Title

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
  • Phase

    Phase 1/Phase 2
  • Study Type

    Interventional
  • Intervention/Treatment

    pen-221 ...
  • Study Participants

    89
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.
Study Started
Dec 08
2016
Primary Completion
Jul 31
2020
Study Completion
Feb 25
2021
Results Posted
Dec 14
2021
Last Update
Dec 14
2021

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.

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.

Phase 1: Dose Escalation Experimental

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.

Phase 2a: Dose Expansion (GI mid-gut NET) Experimental

Gastrointestinal mid-gut NET Cohort

Phase 2a: Dose Expansion (PNET) Experimental

Pancreatic NET Cohort

Phase 2a: Dose Expansion (SCLC) Experimental

Small Cell Lung Cancer Cohort

Criteria

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

Summary

Phase 1 Dose Escalation (Cohort 4)

Phase 1 Dose Escalation (Cohort 1)

Phase 1 Dose Escalation (Cohort 2)

Phase 1 Dose Escalation (Cohort 3)

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)

All Events

Event Type Organ System Event Term 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)

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

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 2a Dose Expansion (SCLC Cohort)

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

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

18.0
mg

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

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.

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)

2.0
participants

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

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.

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

88.5
percentage of participants
95% Confidence Interval: 69.8 to 97.6

Phase 2a Dose Expansion (PNET Cohort

50.0
percentage of participants
95% Confidence Interval: 21.1 to 78.9

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.

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.

Phase 2a Dose Expansion (SCLC Cohort)

Complete Response

Partial Response

Progressive Disease

Stable Disease

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

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 Dose Expansion Participants

8.8
mg/m^2

Phase 2a: Progression Free Survival (PFS)

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.

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

9.0
Months (Median)
95% Confidence Interval: 5.0 to 16.5

Phase 2a Dose Expansion (PNET Cohort)

3.2
Months (Median)
95% Confidence Interval: 2.0 to 5.9

Phase 2a Dose Expansion (SCLC Cohort)

1.4
Months (Median)
95% Confidence Interval: 1.2 to 1.8

Phase 2a: Overall Survival (OS)

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.

Phase 2a Dose Expansion (SCLC Cohort)

3.9
Months (Median)
95% Confidence Interval: 1.8 to 5.5

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

Phase 2a Dose Expansion (PNET Cohort)

21.0
Months (Median)
95% Confidence Interval: 4.9 to 24.0

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

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.

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

Non-Responder

Responder

Phase 2a Dose Expansion (PNET Cohort)

Non-Responder

Responder

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

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.

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

Phase 2a Dose Expansion (PNET Cohort

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

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.

Phase 1 Dose Escalation (Cohort 1)

Plasma PK

1.46
hours (Median)
Full Range: 1.15 to 1.77

Total DM1

4.78
hours (Median)
Full Range: 3.61 to 5.94

Total Peptide

5.33
hours (Median)
Full Range: 3.87 to 6.8

Unconjugated DM1

5.77
hours (Median)
Full Range: 3.61 to 7.92

Phase 1 Dose Escalation (Cohort 2)

Plasma PK

1.41
hours (Median)
Full Range: 1.31 to 1.8

Total DM1

4.48
hours (Median)
Full Range: 3.85 to 7.35

Total Peptide

4.61
hours (Median)
Full Range: 4.15 to 5.29

Unconjugated DM1

7.8
hours (Median)
Full Range: 6.38 to 9.0

Phase 1 Dose Escalation (Cohort 3)

Plasma PK

1.77
hours (Median)
Full Range: 0.86 to 2.69

Total DM1

5.87
hours (Median)
Full Range: 2.94 to 6.13

Total Peptide

5.25
hours (Median)
Full Range: 2.56 to 6.5

Unconjugated DM1

6.07
hours (Median)
Full Range: 5.58 to 6.56

Phase 1 Dose Escalation (Cohort 4)

Free Sulfhydryl DM1

4.57
hours (Median)
Full Range: None

Plasma PK

1.7
hours (Median)
Full Range: 1.59 to 2.32

Total DM1

4.43
hours (Median)
Full Range: 4.19 to 4.49

Total Peptide

4.33
hours (Median)
Full Range: 3.61 to 5.57

Unconjugated DM1

5.36
hours (Median)
Full Range: 4.73 to 5.98

Phase 1 Dose Escalation (Cohort 5)

Free Sulfhydryl DM1

4.93
hours (Median)
Full Range: 4.4 to 5.47

Plasma PK

1.94
hours (Median)
Full Range: 1.8 to 3.76

Total DM1

5.69
hours (Median)
Full Range: 3.25 to 9.13

Total Peptide

5.63
hours (Median)
Full Range: 3.03 to 8.07

Unconjugated DM1

8.49
hours (Median)
Full Range: 8.49 to 8.49

Phase 1 Dose Escalation (Cohort 6)

Free Sulfhydryl DM1

3.87
hours (Median)
Full Range: 2.57 to 4.21

Plasma PK

1.61
hours (Median)
Full Range: 1.26 to 3.64

Total DM1

5.43
hours (Median)
Full Range: 3.67 to 6.38

Total Peptide

4.89
hours (Median)
Full Range: 2.27 to 11.2

Unconjugated DM1

6.89
hours (Median)
Full Range: 4.67 to 9.6

Phase 1 Dose Escalation (Cohort 7)

Free Sulfhydryl DM1

9.01
hours (Median)
Full Range: 7.1 to 10.8

Plasma PK

3.06
hours (Median)
Full Range: 2.5 to 3.45

Total DM1

6.32
hours (Median)
Full Range: 5.66 to 6.98

Total Peptide

7.49
hours (Median)
Full Range: 7.32 to 7.67

Unconjugated DM1

8.94
hours (Median)
Full Range: 8.94 to 8.94

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

Free Sulfhydryl DM1

10.1
hours (Median)
Full Range: 6.22 to 38.1

Plasma PK

4.259
hours (Median)
Full Range: 1.04 to 9.01

Total DM1

25.3
hours (Median)
Full Range: 7.26 to 28.4

Total Peptide

27.9
hours (Median)
Full Range: 10.1 to 35.0

Unconjugated DM1

25.9
hours (Median)
Full Range: 6.98 to 29.4

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

Free Sulfhydryl DM1

20.9
hours (Median)
Full Range: 7.21 to 46.9

Plasma PK

4.18
hours (Median)
Full Range: 1.64 to 12.9

Total DM1

24.2
hours (Median)
Full Range: 5.57 to 27.6

Total Peptide

28.7
hours (Median)
Full Range: 6.71 to 35.8

Unconjugated DM1

24.5
hours (Median)
Full Range: 8.03 to 29.2

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

Free Sulfhydryl DM1

14.3
hours (Median)
Full Range: 8.16 to 47.2

Plasma PK

4.526
hours (Median)
Full Range: 1.27 to 6.93

Total DM1

25.5
hours (Median)
Full Range: 19.9 to 34.1

Total Peptide

30.9
hours (Median)
Full Range: 22.9 to 38.6

Unconjugated DM1

25.0
hours (Median)
Full Range: 19.8 to 34.8

Anti-PEN-221 Antibodies (ADA)

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

Phase 1 Dose Escalation (Cohort 1)

ADA Negative On-Study Treatment

ADA Positive On-Study Treatment

Baseline ADA Negative

Baseline ADA Positive

Only Last Sample Positive

Other Positive

Persistent Positive

Phase 1 Dose Escalation (Cohort 2)

ADA Negative On-Study Treatment

ADA Positive On-Study Treatment

Baseline ADA Negative

Baseline ADA Positive

Only Last Sample Positive

Other Positive

Persistent Positive

Phase 1 Dose Escalation (Cohort 3)

ADA Negative On-Study Treatment

ADA Positive On-Study Treatment

Baseline ADA Negative

Baseline ADA Positive

Only Last Sample Positive

Other Positive

Persistent Positive

Phase 1 Dose Escalation (Cohort 4)

ADA Negative On-Study Treatment

ADA Positive On-Study Treatment

Baseline ADA Negative

Baseline ADA Positive

Only Last Sample Positive

Other Positive

Persistent Positive

Phase 1 Dose Escalation (Cohort 5)

ADA Negative On-Study Treatment

ADA Positive On-Study Treatment

Baseline ADA Negative

Baseline ADA Positive

Only Last Sample Positive

Other Positive

Persistent Positive

Phase 1 Dose Escalation (Cohort 6)

ADA Negative On-Study Treatment

ADA Positive On-Study Treatment

Baseline ADA Negative

Baseline ADA Positive

Only Last Sample Positive

Other Positive

Persistent Positive

Phase 1 Dose Escalation (Cohort 7)

ADA Negative On-Study Treatment

ADA Positive On-Study Treatment

Baseline ADA Negative

Baseline ADA Positive

Only Last Sample Positive

Other Positive

Persistent Positive

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

ADA Negative On-Study Treatment

ADA Positive On-Study Treatment

Baseline ADA Negative

Baseline ADA Positive

Only Last Sample Positive

Other Positive

Persistent Positive

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

ADA Negative On-Study Treatment

ADA Positive On-Study Treatment

Baseline ADA Negative

Baseline ADA Positive

Only Last Sample Positive

Other Positive

Persistent Positive

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

ADA Negative On-Study Treatment

ADA Positive On-Study Treatment

Baseline ADA Negative

Baseline ADA Positive

Only Last Sample Positive

Other Positive

Persistent Positive

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

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

Phase 1 Dose Escalation (Cohort 1)

Complete Response (Confirmed or Unconfirmed)

Partial Response (Confirmed)

Partial Response (Unconfirmed)

Progressive Disease

Stable Disease

Phase 1 Dose Escalation (Cohort 2)

Complete Response (Confirmed or Unconfirmed)

Partial Response (Confirmed)

Partial Response (Unconfirmed)

Progressive Disease

Stable Disease

Phase 1 Dose Escalation (Cohort 3)

Complete Response (Confirmed or Unconfirmed)

Partial Response (Confirmed)

Partial Response (Unconfirmed)

Progressive Disease

Stable Disease

Phase 1 Dose Escalation (Cohort 4)

Complete Response (Confirmed or Unconfirmed)

Partial Response (Confirmed)

Partial Response (Unconfirmed)

Progressive Disease

Stable Disease

Phase 1 Dose Escalation (Cohort 5)

Complete Response (Confirmed or Unconfirmed)

Partial Response (Confirmed)

Partial Response (Unconfirmed)

Progressive Disease

Stable Disease

Phase 1 Dose Escalation (Cohort 6)

Complete Response (Confirmed or Unconfirmed)

Partial Response (Confirmed)

Partial Response (Unconfirmed)

Progressive Disease

Stable Disease

Phase 1 Dose Escalation (Cohort 7)

Complete Response (Confirmed or Unconfirmed)

Partial Response (Confirmed)

Partial Response (Unconfirmed)

Progressive Disease

Stable Disease

Number of Study Participants Who Experienced Treatment-Emergent Adverse Events

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.

Phase 1 Dose Escalation (Cohort 1)

Any TEAE

Dose Limiting Toxicity

Serious TEAEs

TEAEs leading to Death

TEAEs leading to Discontinuation of Study Drug

Treatment Related TEAEs

Phase 1 Dose Escalation (Cohort 2)

Any TEAE

Dose Limiting Toxicity

Serious TEAEs

TEAEs leading to Death

TEAEs leading to Discontinuation of Study Drug

Treatment Related TEAEs

Phase 1 Dose Escalation (Cohort 3)

Any TEAE

Dose Limiting Toxicity

Serious TEAEs

TEAEs leading to Death

TEAEs leading to Discontinuation of Study Drug

Treatment Related TEAEs

Phase 1 Dose Escalation (Cohort 4)

Any TEAE

Dose Limiting Toxicity

Serious TEAEs

TEAEs leading to Death

TEAEs leading to Discontinuation of Study Drug

Treatment Related TEAEs

Phase 1 Dose Escalation (Cohort 5)

Any TEAE

Dose Limiting Toxicity

Serious TEAEs

TEAEs leading to Death

TEAEs leading to Discontinuation of Study Drug

Treatment Related TEAEs

Phase 1 Dose Escalation (Cohort 6)

Any TEAE

Dose Limiting Toxicity

Serious TEAEs

TEAEs leading to Death

TEAEs leading to Discontinuation of Study Drug

Treatment Related TEAEs

Phase 1 Dose Escalation (Cohort 7)

Any TEAE

Dose Limiting Toxicity

Serious TEAEs

TEAEs leading to Death

TEAEs leading to Discontinuation of Study Drug

Treatment Related TEAEs

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

Any TEAE

Dose Limiting Toxicity

Serious TEAEs

TEAEs leading to Death

TEAEs leading to Discontinuation of Study Drug

Treatment Related TEAEs

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

Any TEAE

Dose Limiting Toxicity

Serious TEAEs

TEAEs leading to Death

TEAEs leading to Discontinuation of Study Drug

Treatment Related TEAEs

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

Any TEAE

Dose Limiting Toxicity

Serious TEAEs

TEAEs leading to Death

TEAEs leading to Discontinuation of Study Drug

Treatment Related TEAEs

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

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.

Phase 1 Dose Escalation (Cohort 1)

Free Sulfhydryl DM1

0.09568
ng/mL (Mean)
Standard Deviation: 0.034873

Plasma PK

18.96
ng/mL (Mean)
Standard Deviation: 9.56

Total DM1

11.11
ng/mL (Mean)
Standard Deviation: 2.7669

Total Peptide

16.38
ng/mL (Mean)
Standard Deviation: 3.7112

Unconjugated DM1

4.758
ng/mL (Mean)
Standard Deviation: 0.78830

Phase 1 Dose Escalation (Cohort 2)

Free Sulfhydryl DM1

0.2441
ng/mL (Mean)
Standard Deviation: 0.17198

Plasma PK

50.2
ng/mL (Mean)
Standard Deviation: 24.30

Total DM1

29.88
ng/mL (Mean)
Standard Deviation: 14.304

Total Peptide

40.03
ng/mL (Mean)
Standard Deviation: 15.807

Unconjugated DM1

13.79
ng/mL (Mean)
Standard Deviation: 6.1768

Phase 1 Dose Escalation (Cohort 3)

Free Sulfhydryl DM1

0.6778
ng/mL (Mean)
Standard Deviation: 0.02297

Plasma PK

150.4
ng/mL (Mean)
Standard Deviation: 51.99

Total DM1

94.01
ng/mL (Mean)
Standard Deviation: 2.7951

Total Peptide

129.8
ng/mL (Mean)
Standard Deviation: 5.7813

Unconjugated DM1

42.23
ng/mL (Mean)
Standard Deviation: 12.295

Phase 1 Dose Escalation (Cohort 4)

Free Sulfhydryl DM1

1.975
ng/mL (Mean)
Standard Deviation: 0.46462

Plasma PK

359.7
ng/mL (Mean)
Standard Deviation: 92.42

Total DM1

198.6
ng/mL (Mean)
Standard Deviation: 37.848

Total Peptide

261.4
ng/mL (Mean)
Standard Deviation: 49.269

Unconjugated DM1

78.63
ng/mL (Mean)
Standard Deviation: 6.2100

Phase 1 Dose Escalation (Cohort 5)

Free Sulfhydryl DM1

2.739
ng/mL (Mean)
Standard Deviation: 0.90804

Plasma PK

592.5
ng/mL (Mean)
Standard Deviation: 149.66

Total DM1

340.4
ng/mL (Mean)
Standard Deviation: 87.602

Total Peptide

420.2
ng/mL (Mean)
Standard Deviation: 69.703

Unconjugated DM1

112.0
ng/mL (Mean)
Standard Deviation: 22.186

Phase 1 Dose Escalation (Cohort 6)

Free Sulfhydryl DM1

14.12
ng/mL (Mean)
Standard Deviation: 18.151

Plasma PK

2802.0
ng/mL (Mean)
Standard Deviation: 5068.6

Total DM1

1327.0
ng/mL (Mean)
Standard Deviation: 2157.2

Total Peptide

1925.0
ng/mL (Mean)
Standard Deviation: 3246.8

Unconjugated DM1

218.3
ng/mL (Mean)
Standard Deviation: 73.574

Phase 1 Dose Escalation (Cohort 7)

Free Sulfhydryl DM1

11.04
ng/mL (Mean)
Standard Deviation: 5.011

Plasma PK

1324.0
ng/mL (Mean)
Standard Deviation: 519.94

Total DM1

691.3
ng/mL (Mean)
Standard Deviation: 165.22

Total Peptide

926.9
ng/mL (Mean)
Standard Deviation: 279.02

Unconjugated DM1

266.3
ng/mL (Mean)
Standard Deviation: 46.561

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

Free Sulfhydryl DM1

2.174
ng/mL (Mean)
Standard Deviation: 0.82698

Plasma PK

451.4
ng/mL (Mean)
Standard Deviation: 174.14

Total DM1

261.2
ng/mL (Mean)
Standard Deviation: 70.449

Total Peptide

350.0
ng/mL (Mean)
Standard Deviation: 102.28

Unconjugated DM1

101.0
ng/mL (Mean)
Standard Deviation: 26.560

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

Free Sulfhydryl DM1

5.214
ng/mL (Mean)
Standard Deviation: 8.2827

Plasma PK

1533.0
ng/mL (Mean)
Standard Deviation: 3356.9

Total DM1

762.3
ng/mL (Mean)
Standard Deviation: 1388.0

Total Peptide

1041.0
ng/mL (Mean)
Standard Deviation: 2061.0

Unconjugated DM1

164.5
ng/mL (Mean)
Standard Deviation: 74.435

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

Free Sulfhydryl DM1

6.225
ng/mL (Mean)
Standard Deviation: 12.276

Plasma PK

1064.0
ng/mL (Mean)
Standard Deviation: 2298.7

Total DM1

505.9
ng/mL (Mean)
Standard Deviation: 734.05

Total Peptide

831.5
ng/mL (Mean)
Standard Deviation: 1721.0

Unconjugated DM1

146.3
ng/mL (Mean)
Standard Deviation: 74.755

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

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.

Phase 1 Dose Escalation (Cohort 1)

Plasma PK

38.34
(ng/mL)*h (Mean)
Standard Deviation: 15.88

Total DM1

65.59
(ng/mL)*h (Mean)
Standard Deviation: 16.501

Total Peptide

87.2
(ng/mL)*h (Mean)
Standard Deviation: 30.636

Unconjugated DM1

54.18
(ng/mL)*h (Mean)
Standard Deviation: 15.810

Phase 1 Dose Escalation (Cohort 2)

Plasma PK

89.95
(ng/mL)*h (Mean)
Standard Deviation: 33.64

Total DM1

179.7
(ng/mL)*h (Mean)
Standard Deviation: 97.376

Total Peptide

189.2
(ng/mL)*h (Mean)
Standard Deviation: 64.194

Unconjugated DM1

163.9
(ng/mL)*h (Mean)
Standard Deviation: 86.594

Phase 1 Dose Escalation (Cohort 3)

Plasma PK

192.4
(ng/mL)*h (Mean)
Standard Deviation: 48.66

Total DM1

454.8
(ng/mL)*h (Mean)
Standard Deviation: 136.89

Total Peptide

548.0
(ng/mL)*h (Mean)
Standard Deviation: 156.34

Unconjugated DM1

444.5
(ng/mL)*h (Mean)
Standard Deviation: 100.94

Phase 1 Dose Escalation (Cohort 4)

Free Sulfhydryl DM1

16.86
(ng/mL)*h (Mean)
Standard Deviation: None

Plasma PK

643.6
(ng/mL)*h (Mean)
Standard Deviation: 224.39

Total DM1

981.1
(ng/mL)*h (Mean)
Standard Deviation: 74.477

Total Peptide

1080.0
(ng/mL)*h (Mean)
Standard Deviation: 197.69

Unconjugated DM1

720.6
(ng/mL)*h (Mean)
Standard Deviation: 86.063

Phase 1 Dose Escalation (Cohort 5)

Free Sulfhydryl DM1

17.63
(ng/mL)*h (Mean)
Standard Deviation: 7.6946

Plasma PK

1119.0
(ng/mL)*h (Mean)
Standard Deviation: 330.86

Total DM1

1780.0
(ng/mL)*h (Mean)
Standard Deviation: 652.3

Total Peptide

1730.0
(ng/mL)*h (Mean)
Standard Deviation: 475.69

Unconjugated DM1

1384.0
(ng/mL)*h (Mean)
Standard Deviation: None

Phase 1 Dose Escalation (Cohort 6)

Free Sulfhydryl DM1

37.4
(ng/mL)*h (Mean)
Standard Deviation: 12.335

Plasma PK

2323.0
(ng/mL)*h (Mean)
Standard Deviation: 2267.7

Total DM1

1996.0
(ng/mL)*h (Mean)
Standard Deviation: 489.18

Total Peptide

3147.0
(ng/mL)*h (Mean)
Standard Deviation: 1211.0

Unconjugated DM1

1776.0
(ng/mL)*h (Mean)
Standard Deviation: 660.31

Phase 1 Dose Escalation (Cohort 7)

Free Sulfhydryl DM1

131.4
(ng/mL)*h (Mean)
Standard Deviation: 109.56

Plasma PK

2357.0
(ng/mL)*h (Mean)
Standard Deviation: 798.60

Total DM1

3980.0
(ng/mL)*h (Mean)
Standard Deviation: 1335.4

Total Peptide

4402.0
(ng/mL)*h (Mean)
Standard Deviation: 938.17

Unconjugated DM1

4316.0
(ng/mL)*h (Mean)
Standard Deviation: None

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

Free Sulfhydryl DM1

32.06
(ng/mL)*h (Mean)
Standard Deviation: 20.012

Plasma PK

867.7
(ng/mL)*h (Mean)
Standard Deviation: 329.9

Total DM1

2153.0
(ng/mL)*h (Mean)
Standard Deviation: 526.06

Total Peptide

2988.0
(ng/mL)*h (Mean)
Standard Deviation: 847.68

Unconjugated DM1

1765.0
(ng/mL)*h (Mean)
Standard Deviation: 415.63

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

Free Sulfhydryl DM1

62.05
(ng/mL)*h (Mean)
Standard Deviation: 35.792

Plasma PK

1667.0
(ng/mL)*h (Mean)
Standard Deviation: 1638.6

Total DM1

3328.0
(ng/mL)*h (Mean)
Standard Deviation: 1881.7

Total Peptide

4203.0
(ng/mL)*h (Mean)
Standard Deviation: 1837.2

Unconjugated DM1

2384.0
(ng/mL)*h (Mean)
Standard Deviation: 522.17

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

Free Sulfhydryl DM1

69.48
(ng/mL)*h (Mean)
Standard Deviation: 58.396

Plasma PK

1463.0
(ng/mL)*h (Mean)
Standard Deviation: 1141.8

Total DM1

3419.0
(ng/mL)*h (Mean)
Standard Deviation: 1277.9

Total Peptide

4558.0
(ng/mL)*h (Mean)
Standard Deviation: 1474.5

Unconjugated DM1

2781.0
(ng/mL)*h (Mean)
Standard Deviation: 1057.1

Total

89
Participants

Age, Continuous

65
Years (Median)
Full Range: 27.0 to 82.0

Ethnicity

Race/Ethnicity, Customized

Sex: Female, Male

Phase 1 Dose Escalation

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

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

Phase 2a Dose Expansion (PNET Cohort)

Phase 2a Dose Expansion (SCLC Cohort)