5.3.8. Definition of an Overdose of Investigational Agents for This Protocol For this trial (a fixed-dose regimen), an overdose will be defined as ≥1,000 mg (5 times the dose) of pembrolizumab. No specific information is available on the treatment of overdose of pembrolizumab. In the event of overdose, the patient should be observed closely for signs of toxicity. Appropriate supportive treatment should be provided if clinically indicated. No overdose is defined for galinpepimut-S. SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 163 5.3.9. Toxicity Management of Known/Expected AEs Associated with the Continuing Use of Hypomethylating Agents (HMAs) in Patients Enrolled in the AML Arm Dose modifications for HMA-related (known/expected) toxicities -for either azacitidine or decitabine- in AML patients will be based on the respective US Prescribing Information for these products. These documents are included as Ap pendices 12.1 and 12.2. 5.3.9.1. Toxicity Profile and Dose Modifications for Azacitidine (AML Patients) (Vidaza® US Prescribing Information; Appendix 12.1) Most common adverse reactions (>30%) of azacitidine administered by the subcutaneous route are: nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, neutropenia and ecchymosis. Most common adverse reactions by the IV route also included petechiae, rigors, weakness and hypokalemia. Adverse reactions most frequently (≥ 2%) resulting in medical/clinical intervention and/or dose modification in patients receiving azacitidine (S.C. or IV Route) are as follows: • Discontinuation: leukopenia, thrombocytopenia, neutropenia. • Dose Held: leukopenia, neutropenia, thrombocytopenia, pyrexia, pneumonia, febrile neutropenia. • Dose Reduced: leukopenia, neutropenia, thrombocytopenia. Dose Modifications: A. For hematologic toxicity For patients with baseline (start of treatment) WBC > 3.0 x10 9/L, ANC > 1.5 x109/L, and platelets > 75.0 x109/L, adjust the dose as follows, based on nadir counts for any given cycle: SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 164 Nadir Counts % Dose in the Next Course ANC (x109/L) Less than 0.5 0.5 –1.5 Greater than 1.5 Platelets (x109/L) Less than 25 25-50 Greater than 50 50% 67% 100% For patients whose baseline counts are WBC < 3.0 x109/L, ANC < 1.5x109/L, or platelets < 75.0 x109/L, base dose adjustments on nadir counts and bone marrow biopsy cellularity at the time of the nadir as noted below, unless there is clear improvement in differentiation (percentage of mature granulocytes is higher and ANC is higher than at onset of that course) at the time of the next cycle, in which case continue the current dose. If a nadir as defined in the table above has occurred, give the next course 28 days after the start of the preceding course, provided that both the WBC and the platelet counts are greater than 25% above the nadir and rising. If a greater than 25% increase above the nadir is not seen by day 28, reassess counts every 7 days. If a 25% increase is not seen by day 42, reduce the scheduled dose by 50%. B. For non-hematologic (serum electrolytes and renal) toxicity SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 165 If unexplained reductions in serum bicarbonate levels to less than 20 mEq/L occur, reduce the dosage by 50% for the next course. Similarly, if unexplained elevations of BUN or serum creatinine occur, delay the next cycle until values return to normal or baseline and reduce the dose by 50% for the next course. 5.3.9.2. Toxicity Profile and Dose Modifications for Decitabine (AML Patients) (Dacogen® US Prescribing Information; Appendix 12.2) Most common adverse reactions (> 50%) seen during decitabine therapy include neutropenia, thrombocytopenia, anemia, and pyrexia. Adverse reactions most frequently (≥ 1%) resulting in medical/clinical intervention and/or dose modification in patients receiving decitabine are as follows: • Discontinuation: thrombocytopenia, neutropenia, pneumonia, Mycobacterium avium complex infection, cardio-respiratory arrest, increased blood bilirubin, intracranial hemorrhage, abnormal liver function tests. • Dose Delayed: neutropenia, pulmonary edema, atrial fibrillation, central line infection, febrile neutropenia. • Dose Reduced: neutropenia, thrombocytopenia, an emia, lethargy, edema, tachycardia, depression, pharyngitis. Dose Modifications: A. For hematologic toxicity If hematologic recovery from a previous decitabine treatment cycle requires more than 6 weeks, delay the next cycle of decitabine therapy and reduc e decitabine dose temporarily by following this algorithm: SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 166 • Recovery requiring more than 6, but less than 8 weeks: Delay DACOGEN dosing for up to 2 weeks and reduce the dose temporarily to 11 mg/m2 every 8 hours (33 mg/m2/day, 99 mg/m2/cycle) upon restarting therapy. • Recovery requiring more than 8, but less than 10 weeks: Perform bone marrow aspirate to assess for disease progression. In the absence of progression, delay the decitabine dose up to 2 more weeks and reduce the dose to 11 mg/m 2 every 8 hours (33 mg/m2/day, 99 mg/m2 /cycle) upon restarting therapy, then maintain or increase dose in subsequent cycles as clinically indicated. B. For non-hematologic toxicity Delay subsequent decitabine treatment for any the following non -hematologic toxicities and do not restart until toxicities resolve: • Serum creatinine > 2 mg/dL • SGPT, total bilirubin > 2 x ULN • Active or uncontrolled infection 5.4. Management of Clinical Supplies 5.4.1. Study Drug Packaging and Storage Galinpepimut-S will be provided as a sterile, lyophilized powder filled into a 2 mL colorless glass vial that requires reconstitution with SWFI. Galinpepimut-S should be stored at the site at or below –20°C until use. Montanide will be packaged in 3-mL amber glass vials. The adjuvant should be stored between 15°C and 30°C. This product must not be frozen.