Trial Review

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT04205227




Registration number
NCT04205227
Ethics application status
Date submitted
12/12/2019
Date registered
19/12/2019
Date last updated
15/06/2023

Titles & IDs
Public title
ENB003 Plus Pembrolizumab Phase 1b/2a in Solid Tumors
Scientific title
A Phase 1/2A Trial of ENB 003 in Combination With Pembrolizumab in Subjects With Advanced Solid Tumors
Secondary ID [1] 0 0
ENB-003-101 (MK3475-951)
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cancer 0 0
Melanoma 0 0
Ovary Cancer 0 0
Pancreatic Cancer 0 0
Solid Tumor 0 0
Condition category
Condition code
Cancer 0 0 0 0
Ovarian and primary peritoneal

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - ENB003
Treatment: Drugs - Pembrolizumab

Experimental: ENB003 150 ug + Pembrolizumab - 150 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg)

Experimental: ENB003 300 ug + Pembrolizumab - 300 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg)

Experimental: ENB003 500 ug + Pembrolizumab - 500 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg)

Experimental: ENB003 750 ug + Pembrolizumab - 750 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg)

Experimental: ENB003 1000 ug + Pembrolizumab - 1000 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg)

Experimental: ENB003 2000 ug + 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

Experimental: ENB003 RP2D from dose escalation + 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)


Treatment: Drugs: ENB003
ENB003 is selective Endothelin B Receptor Antagonist

Treatment: Drugs: Pembrolizumab
anti-PD1
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Part A: Incidence of Treatment-Emergent Adverse Events of ENB003 in combination with pembrolizumab, as assessed by NCI CTCAE Version 5
Timepoint [1] 0 0
assessed on every visit while subjects are in the study up to 2 years
Primary outcome [2] 0 0
Part B: Efficacy of ENB003 in combination with pembrolizumab
Timepoint [2] 0 0
up to 2 years while subjects remain in the study
Primary outcome [3] 0 0
Part B: Efficacy of ENB003 in combination with pembrolizumab
Timepoint [3] 0 0
up to 2 years while subjects remain in the study
Secondary outcome [1] 0 0
Part B Efficacy Progression-free survival (PFS),
Timepoint [1] 0 0
up to 2 years
Secondary outcome [2] 0 0
Part B Efficacy: Duration of response
Timepoint [2] 0 0
up to 2 years
Secondary outcome [3] 0 0
Part B Efficacy: Time to progression
Timepoint [3] 0 0
up to 2 years
Secondary outcome [4] 0 0
Part B Efficacy: Overall survival
Timepoint [4] 0 0
up to 2 years
Secondary outcome [5] 0 0
pharmacokinetic (PK) of ENB-003-AUC
Timepoint [5] 0 0
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
Secondary outcome [6] 0 0
pharmacokinetic (PK) of ENB-003-Cmax
Timepoint [6] 0 0
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
Secondary outcome [7] 0 0
pharmacokinetic (PK) of ENB-003-Tmax
Timepoint [7] 0 0
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
Secondary outcome [8] 0 0
pharmacokinetic (PK) of ENB-003-T1/2
Timepoint [8] 0 0
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
Secondary outcome [9] 0 0
pharmacokinetic (PK) of ENB-003-Vss
Timepoint [9] 0 0
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
Secondary outcome [10] 0 0
pharmacokinetic (PK) of ENB-003-CL
Timepoint [10] 0 0
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
Secondary outcome [11] 0 0
Exploratory: IHC assessment of ETBR
Timepoint [11] 0 0
single sample taken between day 5-8
Secondary outcome [12] 0 0
Exploratory: IHC assessment of PD-L1
Timepoint [12] 0 0
single sample taken between day 5-8

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria

Subjects will be excluded if they fulfill any of the following exclusion criteria:

Pregnancy Exclusion

- 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.

- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(in doses exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior the first dose of study drug.

- Has a known additional malignancy that is progressing or has required active treatment
within the past 3 years.

Note: Subjects with basal cell carcinoma of the skin, SCC of the skin, or carcinoma in
situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative
therapy are not excluded.

- Has known active CNS metastases and/or carcinomatous meningitis. Subjects with
previously treated brain metastases may participate provided they are radiologically
stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging
(note that the repeat imaging should be performed during study screening), clinically
stable and without requirement of steroid treatment for at least 14 days prior to
first dose of study treatment.

- Has severe hypersensitivity (= Grade 3) to pembrolizumab and/or any of its excipients.

- Has severe hypersensitivity (= Grade 3) to ENB-003 and/or any of its excipients

- Has an active autoimmune disease that has required systemic treatment in past 2 years
(i.e., with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency) is not considered a form
of systemic treatment and is allowed.

- Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis.

- Has an active infection requiring systemic therapy.

- Subjects with known human immunodeficiency virus (HIV), active HBV or active HCV
infections. Subjects 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
starting treatment (Note: Subjects should remain on HBV antiviral therapy throughout
the study and follow local guidelines for HBV anti-viral therapy post completion of
the study intervention).

Subjects with a history of HCV infection are eligible if HCV viral load is undetectable at
screening (Note: must have completed curative anti-viral therapy at least 4 weeks prior to
starting treatment).

- Has a history or current evidence of any condition, therapy, or laboratory
abnormality, or other circumstance that might confound the results of the study or
interfere with the subject's participation for the full duration of the study, such
that it is not in the best interest of the subject to participate, in the opinion of
the treating Investigator.

- Has a known psychiatric or substance abuse disorder that would interfere with the
subject's ability to cooperate with the requirements of the study.

- History of myocardial infarction = 6 months prior to Screening, or uncontrolled
congestive heart failure or uncontrolled atrial fibrillation or uncontrolled
ventricular arrythmia.

- Has a history of Pulmonary Arterial Hypertension or Renovascular Hypertension

- Blood pressure = (greater than or equal to)150/90 mm Hg.

Other Exclusions

- Has had an allogenic tissue/solid organ transplant.

- Has previously participated in this protocol [ENB-003-101 (MK3475-951)] i.e. a subject
previously enrolled in Part A cannot participate in Part B.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1/Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
18/02/2020
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
31/03/2026
Actual
Sample size
Target
137
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
Border Medical Oncology - Albury
Recruitment hospital [2] 0 0
Blacktown Oncology - Blacktown
Recruitment hospital [3] 0 0
Kinghorn-St Vincent's Hospital - Darlinghurst
Recruitment postcode(s) [1] 0 0
2640 - Albury
Recruitment postcode(s) [2] 0 0
2148 - Blacktown
Recruitment postcode(s) [3] 0 0
2010 - Darlinghurst
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Texas

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
ENB Therapeutics, Inc
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Merck Sharp & Dohme LLC
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT04205227
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT04205227