Require therapeutic use of anticoagulants
INR < 1.3 (or < 3 on anticoagulants)
Current or recent use of therapeutic oral or parenteral anticoagulants or thrombolytic agents
Current or recent (within 10 days of study enrollment) use of anticoagulants that, in the opinion of the investigator, would place the subject at significant risk for bleeding. Prophylactic use of anticoagulants is allowed.
Coagulopathy, including the use of therapeutic anticoagulants that cannot be discontinued for the cryoablation procedure; NOTE: Heparin for line patency without detectable lab abnormalities for coagulation will be allowed
(Bevacizumab-related exclusion) Current or recent (within 10 days of study enrolment) use of aspirin (> 325 mg/day), clopidogrel (> 75 mg/day), or current or recent (within 10 days prior to first dose of bevacizumab) use of therapeutic oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes Note: The use of full-dose oral or parenteral anticoagulants is NOT permitted for at least two weeks at the time of study enrollment. Prophylactic use of anticoagulants is NOT allowed
Current or recent (within 10 days of study enrolment) use of aspirin (> 325 mg/day), clopidogrel (> 75 mg/day), or current or recent (within 10 days prior to first dose of bevacizumab) use of therapeutic oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes\r\n* NOTE: The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits (according to the medical standard of the institution) and the subject has been on a stable dose of anticoagulants for at least two weeks at the time of study enrollment; prophylactic use of anticoagulants is allowed
Current or recent (=< 10 days of study enrollment) use of aspirin (> 325 mg/day), clopidogrel (> 75 mg/day), or therapeutic oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes\r\n* The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits (according to medical standard of the institution) and the patient has been on a stable dose of anticoagulants for at least 2 week at the time of study enrollment; prophylactic use of anticoagulants is allowed
Not on full dose anticoagulants
Patients receiving anticoagulants that are unable to be discontinued
Current or recent (within 10 days of first dose of bevacizumab) use of aspirin (> 325 mg/day) or other nonsteroidal anti-inflammatories known to inhibit platelet function; prophylactic use of anticoagulants is allowed
Exclusion criteria related to study medication:\r\n* Current or recent (within 10 days of study enrollment) use of acetylsalicylic acid (> 325 mg/day), clopidogrel (> 75 mg/day) or current or recent (within 10 days of first dose of bevacizumab) use of therapeutic oral or parenteral anticoagulants or thrombolytic agents for therapeutic purpose. Note: The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or partial thromboplastin time (aPTT) is within therapeutic limits (according to the medical standard of the enrolling institution) and the patient has been on a stable dose of anticoagulants for at least 2 weeks at the time of cycle 1 day 1. Prophylactic use of anticoagulants is allowed\r\n* History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins\r\n* Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells, any components of binimetinib, pembrolizumab, or bevacizumab formulations or any premedications\r\n* Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti-PD-1, anti-PD L1, anti-PD-L2 or MAPK pathway inhibitors (eg; BRAF, MEK, ERK inhibitors)\r\n* Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to randomization
The use of full?dose oral or parenteral anticoagulants is permitted as long as the international normalized ratio (INR) or activated partial thromboplastin time (aPTT) is within therapeutic limits (according to the medical standard of the enrolling institution), and the patient has been on a stable dose of anticoagulants for at least two weeks prior to the first study treatment
International normalized ratio (INR): < 1.5 x institutional upper limit of normal OR < 3 if on warfarin or other anticoagulants; there should be no evidence of active bleeding while on anticoagulants
Patients on any anticoagulants except aspirin are not eligible
Current treatment with therapeutic anticoagulants
Evidence of bleeding diathesis, coagulopathy as documented by an elevated (? 1.5 x ULN) prothrombin time (PT), partial thromboplastin time (PTT), or bleeding time. The use of full-dose oral or parenteral anticoagulants is permitted as long as the PT or aPTT is within therapeutic limits (according to the medical standard of the enrolling institution) and the subject has been on a stable dose of anticoagulants for at least 2 weeks prior to the first study treatment.
Use of anticoagulants, antiplatelet agents, antithrombotics and thrombolytics within the 72 hours prior to first does of study drug.
Current or recent (=< 10 days prior to randomization) use of therapeutic oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes, unless the patient has been on a stable dose of anticoagulants for at least 2 weeks at the time of randomization; Note: the use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or activated partial thromboplastin time (aPTT) is within therapeutic limits (according to the medical standard of the institution) and the patient has been on a stable dose of anticoagulants >= 14 days at the time of randomization; prophylactic use of anticoagulants is allowed
Within 4 weeks of administration of study therapy: International normalized ration (INR) or prothrombin time (PT) =< 1.5 x ULN (only if not using anticoagulants); if patient is receiving anticoagulants, then value must be within therapeutic range for the condition that patient is being treated for
Within 4 weeks of administration of study therapy: Activated partial thromboplastin time (aPTT) =< 1.5 x ULN (only if not using anticoagulants); if patient is receiving anticoagulants, then value must be within therapeutic range for the condition that patient is being treated for
Ongoing therapy with oral or parenteral anticoagulants (e.g., heparin, warfarin); low-dose anticoagulants for maintenance of catheter patency are not exclusionary
Subjects who require therapeutic doses of anticoagulants.
Use of anticoagulants that cannot be discontinued both 5 days before and 5 days after EUS
No current or recent (within 28 days of enrollment) full dose anticoagulants or thrombolytic agents
Current use of anticoagulants
Use of aspirin (>325 mg/day) within 10 days prior to the first dose of study treatment. The use of prophylactic therapeutic anti-coagulants are allowed provided that INR or aPTT are within therapeutic limits (according to the medical standard of the enrollment institution) and patient has been on a stable dose of anticoagulants for at least two weeks prior to the first dose of study treatment.
Medications that inhibit platelet function and anticoagulants
Requiring anticoagulants at therapeutic doses or platelet inhibitor.
Concurrent anticoagulation will be permitted providing the patient is receiving a stable dose of anticoagulants before study entry; patients receiving anticoagulants will be eligible for this trial; evidence of clinically significant bleeding diathesis or underlying coagulopathy (e.g., INR > 1.5 without vitamin K antagonist therapy) will not be permitted
Patients on systemic anticoagulants are excluded from this study
for intratumoral cohort, bleeding diathesis or use of anticoagulants/antiplatelet agents that cannot be stopped
Activated partial thromboplastin time (aPTT) =< 2.0 x IULN if not using anticoagulants within 28 days prior to registration; if using anticoagulants, then the value must be within therapeutic range according to the condition for which the patient is being treated within 28 days prior to registration
Use of anticoagulants that cannot be discontinued in order to guarantee an INR below 1.5