BXCL701 and Pembrolizumab for the Treatment of Patients with Metastatic Pancreatic Ductal Cancer

Inclusion Criteria

• Histologically-confirmed pancreatic ductal adenocarcinoma with metastatic disease (mixed histology is acceptable as long as adenocarcinoma is the dominant histological subtype)
• Patient must consent to two mandatory biopsies and have tumor amenable to serial core biopsies
• Measurable disease by Immune Response Evaluation Criteria in Solid Tumors (iRECIST) version (v.) 1.1 criteria (tumor ≥ 1 cm in longest diameter on axial image on CT or MRI and/or lymph node[s] ≥ 1.5 cm in short axis on CT or MRI) on baseline imaging
• Documented progression of disease or intolerance on at least one regimen for metastatic disease (progression during or within 3 months of the completion of neoadjuvant/adjuvant therapy is acceptable)
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1
• Age ≥ 18 years
• Criteria for known hepatitis B and C positive subjects * Hepatitis B and C screening tests are not required unless: ** Known history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection ** As mandated by local health authority ** Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization. ** Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post-completion of study intervention. ** Participants with history of HCV infection are eligible if HCV viral load is undetectable at screening; participants must have completed curative anti-viral therpay at least 4 weeks prior to cycle 1 day 1 (C1D1)
• Subjects with no brain metastases or a history of previously treated brain metastases who have been treated by surgery or stereotactic radiosurgery (SRS) at least 4 weeks prior to enrollment and have a baseline MRI that shows no evidence of active intracranial disease
• Patients with available standard 12-lead electrocardiogram (ECG) with the following parameters at screening (defined as the mean of the triplicate ECGs): * Corrected QT interval QTcB (Bazett’s formula) interval at screening < 480msec
• Absolute neutrophil count (ANC) ≥ 1,500/mm^3
• Platelets ≥ 100 × 10^9/L
• Hemoglobin ≥ 9.0 g/dL (with no prior red blood cell transfusions during the prior 14 days)
• Serum creatinine ≤ 1.5 × upper normal limit of institution's normal range or creatinine clearance ≥ 50 mL/min/1.73 m^2 for subjects with creatinine levels above institutional normal
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × the upper normal limit of institution's normal range
• Total bilirubin ≤ 1.5 × the upper normal limit of institution's normal range
• For subjects with liver metastases, AST and ALT < 5 × the upper normal limit of institution's normal range, and total bilirubin >1.5 - 3.0 x the upper normal limit of institution's normal range are acceptable as long as there is no persistent nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia
• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x the upper limit of normal unless patient is receiving anticoagulant therapy as long as the PT or activated partial thromboplastin time (aPTT) is within the therapeutic range of intended use of anticoagulants
• Patients must have fully recovered from all effects of surgery. Patients must have had at least two weeks after minor surgery and four weeks after major surgery before starting therapy. Minor procedures requiring “twilight” sedation such as endoscopies or mediport placement may only require a 24-hour waiting period, but this must be discussed with the principal investigator
• Women of childbearing potential must have a negative serum pregnancy test during the screening period and on C1D1 and/or postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential
• Patient is capable of swallowing pills whole
• Patient is capable of understanding and complying with parameters as outlined in the protocol and able to sign and date the informed consent, approved by the Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures
• Patient’s acute toxic effects of previous anticancer therapy have resolved to ≤ grade 1 except for grade 2 peripheral neuropathy or any grade of alopecia
• Male patients and their female partners of childbearing potential who engage in vaginal sex must agree and commit to use a barrier contraception (e.g., condom with spermicidal foam/gel/film/cream/ suppository) throughout the duration of the study until at least 6 months following the last dose of study drug, in addition to their female partners using either an intrauterine device or hormonal contraception and continuing until at least 6 months following the last dose of study drug. This criterion may be waived for male patients who have had a vasectomy > 6 months before signing the informed consent form

Exclusion Criteria

• Prior anti-tumor therapy within 4 weeks of C1D1 (defined as, but not limited to, anti-cancer agents [cytotoxic chemotherapy, immunotherapy, biologic therapy, and investigational agents]), and radiotherapy within 2 weeks of C1D1, the “washout period"
• Patients previously exposed to FAP inhibitors, DPP inhibitors, or monoclonal antibodies targeting anti-PD-1, anti-PD-L1, anti-PD-L2, or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g. CTLA-4, OX-40, CD137)
• Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator’s judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol (e.g. chronic symptomatic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial, or viral infection)
• Patient has a history of allogenic tissue/solid organ transplant
• Women who are pregnant or breastfeeding; women of child bearing potentional whose pregnancy test is positive within 72 hours prior to enrollment
• Psychiatric illness or social situation that would limit compliance with study requirements
• Concurrent malignancy or malignancy within 2 years prior to C1D1, with the exception of adequately treated cutaneous basal or squamous cell carcinoma, non-melanomatous skin cancer, curatively resected cervical cancer, or any locally treated malignancy deemed low likelihood for recurrence or metastasis by the investigator
• Patients with central nervous system (CNS) involvement unless they meet ALL of the following criteria:
• At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment
• Clinically stable CNS tumor at the time of screening and not receiving steroids at least 14 days prior to C1D1 and/or enzyme-inducing anti-epileptic medications for brain metastases
• Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
• Patient has a known history of human immunodeficiency virus (HIV) infection or chronic, active hepatitis B or C (testing is not mandatory) – patients with hepatitis B and/or hepatitis C status-post treatment with undetectable viral load are eligible (see above inclusion criteria)
• Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator’s judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol (e.g. chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or viral infections, etc.)
• Patient has uncontrolled, clinically significant pulmonary disease (e.g. chronic obstructive pulmonary disease, pulmonary hypertension) that in the opinion of the investigator would put the patient at significant risk for pulmonary complications during the study
• Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormalities, including any of the following:
• History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 6 months prior to screening
• History of documented congestive heart failure (New York Heart Association functional classification III-IV)
• Documented cardiomyopathy
• Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO) at screening
• Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia), complete left bundle branch block, high-grade atrioventricular (AV) block (e.g. bifascicular block, Mobitz type II and third-degree AV block)
• Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
• Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia
• Concomitant use of medication(s) with a known risk to prolong the QT interval and/or known to cause Torsades de Pointe that cannot be discontinued (within 5 half-lives or 7 days prior to starting study drug) or replaced by safe alternative medication
• Inability to determine the QT interval on screening
• Patients with history of symptomatic orthostatic hypotension within 3 months prior to enrollment, defined as a drop in systolic blood pressure (SBP) of ≥ 20 mmHg or diastolic blood pressure (DBP) of ≥ 10 mmHg with assumption of an upright posture
• Patients with a history of (non-infectious) pneumonitis that required steroids, current pneumonitis, or those who have a history of interstitial lung disease
• Patients who have received a live-virus vaccination within 30 days of planned treatment start date, killed vaccines are allowed
• Patient must not have active known or suspected autoimmune disease requiring systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (e.g., celiac disease) are permitted to enroll
• Patient must not have a condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid doses ≤ 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
• Prisoners