A Phase 1 Study of PT217 in Patients With Advanced Refractory Cancers Expressing DLL3

Study Overview
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Brief Summary
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PT217 is a bispecific antibody (bsAb) against human DLL3 (huDLL3) and human CD47 (huCD47). This is an open label, Phase I study to evaluate the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of PT217 in subjects with advanced or refractory cancers. Patients with the following tumor types will be eligible for screening: unresectable or small cell lung cancer (SCLC), large cell neuroendocrine cancer (LCNEC), neuroendocrine prostate cancer (NEPC) and gastroenteropancreatic neuroendocrine tumors (GEP-NET). Subjects must have progressed after standard therapy (platinum-based chemotherapy) or standard therapy has proven to be ineffective, intolerable or was considered inappropriate.

Official Title
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A Phase 1 Open-label, Multicenter, Dose Escalation and Dose Expansion Study of PT217 in Patients With Advanced Refractory Cancers Expressing DLL3

Conditions
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Small Cell Lung Cancer (SCLC), Large Cell Neuroendocrine Cancer (LCNEC), Neuroendocrine Prostate Cancer (NEPC), Gastroenteropancreatic Neuroendocrine Tumors (GEP-NET)

Intervention / Treatment
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* Drug: PT217


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years or older and able to sign informed consent and comply with the protocol. Measurable disease as defined by RECIST V1.1 criteria for solid tumors. Histologically or cytologically confirmed unresectable advanced or metastatic small cell lung cancer (SCLC), large cell neuroendocrine cancer (LCNEC), neuroendocrine prostate cancer (NEPC) and gastroenteropancreatic neuroendocrine tumors (GEP-NET), previously treated with all existing standard of care treatments (at least one line of platinum-based chemotherapy with or without immune checkpoint inhibitor for SCLC patients), and progressed after treatment, or for which treatment is not available or not tolerated. Treatment for limited stage disease qualifies as a line of therapy. SCLC that was transformation from an EGFR NSCLC are eligible for this study, given they meet the above criteria. Patients with tumors that are of mixed histologies for any above type are eligible only if neuroendocrine carcinoma/small tumor cells component is predominant and represent at least 50% of the overall tumor tissue. Able to provide a formalin fixed, paraffin embedded (FFPE) tumor tissue sample (archival tissue or fresh biopsy) to be assessed for DLL3 expression and other biomarkers. Biopsy must be excisional, incisional, or core needle. Fine needle aspiration is insufficient. Archival tissue is acceptable if biopsy was completed within 6 months. For enrollment in the dose escalation phase, the assessment of DLL3 expression will not be part of the entry criteria; however, the assessment will be carried out during the study to support the analysis of potential responders. For enrollment in the dose expansion phase of the study ONLY, patient's tumor sample must express DLL3 in tumor cells as determined by central lab immunohistochemistry (IHC) testing. The minimal level of DLL3 expression is to be determined by assessment of tumor samples from the dose escalation phase. ECOG performance status of 0 or 1. Adequate organ function confirmed at screening and within 96 hours of initiating treatment, as evidenced by: Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L Hemoglobin (Hgb) ≥ 9.5 g/dl (RBC transfusions not permitted in the 4-week period before enrollment). Platelets (plt) ≥ 100 × 109 /L AST/SGOT and ALT/SGPT ≤ 2.5 × Upper Limit of Normal (ULN) or ≤ 5.0 × ULN if liver metastases are present Total bilirubin ≤ 1.5 × ULN without liver metastases (or < 3.0 x ULN if liver metastases are present) Calculated creatinine clearance ≥ 30 mL/min (Cockcroft Gault formula) Resolution of all acute adverse events resulting from prior cancer therapies to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE V5.0) Grade ≤ 1 or baseline (except alopecia or neuropathy). Negative serum pregnancy test within 72 hours before starting study treatment in all pre-menopausal women, and women < 24 months after the onset of menopause (had a menstrual period in past 24 months) and are of childbearing potential (women who underwent hysterectomy or bilateral oophorectomy do not need a pregnancy test). Must agree to use effective contraceptive methods to avoid pregnancy (including male and female participants and partners of study subjects) during the study and until at least 7 months after the last dose of study treatment. Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, established, proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception. Exclusion Criteria: Women who are pregnant or lactating. Women of child-bearing potential (WOCBP) who do not use adequate birth control. Autoimmune disease requiring systemic treatment within the past twelve months. Condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days prior to study treatment. Corticosteroids doses equivalent to Prednisone 10mg per day or less are allowed. Patients with a history of (non-infectious) pneumonitis that required steroids, current pneumonitis, or has a history of interstitial lung disease. History of COVID-19 pneumonia with fibrotic changes. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (e.g., biweekly or more frequently pericardiocentesis or thoracentesis). Patients with untreated brain or central nervous system (CNS) metastases or brain/CNS metastases that have progressed (e.g., evidence of new or enlarging brain metastasis or new neurological symptoms attributable to brain/CNS metastases). Note: Patients with treated brain metastases that are off corticosteroids and have been clinically stable for 14 days are eligible for enrollment. Patients with a known concurrent malignancy that is progressing or has required treatment for active disease within the previous 24 months. Exceptions include basal cell carcinoma of the skin, carcinoma in situ of the cervix or other noninvasive or indolent malignancy that has either previously undergone potentially curative therapy or doesn't have active treatment indication (e.g., low grade prostate cancer). Patients who have received an investigational product, < 5 half-lives duration. Prior T-cell, NK cell, DLL3 inhibitor therapy or CD47 inhibitor therapy, or anti-SIRPα (signal regulatory protein alpha) targeting agents (Prior Checkpoint inhibitor anti PD-1 and anti PD-L1 therapies are allowed). Patients that have received a live-virus vaccination within 30 days of planned treatment start (exception Janssen JNJ-78436735 COVID-19 vaccine). Impaired cardiac function or significant diseases, including but not limited to any of the following: LVEF < 45% as determined by MUGA scan or ECHO Congenital long QT syndrome QTcF ≥ 480 msec on screening ECG Unstable angina pectoris ≤ 3 months prior to starting study drug Acute myocardial infarction or stroke ≤ 3 months prior to starting study drug Patients with uncontrolled hypertension (defined as blood pressure of ≥ 150 mmHg systolic and/or ≥ 90 mmHg diastolic at Screening). Prior hemolytic anemia or Evans Syndrome in the last 3 months. RBC transfusion during the 4-week period prior to enrollment. RBC transfusions are not permitted during the screening period and prior to enrollment to meet the hemoglobin inclusion criteria. Patients who have ≥ Grade 3 neuropathy. Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., uncontrolled hypertriglyceridemia [triglycerides > 500 mg/dL], or active infection requiring parenteral treatment) that could cause unacceptable safety risks or compromise compliance with the protocol. Patients who have received chemotherapy, ≤ 5 half-lives or 3 weeks, whichever is shorter (6 weeks for nitrosourea or mitomycin-C), targeted therapy, or immunotherapy within 4 weeks prior to starting study drug. Concurrent use of hormone deprivation therapy for hormone refractory prostate is permitted; participants on a stable bisphosphonate or denosumab for ≥ 30 days prior to study day 1 are eligible Patients who have received wide field radiotherapy ≤ 2 weeks prior to starting study drug or who have not recovered from adverse events of prior therapy Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from adverse events of prior therapy. Patients who are currently receiving treatment with therapeutic doses of warfarin sodium (Coumadin®) or any other coumarin-derivative anticoagulants (Other anticoagulants such as anti-thrombin or factor X inhibitors are allowed). Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory; patients with well controlled HIV might be enrolled per investigator's discretion and Sponsor approval). Evidence of active infection with Hepatitis B or Hepatitis C that is not adequately controlled. (For patients with known prior history of Hepatitis B or Hepatitis C, enrollment may be allowed per investigator's discretion and Sponsor approval.) Has a history or current evidence of any medical or psychiatric condition, therapy, or laboratory abnormality that, in the opinion of the investigator, might confound the results of the trial, interfere with the patient's safe participation and compliance in the trial. For example, conditions that depend on the establishment of collateral circulation, such as peripheral arterial vascular disease, myocardial infarction recovery period, etc. Has allergies or hypersensitivity to polysorbate 80, L-Histidine, Sucrose, (PT217 inactive ingredients).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Dose escalation and expansion study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation<br>A standard 3+3 dose escalation design will be employed. The starting dose to be evaluated in the dose escalation study is 0.2 mg/kg weekly (QW). Additional provisional dose levels include: 0.6 mg/kg QW, 2 mg/kg QW, 6 mg/kg QW, 12 mg/kg QW. | Drug: PT217<br>* A bispecific antibody (bsAb) against human DLL3 (huDLL3) and human CD47 (huCD47).<br>|
| Experimental: Dose Expansion<br>Two doses from dose escalation phase will be evaluated in dose expansion, likely the Maximum Tolerated Dose (MTD) and a lower dose, or 2 lower doses. | Drug: PT217<br>* A bispecific antibody (bsAb) against human DLL3 (huDLL3) and human CD47 (huCD47).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the dose-limiting toxicity (DLT) of PT217. | Monitor grade 3 and higher related adverse events. | Through study completion, an average of 2 years. | 
| To determine the maximum tolerated dose (MTD) of PT217 if reached. | Monitor for 2 DLTs in 3 to 6 patients in each cohort. | Through study completion, an average of 2 years. | 
| To determine recommended Phase 2 dose (RP2D) of PT217. | Monitor for MTD, and minimal efficacious dose by monitoring responses at different dose levels. | Through study completion, an average of 2 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Preliminary efficacy of PT217 | Preliminary Efficacy (assessed by the response rate by iRECIST and RECIST 1.1). Objective Response Rate (ORR = PR+CR). | Through study completion, an average of 2 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DLL3, DLL3 expressing tumors, Lung cancer, Neuroendocrine tumors, SCLC, LCNEC, NEPC, GEP-NET, Small Cell Lung Cancer, Large cell neuroendocrine cancer, Neuroendocrine prostate cancer, Gastroenteropancreatic neuroendocrine tumors