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Somatostatin

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.

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.

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.

Chief Medical Officer

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.

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.

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

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

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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

Tarveda Therapeutics

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.

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).

Phase 1 Dose Escalation (Cohort 1)

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).

Phase 1 Dose Escalation (Cohort 2)

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).

Phase 1 Dose Escalation (Cohort 3)

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).

Phase 1 Dose Escalation (Cohort 4)

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).

Phase 1 Dose Escalation (Cohort 5)

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).

Phase 1 Dose Escalation (Cohort 6)

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).

Phase 1 Dose Escalation (Cohort 7)

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.

Phase 2a Dose Expansion (<8.8 mg/m^2)

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)

Phase 2a Dose Expansion (8.8 mg/m^2)

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.

Phase 2a Dose Expansion (>8.8 mg/m^2)

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).

Phase 2a Dose Expansion (GI Mid-gut NET Cohort)

Participants were enrolled with advanced or metastatic, well-differentiated, low or intermediate grade pancreatic Neuroendocrine Tumor (PNET).

Phase 2a Dose Expansion (PNET Cohort)

Participants were enrolled with advanced or metastatic Small Cell Lung Cancer (SCLC).

Phase 2a Dose Expansion (SCLC Cohort)

Total

Age, Continuous

Sex: Female, Male

Caucasian/White

Black

Asian

Native American or Alaska Native

Hawaiian or Other Pacific Islander

Not collected

Other

Race/Ethnicity, Customized

Hispanic or Latino

Not Hispanic or Latino

Ethnicity

The analysis population was the Full Analysis Set (FAS) which consisted of all participants enrolled into the study and who receive any amount of study drug.

Tarveda Clinical Information Center

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.

All Participants in Phase 1 Dose Escalation (Cohorts 1-7)

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.

Phase 1: Maximum Tolerated Dose of PEN-221 and Recommended Phase 2a Dose (RP2D)

Phase 1: Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs)

Phase 2a Dose Expansion (PNET Cohort

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.

Phase 2a: Percentage of Gastrointestinal Mid-gut NETs and Pancreatic NETs Participants Who Achieved Clinical Benefit as Determined by RECIST 1.1

Complete Response

Partial Response

Stable Disease

Progressive Disease

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

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.

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 2a: Duration of Response (DOR) for Small Cell Lung Cancer (SCLC)

Any TEAE

Serious TEAEs

Treatment Related TEAEs

TEAEs leading to Discontinuation of Study Drug

TEAEs leading to Death

Dose Limiting Toxicity

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 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.

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.

Number of Study Participants Who Experienced Treatment-Emergent Adverse Events

Plasma PK

Total Peptide

Total DM1

Unconjugated DM1

Free Sulfhydryl DM1

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.

Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide

Area Under the Curve (AUC) of PEN-221, DM1, and Peptide

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.

Half-life (t1/2) of PEN-221, DM1, and Peptide

Complete Response (Confirmed or Unconfirmed)

Partial Response (Confirmed)

Partial Response (Unconfirmed)

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

Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease.

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.

All Phase 2a Dose Expansion Participants

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.

Phase 2a: Maximum Tolerated Dose (MTD) and Recommended Phase 2a Dose (RP2D) Based on Body Surface Area

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.

Phase 2a: Progression Free Survival (PFS)

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.

Phase 2a: Overall Survival (OS)

Responder

Non-Responder

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).

Phase 2a: ORR for Gastrointestinal Mid-gut NETs (GI Mid-gut NET) and Pancreatic NETs (PNET)

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

Phase 2a: Duration of Response (DOR) for Gastrointestinal Mid-gut NETs (GI Mid-gut NET) and Pancreatic NETs (PNET)

Baseline ADA Positive

Baseline ADA Negative

ADA Positive On-Study Treatment

Persistent Positive

Only Last Sample Positive

Other Positive

ADA Negative On-Study Treatment

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 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.

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.

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