Pembrolizumab and Hsp90 inhibitor XL888 in Treating Patients with Advanced Gastrointestinal Cancer

Inclusion Criteria

• Patients with stage IV or locally advanced unresectable gastrointestinal adenocarcinomas (gastric, gastroesophageal junction [GEJ], cholangiocarcinoma, hepatocellular, pancreas, small intestinal tumors) who have failed at least one prior therapy; patients with colorectal cancer must have previously received oxaliplatin, irinotecan, and a fluoropyrimidine (dose escalation phase)
• Patients with pancreatic adenocarcinoma; patients must have histologic diagnosis and either locally advanced unresectable or metastatic disease that has failed at least one standard regimen; eight patients will participate in the paired biopsy studies; patient selected for biopsy must have a primary or metastatic non-bone site that is amenable to safe biopsy; bone only lesions are not suitable for biopsy; these patients will provide informed consent for the paired biopsy study (dose expansion phase, arm A)
• Patients with colorectal adenocarcinoma; patients must have histologic diagnosis and either locally advanced unresectable or metastatic disease and have previously received oxaliplatin, irinotecan, and a fluoropyrimidine; eight patients will participate in the paired biopsy studies; patient selected for biopsy must have a primary or metastatic non-bone site that is amenable to safe biopsy; bone only lesions are not suitable for biopsy; these patients will provide informed consent for the paired biopsy study (dose expansion phase, arm B)
• Be willing and able to provide written informed consent/assent for the trial
• Be >= 18 years of age on day of signing informed consent
• Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
• Absolute neutrophil count (ANC) >= 1,500/mcL
• Platelets >= 100,000/mcL
• Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)
• Serum 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]) >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN * Creatinine clearance should be calculated per institutional standard
• Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x ULN OR =< 5 x ULN for subjects with liver metastases (only in the phase II portion)
• Albumin >= 2.5 mg/dL
• 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
• 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
• Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; 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 for the course of the study through 120 days after the last dose of study medication * 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, starting with the first dose of study therapy through 120 days after the last dose of study therapy. * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject

Exclusion Criteria

• 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
• 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
• Has a known history of active tuberculosis (TB) (Bacillus tuberculosis)
• Hypersensitivity to pembrolizumab or history of severe allergic or hypersensitivity reactions to excipients (e.g., polyethylene glycol [PEG] 300 and polysorbate 80)
• Clinically significant cardiovascular disease or peripheral vascular (e.g. myocardial infarction, unstable angina within 6 months of study entry), symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia requiring medications, baseline corrected QT (QTc) > 450 msec or previous history of QT prolongation while taking other medications
• Other medications, or severe acute/chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the subject inappropriate for entry into this study
• 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 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 agent * Note: Subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study * Note: Major surgical procedure, or significant traumatic injury within 28 days of registration or incompletely healed surgical wounds are exclusions; minor surgical procedures such as placement of central venous device (excluding peripherally inserted central catheter [PICC] line) are allowed 7 days prior to enrollment to the study
• Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging 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 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
• Has active autoimmune disease that has required systemic treatment in the 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 known history of, or any evidence of active, non-infectious pneumonitis
• Has an active infection requiring systemic therapy
• Has known 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 therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2, or HSP inhibitor
• Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
• Has known active hepatitis B (e.g., hepatitis surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
• History of malabsorption or other condition that would interfere with absorption of study drugs
• History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, RVO (retinal vein occlusion), or neovascular macular degeneration; the risk factors for RVO are listed below; patients should be excluded if they have the following current conditions: * Uncontrolled glaucoma with intra-ocular pressures > 21 mmHg * Serum cholesterol > grade 2 * Hypertriglyceridemia > grade 2 * Hyperglycemia (fasting) > grade 2
• Has received a live vaccine within 30 days of planned start of study therapy * Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist [registered trademark]) are live attenuated vaccines, and are not allowed