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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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

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.

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.

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.

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.

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.

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.

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.

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).

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.

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

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

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.