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Supplementary Data 3 & 4

Purpose:HER2/neu is overexpressed in up to 30% of gastroesophageal adenocarcinomas (GEA) and linked to poor prognosis. Recombinant mAbs to treat HER2/neu-overexpressing cancers are effective with limitations, including resistance and toxicity. Therefore, we developed a therapeutic B-cell epitope vaccine (IMU-131/HER-Vaxx) consisting of three fused B-cell epitopes from the HER2/neu extracellular domain coupled to CRM197 and adjuvanted with Montanide. This phase Ib study aimed to evaluate the optimal/safe dose leading to immunogenicity and clinical responses (https//clinicaltrials.gov/ct2/show/NCT02795988).Patients and Methods:A total of 14 patients with HER2/neu-overexpressing GEA were enrolled, and dose escalation (10, 30, 50 μg) was performed in three cohorts (C). Immunogenicity was evaluated by HER2-specific Abs and cellular responses, clinical responses by CT scans according to RECIST version 1.1.Results:IMU-131 was safe without vaccine-related significant local/systemic reactions or serious adverse events. A total of 11 of 14 patients were evaluable for changes in tumor size and vaccine-specific immune responses. One patient showed complete, 5 partial responses, and 4 stable diseases as their best response. HER2-specific IgG levels were dose dependent. In contrast to patients in C1 and C2, all patients in C3 mounted substantial HER2-specific Ab levels. In addition, cellular vaccine responses, such as Th1-biased cytokine ratios and reduced regulatory T cell numbers, were generated. Progression-free survival was prolonged in C3, correlating with the vaccine-specific humoral and cellular responses.Conclusions:IMU-131 was well tolerated and safe. The induced HER2-specific Abs and cellular responses were dose dependent and correlated with clinical responses. The highest dose (50 μg) was recommended for further evaluation in a phase II trial, with chemotherapy + IMU-131 or chemotherapy alone, which is currently ongoing.

Supp. Table 1; Supp. Table 2; Supp. Table 3 A,B; Supp. Table 4; Supp. Table 5; Supp. Table 6; Supplementary Data 1; Supplementary Data 2

This study aimed to assess survival outcomes, prognostic factors, and adverse events following chemotherapy treatment for osteosarcoma and Ewing’s sarcoma. This retrospective observational study was conducted to collect the data of the patients with osteosarcoma or Ewing’s sarcoma who received chemotherapy treatment between 2008 and 2019. The flexible parametric survival model was performed to explore the adjusted survival probability and the prognostic factors. A total of 102 patients (79 with osteosarcoma and 23 with Ewing’s sarcoma) were included. The estimated 5-year disease-free survival (DFS) and 5-year overall survival (OS) probabilities in patients with resectable disease were 60.9% and 63.3% for osteosarcoma, and 54.4% and 88.3% for Ewing’s sarcoma, respectively, whereas the 5-year DFS and 5-year OS for those with unresectable/metastatic disease remained below 25%. Two prognostic factors for osteosarcoma included a response to neoadjuvant chemotherapy and female gender. Ewing’s sarcoma patients aged 25 years and older were significantly associated with poorer survival outcomes. Of 181 chemotherapy treatment cycles, common self-reported adverse symptoms included tumor pain (n = 32, 17.7%), fever (n = 21, 11.6%), and fatigue (n = 16, 8.8%), while common grade III adverse events included febrile neutropenia (n = 13, 7.3%) and neutropenia (n = 9, 5.1%). There was no chemotherapy-related mortality (grade V) or anaphylaxis events.

Background MB02 (bevacizumab biosimilar) showed similar structural, functional, and pharmacokinetic properties to reference bevacizumab (Avastin®; EU-bevacizumab). Objectives To confirm clinical similarity between MB02 and EU-bevacizumab, a comparability study was undertaken in the first-line treatment of stage IIIB/IV non-squamous non-small cell lung cancer (NSCLC). Patients and Methods This multinational, double-blind, randomized, phase III study (STELLA) compared MB02 or EU-bevacizumab (15 mg/kg) administered with chemotherapy (paclitaxel 200 mg/m2 and carboplatin AUC6) on Day 1 of every 3-week cycle for 6 cycles (Week 18), followed by MB02/EU-bevacizumab in blinded monotherapy until disease progression, unacceptable toxicity, death, withdrawal of consent or end of study (Week 52). The primary efficacy endpoint was objective response rate (ORR) evaluated by an independent radiological review committee (IRC) at Week 18 (intent-to-treat population). Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety and immunogenicity. Results A total of 627 subjects were randomized 1:1 to MB02 (n = 315) or EU-bevacizumab (n = 312). ORR, assessed by the IRC at Week 18, was comparable in MB02 (40.3%) and EU-bevacizumab (44.6%) groups. ORR risk ratio of 0.910 (90% CI 0.780 to 1.060; 95% CI 0.758 to 1.092) and ORR risk difference of −4.02 (90% CI −10.51 to 2.47; 95% CI −11.76 to 3.71) were within the similarity predefined margins. There were no significant differences between MB02 and EU-bevacizumab groups in median PFS (36.0 vs 37.3 weeks, respectively; HR 1.187; 95% CI 0.98 to 1.44) and median OS (not achieved; HR 1.108; 95% CI: 0.83 to 1.49) at the end of study. The safety profile of MB02 and EU-bevacizumab regarding nature, frequency and severity of the adverse events (AE) was comparable. The most frequent grade ≥3 investigational-product-related AEs were hypertension and anemia, with a difference between treatment groups of

Background Clinical outcomes of patients with osteosarcoma remain unsatisfactory, with little improvement in a 5-year overall survival over the past three decades. There is a substantial need for further research and development to identify and develop more efficacious agents/regimens in order to improve clinical outcomes of patients for whom the prognosis is unfavorable. Recently, mycophenolate mofetil, a prodrug of mycophenolic acid, has been found to have anticancer activity against osteosarcoma in both in vitro and animal experiments, so that further investigation in humans is warranted. Methods A total of 27 patients with high-grade locally advanced or metastatic osteosarcoma will be enrolled into this phase II, multi-center, open-label, single-arm, two-stage clinical trial. The main objectives of this study are to determine the efficacy and safety of mycophenolate mofetil in the patients. The primary endpoint is progression-free survival at 16 weeks; the secondary endpoints include progression-free survival, overall survival, overall response rate, safety parameters, pharmacokinetic parameters, biomarkers, pain score, and quality of life. Mycophenolate mofetil at the initial dose of 5 g/day or lower will be administered for 4 cycles (28 days/cycle) or until disease progression or unacceptable toxicity. The dose of mycophenolate mofetil may be reduced by 1–2 g/day or withheld for some Grade 3 or Grade 4 toxicities whenever clinically needed. The duration of study participation is approximately 4–5 months, with a minimum of 12 study visits. If mycophenolate mofetil proves beneficial to some patients, as evidenced by stable disease or partial response at 16 weeks, administration of mycophenolate mofetil will continue in the extension period. Discussion This trial is the first step in the translation of therapeutic potential of mycophenolate mofetil emerging from in vitro and animal studies into the clinical domain. It is designed to assess the efficacy and safety of mycophenolate mofetil in patients with high-grade locally advanced or metastatic osteosarcoma. The results will provide important information about whether or not mycophenolate mofetil is worth further development. Trial registration This trial was prospectively registered on Thai Clinical Trials Registry (registration number: TCTR20190701001). The posted information will be updated as needed to reflect protocol amendments and study progress.

Purpose: HER2/neu is overexpressed in up to 30% of gastroesophageal adenocarcinomas (GEA) and linked to poor prognosis. Recombinant mAbs to treat HER2/neu-overexpressing cancers are effective with limitations, including resistance and toxicity. Therefore, we developed a therapeutic B-cell epitope vaccine (IMU-131/HER-Vaxx) consisting of three fused B-cell epitopes from the HER2/neu extracellular domain coupled to CRM197 and adjuvanted with Montanide. This phase Ib study aimed to evaluate the optimal/safe dose leading to immunogenicity and clinical responses (https//clinicaltrials.gov/ct2/show/NCT02795988). Patients and Methods: A total of 14 patients with HER2/neu-overexpressing GEA were enrolled, and dose escalation (10, 30, 50 μg) was performed in three cohorts (C). Immunogenicity was evaluated by HER2-specific Abs and cellular responses, clinical responses by CT scans according to RECIST version 1.1. Results: IMU-131 was safe without vaccine-related significant local/systemic reactions or serious adverse events. A total of 11 of 14 patients were evaluable for changes in tumor size and vaccine-specific immune responses. One patient showed complete, 5 partial responses, and 4 stable diseases as their best response. HER2-specific IgG levels were dose dependent. In contrast to patients in C1 and C2, all patients in C3 mounted substantial HER2-specific Ab levels. In addition, cellular vaccine responses, such as Th1-biased cytokine ratios and reduced regulatory T cell numbers, were generated. Progression-free survival was prolonged in C3, correlating with the vaccine-specific humoral and cellular responses. Conclusions: IMU-131 was well tolerated and safe. The induced HER2-specific Abs and cellular responses were dose dependent and correlated with clinical responses. The highest dose (50 μg) was recommended for further evaluation in a phase II trial, with chemotherapy + IMU-131 or chemotherapy alone, which is currently ongoing.

BGJ398, a potent and selective pan-FGFR antagonist, was prospectively evaluated in patients with metastatic urothelial carcinoma bearing a diverse array of FGFR3 alterations. Patients (N = 67) who were unable to receive platinum chemotherapy were enrolled. The majority (70.1%) had received two or more prior antineoplastic therapies. BGJ398 was administered orally at 125 mg/day on a 3 weeks on, 1 week off schedule until unacceptable toxicity or progression. The primary endpoint was the response rate. Among 67 patients treated, an overall response rate of 25.4% was observed and an additional 38.8% of patients had disease stabilization, translating to a disease control rate of 64.2%. The most common treatment-emergent toxicities were hyperphosphatemia, elevated creatinine, fatigue, constipation, and decreased appetite. Further examination of BGJ398 in this disease setting is warranted.Significance: BJG398 is active in patients with alterations in FGFR3, resulting in both reductions in tumor volume and stabilization of disease. Our data highlight putative mechanisms of resistance to the agent, which may be useful in following disease status. Cancer Discov; 8(7); 812–21. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 781

Objective: This study was attempted to investigate overall survival by stage at diagnosis in female breast cancer patients in Northern Thailand by using 2 different staging systems; namely, American Joint Committee on Cancer (AJCC) Tumor (T), Nodal (N) and Metastatic (M) staging system and Surveillance Epidemiology and End Results (SEER) summary staging system. Methods: We studies female breast cancer patients whose data were registered in Chiang Mai cancer registries between January 2006 and December 2015. Data were recorded in SEER summary staging system. The TNM AJCC staging was searched in the medical records. Results: A total of 3,873 female breast cancer patients were diagnosed from 2006-2015. All data sets were recorded in SEER summary stage 2000. Early stage was the most prevalent stage at the time of diagnosis (58%), followed by loco-regional advanced stage (32%), and metastatic breast cancer (10%). The 5-year overall survival rate of early, loco-regional advanced, and metastatic stages were 85.3%, 66.4%, and 26.2%, respectively. After examining the medical records, we excluded patients who had no data on T, N, and M in their records. Finally, only 3,251 patients were analyzed for AJCC stage-specific survival. The 5-year overall survival rate in stages I, II, III, and IV were 94.4%, 85.0%, 56.6%, and 28.3%, respectively. Conclusion: Comparing to more stable economic countries, the 5-year overall survival rate for a specific stage of breast cancer in Northern Thailand was slightly lower in early stage and stage I-II in accordance with AJCC, but much lower in loco-regional stage and stage III with respect to AJCC. Nevertheless, it was similar in metastatic stage and stage IV according to AJCC.

e15003 Background: Stella Trial is a phase III, multinational, double-blind and randomized study to confirm clinical similarity between MB02 and EU-bevacizumab in patients with stage IIIB/IV no squamous NSCLC. 627 subjects with newly diagnosed or recurrent stage IIIb/IV NSCLC were randomized 1:1 to receive either MB02 or EU-bevacizumab plus chemotherapy (paclitaxel and carboplatin) every 3-week cycle for six cycles (week 18) followed by MB02/bevacizumab in blinded monotherapy until disease progression, treatment intolerance, death, patient withdrawal or end of study (w52). An approach targeting the MI of the continuous sum of target diameters (mm), and subsequent categorization of Overall Response (OR) was performed as sensitivity analysis for the assessment of the primary endpoint. Multiple Imputation (MI) has emerged as a credible method to assess the effects of missing data (MD), an inescapable problem with a potential ability to undermine research results' strength and validity in a clinical study, providing the user with a valuable toolset to sufficiently account for the varying types of MD and appropriately adjust the assumptions. Methods: The primary endpoint of the study was Objective Response Rate (ORR) at week 18 per an Independent Radiological Committee (IRC) in the Intention to treat set (ITT). The ORR was analysed with a Cochran-Mantel-Haenszel model, including the stratification factors of sex, smoking status, disease diagnosis and disease stage, comparing the stratified estimates risk difference (RD). In addition, these results were analysed implementing a pattern-mixture MI process accounting for missing at random (MAR) and missing not at random (MNAR) data based on the sum of target diameters in subjects without tumour response data or falling into the categories NonCR/NonPD or non-evaluable (NE). Results: The clinical equivalence of MB02 with EU-bevacizumab is demonstrated by the efficacy data provided through the primary endpoint and the MI sensitive analysis applied. The MI (MAR and MNAR) represents an added value that supports the biosimilarity of MB02 and EU-bevacizumab. The results for the primary analysis of the RD in ORR at w18 in the ITT set were entirely contained within the boundaries of predefined margins (±12): -4.02 [95% CI: -11.76 to 3.71]). Under MI, the ORR RD showed similarity at 95% CIs (-1.92; 95% CI: -10.02 to 6.19) and using the multiple imputations for subjects without tumour response data (missing, NonCR/NonPD or NE), the ORR RD was -2.22 with 95% CI of (-10.54 to 6.10) at w18 in the ITT. Conclusions: The clinical equivalence of MB02 with EU-bevacizumab is demonstrated by the efficacy data provided through the primary endpoint and the MI sensitive analysis applied. The MI (MAR and MNAR) represent an added value that supports the biosimilarity of MB02 and EU-bevacizumab. Clinical trial information: NCT03296163.

Background HER2/neu is overexpressed in 15-25% of gastric cancer patients and associated with poor prognosis. Treatment with recombinant monoclonal Abs against HER2/neu is effective yet alternatives are needed due to cost and global availability issues. Thus a peptide vaccine (IMU-131) was developed, consisting of 3 fused B-cell epitopes (p467) from the HER2/neu extracellular domain coupled to CRM197 and administered with the adjuvant Montanide. The present study evaluated the optimal/safe vaccine dose leading to immunogenicity and clinical responses. Methods In an open-label multicenter Phase Ib trial (SE-Asia & Eastern Europe), 14 patients with HER2/neu overexpressing ( ++/ +++) gastric adenocarcinoma were recruited to receive 3 injections of IMU-131 (days 0, 14, 35) in combination with chemotherapy (CT). Dose escalation (10, 30 and 50 µg) was performed in 3 cohorts (C) to evaluate safety, immunogenicity and clinical responses. Results No SAEs related to IMU-131 administration were reported. Eleven patients were evaluable for vaccine-specific immune responses and RECIST assessment. Higher HER2-specific IgG levels were observed in C2 (30 µg) vs. C1 (10 µg). 3/5 patients in C2 showed moderate or little increase in HER2-specific Abs, while all C3 patients (50µg) responded with moderate to high Ab levels. According to RECIST, 1 patient showed complete response, 5 partial response and 4 stable disease. Strong correlation between high Ab levels and clinical responses was observed in C3, while this was only moderate in C2. Capacity to inhibit HER2 phosphorylation was tested in patient sera and could be detected in association with strong tumor reduction. Furthermore, patients with good clinical responses, but low Ab titers featured cellular responses with high IFNγ and TNFα/IL-10 ratios. Conclusions The vaccine was well tolerated and safe with Ab responses at the highest dose showing strong correlation with clinical responses. Currently, the 50 µg dose is being evaluated in a Phase II trial with two arms (IMU 131 + CT and CT only). Clinical trial identification NCT02795988. Legal entity responsible for the study Imugene Ltd. Funding Imugene Ltd. Disclosure U. Wiedermann: Research grant / Funding (institution), Officer / Board of Directors, CSO until September 2018: Imugene; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Themis. I. Bulat: Advisory / Consultancy, Research grant / Funding (self), Full / Part-time employment: Arensia Exploratory Medicine . T. Yau: Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb. M. Maglakelidzde: Advisory / Consultancy, Research grant / Funding (self), Full / Part-time employment: ARENSIA Exploratory Medicine . T. Ungtrakul: Travel / Accommodation / Expenses: AstraZeneca. C.C. Zielinski: Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy, Officer / Board of Directors, Scientific Advisory Board Member until June 2018: Imugene; Honoraria (self), Advisory / Consultancy: Ariad; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy: Merrimack; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: KGaA; Honoraria (self), Advisory / Consultancy: Fibrogen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy: Tesaro; Honoraria (self), Advisory / Consultancy: Gilead; Honoraria (self), Advisory / Consultancy: Servier; Honoraria (self), Advisory / Consultancy: Shire; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: Athenex. L. Chong: Honoraria (self), Advisory / Consultancy, Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Imugene Ltd. N. Ede: Leadership role, Research grant / Funding (institution), Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment: Imugene Ltd. A. Good: Advisory / Consultancy, Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Imugene Ltd; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Kazia Therapeutics; Shareholder / Stockholder / Stock options: Living Cell Technologies. All other authors have declared no conflicts of interest.

Background Cosibelimab is a high affinity, fully-human IgG1 monoclonal antibody (mAb), with functional Fc domain capable of inducing ADCC, that directly binds to programmed death ligand-1 (PD-L1) and blocks the PD-L1 interaction with the programmed death receptor-1 (PD-1) and B7.1 receptors. Cosibelimab is being evaluated in a multicenter phase 1 study (NCT03212404) in pts with advanced cancers. We present preliminary safety, efficacy and PK data. Methods Pts were ≥18 years old with advanced cancers and adequate organ function. In dose escalation, pts received cosibelimab administered intravenously at sequential fixed doses of 200 mg, 400 mg, or 800 mg every 2 weeks (q2w) or 1200 mg every 3 weeks (q3w) using a 3 + 3 design. Following dose escalation, multiple tumor-specific expansion cohorts are being enrolled at 800 mg q2w to further evaluate safety and efficacy. Results As of April 23, 2019, 65 pts (47M/18F, median age 64 years) with diverse tumor types received cosibelimab in dose escalation and expansion cohorts. Cosibelimab has demonstrated acceptable tolerability with no dose‐limiting toxicities. Treatment‐related adverse events (AEs) occurred in 32/65 (49%) pts, most commonly rash (n = 9, 14%) and fatigue (n = 6, 9%). Treatment‐related grade ≥3 AEs occurred in 5/65 (8%) pts, all grade 3, and included anemia, asthenia, hypertension, hyponatremia, and high blood pressure (n = 1 [2%] each). Cosibelimab demonstrated linear PK with features consistent with marketed anti-PD-L1 mAbs. Thirty-six pts were response evaluable of which 10/36 (28%) pts achieved a partial response by RECIST 1.1 criteria (including cutaneous squamous cell carcinoma, non-small cell lung cancer, head and neck squamous cell carcinoma and melanoma), 17/36 (47%) pts achieved stable disease, and 24/36 (67%) pts experienced target lesion reductions versus baseline. Forty-two pts remain on treatment (range, 1-17+ mos). Conclusions Cosibelimab has demonstrated a safe and well-tolerated safety profile with evidence of durable anti‐tumor activity in several advanced cancers, and linear PK. Cosibelimab is being further evaluated in multiple tumor-specific expansion cohorts. Updated results will be presented. Clinical trial identification NCT03212404. Legal entity responsible for the study Checkpoint Therapeutics, Inc. Funding Checkpoint Therapeutics, Inc. Disclosure P.R. Clingan: Research grant / Funding (institution): Merck Sharp & Dohme Corp; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Bristol Myers; Research grant / Funding (institution): Checkpoint Therapeutics, Inc. A.M. Mant: Research grant / Funding (institution): Checkpoint Therapeutics, Inc. G.E. Richardson: Research grant / Funding (institution): Novotech; Research grant / Funding (institution): Roche; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Alphapharm; Research grant / Funding (institution): Checkpoint Therapeutics. D.M. Kowalski: Research grant / Funding (institution): Checkpoint Therapeutics, Inc. P. Koralewski: Research grant / Funding (institution): Checkpoint Therapeutics, Inc. I. Lugowska: Research grant / Funding (institution): Checkpoint Therapeutics, Inc.; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol Myers; Honoraria (self): Merck; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self): Amgen; Honoraria (self): Janssen; Honoraria (self), Research grant / Funding (institution): Novartis. A. Dechaphunkul: Speaker Bureau / Expert testimony: Roche; Travel / Accommodation / Expenses: Eisai; Research grant / Funding (institution): Checkpoint Therapeutics. C. Charoentum: Research grant / Funding (institution): Roche; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Checkpoint Therapeutics. A. Sookprasert: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Honoraria (self): Eisai; Research grant / Funding (institution): Checkpoint Therapeutics, Inc. V. Sriuranpong: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self): Sanofi; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Honoraria (self), Research grant / Funding (institution): Boehringer; Honoraria (self), Research grant / Funding (institution): Taiho; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck Sharp & Dohme; Honoraria (self): Bristol Myers; Advisory / Consultancy: Amgen; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Checkpoint Therapeutics. A. Akopov: Research grant / Funding (institution): Checkpoint Therapeutics, Inc. V. Kozlov: Research grant / Funding (institution): Checkpoint Therapeutics, Inc. N. Fadeeva: Research grant / Funding (institution): Checkpoint Therapeutics, Inc. B. Kasparov: Research grant / Funding (institution): Checkpoint Therapeutics, Inc. N.V. Kovalenko: Research grant / Funding (institution): Checkpoint Therapeutics, Inc. V. Oschepkov: Research grant / Funding (institution): Checkpoint Therapeutics, Inc. L. Gorelik: Shareholder / Stockholder / Stock options, Full / Part-time employment: Checkpoint Therapeutics, Inc. Y. Kunes: Shareholder / Stockholder / Stock options: Checkpoint Therapeutics, Inc. J. Oliviero: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Checkpoint Therapeutics, Inc. D.L. Harris: Research grant / Funding (institution): Merck; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Checkpoint Therapeutics; Research grant / Funding (institution): Targovax.

Background: HER2/neu is overexpressed in 15-25% of gastric cancer patients and associated with poor prognosis. Alternative treatments to monoclonal antibodies are needed due to cost and global availability issues of mAbs. Thus a B-cell peptide vaccine (IMU-131) was developed, consisting of 3 fused B-cell epitopes (p467) from the HER2/neu extracellular domain coupled to CRM197 applied with the adjuvant Montanide. The current study evaluated the optimal and safe vaccine dose leading to immunogenicity and clinical responses. Material & Methods: In an open-label multicenter Phase Ib trial in SE-Asia and Eastern Europe, 14 patients with HER2/neu overexpressing (++/+++) gastric or gastroesophageal junction adenocarcinoma were recruited to receive 3 injections of IMU-131 (days 0, 14, 35) in combination with chemotherapy (CT) every 21 days. Dose escalation with 10 µg, 30 µg and 50 µg was performed in 3 cohorts. Safety, immunogenicity and clinical responses were evaluated. Results: No SAEs related to administration of IMU-131 were reported. Eleven of 14 patients were evaluable for vaccine-specific immune responses and 10 for tumor growth assessment. Higher p467- and Her-2 specific IgG levels were observed in cohort 2 (30 µg/dose) compared to cohort 1 (10 µg/dose). Two of five patients in cohort 2 showed minimal antibody titers. In contrast, all patients in cohort 3 (50µg/dose) responded to the vaccine with equally high antibody levels. Response rate was an exploratory endpoint and of 10 evaluable patients, 5 patients showed partial response and 4 patients showed stable disease. In cohort 3 the high antibody levels correlated with clinical response, while in cohort 2 only moderate correlations between humoral and clinical responses were observed. In cohort 1 partial response did not correlate with Ab levels, but rather with a high percentage of CD8 T-cells and increased inflammatory cytokine levels (high IFN-γ and TNF-α/IL-10 ratio). Conclusions: The vaccine was well tolerated and safe with antibody responses at the highest dose (50 µg) showing a strong correlation with clinical responses. Thus, a dose of 50 µg was recommended for further evaluation in Phase II, featuring two arms of either IMU 131 plus CT or CT alone. We propose that this vaccine might be of significant medical benefit and further trials are warranted. Citation Format: Ursula Wiedermann, Erika Garner-Spitzer, Yee Chao, Iurie Bulat, Arunee Dechaphunkul, Wichit Arpornwirat, Chaiyut Charoentum, Chia-Jui Yen, Thomas Cheung Yau, Marina Maglakelidze, Suebpong Tanasanvimon, Jedzada Maneechavakajorn, Aumkhae Sookprasert, Li-Yuan Bai, Wen-Chi Chou, Teerapat Ungtrakul, Christoph C. Zielinski, Leslie Chong, Nick Ede, Anthony J Good. A Phase Ib open label multicenter study with a HER2/neu peptide vaccine administered with cisplatin and 5-fluorouracil or capecitabine chemotherapy shows safety, immunogenicity and clinical response in patients with HER2/Neu overexpressing advanced cancer of the stomach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT059.

TPS176 Background: Gastric cancer is the 5th most frequently diagnosed cancer and the 3rd leading cause of cancer deaths. HER2/neu is overexpressed in 15% to 25% of patients with gastric cancer and associated with a poor prognosis. Monoclonal antibodies against HER2/neu have been shown to be effective but alternative treatments are needed due to cost and global availability issues. IMU-131 is a B-cell peptide vaccine composed of 3 B cell epitopes derived from the extracellular domain of HER2/neu. Polyclonal antibodies against IMU-131 peptides binding 3 separate regions (DIII, IV) of HER2/neu have been shown to elicit antitumor activity in vitro and a phase I study demonstrated safety and immunogenicity in Her-2 +/++ metastatic breast cancer patients. Fusion of the single peptides into a hybrid peptide conjugated to CRM197 in conjunction with the adjuvant Montanide (P467-CRM-Montanide) improved formulation and stability of the vaccine. With the present Phase 1b/2 trial performed in patients with HER2/neu overexpressing gastric or gastroesophageal junction (GEJ) adenocarcinoma, we hypothesized that administration of IMU-131 in addition to chemotherapy is safe and immunogenic, and will prolong survival and may delay tumor progression and/or reduce tumor burden. Methods: This study is an international open-label multicenter study performed in 16 Asian and Eastern European sites with a maximum of 18 patients enrolled in Phase 1b. This dose escalation study is designed to assess safety, tolerability, immunogenicity and recommended phase 2 dose (RP2D) of IMU-131. Each patient is administered three injections of IMU-131, at a single dose level on Days 0, 14, and 35, accompanied by chemotherapy cycles of cisplatin and 5-fluorouracil or capecitabine every 21 days. The RP2D will be evaluated in the dose expansion Phase 2 study with 68 patients being enrolled. Results: The study is ongoing with the completion of the phase 1b portion in 4Q18. Conclusions: No conclusions can be drawn at this time. Clinical trial information: NCT02795988.

Aim: Carboplatin plus paclitaxel is a more costly chemotherapy regimen than cisplatin plus etoposide; however there have been reports of higher efficacy and less toxicity of this regimen. Thus, this study aimed to assess the cost-effectiveness of these two chemotherapy regimens in advanced non-small cell lung cancer (NSCLC). Methods: Using the perspective of Maharaj Nakorn Chiang Mai Hospital, Thailand, direct medical costs, including chemotherapy, drugs, medical service charges, costs of adverse events, concomitant medication and survival time were directly gathered from 65 patients enrolled from August 2005 to November 2008. A one-way sensitivity analysis was performed. An incremental cost-effectiveness ratio (ICER) was also calculated. Results: Of these 65 patients, 30 received cisplatin plus etoposide (Arm I) and 35 received carboplatin plus paclitaxel (Arm II). The median survival time was not statistically significant (8.23 months vs 8.80 months in Arm I and II, respectively; P = 0.99). The total cost per patient in Arm II was about three times that in Arm I (95,548 Baht vs 29,692 Baht) while quality-adjusted life-years (QALY) in Arm II were slightly above those in Arm I (0.587 vs 0.412). The ICER was equal to 375,958 Baht per QALY. Conclusion: With a cost-effectiveness threshold of 100,000 Baht in Thailand, carboplatin plus paclitaxel was still not cost-effective. While the selection of a suitable regimen for individual patients should not rely on drug and hospital costs alone, the overall cost, including the burden on patients, should be taken into consideration.

Radiotherapy concurrent with cisplatin either weekly or every 3 weeks’ regimen has been accepted as the standard of care for locoregional advanced stage of nasopharyngeal cancer for decades (1-5). Although it has shown a statistically significant benefit in terms of locoregional control and survival rate when compared with radiotherapy alone, but severe acute and late toxicities might affect the quality of life (QoL), mainly nausea, vomiting, impaired renal function, and hearing toxicity (6-9).

To describe the pattern of disease progression and to describe locoregional recurrence, distant recurrence, and death rates in breast cancer patients after complete treatment.Medical records of women diagnosed with breast cancer at two university affiliated tertiary care hospitals in the Northern Thailand that had complete treatments between 2006 and 2010 were traced. Extracted key information included patient clinical profiles and documented recurrence of cancer The causes of death were verified from breast cancer case registration database, death certificates through The Ministry of Internal Affairs'civil registration, by direct telephone contact, or by distributed prepaid postcards.Medical records of 829 women diagnosed with breast cancer without prior evidence ofdistant metastasis, and had complete recommended treatment were included. Six hundred thirty seven women had not experienced any events up to the end of the follow-up (76.8%). The first occurring events were focused and categorized into three distinct types, locoregional recurrence (n = 83, median follow-up time = 34.2 months), distant recurrence (n = 78, median follow-up time = 35.4 months), and death without any evidences of locoregional or distant recurrences (n = 12, median follow-up time = 36.7 months). Distant recurrence after locoregional recurrence was reported (n = 33). There were 109 patient who had died (breast cancer related death) up to the end of the follow-up (13.2%). The three types of consecutively occurring deaths were death after locoregional recurrence without any distant recurrences (n = 15), death after distant recurrence with locoregional recurrence (n = 21), and death after documenited distant recurrence without any locoregional recurrences (n = 61).The trend was that the rate of the first occurring locoregional recurrence was slightly higher than that of distant recurrence, The death rate in patients without any recurrences was much lower than in those experiencing prior recurrences. The rates of disease progression from local recurrence to distant recurrence and to death were approximately 5 to 7 times faster in patients who had experienced earlierprogressions.

Colorectal cancer (CRC) is among the most common cancers worldwide, but marked epidemiological differences exist between Asian and non-Asian populations. Hence, a consensus meeting was held in Hong Kong in December 2012 to develop Asia-specific guidelines for the management of metastatic CRC (mCRC). A multidisciplinary expert panel, consisting of 23 participants from 10 Asian and 2 European countries, discussed current guidelines for colon or rectal cancer and developed recommendations for adapting these guidelines to Asian clinical practice. Participants agreed that mCRC management in Asia largely follows international guidelines, but they proposed a number of recommendations based on regional 'real-world' experience. In general, participants agreed that 5-fluorouracil (5-FU) infusion regimens in doublets can be substituted with UFT (capecitabine, tegafur-uracil) and S1 (tegafur, 5-chloro-2,4-dihydroxypyridine and oxonic acid), and that the monoclonal antibodies cetuximab and panitumumab are recommended for KRAS wild type tumors. For KRAS mutant tumors, bevacizumab is the preferred biological therapy. FOLFOX (folinic acid, 5-FU, and oxaliplatin) is preferred for initial therapy in Asian patients. The management of mCRC is evolving, and it must be emphasized that the recommendations presented here reflect current treatment practices and thus might change as more data become available.

Carboplatin plus paclitaxel is a more costly chemotherapy regimen than cisplatin plus etoposide; however there have been reports of higher efficacy and less toxicity of this regimen. Thus, this study aimed to assess the cost-effectiveness of these two chemotherapy regimens in advanced non-small cell lung cancer (NSCLC).Using the perspective of Maharaj Nakorn Chiang Mai Hospital, Thailand, direct medical costs, including chemotherapy, drugs, medical service charges, costs of adverse events, concomitant medication and survival time were directly gathered from 65 patients enrolled from August 2005 to November 2008. A one-way sensitivity analysis was performed. An incremental cost-effectiveness ratio (ICER) was also calculated.Of these 65 patients, 30 received cisplatin plus etoposide (Arm I) and 35 received carboplatin plus paclitaxel (Arm II). The median survival time was not statistically significant (8.23 months vs 8.80 months in Arm I and II, respectively; P = 0.99). The total cost per patient in Arm II was about three times that in Arm I (95,548 Baht vs 29,692 Baht) while quality-adjusted life-years (QALY) in Arm II were slightly above those in Arm I (0.587 vs 0.412). The ICER was equal to 375,958 Baht per QALY.With a cost-effectiveness threshold of 100,000 Baht in Thailand, carboplatin plus paclitaxel was still not cost-effective. While the selection of a suitable regimen for individual patients should not rely on drug and hospital costs alone, the overall cost, including the burden on patients, should be taken into consideration.

To assess the activity and toxicity of cisplatin and irinotecan alternating with docetaxel in patients with advanced non-small cell lung cancer (NSCLC).Eligibility included chemo-naïve stage IIIB with malignant effusion and stage IV NSCLC patients with measurable disease and a good performance status. Twenty-four patients were enrolled into the present study. There were 19 males and 5 females with a median age of 58.5 years and the median performance status was 1. Ninety-six percent had stage IV disease. These patients received cisplatin at 80 mg/ m2 and irinotecan at 200 mg/m2 on day 1, followed by docetaxel at 75 mg/m2 on day 22, in 6-week cycle for a maximum of 3 cycles.Eight out of twenty-two evaluable patients obtained a partial response (36%). The median time to tumor progression was 6 months. The median survival time and 1-year survival rate were 10.4 months and 45% respectively. The most frequent severe toxicities were neutropenia, anemia, and diarrhea. Febrile neutropenia occurred in four patients (16%), and was the cause of treatment-related deaths in two (8%). Other nonhematologic toxicities were mild including nausea, vomiting, and skin rash.Alternating cisplatin and irinotecan with docetaxel, as used in the present study was feasible and demonstrated encouraging efficacy in patients with non-small cell lung cancer However, this approach appears to be more toxic, especially in myelosuppression, than in previous reports of the sequential use of the similar agents.

To determine the activity and toxicity of combined 24-hour infusion of paclitaxel with carboplatin in advanced non-small cell lung cancer.Eligibility required measurable disease; stage III B with malignant pleural effusion or stage IV disease, with a performance status (PS) of ECOG 0-2. Chemotherapy consisted of 24 hours continuous infusion of paclitaxel at 135 mg/m(2) on day 1, followed by carboplatin (AUC=6) on day 2. Treatment was repeated at 3-week intervals for a total of 6 cycles.Thirty-nine patients were enrolled. Twenty six patients were male and 13 female, with a median age of 57 years (range, 38 to 72). Six patients (15%) had stage III B and 33 (85%) had stage IV. PS 0-1/2 was 67%/33%. A total of 131 cycles was administered and the median number of cycles was 4 (range, 2-6). Grade 3-4 neutropenia, grade 3-4 leukopenia and grade 3 anemia occurred in 3%, 3% and 23%, respectively. One patient (3%) developed febrile neutropenia. Grade 3 diarrhea occurred in 3 patients (8%). Other non-hematologic toxicities were mild including mucositis and skin rash. The overall response rate was 15%. Median survival was 8 months (range 6-9.5 months) and 1-year survival rate was 20%.The combined 24-hour infusion of paclitaxel (Intaxel) with carboplatin is a feasible and well-tolerated regimen in the treatment of advanced NSCLC patients.

A 53-year old non-smoking Thai female was diagnosed with metastatic non-small cell lung cancer to bone. The initial biopsy from the bone lesion showed metastatic adenocarcinoma. She achieved partial response after treatments with radiation therapy to the bones, followed by 6 cycles of combination chemotherapy. About 4 months later, recurrence of the pulmonary and osseous disease was apparent. She has ECOG performance status of 3. Gefitinib 250 mg/day was administered until disease progression for about 14 months. After 6 weeks on this therapy, she had dramatic improvement of all symptoms including her performance status and had nearly complete resolution of all pulmonary lesions. Tolerability was good, with only mild fatigue. The overall survival was 28 months. This illustrates that gefitinib could produce significant clinical benefits in selected Thai patients even with poor performance status. This result is consistent with previous reports that the clinical characteristics of female, non-smoker and adenocarcinoma histology seem to predict response to gefitinib.

This phase II study aimed to assess the effectiveness of the docetaxel plus carboplatin combination in chemotherapy-naive Thai patients with advanced non-small-cell lung cancer (NSCLC).Forty patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1, stage IIIB/IV NSCLC were enrolled in a phase H study between August 2001 and April 2003. Docetaxel 75 mg/m2 and Carboplatin AUC = 6 were given every 3 weeks. Response to treatment and toxicity were graded using standard WHO criteria. The Thai Functional Living Index Cancer (T-FLIC) scale was used to assess the Quality of Life (QoL) of all treated patients.Forty patients (median age: 55 years, range, 39-68 years; PS:0-1) were enrolled: one had stage IIIB disease with effusion, while thirty-nine had stage IV disease. Five patients were non-evaluable due to death within the first cycle; two dying of febrile neutropenia and sepsis, two of pulmonary infection, and one of unknown etiology. Partial response (PR) was seen in 28.6% patients, stable disease (SD) in 25.7%, and progressive disease (PD) in 45.7%. The median survival time was 32 weeks and the 1-year survival rate was 30.7%. Body mass index (BMI) was the only factor associated with survival time (univariate analysis: p = 0.006; multivariate analysis: p = 0.004). Other factors (gender, age, histology, ECOG PS, and glomerular filtration rate) were not predict for survival. The major treatment-related toxicities were neutropenia (from 152 treatment cycles there were grade 4: 19.7%; grade 3: 23.7%), febrile neutropenia (from 152 treatment cycles there was 3.95%), and diarrhea (grades 3/4: 0.66%). The QoL scores improved significantly throughout the treatment period.The regimen of docetaxel and carboplatin is active in advanced NSCLC and may be considered for first-line therapy.

We performed a study to determine the feasibility of a rapidly alternating administration of cisplatin/vinorelbine (CV) and docetaxel/gemcitabine (DG) in the treatment of advanced non-small-cell lung cancer (NSCLC). Thirty-four patients with NSCLC (6% stage IIIB, 94% stage IV) were enrolled. The initial schema was to give CV on days 1 and 8 followed by DG on days 15 and 22, every 28 days. Granulocyte colony-stimulating factor (G-CSF) was used on days 9-14 and 23-28. Despite dose reductions, this sequence was not feasible. Therefore, the sequence was switched to give DG before CV, cycle duration was extended to 35 days, and G-CSF was given on days 2-7 and 23-28. Neutropenia and thrombocytopenia were dose-limiting toxicities. The recommended doses for phase II studies are docetaxel 75 mg/m2 on day 1, gemcitabine 1000 mg/m2 on days 1 and 8, cisplatin 60 mg/m2 on day 15, and vinorelbine 25 mg/m2 on days 15 and 22, every 35 days with G-CSF 5 microg/kg on days 2-7 and 23-28. However, treatment delays were required in subsequent cycles due to cumulative myelosuppression. A less intensive schedule is recommended for subsequent cycles for further testing. Overall response rate was 29% (95% confidence interval [CI], 14%-45%), and median survival for all patients was 11.8 months. One- and 2-year survival rates were 47% (95% CI, 30%-63%) and 14% (95% CI, 1.4%-40%), respectively. Although initial administration of this regimen was feasible, dose intensity could not be maintained in subsequent cycles due to cumulative myelosuppression. A sequential rather than alternating use of doublet regimens might be more readily feasible and may permit greater maintenance of dose intensity.

265 Background: Combination of gemcitabine/cisplatin becomes a recent standard regimen for pts with advanced (ABC). We previously reported the encouraging activity of gemcitabine (1250 mg/m2) with cisplatin and reported grade 3/4 toxicities of anemia and neutropenia in 33% and 22% respectively. (Charoentum et al. World J Gastroenterol 2007.). This study examines the toxicity and activity of attenuated dose gemcitabine (1000 mg/m2) with cisplatin in Thai pts with ABC. Methods: Chemotherapy-naive patients with histological/cytological proven ABC, aged > 18 years, ECOG 0-2 and adequate organs function were treated with gemcitabine (1000 mg/m2 in a 30-min infusion D1, 8 q 21 d) followed by cisplatin (75 mg/m2D1) for maximum 6 cycles. Results: From November 2007 to June 2012, 37 patients were evaluated. Median age was 56 yrs (range 34 - 66), 54% were male, 76% were metastatic disease and 97% were ECOG PS 0/1. The median number of cycle was 4 (range 3-6). Among the 34 pts with measurable disease, there were 11 PR, 15 SD and 8 PD (response rate 32%). The most common hematologic toxicity of interests was gr 3 anemia in 11% and gr 4 neutropenia in 6%. Non-hematologic toxicity was generally mild. No cases of febrile neutropenia or treatment-related death were observed. The median progression free survival was 6 months (range 3-13). Conclusions: Treatment with attenuated dose of gemcitabine in combination with cisplatin in this study appears more tolerable than our previous reports in Thai pts with advanced ABC. The efficacy of both regimen appears similar.

To study the activity of gemcitabine and cisplatin in a cohort of patients with inoperable or metastatic cholangiocarcinoma.Chemotherapy-naive patients with pathologically proven cholangiocarcinoma, receiving treatment that consisted of gemcitabine at 1250 mg/m(2) in a 30-min infusion on d 1 and 8, and cisplatin at 75 mg/m(2) at every 21-d cycle, were retrospectively analyzed.From June 2003 to December 2005, 42 patients were evaluated. Twelve patients (28%) had unresectable disease and 30 (72%) had metastatic disease. There were 28 males and 14 females with a median age of 51 years (range 33-67) and median ECOG PS of 1 (range 0-2). A total of 171 cycles were given with a median number of cycles of 4 (range 1-6). There were 0 CR, 9 PR, 11 SD and 13 PD (response rate 21%). Grade 3-4 hematologic toxicities were: anemia in 33%, neutropenia in 22% and thrombocytopenia in 5%. Non-hematologic toxicity was generally mild. No cases of febrile neutropenia or treatment-related death were noted. The median survival was 10.8 mo (range 8.4-13 mo) and progression free survival was 8.5 mo. One-year survival rate was 40%.Our results indicate that the combination of gemcitabine and cisplatin had consistent efficacy in patients with unresectable or metastatic cholangiocarcinoma.