This will be an open-label, two-cohort, phase IIa study in subjects with metastatic
pancreatic adenocarcinoma.
The study will be comprised of 2 cohorts,. Each includes approximately 40 subjects with
unresectable metastatic pancreatic adenocarcinoma.
Each cohort study consists of two periods:
- Monotherapy period: One week, with BL-8040 administered daily on days 1-5.
- Combination therapy:
Cohort 1: Three-week cycles of a combination of BL-8040 administered three times a week (TIW)
and pembrolizumab administered once every three weeks.
Cohort 2: Onivyde®/5-FU/LV every 2 weeks, pembrolizumab once every 3 weeks and BL-8040 twice
a week.
Cohort 1: Subjects with metastatic pancreatic adenocarcinoma will be enrolled and receive
BL-8040 monotherapy for five days followed by a combination treatment of BL-8040 and
pembrolizumab. During the monotherapy period, eligible subjects will receive daily
subcutaneous (SC) injections of BL-8040 (1.25 mg/kg) on Days 1 - 5.
From Day 8, subjects will begin a combination period consisting of treatment with SC BL-8040
TIW and pembrolizumab once every three weeks. The combination therapy will continue for up to
35 cycles of pembrolizumab approximately two years), or until progression, clinical
deterioration or Early Termination, whichever comes first.
Cohort 2: Subjects with metastatic pancreatic adenocarcinoma that have progressed following
first-line treatment with gemcitabine-based chemotherapy will be enrolled and receive BL-8040
monotherapy for five days followed by a combination treatment of BL-8040, pembrolizumab and
chemotherapy. During the monotherapy period, eligible subjects will receive daily SC
injections of BL-8040 on Days 1 - 5.
From Day 8, subjects will begin a combination period consisting of:
- IV Onivyde® followed by IV leucovorin (LV), followed by IV fluorouracil (5-FU), every 2
weeks.
- Pembrolizumab every three weeks.
- BL-8040 twice a week
The combination therapy will continue for up to 35 treatments (approximately two years), or
until progression, clinical deterioration or Early Termination, whichever comes first.
Inclusion Criteria:
1. 18 years and older.
2. Patients must sign a written informed consent prior to entering the study.
3. Histologically confirmed (either previously or newly biopsied) metastatic unresectable
pancreatic adenocarcinoma, including with intraductal papillary mucinous neoplasm.
4. Have measurable disease (≥ 1 measurable lesion) based on Response Evaluation Criteria
In Solid Tumors (RECIST) v1.1 as determined by the site study team. Tumor lesions
situated in a previously irradiated area are considered measurable if progression has
been demonstrated in such lesions.
5. Previous treatment lines
1. Cohort 1: Have documented objective radiographic progression after stopping
treatment with first-line or further therapy, i.e. chemotherapy and or
radiotherapy. Surgery not followed with neoadjuvant therapy will not be
considered as first-line therapy.
2. Cohort 2: Have documented objective radiographic progression after stopping
treatment with first-line, gemcitabine-based chemotherapy. Only primary
metastatic patients will be allowed to participate. Patients with previous
surgery for their pancreatic cancer will not be allowed to participate.
6. Willing to submit an evaluable tumor tissue sample, preferably from a liver
metastasis, unless tumor is considered inaccessible or biopsy is otherwise considered
not in the subject's best interest
7. Complete resolution of toxic effect(s) of the most recent prior chemotherapy to Grade
1 or less (except alopecia). If the subject received major surgery or radiation
therapy of > 30 Gy, they must have recovered from the toxicity and/or complications
from the intervention.
8. ECOG status ≤1.
9. Life expectancy of at least 3 months.
10. Adequate organ function at Baseline as defined below. All laboratory assessments
should be performed within 10 days of treatment initiation
1. Hematological:
- White blood cell (WBC) ≥ 2,500/mm^3
- Absolute neutrophil count
- Cohort 1: ≥ 1000 /mm^3
- Cohort 2: ≥ 1500 /mm^3
- Platelet count ≥ 100,000/mm^3
- Hemoglobin ≥9 g/dL or ≥5.6 mmol/L
- Hematocrit ≥30%
2. Renal function:
• Creatinine ≤1.5x Upper limit of normal (ULN) OR measured or calculated
creatinine clearance (glomerular filtration rate [GFR]) can also be used in place
of creatinine or (CrCl) > 60 mL/min for subject with creatinine levels > 1.5x
institutional ULN
3. Hepatic function:
- Total Bilirubin: within institutional normal ranges
- Aspartate Aminotransferase/Serum Glutamic Oxaloacetic Transaminase
(AST/SGOT) and Alanine Transaminase/Serum Glutamic Pyruvic Transaminase
(ALT/SGPT): ≤2.5xULN OR ≤5xULN for subjects with liver metastases
4. Coagulation:
- INR or PT: ≤1.5xULN unless subject is receiving anticoagulant therapy as
long as PT or PTT is within therapeutic range of intended use of
anticoagulants
- Activated Partial Thromboplastin Time (aPTT): ≤1.5xULN unless subject is
receiving anticoagulant therapy as long as PT or PTT is within therapeutic
range of intended use of anticoagulants
11. Subjects must use effective contraception:
1. Female subjects must be of non-childbearing potential or, if of childbearing
potential, must have a negative urine or serum pregnancy test within 72 hours
prior to taking study medication. If the urine test is positive or cannot be
confirmed as negative, a serum pregnancy test will be required. The serum
pregnancy test must be negative for the subject to be eligible. Non-childbearing
potential is defined as (by other than medical reasons):
- ≥45 years of age and has not had menses for over 2 years
- Amenorrhoeic for > 2 years without a hysterectomy and oophorectomy and a
Follicle Stimulating Hormone (FSH) value in the postmenopausal range upon
pretrial (Screening) evaluation
- Post hysterectomy, bilateral oophorectomy, bilateral salpingectomy or
bilateral tubal ligation at least 6 weeks prior to Screening. Documented
hysterectomy or oophorectomy must be confirmed with medical records of the
actual procedure or confirmed by ultrasound. Tubal ligation must be
confirmed with medical records of the actual procedure otherwise the subject
must be willing to use two adequate barrier methods throughout the study,
starting with the Screening visit through 120 days after the last dose of
study therapy. Information must be captured appropriately within the site's
source documents
2. Male subjects must agree to use an adequate method of contraception starting with
the first dose of study therapy through 120 days after the last dose of study
therapy.
Exclusion Criteria:
1. Has a pancreatic tumor other than adenocarcinoma, including: acinar cell carcinoma,
pancreaticoblastoma, malignant cystic neoplasms, endocrine neoplasms, squamous cell
carcinoma, Vater and periampullary duodenal or common bile duct malignancies.
2. For Cohort 2 only: subjects with a bowel obstruction.
3. Has an active infection requiring systemic therapy or has an uncontrolled infection.
4. Has a known additional malignancy that is progressing or requires active treatment.
Exceptions are adequately treated basal cell or squamous cell carcinoma that has
undergone potentially curative therapy or carcinoma in situ of the cervix.
5. Has an underlying medical condition that would preclude study participation.
6. Has a disease that is suitable for therapy administered with curative intent.
7. Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 4 weeks of the first dose of treatment.
8. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment.
9. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at Baseline) from AE due to agents
administered more than 4 weeks earlier.
10. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study Day 1 or has not recovered (i.e., ≤ Grade 1 or at
Baseline) from AE due to a previously administered agent .
11. An active autoimmune disease that has required systemic treatment in the 2 years
preceding the study (i.e., with the use of disease-modifying agents, corticosteroids
or immunosuppressive drugs). Note: Replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency,
etc.) is not considered a form of systemic treatment and is allowed.
12. Has received transfusions of blood products (including platelets or red blood cells)
or administration of colony stimulating factors (including Granulocyte Colony
Stimulating Factor [G-CSF], GM-CSF or recombinant erythropoietin) within 4 weeks prior
to study Day 1.
13. Has a history of (non-infectious) pneumonitis that required steroids or current
pneumonitis.
14. Has a history of interstitial lung disease.
15. O2 saturation < 92% (on room air).
16. For both Cohorts: Has unstable angina, new onset angina within the last 3 months,
myocardial infarction within the last 6 months, and current congestive heart failure
New York Heart Association Class III or higher. For Cohort 2: has ventricular
arrhythmias or uncontrolled blood pressure, or severe arterial thromboembolic events
less than 6 months prior to study initiation.
17. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating Investigator.
18. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
19. Is pregnant or breastfeeding or expecting to conceive or father children within the
projected duration of the trial, starting with the Screening visit through 120 days
after the last dose of trial treatment. Women with a positive pregnancy test within 72
hours from Baseline.
20. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or if
the subject has previously participated in Merck MK-3475 clinical trials.
21. Has a positive HIV test at Screening or at any time prior to Screening. Patients
without a prior positive HIV test result will undergo an HIV test at Screening, unless
not permitted per local regulations.
22. Has known active Hepatitis B (defined as having a positive Hepatitis B surface antigen
(HBsAg) test at Screening) or Hepatitis C (defined as having a positive HCV antibody
test or a positive HCV RNA test at Screening)
23. Has known history of Chronic Hepatitis B or C
24. Has received a live vaccine within 30 days of the planned start of study therapy.
Seasonal flu vaccines that do not contain live virus are permitted.
25. Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Note: Subjects with previously treated brain metastases may participate
provided they are stable (without evidence of progression by imaging using the
identical imaging modality for each assessment, either MRI or computerized tomography
(CT) scan, for at least four weeks prior to the first dose of trial treatment and any
neurologic symptoms have returned to Baseline), have no evidence of new or enlarging
brain metastases, and are not using steroids for at least 14 days prior to trial
treatment. This exception does not include carcinomatous meningitis which is excluded
regardless of clinical stability.
26. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
27. Cohort 2: Has clinical ascites requiring treatment
