In this study, all HLA subtypes were eligible. Patients with AML were ≥ 65 years of age and had previously completed induction chemotherapy, achieved clinical remission, and completed postremission therapy, or completed induction chemotherapy, achieved clinical remission , and had no plans for further postremission therapy. AML patients had documented WT1-positive disease as demonstrated by WT1 protein on a pretreatment bone marrow (BM) biopsy or detectable disease with real-time quantitative reverse transcription polymerase chain reaction (RT-PCR). Mesothelioma patients were required to have malignant pleural mesothelioma or peritoneal mesothelioma, unresectable or relapsed disease, and had to have received no more than 1 prior pemetrexed-containing chemotherapy regimen. Patients with NSCLC were either stage III or IV and had completed initial treatment with surgery and/or chemotherapy and/or radiatio n therapy. Both mesothelioma and NSCLC patients were required to have neoplasms that showed immunohistochemical (IHC) staining for WT1 in greater than 10% of cells. Patients were stratified according to disease type : AML (Myeloid Group) versus NSCLC or mesothelioma (Thoracic Group). Results from the myeloid group are presented in the following sections. Results from the thoracic group can be found in the Galinpepimut-S Investigator Brochure v2.0, June 2017. SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 74 Galinpepimut-S as a pharmaceutical preparation is a multicomponent direct immunogen mixture, consisting of the 4 WT1 peptides defining the galinpepimut-S drug substance suspended in Montanide adjuvant. Sargramostim (hereafter referred to as GM-CSF) was administered at the injection site before each treatment. Treatment was administered on Weeks 0, 4, 6, 8, 10, and 12 for a total of 6 injections . Patients who had a clinical, molecular, or immunologic response and did not have disease progression were able to receive up to 6 additional administrations administered approximately 1 administration every month for 6 months. Ten patients were enrolled in the AML arm. Seven patients (70.0%) prematurely discontinued; the most frequently reported primary reason for discontinuing active treatment was progressive disease/disease relapse (4 patients). The remaining patients discontinued to the following reasons: 1 patient due to excessive toxicity, 1 patient due to another complicating disease, and 1 due to other reasons. The median age of patients was 67 years (range: 24 to 78 years). Seven patients (70.0%) were male and 3 patients (30.0%) were female. In the myeloid group, all 10 patients received at least 1 administration with WT1 peptide. Eight patients (80.0%) received ≥6 administrations, and 5 patients (50.0%) received > 8 administrations. The total exposure to WT1 peptide ranged from 28 to 295 days, with a median of 144.5 days. With regard to safety, in the myeloid group, hyperglycemia (10 patients; 100.0%) was the most common treatment-emergent adverse event (TEAE), followed by platelet count (8 patients; 80.0%); hemoglobin and white blood cell disorder (6 patients each; 60.0%); and hepatic enzyme abnormal, white blood cell analysis, and hypernatremia (5 patients each; 50.0%). Eight study treatment-related TEAEs were reported in 3 patients (30.0%) and were mild (all were ≤ Grade 2). The study treatment-related TEAEs were edema peripheral, erythema multiforme, injection site extravasation, platelet count, pruritus, white blood cell disorder, and white blood cell analysis. No serious TEAEs were reported in the myeloid group. SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 75 Four patients (40.0%) in the myeloid group were known to be alive with no progression of disease at the time of last contact and 6 patients (60.0%) died. The median overall survival (OS) in the myeloid group was 31 months (2.6 years; see Figure 1). One patient who received 7 treatments with galinpepimut-S was still alive as of Month 54.3 (4.5 years); another patient who received 8 treatments with galinpepimut-S was still alive as of Month 78.2 (6.5 years). Another patient, after completion of at least 12 treatments, had no progression of disease at the time of her death, on Month 54.6 (4.6 years). Figure 1 Kaplan-Meier Plot for Overall Survival by Disease Group The results from the myeloid arm of this Phase 1 study were superior to published AML outcome data (Ries et al, 2007; Appelbaum et al, 2006; Deschler and Lübbert 2006). Age appears to be a major determinant in patient outcomes , with the oldest populations deriving little benefit from many of the dose-intensive therapies introduced in the last few years. Appelbaum et al (2006) reported a median OS of 18.8 months in patients younger than 56 years of age, 9.0 months in patients 56 to 65 years of age, and 6.9 months in patients 66 to Overall Survival (%) 0102030405060708090100 Time (Days)0 500 1000 1500 2000 2500Overall Survival (%) 0102030405060708090100 Time (Days)0 500 1000 1500 2000 2500Myeloid Group Thoracic Group Number at Risk Time (Days)Myeloid GroupThoracic Group0105005100031500320001250000 12500 51000 11500 12000 12500 0+ Censored SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 76 75 years of age (Appelbaum et al, 2006). The median age of AML patients treated in the Phase 1 pilot study was 67 years of age; therefore, the outcomes for this study’s AML group compare favorably with published data from Appelbaum et al where the youngest cohorts had the best outcomes. Though caution needs to be exercised in interpreting these results as there may be a bias regarding patient selection and reduced sample size in the study group, the results were intriguing enough to warrant further study in a larger clinical study examining the role of galinpepimut-S administration as a viable treatment for AML in complete remission status. Hence, additional Phase 2 studies were undertaken at the MSKCC. 1.1.2.2. Phase 2 Clinical Experience with Galinpepimut -SFour additional studies with galinpepimut-S were initiated at the MSKCC (A Phase 2 study in AML and acute lymphoblastic leukemia, a Phase 2 study in MPM, a Phase 1/2 pilot study in patients with multiple myeloma (MM), and a Phase 1/pilot study in ovarian cancer [OvC]). One additional Phase 1/2/pilot study was performed at the Moffitt Cancer Center (MCC) in patients with AML. Results from the Phase 1 and Phase 2 studies in AML and Phase 1/pilot study in OvC are discussed in the following section, as they are pertinent to 2 of the arms in the present study, while results from the other 2 studies (in MPM and MM) can be found in the galinpepimut-S investigator’s brochure (IB). While not all primary endpoint data for all above studies have been reached, their preliminary resu lts extend the observations from the the earlier trials and form the basis to investigate galinpepimut-S efficacy in randomized Phase 3 clinical trials of galinpepimut-S (given in the maintenance setting ) in both AML and MPM after initial debulking therapy . 1.1.2.2.1. Study 10-143 (AML Patients)This open-label, Phase 2 trial (Maslak et al, 2018; ClinicalTrials.gov identifier : NCT01266083) evaluated the safety and efficacy (as measured by OS at 3 years) of galinpepimut-S used as postremission therapy in patients in complete remission (CR) from leukemia. In addition, this study assessed disease-free survival at 3 years, immunologic responses (as measured by CD4+ T-cell proliferation, CD 3+ T-cell interferon- g release, and WT1 peptide tetramer staining), and any effect the galinpepimut-S SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 77 had on minimal residual disease (MRD) (as measured by RT-PCR for WT1 transcript). Eligible patients were ≥18 years of age, had a morphological confirmation of a diagnosis of AML or acute lymphoblastic leukemia, and had achieved CR (within 2 years of first treatment administration) after completing induction therapy and any planned post -remission therapy. In addition, eligible patients could not be candidates for allogeneic stem cell transplantation. Potential patients who were ≥ 60 years of age, who achieved CR (within 2 years of first treatment administration) and in whom no further postremission chemotherapy was planned were eligible for enrollment. Eligible patients had documented WT1-positive disease, defined as the detectable presence of any WT1 transcript via RT -PCR on a BM performed at the MSKCC within 4 weeks before the administration of the first dose of treatment. At least 4 weeks must have elapsed between the patient's last che motherapy or radiation treatment and the first administration. In this trial, patients were administered the treatment, prepared as an emulsion of galinpepimut-S and Montanide, every 2 weeks for a total of 6 administrations. Those who were clinically stable and without disease recurrence could continue with up to 6 more treatments administered approximately every month. All patients receive sargramostim (GM-CSF, 70 µg) administered subcutaneously 2 days prior to each treatment as well as on the actual day of each administration to prestimulate the injection site. The data cut-off date for the disposition, demographic, and safety information was 22 May 2015; the data cut-off date for patient survival was 30 October 2015. As of the data cut-off date, 22 patients had been enrolled. No additional patients were enrolled, as the study has been closed to enrollment. A total of 22 patients (7 men and 15 women) were enrolled on the study, were treated, and were evaluable for response. The median age was 64 years (range 25 to 76 years). Fifty percent (11 of 22) of study patients had a normal karyotype. Of the 22 patients enrolled, 14 (64%) received the planned 6 galinpepimut-S administrations and 10 (46%) completed all 12 galinpepimut-S administrations. Overall, 15 (68%) patients relapsed: 10 while receiving treatment, 4 after the entire series of 12 galinpepimut-S SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 78 administrations, and 1 patient 13 months following discontinuation of therapy secondary to a delayed- type hypersensitivity reaction. Four of the 15 patients relapsed after 1 galinpepimut- S administration, likely an insufficient amount of time to induce an immune response. Ten relapsed patients died due to complications from progressive leukemia. Five of the 15 relapsed patients underwent hematopoetic stems cell transplant (HSCT) following successful re-induction chemotherapy. Three of these patients remained alive without evidence of recurrent disease, ranging from 11 to 31 months post-HSCT. There was no statistically significant difference in either relapse rate or OS in patients who were treated prior to spending 8 months in first complete remission (CR1) compared with those treated at or after this timepoint. From first galinpepimut-S administrations, 19 of 22 (86%) patients were evaluable for survival at 3 years, and 9 of these 19 (47%) evaluable patients were alive for ≥3 years. Consequently, the study met its prespecified endpoint of ≥34% OS at 3 years. From CR1, the median disease-free survival (DFS) was 16.9 months (Figure 2). The median OS from diagnosis (Figure 3) was not reached but is poised to reach or exceed 67.6 months (5.6 years by log-rank analysis). The median event free survival (EFS ) from the time of first galinpepimut-S administration was 9.4 months, while the median OS from the time of administration has not been reached (Figure 4 and Figure 5). The probabilities of EFS at 6 and 9 months post galinpepimut-S administration were 64% (CI: 40%, 80%) and 54% (CI: 32%, 72%), respectively. Likewise, the probabilities of OS at 6 and 9 months post galinpepimut-S administration were 100% (CI: 100%, 100%) and 77% (CI: 54%, 90%), respectively. For patients <60 years of age (n=9), neither the median DFS nor OS times were reached (Figure 6 and Figure 7). However, for patients in the older cohort (age >60; n=13), median DFS from CR1 was 10.8 months and median OS time post- diagnosis was 35.8 months (Figure 8 and Figure 9). Likewise, from first galinpepimut-S treatment, median EFS and OS times in the older cohort were 7.8 and 30.2 months, respectively. Lastly, landmark EFS in the older cohort at 6 and 9 months post first galinpepimut-S treatment were 54% (CI: 25%, 76%) SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 79 and 46% (CI: 19%,70%), respectively, while OS 6 and 9 months post first galinpepimut-S were 100% (CI: 100%,100%) and 62% (CI: 31%,82%). Figure 2 Study 10-143 (AML Patients): Kaplan-Meier Plot for Median Disease-Free Survival Figure 3 Study 10-143 (AML Patients): Kaplan-Meier Plot for Median Overall Survival SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 80 Figure 4 Study 10-143 (AML Patients): Kaplan-Meier Plot for Median EFS from First Galinpepimut-S Administration Figure 5 Study 10-143 (AML Patients): Kaplan-Meier Plot for Median Overall Survival from First Galinpepimut-S Administration SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 81 Figure 6 Study 10-143 (AML Patients): Kaplan-Meier Plot for Median Disease-Free Survival of Patients < 60 Years of Age Figure 7 Study 10-143 (AML Patients): Kaplan-Meier Plot for Median Overall Survival of Patients < 60 Years of Age SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 82 Figure 8 Study 10-143 (AML Patients): Kaplan-Meier Plot for Median Disease-Free Survival of Patients ≥ 60 Years of Age Figure 9 Study 10-143 (AML Patients): Kaplan-Meier Plot for Median Overall Survival of Patients ≥ 60 Years of Age Galinpepimut-S administration was generally well tolerated and the toxicity profile is consistent with other WT1 vaccine-adjuvant combinations (Oka, et al, 2004; Keilholz et al, 2009; Rezvani et al, 2008; Rezvani et al, 2011; Uttenthal et al, 2014). The montanide adjuvant is a known irritant (van Doorn et al, 2015) and many of the most frequent toxicities consisted of mild to moderate local reactions and inflammation: injection site reaction (46%), fatigue (32%), skin induration (32%), and injection site p ruritus (27%). These toxicities were self-limited and responded to local supportive measures and analgesics. Several transient occurrences of decreased white blood cell, neutrophil, lymphocyte, and platelet counts were noted and these resolved, often on the same day of testing, and resulted in no significant SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 83 infectious complications or supportive transfusions. None of the patients developed significant hepatic or renal insufficiency and no episodes of systemic anaphylaxis were observed. Overall, galinpepimut-S in this population of AML patients was safe and well tolerated, with a majority of TEAEs being of mild or moderate severity (150/244, 61.5%). There were no reported deaths and a majority of Grade 3/4 TEAEs were unrelated to study treatment. The majority of injection site reactions, skin induration, and pruritus were easily managed with supportive care. Two patients discontinued therapy due to probable hypersensitivity reactions that were believed to be related to study treatment. One patient developed 2 episodes of a maculopapular rash (Grade 1) and then developed, on a separate occasion, an episode of flushing (Grade 3) immediately following the second study treatment administration. The patient remained hemodynamically stable and developed no signs of anaphylaxis but, given the severity of the episode, he discontinued further treatment. The patient subsequently relapsed and died from complications of recurrent AML 29 mo nths after discontinuing galinpepimut-S treatment. The second patient developed bone pain, dyspnea, flushing, and non-cardiac chest pain (G rade 3) leading to hospitalization immediately following the fourth administration. The patient responded to standard supportive measures and the symptoms resolved the same day without further incident. The patient recovered without sequelae and remains alive as of the last study follow -up (approximately 36 months after discontinuing galinpepimut-S). Although this is a relatively small study (22 patients), several clinical observations regarding the potential for therapeutic efficacy can be made. The study met its pre -specified endpoint of ≥34% actual OS rate at 3 years . The actual OS rate of 47.4% at 3 years post galinpepimut-S administration exceeded historical published data of 20 -25% by 2.4-1.9-fold (or 240% to 190%), respectively. In addition, 11 of the 22 (50%) patients were alive at the time of their last assessment. Nine of these remained in CR1, while 3 relapsed during or following galinpepimut-S administration and were successfully salvaged with HSCT. The median DFS from CR1 was 16.9 months, with the median OS not reached, but poised to be at SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 84 least 67.6 months. These survival outcomes are higher than published results for similar patients treated with conventional post-remission therapies and compare favorably to subsets of patients treated with HSCT (Lowenberg et al, 2009; Fernandez et al, 2009; Kolitz et al, 2010; Nand et al, 2013; Dombret et al, 2015; McClune et al, 2010; Saber et al, 2012; Walter et al, 2010; Yanada et al, 2007). However, there are several potential caveats in interpreting the results of this study with regard to therapeutic efficacy. The study population is relatively heterogeneous with several different prognostic groups contained within the data set which co uld skew outcomes (Rollig et al, 2011). The patients enrolled in this study may represent those with the best possible response in that not only were they able to achieve CR1, they remained in CR1 for a median of 8 months prior to treatment with galinpepimut-S. The immunologic correlates provid e information regarding biologic effect but are not surrogates for clinical response. Several patients did not exhibit an immune response, yet still did well. We do not know if the patients that were negative were false negatives, as the assays are not sen sitive, nor directed at most relevant key epitopes , nor are all technical issues regarding testing of this type resolved to date (Butterfield, 2015). Despite these potentially confounding factors, this study supports the continued investigation of galinpepimut-S as a strategy for AML postremission therapy. Galinpepimut-S can be administered on an outpatient basis with minimal toxicity in most patients. This cohort of patients appears to do well compared with historical outcome data and the immunologic correlates which have been used in this study show the generation of an immune response in most tested patients. 1.1.2.2.2. Study MCC -15025 (AML Patients) Galinpepimut-S was studied at the same dose, schedule, and overall manner of administration as in the previously discussed studies has been used in only 1 other known study in patients with AML. In 2015, Brayer et al published the findings of a study conducted at the Moffitt Cancer Center (MCC) that enrolled patients with either WT1 -positive AML in CR1 SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 85 or sec ond complete remission (CR2), or MDS following at least 1 prior line of therapy (Brayer et al, 2015; ClinicalTrials.gov identifier: NCT00665002 ). Patients enrolled in the study received galinpepimut-S, along with GM-CSF on Days -2 and 0 of each galinpepimut- S dose. Patients received 6 bi-weekly galinpepimut-S administrations, and continued monthly until they had received 12 doses in total or showed evidence of disease relapse. Patients were evaluated for overall survival and progression free survival (PFS) from the time of the last remission, and immune response was evaluated by delayed -type hypersensitivity testing (DTH) and T cell interferon- g enzyme-linked immunospot (ELISPOT) assay at specific intervals. The key findings of this study pertain to the subgroup of patients with AML who successfully achieved CR2 after 2nd line standard antileukemic therapy, and more specifically a cohort of 10 patients who received >2 galinpepimut -S inoculations and therefore had adequate exposure to the vaccine so that they could become immunized. The clinical outcomes (PFS and OS) in these patients were compared to post -hoc matched, contemporaneously treated patients with AML in CR2 status, a cohort that was used for ‘historical’ controls in the comparison.In more detail, a total of sixteen (16) patients (2 with refractory MDS and 14 with AML [4 in first CR and 10 in second CR]) were enrolled in the study. Five of the 14 AML patients had a prior diagnosis of MDS or myeloproliferative neoplasm. Nine of the 14 AML patients and both of the MDS patients exhibited a normal karyotype on cytogenetic analysis of the BM. Of the 5 AML patients with abnormal karyotype at baseline, 3 had complex karyotype, 1 contained a t (15;17) translocation not involving the classic promyelocytic leuk emia-retinoic acid receptor alpha (PML-RAR- a) translocation, and 1 contained a core-binding factor beta subunit-myosin heavy chain 11 (CBFB/MYH11) (inversion 16) translocation (Brayer et al, 2015). The median age of patients was 74 years. Of the 16 patients, 9 completed the planned 6 galinpepimut-S doses, and 6 continued for up to 6 additional doses. Of the 14 patients with AML, 10 received >2 inoculations of galinpepimut-S and were eligible for formal PFS and OS endpoint analysis. Out of these 10, 4 completed a total of 12 galinpepimut-S doses while all other AML patients discontinued this agent due to disease progression. Of the 2 patients with MDS, 1 completed the planned 6 galinpepimut-S doses and went on to receive a total of 10 doses. SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 86 The remaining patient received 4 galinpepimut-S doses but discontinued due to progressive disease with transformation to AML. For the patients with AML, the mean time to disease progression (AML relapse) was 8.0 months and the mean OS from time of CRs was 19.9 months (range 6.6 to 35.2 months). At the time of the published study manuscript in 2015, (Brayer, et al, 2015), 11 of the 14 patients had died and 3 remained alive but with progressive disease. Four of the 14 patients had sustained responses either equaling or exceeding the time period of their initial remission. An ad hoc analysis comparing the outcomes of 10 eligible AML patients in CR2 enrolled in the study who received >2 inoculations of galinpepimut-S with those of a contemporaneously treated historical matched cohort (n=15) demonstrated a numerical difference in median PFS (10.5 months versus 4.3 months; P = 0.19) in patients treated with study drug, but demonstrated a statistically significant and clinically meaningful improvement in median OS in the same comparison in favor of the active arm (16.3 months versus 5.4 months, P = 0.0175). These data are shown in Fig. 10 below : Figure 10 Study MCC-15025 (AML Patients in CR2): K-M Plot for Median OS in Galinpepimut-S-treated pts who Received >2 Vaccine Inoculations (N=10) versus Contemporaneously Treated Historical Matched Controls (N=15) Both MDS patients remained transfusion-dependent but 1 patient demonstrated a 50% reduction in the need for transfusion as compared to the 4 months prior to enrollment. An analysis of the patient’s BM SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 87 showed an approximately 40% reduction in myeloblast percentage. The second patient demonstrated no response while receiving galinpepimut-S treatment but became transfusion- independent after study completion and had remained so for over 14 months prior to publication of the manuscript. Four of the 14 AML patients developed a DTH response, while neither of the MDS patients did. An interferon- g response by CD4 T cells was observed in 4 patients, with 3 of these patients also demonstrating CD8 T-cell-mediated interferon- g responses. Galinpepimut-S was well tolerated, with most AEs reported as Grades 1 or 2. There was a single Grade 3/4 AE of neutropenia. Six of the 14 patients experienced injection site reactions. Two of these patients developed local induration and erythema after completion of the protocol; both developed delayed-type hypersensitivity responses. Note: As galinpepimut-S is always co-administered with the light oil Montanide in the form of an emulsion, as will be the case in this study, specific information about this emulsifying agent is provided in the Montanide Investigator Brochure. Note: As patients will be administered SC sargramostim (GM-CSF) at the site of the planned galinpepimut-S injection 2 days before (Day –2) and the day of (Day 1) each injection of galinpepimut-S (emulsified in Montanide), specific information about sargramostim (GM-CSF) is provided in the US Prescribing Information for Leukine®. 1.1.2.2.3. Study 15 -247 (Ovarian Cancer Patients) Galinpepimut-S was studied a phase 1 single-arm trial at MSKCC to evaluate its safety and immunogenicity in combination with the PD1 inhibitor nivolumab (Opdivo®; Bristol -Myers Squibb) in patients with WT1(+) ovarian cancer in second or greater remission after successful debulking with standard chemotherapy. The prelimina ry results were reported in 2018 (O’Cearbhaill et al, 2018; ClinicalTrials.gov identifier: NCT02737787). SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 88 Patients were enrolled from June 2016 to July 2017, and received 6 galinpepimut -S inoculations over a period of 12 weeks (on weeks 0, 2, 4, 6, 8 and 10). GM-CSF (70 µg) was administered 2 days prior to and on the day of each vaccine administration. All galinpepimut - S inoculations were administered subcutaneously in extremities, with rotation of the injection site with each vaccination. Nivolumab at a do se of 3mg/kg per administration was given IV q 2weeks over 12 weeks. Patients who remained in remission were offered a maintenance course of galinpepimut-S at weeks 19, 27, 35, 43. Dose modification was not permitted. Treatment was continued until disease progression (assessed by RECIST 1.1) or toxicity (assessed by NCI CTCAE v4.03). The primary endpoint is to evaluate the safety of the combination. Dose limiting toxicity (DLT) was defined as an adverse event (AE) at least possibly related to the galinpepimut-S plus nivolumab combination occurring with 30 days from the 1 st galinpepimut-S administration, and included (among other criteria) grade 2 uveitis, grade 3 injection site reaction, grade 3 fever, grade 3 AEs lasting >72 hours, grade 4 AE’s (with the exception of clinically non-significant lab toxicities) or grade 5 AEs. Detection of greater than 2 DLTs among 10 treated patients would have deem the combination unsafe, but this was not observed. An exploratory objective was the progression-free survival (PFS) landmark rate at 1-year. PFS was measured from the start date of the immediately preceding chemotherapy to the date of progression of disease or death. IgM & IgG antibody (Ab) responses were measured by ELISA against individual WT1 peptides contained within the galinpepimut-S mixture, as well as full length WT1. Immune responders were defined as those with Ab titers going from undetectable to ≥1:40 or ≥8 -fold increase if such patients had detectable pretreatment levels. WT1 -specific CD4+ and CD8+ T cell responses were compared to baseline via intracellular cytokine staining flow cytometry and values ≥0.6% were considered positive. Eleven patients with recurrent serous ovarian cancer in their 2 nd or 3rd remission were treated on-protocol with the combination of galinpepimut-S and nivolumab. Their baseline demographics and disease characteristics were representative of similar cohorts of patients in SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 89 the published literature - mainly by the Gynecologic Oncology Group (GOG) in the US and the Arbeitsgemeinschaft Gynaekologische Onkologie - Studiengruppe Ovarialkarzinom (AGO-OVAR) in Germany. The most common treatment-related AEs with the combination were injection site reaction (maximum [max] grade 1), arthralgia (max grade 2) and fatigue (max grade 2). DLT was observed in one patient, who developed grade 3 panmyositis (including cardiac involvement) following the 2 nd dose of galinpepimut-S and nivolumab and required insertion of a permanent cardiac pacemaker. With regard to immune responses, serum levels of antigen-specific IgG, against both individual WT1 peptides within galinpepimut-S and the full-length WT1 protein were induced in 86% of evaluable patients between week 6 and week 27 following treatment with the combination. Antigen -specific T cell responses to individual WT1 peptides were observed between weeks 6 -15. These responses were primarily CD4+, with best responses seen against the heteroclitic peptide 122A1-Long and its corresponding native counterpart 122A -Long, and to a lesser extent CD8+, mainly for peptides 427 and 331 in patients with HLA class I allelic types other than HLA-A02. The landmark PFS rate at 1-year was 64% in the intent-to-treat group as shown in Figure 11 below. The 1-year PFS rate was 70% for patients who received >2 doses of galinpepimut-S and nivolumab. SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 90 Figure 11 Study 15-247 (Ovarian Cancer Patients): Kaplan-Meier Plot for Median Progression-Free Survival Showing the Landmark 1-year PFS Rate in the ITT Population This Phase 1/Pilot study concluded that administration of the i mmune-targeted combination of the subcutaneously inoculated galinpepimut-S vaccine and the intravenous anti-PD1 agent nivolumab to patients with WT1-positive ovarian cancer in second or third remission was safe and well tolerated and resulted in high rates of antigen-specific immunization. Furthermore, the landmark PFS rate of 70% in patients who received >2 doses of the combination (N=9) compares favorably to historic rates that do not exceed approximately 50% in comparable populations treated with chemoth erapy regimens that are currently considered standard of care (but without post-chemotherapy maintenance). The findings suggested that the combination of galinpepimut-S and anti-PD1 antibodies warrants further evaluation in patients with WT1-positive ovarian cancer, and provides strong background rationale for the launch of the ovarian cancer arm in the present study. SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 91 1.2 Pembrolizumab Background 1.2.1. General Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) with high specificity of binding to the programmed cell death 1 (PD 1) receptor, thus inhibiting its interaction with programmed cell death ligand 1 (PD -L1) and programmed cell death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD 1. Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as an intravenous (IV) immunotherapy for advanced malignancies. Keytruda® (pembrolizumab) is indicated for the treatmen t of patients across a number of indications. For more details on specific indications refer to the Investigator’s Brochure (edition 16.0, dated 29 June 2018). Refer to the Pembrolizumab Investigator’s Brochure/approved labeling for detailed background information on MK-3475. 1.2.2. Pharmaceutical and Therapeutic Background The importance of intact immune surveillance function in controlling outgrowth of neoplastic transformations has been known for decades (Disis, 2010). Accumulating evidence shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various malignancies. In particular, the presence of CD8+ T -cells and the ratio of CD8+ effector T cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. Tumor -infiltrating lymphocytes can be expanded ex vivo and rein fused, inducing durable objective tumor responses in cancers such as melanoma (Dudley et al, 2005; Hunder et al, 2008). The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune control. The normal function of PD -1, expressed on the cell surface of activated T SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 92 cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, including autoimmune reactions. PD -1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) superfamily member related to cl uster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-associated protein 4 (CTLA -4) that has been shown to negatively regulate antigen receptor signaling upon engagement of its ligands (PD L1 and/or PD -L2) (Greenwald et al, 2005; Okazaki et al, 200 1). The structure of murine PD-1 has been resolved (Zhang et al, 2004). PD -1 and its family members are type I transmembrane glycoproteins containing an Ig -variable–type (IgV type) domain responsible for ligand binding and a cytoplasmic tail responsible fo r the binding of signaling molecules. The cytoplasmic tail of PD -1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine -based switch motif. Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta (PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are involved in the CD3 T-cell signaling cascade (Okazaki et al, 2001; Chemnitz et al, 2004; Sheppard et al, 2004; Riley, 2009). The mechanism by which PD -1 down-modulates T cell responses is similar to, but distinct from, that of CTLA-4, because both molecules regulate an overlapping set of signaling proteins (Parry et al, 2005; Francisco, 2010). As a consequence, the PD 1/PD-L1 pathway is an attractive target for therapeutic intervention in the 5 malignancy types investigated in this study. 1.2.3. Pre -clinical and Clinical Trials Therapeutic studies in mouse models have shown that administration of antibodies blocking PD-1/PD-L1 interaction enhances infiltration of tumor -specific CD8+ T cells and ultimately leads to tumor rejection, either as a monotherapy or in combination with ot her treatment modalities (Hirano et al, 2005; Blank et al, 2004; Weber, 2010; Strome et al, 2003; Spranger et al, 2014; Curran et al, 2010; Pilon-Thomas et al, 2010). Anti-mouse PD-1 or anti-mouse SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 93 PD-L1 antibodies have demonstrated antitumor responses in models of squamous cell carcinoma, pancreatic carcinoma, melanoma, acute myeloid leukemia and colorectal carcinoma (Strome et al, 2003; Curran et al, 2010; Pilon -Thomas et al, 2010; Nomi et al, 2007; Zhang et al, 2004). In such studies, tumor infiltration by CD8+ T cells and increased IFN-γ, granzyme B and perforin expression were observed, indicating that the mechanism underlying the antitumor activity of PD -1 checkpoint inhibition involved local infiltration and activation of effector T cell function in vivo (Curran et al, 2010). Experiments have confirmed the in vivo efficacy of anti-mouse PD-1 antibody as a monotherapy, as well as in combination with chemotherapy, in syngeneic mouse tumor models (see the Pembrolizumab Investigator’s Brochure [I.B.]). 1.2.4. Justification for Pembrolizumab Dose The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). Based on the totality of data generated in the Keytruda development program, 200 mg Q3W is the appropriate dose of pembrolizumab for adults across all indications and regardless of tumor type. As outlined below, this dose is justified by: Clinical data from 8 randomized studies demonstrating flat dose - and exposure-efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W), Clinical data showing meaningful improvement in benefit -risk including overall survival at 200 mg Q3W across multiple indications, and pharmacology data showing full target saturation in both systemic circulation (inferred from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK [PBPK] analysis) at 200 mg Q3W. Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled with melanoma and non-small cell lung cancer (NSCLC), covering different disease se ttings (treatment naïve, previously treated, PD -L1 enriched, and all-comers) and different treatment settings (monotherapy and in combination with chemotherapy). Five studies compared 2 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, SELLAS Life Sciences Group Galinpepimut -S Protocol : SLS17 -201/MK3475 -770 Protocol v1.1 (Amendment 1.0) 12 April 2019 Page 94 and KN021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and KN006). All of these studies demonstrated flat dose- and exposure-response relationships across the doses studied representing an approximate 5- to 7.5-fold difference in exposure. The 2 mg/kg (or 200 mg fixed -dose) Q3W provided similar responses to the highest doses studied. Subsequently, flat dose-exposure-response relationships were also observed in other tumor types including head and neck c ancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of the tumor type. These findings are consistent with the mechanism of action of pembrolizumab, which acts by interaction with i mmune cells, and not via direct binding to cancer cells. Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK data in KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W. Second, a PBPK analysis was conducted to predict tumor PD -1 saturation over a wide range of tumor penetration and PD -1 expression. This evaluation concluded that pembrolizumab at 200 mg Q3W achiev es full PD-1 saturation in both blood and tumor. Finally, population PK analysis of pembrolizumab, which characterized the influence of body weight and other participant covariates on exposure, has shown that the fixed -dosing provides similar control of PK variability as weight-based dosing, with considerable overlap in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. Supported by these PK characteristics and given that fixed -dose has advantages of reduced dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed -dose was selected for evaluation across all pembrolizumab protocols. 1.3.