5.3.5. Overall Treatment Schedule The overall treatment administration schedule is shown in Figure 13 below: SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 141 Figure 13 Overall Treatment Administration Schedule 5.3.6. Toxicities Galinpepimut-S: The potential toxicities/side effects of galinpepimut-S include: Likely: • Induration at injection site SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 142 Less likely: • Arthralgias, myalgias • Fever • Headache • Edema • Allergic reaction Rare: • Elevated liver function tests • Elevated kidney function tests • Shortness of breath Montanide ISA 51 VG: The potential toxicities/side effects of Montanide ISA 51 VG include: • Mild inflammation at injection sites • Occasional fever • Allergic reactions have been observed rarely Sargramostim (GM-CSF): Sargramostim is an approved product, available in the US since 1991. It has been used in a number of studies as an immunologic adjuvant with the presumed benefit mediated through effects on dendritic and other antigen -presenting cells. Several human vaccine studies in melanoma and other human malignancies have reported both SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 143 encouraging immunologic and clinical results. More recently, 2 melanoma vaccine studies have reported a harmful effect of GM-CSF when used as a vaccine adjuvant (Faries et al, 2009; Slingluff et al, 2009). While it is important to recognize a potential negative effect, this study uses a different vaccine with a different dose of GM -CSF in a different disease. The potential toxicities/side effects of GM-CSF include (at standard doses of 250 µg/m2/day for 5 to 14 days): • Edema • Fluid retention • Headache • Myalgia • Arthralgia • Dyspnea • Allergic reactions • Patients with pre-existing renal and/or hepatic disorders may demonstrate elevations in serum creatinine or bilirubin/transaminases, respectively. Pembrolizumab toxicities are detailed in Section 5.3.6.3.1. SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 144 5.3.6.1. Dose -Limiting Toxicities All toxicities will be graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0, (published in November 2017), as per the following link:. https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Q uick_Reference_5x7.pdf. For patients enrolled across all active solid tumor cohorts (colorectal, ovarian, small cell lung cancer, breast cancer), the dose-limiting toxicity (DLT) window of observation will be at least one (1) cycle following the co -administration of galinpepimut-S in combination with pembrolizumab. A DLT is judged by the investigator to be possibly, probably, or definitely related to study drug administration. AML-specific DLTs will be considered separately (Section 5.3.6.2). The occurrence of any of the following toxicities will be considered a DLT (except for AML; please see Section 5.3.6.2), if judged by the investigator to be possibly, probably, or definitely related to study drug administration: 1. Grade 4 nonhematologic toxicity (not laboratory) 2. Grade 4 hematologic toxicity las ting ≥ 7 days, except thrombocytopenia: • Grade 4 thrombocytopenia of any duration • Grade 3 thrombocytopenia associated with bleeding 3. Any nonhematologic AE ≥ Grade 3 in severity should be considered a DLT, with the following exceptions: Grade 3 fatigue lasting ≤ 3 days; Grade 3 diarrhea, nausea, or vomiting without use of anti-emetics or anti-diarrheals per standard of care; Grade 3 rash without use of corticosteroids or anti-inflammatory agents per standard of care. 4. Grade 3 nonhematologic toxicity (not labor atory) lasting > 3 days despite optimal supportive care. 5. Any Grade 3 or Grade 4 nonhematologic laboratory value if: SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 145 • Clinically significant medical intervention is required to treat the patient, or • The abnormality leads to hospitalization, or • The abnormality persists for > 1 week. • The abnormality results in a drug-induced liver injury (DILI) • Exceptions: clinically nonsignificant, treatable, or reversible laboratory abnormalities, including liver tests, uric acid, etc. 6. Febrile neutropenia (FN) Grade 3 or Grade 4: • Grade 3 is defined as absolute neutrophil count (ANC) < 1000/mm3 with a single temperature of > 38.3°C (101°F) or a sustained temperature of ≥ 38°C (100.4°F) for more than 1 hour • Grade 4 is defined as ANC < 1000/mm3 with a single temperature of > 38.3°C (101°F) or a sustained temperature of ≥ 38°C (100.4°F) for more than 1 hour, with life-threatening consequences and urgent intervention indicated. 7. Any treatment-related toxicity that causes the patient to discontinue treatment durin g the period from the first administration of galinpepimut -S until the completion of the first cycle of galinpepimut-S plus pembrolizumab combination therapy . 8. Missing > 25% of pembrolizumab doses as a result of drug-related AE(s) during the first cycle of combination therapy. 9. Thrombocytopenia < 25,000/mm 3 if associated with: • A bleeding event which does not result in hemodynamic instability but requires an elective platelet transfusion, or • A life-threatening bleeding event which results in urgent interventio n and admission to an Intensive Care Unit (ICU) 10. Prolonged delay (> 2 weeks) in initiating Cycle 2 of combination therapy due to treatment-related toxicity 11. Grade 5 toxicity. Missing > 25% of the doses of either investigational agent as a result of drug -related AE(s) during the period from first administration of galinpepimut -S and up until the completion of SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 146 the first cycle of the co-administration of galinpepimut-S in combination with pembrolizumab. Staggered Early Enrollment: To minimize exposing subjects to the risk of potential unknown acute and subacute toxicities of combining pembrolizumab with galinpepimut-S, the inter-dosing interval in-between the first consecutive three (3) subjects to be enrolled in this study arm will be one (1) week following the administration of the first dose of pembrolizumab in these patients. DLT assessment and actions will be as follows (unless stopping rules apply): • If 2 or fewer patients of these first 6 patients have DLTs, enrollment can continue for up to another 6 patients across these arms with no dose adjustments made. If DLTs are observed in more than 2 patients of the first 6, the time interval between galinpepimut-S doses for the inoculation following the one associated with the DLT will be doubled. For example, if galinpepimut-S was given on a Q3W schedule before the DLT occurred, it should be given Q6W for the immediately subsequent administration after the dosing event associated with the DLT, while keeping the pembrolizumab dose and frequency stable. • In the next 6 patients (patients 7 to 12), if again, 2 or fewer of these patients have DLTs observed, enrollment can continue. If DLTs are observed in more than 2 of patients 7 to 12, the time interval between galinpepimut -S doses for the inoculation following the one associated with the DLT will be doubled, , but pembrolizumab will continue as scheduled. • If DLTs are observed in more than 2 patients of the first 6 (patients 1 to 6) and again in more than 2 patients of the next 6 (patients 7 to 12), the time interval between galinpepimut-S doses will be doubled for two (2) inoculations following the one associated with the DLT. For example, if galinpepimut -S was given on a Q3W schedule before the DLT occurred, it should be given Q6W for the 2 immediately subsequent administrations after the dosing event associated with the DLT, while keeping the pembrolizumab dose and frequency stable. SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 147 • If DLTs continue to be observed above 2 per every 6 patients beyond these first 12 patients, and even after the changes in administr ation of galinpepimut-S, the study will be stopped and the safety data will be examined by the sponsor in consultation with investigators in order to determine how to proceed or whether to discontinue the study. • Should a given patient experience any of the above DLTs at any time after the completion of the first cycle of co -administration of galinpepimut-S in combination with pembrolizumab, the time interval between galinpepimut -S doses for the inoculation following the one associated with the DLT will be d oubled, but pembrolizumab will continue as scheduled. • If another DLT occurs in that next cycle, the time interval between galinpepimut -S doses will be doubled for two (2) inoculations following the one associated with the DLT, but pembrolizumab will continue as scheduled. • If no DLTs re-occur after the above periods of doubly ‘spaced out’ administrations, then the patient should revert back to the initial GPS Q3W schedule (as per the initial dosing frequency/ investigational agent administration schedule). • If a DLT occurs after these dose modifications in subsequent cycles, the patient will be discontinued from the study. The above dose density modifications in response to DLTs is further summarized in the bulleted list of actions below: • First DLT à skip the next GPS inoculation (scheduled for the next cycle, i.e., 3 wks ahead) and administer GPS 6 wks ahead (i.e., ‘spread out’) once thereafter, i.e. for 1 additional cycle à DLT resolution à Return to per protocol schedule of GPS administration • Second DLT (after reverting to the per protocol schedule) à skip the next GPS inoculation (scheduled for the next cycle, i.e., 3 wks ahead) and administer GPS 6 wks ahead (i.e., ‘spread out’) twice thereafter, i.e. for 2 additional cycles à DLT resolution à Return to per protocol schedule of GPS administration SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 148 • Third DLT (occurring either after reverting to the per protocol schedule or during the ‘spread out’ schedule to manage the 2nd DLT above) à Discontinue patient from study. • N.B.: In all above modifications of the dose density of galinpepimut-S, as all intervals (in weeks) between 2 successive GPS administrations are multiples of three (3) by design, following these rules, co-administration with pembrolizumab is always secured. Stopping Rules: • Development of any SAEs at least “possibly attributable” to the study agent(s) in 2 out of the first 6 patients in the study. In this case, the upper 90% one-sided CI bound for 2 patients with SAEs within 6 patients would be 66.7%, consistent with an excessive rate of toxicity. • The fraction of patients experiencing an SAE at least “possibly attributable” to the study agent(s) exceeds 1/3, at any time during study implementation beyond the first 6 patients. • Death at least “possibly attributable” to the study agent(s) within 30 days after the administration of the investigational treatment (GPS plus pembrolizumab). If the study is stopped due to activation of the above rules, the safety data will be examined by the Sponsor in consultation with investigators in order to determine how to proceed or whether to discontinue the study at large. SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 149 5.3.6.2. AML -Specific Dose -Limiting Toxicities For patients enrolled in the AML arm, the DLT window of observation will be defined by the first 8 weeks from study entry/administration of first galinpepimut-S inoculation. The occurrence of any of the following toxicities during the first 8 weeks (from the time of administration of the first galinpepimut-S inoculation), if assessed by the investigator to be reasonably possibly related to study drug, will be considered a DLT: 1. Missing > 25% of the doses of investigational agent(s) as a result of drug-related AE during cycle 1 and/or 2 2. Drug-related AE which causes patient to discontinue treatment during cycle 1 and/or 2 3. Grade 5 toxicity 4. Grade 4 non-hematological toxicity (other than laboratory abnormality) 5. Grade 3 non-hematological toxicity (other than laboratory abnormality; exception: fatigue, nausea, emesis, diarrhea, rash, infection, fever, or bleeding unless the event lasts more than 3 days despite optimal care) 6. Grade 3 and 4 non-hematological lab abnormality, if any of the following occurs: a. Medical intervention is required b. Abnormality persists > 1 week c. Abnormality results in drug-induced liver injury 7. Any treatment-related toxicity that causes a greater than 3 -week delay in initiation of cycle 2 and/or 3 (the latter cycle being the first one whereby galinpepimut -S and pembrolizumab are co-administered). 8. Development of an immune-related AE (irAE) resulting in withholding of pembrolizumab and initiation of steroids, for example , grade 2 or higher colitis/diarrhea, grade 2 or higher pneumonitis, grade 2 or higher transaminitis, any grade myocarditis (complete list currently shown in Table 5) SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 150 Any other toxicities in the AML arm will not be considered dose-limiting. Staggered Early Enrollment: To minimize exposing subjects to the risk of potential unknown acute and subacute toxicities of combining HMA with the investigational therapy (pembrolizumab and galinpepimut -S) in the AML arm, the inter-dosing interval between the first two (2) subjects to be enrolled in this study arm will be 12 weeks. AML-specific DLT assessment and actions will be as follows (unless stopping rules apply): • Initially up to 6 patients will be enrolled in the AML cohort. If 2 or fewer patients of these first 6 patients have DLTs, enrollment can continue for up to another 6 patients in the AML arm with no dose adjustments made. If DLTs are observed in more than 2 patients of the first 6, the time interval between galinpepimut -S doses for the inoculation following the one associated with the DLT will be doubled. For example, if galinpepimut-S was given on a Q3W schedule before the DLT occurred, it should be given Q6W for the immediately subsequent administration after the dosing event associated with the DLT, while keeping the pembrolizumab dose and frequency stable. • In the next 6 patients (patients 7 to 12), if again, 2 or fewer of these patients have DLTs observed, enrollment can continue. If DLTs are observed in more than 2 of patients 7 to 12, the time interval between galinpepimut-S doses for the inoculation following the one associated with the DLT will be doubled, but pembrolizumab will continue as scheduled. • If DLTs are observed in more than 2 patients of the first 6 (patients 1 to 6) and again in more than 2 patients of the next 6 (patients 7 to 12), the time interval between galinpepimut-S doses will be doubled for two (2) inoculations following the one associated with the DLT. For example, if galinpepimut -S was given on a Q3W schedule before the DLT occurred, it should be given Q6W for the 2 immediately subsequent administrations after the dosing event associated with the DLT, while keeping the pembrolizumab dose and frequency stable. SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 151 • If DLTs continue to be observed above 2 per every 6 patients beyond the se first 12 patients, and even after the changes in administration of galinpepimut-S, the study will be stopped and the safety data will be examined by the sponsor in consultation with investigators in order to determine how to proceed or whether to discon tinue the study. • Should a given patient experience any of the above DLTs at any time after the completion of the first cycle of co -administration of galinpepimut-S in combination with pembrolizumab, the time interval between galinpepimut -S doses for the inoculation following the one associated with the DLT will be doubled, but pembrolizumab will continue as scheduled. • If another DLT occurs in that next cycle, the time interval between galinpepimut -S doses will be doubled for two (2) inoculations following the one associated with the DLT, but pembrolizumab will continue as scheduled. • If no DLTs re-occur after the above periods of doubly ‘spaced out’ administrations, then the patient should revert back to the initial GPS Q3W schedule (as per the initial dosing frequency/ investigational agent administration schedule). • If a DLT occurs after these dose modifications in subsequent cycles, the patient will be discontinued from the study. The above dose density modifications in response to DLTs is further summarized in the bulleted list of actions below: • First DLT à skip the next GPS inoculation (scheduled for the next cycle, i.e., 3 wks ahead) and administer GPS 6 wks ahead (i.e., ‘spread out’) once thereafter, i.e. for 1 additional cycle à DLT resolution à Return to per protocol schedule of GPS administration • Second DLT (after reverting to the per protocol schedule) à skip the next GPS inoculation (scheduled for the next cycle, i.e., 3 wks ahead) and administer GPS 6 wks ahead (i.e., ‘spread out’) twice thereafter, i.e. for 2 additional cycles à DLT resolution à Return to per protocol schedule of GPS administration SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 152 • Third DLT (occurring either after reverting to the per protocol schedule or during the ‘spread out’ schedule to manage the 2nd DLT above) à Discontinue patient from study. • N.B.: In all above modifications of the dose density of galinpepimut -S, as all intervals (in weeks) between 2 successive GPS administrations are multiples of three (3) by design, following these rules, co-administration with pembrolizumab is always secured. Stopping rules (for AML patients): • Development of any SAEs at least “possibly attributable” to the study agent(s) in 2 out of the first 6 patients in the study. In this case, the upper 90% one-sided CI bound for 2 patients with SAEs within 6 patients would be 66.7%, consistent with an excessive rate of toxicity. • The fraction of patients experiencing an SAE at least “possibly attributable” to the study agent(s) exceeds 1/3, at any time during study implementation beyond the first 6 patients. • Death at least “possibly attributable” to the study agent(s) within 30 days after the administration of the investigational treatment (GPS plus pembrolizumab) • Development of grade 3 or higher colitis/diarrhea, grade 3 or higher pneumonitis, grade 3 or higher nephritis, grade 3 or higher transaminitis, or any grade myocarditis in 2 out of the first 6 patients in the AML arm of the study. In this case, the upper 90% one-sided CI bound for 2 patients with SAEs within 6 patients would be 66.7%, consistent with an excessive rate of toxicity. • The fraction of patients experiencing grade 3 or higher colitis/d iarrhea, grade 3 or higher pneumonitis, grade 3 or higher nephritis, grade 3 or higher transaminitis, or any grade myocarditis exceeds 40%, at any time during study implementation beyond the first 6 patients in the AML arm. SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 153 If the study is stopped due to activation of the above rules, the safety data will be examined by the sponsor in consultation with investigators in order to determine how to proceed or whether to discontinue the study at large. 5.3.6.3. Dose Modification and Toxicity Management Guidelines for Pembrolizumab 5.3.6.3.1. Dose Modification and Toxicity M anagement for Immune -related AEs (irAEs) Associated with Pembrolizumab AEs associated with pembrolizumab exposure may represent an immunologic etiology. These immune-related AEs (irAEs) may occur shortly after the first dose or several months after the last dose of pembrolizumab treatment and may affect more than on e body system simultaneously. Therefore, early recognition and initiation of treatment is cri tical to reduce complications. Based on existing clinical trial data, most irAEs were reversible and could be managed with interruptions of pembrolizumab, administration of corticosteroids and/or other supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. Based on the severity of irAEs, withhold or permanently discontinue pembrolizumab and administer corticosteroids. Dose modification and toxicity management guidelines for irAEs associated with pembrolizumab are provided in Table 5. SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 154 Table 5 Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab General instructions: 1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment sh ould be initiated if irAEs cannot be controlled by corticosteroids. Immune-related AEs Toxicity grade or conditions (CTCAEv 5.0) Action taken to pembrolizumab irAE management with corticosteroid and/or other therapies Monitor and follow-up Pneumonitis Grade 2 Withhold Administer corticosteroids (initial dose of 1 -2 mg/kg prednisone or equivalent) followed by taper Monitor participants for signs and symptoms of pneumonitis Evaluate participants with suspected pneumonitis with radiographic imaging and initiate corticosteroid treatment Add prophylactic antibiotics for opportunistic infections Grade 3 or 4, or recurrent Grade 2 Permanently discontinue SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 155 Diarrhea / Colitis Grade 2 or 3 Withhold Administer corticosteroids (initial dose of 1 -2 mg/kg prednisone or equivalent) followed by taper Monitor participants for signs and symptoms of enterocolitis (i.e., diarrhea, abdominal pain, blood or mucus in stool with or without fever) and of bowel perforation (i.e., peritoneal signs and ileus). Participants with ≥ Grade 2 diarrhea suspecting colitis should consider GI consultation and performin g endoscopy to rule out colitis.