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Janus kinase inhibitors (JAKi) approved for myelofibrosis provide spleen and symptom improvements but do not address anemia, a negative prognostic factor. Momelotinib, an inhibitor of ACVR1/ALK2, JAK1 and JAK2, demonstrated activity against anemia, symptoms, and splenomegaly in the phase 3 SIMPLIFY trials. Here, we report mature overall survival (OS) and leukemia-free survival (LFS) from both studies, and retrospective analyses of baseline characteristics and efficacy endpoints for OS associations. Survival distributions were similar between JAKi-naïve patients randomized to momelotinib, or ruxolitinib then momelotinib, in SIMPLIFY-1 (OS HR = 1.02 [0.73, 1.43]; LFS HR = 1.08 [0.78, 1.50]). Two-year OS and LFS were 81.6% and 80.7% with momelotinib and 80.6% and 79.3% with ruxolitinib then momelotinib. In ruxolitinib-exposed patients in SIMPLIFY-2, two-year OS and LFS were 65.8% and 64.2% with momelotinib and 61.2% and 59.7% with best available therapy then momelotinib (OS HR = 0.98 [0.59, 1.62]; LFS HR = 0.97 [0.59, 1.60]). Baseline transfusion independence (TI) was associated with improved survival in both studies (SIMPLIFY-1 HR = 0.474, p = 0.0001; SIMPLIFY-2 HR = 0.226, p = 0.0005). Week 24 TI response in JAKi-naïve, momelotinib-randomized patients was associated with improved OS in univariate (HR = 0.323; p p

Introduction Myelofibrosis (MF) typically presents with constitutional symptoms, splenomegaly, and anemia with the degree of anemia and transfusion dependency being among the most important predictors of poor overall survival (OS). Momelotinib (MMB) is a differentiated JAK1, JAK2 inhibitor with potent activity against ACVR1/ALK2, a critical regulator of hepcidin production and iron metabolism. MMB has demonstrated clinical activity against all 3 of these hallmark features of MF in the SIMPLIFY Ph 3 studies including SIMPLIFY-1 (S1) in the JAK inhibitor (JAKi) naïve setting compared directly to ruxolitinib (RUX) and in the previously JAKi experienced patients (SIMPLIFY-2 [S2]) in comparison to best available therapy (BAT) which was predominately RUX. MMB has also demonstrated robust OS in the JAKi naïve population (S1) and JAKi experienced population (S2) (Verstovsek et al. ASH 2020). Critically, patients randomized to MMB who maintain or achieve transfusion independence (TI) by Week 24 (W24) had better OS, further suggesting that MMB's anemia benefits positively impact long term outcomes in patients with MF (Mesa et al. EHA 2021). Increased hepcidin and ferritin are associated with dysregulated iron metabolism and inflammation, both of which have previously been shown to be strong negative prognostic factors for OS in patients with MF at the time of first referral (Pardanani et al. 2013). A Ph 2 translational biology study previously demonstrated MMB acutely and chronically suppresses elevated levels of hepcidin and restores iron homeostasis in transfusion dependent patients who achieve a W24 TI-response (TI-R; Oh et al. 2020). Interestingly, several baseline factors, such as hepcidin, ferritin and CRP from this study suggested a potential threshold of W24 TI-R for patients treated with MMB, warranting further exploration. Methods Based on the findings from the Ph 2 translational biology study we retrospectively analyzed the relationship between serum ferritin, hepcidin and CRP and the W24 TI-R rates for patients randomized to MMB and RUX in S1 using generalized linear regression models where the degree of predictiveness measured by the interaction between treatment and the biomarkers as continuous or categorical variables using various cutoffs were examined. These findings were then independently confirmed in the previously RUX treated patients from S2. Results These analyses identified pre-treatment serum ferritin level as the most predictive biomarker for the treatment effect of MMB vs RUX on W24 TI-R rate in S1. The TI-R treatment effect of MMB vs RUX was significantly greater (p=0.0051) in the ≥90ng/mL cohort (62% vs 35% respectively, with response ratio [RR]=1.8) than in the Data also demonstrated a significant increase in serum ferritin for RUX vs MMB at W24 vs baseline (RUX mean ferritin change +226.1ng/mL vs MMB +13.8ng/mL, p=0.0003), irrespective of baseline ferritin. Conclusion Ferritin is a well-established and easily measured clinical biomarker that is associated with both iron metabolism and uncontrolled inflammation. Prior analyses demonstrate patients randomized to MMB who achieve a W24 TI-R have increased OS compared to non-TI responders. These new analyses expand on these findings, demonstrating that the MMB vs RUX treatment effect is greater in baseline serum ferritin ≥90ng/mL vs Figure 1 Figure 1. Disclosures Oh: Abbvie: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees; Celgene Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Constellation: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Disc Medicine: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Kartos Therapeutics: Membership on an entity's Board of Directors or advisory committees; PharamaEssentia: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees. Gerds: PharmaEssentia Corporation: Consultancy; CTI BioPharma: Research Funding; Sierra Oncology: Consultancy; AbbVie: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; Constellation: Consultancy; Novartis: Consultancy. Mesa: CTI: Research Funding; Pharma: Consultancy; Incyte Corporation: Consultancy, Research Funding; Abbvie: Research Funding; AOP: Consultancy; Constellation Pharmaceuticals: Consultancy, Research Funding; Samus: Research Funding; Celgene: Research Funding; Gilead: Research Funding; Promedior: Research Funding; La Jolla Pharma: Consultancy; Sierra Oncology: Consultancy, Research Funding; CTI: Research Funding; Novartis: Consultancy; Genentech: Research Funding. Gupta: Pfizer: Consultancy; Roche: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Constellation Pharma: Consultancy, Honoraria; BMS-Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria; Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding. Huang: Sierra Oncology: Current Employment; BioMarin: Ended employment in the past 24 months. Ro: Sierra Oncology: Current Employment; BeiGene: Ended employment in the past 24 months. Strouse: Sierra Oncology: Current Employment. Klencke: Sierra Oncology: Current Employment, Current equity holder in publicly-traded company. Verstovsek: Blueprint Medicines Corp: Research Funding; Roche: Research Funding; PharmaEssentia: Research Funding; NS Pharma: Research Funding; Ital Pharma: Research Funding; Protagonist Therapeutics: Research Funding; Incyte Corporation: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; CTI BioPharma: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Sierra Oncology: Consultancy, Research Funding; Promedior: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy.

Ronald L Van Heertum,1 Robert Scarimbolo,1 John G Wolodzko,1 Barbara Klencke,2 Richard Messmann,3 Feza Tunc,4 Levi Sokol,4 Rajan Agarwal,5 James A Strafaci,1 Michael O’Neal1 1Medical Affairs, Bioclinica, Inc., Princeton, NJ, 2Medical Affairs, Sierra Oncology, Brisbane, CA, 3Medical Affairs, Apexian Pharmaceuticals, Indianapolis, IN, 4Radiology, University Radiology at RWJ University Hospital, New Brunswick, NJ, 5Radiology, Abington Hospital, Abington, PA, USA Abstract: An operationalized workflow paradigm is presented and validated with pilot subject data. This approach is reproducible with a high concordance rate between individual readers (kappa 0.73 [confidence interval 0.59–0.87; P=

Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is active in glioblastoma. We evaluated erlotinib efficacy in patients with first-relapse glioblastoma and assessed whether response was related to EGFR amplification and/or concomitant use of enzyme-inducing antiepileptic drugs (EIAEDs) in a phase II open-label study of glioblastoma patients in first relapse. Patients took erlotinib daily until progression. Starting dose was 150 mg for patients not taking EIAEDs and 300 mg for patients taking EIAEDs. Tumors were radiographically assessed every 8 weeks. Response was evaluated by investigators and confirmed by an independent radiology facility (IRF). The primary efficacy outcome was the objective response (OR) rate, according to the modified WHO criteria. Enrollment (n = 48) was terminated after a planned interim analysis due to an insufficient number of responses. The IRF confirmed 1 complete and 2 partial responses (PRs), for an OR rate of 6.3% (95% confidence interval [CI]: 1.7-17.0). Investigators determined 1 complete response and 3 PRs, median response duration of 7.0 months, 6-month progression-free survival (PFS) of 20% (95% CI: 10.0-32.4), and median survival of 9.7 months (95% CI: 5.9-11.6). Outcomes were not related to EGFR amplification or EIAED status. Diarrhea and rash were the most common adverse events (AEs); 23% of patients experienced grade 3-4 drug-related AEs. Despite the limited number of responses, 6-month PFS and median survival reached or exceeded the previously reported values for patients undergoing chemotherapy for recurrent glioblastoma. EGFR amplification was not associated with erlotinib activity. Given the large CIs and nonrandomized nature of the study, results should be interpreted cautiously.

BACKGROUND 131I-Metaiodobenzylguanidine (131I-MIBG) can be used systemically to treat malignant pheochromocytoma. To improve outcome, the authors used higher levels of activity of 131I-MIBG than previously reported. The authors reported the response rates and toxicity levels in patients with malignant pheochromocytoma or paraganglioma who were treated with high-dose 131I-MIBG. METHODS Following debulking surgery and stem cell harvest, 12 patients with malignant pheochromocytoma or paraganglioma were treated with 131I-MIBG. Five had received previous external beam radiation and/or chemotherapy. The median single treatment dose was 800 mCi (37 gigabecquerels; range, 386–866 mCi) or 11.5 mCi/kg (range, 5.6–18.3 mCi/kg). The median cumulative dose was 1015 mCi (range, 386–1690 mCi). RESULTS Three patients had a complete response, two of whom had soft tissue and skeletal metastases. Their median follow-up was 45 months (range, 23–101 months). Seven patients had a partial response (PR), with a median follow-up 43 months (range, 6–47 months). Two patients without a response died with progressive disease (PD) and 2 patients with an initial PR died of PD at 13 and 11 months, respectively. Grade 3 thrombocytopenia occurred after 79% (15 of 19) of treatments had been administered. Grade 3 and 4 neutropenia followed 53% (10 of 19) and 19% (4 of 19) of treatments, respectively. One patient required stem cell infusion, and one developed primary ovarian failure. CONCLUSIONS The single and cumulative doses of 131I-MIBG were approximately 2–3.5 times higher than those used at other centers. Unlike previous reports, two patients with both skeletal and soft tissue metastases had a complete response. Hematologic toxicity was significant but tolerable. High-dose 131I-MIBG may lead to long-term survival in patients with malignant pheochromocytoma. Cancer 2003;98:239–48. © 2003 American Cancer Society. DOI 10.1002/cncr.11518

Background Carfilzomib is a next-generation proteasome inhibitor with single-agent activity in patients with relapsed and refractory multiple myeloma (R/R MM). In PX-171-003-A1, a single-arm phase 2 study of carfilzomib monotherapy in heavily pretreated patients, the overall response rate was 23.7%, 37% of patients achieved ≥ minimal response and median overall survival (OS) was 15.6 months. Based on this study, carfilzomib was recently approved by the US Food and Drug Administration for the treatment of R/R MM. Herein we describe the trial design and rationale for a phase 3 randomized study, FOCUS (CarFilzOmib for AdvanCed Refractory MUltiple Myeloma European Study), being conducted to compare OS after treatment with single-agent carfilzomib to best supportive care (BSC) regimen in R/R MM. Methods Patients must have received ≥3 prior regimens, must be responsive to at least 1 line of therapy, and be refractory to their most recent therapy. Eligible patients are randomized 1:1 to receive either carfilzomib (28-day cycles at 20 mg/m2 IV on Days 1–2 of Cycle 1, escalating to 27 mg/m2 IV on Days 8, 9, 15, and 16 and continuing at 27 mg/m2 through Cycle 9 and Days 1, 2, 15, and 16 ≥ Cycle 10) or an active BSC regimen (corticosteroid treatment of prednisolone 30 mg, dexamethasone 6 mg, or equivalent every other day with optional cyclophosphamide 50 mg PO once daily). Patients will continue treatment until disease progression, unacceptable toxicity, or treatment discontinuation and will then enter long-term follow-up for survival. The primary endpoint is OS and secondary endpoints include progression-free survival, overall response rate, and safety. Disease assessments will be determined according to the International Myeloma Working Group Uniform Response Criteria with minimal response per European Blood and Marrow Transplantation Group criteria. Conclusions This phase 3 trial will provide more rigorous data for carfilzomib, as this is the first carfilzomib study with OS as the primary endpoint and will not be confounded by crossover and will provide more robust secondary response and safety results that will add to the data set from prior phase 2 studies. FOCUS will facilitate regulatory approvals around the world and expand treatment options for patients with R/R MM. Trial registration EudraCT No. 2009-016840-38; NCT01302392.

High-grade dysplasia induced by high-risk types of human papillomavirus (HPV) precedes invasive cancer in anal squamous epithelium just as it does in the cervix. A therapeutic HPV vaccine strategy as a potential treatment for anal dysplasia was tested in a standard Phase I dose escalation trial. The primary objective was to evaluate the safety of the agent; additional study aims were to evaluate the histological response, immune response, and effect on anal HPV-16 infection. Each subject was treated with four i.m. injections of 50-400 microg of ZYC101 at 3-week intervals. ZYC101 is composed of plasmid DNA encapsulated in biodegradable polymer microparticles. The plasmid DNA encodes for multiple HLA-A2-restricted epitopes derived from the HPV-16 E7 protein, one of two HPV oncoproteins consistently expressed in neoplastic cells. Fifty-six potential anal dysplasia subjects were screened to identify 12 eligible subjects with HPV-16 anal infection and a HLA-A2 haplotype. The investigational agent was well tolerated in all subjects at all dose levels tested. Three subjects experienced partial histological responses, including one of three subjects receiving the 200-microg dose and two subjects at the 400-microg dose level. Using a direct Elispot, 10 of 12 subjects demonstrated increased immune response to the peptide epitopes encoded within ZYC101; each continued to show elevated immune responses 6 months after the initiation of therapy. These results support the continued investigation of a therapeutic vaccination strategy for anal dysplasia.