PRIMARY OBJECTIVES:
I. To assess the overall response rate (complete response or partial response) after
treatment with CXCR4 antagonist BL-8040 (BL-8040) and pembrolizumab.
SECONDARY OBJECTIVES:
I. To determine the ability of BL-8040 by itself and in combination with pembrolizumab to
increase T cell infiltration into the tumor.
II. To determine if BL-8040 treatment results in increases in circulating immune cells.
III. To estimate the safety and tolerability of intravenous administration of pembrolizumab
in combination with sub-cutaneously injected BL-8040 in subjects with advanced pancreatic
cancer.
EXPLORATORY OBJECTIVES:
I. To evaluate overall response rate (ORR) per immune-related (ir) Response Evaluation
Criteria in Solid Tumors (RECIST) and duration of response (DOR), disease control rate (DCR),
time to progression (TTP), progression free survival (PFS), and overall survival (OS) per
RECIST and irRECIST assessed by MD Anderson investigators.
II. To explore the association between PD-L1 expression by immunohistochemistry, shed PD-L1
level, somatic gene expression profiling and antitumor efficacy of pembrolizumab based on
RECIST 1.1 imaging criteria as well as overall survival.
III. To explore the relationship between genomic variation and response to the treatment
administered.
IV. Tissue and blood immune monitoring will be conducted through our immune platform group as
detailed per the biomarker section based on 3 biopsies done at the following time points: 1)
pre-treatment, 2) during the third week of cycle 2 or beginning of cycle 3, and 3) voluntary
upon end of cycle 1 (BL-8040 [BL] monotherapy) on days 10 to 14.
OUTLINE:
Patients receive CXCR4 antagonist BL-8040 subcutaneously (SC) on days 1-5 and 8-12 of cycle 1
and days 1, 4, 8, and 11 of subsequent cycles. Beginning cycle 2, patients also receive
pembrolizumab intravenously (IV) over about 30 minutes on day 1. Cycles repeat every 21 days
for up to 1 year in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then every 10
and 12 weeks.
Inclusion Criteria:
- Have histologically or cytologically confirmed diagnosis of pancreatic adenocarcinoma
based on pathology report
- Be willing and able to provide written informed consent for the trial
- Have measurable disease based on RECIST 1.1; target lesions situated in a previously
irradiated area are considered measurable if progression has been demonstrated in such
lesions
- Have documented objective radiographic progression after stopping treatment with
first-line therapy; Note: the same image acquisition and processing parameters should
be used throughout the study for a given subject
- Be willing to provide tissue from a newly obtained core or excisional biopsy of a
tumor lesion from a metastatic site; newly-obtained is defined as a specimen obtained
up to 6 weeks (42 days) prior to initiation of treatment on day 1; subjects for whom
newly-obtained samples cannot be provided (e.g. inaccessible or subject safety
concern) may submit an archived specimen only upon agreement from Merck; the specimen
must be from a biopsy site that would be accessible for at least one subsequent biopsy
after initiation on the trial
- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
performance scale
- Have a predicted life expectancy of greater than 3 months
- Absolute neutrophil count (ANC) >= 1,000 /mcL (performed within 10 days of treatment
initiation)
- Platelets >=100,000 /mcL (performed within 10 days of treatment initiation)
- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO)
dependency (within 14 days of assessment) (performed within 10 days of treatment
initiation)
- Serum creatinine OR measured or calculated creatinine clearance (should be calculated
per institutional standard) (glomerular filtration rate [GFR] can also be used in
place of creatinine or creatinine clearance [CrCl]) =< 1.5 X upper limit of normal
(ULN) OR >= 60 mL/min for subject with creatinine levels =< 1.5 X institutional ULN
(performed within 10 days of treatment initiation)
- Serum total bilirubin =< ULN OR direct bilirubin =< ULN for subjects with total
bilirubin levels > ULN (performed within 10 days of treatment initiation)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase [SGPT]) =< 1.5 X
ULN (performed within 10 days of treatment initiation)
- Albumin >= 3.3 mg/dL in the absence of dehydration (performed within 10 days of
treatment initiation)
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless
subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
time (PTT) is within therapeutic range of intended use of anticoagulants (performed
within 10 days of treatment initiation)
- Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving
anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
of anticoagulants (performed within 10 days of treatment initiation)
- Have a negative urine or serum pregnancy test within 72 hours prior to receiving the
first dose of study medication (cycle 1, day 1) (female subjects of childbearing
potential); if the urine test is positive or cannot be confirmed as negative, a serum
pregnancy test will be required
- Female subjects of childbearing potential must be willing to use an adequate method of
contraception; contraception, for the course of the trial through 120 days after the
last dose of trial drug; note: abstinence is acceptable if this is the usual lifestyle
and preferred contraception for the subject; male subjects of childbearing potential
must agree to use an adequate method of contraception; contraception, starting with
the first dose of trial therapy through 120 days after the last dose of trial therapy
Exclusion Criteria:
- Has 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
- Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy, herbal/complementary oral or
IV medicine, or used an investigation device within 4 weeks of the first dose of
treatment
- 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
- Had a solid organ or hematologic transplant
- Has 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, etc.) is not considered a
form of systemic treatment
- Has a diagnosed additional malignancy within 1 year prior to first dose of study
treatment with the exception of curatively treated basal cell carcinoma of the skin,
squamous cell carcinoma of the skin and/or curatively resected in situ cervical and/or
breast cancers
- Has radiographically detectable (even if asymptomatic and/or previously treated)
central nervous system (CNS) metastases and/or carcinomatous meningitis as assessed by
principal investigator (PI) and radiology review
- Subjects excluded if there is a history of (non-infectious) pneumonitis that required
steroids, evidence of interstitial lung disease, or active, non-infectious pneumonitis
- Has an active infection requiring systemic therapy
- 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, including
dialysis
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial
- 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
- Has received prior immunotherapy with agents that target PD-1, PD-L1, PD-L2, CTLA-4,
OX-40, or CD-137 agents, or if the subject has previously participated in Merck
pembrolizumab clinical trials
- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
- Has known hepatitis B or hepatitis C
- Has received a live vaccine within 30 days of planned start of study therapy (cycle 1,
day 1); Note: the killed virus vaccines used for seasonal influenza vaccines for
injection are allowed; however intranasal influenza vaccines (e.g., FluMist) are live
attenuated vaccines and are not allowed
- Has a known history of active TB (Bacillus tuberculosis)
- Unable to tolerate a contrast enhanced computed tomography (CT) or magnetic resonance
imaging (MRI) for staging/restaging purposes
- Hypersensitivity to pembrolizumab or any of its excipients
- 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 adverse events
due to such agents administered more than 4 weeks earlier
- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at
baseline) from adverse events due to a previously administered small molecule agent;
a. Note: subjects with =< grade 2 neuropathy or alopecia are an exception to this
criterion and may qualify for the study; b. Note: if subject received major surgery,
they must have recovered adequately from the toxicity and/or complications from the
intervention prior to starting therapy
- Patients requiring beta blockade are disqualified from participating in this study
- Patients who, in the estimation of the treating physician or primary investigator,
have had a clinical deterioration of their ECOG performance within the month prior to
enrollment
- The use of natural or synthetic cannabinoids
- Patients with 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
