Nivolumab, Cabiralizumab, and Gemcitabine Combination Therapy for the Treatment of Metastatic Pancreatic Cancer, Gem CaN Study

Inclusion Criteria

• Be willing and able to provide written informed consent for the trial. Participants must have signed and dated an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal participant care
• Histologically or cytologically confirmed pancreatic adenocarcinoma with metastasis, who have achieved disease control on prior first-line chemotherapy for their metastatic disease, defined as: Must have obtained at least stable disease (SD) or a partial response (PR) for a period of at least 2 months with no further shrinkage of >= 20% on imaging scan. Note: Patients that have had prior chemotherapy as adjuvant or neoadjuvant therapy are permitted
• Must have been off their prior cytotoxic regimen a minimum of two weeks but no more than five weeks from initiating trial treatment on cycle 1 day 1 (C1/D1) (may not exceed 5 weeks unless discussed with sponsor)
• Measurable disease by RECIST 1.1
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Absolute neutrophil count (ANC) >= 1500/uL
• Platelets >= 100 000/uL
• Creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 30 mL/min for participant with creatinine levels >1.5 x institutional ULN * CrCl should be calculated per institutional standard
• Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L * Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks
• Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 x ULN
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) or alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.0 x ULN
• International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
• Creatine kinase within normal limits (WNL)
• Vitamin D >= 20 ng/dL
• Vitamin D level >= 20 ng/dL. Note: Vitamin D supplementation is allowed. Proposed dose: 100,000 loading dose. Followed by 50,000 units 3 times a week for 2 weeks. Recheck level. Final dosing for supplementation is deferred to treating physician. Vitamin D supplementation throughout study treatment is allowed
• Able to submit an archival tumor specimen (primary or metastatic site). Patients with cytology only that do not have adequate archived tumor specimen available, will require a baseline biopsy. * Optional Biopsy: A discussion to be documented with trial investigator at screening regarding the purpose of the optional tissue collection from a newly obtained core or excisional biopsy of a tumor lesion at baseline and a second biopsy 7 weeks (cycle 2 day 15 [C2/D15]) after starting trial treatment, or at time of disease progression, unless tumor is considered inaccessible or biopsy is otherwise considered not in the patients’ best interest. Participation in this trial is not contingent on patient consenting to optional tumor biopsies
• Women of childbearing potential (WOCBP) must not be breast feeding and have a negative serum or urine pregnancy test within 24 hours prior to the start of study treatment
• WOCBP must agree to follow protocol specified method(s) of contraception for the duration of treatment with study treatment(s) and for a total of 6 months post-treatment completion. WOCBP who are continuously not heterosexually active are also exempt from contraceptive requirements, but still must undergo pregnancy testing
• Males who are sexually active with WOCBP must agree to follow protocol specified method(s) of contraception for the duration of treatment with study treatment(s) and for a total of 7 months post-treatment completion. In addition, male participants must be willing to refrain from sperm donation during this time. Azoospermic males are exempt from contraceptive requirements

Exclusion Criteria

• Is currently participating and receiving trial therapy or has participated in a trial of an investigational agent and received trial therapy or used an investigational device within 3 weeks of the first dose of trial 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. The use of physiologic doses of corticosteroids may be approved after consultation with the sponsor
• Has a known history of active TB (Mycobacterium tuberculosis).
• Microsatellite unstable patients as assessed by immunohistochemistry (IHC) for mismatch repair (MMR) protein
• Hypersensitivity to cabiralizumab, nivolumab, or gemcitabine or any of its excipients
• Previous malignancies (except non-melanoma skin cancers, and in situ bladder, gastric, colorectal, endometrial, cervical/dysplasia, melanoma, or breast cancers) unless complete remission was achieved at least 2 years prior to study entry and no additional therapy is required during the study period
• Evidence of central nervous system (CNS) metastasis (negative imaging study, if clinically indicated, within 4 weeks of study treatment)
• Participants with active, known, or suspected autoimmune disease. Participants with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, euthyroid participants with a history of Grave’s disease (participants with suspected autoimmune thyroid disorders must be negative for thyroglobulin and thyroid peroxidase antibodies and thyroid stimulating immunoglobulin prior to first dose of study treatment), psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
• Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study treatment administration except for adrenal replacement steroid doses =< 10 mg daily prednisone equivalent in the absence of active autoimmune disease. Note: Treatment with a short course of steroids (< 5 days) up to 7 days prior to initiating study treatment is permitted
• Current or history of clinically significant muscle disorders (e.g., myositis), recent unresolved muscle injury, or any condition known to elevate serum creatinine kinase (CK) levels
• Uncontrolled or significant cardiovascular disease including, but not limited to, any of the following: * Myocardial infarction or stroke/transient ischemic attack within the past 6 months * Uncontrolled angina within the past 3 months * Any history of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes) * History of other clinically significant heart disease (e.g., cardiomyopathy, congestive heart failure with New York Heart Association functional classification III to IV, pericarditis, significant pericardial effusion, or myocarditis) * Cardiovascular disease-related requirement for daily supplemental oxygen therapy
• Prior organ allograft or allogeneic bone marrow transplantation
• Any major surgery within 4 weeks of study treatment. Participants must have recovered from the effects of major surgery or significant traumatic injury at least 14 days before the first dose of study treatment
• All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must have resolved to grade 1 (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] version [v]5.0) or baseline before administration of study treatment. Participants with toxicities attributed to prior anti-cancer therapy that are not expected to resolve and result in long lasting sequelae after platinum- based therapy, are permitted to enroll. Patients with =< grade 2 neuropathy may qualify for this trial
• Evidence of uncontrolled, active infection, requiring parenteral anti-bacterial, anti-viral or anti-fungal therapy =< 7 days prior to administration of study medication
• Any uncontrolled inflammatory gastrointestinal (GI) disease including Crohn’s disease and ulcerative colitis
• Transfusion completed within 72 hours prior to first dose of study drug administration
• Concomitant use of statins while on study. However, a participant using statins for over 3 months prior to study drug administration and in stable status without CK rise may be permitted to enroll
• Non-oncology vaccine therapies for prevention of infectious diseases (e.g. human papilloma virus vaccine) within 4 weeks of study drug administration. The inactivated seasonal influenza vaccine can be given to participants before treatment and while on therapy without restriction. Influenza vaccines containing live virus or other clinically indicated vaccinations for infectious diseases (i.e. pneumovax, varicella, etc) may be permitted, but must be discussed with the Sponsor and may require a study drug washout period prior to and after administration of vaccine
• Participants with abnormal serum chemistry values, which in the opinion of the investigator is considered to be clinically significant, will be excluded from the study. This will include participants who show clinical signs and symptoms related to their abnormal serum chemistry values, as well as participants whose serum chemistry values are asymptomatic but clinically significant (e.g. hypokalemia or hyponatremia)
• Evidence of coagulopathy or bleeding diathesis
• Treatment with botanical preparations (e.g. herbal supplements, including potential drugs of abuse, or traditional Chinese medicines) intended for general health support or to treat the disease under study within 2 weeks prior to randomization/treatment
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient’s participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Has received prior therapy with a CSF-1R pathway inhibitors, anti-PD-1, anti-PD-L1, anti PD-L2, anti-CTLA-4
• Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies), hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleotide acid [RNA] [qualitative] is detected). Note: Participants with positive hepatitis C antibody and negative quantitative hepatitis C by polymerase chain reaction (PCR) are eligible
• Female who is pregnant or breast-feeding
• Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific circumstances a person who has been imprisoned may be included or permitted to continue as a participant. Strict conditions apply and sponsor approval is required