Cancer, Melanoma, Ovary Cancer, Pancreatic Cancer, Solid Tumor
Conditions
Keywords
solid tumors
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.
Detailed description
Part A: Dose Escalation (with Run-in) A 7-day run-in period of ENB-003 monotherapy, will be administered to all Part A subjects on Days -7, -5 and -3, prior to initiating combination therapy with pembrolizumab at Day 1. ENB-003 will also be administered on Days 1, 3 and 5 in Cycle 1. In subsequent cycles, ENB-003 will be administered on Days 1, 3, 5, 8, 10, and 12 of alternate 21-day treatment cycles, starting with Cycle 3. Dose escalation will follow a standard 3+3 design, with the following doses being administered during Part A: * 150 µg ENB-003 * 300 µg ENB-003 * 500 µg ENB-003 * 750 µg ENB-003 * 1000 µg ENB-003 and 2000 µg ENB-003. For 2000 µg doses and above, ENB003 will be administered every 21 day cycle. Pembrolizumab will be administered as 200 mg on Day 1 of each 21-day cycle in all Part A cohorts. Part B: Dose Expansion Twelve (12) subjects with malignant melanoma, ovarian cancer, or pancreatic cancer will receive 1 x 21-day treatment cycle of ENB-003 at the recommended phase 2 dose (RP2D) selected in Part A + pembrolizumab. If dose limiting toxicities (DLT) occur in no more than 3 subjects , Part B will be expanded with an additional 27 subjects, plus 6 additional subjects with sarcoma. A review of efficacy will be conducted by a Data Safety Monitoring Board (DSMB) in Part B once 39 RP2D subjects (including 9 malignant melanoma subjects, 16 ovarian cancer subjects and 14 pancreatic cancer subjects) have completed their scheduled 12 week CT/MRI scans. Upon approval by the DSMB, a maximum of 64 further subjects will be treated at the RP2D.
Interventions
DRUGENB003
ENB003 is selective Endothelin B Receptor Antagonist
DRUGPembrolizumab
anti-PD1
Sponsors
Merck Sharp & Dohme LLC
ENB Therapeutics, Inc
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
3+3 Dose Escalation and Open Label Expansion
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Subjects must fulfill all the following inclusion criteria relevant to their tumor type to be eligible for participation in the study: Inclusion Criteria 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. * Pancreatic 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. Basket Study: * The first 10 subjects for each indication must be ETBR+. * Subjects must have progressed on at least one standard of care therapy and must not have received more than 3 prior systemic therapies. SCC of the Head and Neck * Histologically confirmed metastatic SCC of the head and neck. * 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. Triple Negative Breast Cancer * Histologically proven diagnosis of metastatic TNBC * TNBC subjects must be tested for PD-L1 expression. For CPS \>10, 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. All Subjects: * Be willing and able to provide written informed consent for the trial. * Be ≥18 years of age on day of signing informed consent. * Has a life expectancy of \>3 months. * Must have confirmed slides or a tumor block available prior to dosing. * Fresh biopsies for ETBR and biomarker analysis are preferred for all subjects, especially those that have superficial (cutaneous or subcutaneous e.g. lymph nodes) primary or metastatic lesions. If obtaining a fresh biopsy is not possible, subjects must have archival tumor tissue obtained within 24 months of Screening and that is suitable for performing IHC and biomarker analyses. * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. * A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: * Not a woman of childbearing potential (WOCBP), where a WOCBP is defined as: * Not surgically sterile i.e. bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy, or * Not post-menopausal, defined as amenorrhea for ≥ 2 years without an alternative medical cause. Note: Women with amenorrhea for \< 2 years and who are not surgically sterile i.e. tubal ligation, bilateral oophorectomy, or complete hysterectomy will only be considered not to be of reproductive potential if they have a documented follicle stimulating hormone (FSH) value in the postmenopausal range. * A WOCBP who agrees to follow contraceptive guidance from the date of informed consent and for at least 150 days after the last dose of study treatment. * A male subject must agree to use contraception from the date of informed consent and for at least 120 days after the last dose of study treatment AND must refrain from donating sperm during this period. * Has measurable disease per RECIST Version 1.1, defined as at least one lesion that can be accurately measured by CT scan or MRI. Minimum measurement must be ≥10 mm as assessed by the Investigator. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. * Has adequate organ function, as defined in table below. Specimens must be collected within 3 days prior to the start of study treatment. System Laboratory Value Hematological * Absolute neutrophil count (ANC) ≥1500/µL or ≥1500/mm3 * Platelets ≥100 000/µL or ≥100 000/mm3 Hemoglobin ≥90.0 g/L or ≥5.6 mmol/L1 Renal * Creatinine OR * Measured or calculated2 creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 ×ULN OR ≥60 mL/min for subject with creatinine levels \>1.5 × institutional ULN Hepatic * Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for subjects with total bilirubin levels \>1.5 × ULN * AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for subjects with liver metastases) Coagulation * International normalized ratio (INR) OR prothrombin time (PT) * Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless subject is receiving anticoagulant therapy provided PT or aPTT is within therapeutic range of intended use of anticoagulants * ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT) = aspartate aminotransferase (serum glutamic oxaloacetic transaminase); * GFR = glomerular filtration rate; ULN = upper limit of normal. 1. Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks. 2. Creatinine clearance (CrCl) will be calculated using the Cockcroft-Gault equation. Capable of understanding and complying with protocol requirements.
Exclusion criteria
Subjects will be excluded if they fulfill any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Incidence of Treatment-Emergent Adverse Events of ENB003 in combination with pembrolizumab, as assessed by NCI CTCAE Version 5 | assessed on every visit while subjects are in the study up to 2 years | Based on observed or reported AEs. AEs will be evaluated and classified according to NCI CTCAE Version 5.0 |
| Part B: Efficacy of ENB003 in combination with pembrolizumab | up to 2 years while subjects remain in the study | Melanoma and Ovarian Cancer: • ORR, based on RECIST (evaluated in the context of ETBR expression) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part B Efficacy: Time to progression | up to 2 years | defined as time from first dosing to date of first observed progression, based on RECIST |
| Part B Efficacy: Overall survival | up to 2 years | defined as time from first dosing to date of death |
| 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 | AUC, measured through blood samples from 0 up to 8 hrs, for all subjects in the dose escalation and the first 12 subjects in the dose expansion |
| pharmacokinetic (PK) of ENB-003-Cmax | 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 | Cmax, measured through blood samples from 0 up to 8 hrs, for all subjects in the dose escalation and the first 12 subjects in the dose expansion |
| pharmacokinetic (PK) of ENB-003-Tmax | 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 | Tmax, measured through blood samples from 0 up to 8 hrs, for all subjects in the dose escalation and the first 12 subjects in the dose expansion |
| Part B Efficacy Progression-free survival (PFS), | up to 2 years | defined as time from first dosing to date of first observed progression, based on RECIST, or death from any cause (whichever comes first). |
| pharmacokinetic (PK) of ENB-003-Vss | 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 | Vss measured through blood samples from 0 up to 8 hrs, for all subjects in the dose escalation and the first 12 subjects in the dose expansion |
| pharmacokinetic (PK) of ENB-003-CL | 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 | CL measured through blood samples from 0 up to 8 hrs, for all subjects in the dose escalation and the first 12 subjects in the dose expansion |
| Exploratory: IHC assessment of ETBR | single sample taken between day 5-8 | changes in immunohistochemistry (IHC) for Endothelin B Receptor (ETBR) based on tissue staining measured as a percent of the tissue sample stained, after administration of ENB-003 in combination with pembrolizumab (for subjects with accessible tumors, in whom biopsies can be safely performed). |
| Exploratory: IHC assessment of PD-L1 | single sample taken between day 5-8 | changes in immunohistochemistry (IHC) for PDL-1 receptor based on tissue staining measured as a percent of the tissue sample stained, after administration of ENB-003 in combination with pembrolizumab (for subjects with accessible tumors, in whom biopsies can be safely performed). |
| pharmacokinetic (PK) of ENB-003-T1/2 | 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 | t1/2, measured through blood samples from 0 up to 8 hrs, for all subjects in the dose escalation and the first 12 subjects in the dose expansion |
| Part B Efficacy: Duration of response | up to 2 years | based on RECIST |
Countries
Australia, United States
Outcome results
None listed