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.
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 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.
- Subjects must fulfill all the following inclusion criteria relevant to their tumor
type to be eligible for participation in the study:
1. Histopathologically confirmed diagnosis of advanced, unresectable or metastatic
2. 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 is defined by
meeting all of the following criteria:
1. Has received at least 2 doses of an approved anti-PD-1/L1 mAb.
2. Has demonstrated disease progression (PD) after PD-1/L1 as defined by RECIST
Version 1.1. The initial evidence of PD is to be confirmed by a second assessment
no less than four weeks from the date of the first documented PD, in the absence
of rapid clinical progression.1
3. Progressive disease has been documented within 12 weeks from the last dose of
i. This determination is made by the investigator. Once PD is confirmed, the initial
date of PD documentation will be considered the date of PD.
3. Histologically confirmed (previously obtained biopsied) metastatic unresectable
pancreatic adenocarcinoma, including with intraductal papillary mucinous neoplasm.
4. Subjects with one or more prior treatments for their pancreatic cancer.
5. 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.
6. Histologically proven diagnosis of high grade serous, high grade endometroid or clear
cell ovarian cancer, fallopian tube or primary peritoneal carcinoma.
7. Recurrent platinum-resistant disease, defined as PD within 6 months (182 days) of the
last receipt of platinum-based chemotherapy OR greater than 6 months from completion
of most recent platinum-based chemotherapy, but not suitable for further platinum
8. Histologically confirmed diagnosis of leiomyosarcoma, poorly differentiated or
dedifferentiated liposarcoma, undifferentiated pleomorphic sarcoma, malignant fibers
histiocytoma, synovial sarcoma, Ewing's sarcoma, osteosarcoma, or dedifferentiated or
9. All cases should be classified histologically as being intermediate- or high grade.
For soft-tissue sarcomas, this would correspond to Grade 2 or 3 according to the
FNCLCC (Fédération Nationale des Centres de Lutte Contre le Cancer) grading system.
10. Locally advanced/unresectable or metastatic disease not amenable to curative surgical
11. Receipt of at least 1 systemic line of therapy for advanced disease. For subjects
diagnosed with diseases for which no standard therapy exists (e.g. dedifferentiated
chondrosarcoma), this requirement is waived.
12. Subjects may have received up to 3 previous lines of systemic anti-cancer therapy for
advanced disease. Systemic therapy administered with neoadjuvant or adjuvant intent is
not considered a therapy for advanced disease.
13. Be willing and able to provide written informed consent for the trial.
14. Be ≥18 years of age on day of signing informed consent.
15. For subjects with tumor types other than malignant melanoma, ovarian cancer or
pancreatic cancer with histologically or cytologically confirmed advanced or
metastatic solid tumors who have PD after treatment with at least 1 available therapy
for metastatic disease that is known to confer clinical benefit, or are intolerant to
treatment, or refuse standard treatment.
16. For the dose-escalation phase (Part A), tumor vasculature, stroma and/or tumor cells
are marker positive for ETBR, as determined by IHC staining >25%. Subjects who do not
satisfy this criterion may be enrolled in the dose expansion phase (Part B).
17. Has a life expectancy of >3 months.
18. All subjects must have an archived tumor tissue biopsy sample obtained within 24
months of Screening that is suitable for performing IHC and biomarker analyses.
19. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
20. A female subject is eligible to participate if she is not pregnant, not breastfeeding,
and at least one of the following conditions applies:
a. Not a woman of childbearing potential (WOCBP), where a WOCBP is defined as: i. Not
surgically sterile i.e. bilateral tubal ligation, bilateral oophorectomy, or complete
hysterectomy, or ii. 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.
b. 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.
21. 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.
22. 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.
23. 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 ≥30 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.
1. 2 Creatinine clearance (CrCl) will be calculated by the central laboratory using the
24. Capable of understanding and complying with protocol requirements.
Subjects will be excluded if they fulfill any of the following exclusion criteria:
1. 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.
2. 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.
3. 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).
4. Has received prior systemic anti-cancer therapy including investigational agents
within 4 weeks 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
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.
5. Has received prior radiotherapy within 2 weeks of start of study treatment. Subjects
must have recovered from all radiation-related toxicities, not currently require
corticosteroids, and have never had radiation pneumonitis. A 1-week washout is
permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous
system (CNS) disease.
6. 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
7. 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
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
8. Average Fridericia-corrected QT interval (QTcF) >460 msec for males and QTcF >480 msec
for females as measured by electrocardiogram (ECG) at Screening.
9. A family history of congenital long QT syndrome, Brugada syndrome or unexplained
sudden cardiac death.
10. 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.
11. 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 (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially
curative therapy are not excluded.
12. 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.
13. Has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients.
14. Has severe hypersensitivity (≥ Grade 3) to ENB-003 and/or any of its excipients
15. 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.
16. Has a history of (non-infectious) pneumonitis that required steroids or has current
17. Has an active infection requiring systemic therapy.
18. Subjects with known human immunodeficiency virus (HIV) and/or history of Hepatitis B
or C infections or known to be positive for Hepatitis B antigen (HBcAb) or Hepatitis C
19. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the study, interfere with the subject's
participation for the full duration of the study, or it is not in the best interest of
the subject to participate, in the opinion of the treating Investigator.
20. Has a known psychiatric or substance abuse disorder that would interfere with the
subject's ability to cooperate with the requirements of the study.
21. History of myocardial infarction ≤ 6 months prior to Screening, or congestive heart
failure requiring use of ongoing maintenance therapy for life-threatening ventricular
22. Has a history of Pulmonary Arterial Hypertension or Renovascular Hypertension
Other Exclusions 23. Has had an allogenic tissue/solid organ transplant. 24. 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.