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

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ClinicalTrials.gov Identifier: NCT04205227
Recruitment Status : Not yet recruiting
First Posted : December 19, 2019
Last Update Posted : December 19, 2019
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Cancer Melanoma Ovary Cancer Pancreatic Cancer Solid Tumor Drug: ENB003 Drug: Pembrolizumab Phase 1 Phase 2

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 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 130 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Intervention Model Description: 3+3 Dose Escalation and Open Label Expansion
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2A Trial of ENB 003 in Combination With Pembrolizumab in Subjects With Advanced Solid Tumors
Estimated Study Start Date : January 18, 2020
Estimated Primary Completion Date : September 30, 2023
Estimated Study Completion Date : November 30, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: ENB003 150 ug + Pembrolizumab
150 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg)
Drug: ENB003
ENB003 is selective Endothelin B Receptor Antagonist

Drug: Pembrolizumab
anti-PD1
Other Name: Keytruda, MK-3475

Experimental: ENB003 300 ug + Pembrolizumab
300 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg)
Drug: ENB003
ENB003 is selective Endothelin B Receptor Antagonist

Drug: Pembrolizumab
anti-PD1
Other Name: Keytruda, MK-3475

Experimental: ENB003 500 ug + Pembrolizumab
500 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg)
Drug: ENB003
ENB003 is selective Endothelin B Receptor Antagonist

Drug: Pembrolizumab
anti-PD1
Other Name: Keytruda, MK-3475

Experimental: ENB003 750 ug + Pembrolizumab
750 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg)
Drug: ENB003
ENB003 is selective Endothelin B Receptor Antagonist

Drug: Pembrolizumab
anti-PD1
Other Name: Keytruda, MK-3475

Experimental: ENB003 1000 ug + Pembrolizumab
1000 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg)
Drug: ENB003
ENB003 is selective Endothelin B Receptor Antagonist

Drug: Pembrolizumab
anti-PD1
Other Name: Keytruda, MK-3475

Experimental: ENB003 RP2D from dose eascalation + 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)
Drug: ENB003
ENB003 is selective Endothelin B Receptor Antagonist

Drug: Pembrolizumab
anti-PD1
Other Name: Keytruda, MK-3475




Primary Outcome Measures :
  1. Incidence of Treatment-Emergent Adverse Events of ENB003 in combination with pembrolizumab, as assessed by NCI CTCAE Version 5 [ Time Frame: 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

  2. Efficacy of ENB003 in combination with pembrolizumab measured by tumor ORR [ Time Frame: up to 2 years while subjects remain in the study ]
    ORR measured by change in tumor size based on CT or MRI imaging. Imaging will be done at baseline, week 7, week 13 and every 12 weeks thereafter and ORR will be evaluated according to Recist and iRecist


Secondary Outcome Measures :
  1. pharmacokinetic (PK) of ENB-003-AUC [ Time Frame: 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

  2. pharmacokinetic (PK) of ENB-003-Cmax [ Time Frame: 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

  3. pharmacokinetic (PK) of ENB-003-Tmax [ Time Frame: 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

  4. pharmacokinetic (PK) of ENB-003-T1/2 [ Time Frame: 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

  5. pharmacokinetic (PK) of ENB-003-Vss [ Time Frame: 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

  6. pharmacokinetic (PK) of ENB-003-CL [ Time Frame: 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

  7. Exploratory: IHC assessment of ETBR [ Time Frame: single sample taken between day 5-8 ]
    changes in immunohistochemistry (IHC) for Endothelin B Receptor (ETBR) based on tissue staining measured as a % 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).

  8. Exploratory: IHC assessment of PD-L1 [ Time Frame: single sample taken between day 5-8 ]
    changes in immunohistochemistry (IHC) for PDL-1 receptor based on tissue staining measured as a % 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).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subjects must fulfill all the following inclusion criteria relevant to their tumor type to be eligible for participation in the study:

Malignant Melanoma

  1. Histopathologically confirmed diagnosis of advanced, unresectable or metastatic malignant melanoma.
  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 anti-PD-1/L1 mAb.1

    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.

    Pancreatic Cancer

  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.

    Ovarian Cancer

  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 therapy.

    Sarcoma

  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 mesenchymal chondrosarcoma.
  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 resection.
  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.

    All Subjects

  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 Cockcroft-Gault equation.

24. Capable of understanding and complying with protocol requirements.

Exclusion Criteria:

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

Pregnancy Exclusion

  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.

    Prior/Concomitant Therapy

  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 Investigator's discretion.

    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 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

  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 pneumonitis.
  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 Antibody (HCab).
  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 arrhythmias.
  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.

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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04205227


Contacts
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Contact: Sumayah Jamal, MD, PhD (212)792-2317 sjamal@enbpharma.com
Contact: Sandra Harm, MS,MBA 4849046450 sharm@enbpharma.com

Sponsors and Collaborators
ENB Therapeutics, Inc
Merck Sharp & Dohme Corp.
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Responsible Party: ENB Therapeutics, Inc
ClinicalTrials.gov Identifier: NCT04205227    
Other Study ID Numbers: ENB-003-101 (MK3475-951)
First Posted: December 19, 2019    Key Record Dates
Last Update Posted: December 19, 2019
Last Verified: December 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by ENB Therapeutics, Inc:
solid tumors
Additional relevant MeSH terms:
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Ovarian Neoplasms
Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Endocrine System Diseases
Ovarian Diseases
Adnexal Diseases
Genital Neoplasms, Female
Urogenital Neoplasms
Gonadal Disorders
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents