ENB003 Plus Pembrolizumab Phase 1b/2a in Solid Tumors

NCT04205227 | Active Not Recruiting Phase 1 FDA Drug

• 1 other identifier: ENB-003-101 (MK3475-951)
• Study Type: interventional
• Target: 137
• Locations: 2 countries
• Sites: 5

Brief Summary

First-in Human study evaluating the safety, tolerability and efficacy of ENB003 in combination with Pembrolizumab in solid tumors. The study is separated into two parts. Part A is a 3+3 dose escalation to define the recommended RP2D; this part will include metastatic melanoma, platinum resistant ovarian cancer, and pancreatic cancer patients subjects, but other solid tumors will be allowed. Once the RP2D is selected, the study will be expanded into metastatic melanoma, platinum resistant ovarian cancer, and pancreatic cancer subjects. A small number of sarcoma subjects will be included, as exploratory.

Conditions

Cancer; Melanoma; Ovary Cancer; Pancreatic Cancer; Solid Tumor

Keywords

solid tumors

Outcome Measures

Primary Outcomes (3)

• Part A: Incidence of Treatment-Emergent Adverse Events of ENB003 in combination with pembrolizumab, as assessed by NCI CTCAE Version 5

  Based on observed or reported AEs. AEs will be evaluated and classified according to NCI CTCAE Version 5.0

  assessed on every visit while subjects are in the study up to 2 years

• Part B: Efficacy of ENB003 in combination with pembrolizumab

  Melanoma and Ovarian Cancer: • ORR, based on RECIST (evaluated in the context of ETBR expression)

  up to 2 years while subjects remain in the study

• Part B: Efficacy of ENB003 in combination with pembrolizumab

  Pancreatic Cancer: • 6-months OS (evaluated in the context of ETBR expression) Note, these outcomes will be measured by tumor type and not in an aggregate as both the futility and final analysis are independently powered for each tumor type

  up to 2 years while subjects remain in the study

Secondary Outcomes (12)

• Part B Efficacy Progression-free survival (PFS),

  up to 2 years

• Part B Efficacy: Duration of response

  up to 2 years

• Part B Efficacy: Time to progression

  up to 2 years

• Part B Efficacy: Overall survival

  up to 2 years

• pharmacokinetic (PK) of ENB-003-AUC

  at 05,10,15, 20, 30 45, 60 and 90 minutes, 2 hours, 3 hours, 5 hours, and 8 hours after administration of the ENB003, on Days -7 and -5 during dose escalation and days 1 and 5 during dose expansion

Study Arms (7)

ENB003 150 ug + Pembrolizumab

EXPERIMENTAL

150 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg)

Drug: ENB003; Drug: Pembrolizumab

ENB003 300 ug + Pembrolizumab

EXPERIMENTAL

300 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg)

Drug: ENB003; Drug: Pembrolizumab

ENB003 500 ug + Pembrolizumab

EXPERIMENTAL

500 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg)

Drug: ENB003; Drug: Pembrolizumab

ENB003 750 ug + Pembrolizumab

EXPERIMENTAL

750 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg)

Drug: ENB003; Drug: Pembrolizumab

ENB003 1000 ug + Pembrolizumab

EXPERIMENTAL

1000 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg)

Drug: ENB003; Drug: Pembrolizumab

ENB003 2000 ug + Pembrolizumab

EXPERIMENTAL

2000 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg). In this treatment arm, ENB003 will be administered during each 21 day cycle, as opposed to every other cycle in early arms

Drug: ENB003; Drug: Pembrolizumab

ENB003 RP2D from dose escalation + Pembrolizumab

EXPERIMENTAL

The recommended phase 2 dose (RP2D) of ENB003 will be selected from the dose escalation portion of the study and administered in combination with a fixed dose of pembrolizumab (200mg)

Drug: ENB003; Drug: Pembrolizumab

Interventions

ENB003 DRUG

ENB003 is selective Endothelin B Receptor Antagonist

ENB003 1000 ug + Pembrolizumab; ENB003 150 ug + Pembrolizumab; ENB003 2000 ug + Pembrolizumab; ENB003 300 ug + Pembrolizumab; ENB003 500 ug + Pembrolizumab; ENB003 750 ug + Pembrolizumab; ENB003 RP2D from dose escalation + Pembrolizumab

Pembrolizumab DRUG

anti-PD1

Also known as: KEYTRUDA®, MK-3475

ENB003 1000 ug + Pembrolizumab; ENB003 150 ug + Pembrolizumab; ENB003 2000 ug + Pembrolizumab; ENB003 300 ug + Pembrolizumab; ENB003 500 ug + Pembrolizumab; ENB003 750 ug + Pembrolizumab; ENB003 RP2D from dose escalation + Pembrolizumab

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Malignant Melanoma
• Histopathologically confirmed diagnosis of advanced, unresectable or metastatic malignant melanoma.
• Subjects may have received no more than 3 previous lines of systemic anti-cancer therapy for advanced disease.
• Subjects must have progressed on treatment with an anti-PD1/Ligand 1 (L1) monoclonal antibody (mAb) administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies. PD-1 treatment progression as defined by meeting all of the following criteria:
• Has at least six weeks of anti PD-1/L1 exposure with an approved anti-PD-1/L1 mAb.
• Has a best objective response (according to RECIST) of PD or SD \< 6 months. If RECIST not performed, must be determined to have clinical progression within 6 months of initial treatment with anti-PD1 / PD-L1.
• Ovarian Cancer
• Histologically proven diagnosis of high grade serous, high grade endometroid or clear cell ovarian cancer, fallopian tube or primary peritoneal carcinoma.
• Platinum refractory disease, defined as PD during the administration period of first-line platinum-based chemotherapy. Platinum resistant disease defined as PD within 6 months (182 days) after last receipt of first-line platinum-based chemotherapy.
• Subjects may have received up to 3 previous lines of systemic anti-cancer therapy for advanced disease.
• Ovarian cancer patients must be tested for the MSI phenotype. If subjects have high microsatellite instability (MSI-H) or mismatch-repair deficiency (dMMR) phenotype they must have been previously treated with anti-PD1 and demonstrated either PD or disease stabilization, for less than 6 months as best response.
• Pancreatic Cancer
• Histologically confirmed (previously obtained biopsied) metastatic or locally advanced unresectable pancreatic adenocarcinoma or pancreatic adenocarcinoma that is recurrent after resection, including with intraductal papillary mucinous neoplasm.
• Subjects must have previously received and progressed on FOLFIRINOX or a gemcitabine-based regimen for their pancreatic cancer.
• Subjects may have received no more than 2 previous lines of therapy for advanced/metastatic disease.

You may not qualify if:

• A WOCBP who has a positive urine pregnancy test (e.g. within 72 hours) prior to treatment. If the urine test is positive or cannot be confirmed as negative, a negative serum pregnancy test will be required.
• Is breastfeeding or expecting to conceive or father children within the projected duration of the study, from the day date of informed consent through to 150 days after the last dose of study treatment for females, and 120 days after the last dose of study treatment for males.
• Prior/Concomitant Therapy
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137) and was discontinued from that treatment due to a Grade 3 or higher immune-related adverse event (irAE).
• Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks or 5 half-lives, whichever is shorter, prior to treatment.
• Note: Subjects must have recovered from all AEs due to previous therapies to ≤Grade 1 severity or baseline. Subjects with ≤Grade 2 neuropathy may be eligible at Investigator's discretion. Subjects with endocrine-related AEs Grade ≤2 requiring treatment or hormone replacement may be eligible.
• Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the surgery prior to starting study treatment, as determined by the Investigator.
• Has received prior radiotherapy within 2 weeks of start of study treatment or have had a history of radiation pneumonitis. Note: Subjects must have recovered from all radiation-related toxicities, and not require corticosteroids. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system (CNS) disease.
• Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
• Prior/Concurrent Clinical Study Experience
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
• Note: Subjects who have entered the follow-up phase of an investigational study may participate provided it has been 4 weeks after the last dose of the previous investigational agent.
• Diagnostic Assessments
• Average Fridericia-corrected QT interval (QTcF) \>460 msec for males and QTcF \>480 msec for females as measured by electrocardiogram (ECG) at Screening.
• A family history of congenital long QT syndrome, Brugada syndrome or unexplained sudden cardiac death.

Sponsors & Collaborators

• ENB Therapeutics, Inc: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (5)

Cedars Sinai-The Angeles Clinic

Los Angeles, California, 90025, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Border Medical Oncology

Albury, New South Wales, 2640, Australia

Location

Blacktown Oncology

Blacktown, New South Wales, 2148, Australia

Location

Kinghorn-St Vincent's Hospital

Darlinghurst, New South Wales, 2010, Australia

Location

MeSH Terms

Conditions

Neoplasms; Melanoma; Ovarian Neoplasms; Pancreatic Neoplasms

Interventions

pembrolizumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Endocrine Gland Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders; Digestive System Neoplasms; Digestive System Diseases; Pancreatic Diseases

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 3+3 Dose Escalation and Open Label Expansion

Study Record Dates

• First Submitted: December 12, 2019
• First Posted: December 19, 2019
• Study Start: February 18, 2020
• Primary Completion: January 1, 2026
• Study Completion: March 31, 2026
• Last Updated: September 19, 2024

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will not share

Locations

AU (3); US (2)