Phase Ib/II trial of ibrutinib and nivolumab in patients with advanced refractory renal cell carcinoma1

Background: Although immune checkpoint inhibitor-based therapy has improved the outcomes of many patients with metastatic renal cell carcinoma (mRCC), most eventually develop disease progression. Newer agents that modulate immune response can possibly potentiate checkpoint inhibitor therapy. The ITK/ETK/BTK inhibitor ibrutinib has been reported to inhibit myeloid derived suppressor cells in preclinical models and to potentiate immunotherapy. We conducted an investigator-initiated trial of ibrutinib plus the PD1 inhibitor nivolumab in mRCC patients, particularly in those previously exposed to immune checkpoint inhibitors. Methods: Eligible patients had mRCC of any histologic subtype, completed at least one line of prior systemic therapy which could have included prior immunotherapy, and had acceptable end-organ function with ECOG performance status of 0–2. Treatment consisted of nivolumab 240 mg intravenously every 2 weeks plus ibrutinib 560 mg (dose level 0) or 420 mg (dose level -1) orally once daily. Cycle length was 28 days. Dose limiting toxicity (DLT) was defined as any Grade 3 or higher adverse event (AE) attributable to therapy. After identification of the recommended phase 2 dose (RP2D), up to 19 patients were enrolled to an expansion cohort to further evaluate toxicities and any early evidence of efficacy. The primary endpoints of the trial were establishment of RP2D and progression-free survival (PFS). Results: A total of 31 patients were enrolled, 6 to dose level 0, 7 (of which one was not evaluable for DLT) in dose level -1, and 18 in the expansion cohort. Median age was 60 years (range, 36–90), most had clear cell histology (n = 27; 87%), and most had prior immune checkpoint inhibitor therapy (n = 28; 90%). Three patients experienced one DLT each, all in dose level 0 (all Grade 3), namely elevated lipase, hypoalbuminemia, and nausea. No DLTs were seen in dose level –1 which was declared the RP2D. The most common Grade 3 or higher AEs include anemia (n = 5), lymphocyte count decrease (4), nausea (2), and hypotension (2). Of 28 patients evaluable for response, one patient (3.6%) had a complete response, 2 (7.1%) had a partial response, and 11 (39.2%) had stable disease, for an objective response rate of 10.7%(95%CI: 3.7%–27.2%) and a disease control rate of 50%(95%CI: 32.6%–67.4%). All responders had received prior immune checkpoint inhibitor therapy. Median PFS was 2.5 months (95%CI, 1.9 –4.8) while median OS was 9.1 months (95%CI, 6.6 –19.0). Conclusions: Ibrutinib at a dose of 420 mg orally once daily in combination with nivolumab 240 mg IV every 2 weeks is feasible and tolerable in mRCC patients. No unique immune-related AEs were observed. Anti-tumor activity was seen in patients previously exposed to PD-1 targeted therapy.

A Multicenter, Single-Arm, Phase I/II Dose Finding and Efficacy Study of Venetoclax, CC-486, and Obinutuzumab in Minimally-Pretreated Follicular Lymphoma

KC and ML are co-first authors. Background: Follicular lymphoma (FL) is the most common indolent B-cell lymphoma and has a relapsing and remitting course with risk of transformation to aggressive disease. Long-term toxicity can accumulate with repeated exposure to palliative cytotoxic chemotherapy. Rationally targeted agents have demonstrated disease control with limited toxicity in hematologic malignancies, representing a potential chemotherapy-sparing option. BCL2 rearrangements leading to overexpression are nearly universal in FL, but BCL2 inhibition monotherapy has disappointing efficacy in FL. Potential reasons include known resistance mechanisms, such as MCL-1 overexpression, or redundant survival pathways. Founder mutations in FL often involve epigenetic regulation, and BCL2 rearrangements are necessary but not sufficient for FL lymphomagenesis. In patients with FL, abnormal DNA methylation programming cooperates with somatic mutations to drive lymphomagenesis. The resulting epigenetic deregulation may be targetable by hypomethylating agents, including azacitadine (AZA). There are no published studies of venetoclax and AZA in preclinical models of FL, but there are extensive preclinical data in acute myeloid leukemia. AZA is an epigenetic modulator with synergistic anti-leukemic effect when paired with venetoclax. Treatment with AZA results in MCL-1 downregulation, which may abrogate FL resistance to BCL2 inhibition. AZA also induces re-expression of CD20 and re-sensitizes FL patients to anti-CD20 therapy. In lymphoma xenograft models, the combination of obinutuzumab and venetoclax causes more tumor growth inhibition compared to rituximab with venetoclax, possibly from more potent direct cytotoxicity. These preclinical studies suggest that epigenetic modulation of FL cells with AZA may increase the sensitivity to BCL2 inhibition and anti-CD20 therapy. The foundational position of epigenetic dysregulation in the clonal evolution of FL suggests the optimal time for this strategy may be early in the course of the disease. We hypothesize that a safe and tolerable dose of venetoclax, CC-486 (oral AZA), and obinutuzumab can be found with treatment efficacy equal to or better than other non-chemotherapy agents in the frontline treatment of FL. We present a dose-finding and efficacy trial of venetoclax, CC-486, and obinutuzumab in minimally pre-treated FL patients. Study Design: This is a single arm, multi-center phase I/II clinical trial (Figure 1). The dose finding phase is a 3+3 design with 3 escalating dose levels and two optional de-escalation levels (12-18 patients). Venetoclax (400-800mg) will be given days 1-28 of each 28 day cycle; CC-486 (150-200mg) will be given days 1-14; and obinutuzumab will be given at a fixed dose of 1000mg on days 1, 8, and 15 of cycle 1 and then day 1 of each subsequent cycle. Venetoclax and CC-486 will be given up to 12 cycles and obinutuzumab for a total of 9 cycles. Once the recommended phase 2 dose (RP2D) is identified, the study will proceed to a Simon two-stage expansion cohort. In this cohort, a three month "window" of the doublet venetoclax and CC-486 prior to introduction of obinutuzumab at cycle 4 will allow an assessment of activity of the two-drug combination. Obinutuzumab is given on days 1, 8, and 15 of cycle 4, and day 1 of each subsequent cycle. Key inclusion criteria are: age ≥ 18, ECOG ≤2; adequate kidney/liver function; and grade 1-3a FL with an indication for treatment who are either untreated or have ≤2 courses (16 doses) of lifetime anti-CD20 therapy. Patients with clinical or histologic evidence of FL transformation are excluded. Up to 32 patients will be enrolled to test the null hypothesis of a 30% CR rate against a 50% alternative (80% power, one-sided alpha=0.10). The primary objectives are the RP2D and safety based on adverse events for the dose-finding cohort, and the CR rate by PET in the expansion cohort. Secondary objectives include progression free survival, overall survival, effect of 3 cycles of venetoclax/CC-486 in the window design of the expansion cohort, and CR rate at 30 months post-treatment with PET. Exploratory objectives include pre-treatment mutation biomarkers, minimal residual disease by circulating tumor DNA, and circulating cell-free DNA methylation patterns. This trial design was reviewed and revised at ASH CRTI. Recruitment is ongoing and this trial is registered with ClinicalTrials.gov: NCT04722601. Figure 1 Figure 1. Disclosures Kline: Kite/Gilead: Speakers Bureau; Seagen: Membership on an entity's Board of Directors or advisory committees; Regeneron: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Research Funding; Verastem: Research Funding; SecuraBio: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees. Smith: Celgene, Genetech, AbbVie: Consultancy; Alexion, AstraZeneca Rare Disease: Other: Study investigator.

A Phase 2a Study Evaluating the Safety and Pharmacokinetics (PK) of Luspatercept in Pediatric Patients with Transfusion-Dependent β-Thalassemia (TDT)

Background: β-thalassemia is an inherited hemoglobinopathy caused by mutations in the gene encoding the β-globin chain of hemoglobin (Hb), resulting in ineffective erythropoiesis, impaired red blood cell (RBC) maturation, and anemia. Patients (pts) with severe disease require regular, lifelong RBC transfusions and iron chelation therapy (ICT) shortly after diagnosis in early childhood. There is an unmet need for safe and effective treatments for pediatric pts to address the underlying pathophysiology of β-thalassemia and reduce the burden of chronic RBC transfusions early to prevent secondary iron overload and associated morbidity. Luspatercept is a first-in-class erythroid maturation agent approved in the USA and EU for the treatment of anemia in adult pts with β-thalassemia who require regular RBC transfusions. In previous studies, treatment with luspatercept resulted in clinically significant reductions in RBC transfusion burden in adults with TDT (phase 3 BELIEVE; Cappellini MD, et al. N Engl J Med 2020;382:1219-1231) and increased Hb levels in adults with non-TDT (phase 2 BEYOND study; Taher AT, et al. HemaSphere 2021;5[Suppl 2];Abstract S101). This phase 2a study (NCT04143724, EudraCT 2019-000208-13) will evaluate the safety and PK of luspatercept in pediatric pts with β-thalassemia who require regular RBC transfusions. The results will determine a recommended dose (RD) for each age group. Study Design and Methods: Eligible pts will be 6 to < 18 years of age; diagnosed with β-thalassemia, Hb E/β-thalassemia, or α-thalassemia/β-thalassemia; require ≥ 4 RBC units in the 24 weeks prior to enrollment (with no transfusion-free period ≥ 42 days and with a regular history of transfusions for ≥ 2 years); and have Karnofsky (≥ 16 years of age) or Lansky (< 16 years of age) performance status score ≥ 50 at baseline. Exclusion criteria include: a Hb S/β-thalassemia or α-thalassemia diagnosis, chronic anticoagulant therapy ≤ 28 days prior to enrollment, erythropoiesis-stimulating agent or hydroxyurea use ≤ 24 weeks prior to enrollment, ICT initiation ≤ 8 weeks prior to enrollment, use of any investigational drug ≤ 28 days prior to enrollment, or have undergone or are scheduled for transplant or gene therapy. A total of 54 pts will be enrolled in a staggered study design by age, beginning with a 12-week screening/run-in period. During Part A, pts 12 to < 18 years of age will receive luspatercept at 0.75 mg/kg (n = 6; Cohort 1) or 1.0 mg/kg (n = 6; Cohort 2) subcutaneously (s.c.) once every 21 days for ≤ 4 cycles (Figure A). The RD will be determined for each age group strata at the time of enrollment using descriptive statistics or frequency tabulations between and in aggregate across age-group arms. An expansion cohort (n = 30 pts 12 to < 18 years of age; Cohort 3) will then receive luspatercept for at least 1 year at the RD based on tolerability and safety data from Cohorts 1 and 2; if the RD is 1 mg/kg, titration up to 1.25 mg/kg is allowed in the expansion cohort based on erythroid response during the previous 2 dose cycles. Part B will be initiated following completion of Part A and review of overall safety data with the Data Monitoring Committee, Scientific Steering Committee, and health authorities. Pts 6 to < 12 years of age will be treated with luspatercept at 1.0 mg/kg (n = 6; Cohort 4) or 1.25 mg/kg (n = 6; Cohort 5) s.c. once every 21 days for ≤ 4 cycles (Figure B). Any pt who benefits from treatment can continue to receive luspatercept for ≤ 5 years from first dose and will be monitored for 5 years from first dose or 3 years from last dose, whichever occurs later. Pts may receive best supportive care, including RBC transfusions, ICT, antibiotics, antifungal or antiviral therapy, and/or nutritional support, as needed. The primary objectives are to determine the RD of luspatercept that is safe and tolerable and the PK of luspatercept in pediatric pts with TDT. Key secondary objectives include evaluating mean change in RBC transfusion burden, change in Hb levels, mean change in daily dose of ICT, mean change in serum ferritin, and the immunogenicity and safety of luspatercept in pediatric pts. Safety endpoints include evaluating the type, frequency, seriousness, and severity of adverse events and their relationship to luspatercept treatment. Exploratory endpoints include evaluating exposure-response, health-related quality of life, biomarkers/markers of iron overload and ineffective erythropoiesis, and SARS-CoV-2 serology. Figure 1 Figure 1. Disclosures Viprakasit: Bristol Myers Squibb: Research Funding. Coates: Celgene: Consultancy, Honoraria, Research Funding; Forma Pharma: Consultancy; Sangamo: Consultancy; UpToDate: Patents & Royalties; Vifor Pharma: Consultancy; Apo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Chiesi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Musallam: Celgene, Bristol Myers Squibb: Consultancy; Novartis: Consultancy; Agios Pharmaceuticals: Consultancy; CRISPR Therapeutics: Consultancy; Vifor Pharma: Consultancy. Vienne Buerki: Bristol Myers Squibb: Current Employment. Patturajan: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Holot: Bristol Myers Squibb: Current Employment. Aydinok: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Resonance Health: Research Funding; CRISPR Therapeutics: Consultancy; SLN Therapeutics: Consultancy; Imara: Research Funding; Protagonist: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ionis Pharmaceuticals: Research Funding; La Jolla: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Phase I Dose-Escalation Study of Venetoclax Plus BEAM Followed By Autologous Stem Cell Transplant (ASCT) for Chemoresistant or High-Risk Relapsed/Refractory Non-Hodgkin Lymphoma (NHL)

Introduction: Salvage chemotherapy followed by high dose therapy with carmustine, etoposide, cytarabine, and melphalan (BEAM) with ASCT is standard treatment for patients with chemosensitive, relapsed/refractory (r/r) NHL. Patients with inadequate response to salvage chemotherapy portend a worse prognosis. We present a phase I dose-escalation trial of venetoclax combined with BEAM conditioning followed by ASCT for the treatment of r/r or high-risk NHL. An expansion cohort of 10 patients was added at the highest tolerated dose. Venetoclax is an oral BCL-2 inhibitor that has significant single-agent and combination activity in r/r NHL. Preclinical observations showed that venetoclax potentiates the cytotoxicity of chemotherapy, increases synergistic cell kill, and can overcome chemoresistance even in highly aggressive lymphomas. In this trial, we aim to test the safety of the combination of venetoclax plus BEAM followed by ASCT. We hypothesize that venetoclax will help overcome the chemoresistance of these tumors and decrease post-ASCT relapse. Methods: This is an open-label, single-center, phase I trial (NCT03583424) with a dose expansion cohort of venetoclax in combination with BEAM and ASCT for patients with r/r or high-risk NHL. Venetoclax is given for 10 days, starting at D-10 before ASCT, in three dosing cohorts (400, 800, 1200 mg) using a quick ramp-up schedule. There were no dose limiting toxicities; therefore an expansion cohort of 10 additional patients accrued at the 1200 mg dose. Eligible participants include adult, fit patients with B and T-cell NHL refractory after upfront induction therapy, in partial remission or progressed after salvage, requiring ≥ 3 lines of therapy, relapsed within 1 year of induction, or at a high risk of relapse after ASCT (in first complete or partial remission). Patients with small lymphocytic lymphomas, with primary, or uncontrolled secondary, CNS lymphoma patients are excluded. Primary outcome is safety and determination of maximal tolerated dose (MTD). Adverse events (AEs) were recorded using CTCAE v 4.1 between days -10 to -6 then the Bearman scale was used from day -6 until engraftment. Results: Dose-escalation proceeded with no DLT and 19 patients were accrued across three cohorts. Baseline characteristics and safety data for all three cohorts are presented in Table 1. The majority were male (79%) and had stage IV disease (79%). The media age was 61. No unusual toxicities were encountered beyond what is expected with BEAM. No serious AEs were observed between days -10 to -6 that was related to treatment. No tumor lysis syndrome or other toxicities attributable to venetoclax were observed. Engraftment was as expected. Post-transplant, on the Bearman scale, there were no grade 3 toxicities, 5 grade 2, and 8 grade 1 toxicities. In cohort 3, 1 patient died prior to engraftment from fulminant sepsis. At 100 days post-transplant, 63% were in CR and 11% had stable disease. Fourty-seven percent remained in CR at 1 year post transplant (Table 2). After a median follow-up of 654 (range 335-957) days, median progression-free survival (PFS) was 398 days and median overall survival (OS) was not reached (Figure 1). Six patients went on to receive CD19 chimeric antigen receptor T-cell (CAR-T) therapy. Data of response according to BCL2 expression by IHC is presented in Table 3 for the 12 patients who had available data. Median PFS was superior in BCL2 positive group (p=0.04; figure 1C) Discussion: The addition of venetoclax to BEAM appears to be safe and well-tolerated in a typical, elderly population with high-risk disease and produced promising results. While CD19 CAR-T are a consideration, many patients may not have access to these therapies. Venetoclax in combination with BEAM can represent an option for patients with relapsed and refractory NHL. Figure 1 Figure 1. Disclosures Brammer: Celgene: Research Funding; Seattle Genetics: Speakers Bureau; Kymera Therapeutics: Consultancy. Maddocks: Celgene: Divested equity in a private or publicly-traded company in the past 24 months; Karyopharm: Divested equity in a private or publicly-traded company in the past 24 months; Beigene: Divested equity in a private or publicly-traded company in the past 24 months; ADC Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months; Morphosys: Divested equity in a private or publicly-traded company in the past 24 months; KITE: Divested equity in a private or publicly-traded company in the past 24 months; Pharmacyclics: Divested equity in a private or publicly-traded company in the past 24 months; BMS: Divested equity in a private or publicly-traded company in the past 24 months; Merck: Divested equity in a private or publicly-traded company in the past 24 months; Novatis: Divested equity in a private or publicly-traded company in the past 24 months; Janssen: Divested equity in a private or publicly-traded company in the past 24 months; Seattle Genetics: Divested equity in a private or publicly-traded company in the past 24 months. Saad: Kadmon: Research Funding; Amgen: Research Funding; careDx: Consultancy; Incyte Pharmaceuticals: Consultancy; Magenta Therapeutics: Consultancy; OrcaBio: Research Funding. Jaglowski: Novartis: Consultancy, Research Funding; CRISPR Therapeutics: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Juno: Consultancy; Takeda: Consultancy. William: Guidepoint Global: Consultancy; Dova Pharmaceuticals: Research Funding; Merck: Research Funding; Kyowa Kirin: Consultancy; Incyte: Research Funding. OffLabel Disclosure: Venetoclax is a BCL2 inhibitor approved for treatment of hematological malignancies (AML and CLL).

CTNI-36. SAFETY OF ONC201 ADMINISTERED TWO CONSECUTIVE DAYS PER WEEK IN PEDIATRIC H3 K27M-MUTANT GLIOMA PATIENTS

ONC201, an anti-cancer DRD2 antagonist and ClpP agonist, is in Phase II trials for adult H3 K27M-mutant diffuse midline gliomas. The recommended phase 2 dose (RP2D) of 625mg ONC201 once a week has been established as a biologically active dose that is well tolerated in adult and pediatric populations. Radiographic regressions with single agent ONC201 have been reported in recurrent H3 K27M-mutant glioma patients. In another study, twice/week dosing was explored in adult patients and deemed to be safe (no DLTs observed). This warranted exploration of twice/week dosing in pediatric patients and will be discussed in this presentation. This multi-arm, dose-escalation and dose-expansion trial (ONC014; NCT03416530) determined the pediatric RP2D of ONC201 administered once per week and twice per week on two consecutive days. ONC201 was orally administered and scaled by body weight. Dose escalation was performed by a 3 + 3 design beginning with two 125mg capsules less than the adult RP2D equivalent. Twelve children (8 females; 4 males) with H3 K27M-mutant gliomas (pons: 8; thalamus: 2; spinal cord: 2) aged 4-19 years have been treated post-radiation: 3 at dose level -1; 3 at dose level 1; 6 as part of the dose expansion cohort on dose level 2. Median KPS was 90 (range 70-100). One treatment cycle was 21 days (6 doses), which also defined the DLT window. Patients were on-treatment for a median length of 4 cycles (range: 2-11). Twice weekly dosing of ONC201 was tolerated well, as observed with weekly dosing, with no instance of DLT. A total of 4 SAEs were reported, none of which were related to the study drug. The most common AEs (regardless of relatedness) included headache, facial nerve disorder, abducens nerve disorder, nausea, fatigue and ataxia. Additional safety data, PK, and clinical outcomes from this arm will be reported.

378 Efficacy, safety and ancillary analyses of pembrolizumab in combination with nintedanib for the treatment of patients with relapsed advanced mesothelioma

BackgroundWe report the results from the advanced malignant mesothelioma (aMM) expansion cohort of the PEMBIB Phase Ib trial (NCT02856425) evaluating the safety, efficacy & biomarkers of an antiangiogenic tyrosine kinase inhibitor (nintedanib) with an anti-PD1 immunotherapy (pembrolizumab).MethodsPatients with aMM relapsing after at least one line of platinum doublet chemotherapy and not previously pre-exposed to IO were treated with a combination of oral nintedanib (150mg BID) & IV pembrolizumab (200mg Q3W) with a 7 days nintedanib lead-in preceding pembrolizumab initiation. Baseline and on-treatment (cycle D2, day 1 [C2D1]) fresh tumor & blood samples were prospectively phenotyped by flow cytometry (FC). RNAseq was run on tumor samples. Immune factors were titrated on tumor secretome and plasma.Results30 aMM patients were treated and 29 evaluable for response. Median age was 68 years old (38–85) and 86% of aMM were epithelioid. The most frequent adverse events (AE) (grades 1–3) related to the combination were liver enzymes increase, fatigue, nausea, and diarrhea. 4 (13.3%) patients developed grade 3–5 immune- related AE. Patients died of cancer progression (n=14, 46.7%), myocarditis with thrombo-embolic event (n=1, 3.3%) and COVID-19 (n=1, 3.3%). Median follow-up was 14.8 months (95%CI [9.70–18.2]). Best Overall Response Rates (BORR) per RECISTv1.1 were Partial Response (PR, n=7/29; 24.1%), Stable Disease (SD, n=17/29; 58.6%) and Progressive Disease (n=5/29; 17.2%). Disease Control Rate (DCR) (defined as PR + SD) was 46.6% at 6 months. Patients with DCR at 6 months had significantly higher percentage of PDL1 expression on tumor cells (by Immuno-Histo-Chemistry, antibody clone SP263) and higher CD8+ T cells infiltrate in tumor biopsies (by FC) at screening. Upon treatment, soluble plasma rate of CXCL9 and CXCL13 increased in all patients, as well as tumor immune infiltrates estimated by deconvolution of tumor biopsies RNA-seq. But deconvoluted estimates of NK cells, T cells and myeloid dendritic cells infiltrates on baseline tumors and C2D1 biopsies were higher in patients with DCR at 6 months. Pre & on-treatment IL6 and IL8 rates in tumor secretome & plasma were higher in patients without DCR. Gene Set Enrichment Analyses on RNA-seq from screening biopsies highlighted an enrichment in E2F, MYC and KRAS gene pathways and lower expression of type 1 interferon signature in patients without DCR than those with DCR at 6 months.ConclusionsWith a BORR of 24% and a DCR of 47% at 6 months, pembrolizumab and nintedanib combination provided valuable therapeutic benefits for patients with aMM.Trial RegistrationClinicalTrialsgov, NCT02856425. Registered August 4, 2016 — Prospectively registered,https://clinicaltrials.gov/ct2/show/NCT02856425?term=PEMBIB&draw=2&rank=1.Ethics ApprovalThe protocol was first approved by the Agence Nationale de Sécurité du Médicament (ANSM) on June 24th 2016 (Ref #160371A-12). The protocol was also approved by the Ethical Committee (Comité de Protection des Personnes Ile de France 1) on Jul 12th 2016 (Ref #2016-mai-14236ND).

422 Safety and efficacy of neoadjuvant intravesical oncolytic MV-NIS in patients with urothelial carcinoma

BackgroundBladder cancer is a leading cause of cancer death in the United States.1 The histology in > 90% of cases is urothelial carcinoma (UC). Tumors may present either as non-muscle-invasive (NMIBC) or muscle-invasive disease (MIBC). Current standard of care for patients with high risk NMIBC includes transurethral resection of bladder tumor (TURBT) followed by intravesical immunotherapy with Bacillus Calmette-Guerin (BCG).2 Meanwhile, patients with BCG unresponsive NMIBC or MIBC are recommended to undergo radical cystectomy (RC), which adversely impacts quality of life and is associated with significant morbidity.3 MV-NIS is an investigational oncolytic measles virus with an excellent clinical safety profile.4 This ongoing phase I clinical study is designed to test the safety, efficacy and identify the recommended phase 2 dose (RP2D) of intravesical MV-NIS in patients with NMIBC or MIBC who are scheduled for RC and not eligible for neoadjuvant chemotherapy.MethodsBladder UC patients were evaluated for eligibility and provided informed consent prior to enrolling. To date 8 patients have been enrolled: 4 to the single dose safety cohort, and 4 to the multi-dose expansion cohort. Patients were administered intravesical ~1x109 TCID50 MV-NIS once at least 1 week prior to RC (safety cohort), or twice at 4 and 2 weeks prior to RC (expansion cohort). Patients were closely monitored during the 2-hour instillation period. Tumor specimens from the pre-treatment TURBT and post-treatment RC were analyzed to determine pre- and post-treatment pathological stage and evaluate tumor killing and immune cell infiltrate.ResultsIntravesical MV-NIS treatment was well tolerated in all patients. Only a single Adverse Event (AE) attributable to MV-NIS treatment (Grade 1 hematuria). AEs Grade>2 were related to post-surgical complications. Tumor pathology findings are summarized in table 1. Tumor downstaging was observed in 4 of 8 patients. Among 4 patients in the expansion cohort, 2 had no residual disease (pT0). Central assessment of RC tissues showed significant inflammatory infiltrate in all treated bladder specimens. Detailed analyses are ongoing to characterize MV infection and immune infiltrate in bladder tissueAbstract 422 Table 1Pre-treatment (TURBT) and post- treatment (RC) pathologyConclusionsThe higher-than-expected rate of tumor downstaging and pT0 pathology, paired with the significant immune infiltrate observed in post-treatment bladder tissue, provide compelling evidence that intravesical MV-NIS has clinical activity against UC. These results support the use of two doses of ~1x109 TCID50 as the RP2D in future clinical studies for BCG unresponsive NMIBC or MIBC patients. MV-NIS induced inflammation may act synergistically with checkpoint blockade therapies.Trial RegistrationNCT03171493ReferencesSiegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019;69(1):7–34.Knowles MA, Hurst CD. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer 2015;15(1):25–41.Zakaria AS, Santos F, Dragomir A, Tanguay S, Kassouf W, Aprikian AG. Postoperative mortality and complications after radical cystectomy for bladder cancer in Quebec: A population-based analysis during the years 2000–2009. Can Urol Assoc J 2014;8(7–8):259–267.Galanis E, Atherton PJ, Maurer MJ, Knutson KL, Dowdy SC, Cliby WA, Haluska P Jr, Long HJ, Oberg A, Aderca I, Block MS, Bakkum-Gamez J, Federspiel MJ, Russell SJ, Kalli KR, Keeney G, Peng KW, Hartmann LC. Oncolytic measles virus expressing the sodium iodide symporter to treat drug-resistant ovarian cancer. Cancer Res 2015;75(1):22–30.Ethics ApprovalApproval was received from the Institutional Review boards (IRBs) at all clinical sites including Mayo Clinic (#17–004167); Ochsner Health (#2020 060); and University of Miami (#20200174). All study participants are required to review and sign an IRB approved informed consent before taking part in the clinical trial.

340 A phase Ib study of the safety and tolerability of pixatimod plus nivolumab in subjects with advanced solid tumors with an expansion cohort in metastatic pancreatic adenocarcinoma (mPDAC)

BackgroundPixatimod is a novel immunomodulatory agent which stimulates dendritic cells (DC) via Toll-Like Receptor (TLR9) pathway to activate natural killer (NK) cells.1 In combination with PD1 inhibitors, it also enhances T cell infiltration in vivo.2 We report on safety, pharmacokinetics (PK) and pharmacodynamics (PD), and antitumor activity of pixatimod plus nivolumab in advanced cancer patients (stage 1) and in an expansion cohort of mPDAC (stage 2).MethodsIn the dose escalation stage (3+3 design), eligible patients (ECOG≤1) with advanced solid malignancies who failed standard therapies received pixatimod once weekly as a 1-hour i.v. infusion plus nivolumab (240 mg, every other week) until disease progression or discontinuation due to intolerability. The primary objective was determination of the maximum tolerated dose (MTD). Secondary objectives evaluated safety, antitumor activity per RECIST v1.1, PK of pixatimod, and PD (PBMC, plasma cytokines and chemokines). Stage 2 comprised mPDAC subjects who had received no more than one prior line of chemotherapy in the metastatic setting.ResultsThe dose-escalation stage recruited 16 subjects across two cohorts (25 & 50 mg pixatimod). Two dose limiting toxicities (DLTs) in 50 mg cohort were pulmonary edema and multi-organ failure. Of note, the subject with multi-organ failure had substantially higher CA19.9, Pan-immune-Inflammatory Value (PIV = Neutrophils x Platelets x Monocytes/Lymphocytes) and interleukins (IL) IL-1α and IL-23 at baseline compared with the cohort. One DLT occurred in the 25 mg cohort, pneumonitis, which was identified as the MTD. A further 14 mPDAC subjects were recruited to the expansion stage (25 mg). Seven SAEs were reported to be possibly or likely related to the combination. No objective responses were reported in the mPDAC stage, the best response was SD (n = 3). In another submitted abstract by Lemech et al, we report two subjects in the dose escalation stage with MSS mCRC were confirmed PR, and data from the amended study to include an MSS mCRC expansion cohort will also be presented. Time versus concentration data for pixatimod in advanced cancer patients was similar to that previously reported in monotherapy setting. In mPDAC subjects, there was minimal immune activation as evidenced by a lack of change in effector memory T cells or NK cells in PBMC, plasma cytokines and chemokines.ConclusionsPixatimod is well tolerated at 25 mg in combination with nivolumab but did not provide clear clinical benefit or evidence of immune activation in the mPDAC cohort.AcknowledgementsResearch funding was provided by Zucero Therapeutics Ltd and Bristol Myers Squibb (BMS), Australia.Trial RegistrationClinical trial informationACTRN12617001573347.ReferencesBrennan TV, Lin L, Brandstadter JD, Rendell VR, Dredge K, Huang X, et al. Heparan sulfate mimetic PG545-mediated antilymphoma effects require TLR9-dependent NK cell activation. J Clin Invest 2016;126(1):207–19.Hammond E, Haynes NM, Cullinane C, Brennan TV, Bampton D, Handley P, et al. Immunomodulatory activities of pixatimod: emerging nonclinical and clinical data, and its potential utility in combination with PD-1 inhibitors. J Immunother Cancer 2018;6(1):54.Ethics ApprovalThe clinical trial entitled “An open-label, multi-centre Phase Ib study of the safety and tolerability of IV infused PG545 in combination with nivolumab in patients with advanced solid tumours with an expansion cohort in patients with metastatic pancreatic cancer. Protocol ZU545102” obtained ethics approval from the Royal Adelaide Hospital (HREC Reference number, HREC/17/RAH/195 and the CALHN Reference number, R20170515) and Bellberry Limited (Application No: 2018-08-695). All participants in the study gave informed consent before taking part in ZU545102.

Adaptive Design For Identifying Maximum Tolerated Dose Early To Accelerate Dose-Finding Trial

Purpose: The early identification of maximum tolerated dose (MTD) in phase I trial leads to faster progression to a phase II trial or an expansion cohort to confirm efficacy.Methods: We propose a novel adaptive design for identifying MTD early to accelerate dose-finding trials. The early identification of MTD is determined adaptively by dose-retainment probability using a trial data via Bayesian analysis. We applied the early identification design to an actual trial. A simulation study evaluates the performance of the early identification design.Results: In the actual study, we confirmed the MTD could be early identified and the study period was shortened. In the simulation study, the percentage of the correct MTD selection in the early identification Keyboard and early identification Bayesian optimal interval (BOIN) designs was almost same from the non-early identification version. The early identification Keyboard and BOIN designs reduced the study duration by about 50% from the model-assisted designs. In addition, the early identification Keyboard and BOIN designs reduced the study duration by about 20% from time-to-event model-assisted designs.Conclusion: We proposed the early identification of MTD maintaining the accuracy to be able to short the study period.

Doxorubicin plus lurbinectedin in patients with advanced endometrial cancer: results from an expanded phase I study

ObjectiveSecond-line treatment of endometrial cancer is an unmet medical need. We conducted a phase I study evaluating lurbinectedin and doxorubicin intravenously every 3 weeks in patients with solid tumors. The aim of this study was to characterise the efficacy and safety of lurbinectedin and doxorubicin for patients with endometrial cancer.MethodsThirty-four patients were treated: 15 patients in the escalation phase (doxorubicin 50 mg/m2 and lurbinectedin 3.0–5.0 mg) and 19 patients in the expansion cohort (doxorubicin 40 mg/m2 and lurbinectedin 2.0 mg/m2). All histological subtypes were eligible and patients had received one to two prior lines of chemotherapy for advanced disease. Antitumor activity was evaluated every two cycles according to the Response Evaluation Criteria in Solid Tumors version 1.1. Adverse events were graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.ResultsMedian age (range) was 65 (51–78) years. Eastern Cooperative Oncology Group performance status was up to 1 in 97% of patients. In the escalation phase, 4 (26.7%) of 15 patients had confirmed response: two complete and two partial responses (95% CI 7.8% to 55.1%). Median duration of response was 19.5 months. Median progression-free survival was 7.3 (2.5 to 10.1) months. In the expansion cohort, confirmed partial response was reported in 8 (42.1%) of 19 patients (95% CI 20.3% to 66.5%). Median duration of response was 7.5 (6.4 to not reached) months, median progression-free survival was 7.7 (2.0 to 16.7) months and median overall survival was 14.2 (4.5 to not reached) months. Fatigue (26.3% of patients), and transient and reversible myelosuppression (neutropenia, 78.9%; febrile neutropenia, 21.1%; thrombocytopenia, 15.8%) were the main grade 3 and higher toxicities in the expanded cohort.ConclusionsIn patients with recurrent advanced endometrial cancer treated with doxorubicin and lurbinectedin, response rates (42%) and duration of response (7.5 months) were favorable. Further evaluation of doxorubicin and lurbinectedin is warranted in this patient population.