 and within 3 weeks for each subsequent cohort that was not related to underlying disease, disease progression, intercurrent illness, or concomitant medications. The RP2D was established by achieving the Maximum Tolerated Dose (MTD). The RP2D may be equal to or below the MTD.

7. Phase 2a: Progression Free Survival (PFS) [From date of first treatment/trial entry until first documented progression or date of death from any cause, whichever came first, assessed up to data cutoff of 31 Jul 2020]

   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 participant had not progressed or died before the analysis cutoff date (31 Jul 2020), PFS was censored at the date of last adequate tumor assessment. Results based on Kaplan-Meier estimates.

8. Phase 2a: Overall Survival (OS) [For each GI mid-gut NET, PNET, and SCLC, from date of first treatment/trial entry until the date of death from any cause, assessed up to data cutoff of 31 Jul 2020]

   Overall survival (OS) was defined as the time from the first dose of PEN-221 to the date of death due to any cause. If the participant had not died before data lock (31 Jul 2020), OS was censored at the date of last contact.

9. Phase 2a: ORR for Gastrointestinal Mid-gut NETs (GI Mid-gut NET) and Pancreatic NETs (PNET) [For each GI mid-gut NET and PNET participant from the date of first treatment through the date of first documented progression, assessed up to data cutoff 31 Jul 2020]

   The Objective Response Rate (ORR) 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 electronic Case Report Form.

10. Phase 2a: Duration of Response (DOR) for Gastrointestinal Mid-gut NETs (GI Mid-gut NET) and Pancreatic NETs (PNET) [For each GI mid-gut NET and PNET participant, from the date of first treatment through the date of first documented progression, assessed up to data cutoff (31 Jul 2020)]

    Duration of Response (DOR) is defined as the time from the 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 did not progress or die before the data cutoff date (31 Jul 2020), DOR was censored at the date of last adequate tumor assessment.

11. Anti-PEN-221 Antibodies (ADA) [Baseline and every 6 weeks up to end of treatment for each patient.]

    Plasma Samples Using an Electrochemiluminescent Method for the Detection of Anti-PEN-221 Antibodies in Human Serum.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• M/F at least 18 years old

• ECOG performance status 0 or 1

• Adequate bone marrow, liver, and kidney function within 2 weeks prior to first dose

• Serum potassium, calcium, magnesium, phosphorus within normal limits (may be supplemented)

• Adequate birth control

• Somatostatin receptor 2 positive tumor as assessed at pre-screening or within 180 d of first drug dose using indium SPECT or gallium PET

Patients in Phase 1 must have a histologically or cytologically-confirmed solid tumor in 1 of the following categories:

• Advanced small cell lung cancer (SCLC) or large cell neuroendocrine carcinoma (LCNEC) of lung progressed after at least 1 line of anticancer chemotherapy

• Advanced low or intermediate grade gastroenteropancreatic or lung or thymus neuroendocrine tumor (NET), or NET of unknown primary, progressed after at least 1 line of anticancer therapy (unless no standard treatments available or such treatments are deemed not appropriate)

• Advanced paraganglioma, pheochromocytoma, medullary thyroid carcinoma, Merkel cell carcinoma, or high grade extrapulmonary neuroendocrine carcinoma having progressed after 1 or more lines of anticancer chemotherapy (unless no standard treatments available or such treatments are deemed not appropriate)

For patients enrolling once escalation is complete (Phase 2a), disease must be measurable per RECIST 1.1 criteria with last imaging performed within 28 days prior to first drug dose

In addition to the criterion listed above, Patients in Phase 2a must have a histologically- or cytologically-confirmed, advanced or metastatic solid tumor, in 1 of the following categories: disease history specified in one of the criteria listed below:

• 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 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 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.

Exclusion Criteria:

• Treatment with anticancer therapy or investigational drug or device within 3 wk (6 wk for nitrosureas or mitomycin C) or 5 half-lives of agent, whichever is shorter, prior to first PEN-221 drug dose, and any drug-related toxicities must have recovered to grade 1 or less

• Any other malignancy known to be active or treated within 3 years of start of screening, except cervical intra-epithelial neoplasia, superficial (non-invasive) bladder cancer, and non-melanoma skin cancer

• Cardiac criteria such as unstable angina, myocardial infarction within 6 months of screening, NY Heart Association Class 1 or 2 heart failure, QTc greater than 470 msec, congenital long Qt syndrome, symptomatic orthostatic hypotension within 6 months of screening, uncontrolled hypertension, or clinically important abnormalities in heart rhythm, conduction, morphology of resting ECG

• Stroke or transient ischemic attack within 6 months of screening

• Peripheral neuropathy greater than grade 1

• Requirement for medication with strong CYP3A4 inhibitor

• History of leptomeningeal disease or spinal cord compression

• Brain metastases unless asymptomatic on a stable low dose of steroids. Patients with SCLC or LCNEC of lung only must have CT or MRI of brain during screening, and if metastases found, must have radiotherapy with 14 day washout or stereotactic radiotherapy or radio surgery with 7 day washout prior to first drug dose.

• Major surgery within 28 days of first drug dose

• Female who is pregnant or breast feeding

• Evidence of severe uncontrolled systemic disease, bleeding diatheses, renal or liver transplant, active infection with hepatitis B or C, or HIV

• Hypersensitivity or anaphylactic reaction to any somatostatin analog or to maytansinoids

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Florida Cancer Specialists South	Fort Myers	Florida	United States	33901
2	Florida Cancer Specialists North	Saint Petersburg	Florida	United States	33705
3	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
4	Boston Medical Center	Boston	Massachusetts	United States	02118
5	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
6	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
7	Columbia University Medical Center/ NY Presbyterian	Manhattan	New York	United States	10032
8	University Hospitals Cleveland Medical Center	Cleveland	Ohio	United States	44106
9	Sarah Cannon Research Institute/Tennessee Oncology	Nashville	Tennessee	United States	37203
10	MD Anderson Cancer Center	Houston	Texas	United States	77030
11	University College London	London		United Kingdom
12	The Christie NHS Trust	Manchester		United Kingdom
13	Southampton General Hospital	Southampton		United Kingdom

Sponsors and Collaborators

• Tarveda Therapeutics

Investigators

• Study Director: Chief Medical Officer, Tarveda Therapeutics

Study Documents (Full-Text)

• Study Protocol - Jul 12, 2019
• Statistical Analysis Plan - Jul 21, 2020

More Information

Publications

None provided.

• Responsible Party: Tarveda Therapeutics
• ClinicalTrials.gov Identifier: NCT02936323
• Other Study ID Numbers: PEN-221-001
• First Posted: Oct 18, 2016
• Last Update Posted: Dec 14, 2021
• Last Verified: Nov 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Tarveda Therapeutics: SCLC small cell lung cancer; pancreatic neuroendocrine NET; GI neuroendocrine NET
• Additional relevant MeSH terms: Carcinoma; Lung Neoplasms; Small Cell Lung Carcinoma; Neuroendocrine Tumors; Carcinoma, Neuroendocrine; Carcinoma, Small Cell

Study Results

Participant Flow

Recruitment Details

Participants enrolled with SSTR2 expressing advanced gastroenteropancreatic or lung or thymus or other NETs or SCLC or LCNEC of the lung. A total of 23 participants enrolled into the Phase 1 Dose Escalation stage of the study receiving at least one dose of PEN-221 and a total of 66 patients enrolled into the Phase 2a Disease-Specific Dose Expansion stage of the study receiving at least one dose of PEN-221.

Pre-assignment Detail

Each eligible participant must have demonstrated a tumor that was positive for expression of SSTR2 by historical or study-related somatostatin analog radioimaging (SARI). Participants who discontinued treatment entered a follow-up period (Disease Progression Follow-up and/or Long-Term Follow-up). Results for data collected up to cut-off 31 July 2020 are reported here.

Arm/Group Title	Phase 1 Dose Escalation (Cohort 1)	Phase 1 Dose Escalation (Cohort 2)	Phase 1 Dose Escalation (Cohort 3)	Phase 1 Dose Escalation (Cohort 4)	Phase 1 Dose Escalation (Cohort 5)	Phase 1 Dose Escalation (Cohort 6)	Phase 1 Dose Escalation (Cohort 7)	Phase 2a Dose Expansion (GI Mid-gut NET Cohort)	Phase 2a Dose Expansion (PNET Cohort)	Phase 2a Dose Expansion (SCLC Cohort)
Arm/Group Description	Participants in Cohort 1 received PEN-221 administered IV over 1 hour at the starting dose of 1.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 2 received PEN-221 administered IV over 1 hour at the starting dose of 2.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 3 received PEN-221 administered IV over 1 hour at the starting dose of 4.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 4 received PEN-221 administered IV over 1 hour at the starting dose of 8.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 5 received PEN-221 administered IV over 1 hour at the starting dose of 12.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 6 received PEN-221 administered IV over 1 hour at the starting dose of 18.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 7 received PEN-221 administered IV over 1 hour at the starting dose of 25.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants were enrolled with advanced or metastatic, well-differentiated, low or intermediate grade gastrointestinal mid-gut Neuroendocrine Tumor (GINET). Participants in the GINET cohort were enrolled into one of two groups which included 25 participants without prior Peptide Receptor Radionuclide Therapy [PRRT] (GINET PRRT Naïve) and 7 participants with prior PRRT (GINET PRRT Recurrent).	Participants were enrolled with advanced or metastatic, well-differentiated, low or intermediate grade pancreatic Neuroendocrine Tumor (PNET).	Participants were enrolled with advanced or metastatic Small Cell Lung Cancer (SCLC).
Period Title: Phase 1 Dose Escalation
STARTED	2	3	3	3	3	6	3	0	0	0
COMPLETED	0	1	0	1	0	1	0	0	0	0
NOT COMPLETED	2	2	3	2	3	5	3	0	0	0
Period Title: Phase 1 Dose Escalation
STARTED	0	0	0	0	0	0	0	32	15	19
COMPLETED	0	0	0	0	0	0	0	15	2	5
NOT COMPLETED	0	0	0	0	0	0	0	17	13	14

Baseline Characteristics

Arm/Group Title	Phase 1 Dose Escalation (Cohort 1)	Phase 1 Dose Escalation (Cohort 2)	Phase 1 Dose Escalation (Cohort 3)	Phase 1 Dose Escalation (Cohort 4)	Phase 1 Dose Escalation (Cohort 5)	Phase 1 Dose Escalation (Cohort 6)	Phase 1 Dose Escalation (Cohort 7)	Phase 2a Dose Expansion (GI Mid-gut NET Cohort)	Phase 2a Dose Expansion (PNET Cohort)	Phase 2a Dose Expansion (SCLC Cohort)	Total
Arm/Group Description	Participants in Cohort 1 received PEN-221 administered IV over 1 hour at the starting dose of 1.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 2 received PEN-221 administered IV over 1 hour at the starting dose of 2.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 3 received PEN-221 administered IV over 1 hour at the starting dose of 4.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 4 received PEN-221 administered IV over 1 hour at the starting dose of 8.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 5 received PEN-221 administered IV over 1 hour at the starting dose of 12.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 6 received PEN-221 administered IV over 1 hour at the starting dose of 18.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 7 received PEN-221 administered IV over 1 hour at the starting dose of 25.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants were enrolled with advanced or metastatic, well-differentiated, low or intermediate grade gastrointestinal mid-gut Neuroendocrine Tumor (GINET). Participants in the GINET cohort were enrolled into one of two groups which included 25 participants without prior Peptide Receptor Radionuclide Therapy [PRRT] (GINET PRRT Naïve) and 7 participants with prior PRRT (GINET PRRT Recurrent).	Participants were enrolled with advanced or metastatic, well-differentiated, low or intermediate grade pancreatic Neuroendocrine Tumor (PNET).	Participants were enrolled with advanced or metastatic Small Cell Lung Cancer (SCLC).	Total of all reporting groups
Overall Participants	2	3	3	3	3	6	3	32	15	19	89
Age (Years) [Median (Full Range) ]
Median (Full Range) [Years]	48.5	57.0	67.0	46.0	67.0	63.5	52.0	66.0	58.0	65.0	65
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	2 66.7%	1 33.3%	2 66.7%	3 50%	2 66.7%	15 46.9%	8 53.3%	10 52.6%	43 48.3%
Male	2 100%	3 100%	1 33.3%	2 66.7%	1 33.3%	3 50%	1 33.3%	17 53.1%	7 46.7%	9 47.4%	46 51.7%
Race/Ethnicity, Customized (Count of Participants)
Caucasian/White	2 100%	2 66.7%	3 100%	3 100%	1 33.3%	6 100%	3 100%	27 84.4%	10 66.7%	19 100%	76 85.4%
Black	0 0%	1 33.3%	0 0%	0 0%	0 0%	0 0%	0 0%	3 9.4%	2 13.3%	0 0%	6 6.7%
Asian	0 0%	0 0%	0 0%	0 0%	1 33.3%	0 0%	0 0%	0 0%	1 6.7%	0 0%	2 2.2%
Native American or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 3.1%	0 0%	0 0%	1 1.1%
Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Not collected	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	2 13.3%	0 0%	2 2.2%
Other	0 0%	0 0%	0 0%	0 0%	1 33.3%	0 0%	0 0%	1 3.1%	0 0%	0 0%	2 2.2%
Ethnicity (Count of Participants)
Hispanic or Latino	1 50%	0 0%	0 0%	0 0%	1 33.3%	0 0%	0 0%	2 6.3%	2 13.3%	0 0%	6 6.7%
Not Hispanic or Latino	1 50%	3 100%	3 100%	3 100%	2 66.7%	5 83.3%	2 66.7%	30 93.8%	13 86.7%	19 100%	81 91%
Not collected	0 0%	0 0%	0 0%	0 0%	0 0%	1 16.7%	1 33.3%	0 0%	0 0%	0 0%	2 2.2%

Outcome Measures

1. Primary Outcome

Title	Phase 1: Maximum Tolerated Dose of PEN-221 and Recommended Phase 2a Dose (RP2D)
Description	MTD was determined by testing increasing doses up to 25 mg flat dose IV over 1 hour on an every 3 week cycle on dose escalation cohorts 1 to 7 with 2 participants in cohort 1 and 3-6 participants each in cohorts 2-7. The MTD was defined as the highest drug dosage not causing a Dose Limiting Toxicity (DLT) in > 33% of the treated participants during the first cycle of treatment. DLTs were defined as any Grade 3 or 4 adverse event (AE) using the Common Terminology Criteria for Adverse Events Version 4.03 occurring within the first 4 weeks for cohort 1 and within 3 weeks for each subsequent cohort that was not related to underlying disease, disease progression, intercurrent illness, or concomitant medications. The RP2D was established by achieving the Maximum Tolerated Dose (MTD). The RP2D may be equal to or below the MTD.
Time Frame	Up to 4 weeks in the first cohort and up to 3 weeks for each subsequent cohort

Outcome Measure Data

Analysis Population Description

All Phase 1 participants who received at least one dose of PEN-221 and either experienced a DLT or had been followed for the full DLT evaluation period.

Arm/Group Title	All Participants in Phase 1 Dose Escalation (Cohorts 1-7)
Arm/Group Description	All participants who received at least 1 dose of PEN-221, either at 1.0 mg, 2.0 mg, 4.0 mg, 8.0 mg, 12.0 mg, 18.0 mg, 25.0 mg via IV.
Measure Participants	23
Number [mg]	18.0

2. Primary Outcome

Title	Phase 1: Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs)
Description	DLTs were defined as any Grade 3 or 4 adverse event (AE) using the Common Terminology Criteria for Adverse Events Version 4.03 occurring within the first 4 weeks for cohort 1 and within 3 weeks for each subsequent cohort that was not related to underlying disease, disease progression, intercurrent illness, or concomitant medications. Grade 3 is a severe AE and Grade 4 is a life-threatening or disabling AE. DLTs were collected to determine the Maximum-Tolerated Dose (MTD), which is defined as the dose level below the dose at which > 33% of participants experienced a DLT during the first cycle of treatment.
Time Frame	Up to 4 weeks in the first cohort and up to 3 weeks for each subsequent cohort

Outcome Measure Data

Analysis Population Description

All Phase 1 participants who received at least one dose of PEN-221 and either experienced a DLT or had been followed for the full DLT evaluation period.

Arm/Group Title	Phase 1 Dose Escalation (Cohort 1)	Phase 1 Dose Escalation (Cohort 2)	Phase 1 Dose Escalation (Cohort 3)	Phase 1 Dose Escalation (Cohort 4)	Phase 1 Dose Escalation (Cohort 5)	Phase 1 Dose Escalation (Cohort 6)	Phase 1 Dose Escalation (Cohort 7)
Arm/Group Description	Participants in Cohort 1 received PEN-221 administered IV over 1 hour at the starting dose of 1.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 2 received PEN-221 administered IV over 1 hour at the starting dose of 2.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 3 received PEN-221 administered IV over 1 hour at the starting dose of 4.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 4 received PEN-221 administered IV over 1 hour at the starting dose of 8.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 5 received PEN-221 administered IV over 1 hour at the starting dose of 12.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 6 received PEN-221 administered IV over 1 hour at the starting dose of 18.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 7 received PEN-221 administered IV over 1 hour at the starting dose of 25.0 mg on an every 3-week cycle (21 days +/-2 days).
Measure Participants	2	3	3	3	3	6	3
Number [participants]	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	2 66.7%

3. Primary Outcome

Title	Phase 2a: Percentage of Gastrointestinal Mid-gut NETs and Pancreatic NETs Participants Who Achieved Clinical Benefit as Determined by RECIST 1.1
Description	Efficacy of PEN-221 in gastrointestinal mid-gut NETs and pancreatic NETs using clinical benefit rate (CBR) defined as the best overall response of complete response (CR), partial response (PR), or stable disease (SD) according to RECIST 1.1 using the investigator assessment.
Time Frame	Baseline and every 9 weeks up to time of disease progression (per RECIST 1.1) or death, up to data cut-off (31 Jul 2020).

Outcome Measure Data

Analysis Population Description

Outcome measured by cancer type. GI mid-gut NET or PNET participants who received any amount of study drug and had at least 1 post-baseline efficacy assessment.

Arm/Group Title	Phase 2a Dose Expansion (GI Mid-gut NET Cohort)	Phase 2a Dose Expansion (PNET Cohort
Arm/Group Description	Participants were enrolled with advanced or metastatic, well-differentiated, low or intermediate grade gastrointestinal mid-gut Neuroendocrine Tumor (GINET). Participants in the GINET cohort were enrolled into one of two groups which included 25 participants without prior Peptide Receptor Radionuclide Therapy [PRRT] (GINET PRRT Naïve) and 7 participants with prior PRRT (GINET PRRT Recurrent).	Participants were enrolled with advanced or metastatic, well-differentiated, low or intermediate grade pancreatic Neuroendocrine Tumor (PNET).
Measure Participants	26	12
Number (95% Confidence Interval) [percentage of participants]	88.5 4425%	50 1666.7%

4. Primary Outcome

Title	Phase 2a: Number of Small Cell Lung Cancer (SCLC) Participants Who Achieved an Objective Response of Complete Response (CR) or Partial Response (PR) as Defined by RECIST 1.1.
Description	Efficacy of PEN-221 in Small Cell Lung Cancer (SCLC) using objective response rate (ORR) as defined as the best overall response of CR or PR using tumor response criteria defined by RECIST 1.1.
Time Frame	Baseline and every 6 weeks up to time of disease progression (per RECIST 1.1) or death, up to data cut-off (31 Jul 2020).

Outcome Measure Data

Analysis Population Description

Outcome measured by cancer type. SCLC participants who received any amount of study drug and had at least 1 post-baseline efficacy assessment.

Arm/Group Title	Phase 2a Dose Expansion (SCLC Cohort)
Arm/Group Description	Participants were enrolled with advanced or metastatic Small Cell Lung Cancer (SCLC).
Measure Participants	12
Complete Response	0 0%
Partial Response	0 0%
Stable Disease	3 150%
Progressive Disease	9 450%

5. Primary Outcome

Title	Phase 2a: Duration of Response (DOR) for Small Cell Lung Cancer (SCLC)
Description	Duration of Response (DOR) is defined as the time from the 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 patient did not progress or die before the data cutoff date (31-July-2020), DOR was censored at the date of last adequate tumor assessment.
Time Frame	From the date of first treatment through the date of first documented progression, assessed up to data cut-off (31 Jul 2020).

Outcome Measure Data

Analysis Population Description

Outcome measured by cancer type. SCLC participants who received any amount of study drug and had at least 1 post-baseline efficacy assessment. No participants in the SCLC cohort had an objective response, so no data is presented for this Outcome Measure.

Arm/Group Title	Phase 2a Dose Expansion (SCLC Cohort)
Arm/Group Description	Outcome measured by cancer type. SCLC participants who received any amount of study drug and had at least 1 post-baseline efficacy assessment. No participants in the SCLC cohort had an objective response, so no data is presented for this Outcome Measure.
Measure Participants	0

6. Secondary Outcome

Title	Number of Study Participants Who Experienced Treatment-Emergent Adverse Events
Description	Phase 1 and Phase 2a participants who experienced any Treatment-Emergent Adverse Event (TEAE) to determine the safety and tolerability of PEN-221. TEAEs are any AE that occurred after first dose of study drug through 28 days after the last dose of study drug, any event considered study drug related regardless of start date of the event, or any event that was present at baseline but worsened in intensity or was subsequently considered study drug related by the Investigator. Phase 2a TEAEs were collected for reporting in the BSA dosing format only.
Time Frame	From date of first treatment/trial entry until 28 days after last treatment for each participant, up to data cut-off (31 Jul 2020).

Outcome Measure Data

Analysis Population Description

The Safety Analysis population was comprised of all enrolled participants who received any amount of study drug and had at least 1 post-baseline safety evaluation. All non-BSA based doses in Phase 2a were converted to BSA dosing units. Participants dosed under the initial MTD dosing regimen were assigned to the < 8.8 mg/m^2 or > 8.8 mg/m^2 dose groups based on the BSA conversion of the initial study dose.

Arm/Group Title	Phase 1 Dose Escalation (Cohort 1)	Phase 1 Dose Escalation (Cohort 2)	Phase 1 Dose Escalation (Cohort 3)	Phase 1 Dose Escalation (Cohort 4)	Phase 1 Dose Escalation (Cohort 5)	Phase 1 Dose Escalation (Cohort 6)	Phase 1 Dose Escalation (Cohort 7)	Phase 2a Dose Expansion (<8.8 mg/m^2)	Phase 2a Dose Expansion (8.8 mg/m^2)	Phase 2a Dose Expansion (>8.8 mg/m^2)
Arm/Group Description	Participants in Cohort 1 received PEN-221 administered IV over 1 hour at the starting dose of 1.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 2 received PEN-221 administered IV over 1 hour at the starting dose of 2.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 3 received PEN-221 administered IV over 1 hour at the starting dose of 4.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 4 received PEN-221 administered IV over 1 hour at the starting dose of 8.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 5 received PEN-221 administered IV over 1 hour at the starting dose of 12.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 6 received PEN-221 administered IV over 1 hour at the starting dose of 18.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 7 received PEN-221 administered IV over 1 hour at the starting dose of 25.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in GINET, PNET, and SCLC received PEN-221 BSA calculated starting dose of less than 8.8 mg/m^2 on an every 3-week cycle (21 days +/-2 days) All non-BSA based doses in Phase 2a were converted to BSA dosing units. Participants dosed under the initial MTD dosing regimen were assigned to the < 8.8 mg/m^2 or > 8.8 mg/m^2 dose groups based on the BSA conversion of the initial study dose.	Participants in GINET, PNET, and SCLC received PEN-221 BSA starting dose of 8.8 mg/m^2 on an every 3-week cycle (21 days +/-2 days)	Participants in GINET, PNET, and SCLC received PEN-221 BSA calculated starting dose of more than 8.8 mg/m^2 on an every 3-week cycle (21 days +/-2 days) All non-BSA based doses in Phase 2a were converted to BSA dosing units. Participants dosed under the initial MTD dosing regimen were assigned to the < 8.8 mg/m^2 or > 8.8 mg/m^2 dose groups based on the BSA conversion of the initial study dose.
Measure Participants	2	3	3	3	3	6	3	12	34	20
Any TEAE	2 100%	3 100%	3 100%	3 100%	3 100%	6 100%	3 100%	12 37.5%	32 213.3%	20 105.3%
Serious TEAEs	2 100%	1 33.3%	3 100%	0 0%	0 0%	2 33.3%	2 66.7%	3 9.4%	7 46.7%	15 78.9%
Treatment Related TEAEs	0 0%	3 100%	3 100%	3 100%	3 100%	6 100%	3 100%	10 31.3%	29 193.3%	19 100%
TEAEs leading to Discontinuation of Study Drug	1 50%	0 0%	2 66.7%	0 0%	0 0%	0 0%	2 66.7%	2 6.3%	7 46.7%	6 31.6%
TEAEs leading to Death	1 50%	0 0%	1 33.3%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	2 10.5%
Dose Limiting Toxicity	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	2 66.7%	0 0%	0 0%	0 0%

7. Secondary Outcome

Title	Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide
Description	Blood samples were obtained and plasma concentrations were determined using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. Phase 2a data were collected for reporting in the BSA dosing format only.
Time Frame	Phase 1: Day 1 of Cycles 1 and 3 pre-start of infusion (SOI), at 0.5, 1, 1.5, 2, 4, 6, 8, 10 hours post-start of infusion. Phase 2a: Day 1 Cycle 1 pre-start of infusion, at 0.5,1, 1.5, 2, 4, 6, 8, 24 hours post-SOI; once at Day 8 Cycle 1.

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic Analysis set comprises all participants who received any amount of study drug and provided adequate PK samples. Phase 2a participants dosed under the initial MTD dosing regimen were assigned to the < 8.8 mg/m^2 or > 8.8 mg/m^2 dose groups based on the BSA conversion of the initial study dose.

Arm/Group Title	Phase 1 Dose Escalation (Cohort 1)	Phase 1 Dose Escalation (Cohort 2)	Phase 1 Dose Escalation (Cohort 3)	Phase 1 Dose Escalation (Cohort 4)	Phase 1 Dose Escalation (Cohort 5)	Phase 1 Dose Escalation (Cohort 6)	Phase 1 Dose Escalation (Cohort 7)	Phase 2a Dose Expansion (<8.8 mg/m^2)	Phase 2a Dose Expansion (8.8 mg/m^2)	Phase 2a Dose Expansion (>8.8 mg/m^2)
Arm/Group Description	Participants in Cohort 1 received PEN-221 administered IV over 1 hour at the starting dose of 1.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 2 received PEN-221 administered IV over 1 hour at the starting dose of 2.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 3 received PEN-221 administered IV over 1 hour at the starting dose of 4.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 4 received PEN-221 administered IV over 1 hour at the starting dose of 8.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 5 received PEN-221 administered IV over 1 hour at the starting dose of 12.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 6 received PEN-221 administered IV over 1 hour at the starting dose of 18.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 7 received PEN-221 administered IV over 1 hour at the starting dose of 25.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in GINET, PNET, and SCLC received PEN-221 BSA calculated starting dose of less than 8.8 mg/m^2 on an every 3-week cycle (21 days +/-2 days) All non-BSA based doses in Phase 2a were converted to BSA dosing units. Participants dosed under the initial MTD dosing regimen were assigned to the < 8.8 mg/m^2 or > 8.8 mg/m^2 dose groups based on the BSA conversion of the initial study dose.	Participants in GINET, PNET, and SCLC received PEN-221 BSA starting dose of 8.8 mg/m^2 on an every 3-week cycle (21 days +/-2 days)	Participants in GINET, PNET, and SCLC received PEN-221 BSA calculated starting dose of more than 8.8 mg/m^2 on an every 3-week cycle (21 days +/-2 days) All non-BSA based doses in Phase 2a were converted to BSA dosing units. Participants dosed under the initial MTD dosing regimen were assigned to the < 8.8 mg/m^2 or > 8.8 mg/m^2 dose groups based on the BSA conversion of the initial study dose.
Measure Participants	2	3	3	3	3	6	3	12	28	20
Plasma PK	18.96 (9.56)	50.20 (24.30)	150.40 (51.99)	359.70 (92.42)	592.50 (149.66)	2802 (5068.6)	1324 (519.94)	451.4 (174.14)	1533 (3356.9)	1064 (2298.7)
Total Peptide	16.38 (3.7112)	40.03 (15.807)	129.8 (5.7813)	261.4 (49.269)	420.2 (69.703)	1925 (3246.8)	926.9 (279.02)	350.0 (102.28)	1041 (2061.0)	831.5 (1721.0)
Total DM1	11.11 (2.7669)	29.88 (14.304)	94.01 (2.7951)	198.6 (37.848)	340.4 (87.602)	1327 (2157.2)	691.3 (165.22)	261.2 (70.449)	762.3 (1388.0)	505.9 (734.05)
Unconjugated DM1	4.758 (0.78830)	13.79 (6.1768)	42.23 (12.295)	78.63 (6.2100)	112.0 (22.186)	218.3 (73.574)	266.3 (46.561)	101.0 (26.560)	164.5 (74.435)	146.3 (74.755)
Free Sulfhydryl DM1	0.09568 (0.034873)	0.2441 (0.17198)	0.6778 (0.02297)	1.975 (0.46462)	2.739 (0.90804)	14.12 (18.151)	11.04 (5.011)	2.174 (0.82698)	5.214 (8.2827)	6.225 (12.276)

8. Secondary Outcome

Title	Area Under the Curve (AUC) of PEN-221, DM1, and Peptide
Description	Blood samples were obtained and plasma concentrations were determined using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. Phase 2a data were collected for reporting in the BSA dosing format only.
Time Frame	Phase 1: Day 1 of Cycles 1 and 3 pre-start of infusion (SOI), at 0.5, 1, 1.5, 2, 4, 6, 8, 10 hours post-start of infusion. Phase 2a: Day 1 Cycle 1 pre-start of infusion, at 0.5,1, 1.5, 2, 4, 6, 8, 24 hours post-SOI; once at Day 8 Cycle 1.

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic Analysis set comprises all participants who received any amount of study drug and provided adequate PK samples. Phase 2a participants dosed under the initial MTD dosing regimen were assigned to the < 8.8 mg/m^2 or > 8.8 mg/m^2 dose groups based on the BSA conversion of the initial study dose.

Arm/Group Title	Phase 1 Dose Escalation (Cohort 1)	Phase 1 Dose Escalation (Cohort 2)	Phase 1 Dose Escalation (Cohort 3)	Phase 1 Dose Escalation (Cohort 4)	Phase 1 Dose Escalation (Cohort 5)	Phase 1 Dose Escalation (Cohort 6)	Phase 1 Dose Escalation (Cohort 7)	Phase 2a Dose Expansion (<8.8 mg/m^2)	Phase 2a Dose Expansion (8.8 mg/m^2)	Phase 2a Dose Expansion (>8.8 mg/m^2)
Arm/Group Description	Participants in Cohort 1 received PEN-221 administered IV over 1 hour at the starting dose of 1.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 2 received PEN-221 administered IV over 1 hour at the starting dose of 2.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 3 received PEN-221 administered IV over 1 hour at the starting dose of 4.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 4 received PEN-221 administered IV over 1 hour at the starting dose of 8.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 5 received PEN-221 administered IV over 1 hour at the starting dose of 12.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 6 received PEN-221 administered IV over 1 hour at the starting dose of 18.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 7 received PEN-221 administered IV over 1 hour at the starting dose of 25.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in GINET, PNET, and SCLC received PEN-221 BSA calculated starting dose of less than 8.8 mg/m^2 on an every 3-week cycle (21 days +/-2 days) All non-BSA based doses in Phase 2a were converted to BSA dosing units. Participants dosed under the initial MTD dosing regimen were assigned to the < 8.8 mg/m^2 or > 8.8 mg/m^2 dose groups based on the BSA conversion of the initial study dose.	Participants in GINET, PNET, and SCLC received PEN-221 BSA starting dose of 8.8 mg/m^2 on an every 3-week cycle (21 days +/-2 days)	Participants in GINET, PNET, and SCLC received PEN-221 BSA calculated starting dose of more than 8.8 mg/m^2 on an every 3-week cycle (21 days +/-2 days) All non-BSA based doses in Phase 2a were converted to BSA dosing units. Participants dosed under the initial MTD dosing regimen were assigned to the < 8.8 mg/m^2 or > 8.8 mg/m^2 dose groups based on the BSA conversion of the initial study dose.
Measure Participants	2	3	3	3	3	6	3	12	28	20
Plasma PK	38.34 (15.88)	89.95 (33.64)	192.40 (48.66)	643.60 (224.39)	1119 (330.86)	2323 (2267.7)	2357 (798.60)	867.7 (329.9)	1667 (1638.6)	1463 (1141.8)
Total Peptide	87.20 (30.636)	189.2 (64.194)	548.0 (156.34)	1080 (197.69)	1730 (475.69)	3147 (1211.0)	4402 (938.17)	2988 (847.68)	4203 (1837.2)	4558 (1474.5)
Total DM1	65.59 (16.501)	179.7 (97.376)	454.8 (136.89)	981.1 (74.477)	1780 (652.3)	1996 (489.18)	3980 (1335.4)	2153 (526.06)	3328 (1881.7)	3419 (1277.9)
Unconjugated DM1	54.18 (15.810)	163.9 (86.594)	444.5 (100.94)	720.6 (86.063)	1384	1776 (660.31)	4316	1765 (415.63)	2384 (522.17)	2781 (1057.1)
Free Sulfhydryl DM1	16.86	17.63 (7.6946)	37.40 (12.335)	131.4 (109.56)	32.06 (20.012)	62.05 (35.792)	69.48 (58.396)

9. Secondary Outcome

Title	Half-life (t1/2) of PEN-221, DM1, and Peptide
Description	Blood samples were obtained and plasma concentrations were determined using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. Phase 2a data collected for reporting in the BSA dosing format only.
Time Frame	Phase 1: Day 1 of Cycles 1 and 3 pre-start of infusion (SOI), at 0.5, 1, 1.5, 2, 4, 6, 8, 10 hours post-start of infusion. Phase 2a: Day 1 Cycle 1 pre-start of infusion, at 0.5,1, 1.5, 2, 4, 6, 8, 24 hours post-SOI; once at Day 8 Cycle 1.

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic Analysis set comprises all participants who received any amount of study drug and provided adequate PK samples. Phase 2a participants dosed under the initial MTD dosing regimen were assigned to the < 8.8 mg/m^2 or > 8.8 mg/m^2 dose groups based on the BSA conversion of the initial study dose.

Arm/Group Title	Phase 1 Dose Escalation (Cohort 1)	Phase 1 Dose Escalation (Cohort 2)	Phase 1 Dose Escalation (Cohort 3)	Phase 1 Dose Escalation (Cohort 4)	Phase 1 Dose Escalation (Cohort 5)	Phase 1 Dose Escalation (Cohort 6)	Phase 1 Dose Escalation (Cohort 7)	Phase 2a Dose Expansion (<8.8 mg/m^2)	Phase 2a Dose Expansion (8.8 mg/m^2)	Phase 2a Dose Expansion (>8.8 mg/m^2)
Arm/Group Description	Participants in Cohort 1 received PEN-221 administered IV over 1 hour at the starting dose of 1.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 2 received PEN-221 administered IV over 1 hour at the starting dose of 2.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 3 received PEN-221 administered IV over 1 hour at the starting dose of 4.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 4 received PEN-221 administered IV over 1 hour at the starting dose of 8.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 5 received PEN-221 administered IV over 1 hour at the starting dose of 12.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 6 received PEN-221 administered IV over 1 hour at the starting dose of 18.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 7 received PEN-221 administered IV over 1 hour at the starting dose of 25.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in GINET, PNET, and SCLC received PEN-221 BSA calculated starting dose of less than 8.8 mg/m^2 on an every 3-week cycle (21 days +/-2 days) All non-BSA based doses in Phase 2a were converted to BSA dosing units. Participants dosed under the initial MTD dosing regimen were assigned to the < 8.8 mg/m^2 or > 8.8 mg/m^2 dose groups based on the BSA conversion of the initial study dose.	Participants in GINET, PNET, and SCLC received PEN-221 BSA starting dose of 8.8 mg/m^2 on an every 3-week cycle (21 days +/-2 days)	Participants in GINET, PNET, and SCLC received PEN-221 BSA calculated starting dose of more than 8.8 mg/m^2 on an every 3-week cycle (21 days +/-2 days) All non-BSA based doses in Phase 2a were converted to BSA dosing units. Participants dosed under the initial MTD dosing regimen were assigned to the < 8.8 mg/m^2 or > 8.8 mg/m^2 dose groups based on the BSA conversion of the initial study dose.
Measure Participants	2	3	3	3	3	6	3	12	28	20
Plasma PK	1.46	1.41	1.77	1.70	1.94	1.61	3.06	4.259	4.180	4.526
Total Peptide	5.33	4.61	5.25	4.33	5.63	4.89	7.49	27.9	28.7	30.9
Total DM1	4.78	4.48	5.87	4.43	5.69	5.43	6.32	25.3	24.2	25.5
Unconjugated DM1	5.77	7.80	6.07	5.36	8.49	6.89	8.94	25.9	24.5	25.0
Free Sulfhydryl DM1	4.57	4.93	3.87	9.01	10.1	20.9	14.3

10. Secondary Outcome

Title	Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease.
Description	Assess the potential of preliminary anti-tumor activity of PEN-221 using tumor response criteria as defined by RECIST 1.1.
Time Frame	Baseline, every 6 or 9 weeks depending on the tumor type, up to time of disease progression (per RECIST 1.1) or death, up to data cut-off (31 Jul 2020).

Outcome Measure Data

Analysis Population Description

Phase 1 participants who received at least 1 dose of study drug and had at least 1 post-baseline efficacy assessment.

Arm/Group Title	Phase 1 Dose Escalation (Cohort 1)	Phase 1 Dose Escalation (Cohort 2)	Phase 1 Dose Escalation (Cohort 3)	Phase 1 Dose Escalation (Cohort 4)	Phase 1 Dose Escalation (Cohort 5)	Phase 1 Dose Escalation (Cohort 6)	Phase 1 Dose Escalation (Cohort 7)
Arm/Group Description	Participants in Cohort 1 received PEN-221 administered IV over 1 hour at the starting dose of 1.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 2 received PEN-221 administered IV over 1 hour at the starting dose of 2.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 3 received PEN-221 administered IV over 1 hour at the starting dose of 4.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 4 received PEN-221 administered IV over 1 hour at the starting dose of 8.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 5 received PEN-221 administered IV over 1 hour at the starting dose of 12.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 6 received PEN-221 administered IV over 1 hour at the starting dose of 18.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 7 received PEN-221 administered IV over 1 hour at the starting dose of 25.0 mg on an every 3-week cycle (21 days +/-2 days).
Measure Participants	2	3	2	3	3	6	2
Complete Response (Confirmed or Unconfirmed)	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Partial Response (Confirmed)	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Partial Response (Unconfirmed)	0 0%	0 0%	1 33.3%	0 0%	0 0%	0 0%	0 0%
Stable Disease	1 50%	3 100%	1 33.3%	3 100%	2 66.7%	2 33.3%	2 66.7%
Progressive Disease	1 50%	0 0%	0 0%	0 0%	1 33.3%	4 66.7%	0 0%

11. Secondary Outcome

Title	Phase 2a: Maximum Tolerated Dose (MTD) and Recommended Phase 2a Dose (RP2D) Based on Body Surface Area
Description	Confirm the MTD identified during the dose-escalation phase and further investigate the safety and tolerability of the RP2D and schedule of PEN-221. Initial Phase 2a PEN-221 start dose at Phase 1 MTD and RP2D was determined at 18 mg flat dose. The MTD was defined as the highest drug dosage not causing a Dose Limiting Toxicity (DLT) in > 33% of the treated participants during the first cycle of treatment. DLTs were defined as any Grade 3 or 4 adverse event (AE) using the Common Terminology Criteria for Adverse Events Version 4.03 occurring within the first 4 weeks for cohort 1 and within 3 weeks for each subsequent cohort that was not related to underlying disease, disease progression, intercurrent illness, or concomitant medications. The RP2D was established by achieving the Maximum Tolerated Dose (MTD). The RP2D may be equal to or below the MTD.
Time Frame	From date of first treatment/trial entry until 28 days after last treatment for each Phase 2a participant, up to data cut-off (31 Jul 2020)

Outcome Measure Data

Analysis Population Description

All Phase 2a participants who received any amount of study drug and had at least 1 post-baseline safety evaluation. SRC reviewed all Phase 1 and 31 Phase 2a participants and changed flat dose (mg) to Body Surface Area (BSA) based dose of 8.8 mg/m^2 due to correlation between BSA and drug exposure associated with higher rate of participant discontinuation. Calculated BSA capped at 2.0 m^2 so not to exceed Phase 1 MTD of 18 mg. Phase 2a data collected for reporting in the BSA dosing format only.

Arm/Group Title	All Phase 2a Dose Expansion Participants
Arm/Group Description	All GINET, PNET, and SCLC participants who received at least 1 PEN-221 BSA calculated starting dose of either < 8.8 mg/m^2, 8.8 mg/m^2, or > 8.8 mg/m^2 on an every 3-week cycle (21 days +/-2 days) All non-BSA based doses (flat dose) in Phase 2a were converted to BSA dosing units. Participants dosed under the initial MTD flat dosing regimen were assigned to the < 8.8 mg/m^2 or > 8.8 mg/m^2 dose groups based on the BSA conversion of the initial study flat dose.
Measure Participants	66
Number [mg/m^2]	8.8

12. Secondary Outcome

Title	Phase 2a: Progression Free Survival (PFS)
Description	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 participant had not progressed or died before the analysis cutoff date (31 Jul 2020), PFS was censored at the date of last adequate tumor assessment. Results based on Kaplan-Meier estimates.
Time Frame	From date of first treatment/trial entry until first documented progression or date of death from any cause, whichever came first, assessed up to data cutoff of 31 Jul 2020

Outcome Measure Data

Analysis Population Description

Outcome measured by cancer type. GI mid-gut NET, PNET, and SCLC participants enrolled into the study and who received any amount of study drug.

Arm/Group Title	Phase 2a Dose Expansion (GI Mid-gut NET Cohort)	Phase 2a Dose Expansion (PNET Cohort)	Phase 2a Dose Expansion (SCLC Cohort)
Arm/Group Description	Participants were enrolled with advanced or metastatic, well-differentiated, low or intermediate grade gastrointestinal mid-gut Neuroendocrine Tumor (GINET). Participants in the GINET cohort were enrolled into one of two groups which included 25 participants without prior Peptide Receptor Radionuclide Therapy [PRRT] (GINET PRRT Naïve) and 7 participants with prior PRRT (GINET PRRT Recurrent).	Participants were enrolled with advanced or metastatic, well-differentiated, low or intermediate grade pancreatic Neuroendocrine Tumor (PNET).	Participants were enrolled with advanced or metastatic Small Cell Lung Cancer (SCLC).
Measure Participants	32	15	19
Median (95% Confidence Interval) [Months]	9.0	3.2	1.4

13. Secondary Outcome

Title	Phase 2a: Overall Survival (OS)
Description	Overall survival (OS) was defined as the time from the first dose of PEN-221 to the date of death due to any cause. If the participant had not died before data lock (31 Jul 2020), OS was censored at the date of last contact.
Time Frame	For each GI mid-gut NET, PNET, and SCLC, from date of first treatment/trial entry until the date of death from any cause, assessed up to data cutoff of 31 Jul 2020

Outcome Measure Data

Analysis Population Description

Outcome measured by cancer type. GI mid-gut NET, PNET, and SCLC patients enrolled into the study and who received any amount of study drug.

Arm/Group Title	Phase 2a Dose Expansion (GI Mid-gut NET Cohort)	Phase 2a Dose Expansion (PNET Cohort)	Phase 2a Dose Expansion (SCLC Cohort)
Arm/Group Description	Participants were enrolled with advanced or metastatic, well-differentiated, low or intermediate grade gastrointestinal mid-gut Neuroendocrine Tumor (GINET). Participants in the GINET cohort were enrolled into one of two groups which included 25 participants without prior Peptide Receptor Radionuclide Therapy [PRRT] (GINET PRRT Naïve) and 7 participants with prior PRRT (GINET PRRT Recurrent).	Participants were enrolled with advanced or metastatic, well-differentiated, low or intermediate grade pancreatic Neuroendocrine Tumor (PNET).	Participants were enrolled with advanced or metastatic Small Cell Lung Cancer (SCLC).
Measure Participants	32	15	19
Median (95% Confidence Interval) [Months]	NA	21.0	3.9

14. Secondary Outcome

Title	Phase 2a: ORR for Gastrointestinal Mid-gut NETs (GI Mid-gut NET) and Pancreatic NETs (PNET)
Description	The Objective Response Rate (ORR) 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 electronic Case Report Form.
Time Frame	For each GI mid-gut NET and PNET participant from the date of first treatment through the date of first documented progression, assessed up to data cutoff 31 Jul 2020

Outcome Measure Data

Analysis Population Description

Outcome measured by cancer type. GI mid-gut NET and PNET participants who received any amount of study drug and had at least 1 post-baseline efficacy assessment (RECIST 1.1).

Arm/Group Title	Phase 2a Dose Expansion (GI Mid-gut NET Cohort)	Phase 2a Dose Expansion (PNET Cohort)
Arm/Group Description	Participants were enrolled with advanced or metastatic, well-differentiated, low or intermediate grade gastrointestinal mid-gut Neuroendocrine Tumor (GINET). Participants in the GINET cohort were enrolled into one of two groups which included 25 participants without prior Peptide Receptor Radionuclide Therapy [PRRT] (GINET PRRT Naïve) and 7 participants with prior PRRT (GINET PRRT Recurrent).	Participants were enrolled with advanced or metastatic, well-differentiated, low or intermediate grade pancreatic Neuroendocrine Tumor (PNET).
Measure Participants	26	12
Responder	0 0%	0 0%
Non-Responder	26 1300%	12 400%

15. Secondary Outcome

Title	Phase 2a: Duration of Response (DOR) for Gastrointestinal Mid-gut NETs (GI Mid-gut NET) and Pancreatic NETs (PNET)
Description	Duration of Response (DOR) is defined as the time from the 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 did not progress or die before the data cutoff date (31 Jul 2020), DOR was censored at the date of last adequate tumor assessment.
Time Frame	For each GI mid-gut NET and PNET participant, from the date of first treatment through the date of first documented progression, assessed up to data cutoff (31 Jul 2020)

Outcome Measure Data

Analysis Population Description

Outcome measured by cancer type. GI mid-gut NET cohort and PNET cohort participants who received any amount of study drug and had at least 1 post-baseline efficacy assessment (RECIST 1.1). No participants in the GI mid-gut NET cohort or PNET cohort had an objective response, so no data is presented for this Outcome Measure

Arm/Group Title	Phase 2a Dose Expansion (GI Mid-gut NET Cohort)	Phase 2a Dose Expansion (PNET Cohort
Arm/Group Description	Participants were enrolled with advanced or metastatic, well-differentiated, low or intermediate grade gastrointestinal mid-gut Neuroendocrine Tumor (GINET). Participants in the GINET cohort were enrolled into one of two groups which included 25 participants without prior Peptide Receptor Radionuclide Therapy [PRRT] (GINET PRRT Naïve) and 7 participants with prior PRRT (GINET PRRT Recurrent).	Participants were enrolled with advanced or metastatic, well-differentiated, low or intermediate grade pancreatic Neuroendocrine Tumor (PNET).
Measure Participants	0	0

16. Secondary Outcome

Title	Anti-PEN-221 Antibodies (ADA)
Description	Plasma Samples Using an Electrochemiluminescent Method for the Detection of Anti-PEN-221 Antibodies in Human Serum.
Time Frame	Baseline and every 6 weeks up to end of treatment for each patient.

Outcome Measure Data

Analysis Population Description

All participants who received any dose of study drug with at least 1 post-baseline immunogenicity assessment. Phase 2a participants dosed under the initial MTD dosing regimen were assigned to the < 8.8 mg/m^2 or > 8.8 mg/m^2 dose groups based on the BSA conversion of the initial study dose.

Arm/Group Title	Phase 1 Dose Escalation (Cohort 1)	Phase 1 Dose Escalation (Cohort 2)	Phase 1 Dose Escalation (Cohort 3)	Phase 1 Dose Escalation (Cohort 4)	Phase 1 Dose Escalation (Cohort 5)	Phase 1 Dose Escalation (Cohort 6)	Phase 1 Dose Escalation (Cohort 7)	Phase 2a Dose Expansion (<8.8 mg/m^2)	Phase 2a Dose Expansion (8.8 mg/m^2)	Phase 2a Dose Expansion (>8.8 mg/m^2)
Arm/Group Description	Participants in Cohort 1 received PEN-221 administered IV over 1 hour at the starting dose of 1.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 2 received PEN-221 administered IV over 1 hour at the starting dose of 2.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 3 received PEN-221 administered IV over 1 hour at the starting dose of 4.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 4 received PEN-221 administered IV over 1 hour at the starting dose of 8.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 5 received PEN-221 administered IV over 1 hour at the starting dose of 12.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 6 received PEN-221 administered IV over 1 hour at the starting dose of 18.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in Cohort 7 received PEN-221 administered IV over 1 hour at the starting dose of 25.0 mg on an every 3-week cycle (21 days +/-2 days).	Participants in GINET, PNET, and SCLC received PEN-221 BSA calculated starting dose of less than8.8 mg/m^2 on an every 3-week cycle (21 days +/-2 days) All non-BSA based doses in Phase 2a were converted to BSA dosing units. Participants dosed under the initial MTD dosing regimen were assigned to the < 8.8 mg/m^2 or > 8.8 mg/m^2 dose groups based on the BSA conversion of the initial study dose.	Participants in GINET, PNET, and SCLC received PEN-221 BSA starting dose of 8.8 mg/m^2 on an every 3-week cycle (21 days +/-2 days)	Participants in GINET, PNET, and SCLC received PEN-221 BSA calculated starting dose of more than 8.8 mg/m^2 on an every 3-week cycle (21 days +/-2 days) All non-BSA based doses in Phase 2a were converted to BSA dosing units. Participants dosed under the initial MTD dosing regimen were assigned to the < 8.8 mg/m^2 or > 8.8 mg/m^2 dose groups based on the BSA conversion of the initial study dose.
Measure Participants	2	3	3	3	3	6	2	11	22	15
Baseline ADA Positive	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	2 13.3%	0 0%
Baseline ADA Negative	2 100%	3 100%	3 100%	3 100%	3 100%	6 100%	2 66.7%	11 34.4%	20 133.3%	15 78.9%
ADA Positive On-Study Treatment	0 0%	0 0%	0 0%	1 33.3%	0 0%	0 0%	0 0%	0 0%	3 20%	2 10.5%
Persistent Positive	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 6.7%	1 5.3%
Only Last Sample Positive	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 5.3%
Other Positive	0 0%	0 0%	0 0%	1 33.3%	0 0%	0 0%	0 0%	0 0%	2 13.3%	0 0%
ADA Negative On-Study Treatment	2 100%	3 100%	3 100%	2 66.7%	3 100%	6 100%	2 66.7%	11 34.4%	19 126.7%	13 68.4%

Adverse Events

Time Frame	From time of first dose of study drug through 28 days after the last dose of study drug for each participant up to data cut-off 31 Jul 2020.
Adverse Event Reporting Description	The Safety Analysis population was comprised of all enrolled patients who received any amount of study drug and have at least 1 post-baseline safety evaluation (AE, clinical laboratory assessments, vital signs, ECG (electrocardiogram), ECOG scores, physical examination). Participants were analyzed according to treatment received. Dose levels reported for Phase 2a Arms/Groups were collected for reporting in BSA format only.
Arm/Group Title	Phase 1 Dose Escalation (Cohort 1)		Phase 1 Dose Escalation (Cohort 2)		Phase 1 Dose Escalation (Cohort 3)		Phase 1 Dose Escalation (Cohort 4)		Phase 1 Dose Escalation (Cohort 5)		Phase 1 Dose Escalation (Cohort 6)		Phase 1 Dose Escalation (Cohort 7)		Phase 2a Dose Expansion (<8.8 mg/m^2)		Phase 2a Dose Expansion (8.8 mg/m^2)		Phase 2a Dose Expansion (>8.8 mg/m^2)
Arm/Group Description	Participants in Cohort 1 received PEN-221 administered IV over 1 hour at the starting dose of 1.0 mg1 on an every 3-week cycle (21 days +/-2 days).		Participants in Cohort 2 received PEN-221 administered IV over 1 hour at the starting dose of 2.0 mg1 on an every 3-week cycle (21 days +/-2 days).		Participants in Cohort 3 received PEN-221 administered IV over 1 hour at the starting dose of 4.0 mg1 on an every 3-week cycle (21 days +/-2 days).		Participants in Cohort 4 received PEN-221 administered IV over 1 hour at the starting dose of 8.0 mg1 on an every 3-week cycle (21 days +/-2 days).		Participants in Cohort 5 received PEN-221 administered IV over 1 hour at the starting dose of 12.0 mg1 on an every 3-week cycle (21 days +/-2 days).		Participants in Cohort 6 received PEN-221 administered IV over 1 hour at the starting dose of 18.0 mg1 on an every 3-week cycle (21 days +/-2 days).		Participants in Cohort 7 received PEN-221 administered IV over 1 hour at the starting dose of 25.0 mg1 on an every 3-week cycle (21 days +/-2 days).		Participants in GINET, PNET, and SCLC received PEN-221 BSA calculated starting dose of less than 8.8 mg/m^2 on an every 3-week cycle (21 days +/-2 days) All non-BSA based doses in Phase 2a were converted to BSA dosing units. Participants dosed under the initial MTD dosing regimen were assigned to the < 8.8 mg/m2 or > 8.8 mg/m2 dose groups based on the BSA conversion of the initial study dose.		Participants in GINET, PNET, and SCLC received PEN-221 BSA starting dose of 8.8 mg/m^2 on an every 3-week cycle (21 days +/-2 days)		Participants in GINET, PNET, and SCLC received PEN-221 BSA calculated starting dose of more than 8.8 mg/m^2 on an every 3-week cycle (21 days +/-2 days) All non-BSA based doses in Phase 2a were converted to BSA dosing units. Participants dosed under the initial MTD dosing regimen were assigned to the < 8.8 mg/m2 or > 8.8 mg/m2 dose groups based on the BSA conversion of the initial study dose.
All Cause Mortality
	Phase 1 Dose Escalation (Cohort 1)		Phase 1 Dose Escalation (Cohort 2)		Phase 1 Dose Escalation (Cohort 3)		Phase 1 Dose Escalation (Cohort 4)		Phase 1 Dose Escalation (Cohort 5)		Phase 1 Dose Escalation (Cohort 6)		Phase 1 Dose Escalation (Cohort 7)		Phase 2a Dose Expansion (<8.8 mg/m^2)		Phase 2a Dose Expansion (8.8 mg/m^2)		Phase 2a Dose Expansion (>8.8 mg/m^2)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/2 (100%)		1/3 (33.3%)		3/3 (100%)		1/3 (33.3%)		2/3 (66.7%)		3/6 (50%)		3/3 (100%)		4/12 (33.3%)		8/34 (23.5%)		10/20 (50%)
Serious Adverse Events
	Phase 1 Dose Escalation (Cohort 1)		Phase 1 Dose Escalation (Cohort 2)		Phase 1 Dose Escalation (Cohort 3)		Phase 1 Dose Escalation (Cohort 4)		Phase 1 Dose Escalation (Cohort 5)		Phase 1 Dose Escalation (Cohort 6)		Phase 1 Dose Escalation (Cohort 7)		Phase 2a Dose Expansion (<8.8 mg/m^2)		Phase 2a Dose Expansion (8.8 mg/m^2)		Phase 2a Dose Expansion (>8.8 mg/m^2)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/2 (100%)		1/3 (33.3%)		3/3 (100%)		0/3 (0%)		0/3 (0%)		2/6 (33.3%)		2/3 (66.7%)		3/12 (25%)		7/34 (20.6%)		15/20 (75%)
Blood and lymphatic system disorders
Anemia	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Cardiac disorders
Myocardial infarction	0/2 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Gastrointestinal disorders
Abdominal Pain	1/2 (50%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/34 (0%)	0	2/20 (10%)	2
Constipation	0/2 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Nausea	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	2/20 (10%)	3
Vomiting	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	2/20 (10%)	2
Colitis	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Diarrhea	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	2
Gastrointestinal hemorrhage	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Small intestinal obstruction	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/34 (2.9%)	1	0/20 (0%)	0
General disorders
Fatigue	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	2/20 (10%)	2
Influenza like illness	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	2/20 (10%)	2
Asthenia	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Malaise	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Mucosal inflammation	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Non-cardiac chest pain	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/34 (2.9%)	1	0/20 (0%)	0
Oedema	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Hepatobiliary disorders
Drug-induced liver injury	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Gallbladder pain	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/34 (0%)	0	0/20 (0%)	0
Hepatic hemorrhage	0/2 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Hyperbilirubinemia	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Infections and infestations
Sepsis	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/34 (2.9%)	1	1/20 (5%)	1
Urinary tract infection	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Device related infection	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/34 (2.9%)	1	0/20 (0%)	0
Kidney infection	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/34 (2.9%)	1	0/20 (0%)	0
Lung infection	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/34 (2.9%)	1	0/20 (0%)	0
Pneumocystis jirovecii pneumonia	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Pneumonia	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Pulmonary sepsis	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Injury, poisoning and procedural complications
Fall	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Infusion Related Reaction	0/2 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Investigations
Blood bilirubin increased	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	2/20 (10%)	2
Alanine aminotransferase increased	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Amylase increased	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Aspartate aminotransferase increased	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Blood alkaline phosphatase increased	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Lipase increased	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Metabolism and nutrition disorders
Decreased appetite	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	2/20 (10%)	2
Dehydration	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Failure to thrive	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Hyponatremia	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/34 (2.9%)	1	0/20 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate Cancer	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/34 (0%)	0	0/20 (0%)	0
Tumor necrosis	0/2 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Nervous system disorders
Cerebrovascular accident	1/2 (50%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Hemorrhage intercranial	1/2 (50%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Headache	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Metabolic encephalopathy	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/34 (2.9%)	1	0/20 (0%)	0
Posterior reversible encephalopathy syndrome	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/34 (2.9%)	1	0/20 (0%)	0
Psychiatric disorders
Confusional state	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Renal and urinary disorders
Nephrotic syndrome	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/34 (2.9%)	1	1/20 (5%)	1
Chronic obstructive pulmonary disease	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/34 (2.9%)	1	0/20 (0%)	0
Hypoxia	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Pleural effusion	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/34 (0%)	0	0/20 (0%)	0
Pulmonary embolism	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Skin and subcutaneous tissue disorders
Rash maculo-papular	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/34 (2.9%)	1	0/20 (0%)	0
Vascular disorders
Hypertension	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Thrombophlebitis	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/34 (0%)	0	0/20 (0%)	0
Other (Not Including Serious) Adverse Events
	Phase 1 Dose Escalation (Cohort 1)		Phase 1 Dose Escalation (Cohort 2)		Phase 1 Dose Escalation (Cohort 3)		Phase 1 Dose Escalation (Cohort 4)		Phase 1 Dose Escalation (Cohort 5)		Phase 1 Dose Escalation (Cohort 6)		Phase 1 Dose Escalation (Cohort 7)		Phase 2a Dose Expansion (<8.8 mg/m^2)		Phase 2a Dose Expansion (8.8 mg/m^2)		Phase 2a Dose Expansion (>8.8 mg/m^2)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/2 (100%)		3/3 (100%)		3/3 (100%)		3/3 (100%)		3/3 (100%)		6/6 (100%)		3/3 (100%)		12/12 (100%)		32/34 (94.1%)		20/20 (100%)
Blood and lymphatic system disorders
Anemia	0/2 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	3	0/3 (0%)	0	0/3 (0%)	0	3/6 (50%)	12	0/3 (0%)	0	2/12 (16.7%)	2	7/34 (20.6%)	11	5/20 (25%)	12
Lymphopenia	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/34 (2.9%)	1	2/20 (10%)	2
Neutropenia	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	1/12 (8.3%)	1	1/34 (2.9%)	2	0/20 (0%)	0
Thrombocytopenia	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	2/34 (5.9%)	3	1/20 (5%)	3
Febrile neutropenia	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Cardiac disorders
Palpitations	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/3 (66.7%)	2	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	1/34 (2.9%)	2	0/20 (0%)	0
Bradycardia	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Tachycardia	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	2	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Atrial fibrillation	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Endocrine disorders
Hypothyroidism	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	2/20 (10%)	2
Cushing's syndrome	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Eye disorders
Vision blurred	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	1/34 (2.9%)	1	0/20 (0%)	0
Diplopia	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Gastrointestinal disorders
Nausea	1/2 (50%)	1	3/3 (100%)	9	1/3 (33.3%)	1	1/3 (33.3%)	2	2/3 (66.7%)	4	5/6 (83.3%)	10	2/3 (66.7%)	2	6/12 (50%)	7	16/34 (47.1%)	21	10/20 (50%)	17
Diarrhea	0/2 (0%)	0	3/3 (100%)	7	1/3 (33.3%)	2	2/3 (66.7%)	2	2/3 (66.7%)	3	6/6 (100%)	15	0/3 (0%)	0	9/12 (75%)	15	15/34 (44.1%)	22	6/20 (30%)	10
Constipation	1/2 (50%)	1	2/3 (66.7%)	2	2/3 (66.7%)	2	1/3 (33.3%)	1	1/3 (33.3%)	1	2/6 (33.3%)	2	0/3 (0%)	0	2/12 (16.7%)	3	13/34 (38.2%)	17	9/20 (45%)	13
Abdominal Pain	1/2 (50%)	4	1/3 (33.3%)	8	1/3 (33.3%)	2	1/3 (33.3%)	2	0/3 (0%)	0	4/6 (66.7%)	13	1/3 (33.3%)	2	5/12 (41.7%)	8	7/34 (20.6%)	8	5/20 (25%)	9
Vomiting	1/2 (50%)	2	1/3 (33.3%)	3	2/3 (66.7%)	2	1/3 (33.3%)	3	1/3 (33.3%)	1	2/6 (33.3%)	4	2/3 (66.7%)	3	4/12 (33.3%)	8	8/34 (23.5%)	10	4/20 (20%)	10
Abdominal distension	1/2 (50%)	1	1/3 (33.3%)	3	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	2	0/3 (0%)	0	1/12 (8.3%)	1	2/34 (5.9%)	2	1/20 (5%)	1
Abdominal pain upper	0/2 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	2/6 (33.3%)	2	0/3 (0%)	0	1/12 (8.3%)	1	1/34 (2.9%)	1	1/20 (5%)	1
Abdominal discomfort	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	3	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	3/34 (8.8%)	4	1/20 (5%)	1
Dry mouth	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	2	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	1/34 (2.9%)	1	2/20 (10%)	2
Dyspepsia	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/6 (16.7%)	1	1/3 (33.3%)	1	0/12 (0%)	0	0/34 (0%)	0	2/20 (10%)	2
Dysphagia	0/2 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	2/12 (16.7%)	2	1/34 (2.9%)	1	0/20 (0%)	0
Gastroesophageal reflux disease	0/2 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	2/3 (66.7%)	2	0/6 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/34 (0%)	0	0/20 (0%)	0
Abdominal pain lower	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	2/34 (5.9%)	2	0/20 (0%)	0
Hypoaesthesia oral	0/2 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	2/6 (33.3%)	2	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Paraesthesia oral	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	2/34 (5.9%)	3	1/20 (5%)	1
Stomatitis	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	2/34 (5.9%)	2	0/20 (0%)	0
Flatulence	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/34 (2.9%)	1	1/20 (5%)	1
Ascites	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Enteritis	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/34 (0%)	0	0/20 (0%)	0
Hiatus hernia	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Melaena	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Mouth ulceration	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
General disorders
Fatigue	2/2 (100%)	2	3/3 (100%)	9	1/3 (33.3%)	1	1/3 (33.3%)	4	2/3 (66.7%)	2	5/6 (83.3%)	11	0/3 (0%)	0	6/12 (50%)	9	16/34 (47.1%)	26	10/20 (50%)	17
Oedema peripheral	1/2 (50%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	4/12 (33.3%)	5	3/34 (8.8%)	3	3/20 (15%)	5
Asthenia	0/2 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	1/12 (8.3%)	1	2/34 (5.9%)	3	3/20 (15%)	3
Pyrexia	0/2 (0%)	0	0/3 (0%)	0	2/3 (66.7%)	3	1/3 (33.3%)	2	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/12 (0%)	0	2/34 (5.9%)	3	1/20 (5%)	4
Chills	1/2 (50%)	1	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	2/12 (16.7%)	3	0/34 (0%)	0	1/20 (5%)	2
Mucosal inflammation	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/6 (33.3%)	2	1/3 (33.3%)	1	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Chest pain	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Non-cardiac chest pain	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/34 (2.9%)	1	1/20 (5%)	1
Gait disturbance	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	2/34 (5.9%)	2	0/20 (0%)	0
Infusion site erythema	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	1/12 (8.3%)	1	0/34 (0%)	0	0/20 (0%)	0
Infusion site reaction	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/34 (2.9%)	1	1/20 (5%)	1
Infusion site swelling	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/34 (0%)	0	0/20 (0%)	0
Oedema	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Pain	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	2
Extravasation	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Infusion site pain	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/34 (0%)	0	0/20 (0%)	0
Infusion site pruritus	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/34 (0%)	0	0/20 (0%)	0
Injection site pruritus	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Hepatobiliary disorders
Hyperbilirubinemia	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/34 (2.9%)	2	1/20 (5%)	1
Cholelithiasis	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/34 (0%)	0	0/20 (0%)	0
Hepatomegaly	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Immune system disorders
Hypersensitivity	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Infections and infestations
Urinary tract infection	0/2 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	2	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	5/34 (14.7%)	9	2/20 (10%)	2
Upper respiratory tract infection	0/2 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	1/3 (33.3%)	1	0/3 (0%)	0	2/6 (33.3%)	2	0/3 (0%)	0	1/12 (8.3%)	1	1/34 (2.9%)	1	0/20 (0%)	0
Lung infection	0/2 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/34 (2.9%)	1	1/20 (5%)	2
Sinusitis	1/2 (50%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	1/12 (8.3%)	1	1/34 (2.9%)	1	0/20 (0%)	0
Skin infection	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	2/12 (16.7%)	3	0/34 (0%)	0	0/20 (0%)	0
Bronchitis	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	2/34 (5.9%)	2	0/20 (0%)	0
Oral candidiasis	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	2/20 (10%)	2
Conjunctivitis	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/34 (0%)	0	0/20 (0%)	0
Escherichia urinary tract infection	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Genital infection fungal	0/2 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Helicobacter gastritis	1/2 (50%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Influenza	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Lower respiratory tract infection	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Wound infection	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/34 (0%)	0	0/20 (0%)	0
Injury, poisoning and procedural complications
Infusion related reaction	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	4/12 (33.3%)	4	7/34 (20.6%)	16	6/20 (30%)	11
Fall	0/2 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	2/34 (5.9%)	2	1/20 (5%)	1
Contusion	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/34 (0%)	0	0/20 (0%)	0
Laceration	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	2
Procedural nausea	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Skin wound	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Investigations
Alanine aminotransferase increased	0/2 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	2	0/3 (0%)	0	2/3 (66.7%)	3	3/6 (50%)	10	1/3 (33.3%)	1	3/12 (25%)	4	9/34 (26.5%)	12	9/20 (45%)	17
Aspartate aminotransferase increased	0/2 (0%)	0	1/3 (33.3%)	2	0/3 (0%)	0	0/3 (0%)	0	2/3 (66.7%)	5	3/6 (50%)	9	1/3 (33.3%)	1	2/12 (16.7%)	3	7/34 (20.6%)	13	9/20 (45%)	17
Blood alkaline phosphatase increased	0/2 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	3	0/3 (0%)	0	1/3 (33.3%)	2	0/6 (0%)	0	0/3 (0%)	0	3/12 (25%)	5	10/34 (29.4%)	13	5/20 (25%)	8
Blood creatinine increased	0/2 (0%)	0	2/3 (66.7%)	7	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	2/12 (16.7%)	2	7/34 (20.6%)	9	1/20 (5%)	2
Weight decreased	1/2 (50%)	2	1/3 (33.3%)	1	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	5/12 (41.7%)	6	2/34 (5.9%)	3	1/20 (5%)	1
White blood cell count decreased	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	6/34 (17.6%)	10	3/20 (15%)	5
Amylase increased	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	2/34 (5.9%)	4	1/20 (5%)	3
Blood bilirubin increased	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	4/34 (11.8%)	7	0/20 (0%)	0
Neutrophil count decreased	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	2/12 (16.7%)	2	2/34 (5.9%)	3	1/20 (5%)	2
Lipase increased	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/34 (2.9%)	1	2/20 (10%)	4
Electrocardiogram QT prolonged	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	2	0/3 (0%)	0	0/12 (0%)	0	2/34 (5.9%)	3	0/20 (0%)	0
Electrocardiogram T wave inversion	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
International normalized ratio increased	0/2 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	2
Platelet count decreased	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/34 (2.9%)	1	1/20 (5%)	2
Activated partial thromboplastin time prolonged	0/2 (0%)	0	1/3 (33.3%)	2	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Blood glucose increased	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Blood pressure increased	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Blood urea increased	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Escherichia test positive	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Glucose urine present	0/2 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Lymphocyte count decreased	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Pupil dilation procedure	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Weight increased	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
White blood cell count increased	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Metabolism and nutrition disorders
Decreased appetite	0/2 (0%)	0	3/3 (100%)	3	0/3 (0%)	0	2/3 (66.7%)	4	0/3 (0%)	0	1/6 (16.7%)	5	1/3 (33.3%)	1	6/12 (50%)	7	11/34 (32.4%)	13	7/20 (35%)	9
Hypokalaemia	0/2 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	5	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	1/3 (33.3%)	1	2/12 (16.7%)	4	10/34 (29.4%)	15	6/20 (30%)	10
Dehydration	0/2 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	2	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	3	0/3 (0%)	0	0/12 (0%)	0	7/34 (20.6%)	8	2/20 (10%)	3
Hyperglycemia	0/2 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	13	0/3 (0%)	0	1/12 (8.3%)	1	5/34 (14.7%)	9	3/20 (15%)	6
Hypoalbuminemia	0/2 (0%)	0	1/3 (33.3%)	2	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	2	0/3 (0%)	0	1/12 (8.3%)	1	2/34 (5.9%)	2	3/20 (15%)	3
Hypomagnesemia	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/6 (33.3%)	13	0/3 (0%)	0	1/12 (8.3%)	2	4/34 (11.8%)	5	2/20 (10%)	6
Hyponatremia	0/2 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	5/34 (14.7%)	6	1/20 (5%)	2
Hypophosphatemia	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	3/34 (8.8%)	8	4/20 (20%)	6
Hyperkalemia	0/2 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/34 (2.9%)	1	0/20 (0%)	0
Hypoglycemia	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	2	1/34 (2.9%)	1	0/20 (0%)	0
Hypercholesterolemia	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Hypermagnesemia	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Hypernatremia	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Hypertriglyceridemia	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/34 (0%)	0	0/20 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	0/2 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	2	3/3 (100%)	6	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	3/12 (25%)	3	6/34 (17.6%)	9	4/20 (20%)	4
Back pain	1/2 (50%)	3	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	2/6 (33.3%)	2	1/3 (33.3%)	2	1/12 (8.3%)	1	6/34 (17.6%)	10	3/20 (15%)	7
Myalgia	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	4	0/3 (0%)	0	2/6 (33.3%)	2	0/3 (0%)	0	1/12 (8.3%)	1	7/34 (20.6%)	11	4/20 (20%)	4
Pain in extremity	1/2 (50%)	1	0/3 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	2/34 (5.9%)	3	1/20 (5%)	1
Muscle spasms	0/2 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	2	0/3 (0%)	0	0/12 (0%)	0	2/34 (5.9%)	2	0/20 (0%)	0
Musculoskeletal chest pain	0/2 (0%)	0	1/3 (33.3%)	2	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/6 (33.3%)	2	0/3 (0%)	0	0/12 (0%)	0	1/34 (2.9%)	3	0/20 (0%)	0
Musculoskeletal pain	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/6 (16.7%)	2	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	2/20 (10%)	2
Muscular weakness	0/2 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Flank pain	0/2 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/34 (2.9%)	1	0/20 (0%)	0
Arthritis	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	2	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Groin pain	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Joint swelling	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Myositis	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	2	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Neck pain	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Pain in jaw	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Nervous system disorders
Neuropathy peripheral	0/2 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	2	1/3 (33.3%)	4	4/6 (66.7%)	6	1/3 (33.3%)	2	4/12 (33.3%)	12	10/34 (29.4%)	13	4/20 (20%)	5
Headache	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	3/6 (50%)	3	1/3 (33.3%)	1	1/12 (8.3%)	1	8/34 (23.5%)	11	4/20 (20%)	4
Dysgeusia	0/2 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	2/12 (16.7%)	2	6/34 (17.6%)	6	3/20 (15%)	4
Dizziness	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	5	0/3 (0%)	0	3/12 (25%)	4	4/34 (11.8%)	6	1/20 (5%)	1
Paraesthesia	1/2 (50%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/6 (16.7%)	1	1/3 (33.3%)	1	0/12 (0%)	0	1/34 (2.9%)	1	3/20 (15%)	3
Hypoesthesia	0/2 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	3/20 (15%)	3
Peripheral sensory neuropathy	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/34 (0%)	0	2/20 (10%)	3
Somnolence	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/34 (2.9%)	1	1/20 (5%)	1
Syncope	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/34 (2.9%)	1	0/20 (0%)	0
Ageusia	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Aphasia	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Balance disorder	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Cognitive disorder	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Seizure	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Sensory disturbance	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Sinus headache	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Tremor	0/2 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Sixth nerve paralysis	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Psychiatric disorders
Insomnia	0/2 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/3 (33.3%)	3	1/3 (33.3%)	1	2/6 (33.3%)	2	1/3 (33.3%)	3	1/12 (8.3%)	1	3/34 (8.8%)	4	6/20 (30%)	7
Anxiety	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/12 (0%)	0	0/34 (0%)	0	4/20 (20%)	5
Restlessness	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	2	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	2/34 (5.9%)	3	0/20 (0%)	0
Depressed mood	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Depression	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/34 (2.9%)	1	1/20 (5%)	1
Mental status changes	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/34 (2.9%)	1	1/20 (5%)	1
Hallucination	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Nightmare	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Sleep disorder	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Renal and urinary disorders
Acute kidney injury	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	3/34 (8.8%)	3	0/20 (0%)	0
Dysuria	1/2 (50%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	2/20 (10%)	2
Hematuria	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	2/20 (10%)	2
Nephrolithiasis	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/34 (0%)	0	0/20 (0%)	0
Nocturia	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	2	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Proteinuria	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	8	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Reproductive system and breast disorders
Pelvic pain	0/2 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/2 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	3/6 (50%)	4	0/3 (0%)	0	0/12 (0%)	0	7/34 (20.6%)	10	2/20 (10%)	2
Cough	1/2 (50%)	1	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	2/6 (33.3%)	2	0/3 (0%)	0	2/12 (16.7%)	2	0/34 (0%)	0	1/20 (5%)	1
Oropharyngeal pain	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	2/20 (10%)	2
Dyspnea exertional	0/2 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	2/6 (33.3%)	4	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Upper-airway cough syndrome	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	1/12 (8.3%)	1	1/34 (2.9%)	1	0/20 (0%)	0
Rhinorrhea	1/2 (50%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/34 (2.9%)	1	0/20 (0%)	0
Sleep apnea syndrome	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	2/34 (5.9%)	2	0/20 (0%)	0
Dysphonia	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/34 (0%)	0	0/20 (0%)	0
Laryngeal inflammation	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Nasal congestion	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/34 (0%)	0	0/20 (0%)	0
Pleuritic pain	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	2
Productive cough	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Respiratory tract congestion	0/2 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Rhinitis allergic	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/34 (0%)	0	0/20 (0%)	0
Wheezing	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Skin and subcutaneous tissue disorders
Pruritus	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	3/6 (50%)	6	0/3 (0%)	0	2/12 (16.7%)	2	4/34 (11.8%)	4	2/20 (10%)	2
Rash	0/2 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	2	0/3 (0%)	0	3/12 (25%)	3	2/34 (5.9%)	2	1/20 (5%)	1
Rash maculo-papular	0/2 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	3/34 (8.8%)	4	1/20 (5%)	2
Alopecia	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	2/34 (5.9%)	2	2/20 (10%)	2
Erythema	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	1/12 (8.3%)	1	0/34 (0%)	0	1/20 (5%)	1
Hyperhidrosis	0/2 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Pain of skin	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	1/34 (2.9%)	1	0/20 (0%)	0
Dermatitis	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Ecchymosis	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Night sweats	1/2 (50%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Pigmentation disorder	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Skin hyperpigmentation	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Skin tightness	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Skin ulcer	0/2 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	0/20 (0%)	0
Urticaria	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1
Vascular disorders
Flushing	0/2 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	1/3 (33.3%)	1	3/12 (25%)	3	5/34 (14.7%)	6	5/20 (25%)	7
Hypotension	0/2 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	5/34 (14.7%)	7	2/20 (10%)	2
Hypertension	0/2 (0%)	0	1/3 (33.3%)	2	1/3 (33.3%)	2	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	1/3 (33.3%)	1	1/12 (8.3%)	1	2/34 (5.9%)	3	0/20 (0%)	0
Hot flush	0/2 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	3	0/3 (0%)	0	0/12 (0%)	0	1/34 (2.9%)	1	2/20 (10%)	2
Thrombophlebitis superficial	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	4/34 (11.8%)	4	0/20 (0%)	0
Phlebitis	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	1/12 (8.3%)	1	1/34 (2.9%)	1	0/20 (0%)	0
Embolism	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/34 (0%)	0	1/20 (5%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Institute and/or Principal Investigator may submit for publication or public disclosure based on the results of the study only after one of the following occurs as specified in the Clinical Trial Agreement: Sponsor publication of the multi-center clinical trial results; Sponsor notification that the multi-center clinical trial results submission is no longer planned; or The eighteenth (18) month anniversary of the completion or early termination of the multi-center clinical trial.