Accelerated Dose Escalation Research Articles

Safety outcomes of teclistamab accelerated dose escalation.

Teclistamab, a bispecific T-cell engaging antibody targeting B-cell maturation antigen (BCMA), is indicated for the treatment of relapsed or refractory multiple myeloma after at least four lines of therapy. It has boxed warnings for life threatening cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). To mitigate these risks, teclistamab is initiated using step-up doses. This article examines safety event rates following the implementation of a 2-day separation between step-up doses at one institution to streamline patient care. This was a retrospective, single-center study encompassing all patients who received teclistamab within a 1-year period. The primary endpoint was the overall incidence of CRS and ICANS. Secondary endpoints included hospital length of stay, hematological toxicities, infection rates, among other adverse events. A total of 27 patients were included in the analysis and stratified into accelerated (days 1,3,5) or standard (days 1,4,7) dosing groups. CRS occurred in 48% (11) of patients for the accelerated dosing and 50% (2) for the standard dosing group. ICANS was seen in 17% (4) of patients in the accelerated dosing group and none in the standard dosing group. Average length of stay in the accelerated dose was 7.6 days versus 9.2 days in the standard dose group. Accelerated dose escalation of teclistamab yielded safety event rates comparable to those in the literature. These findings may support outpatient administration for teclistamab. Accelerated dose escalation strategy allowed for the optimization of hospitalization and resources.

Phase 1/2 study of ARTS-021, a potent, oral administrated, selective CDK2 inhibitor, in advanced or metastatic solid tumors.

e17546 Background: ARTS-021 is an investigational, reversible, orally available CDK2 selective inhibitor that inhibits CDK2 at nanomolar potency and with over 600-fold selectivity against CDK1 (Liang J et al. AACR 2022). ARTS-021 has shown promising preclinical data, including strong single agent antitumor activity in CCNE1 amplified patient derived xenografts (PDX). Furthermore, consistent with the hypothesis that CDK2 activity may mediate resistance to CDK4/6 inhibitors, ARTS-021 significantly enhanced Palbociclib anti-tumor activity in an estrogen positive (ER+) breast cancer xenograft model. Taken together, these data support the clinical development of ARTS-021 as a monotherapy in CCNE1-amplified cancers and in combination with CDK4/6 inhibitors in ER+ breast cancer. Methods: A first in human, open label, multicenter phase1/2 dose escalation and dose expansion study will be conducted to evaluate the safety, tolerability, PK, pharmacodynamics (PD), and anti-tumor activity of ARTS-021 1) as a single agent in advanced or metastatic solid tumors harboring CCNE-1 gene amplification; 2) in combination with carboplatin to treat refractory/resistant CCNE-1 amplified ovarian cancer that has failed standard therapies; 3) in combination with endocrine therapy and CDK4/6 inhibitor to treat ER+/HER2- breast cancer patients have failed standard therapies. The phase 1 (dose-escalation) portion of the trial will have an accelerated dose escalation followed by a Bayesian Optimal Interval (BOIN) design. After the monotherapy recommended phase 2 dose (R2PD) is identified, the combination arms will be initiated at one dose level below the monotherapy R2PD. Phase1 primary endpoints are assessment of safety, tolerability, and pharmacokinetics (PK). The secondary endpoint is preliminary efficacy. Once the RP2D is defined for both monotherapy and in combination, the trial will be advanced into three Phase 2 expansion cohorts: monotherapy cohort (basket cohort), combination with carboplatin (ovarian cohort), and combination with endocrine therapy + CDK4/6 inhibitor (ER+ breast cancer cohort). The phase 2 primary end point is to estimate the anti-tumor efficacy in CCNE1 amplified cancer patients or CDK4/6 inhibitor resistant breast cancer patients. Objective tumor response rate will be measured per RECIST v1.1. The secondary endpoint of Phase 2 study will be safety/tolerability. Archival tumor and paired fresh tumor biopsy will be collected throughout the study for exploratory pharmacodynamics (PD) and biomarker evaluation. Results: ARTS-021 clinical study is ongoing. Conclusions: ARTS-021 shows potential anti-tumor activities.

Dual Targeting of the EGFR/HER2 Pathway in Combination with Systemic Chemotherapy in Refractory Pancreatic Cancer-The CONKO-008 Phase I Investigation.

Background: Primary objective of this present trial was to define the maximum tolerable dose of lapatinib in combination with oxaliplatin, 5-fluorouracil, and folinic acid (OFF) in refractory pancreatic cancer. The secondary objective was to assess the safety and efficacy of lapatinib plus OFF. Methods: We conducted a phase I trial using an accelerated dose escalation design in patients with refractory pancreatic cancer. Lapatinib was given on days 1 to 42 in combination with folinic acid 200 mg/m2 day + 5-fluorouracil 2000 mg/m2 (24 h) on days 1, 8, 15, and 22, and oxaliplatin 85 mg/m2 days 8 and 22 of a 43-day cycle (OFF). Toxicity and efficacy were evaluated. Results: In total, eighteen patients were enrolled: dose level 1 (1000 mg) was assigned to seven patients, dose level 2 (1250 mg), five patients; and dose level 3 (1500 mg), six patients. Dose-limiting toxicities were diarrhea and/or neutropenic enterocolitis observed in two of six patients: one diarrhea III°, one diarrhea IV°, as well as neutropenic enterocolitis. The maximum tolerable dose of lapatinib was 1250 mg OD. Conclusions: The combination of lapatinib 1250 mg OD with platinum-containing chemotherapy is safe and feasible in patients with refractory pancreatic cancer and warrants further investigation.

Abstract CT176: A phase 1 open label, first in human trial to study safety and tolerability of NK-T cells combined with vvDD: An accelerated dose escalation in multiple tumor types

Abstract Introduction: BioEclipse Therapeutics has developed CRX100 an adoptive NK-T Cells therapy combined with vaccinia vvDD, an oncolytic virus. vvDD is a Western Reserve (WR) strain vaccinia virus (VACV) that has been further attenuated by the removal of the viral thymidine kinase and growth factor genes, and hence its replication and lytic activity is confined to tumor cells. In preclinical studies in immunocompetent mice the combined therapy eradicated tumor cells and initiated an adaptive immune response. Trial Design: Our ongoing phase 1 safety clinical trial (IND 19222 at Clinicaltrials.gov) began in January 2021 and includes planned treatment of approximately 24 patients with the potential for 2 doses each. With the dose of ex vivo activated autologous NK-T cells held constant (2-5 X 109), the dose of vvD is increased at 5 dose levels, 3X107, 1x108, 3x108, 1x109 and 3x109 pfu/dose. The first five doses are accelerated in cohorts of one patient and followed by a non-accelerated phase with a cohort of two patients and then 3 cohorts of three patients to determine the MTD, with an additional 8 patients then treated at the MTD. Dose limiting toxicities evaluated by a BOIN design will assist in the dose decision for phase 2. Inclusion and exclusion criteria: Patients will have tumor progression and have failed standard of care in the indications, triple negative breast cancer, gastric cancer, colorectal carcinoma, hepatocellular carcinoma, ovarian cancer or osteosarcoma. Results: To date, 4 patients have been treated, including 2 patients with ovarian cancer and 2 with CRC at 4 dose levels. No dose limiting toxicities have been observed. The most common AE is mild fever at 6-12 hours after infusion. Two CRC patients treated at a vvDD dose of 3x107 and 1x109 experienced disease progression. Patient 101-005 with ovarian cancer received two separate infusions 3 months apart each at a dose of 1x108 PFU vvDD combined with 2-5 X 109 ex-vivo activated autologous NKT. Tumor assessment after the first dose showed stable disease (+17.2%) by iRECIST. The CA125 serum biomarker increased temporarily about 3 weeks after infusion. The second ovarian patient (101-007) treated with 3x108 vvDD combined with 2-5 X 109 ex-vivo activated autologous NKT had unconfirmed progression (+21%). There was a slight increase and then a decrease of the CA-125 from 303 to 268. The patient developed new ascites 4 weeks after infusion and required a paracentesis. The ascites did not recur after the paracentesis. Conclusion: Thus far in escalation, all doses of the therapy have been safe and well-tolerated. Two patients with ovarian cancer treated with the adoptive NKT cell therapy combined with an oncolytic virus demonstrated changes in CA-125 potentially consistent with immune inflammation. Peripheral blood obtained at 3 and 6 month will be analyzed to assess specific immune responses. Dose escalation and enrollment continue for this study. Citation Format: Oliver Dorigo, Pamela Reilly Contag, Justin Moser, Sandip Pravin Patel, Mark W. Frohlich. A phase 1 open label, first in human trial to study safety and tolerability of NK-T cells combined with vvDD: An accelerated dose escalation in multiple tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT176.

Abstract CT185: A phase I dose escalation study of a tegavivint (BC2059) a first-in-class TBL1 inhibitor for patients with progressive, unresectable desmoid tumors

Abstract Introduction: The hallmark of sporadic desmoid tumors is increased nuclear β-catenin levels. Tegavivint (BC2059) selectively disrupts the interaction of β-catenin and TBL1/TBLR1 resulting in the specific degradation of nuclear β-catenin. The primary objective of this dose escalation study was to determine the maximum tolerated dose (MTD) and safety of tegavivint. Methods: This phase I study (NCT03459469) utilized an accelerated dose escalation phase for the initial two dose levels followed by a 3+3 design to determine the MTD/recommended phase 2 dose (RP2D). The study included adult patients with desmoid tumors that were progressive (20% increase in tumor volume, recurrent in one year from surgery or desmoid symptoms), unresectable, and measurable via WHO criteria. Patients were excluded if they had familial adenomatous polyposis, metabolic bone disease, or history of significant pulmonary disease. Tegavivint was administered IV and dosed weekly (three weeks on, one week off) for up to two years. Results: A total of 17 patients with a median age of 41 years (range 18-66 years) were enrolled in six dose levels from 0.5 mg/kg to 5 mg/kg. The median time from initial desmoid diagnosis to study treatment was 2.1 years with a median of one prior systemic treatment (range 0-6). Prior radiation and/or surgical resection occurred in 42% (n=7). No dose-limiting toxicities were observed and the MTD was not determined. The RP2D was declared at 5 mg/kg based on achieving pharmacologically relevant plasma concentrations and preliminary efficacy. Trough plasma concentrations (Cmin) exceeded in vitro IC50 efficacy estimates at 4 mg/kg and 5 mg/kg. Median half-life was 38 hours supporting once weekly administration. Tegavivint exposure (AUC and Cmax) correlated with total dose administered. Treatment-related adverse events (TRAEs) occurring in ≥20% of patients included fatigue (71%), nausea (35%), headache (35%), decreased appetite (24%) and dysgeusia (24%), mostly Grade 1-2. Grade 3 TRAEs of hypophosphatemia, stomatitis, ALT increased, and headache occurred in 4 separate patients. No grade 4-5 adverse events were observed. One serious adverse event of Grade 2 infusion site extravasation occurred. Median time on study was 11.8 months, with a median relative dose intensity of 97%; one patient remains on study. Three (18%) partial responses (WHO criteria) were observed at 1, 4 and 5 mg/kg with a median duration of response of 329 days and all responses were ongoing. The clinical benefit rate was 82% (n = 14). Conclusions: Tegavivint is well tolerated with mostly Grade 1/2 adverse events and no Grade 3 TRAEs occurring in more than one patient. The preliminary objective response rate of 18% in progressive desmoid tumors warrants continued research in the ongoing dose expansion portion of the study at the 5 mg/kg RP2D. Citation Format: Lee Cranmer, Albiruni A. RAZAK, Ravin Ratan, Edwin Choy, Suzanne George, David Liebner, David Stenehjem, Mrinal Gounder. A phase I dose escalation study of a tegavivint (BC2059) a first-in-class TBL1 inhibitor for patients with progressive, unresectable desmoid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT185.

Phase 1 dose escalation study of DSP107, a first-in-class CD47 and 4-1BB targeting multifunctional immune-recruitment protein, in patients with advanced solid tumors.

2647 Background: DSP107 is a bi-functional, trimeric, fusion protein composed of sequences from the extracellular domain of SIRPα and 4-1BBL. The SIRPα arm targets CD47 overexpressed on tumor cells, blocking the “don’t eat me” checkpoint and triggering tumor cell phagocytosis. The trimeric 4-1BBL arm, once cross-presented and immobilized by SIRPα binding to CD47, interacts with 4-1BB expressed on activated immune cells, mainly T- and NK cells in the tumor microenvironment, and stimulates their proliferation and activation. Thereby, DSP107 triggers both an innate and an adaptive immune response. Here we describe data from the completed DSP107 monotherapy dose escalation portion of study NCT04440735. Methods: Adult patients with advanced solid tumors were treated with weekly intravenous DSP107 infusions (0.01 - 10 mg/kg) during 3-week treatment cycles. An accelerated dose escalation in single patient cohorts (dose levels 1-3) was followed by a standard 3 + 3 design. The primary objective was to determine safety, tolerability and pharmacokinetic (PK) parameters. Paired biopsies were obtained from 8 patients (screening, after cycle 2). Restaging imaging was performed every two months and evaluated by RECIST criteria. Results: In 23 patients, DSP107 demonstrated no treatment related hematologic or hepatic adverse events (AEs) and no dose limiting toxicities. Grade 1-2 treatment related AEs were observed in 70% of patients (16/23). The most frequent AEs included infusion related reaction (IRR; 26%), diarrhea (17%), fatigue (17%), nausea (13%) and constipation (9%). IRRs were managed during subsequent infusions by reducing the infusion rate and administering IV fluids. No significant systemic cytokine release was measured at any dose level using a 10-plex, pro-inflammatory panel. PK analysis revealed 100% CD47 receptor engagement on peripheral T and NK cells at doses of 3 mg/kg and above. DSP107 did not bind CD47 on red blood cells at any dose. Preliminary histologic assessment of paired biopsies by an independent, blinded pathologist demonstrated increased tumor necrosis compared to screening in 3 out of 4 patients associated with immune cell infiltration. Immuno-profiling of tumor by immunofluorescence is on-going. Stable disease as best response was observed in 11/22 patients with treatment duration up to 26 weeks. Conclusions: DSP107 is a novel, CD47 and 4-1BB targeting fusion protein with a differentiated safety, binding and pharmacodynamic profile compared to other CD47 and 4-1BB targeting agents. Clinical trial information: NCT04440735.

Results of a phase I dose escalation and expansion study of tegavivint (BC2059), a first-in-class TBL1 inhibitor for patients with progressive, unresectable desmoid tumor.

11523 Background: Desmoid tumors are known to have increased nuclear β-catenin levels. Tegavivint selectively disrupts the interaction of β-catenin and TBL1/ TBLR1, resulting in specific degradation of nuclear β-catenin. The primary objectives of this study were to determine the maximum tolerated dose (MTD), safety, and preliminary efficacy of tegavivint in patients (pts) with desmoid tumors. Methods: This study ( NCT03459469) utilized an accelerated dose escalation schema for the first two dose levels followed by a 3+3 design to determine the MTD/recommended phase 2 dose (RP2D) of tegavivint, followed by a dose expansion phase. The study included adult pts with sporadic desmoid tumors that were progressive (20% increase in tumor volume, recurrent in one year from surgery, or symptomatic), unresectable, and measurable via WHO criteria. Tegavivint was administered IV weekly (three weeks on, one week off) up to two years. Results: 24 pts were enrolled. Dose escalation enrolled 17 pts in six dose levels from 0.5 - 5 mg/kg. In dose expansion, 7 additional pts were enrolled. Dose expansion cohort also included 6 pts in dose escalation that were escalated to RP2D and 3 pts treated at RP2D in dose escalation (n = 16 total). Median age was 43 years (18-66). Median time from diagnosis was 3.1 years with median of one prior systemic treatment (range 0-6). Median time on study was 9.4 months; 3 pts remain on study at data cut-off. No dose-limiting toxicities were observed; MTD was not determined. RP2D was declared at 5 mg/kg based on pharmacologically relevant plasma concentrations and preliminary efficacy. Trough plasma concentrations (Cmin) exceeded in vitro IC50 efficacy estimates at 4 mg/kg and 5 mg/kg. Median half-life was 38 hours supporting once weekly administration. Treatment-related adverse events (TRAEs) occurring in ≥20% of pts included fatigue (71%), headache (38%), nausea (33%), constipation (21%), decreased appetite (21%), and dysgeusia (21%), mostly Grade 1-2. Grade 3 TRAEs of hypophosphatemia, stomatitis, increased ALT, diarrhea, and headache occurred in 5 separate pts. There were no grade 4-5 adverse events (AEs). One serious AE of Grade 2 extravasation occurred. Objective response rate (ORR) of 17% across all dose levels and 25% at RP2D (WHO and RECIST criteria) were observed. Median duration of response was 8.1 months (range 6 to 11.8 months) with all responses ongoing. The 9-month progression free survival rate was 76% (95% CI: 54 - 90%) among all pts and 79% (95% CI: 51 – 93%) among those treated at RP2D. Patient reported outcomes and correlative science will be included in the presentation. Conclusions: Tegavivint is well tolerated with mostly Grade 1/2 AEs and no serious toxicity associated with WNT inhibition. The ORR of 25% at the RP2D warrants continued development of tegavivint in desmoid tumors. Clinical trial information: NCT03459469.

Phase I study of BJ-001, a tumor-targeting interleukin-15 fusion protein, in patients with solid tumor.

e14545 Background: BJ-001 is the first tumor-targeting Interleukin-15 (IL-15) fusion protein, composed of an integrin-binding Arg-Gly-Asp (RGD)-4C motif, linked with a human IgG1 Fc, and then a modified sushi domain of human IL-15Rα unit and a human IL-15. Tumor-targeting is achieved with RGD-4C motif which binds to αvβ3, αvβ5, and αvβ6 integrins, commonly overexpressed in solid tumors. The molecule has shown an ability to activate Natural Killer (NK) and T cells in vitro and in pre-clinical in vivo studies. Methods: This first in-human (FIH) study has 2 phases: Phase 1a and Phase 1b. Phase 1a consists of 3 parts. In all 3 parts patients receive escalating doses of BJ-001 as a once weekly subcutaneous injection for 4 weeks in 6-week cycles. Part 1 utilizes an accelerated dose escalation design with single patient cohort for the first 3 dose levels. Part 2 uses a 3+3 dose escalation design. Part 3 uses a 3+3 dose escalation of BJ-001 but in combination with a fixed-dose PD-(L)1 inhibitor. Dose escalation will proceed based on clinical safety and tolerability data observed during the Dose Limiting Toxicity (DLT) period, i.e., Cycle 1 Days 1 through 28 for Part 1 and Cycle 1 Days 1 through 42 for Parts 2 and 3. Adult patients (ECOG PS ≤ 2) with locally advanced or metastatic solid tumors refractory to or intolerant of all existing therapies are eligible for Phase 1a. Phase 1b will enroll cohorts of adult patients with selected solid tumors known to have high levels of integrin expression at the Maximum Tolerated Dose or Recommended Phase 2 Dose of BJ-001 in combination with a PD-(L)1 inhibitor, as identified in Phase 1a, Part 3. Results: As of Jan 31, 2021, 9 patients have received BJ-001 dosing as a single agent at 0.21 µg/kg (n = 1), 0.9 µg/kg (n = 1), 3 µg/kg (n = 1), 6 µg/kg (n = 3), or 10 µg/kg (n = 3) in Phase 1a Parts 1 and 2, wherein 7 patients, including 1 patient in the 10 µg/kg cohort, have completed the DLT period. Among these 7 patients, 2 (1 in 3 µg/kg and 1 in 6 µg/kg cohorts) have stable disease and are still receiving BJ-001 treatment beyond Cycle 1. The longest duration in the study, to date, is approximately 4 cycles (over 5 months). Treatment Emergent Adverse Events (TRAEs) include injection site reactions (6/7, Grade 1-2), anorexia (2/7, Grade 1-2), cytokine release syndrome (1/7, Grade 1, resolved in 1 day), and temporal wasting (1/7, Grade 1). The AEs did not result in dose interruption or dose level adjustment. No DLTs observed to date. With escalating doses, a trend of increased post-dose NK cell counts observed, whereas Regulatory T cell (Treg) counts remained stable. Conclusions: To date, BJ-001 is well tolerated up to 6 µg/kg. The safety evaluation for 10 µg/kg is ongoing. The observed NK and Treg cell profiles are consistent with known IL-15 biology. Clinical trial information: NCT04294576.

Early safety and efficacy from a phase I open-label clinical trial of CD137(4-1BB) agonistic antibody LVGN6051 as monotherapy and in combination with pembrolizumab.

2521 Background: LVGN6051, a monoclonal antibody against CD137 (also known as 4-1BB or TNFRSF9) with an engineered Fc capable of selectively binding to the Fcγ receptor IIB, acts as a conditional CD137 agonist, resulting in immune activation optimally in tumor microenvironment ( Qi, Nat. Commun. 2019 ). In preclinical models, LVGN6051 demonstrated robust anti-tumor efficacy and safety as a single agent and in combination with anti-PD-1 antibodies. Therefore, we have initiated this first-in-human study of LVGN6051 alone or in combination with pembrolizumab for the treatment of advanced or metastatic malignancy. Methods: This study includes accelerated dose escalation monotherapy up to 2 mg/kg of LVGN6051, and traditional 3 + 3 design for higher doses of LVGN6051 alone or in combination with pembrolizumab. Then, this study will enroll patients with specific types of malignancies following Simon’s two-stage design. Both agents are administered once every 3 weeks. Primary objectives of this study were to define the safety profile and to establish the recommended phase 2 dose (RP2D) of LVGN6051 alone or in combination with pembrolizumab. Pharmacokinetics, immunogenicity, pharmacodynamics and clinical efficacy will be also evaluated. Results: At the cut-off date on January 18, 2021, 16 subjects have been enrolled into the monotherapy cohorts (n=12, no DLT observed up to 7 mg/kg), and the combination cohort (n=4, ongoing at LVGN6051 2 mg/kg and pembrolizumab 200 mg, one DLT observed). No treatment-related adverse event (TRAE) was observed in monotherapy. Treatment-emergent adverse events (TEAE) in combination included increased ALT/AST, thrombocytopenia, and fatigue. In the combination cohort, one patient with predominant hepatic metastases and history of intermittent grade 2 hepatic impairment experienced grade 3 increased ALT/AST (DLT) on cycle 1 day 15 that were resolved to her baseline without corticosteroids on cycle 1 day 18. TRAE included increased ALT/AST, thrombocytopenia, neutropenia, nausea and fatigue. Seven of 10 evaluable patients in the monotherapy cohorts demonstrated stable disease with the longest treatment being 8+ months. Tumor reductions by >10% were observed in melanoma and neuroendocrine tumor on monotherapy. One patient with metastatic head and neck squamous cell carcinoma who had progressed on an anti-PD-L1 based therapy showed an immune partial response (iPR) for 6+ months to the combination therapy. Conclusions: Preliminary evidence showed that LVGN6051 was well tolerated and tumor shrinkages were observed. While we continue assessing its safety profile, antitumor activity was observed in the LVGN6051 and pembrolizumab cohort. The favorable safety profile and preliminary antitumor activity warrant further evaluation in patients with advanced malignancies. Clinical trial information: NCT04130542.

Accelerated Dose Escalation with 3 Injections of an Aluminum Hydroxide-Adsorbed Allergoid Preparation of 6 Grasses Is Safe for Children and Adolescents with Moderate to Severe Allergic Rhinitis

A high-dose, accelerated escalation schedule during subcutaneous allergen-specific immunotherapy (AIT) is safe and well-tolerated in adults. However, there are no data in children and adolescents. The aim of the present trial was to assess safety and tolerability of an accelerated dose escalation schedule of an AIT with a grass pollen allergoid in children and adolescents with moderate to severe seasonal rhinoconjunctivitis in a multicenter, open-label, randomized phase II trial. The dose escalation scheme for patients in the One Strength Group included 3 injections with 1 strength B (10,000 TU/mL), whereas the dose escalation scheme for the Standard group included 7 injections with 2 strengths A (1,000 TU/mL) and B (10,000 TU/mL) of an allergoid grass pollen preparation. Overall, n = 50 children (n = 25 in each group; mean age 8.9 + 1.54 years) and n = 37 adolescents (n = 20 and n = 17; 14.2 + 1.62 years) were randomized. For all patients, the mean treatment duration was 59.4 days in the One Strength group and 88.6 days in the Standard group. Treatment-emergent adverse events (TEAEs) related to AIT were reported in 52 and 40% in children and 35 and 35.3% in adolescents, respectively. Systemic allergic reactions occurred in about 5% of our patients and were reported in more patients of the One Strength group (6.7 vs. 2.4%). All systemic reactions were classified as WAO Grade 1. Accelerated high-dose escalation with an aluminum hydroxide-adsorbed grass pollen allergoid can be initiated with a safety and tolerability profile comparable to the standard dose escalation schedule in children and adolescents with allergic rhinitis with or without asthma.

First-in-human (FIH) phase I study of GST-HG161, a potent and highly selective c-met inhibitor, in patients with advanced solid tumor.

e16126 Background: GST-HG161 is an orally bioavailable novel potent and highly selective c-Met inhibitor, which displayed significant antitumor activity in preclinical models as well as very desirable pharmaceutical properties for oral dosing. Preclinical studies demonstrated that GST-HG161 has the potential to be effective in HCC patients with active c-Met signaling. Methods: This is an open label, first-in-human, single center, dose-escalation study (NCT04228406) utilizing an accelerated dose escalation design using single patient cohorts for the first two dose levels (60 and 150 mg) followed by a conventional 3+3 design at the 3rd dose cohort (300 mg). Dose escalation is expected to continue to the proposed 7th dose cohort (900 mg). The objective of the study is to determine the maximum tolerated dose and/or recommended Phase II dose, dose limiting toxicities (DLT), safety, pharmacokinetics, pharmacodynamics and preliminary signals of anticancer efficacy of GST-HG161 in patients with advanced solid tumors. Eligible patients are adults with advanced solid tumors refractory to standard therapies with confirmed c-Met positive. The definition of c-Met positive is a) IHC expression of c-Met (positive criteria: 1+ and above) and/or b) FISH amplification of c-Met and/or c) MET exon 14 (METex14) skipping. GST-HG161 is administered orally once-a-day starting on day 1 of each 21 days cycle. Results: To date, 6 patients (CRC 2, Gastric 1, NSCLC 1, HCC 1, Cholangiocarcinoma 1) were enrolled to 3 dose levels (60, 150, and 300 mg). Of these 6 patients, 4 had discontinued GST-HG161 treatment at the data cut-off date of Feb 1, 2020, due to progressive disease (3) and adverse event (1). Two patients at the 300 mg cohort are still on treatment. Overall, 4/6 patients showed no drug-related AEs > Grade 1. One patient reported a DLT: asymptomatic Grade 3 lipase elevation after a single dose of 60mg. To date, no other patients showed elevations of lipase and amylase. Bioanalysis of PK samples from study patients are currently ongoing. PK summary will be reported in the presentation. Conclusions: GST-HG161 has been well tolerated to date in study patients with a manageable safety profile. The dose escalation is expected to continue to the proposed 7th cohort at 900 mg. Clinical trial information: NCT04228406 .

Abstract P5-11-06: Phase 1 study of TTC-352 in patients with metastatic breast cancer progressing on endocrine therapy

Abstract Background: TTC-352 is a selective human ER partial agonist (ShERPA) developed for treatment of ER+ breast cancer (BC). ShERPAs mimic the effects of estradiol (E2) in hormone-independent, endocrine-resistant BC cells, but since it has only partial agonist activity in ER+ cells, it could have an improved side effect profile. Thus, TTC-352 could be a promising option for endocrine-resistant BC. Methods: This is an open-label, accelerated dose escalation study with primary endpoint of maximum tolerated dose (MTD) that is evaluating up to five dose levels of TTC-352 in patients with ER+ endocrine-resistant metastatic BC (NCT03201913). The MTD of TTC-352 is determined using initial single-patient cohort escalations until grade 2 toxicity, then expansion to a modified-Fibonacci dose-escalation 3+3 design. The secondary objectives are: best response (BR), progression-free survival, overall survival, treatment tolerability, and pharmacokinetics (PK) of TTC-352. Patient population: patients with metastatic ER+ BC who received and progressed on at least two lines of endocrine therapy, with one that included a CDK4/CDK6 inhibitor, and with adequate hepatic, renal, and bone marrow function at screening. Results: This study completed enrollment of a total of 15 patients on June 5, 2019. Dose LevelTTC-352 Dose Level (mg)Number of SubjectsTwice-Daily (BID) DoseTotal Daily Dose115302230601360120141202401518036010 No dose limiting toxicity has been seen to date with any of the tested dose levels. There was one treatment-related grade 3 event of asymptomatic pulmonary embolism (30mg BID). The number and percentage (n, %) of patients with treatment-related grade 1 and grade 2 adverse events reported in two or more patients across all dose levels were diarrhea (9, 60), hot flush (4, 26), headache (3, 20), nausea (3, 20), abdominal pain (3, 20), rash (3, 20), blurred vision (2, 13) vomiting (2, 13), dizziness (2, 13), peripheral neuropathy (2, 13), breast pain (2, 13), uterine/vaginal hemorrhage (2, 13) and vaginal discharge (2, 13). BR in the 7 evaluable patients (patients with at least two 28-day cycles of treatment) showed that 3 patients had stable disease (SD) for 4, and 10 months, respectively; 1 patient continues study treatment with SD after 9 months; and 4 patients had progressive disease (PD) after completing two cycles of treatment. All 5 non-evaluable patients had PD prior to completing two cycles of treatment. PK: The intra- and inter-individual variability for AUC0-∞ hampered assessment of the relationship between dose and AUC0-∞., Half-life was 7.6-14.3 hrs. Trough TTC-352 plasma concentrations at steady-state (SS) remained well above the plasma concentrations associated with efficacy in animal models. PKC alpha expression in tumor tissue did not correlate with length of disease control with TTC-352 therapy, though the numbers are small and not all of the available specimens were metastatic. Conclusions: TTC 352 demonstrates manageable safety and early clinical evidence of antitumor activity in patients with BC progressing on endocrine therapy. Based upon SS TTC-352 plasma concentrations and tolerability, the 180mg BID dose is recommended for further testing. Citation Format: Ruth O'Regan, Randolph Hurley, Jasgit Sachdev, Jonathan Bleeker, Debra Tonetti, Gregory Thatcher, Robert Venuti, Arkadiusz Dudek. Phase 1 study of TTC-352 in patients with metastatic breast cancer progressing on endocrine therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-06.

Accelerated Dose Escalation with Three Injections of an Aluminum Hydroxide-Adsorbed Allergoid Preparation of Six Grasses Is Safe for Patients with Moderate to Severe Allergic Rhinitis

Only few data on safety during high-dose, accelerated escalation schedules during subcutaneous allergen immunotherapy (AIT) are available. The aim of this study was to assess the safety and tolerability of an accelerated dose escalation schedule of AIT in adult patients with moderate to severe seasonal rhinoconjunctivitis in a multicenter, open-label, randomized phase II trial. The dose escalation scheme for patients in Group I (1 strength) included 3 injections with 1 strength, B (10,000 TU/mL), whereas the dose escalation scheme for Group II (standard) included 7 injections with 2 strengths, A (1,000 TU/mL) and B (10,000 TU/mL), of an aluminum hydroxide-adsorbed allergoid grass pollen preparation. Overall, 72 of 87 randomized patients (83.7%) reported at least 1 treatment-emergent adverse event (TEAE; 82.2 [Group I] vs. 85.4% [Group II]); 58.8% of all reported TEAEs were assessed as being related to AIT (60.0 vs. 48.8%). The most frequently reported AIT-related TEAEs were swelling (46.7 vs. 34.1%), erythema (28.9 vs. 36.6%), and pruritus (31.1 vs. 17.1%) at the site of the injection. Systemic allergic reactions occurred in 5 (5.8%) patients overall, with more being reported in the 1-strength group (4 [8.9%] vs. 1 [2.4%]). All systemic allergic reactions were classified as World Allergy Organization (WAO) Grade 1 or Grade 2 reactions. Accelerated high-dose escalation with an aluminum hydroxide-adsorbed grass pollen allergoid can be initiated with a safety and tolerability profile comparable to the standard dose escalation schedule in patients with allergic rhinitis with or without asthma.

Abstract CT109: A Phase I dose escalation and expansion study of seclidemstat (SP-2577) a first-in class reversible LSD1 inhibitor for patients with relapsed or refractory Ewing sarcoma

Abstract Introduction: Ewing sarcoma is an aggressive pediatric and young adult bone tumor dependent almost exclusively on the EWS/ETS fusion protein family for transcriptional activity. EWS/FLI is the most common fusion resulting in the repression of vital tumor suppressor genes by the activity of lysine-specific histone demethylase 1 (LSD1). Seclidemstat (SP-2577) is a first in class, orally bioavailable, small molecule with reversible and noncompetitive selective inhibition of LSD1 at low nanomolar concentrations (IC50: 25-50 nM). Seclidemstat has demonstrated disruption of global transcriptional function of EWS/ETS fusions and impairs multiple EWS/ETS-associated oncogenic phenotypes in xenograft models of Ewing sarcoma. This Phase I study aims primarily to assess the safety and tolerability of seclidemstat and to secondarily characterize the pharmacokinetics (PK), food effects, and preliminary anti-tumor activity via RECIST 1.1. Exploratory objectives include using circulating tumor cells, cell-free DNA, and hemoglobin F as pharmacodynamic markers of response. Methods: This multi-center phase I study (NCT03600649) is open-label and non-randomized and utilizes an accelerated dose escalation phase followed by a conventional 3+3 design to determine the maximum tolerated dose (MTD). Initially, one subject per dose cohort will be recruited in the accelerated dose escalation phase until the first instance of grade 2 or greater drug related toxicity or dose limiting toxicity (DLT). Further cohorts will be recruited in cohorts of three subjects in the 3+3 dose escalation phase. Once a declared suitable dose and schedule for further investigation has been identified, 14 additional patients will be enrolled in the dose expansion part of the study for a total of 20 patients treated at the MTD. The starting dose of seclidemstat is 75 mg PO BID with seven dose levels planned by modified Fibonacci schema. Food effects on PK are planned on day 1 and 2 of cycles 1 and 2. Patients at least 12 years of age will be included with histologically confirmed relapsed or refractory Ewing sarcoma with adequate performance status and organ function. Archival tumor tissue is required during screening. Tumor biopsies and measurable disease are required in dose expansion only. This trial is currently open for requirement at five locations in the United States. Dose level 2 (150 mg PO BID) began enrollment in November 2018 with no drug related grade 2 or greater adverse events or DLTs observed in dose level 1. Citation Format: Damon Reed, Steven G. DuBois, Richard Gorlick, Leo Mascarenhas, Douglas Harrison, Jonathan Metts, Stephen L. Lessnick, Brian D. Crompton, David M. Loeb, Rose Hernandez, Jeff Larson, David D. Stenehjem. A Phase I dose escalation and expansion study of seclidemstat (SP-2577) a first-in class reversible LSD1 inhibitor for patients with relapsed or refractory Ewing sarcoma [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 CT109.

Abstract CT051: Phase I study of TTC-352 in patients with estrogen receptor-positive metastatic breast cancer

Abstract Background: TTC-352 is a selective human estrogen receptor (ER) partial agonist (ShERPA). ShERPAs mimic the effects of estradiol in endocrine-resistant breast cancer (ERBC) cells, but has only partial agonist activity, and as such should have an improved side effect profile and be a promising option for ERBC. Methods: This is an open-label, accelerated dose escalation study with primary endpoint of maximum tolerated dose (MTD) that is evaluating up to 5 dose levels of TTC-352 in patients with ER+ metastatic ERBC (ERMBC). The MTD is determined using initial single-patient cohort escalations until grade 2 toxicity, then expansion to a modified-Fibonacci dose-escalation 3+3 design. The secondary objectives are: best response (BR), progression-free survival, overall survival, treatment tolerability, and pharmacokinetics of TTC-352. Patients with ER+ MBC who have experienced disease progression on at least 2 lines of endocrine therapy (ET), with one that included a CDK4/CDK6 inhibitor, and with adequate organ function are eligible. This study is currently enrolling patients (NCT03201913). Results: A total of 9 patients have been enrolled to date. Dose LevelTTC-352 Dose Level (mg)Number of SubjectsTwice-Daily (BID) DoseTotal Daily Dose11530223060136012014120240151803604 No dose limiting toxicity has been seen to date. There was 1 treatment-related grade 3 adverse event (AE) of asymptomatic pulmonary embolism (30mg BID), and single patient grade 2 AEs of anemia (180mg BID), diarrhea (180mg BID), fatigue (180mg BID), hypophosphatemia (180mg BID), peripheral neuropathy (15mg BID), rash (180mg BID), somnolence (60mg BID), and uterine bleeding (60mg BID). Grade 1 AEs included (n, %) diarrhea (6, 67), hot flashes (3, 33), abdominal pain (3, 33), nausea (2, 22), vomiting (2, 22), headache (2, 22) and myalgia/muscle spasms (2, 22%). BR in the 5 evaluable patients (at least 2 cycles of treatment) showed that 3 patients had stable disease (SD) and 2 patients had progressive disease (PD). The large intra- and inter-individual variability for AUC0 hampered assessment of the relationship between dose and AUC0. Half-life was 7.6-14.3 hrs. Trough plasma concentrations at steady-state (SS) remained well above the plasma concentrations associated with efficacy in animal models. Conclusions: TTC 352 has manageable safety and early clinical evidence of activity in patients with MBC progressing on ET. Its PK is characterized by high intra- and inter-individual variability. Based upon SS plasma concentrations and tolerability, the 180mg BID dose is recommended for further testing. Citation Format: Ruth M. ORegan, Randolph Hurley, Jasgit C. Sachdev, Jonathan Bleeker, Debra Tonetti, Gregory Thatcher, Robert Venuti, Arkadiusz Z. Dudek. Phase I study of TTC-352 in patients with estrogen receptor-positive metastatic breast cancer [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 CT051.

Phase I study of DFP-11207, a novel oral 5-FU with enhanced PK and improved tolerability, in patients with solid tumors.

3034 Background: DFP-11207 combines a 5-fluorouracil (5-FU) pro-drug with a reversible dihydropyrimidine dehydrogenase inhibitor and a potent inhibitor of orotate phosphoribosyl transferase resulting in enhanced pharmacological activity of 5-FU with decreased gastrointestinal and myelosuppressive toxicity. Methods: Patients with advanced solid tumors were treated in this single arm, dose escalation study. Accelerated dose escalation using single pt cohorts was followed until drug-related Gr2 adverse events occurred; then a 3+3 design was followed to determine maximum tolerated dose (MTD). Pts were dosed daily in 28-day cycles until intolerable toxicity or disease progression. PK sampling was performed for DFP-11207 metabolites on all pts and a 6 pt cohort received DFP-11207 in fed and fasted states to determine drug bioavailability. Results: Primary tumors among the 23 enrolled pts included esophageal, colorectal, gastric, pancreatic and gallbladder. Seventeen pts were treated at 8 dose levels of oral DFP-11207 administered daily, ranging from 40 to 440 mg/m2/d. At 440 mg/m2/d one pt experienced drug-related Gr3 dehydration and mucosal inflammation, and Gr4 febrile neutropenia; a second pt experienced Gr4 febrile neutropenia. One DLT of Gr3 vomiting occurred among 6 pts treated at 330 mg/m2/d dosed q12hrs confirming the MTD. Six pts were administered 300 mg DFP-11207 q12 hrs in a fed or fasted state to determine drug bioavailability. Among all pts, the most frequently reported drug-related TEAEs were fatigue (47.8%), nausea (47.8%), decreased appetite (39.1%), diarrhea (26.1%), vomiting (21.7%), anemia (13.0%), dysgeusia (13.0%), mucosal inflammation (13.0%) and palmar-plantar erythrodysaesthesia syndrome (13.0%). PK analyses of pts treated at 330 and 440 mg/m2/d indicate 5-FU concentrations of ~20 ng/mL throughout the dose cycle. There was no substantial difference in DFP-11207 bioavailability among pts in a fed or fasted state. Out of 21 efficacy evaluable pts, 7 pts had stable disease (33.3%), of which 2 had prolonged stable disease of > 6 months. No pts achieved CR or PR. Conclusions: DFP-11207 at the dose of 330 mg/m2/d q12hrs is well-tolerated in pts with solid tumors with mild myelosuppressive and gastrointestinal side effects, and results in circulating 5-FU levels conducive to an anti-tumor effect. DFP-11207 can be explored as monotherapy or substitute for 5-FU, capecitabine or S-1 in combination treatment regimens. Clinical trial information: NCT02171221.

Ruxolitinib in Combination with Dasatinib and Dexamethasone Is an Active and Well-Tolerated Chemotherapy-Sparing Oral Induction Regimen for Adults with Philadelphia Chromosome-Positive ALL: Results of a Phase I Trial

Introduction: Induction therapy consisting of dasatinib (DAS) and corticosteroids (CS) yields high rates of morphologic complete response (CR) in adults w/ newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). However, only ~20% of patients (pts) achieve BCR-ABL1 response depth of Methods: We conducted a phase I trial (NCT02494882) w/ accelerated dose escalation of RUX. Pts w/ newly diagnosed Ph+ ALL received CS pre-phase (d -6 to 0) followed by DAS 140 mg daily (starting d1) in combination w/ dexamethasone (DEX) 10 mg/m2 PO daily (d1-24, then taper) and RUX (d1-84). RUX doses were 10 mg PO BID (n=1), 15 mg PO BID (n=1), 20 mg PO BID (n=1), and 25 mg PO BID (n=7). IT methotrexate was given as CNS prophylaxis (d22, 43, 64, 85). Post-induction therapy was left to the discretion of the treating physician. The primary objective was to determine the recommended phase 2 dose (RP2D) of RUX in this combination. Secondary objectives included assessment of response kinetics, including minimal residual disease (MRD) negativity by flow cytometry (FACS) and BCR-ABL1 transcript monitoring, and ABL kinase mutation development. Results: Ten pts enrolled (6M, 4F). Median age at time of screening bone marrow (BM) studies was 63.8 yrs (range, 25.7-77.4; 7/10 age ≥60). BCR-ABL1 transcripts were p190 (n=7), p210 (n=2), atypical (n=1). No dose-limiting toxicity (DLT) has been observed. Enrollment was expanded at the highest RUX dose level (25 mg PO BID). Grade (Gr) 3-4 non-hematologic toxicities possibly/probably attributable to DAS/RUX/CS were limited to Gr 3 hyperglycemia in the setting of CS (n=5), Gr 3 hypofibrinogenemia (n=1), and Gr 3 peripheral edema (n=1). Two pts discontinued DAS after completing the 84d induction due to symptomatic pleural effusions. All pts achieved morphologic CR or CR w/ incomplete hematologic recovery (CRi). Median log reduction in BCR-ABL1 transcript levels (Figure 1A) was 2.7 at d22 (range, 1.3-4.2, n=9), 3.4 at d43 (range, 1.0-CMR, n=8), and CMR at d85 (range, 3.2-CMR, n=5). By FACS, 7/10 achieved MRD Among 6 pts completing the 84d induction, next post-remission therapy included tyrosine kinase inhibitor (TKI) + concurrent blinatumomab (n=3), TKI + hyperCVAD (n=1), and allogeneic hematopoietic cell transplantation (alloHCT, n=1). Of the 4 pts not completing the 84d induction, next therapy included ponatinib + blinatumomab (n=2), ponatinib + hyperCVAD (n=1), or DAS alone (n=1). Overall, 3 pts experienced morphologic relapse, which was observed in the setting of T315I (n=2) or F317L (n=1) ABL kinase mutations. Median EFS and OS (Figure 1B&C) are not yet reached in this small group of pts at median follow-up of 11.2 months among survivors (range, 2.8-20.7). Conclusions: Chemotherapy sparing-induction consisting of DAS, RUX, and initial DEX was well tolerated among adults w/ newly-diagnosed Ph+ ALL and led to CR/CRi in all pts. The RP2D of RUX is 25 mg PO BID. Kinetics of BCR-ABL1 transcript reduction compare favorably w/ other series of TKI + steroid-based induction, w/ rapid achievement of median >3 log reduction in BCR-ABL1 transcripts. Correlation of response kinetics w/ JAK/STAT pathway inhibition may suggest mechanisms of resistance apart from ABL kinase mutations. In future chemotherapy-sparing induction approaches, incorporating ponatinib, asciminib, or other novel therapies (vs. DAS) during induction may suppress leukemic clones bearing T315I mutations and reduce early relapse rates. Disclosures Geyer:Dava Oncology: Honoraria. King:Genentech: Other: Advisory Board . Mauro:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Takeda: Consultancy. Tallman:BioSight: Other: Advisory board; AROG: Research Funding; AbbVie: Research Funding; Cellerant: Research Funding; ADC Therapeutics: Research Funding; Daiichi-Sankyo: Other: Advisory board; Orsenix: Other: Advisory board. Levine:Gilead: Honoraria; Isoplexis: Equity Ownership; Epizyme: Patents & Royalties; Roche: Consultancy, Research Funding; Loxo: Consultancy, Equity Ownership; Novartis: Consultancy; C4 Therapeutics: Equity Ownership; Qiagen: Equity Ownership, Membership on an entity9s Board of Directors or advisory committees; Prelude: Research Funding; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Imago: Equity Ownership. Douer:Jazz Pharmaceuticals: Consultancy; Gilead Sciences: Consultancy; Shire: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria; Spectrum: Consultancy. Park:Novartis: Consultancy; Kite Pharma: Consultancy; Adaptive Biotechnologies: Consultancy; AstraZeneca: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Pfizer: Consultancy; Shire: Consultancy.

Abstract B070: IPI-549-01: A Phase I/Ib first in human study of IPI-549, a PI3K-γ inhibitor, as monotherapy and in combination with an anti-PD-1 antibody in subjects with advanced solid tumors

Abstract Background: IPI-549 is a first-in-class, oral, potent, and selective PI3K-γ inhibitor being developed as an immuno-oncology therapeutic in multiple cancer indications. Preclinical studies demonstrate a role for PI3K-γ in polarization of immune suppressive myeloid cells in the tumor microenvironment. Inhibition of PI3K-γ by IPI-549 enhanced antitumor immune responses and inhibited tumor growth in syngeneic solid tumor preclinical models. In addition, IPI-549 in combination with immune checkpoint inhibitors showed increased tumor growth inhibition compared to each single agent in multiple pre-clinical models. These data served as the scientific foundation for initiating a clinical trial testing IPI-549 as a potential immuno-oncology therapy. This first-in-human clinical study will evaluate the safety and tolerability, and determine the recommended Phase 2 dose (RP2D) of IPI-549 when administered as a monotherapy and in combination with an anti-PD-! antibody (NCT02637531) in solid tumors. Methods: This multi-part Phase 1/1b open-label trial will initiate with monotherapy dose escalation cohorts consisting of an accelerated dose escalation phase followed by a standard phase with a 3+3 design. Evaluation of the PK, PD, and safety data in these cohorts will lead to the determination of the maximum tolerated dose (MTD) and RP2D of IPI-549 monotherapy. Subsequently, combination dose escalation cohorts will be initiated in which the combination of IPI-549 and anti-PD-! antibody will be evaluated. Expansion cohorts evaluating the safety, PK, PD, and preliminary clinical activity of IPI-549 as a monotherapy and in combination with an anti-PD-1 antibody will occur following the dose escalation phase. All subjects in the trial will have advanced and/or metastatic carcinoma or melanoma, and will have failed to respond to standard therapies. Combination expansion cohorts will recruit subjects with non-small cell lung cancer or melanoma who must have received an anti-PD-1 or anti-PD-L1 antibody as their most recent treatment. This trial is currently enrolling patients in the US. To date, 6 patients have been enrolled and dose escalation is continuing (updated data to be presented). Citation Format: Anthony Tolcher, David Hong, Ryan Sullivan, James Mier, Geoffrey Shapiro, Joseph Pearlberg, Les Brail, Jahnavi Kharidia, Lixin Han, Claudio Dansky Ullmann, Howard M. Stern, Jedd D. Wolchok. IPI-549-01: A Phase I/Ib first in human study of IPI-549, a PI3K-γ inhibitor, as monotherapy and in combination with an anti-PD-1 antibody in subjects with advanced solid tumors [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B070.

An accelerated dose escalation with a grass pollen allergoid is safe and well-tolerated: a randomized open label phase II trial.

Background The number of injections in the dose escalation of subcutaneous immunotherapy (SCIT) is small for some currently used hypoallergenic allergoids, but can still be inconvenient to patients and can impair compliance. The aim of this trial was to compare safety and tolerability of an accelerated to the conventional dose escalation scheme of a grass pollen allergoid. MethodsIn an open label phase II trial, 122 patients were 1:1 randomized for SCIT using a grass pollen allergoid with an accelerated dose escalation comprising only 4 weekly injections (Group I) or a conventional dose escalation including 7 weekly injections (Group II). Safety determination included the occurrence of local and systemic adverse events. Tolerability was assessed by patients and physicians.ResultsTreatment-related adverse events were observed in 22 (36.1 %) patients in Group I and 15 (24.6 %) in Group II. Local reactions were reported by 18 patients in Group I and 11 in Group II. Five Grade 1 systemic reactions (WAO classification) were observed in Group I and 2 in Group II. Grade 2 reactions occurred 3 times in Group I and 2 times in Group II. Tolerability was rated as “good” or “very good” by 53 (86.9 %) patients in Group I and 59 (100 %) in Group II by investigators. Forty-eight patients in Group I (80.0 %) and 54 in Group II (91.5 %) rated tolerability as “good” or “very good”.ConclusionsThe dose escalation of a grass pollen allergoid can be accelerated with safety and tolerability profiles comparable to the conventional dose escalation.

Feasibility of PET-CT based hypofractionated accelerated dose escalation in oropharyngeal cancers: Final dosimetric results of the VORTIGERN study. (Secondary endpoint of UK NCRI portfolio: MREC No: 08/H0907/127, UKCRN ID 7341).

Technological advances have enabled clinicians to explore dose escalation strategies in various tumor sites. Intermediate and high risk oropharyngeal cancers have poor 5 year outcomes. This study aimed to assess the feasibility and dosimetric safety of 9% dose escalation in these tumors and compare the dose received by organs at risk (OAR) in escalated plans (67.2 Gy/28 fractions) versus (65 Gy/30 fractions) standard dose plans. FDG-PET fused datasets were used to delineate gross, clinical and planning target volumes. Standard dose plans were created using two non IMRT techniques (conventional and field in field plans) whilst the patient was treated using a helical tomotherapy plan. A fourth dose escalation plan was obtained allowing comparison between the 20 plans of oropharyngeal cancer patients. It was feasible to escalate dose to the FDG-PET avid tumor within the set constraints to that of planning target volume and OAR. Comparison of the escalated dose to that of standard plans showed a statistically significant (P < 0.05) sparing of the mastication apparatus (MA) with escalated plans. Dose to the other critical and functional organs were comparable between the four plans. Hypofractionated, slightly accelerated dose escalation in oropharyngeal cancers is likely to be safe and the chance of trismus is not any higher than when standard dose radiotherapy is used. Active measures to reduce dose to the MA achieves acceptable dose volume parameters even at escalated doses.