A Study of PT217 in Patients With Neuroendocrine Carcinomas Expressing DLL3 (the SKYBRIDGE Study)

Small Cell Lung Cancer (SCLC) Clinical Trial

Official title:

A Phase 1/2 Open-label, Dose Escalation and Dose Expansion Study Designed to Evaluate the Safety, Tolerability, PharmacoKinetics, Pharmacodynamics and EfficacY of PT217 Bispecific Antibody in Patients With NeuRoendocrIne Carcinomas That May Benefit From Treating Their DLL3 expressinG CancEr.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05652686
• Other study ID #: PT217X1101
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: September 5, 2023
• Est. completion date: June 2025

Study information

• Verified date: June 2024
• Source: Phanes Therapeutics
• Contact: Phanes Therapeutics
• Phone: 858-766-0852
• Email: clinical-trials[@]phanestx.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

PT217 is a bispecific antibody (bsAb) against human DLL3 (huDLL3) and human CD47 (huCD47). This is a first-in-human, Phase 1/2, open-label, dose-escalation and expansion study designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of PT217 in subjects with neuroendocrine carcinomas.

Patients with the following tumor types will be eligible for screening: small cell lung cancer (SCLC), large cell neuroendocrine carcinoma of the lung (LCNEC), and extrapulmonary neuroendocrine carcinoma (EP-NEC), including but not limited to neuroendocrine prostate cancer (NEPC) and gastroentero-pancreatic neuroendocrine carcinoma (GEP-NEC). Patients must have progressed after standard therapy (platinum-based chemotherapy) or standard therapy has proven to be ineffective, intolerable or is considered inappropriate.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 61
• Est. completion date: June 2025
• Est. primary completion date: January 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. 18 years or older and able to sign informed consent and comply with the protocol.

2. Measurable disease as defined by RECIST v1.1 criteria for solid tumors.

3. Part A and B: patients with histologically or cytologically confirmed unresectable advanced or metastatic small cell lung cancer (SCLC), large cell neuroendocrine carcinoma of the lung (LCNEC) or extrapulmonary neuroendocrine carcinoma (EP-NEC), including but not limited to neuroendocrine prostate cancer (NEPC) and gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC), previously treated with 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 transformed from an EGFR mutant NSCLC are eligible for this study, given they meet the above criteria.

4. Parts A and B: 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 represents at least 50% of the overall tumor tissue.

5. Able to provide a formalin fixed, paraffin embedded (FFPE) tumor tissue sample (preferably a fresh biopsy, or if not possible, archival tissue) 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 12 months, discuss with Medical Monitor if this is not feasible, for any potential exceptions. This biopsy may not be done if the biopsy poses a risk to the patient and/or per the Investigator's discretion.

6. ECOG performance status of 0 or 1.

7. Adequate organ function confirmed at screening and within 72 hours of initiating treatment, as evidenced by:

• Absolute neutrophil count (ANC) = 1.5 × 109/L

• Hemoglobin (Hgb) = 9.0 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)

8. 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 in Parts A and B ).

9. Negative serum pregnancy test within 72 hours before starting study treatment in all women of child-bearing potential, including pre-menopausal women, and women < 24 months after the onset of menopause (had a menstrual period in past 24 months) Women who underwent hysterectomy or bilateral oophorectomy do not need a pregnancy test.

10. Must agree to use effective contraceptive methods to avoid pregnancy (including male and female patients and partners of study patients) during the study and until at least 7 months after receiving the last dose of study treatment.

11. Life expectancy >3 months.

Exclusion Criteria:

1. Women who are pregnant or lactating.

2. Women of child-bearing potential (WOCBP) who do not use adequate birth control.

3. Autoimmune disease requiring systemic treatment within the past twelve months.

4. Condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days prior to study treatment. Corticosteroid doses equivalent to Prednisone 10 mg per day or less are allowed, or a single application of up to 8 mg Dexamethasone as optional pretreatment for the first two dose applications of PT217 (from Dose Level 3). .

5. Patients who have experienced Grade = 3 immune-related events, such as (non-infectious) pneumonitis, interstitial lung disease, myocarditis. Patients who have experienced Grade < 3 immune-related events that have been resolved for > 6 months, are eligible.

6. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (e.g., biweekly or more frequently pericardiocentesis or thoracentesis).

7. 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.

8. 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 malignancies that have either previously undergone potentially curative therapy or don't have active treatment indication (e.g., low grade prostate cancer).

9. Patients who have received an investigational product, within 4 weeks or 5 half-lives, whichever is shorter, prior to start of study drug or who have not recovered from adverse events of prior therapy, either in the metastatic or adjuvant setting.

10. Prior treatment with T-cell engager, CAR-T, NK cell engager, CAR-NK, DLL3 or CD47 targeting therapies, or anti-SIRPa (signal regulatory protein alpha) targeting agents (prior Checkpoint inhibitor anti PD-1 and anti PD-L1 therapies are allowed).

11. Patients that have received a live-virus vaccination within 30 days of planned treatment start.

12. Impaired cardiac function or significant diseases, including but not limited to any of the following:

1. LVEF < 45% as determined by MUGA scan or ECHO

2. Congenital long QT syndrome

3. QTcF = 480 msec on screening ECG

4. Unstable angina pectoris = 3 months prior to starting study drug.

5. Acute myocardial infarction or stroke = 3 months prior to starting study drug.

13. Patients with uncontrolled hypertension.

14. Prior hemolytic anemia or Evans Syndrome in the last 3 months.

15. 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.

16. Patients who have = Grade 3 neuropathy.

17. 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.

18. Patients who have received chemotherapy or small molecule targeted therapy, = 5 half-lives or 3 weeks, whichever is shorter (6 weeks for nitrosourea or mitomycin-C), other targeted therapy, or immunotherapy within 4 weeks prior to starting study drug. Concurrent use of hormone deprivation therapy for hormone refractory prostate cancer is permitted; patients on a stable bisphosphonate or denosumab for = 30 days prior to study day 1 are eligible.

19. 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.

20. Patients who have undergone major surgery = 4 weeks prior to starting study drug or who have not recovered from adverse events of prior therapy.

21. 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 as long as patients are on a stable dose).

22. 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).

23. 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). Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by a local health authority.

• Patients who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to treatment. Patients should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention.

• Patients with history of HCV infection are eligible if HCV viral load is undetectable at screening. Patients must have completed curative anti-viral therapy at least 4 weeks prior to treatment.

24. 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.

25. Has allergies or hypersensitivity to polysorbate 80, L-Histidine or Sucrose (PT217 inactive ingredients).

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Neuroendocrine
• Lung Neoplasms
• Prostatic Neoplasms
• Small Cell Lung Cancer (SCLC)
• Small Cell Lung Carcinoma

Intervention

Drug:
• PT217
A bispecific antibody (bsAb) against human DLL3 (huDLL3) and human CD47 (huCD47).

Locations

Country	Name	City	State
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	Sarah Cannon Research Institute at HealthONE	Denver	Colorado
United States	NEXT Virginia	Fairfax	Virginia
United States	Sarah Cannon Research Institute University of Oklahoma	Oklahoma City	Oklahoma
United States	Mays Cancer Center / University of Texas, San Antonio	San Antonio	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Phanes Therapeutics

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	To evaluate pharmacodynamic markers of PT217 biological activity		Through study completion, an average of 2 years.
Other	To evaluate pretreatment DLL3 expression in correlation with primary endpoints by immunohistochemistry.		Through study completion, an average of 2 years.
Primary	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.
Primary	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.
Primary	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.
Primary	To evaluate the safety of PT217 by the incidence and severity of adverse events (AEs) (per NCI CTCAE v5.0), with the exception of CRS and ICANS, which are assessed according to ASTCT Consensus Grading.		Through study completion, an average of 2 years.
Secondary	Preliminary efficacy of PT217 as assessed by the Objective Response Rate by iRECIST and RECIST 1.1.	Objective Response Rate	Through study completion, an average of 2 years.
Secondary	Preliminary efficacy of PT217 as assessed by the Disease Control Rate by iRECIST and RECIST 1.1.	Disease Control Rate	Through study completion, an average of 2 years.
Secondary	Preliminary efficacy of PT217 as assessed by Progression Free Survival by iRECIST and RECIST 1.1.	Progression Free Survival	Through study completion, an average of 2 years.
Secondary	Preliminary efficacy of PT217 as assessed by the 6-month Overall Survival by iRECIST and RECIST 1.1.	6-month Overall Survival	Through study completion, an average of 2 years.
Secondary	To evaluate the pharmacokinetics of PT217 by the Area Under the Curve (AUC) from time 0 to last (AUC0-last).	Area Under the Curve (AUC)	Through study completion, an average of 2 years.
Secondary	To evaluate the pharmacokinetics of PT217 by the Maximum Concentration (Cmax).	Maximum Concentration (Cmax)	Through study completion, an average of 2 years.
Secondary	To evaluate the pharmacokinetics of PT217 by the Time of Maximum Concentration (Tmax).	Time of Maximum Concentration (Tmax)	Through study completion, an average of 2 years.
Secondary	To evaluate the pharmacokinetics of PT217 by the Half Life (T1/2).	Half Life (T1/2)	Through study completion, an average of 2 years.
Secondary	To evaluate the pharmacokinetics of PT217 by the Mean Residence Time (MRT).	Mean Residence Time (MRT)	Through study completion, an average of 2 years.
Secondary	To evaluate the pharmacokinetics of PT217 by the Volume of Distribution (Vd).	Volume of Distribution (Vd)	Through study completion, an average of 2 years.