Carcinoma, Small Cell Lung, Neuroendocrine Carcinoma, Neuroendocrine Tumors
Conditions
Keywords
SCLC small cell lung cancer, pancreatic neuroendocrine NET, GI neuroendocrine NET
Brief summary
Protocol PEN-221-001 is an open-label, multicenter Phase 1/2a study evaluating PEN-221 in patients with SSTR2 expressing advanced gastroenteropancreatic (GEP) or lung or thymus or other neuroendocrine tumors or small cell lung cancer or large cell neuroendocrine carcinoma of the lung.
Detailed description
Protocol PEN-221-001 will first enroll patients into a dose escalation phase, where a Bayesian logistic regression model, guided by the escalation with overdose control principle and overseen by a safety review committee, will be used to make dose recommendations and estimate the maximum tolerated dose (MTD). Once the MTD has been confirmed, remaining patients will be enrolled into a full expansion phase to assess PEN-221 efficacy in patients with gastrointestinal mid-gut neuroendocrine tumors or pancreatic neuroendocrine tumors or small cell lung cancer.
Interventions
DRUGPEN-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.
Sponsors
Tarveda Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
United Kingdom, United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1 Dose Escalation (Cohort 1) 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). | 2 |
| Phase 1 Dose Escalation (Cohort 2) 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). | 3 |
| Phase 1 Dose Escalation (Cohort 3) 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). | 3 |
| Phase 1 Dose Escalation (Cohort 4) 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). | 3 |
| Phase 1 Dose Escalation (Cohort 5) 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). | 3 |
| Phase 1 Dose Escalation (Cohort 6) 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). | 6 |
| Phase 1 Dose Escalation (Cohort 7) 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). | 3 |
| Phase 2a Dose Expansion (GI Mid-gut NET Cohort) 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). | 32 |
| Phase 2a Dose Expansion (PNET Cohort) Participants were enrolled with advanced or metastatic, well-differentiated, low or intermediate grade pancreatic Neuroendocrine Tumor (PNET). | 15 |
| Phase 2a Dose Expansion (SCLC Cohort) Participants were enrolled with advanced or metastatic Small Cell Lung Cancer (SCLC). | 19 |
| Total | 89 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Phase 1 Dose Escalation | Death | 2 | 1 | 3 | 1 | 2 | 3 | 3 | 0 | 0 | 0 |
| Phase 1 Dose Escalation | Informed Consent Withdrawn | 0 | 1 | 0 | 1 | 1 | 1 | 0 | 0 | 0 | 0 |
| Phase 1 Dose Escalation | Study Discontinued at Site | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Phase 2a Dose Expansion | Change(s) to patient's condition | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Phase 2a Dose Expansion | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 4 | 8 | 10 |
| Phase 2a Dose Expansion | Informed Consent Withdrawn | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 11 | 4 | 2 |
| Phase 2a Dose Expansion | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1 | 0 |
| Phase 2a Dose Expansion | Physician Decision | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Phase 2a Dose Expansion (SCLC Cohort) | Phase 2a Dose Expansion (PNET Cohort) | Phase 2a Dose Expansion (GI Mid-gut NET Cohort) | Phase 1 Dose Escalation (Cohort 7) | Phase 1 Dose Escalation (Cohort 6) | Phase 1 Dose Escalation (Cohort 5) | Phase 1 Dose Escalation (Cohort 4) | Phase 1 Dose Escalation (Cohort 3) | Phase 1 Dose Escalation (Cohort 1) | Phase 1 Dose Escalation (Cohort 2) |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 65 Years | 65.0 Years | 58.0 Years | 66.0 Years | 52.0 Years | 63.5 Years | 67.0 Years | 46.0 Years | 67.0 Years | 48.5 Years | 57.0 Years |
| Ethnicity Hispanic or Latino | 6 Participants | 0 Participants | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Ethnicity Not collected | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity Not Hispanic or Latino | 81 Participants | 19 Participants | 13 Participants | 30 Participants | 2 Participants | 5 Participants | 2 Participants | 3 Participants | 3 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black | 6 Participants | 0 Participants | 2 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Caucasian/White | 76 Participants | 19 Participants | 10 Participants | 27 Participants | 3 Participants | 6 Participants | 1 Participants | 3 Participants | 3 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native American or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not collected | 2 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 43 Participants | 10 Participants | 8 Participants | 15 Participants | 2 Participants | 3 Participants | 2 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 46 Participants | 9 Participants | 7 Participants | 17 Participants | 1 Participants | 3 Participants | 1 Participants | 2 Participants | 1 Participants | 2 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 2 | 1 / 3 | 3 / 3 | 1 / 3 | 2 / 3 | 3 / 6 | 3 / 3 | 4 / 12 | 8 / 34 | 10 / 20 |
| other Total, other adverse events | 2 / 2 | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 6 / 6 | 3 / 3 | 12 / 12 | 32 / 34 | 20 / 20 |
| serious Total, serious adverse events | 2 / 2 | 1 / 3 | 3 / 3 | 0 / 3 | 0 / 3 | 2 / 6 | 2 / 3 | 3 / 12 | 7 / 34 | 15 / 20 |
Outcome results
Primary
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.
Time frame: Up to 4 weeks in the first cohort and up to 3 weeks for each subsequent cohort
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Phase 1: Maximum Tolerated Dose of PEN-221 and Recommended Phase 2a Dose (RP2D) | 18.0 mg |
Primary
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.
Time frame: Up to 4 weeks in the first cohort and up to 3 weeks for each subsequent cohort
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Phase 1: Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) | 0 participants |
| Phase 1 Dose Escalation (Cohort 2) | Phase 1: Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) | 0 participants |
| Phase 1 Dose Escalation (Cohort 3) | Phase 1: Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) | 0 participants |
| Phase 1 Dose Escalation (Cohort 4) | Phase 1: Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) | 0 participants |
| Phase 1 Dose Escalation (Cohort 5) | Phase 1: Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) | 0 participants |
| Phase 1 Dose Escalation (Cohort 6) | Phase 1: Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) | 0 participants |
| Phase 1 Dose Escalation (Cohort 7) | Phase 1: Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) | 2 participants |
Primary
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.
Time frame: From the date of first treatment through the date of first documented progression, assessed up to data cut-off (31 Jul 2020).
Population: 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.
Primary
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.
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).
Population: Outcome measured by cancer type. SCLC participants who received any amount of study drug and had at least 1 post-baseline efficacy assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | 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. | Progressive Disease | 9 Participants |
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | 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. | Complete Response | 0 Participants |
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | 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. | Partial Response | 0 Participants |
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | 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. | Stable Disease | 3 Participants |
Primary
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.
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).
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Phase 2a: Percentage of Gastrointestinal Mid-gut NETs and Pancreatic NETs Participants Who Achieved Clinical Benefit as Determined by RECIST 1.1 | 88.5 percentage of participants |
| Phase 1 Dose Escalation (Cohort 2) | Phase 2a: Percentage of Gastrointestinal Mid-gut NETs and Pancreatic NETs Participants Who Achieved Clinical Benefit as Determined by RECIST 1.1 | 50 percentage of participants |
Secondary
Anti-PEN-221 Antibodies (ADA)
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.
Population: 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 | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Anti-PEN-221 Antibodies (ADA) | ADA Positive On-Study Treatment | 0 Participants |
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Anti-PEN-221 Antibodies (ADA) | ADA Negative On-Study Treatment | 2 Participants |
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Anti-PEN-221 Antibodies (ADA) | Persistent Positive | 0 Participants |
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Anti-PEN-221 Antibodies (ADA) | Baseline ADA Positive | 0 Participants |
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Anti-PEN-221 Antibodies (ADA) | Other Positive | 0 Participants |
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Anti-PEN-221 Antibodies (ADA) | Baseline ADA Negative | 2 Participants |
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Anti-PEN-221 Antibodies (ADA) | Only Last Sample Positive | 0 Participants |
| Phase 1 Dose Escalation (Cohort 2) | Anti-PEN-221 Antibodies (ADA) | Other Positive | 0 Participants |
| Phase 1 Dose Escalation (Cohort 2) | Anti-PEN-221 Antibodies (ADA) | Only Last Sample Positive | 0 Participants |
| Phase 1 Dose Escalation (Cohort 2) | Anti-PEN-221 Antibodies (ADA) | Persistent Positive | 0 Participants |
| Phase 1 Dose Escalation (Cohort 2) | Anti-PEN-221 Antibodies (ADA) | Baseline ADA Negative | 3 Participants |
| Phase 1 Dose Escalation (Cohort 2) | Anti-PEN-221 Antibodies (ADA) | ADA Negative On-Study Treatment | 3 Participants |
| Phase 1 Dose Escalation (Cohort 2) | Anti-PEN-221 Antibodies (ADA) | ADA Positive On-Study Treatment | 0 Participants |
| Phase 1 Dose Escalation (Cohort 2) | Anti-PEN-221 Antibodies (ADA) | Baseline ADA Positive | 0 Participants |
| Phase 1 Dose Escalation (Cohort 3) | Anti-PEN-221 Antibodies (ADA) | Other Positive | 0 Participants |
| Phase 1 Dose Escalation (Cohort 3) | Anti-PEN-221 Antibodies (ADA) | Baseline ADA Positive | 0 Participants |
| Phase 1 Dose Escalation (Cohort 3) | Anti-PEN-221 Antibodies (ADA) | ADA Negative On-Study Treatment | 3 Participants |
| Phase 1 Dose Escalation (Cohort 3) | Anti-PEN-221 Antibodies (ADA) | Persistent Positive | 0 Participants |
| Phase 1 Dose Escalation (Cohort 3) | Anti-PEN-221 Antibodies (ADA) | Only Last Sample Positive | 0 Participants |
| Phase 1 Dose Escalation (Cohort 3) | Anti-PEN-221 Antibodies (ADA) | ADA Positive On-Study Treatment | 0 Participants |
| Phase 1 Dose Escalation (Cohort 3) | Anti-PEN-221 Antibodies (ADA) | Baseline ADA Negative | 3 Participants |
| Phase 1 Dose Escalation (Cohort 4) | Anti-PEN-221 Antibodies (ADA) | Other Positive | 1 Participants |
| Phase 1 Dose Escalation (Cohort 4) | Anti-PEN-221 Antibodies (ADA) | Baseline ADA Positive | 0 Participants |
| Phase 1 Dose Escalation (Cohort 4) | Anti-PEN-221 Antibodies (ADA) | Baseline ADA Negative | 3 Participants |
| Phase 1 Dose Escalation (Cohort 4) | Anti-PEN-221 Antibodies (ADA) | ADA Positive On-Study Treatment | 1 Participants |
| Phase 1 Dose Escalation (Cohort 4) | Anti-PEN-221 Antibodies (ADA) | Persistent Positive | 0 Participants |
| Phase 1 Dose Escalation (Cohort 4) | Anti-PEN-221 Antibodies (ADA) | Only Last Sample Positive | 0 Participants |
| Phase 1 Dose Escalation (Cohort 4) | Anti-PEN-221 Antibodies (ADA) | ADA Negative On-Study Treatment | 2 Participants |
| Phase 1 Dose Escalation (Cohort 5) | Anti-PEN-221 Antibodies (ADA) | Other Positive | 0 Participants |
| Phase 1 Dose Escalation (Cohort 5) | Anti-PEN-221 Antibodies (ADA) | ADA Negative On-Study Treatment | 3 Participants |
| Phase 1 Dose Escalation (Cohort 5) | Anti-PEN-221 Antibodies (ADA) | ADA Positive On-Study Treatment | 0 Participants |
| Phase 1 Dose Escalation (Cohort 5) | Anti-PEN-221 Antibodies (ADA) | Only Last Sample Positive | 0 Participants |
| Phase 1 Dose Escalation (Cohort 5) | Anti-PEN-221 Antibodies (ADA) | Baseline ADA Positive | 0 Participants |
| Phase 1 Dose Escalation (Cohort 5) | Anti-PEN-221 Antibodies (ADA) | Baseline ADA Negative | 3 Participants |
| Phase 1 Dose Escalation (Cohort 5) | Anti-PEN-221 Antibodies (ADA) | Persistent Positive | 0 Participants |
| Phase 1 Dose Escalation (Cohort 6) | Anti-PEN-221 Antibodies (ADA) | Other Positive | 0 Participants |
| Phase 1 Dose Escalation (Cohort 6) | Anti-PEN-221 Antibodies (ADA) | Baseline ADA Negative | 6 Participants |
| Phase 1 Dose Escalation (Cohort 6) | Anti-PEN-221 Antibodies (ADA) | Persistent Positive | 0 Participants |
| Phase 1 Dose Escalation (Cohort 6) | Anti-PEN-221 Antibodies (ADA) | ADA Negative On-Study Treatment | 6 Participants |
| Phase 1 Dose Escalation (Cohort 6) | Anti-PEN-221 Antibodies (ADA) | Baseline ADA Positive | 0 Participants |
| Phase 1 Dose Escalation (Cohort 6) | Anti-PEN-221 Antibodies (ADA) | Only Last Sample Positive | 0 Participants |
| Phase 1 Dose Escalation (Cohort 6) | Anti-PEN-221 Antibodies (ADA) | ADA Positive On-Study Treatment | 0 Participants |
| Phase 1 Dose Escalation (Cohort 7) | Anti-PEN-221 Antibodies (ADA) | Only Last Sample Positive | 0 Participants |
| Phase 1 Dose Escalation (Cohort 7) | Anti-PEN-221 Antibodies (ADA) | Other Positive | 0 Participants |
| Phase 1 Dose Escalation (Cohort 7) | Anti-PEN-221 Antibodies (ADA) | Baseline ADA Negative | 2 Participants |
| Phase 1 Dose Escalation (Cohort 7) | Anti-PEN-221 Antibodies (ADA) | ADA Negative On-Study Treatment | 2 Participants |
| Phase 1 Dose Escalation (Cohort 7) | Anti-PEN-221 Antibodies (ADA) | Persistent Positive | 0 Participants |
| Phase 1 Dose Escalation (Cohort 7) | Anti-PEN-221 Antibodies (ADA) | ADA Positive On-Study Treatment | 0 Participants |
| Phase 1 Dose Escalation (Cohort 7) | Anti-PEN-221 Antibodies (ADA) | Baseline ADA Positive | 0 Participants |
| Phase 2a Dose Expansion (<8.8 mg/m^2) | Anti-PEN-221 Antibodies (ADA) | ADA Positive On-Study Treatment | 0 Participants |
| Phase 2a Dose Expansion (<8.8 mg/m^2) | Anti-PEN-221 Antibodies (ADA) | ADA Negative On-Study Treatment | 11 Participants |
| Phase 2a Dose Expansion (<8.8 mg/m^2) | Anti-PEN-221 Antibodies (ADA) | Persistent Positive | 0 Participants |
| Phase 2a Dose Expansion (<8.8 mg/m^2) | Anti-PEN-221 Antibodies (ADA) | Only Last Sample Positive | 0 Participants |
| Phase 2a Dose Expansion (<8.8 mg/m^2) | Anti-PEN-221 Antibodies (ADA) | Baseline ADA Negative | 11 Participants |
| Phase 2a Dose Expansion (<8.8 mg/m^2) | Anti-PEN-221 Antibodies (ADA) | Other Positive | 0 Participants |
| Phase 2a Dose Expansion (<8.8 mg/m^2) | Anti-PEN-221 Antibodies (ADA) | Baseline ADA Positive | 0 Participants |
| Phase 2a Dose Expansion (8.8 mg/m^2) | Anti-PEN-221 Antibodies (ADA) | ADA Negative On-Study Treatment | 19 Participants |
| Phase 2a Dose Expansion (8.8 mg/m^2) | Anti-PEN-221 Antibodies (ADA) | Other Positive | 2 Participants |
| Phase 2a Dose Expansion (8.8 mg/m^2) | Anti-PEN-221 Antibodies (ADA) | Baseline ADA Positive | 2 Participants |
| Phase 2a Dose Expansion (8.8 mg/m^2) | Anti-PEN-221 Antibodies (ADA) | ADA Positive On-Study Treatment | 3 Participants |
| Phase 2a Dose Expansion (8.8 mg/m^2) | Anti-PEN-221 Antibodies (ADA) | Persistent Positive | 1 Participants |
| Phase 2a Dose Expansion (8.8 mg/m^2) | Anti-PEN-221 Antibodies (ADA) | Baseline ADA Negative | 20 Participants |
| Phase 2a Dose Expansion (8.8 mg/m^2) | Anti-PEN-221 Antibodies (ADA) | Only Last Sample Positive | 0 Participants |
| Phase 2a Dose Expansion (>8.8 mg/m^2) | Anti-PEN-221 Antibodies (ADA) | ADA Negative On-Study Treatment | 13 Participants |
| Phase 2a Dose Expansion (>8.8 mg/m^2) | Anti-PEN-221 Antibodies (ADA) | ADA Positive On-Study Treatment | 2 Participants |
| Phase 2a Dose Expansion (>8.8 mg/m^2) | Anti-PEN-221 Antibodies (ADA) | Persistent Positive | 1 Participants |
| Phase 2a Dose Expansion (>8.8 mg/m^2) | Anti-PEN-221 Antibodies (ADA) | Other Positive | 0 Participants |
| Phase 2a Dose Expansion (>8.8 mg/m^2) | Anti-PEN-221 Antibodies (ADA) | Baseline ADA Negative | 15 Participants |
| Phase 2a Dose Expansion (>8.8 mg/m^2) | Anti-PEN-221 Antibodies (ADA) | Only Last Sample Positive | 1 Participants |
| Phase 2a Dose Expansion (>8.8 mg/m^2) | Anti-PEN-221 Antibodies (ADA) | Baseline ADA Positive | 0 Participants |
Secondary
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.
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.
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Plasma PK | 38.34 (ng/mL)*h | Standard Deviation 15.88 |
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Total Peptide | 87.20 (ng/mL)*h | Standard Deviation 30.636 |
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Unconjugated DM1 | 54.18 (ng/mL)*h | Standard Deviation 15.81 |
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Total DM1 | 65.59 (ng/mL)*h | Standard Deviation 16.501 |
| Phase 1 Dose Escalation (Cohort 2) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Total Peptide | 189.2 (ng/mL)*h | Standard Deviation 64.194 |
| Phase 1 Dose Escalation (Cohort 2) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Unconjugated DM1 | 163.9 (ng/mL)*h | Standard Deviation 86.594 |
| Phase 1 Dose Escalation (Cohort 2) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Total DM1 | 179.7 (ng/mL)*h | Standard Deviation 97.376 |
| Phase 1 Dose Escalation (Cohort 2) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Plasma PK | 89.95 (ng/mL)*h | Standard Deviation 33.64 |
| Phase 1 Dose Escalation (Cohort 3) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Total DM1 | 454.8 (ng/mL)*h | Standard Deviation 136.89 |
| Phase 1 Dose Escalation (Cohort 3) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Unconjugated DM1 | 444.5 (ng/mL)*h | Standard Deviation 100.94 |
| Phase 1 Dose Escalation (Cohort 3) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Plasma PK | 192.40 (ng/mL)*h | Standard Deviation 48.66 |
| Phase 1 Dose Escalation (Cohort 3) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Total Peptide | 548.0 (ng/mL)*h | Standard Deviation 156.34 |
| Phase 1 Dose Escalation (Cohort 4) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Plasma PK | 643.60 (ng/mL)*h | Standard Deviation 224.39 |
| Phase 1 Dose Escalation (Cohort 4) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Free Sulfhydryl DM1 | 16.86 (ng/mL)*h | — |
| Phase 1 Dose Escalation (Cohort 4) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Total Peptide | 1080 (ng/mL)*h | Standard Deviation 197.69 |
| Phase 1 Dose Escalation (Cohort 4) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Total DM1 | 981.1 (ng/mL)*h | Standard Deviation 74.477 |
| Phase 1 Dose Escalation (Cohort 4) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Unconjugated DM1 | 720.6 (ng/mL)*h | Standard Deviation 86.063 |
| Phase 1 Dose Escalation (Cohort 5) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Total Peptide | 1730 (ng/mL)*h | Standard Deviation 475.69 |
| Phase 1 Dose Escalation (Cohort 5) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Unconjugated DM1 | 1384 (ng/mL)*h | — |
| Phase 1 Dose Escalation (Cohort 5) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Plasma PK | 1119 (ng/mL)*h | Standard Deviation 330.86 |
| Phase 1 Dose Escalation (Cohort 5) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Total DM1 | 1780 (ng/mL)*h | Standard Deviation 652.3 |
| Phase 1 Dose Escalation (Cohort 5) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Free Sulfhydryl DM1 | 17.63 (ng/mL)*h | Standard Deviation 7.6946 |
| Phase 1 Dose Escalation (Cohort 6) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Total Peptide | 3147 (ng/mL)*h | Standard Deviation 1211 |
| Phase 1 Dose Escalation (Cohort 6) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Unconjugated DM1 | 1776 (ng/mL)*h | Standard Deviation 660.31 |
| Phase 1 Dose Escalation (Cohort 6) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Total DM1 | 1996 (ng/mL)*h | Standard Deviation 489.18 |
| Phase 1 Dose Escalation (Cohort 6) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Free Sulfhydryl DM1 | 37.40 (ng/mL)*h | Standard Deviation 12.335 |
| Phase 1 Dose Escalation (Cohort 6) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Plasma PK | 2323 (ng/mL)*h | Standard Deviation 2267.7 |
| Phase 1 Dose Escalation (Cohort 7) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Unconjugated DM1 | 4316 (ng/mL)*h | — |
| Phase 1 Dose Escalation (Cohort 7) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Plasma PK | 2357 (ng/mL)*h | Standard Deviation 798.6 |
| Phase 1 Dose Escalation (Cohort 7) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Total Peptide | 4402 (ng/mL)*h | Standard Deviation 938.17 |
| Phase 1 Dose Escalation (Cohort 7) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Total DM1 | 3980 (ng/mL)*h | Standard Deviation 1335.4 |
| Phase 1 Dose Escalation (Cohort 7) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Free Sulfhydryl DM1 | 131.4 (ng/mL)*h | Standard Deviation 109.56 |
| Phase 2a Dose Expansion (<8.8 mg/m^2) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Plasma PK | 867.7 (ng/mL)*h | Standard Deviation 329.9 |
| Phase 2a Dose Expansion (<8.8 mg/m^2) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Total Peptide | 2988 (ng/mL)*h | Standard Deviation 847.68 |
| Phase 2a Dose Expansion (<8.8 mg/m^2) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Free Sulfhydryl DM1 | 32.06 (ng/mL)*h | Standard Deviation 20.012 |
| Phase 2a Dose Expansion (<8.8 mg/m^2) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Unconjugated DM1 | 1765 (ng/mL)*h | Standard Deviation 415.63 |
| Phase 2a Dose Expansion (<8.8 mg/m^2) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Total DM1 | 2153 (ng/mL)*h | Standard Deviation 526.06 |
| Phase 2a Dose Expansion (8.8 mg/m^2) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Total Peptide | 4203 (ng/mL)*h | Standard Deviation 1837.2 |
| Phase 2a Dose Expansion (8.8 mg/m^2) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Unconjugated DM1 | 2384 (ng/mL)*h | Standard Deviation 522.17 |
| Phase 2a Dose Expansion (8.8 mg/m^2) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Plasma PK | 1667 (ng/mL)*h | Standard Deviation 1638.6 |
| Phase 2a Dose Expansion (8.8 mg/m^2) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Free Sulfhydryl DM1 | 62.05 (ng/mL)*h | Standard Deviation 35.792 |
| Phase 2a Dose Expansion (8.8 mg/m^2) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Total DM1 | 3328 (ng/mL)*h | Standard Deviation 1881.7 |
| Phase 2a Dose Expansion (>8.8 mg/m^2) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Total DM1 | 3419 (ng/mL)*h | Standard Deviation 1277.9 |
| Phase 2a Dose Expansion (>8.8 mg/m^2) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Total Peptide | 4558 (ng/mL)*h | Standard Deviation 1474.5 |
| Phase 2a Dose Expansion (>8.8 mg/m^2) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Unconjugated DM1 | 2781 (ng/mL)*h | Standard Deviation 1057.1 |
| Phase 2a Dose Expansion (>8.8 mg/m^2) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Plasma PK | 1463 (ng/mL)*h | Standard Deviation 1141.8 |
| Phase 2a Dose Expansion (>8.8 mg/m^2) | Area Under the Curve (AUC) of PEN-221, DM1, and Peptide | Free Sulfhydryl DM1 | 69.48 (ng/mL)*h | Standard Deviation 58.396 |
Secondary
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.
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.
Population: 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 | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Plasma PK | 1.46 hours |
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Total Peptide | 5.33 hours |
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Unconjugated DM1 | 5.77 hours |
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Total DM1 | 4.78 hours |
| Phase 1 Dose Escalation (Cohort 2) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Total Peptide | 4.61 hours |
| Phase 1 Dose Escalation (Cohort 2) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Unconjugated DM1 | 7.80 hours |
| Phase 1 Dose Escalation (Cohort 2) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Total DM1 | 4.48 hours |
| Phase 1 Dose Escalation (Cohort 2) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Plasma PK | 1.41 hours |
| Phase 1 Dose Escalation (Cohort 3) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Total DM1 | 5.87 hours |
| Phase 1 Dose Escalation (Cohort 3) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Unconjugated DM1 | 6.07 hours |
| Phase 1 Dose Escalation (Cohort 3) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Plasma PK | 1.77 hours |
| Phase 1 Dose Escalation (Cohort 3) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Total Peptide | 5.25 hours |
| Phase 1 Dose Escalation (Cohort 4) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Plasma PK | 1.70 hours |
| Phase 1 Dose Escalation (Cohort 4) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Free Sulfhydryl DM1 | 4.57 hours |
| Phase 1 Dose Escalation (Cohort 4) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Total Peptide | 4.33 hours |
| Phase 1 Dose Escalation (Cohort 4) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Total DM1 | 4.43 hours |
| Phase 1 Dose Escalation (Cohort 4) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Unconjugated DM1 | 5.36 hours |
| Phase 1 Dose Escalation (Cohort 5) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Total Peptide | 5.63 hours |
| Phase 1 Dose Escalation (Cohort 5) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Unconjugated DM1 | 8.49 hours |
| Phase 1 Dose Escalation (Cohort 5) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Plasma PK | 1.94 hours |
| Phase 1 Dose Escalation (Cohort 5) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Total DM1 | 5.69 hours |
| Phase 1 Dose Escalation (Cohort 5) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Free Sulfhydryl DM1 | 4.93 hours |
| Phase 1 Dose Escalation (Cohort 6) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Total Peptide | 4.89 hours |
| Phase 1 Dose Escalation (Cohort 6) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Unconjugated DM1 | 6.89 hours |
| Phase 1 Dose Escalation (Cohort 6) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Total DM1 | 5.43 hours |
| Phase 1 Dose Escalation (Cohort 6) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Free Sulfhydryl DM1 | 3.87 hours |
| Phase 1 Dose Escalation (Cohort 6) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Plasma PK | 1.61 hours |
| Phase 1 Dose Escalation (Cohort 7) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Unconjugated DM1 | 8.94 hours |
| Phase 1 Dose Escalation (Cohort 7) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Plasma PK | 3.06 hours |
| Phase 1 Dose Escalation (Cohort 7) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Total Peptide | 7.49 hours |
| Phase 1 Dose Escalation (Cohort 7) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Total DM1 | 6.32 hours |
| Phase 1 Dose Escalation (Cohort 7) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Free Sulfhydryl DM1 | 9.01 hours |
| Phase 2a Dose Expansion (<8.8 mg/m^2) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Plasma PK | 4.259 hours |
| Phase 2a Dose Expansion (<8.8 mg/m^2) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Total Peptide | 27.9 hours |
| Phase 2a Dose Expansion (<8.8 mg/m^2) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Free Sulfhydryl DM1 | 10.1 hours |
| Phase 2a Dose Expansion (<8.8 mg/m^2) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Unconjugated DM1 | 25.9 hours |
| Phase 2a Dose Expansion (<8.8 mg/m^2) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Total DM1 | 25.3 hours |
| Phase 2a Dose Expansion (8.8 mg/m^2) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Total Peptide | 28.7 hours |
| Phase 2a Dose Expansion (8.8 mg/m^2) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Unconjugated DM1 | 24.5 hours |
| Phase 2a Dose Expansion (8.8 mg/m^2) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Plasma PK | 4.180 hours |
| Phase 2a Dose Expansion (8.8 mg/m^2) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Free Sulfhydryl DM1 | 20.9 hours |
| Phase 2a Dose Expansion (8.8 mg/m^2) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Total DM1 | 24.2 hours |
| Phase 2a Dose Expansion (>8.8 mg/m^2) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Total DM1 | 25.5 hours |
| Phase 2a Dose Expansion (>8.8 mg/m^2) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Total Peptide | 30.9 hours |
| Phase 2a Dose Expansion (>8.8 mg/m^2) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Unconjugated DM1 | 25.0 hours |
| Phase 2a Dose Expansion (>8.8 mg/m^2) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Plasma PK | 4.526 hours |
| Phase 2a Dose Expansion (>8.8 mg/m^2) | Half-life (t1/2) of PEN-221, DM1, and Peptide | Free Sulfhydryl DM1 | 14.3 hours |
Secondary
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.
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.
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Unconjugated DM1 | 4.758 ng/mL | Standard Deviation 0.7883 |
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Total Peptide | 16.38 ng/mL | Standard Deviation 3.7112 |
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Free Sulfhydryl DM1 | 0.09568 ng/mL | Standard Deviation 0.034873 |
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Plasma PK | 18.96 ng/mL | Standard Deviation 9.56 |
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Total DM1 | 11.11 ng/mL | Standard Deviation 2.7669 |
| Phase 1 Dose Escalation (Cohort 2) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Total DM1 | 29.88 ng/mL | Standard Deviation 14.304 |
| Phase 1 Dose Escalation (Cohort 2) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Free Sulfhydryl DM1 | 0.2441 ng/mL | Standard Deviation 0.17198 |
| Phase 1 Dose Escalation (Cohort 2) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Unconjugated DM1 | 13.79 ng/mL | Standard Deviation 6.1768 |
| Phase 1 Dose Escalation (Cohort 2) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Plasma PK | 50.20 ng/mL | Standard Deviation 24.3 |
| Phase 1 Dose Escalation (Cohort 2) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Total Peptide | 40.03 ng/mL | Standard Deviation 15.807 |
| Phase 1 Dose Escalation (Cohort 3) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Total DM1 | 94.01 ng/mL | Standard Deviation 2.7951 |
| Phase 1 Dose Escalation (Cohort 3) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Total Peptide | 129.8 ng/mL | Standard Deviation 5.7813 |
| Phase 1 Dose Escalation (Cohort 3) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Plasma PK | 150.40 ng/mL | Standard Deviation 51.99 |
| Phase 1 Dose Escalation (Cohort 3) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Unconjugated DM1 | 42.23 ng/mL | Standard Deviation 12.295 |
| Phase 1 Dose Escalation (Cohort 3) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Free Sulfhydryl DM1 | 0.6778 ng/mL | Standard Deviation 0.02297 |
| Phase 1 Dose Escalation (Cohort 4) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Total DM1 | 198.6 ng/mL | Standard Deviation 37.848 |
| Phase 1 Dose Escalation (Cohort 4) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Plasma PK | 359.70 ng/mL | Standard Deviation 92.42 |
| Phase 1 Dose Escalation (Cohort 4) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Total Peptide | 261.4 ng/mL | Standard Deviation 49.269 |
| Phase 1 Dose Escalation (Cohort 4) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Unconjugated DM1 | 78.63 ng/mL | Standard Deviation 6.21 |
| Phase 1 Dose Escalation (Cohort 4) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Free Sulfhydryl DM1 | 1.975 ng/mL | Standard Deviation 0.46462 |
| Phase 1 Dose Escalation (Cohort 5) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Unconjugated DM1 | 112.0 ng/mL | Standard Deviation 22.186 |
| Phase 1 Dose Escalation (Cohort 5) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Free Sulfhydryl DM1 | 2.739 ng/mL | Standard Deviation 0.90804 |
| Phase 1 Dose Escalation (Cohort 5) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Plasma PK | 592.50 ng/mL | Standard Deviation 149.66 |
| Phase 1 Dose Escalation (Cohort 5) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Total DM1 | 340.4 ng/mL | Standard Deviation 87.602 |
| Phase 1 Dose Escalation (Cohort 5) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Total Peptide | 420.2 ng/mL | Standard Deviation 69.703 |
| Phase 1 Dose Escalation (Cohort 6) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Unconjugated DM1 | 218.3 ng/mL | Standard Deviation 73.574 |
| Phase 1 Dose Escalation (Cohort 6) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Total Peptide | 1925 ng/mL | Standard Deviation 3246.8 |
| Phase 1 Dose Escalation (Cohort 6) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Plasma PK | 2802 ng/mL | Standard Deviation 5068.6 |
| Phase 1 Dose Escalation (Cohort 6) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Total DM1 | 1327 ng/mL | Standard Deviation 2157.2 |
| Phase 1 Dose Escalation (Cohort 6) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Free Sulfhydryl DM1 | 14.12 ng/mL | Standard Deviation 18.151 |
| Phase 1 Dose Escalation (Cohort 7) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Unconjugated DM1 | 266.3 ng/mL | Standard Deviation 46.561 |
| Phase 1 Dose Escalation (Cohort 7) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Total DM1 | 691.3 ng/mL | Standard Deviation 165.22 |
| Phase 1 Dose Escalation (Cohort 7) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Plasma PK | 1324 ng/mL | Standard Deviation 519.94 |
| Phase 1 Dose Escalation (Cohort 7) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Free Sulfhydryl DM1 | 11.04 ng/mL | Standard Deviation 5.011 |
| Phase 1 Dose Escalation (Cohort 7) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Total Peptide | 926.9 ng/mL | Standard Deviation 279.02 |
| Phase 2a Dose Expansion (<8.8 mg/m^2) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Total DM1 | 261.2 ng/mL | Standard Deviation 70.449 |
| Phase 2a Dose Expansion (<8.8 mg/m^2) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Unconjugated DM1 | 101.0 ng/mL | Standard Deviation 26.56 |
| Phase 2a Dose Expansion (<8.8 mg/m^2) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Total Peptide | 350.0 ng/mL | Standard Deviation 102.28 |
| Phase 2a Dose Expansion (<8.8 mg/m^2) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Free Sulfhydryl DM1 | 2.174 ng/mL | Standard Deviation 0.82698 |
| Phase 2a Dose Expansion (<8.8 mg/m^2) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Plasma PK | 451.4 ng/mL | Standard Deviation 174.14 |
| Phase 2a Dose Expansion (8.8 mg/m^2) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Total DM1 | 762.3 ng/mL | Standard Deviation 1388 |
| Phase 2a Dose Expansion (8.8 mg/m^2) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Total Peptide | 1041 ng/mL | Standard Deviation 2061 |
| Phase 2a Dose Expansion (8.8 mg/m^2) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Free Sulfhydryl DM1 | 5.214 ng/mL | Standard Deviation 8.2827 |
| Phase 2a Dose Expansion (8.8 mg/m^2) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Unconjugated DM1 | 164.5 ng/mL | Standard Deviation 74.435 |
| Phase 2a Dose Expansion (8.8 mg/m^2) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Plasma PK | 1533 ng/mL | Standard Deviation 3356.9 |
| Phase 2a Dose Expansion (>8.8 mg/m^2) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Unconjugated DM1 | 146.3 ng/mL | Standard Deviation 74.755 |
| Phase 2a Dose Expansion (>8.8 mg/m^2) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Plasma PK | 1064 ng/mL | Standard Deviation 2298.7 |
| Phase 2a Dose Expansion (>8.8 mg/m^2) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Free Sulfhydryl DM1 | 6.225 ng/mL | Standard Deviation 12.276 |
| Phase 2a Dose Expansion (>8.8 mg/m^2) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Total Peptide | 831.5 ng/mL | Standard Deviation 1721 |
| Phase 2a Dose Expansion (>8.8 mg/m^2) | Maximum Concentration (Cmax) of PEN-221, DM1, and Peptide | Total DM1 | 505.9 ng/mL | Standard Deviation 734.05 |
Secondary
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.
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).
Population: 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 | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | TEAEs leading to Death | 1 Participants |
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Dose Limiting Toxicity | 0 Participants |
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Treatment Related TEAEs | 0 Participants |
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Serious TEAEs | 2 Participants |
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | TEAEs leading to Discontinuation of Study Drug | 1 Participants |
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Any TEAE | 2 Participants |
| Phase 1 Dose Escalation (Cohort 2) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Serious TEAEs | 1 Participants |
| Phase 1 Dose Escalation (Cohort 2) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Dose Limiting Toxicity | 0 Participants |
| Phase 1 Dose Escalation (Cohort 2) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | TEAEs leading to Death | 0 Participants |
| Phase 1 Dose Escalation (Cohort 2) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Any TEAE | 3 Participants |
| Phase 1 Dose Escalation (Cohort 2) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | TEAEs leading to Discontinuation of Study Drug | 0 Participants |
| Phase 1 Dose Escalation (Cohort 2) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Treatment Related TEAEs | 3 Participants |
| Phase 1 Dose Escalation (Cohort 3) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Any TEAE | 3 Participants |
| Phase 1 Dose Escalation (Cohort 3) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Dose Limiting Toxicity | 0 Participants |
| Phase 1 Dose Escalation (Cohort 3) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | TEAEs leading to Death | 1 Participants |
| Phase 1 Dose Escalation (Cohort 3) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Treatment Related TEAEs | 3 Participants |
| Phase 1 Dose Escalation (Cohort 3) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Serious TEAEs | 3 Participants |
| Phase 1 Dose Escalation (Cohort 3) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | TEAEs leading to Discontinuation of Study Drug | 2 Participants |
| Phase 1 Dose Escalation (Cohort 4) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | TEAEs leading to Discontinuation of Study Drug | 0 Participants |
| Phase 1 Dose Escalation (Cohort 4) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Any TEAE | 3 Participants |
| Phase 1 Dose Escalation (Cohort 4) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | TEAEs leading to Death | 0 Participants |
| Phase 1 Dose Escalation (Cohort 4) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Serious TEAEs | 0 Participants |
| Phase 1 Dose Escalation (Cohort 4) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Treatment Related TEAEs | 3 Participants |
| Phase 1 Dose Escalation (Cohort 4) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Dose Limiting Toxicity | 0 Participants |
| Phase 1 Dose Escalation (Cohort 5) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Dose Limiting Toxicity | 0 Participants |
| Phase 1 Dose Escalation (Cohort 5) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Treatment Related TEAEs | 3 Participants |
| Phase 1 Dose Escalation (Cohort 5) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Any TEAE | 3 Participants |
| Phase 1 Dose Escalation (Cohort 5) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Serious TEAEs | 0 Participants |
| Phase 1 Dose Escalation (Cohort 5) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | TEAEs leading to Discontinuation of Study Drug | 0 Participants |
| Phase 1 Dose Escalation (Cohort 5) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | TEAEs leading to Death | 0 Participants |
| Phase 1 Dose Escalation (Cohort 6) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Treatment Related TEAEs | 6 Participants |
| Phase 1 Dose Escalation (Cohort 6) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | TEAEs leading to Death | 0 Participants |
| Phase 1 Dose Escalation (Cohort 6) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Any TEAE | 6 Participants |
| Phase 1 Dose Escalation (Cohort 6) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | TEAEs leading to Discontinuation of Study Drug | 0 Participants |
| Phase 1 Dose Escalation (Cohort 6) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Dose Limiting Toxicity | 0 Participants |
| Phase 1 Dose Escalation (Cohort 6) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Serious TEAEs | 2 Participants |
| Phase 1 Dose Escalation (Cohort 7) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Serious TEAEs | 2 Participants |
| Phase 1 Dose Escalation (Cohort 7) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Any TEAE | 3 Participants |
| Phase 1 Dose Escalation (Cohort 7) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Treatment Related TEAEs | 3 Participants |
| Phase 1 Dose Escalation (Cohort 7) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | TEAEs leading to Discontinuation of Study Drug | 2 Participants |
| Phase 1 Dose Escalation (Cohort 7) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Dose Limiting Toxicity | 2 Participants |
| Phase 1 Dose Escalation (Cohort 7) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | TEAEs leading to Death | 0 Participants |
| Phase 2a Dose Expansion (<8.8 mg/m^2) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Treatment Related TEAEs | 10 Participants |
| Phase 2a Dose Expansion (<8.8 mg/m^2) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | TEAEs leading to Discontinuation of Study Drug | 2 Participants |
| Phase 2a Dose Expansion (<8.8 mg/m^2) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Dose Limiting Toxicity | 0 Participants |
| Phase 2a Dose Expansion (<8.8 mg/m^2) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Any TEAE | 12 Participants |
| Phase 2a Dose Expansion (<8.8 mg/m^2) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Serious TEAEs | 3 Participants |
| Phase 2a Dose Expansion (<8.8 mg/m^2) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | TEAEs leading to Death | 0 Participants |
| Phase 2a Dose Expansion (8.8 mg/m^2) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Treatment Related TEAEs | 29 Participants |
| Phase 2a Dose Expansion (8.8 mg/m^2) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Dose Limiting Toxicity | 0 Participants |
| Phase 2a Dose Expansion (8.8 mg/m^2) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Serious TEAEs | 7 Participants |
| Phase 2a Dose Expansion (8.8 mg/m^2) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | TEAEs leading to Death | 0 Participants |
| Phase 2a Dose Expansion (8.8 mg/m^2) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Any TEAE | 32 Participants |
| Phase 2a Dose Expansion (8.8 mg/m^2) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | TEAEs leading to Discontinuation of Study Drug | 7 Participants |
| Phase 2a Dose Expansion (>8.8 mg/m^2) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Any TEAE | 20 Participants |
| Phase 2a Dose Expansion (>8.8 mg/m^2) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Dose Limiting Toxicity | 0 Participants |
| Phase 2a Dose Expansion (>8.8 mg/m^2) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Serious TEAEs | 15 Participants |
| Phase 2a Dose Expansion (>8.8 mg/m^2) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | TEAEs leading to Discontinuation of Study Drug | 6 Participants |
| Phase 2a Dose Expansion (>8.8 mg/m^2) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | TEAEs leading to Death | 2 Participants |
| Phase 2a Dose Expansion (>8.8 mg/m^2) | Number of Study Participants Who Experienced Treatment-Emergent Adverse Events | Treatment Related TEAEs | 19 Participants |
Secondary
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.
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).
Population: Phase 1 participants who received at least 1 dose of study drug and had at least 1 post-baseline efficacy assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Partial Response (Unconfirmed) | 0 Participants |
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Partial Response (Confirmed) | 0 Participants |
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Progressive Disease | 1 Participants |
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Stable Disease | 1 Participants |
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Complete Response (Confirmed or Unconfirmed) | 0 Participants |
| Phase 1 Dose Escalation (Cohort 2) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Partial Response (Unconfirmed) | 0 Participants |
| Phase 1 Dose Escalation (Cohort 2) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Partial Response (Confirmed) | 0 Participants |
| Phase 1 Dose Escalation (Cohort 2) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Complete Response (Confirmed or Unconfirmed) | 0 Participants |
| Phase 1 Dose Escalation (Cohort 2) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Progressive Disease | 0 Participants |
| Phase 1 Dose Escalation (Cohort 2) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Stable Disease | 3 Participants |
| Phase 1 Dose Escalation (Cohort 3) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Stable Disease | 1 Participants |
| Phase 1 Dose Escalation (Cohort 3) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Complete Response (Confirmed or Unconfirmed) | 0 Participants |
| Phase 1 Dose Escalation (Cohort 3) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Partial Response (Unconfirmed) | 1 Participants |
| Phase 1 Dose Escalation (Cohort 3) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Progressive Disease | 0 Participants |
| Phase 1 Dose Escalation (Cohort 3) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Partial Response (Confirmed) | 0 Participants |
| Phase 1 Dose Escalation (Cohort 4) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Partial Response (Unconfirmed) | 0 Participants |
| Phase 1 Dose Escalation (Cohort 4) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Partial Response (Confirmed) | 0 Participants |
| Phase 1 Dose Escalation (Cohort 4) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Complete Response (Confirmed or Unconfirmed) | 0 Participants |
| Phase 1 Dose Escalation (Cohort 4) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Stable Disease | 3 Participants |
| Phase 1 Dose Escalation (Cohort 4) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Progressive Disease | 0 Participants |
| Phase 1 Dose Escalation (Cohort 5) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Complete Response (Confirmed or Unconfirmed) | 0 Participants |
| Phase 1 Dose Escalation (Cohort 5) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Progressive Disease | 1 Participants |
| Phase 1 Dose Escalation (Cohort 5) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Partial Response (Unconfirmed) | 0 Participants |
| Phase 1 Dose Escalation (Cohort 5) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Stable Disease | 2 Participants |
| Phase 1 Dose Escalation (Cohort 5) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Partial Response (Confirmed) | 0 Participants |
| Phase 1 Dose Escalation (Cohort 6) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Complete Response (Confirmed or Unconfirmed) | 0 Participants |
| Phase 1 Dose Escalation (Cohort 6) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Progressive Disease | 4 Participants |
| Phase 1 Dose Escalation (Cohort 6) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Stable Disease | 2 Participants |
| Phase 1 Dose Escalation (Cohort 6) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Partial Response (Confirmed) | 0 Participants |
| Phase 1 Dose Escalation (Cohort 6) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Partial Response (Unconfirmed) | 0 Participants |
| Phase 1 Dose Escalation (Cohort 7) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Stable Disease | 2 Participants |
| Phase 1 Dose Escalation (Cohort 7) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Partial Response (Confirmed) | 0 Participants |
| Phase 1 Dose Escalation (Cohort 7) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Complete Response (Confirmed or Unconfirmed) | 0 Participants |
| Phase 1 Dose Escalation (Cohort 7) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Partial Response (Unconfirmed) | 0 Participants |
| Phase 1 Dose Escalation (Cohort 7) | Phase 1: Number of Participants With a Best Response of an Objective Response, Stable Disease, or Progressive Disease. | Progressive Disease | 0 Participants |
Secondary
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.
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)
Population: 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
Secondary
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.
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)
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Phase 2a: Maximum Tolerated Dose (MTD) and Recommended Phase 2a Dose (RP2D) Based on Body Surface Area | 8.8 mg/m^2 |
Secondary
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.
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
Population: 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 | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Phase 2a: ORR for Gastrointestinal Mid-gut NETs (GI Mid-gut NET) and Pancreatic NETs (PNET) | Responder | 0 Participants |
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Phase 2a: ORR for Gastrointestinal Mid-gut NETs (GI Mid-gut NET) and Pancreatic NETs (PNET) | Non-Responder | 26 Participants |
| Phase 1 Dose Escalation (Cohort 2) | Phase 2a: ORR for Gastrointestinal Mid-gut NETs (GI Mid-gut NET) and Pancreatic NETs (PNET) | Responder | 0 Participants |
| Phase 1 Dose Escalation (Cohort 2) | Phase 2a: ORR for Gastrointestinal Mid-gut NETs (GI Mid-gut NET) and Pancreatic NETs (PNET) | Non-Responder | 12 Participants |
Secondary
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.
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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Phase 2a: Overall Survival (OS) | NA Months |
| Phase 1 Dose Escalation (Cohort 2) | Phase 2a: Overall Survival (OS) | 21.0 Months |
| Phase 1 Dose Escalation (Cohort 3) | Phase 2a: Overall Survival (OS) | 3.9 Months |
Secondary
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.
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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants in Phase 1 Dose Escalation (Cohorts 1-7) | Phase 2a: Progression Free Survival (PFS) | 9.0 Months |
| Phase 1 Dose Escalation (Cohort 2) | Phase 2a: Progression Free Survival (PFS) | 3.2 Months |
| Phase 1 Dose Escalation (Cohort 3) | Phase 2a: Progression Free Survival (PFS) | 1.4 Months |