ENB003 Plus Pembrolizumab Phase 1b/2a in Solid Tumors
- Conditions
- MelanomaOvary CancerCancerPancreatic CancerSolid Tumor
- Interventions
- Registration Number
- NCT04205227
- Lead Sponsor
- ENB Therapeutics, Inc
- 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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 137
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description ENB003 150 ug + Pembrolizumab Pembrolizumab 150 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg) ENB003 300 ug + Pembrolizumab ENB003 300 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg) ENB003 150 ug + Pembrolizumab ENB003 150 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg) ENB003 300 ug + Pembrolizumab Pembrolizumab 300 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg) ENB003 500 ug + Pembrolizumab ENB003 500 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg) ENB003 500 ug + Pembrolizumab Pembrolizumab 500 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg) ENB003 750 ug + Pembrolizumab ENB003 750 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg) ENB003 750 ug + Pembrolizumab Pembrolizumab 750 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg) ENB003 1000 ug + Pembrolizumab ENB003 1000 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg) ENB003 1000 ug + Pembrolizumab Pembrolizumab 1000 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg) ENB003 2000 ug + Pembrolizumab Pembrolizumab 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 ENB003 RP2D from dose escalation + Pembrolizumab Pembrolizumab 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) ENB003 2000 ug + Pembrolizumab ENB003 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 ENB003 RP2D from dose escalation + Pembrolizumab ENB003 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)
- Primary Outcome Measures
Name Time Method 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 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
- Secondary Outcome Measures
Name Time Method 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
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
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).
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).
Part B Efficacy: Duration of response up to 2 years based on RECIST
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
Trial Locations
- Locations (5)
Kinghorn-St Vincent's Hospital
🇦🇺Darlinghurst, New South Wales, Australia
Blacktown Oncology
🇦🇺Blacktown, New South Wales, Australia
Cedars Sinai-The Angeles Clinic
🇺🇸Los Angeles, California, United States
Border Medical Oncology
🇦🇺Albury, New South Wales, Australia
MD Anderson Cancer Center
🇺🇸Houston, Texas, United States