Dose-finding Part Research Articles

Triplet therapy with pembrolizumab (PEM), encorafenib (ENC) and binimetinib (BIN) in advanced, BRAF V600 mutant melanoma: Final results from the dose-finding phase I part of the IMMU-Target trial.

9532 Background: Survival of BRAF-mutated melanoma profoundly improved since the introduction of immune checkpoint inhibitors (ICI) and MAPK pathway inhibitors (MAPKi). Response kinetics of ICI and MAPKi are complementary, mechanistic evidence indicates that MAPKi may affect the tumor immune microenvironment. Combined use of both drug classes may further enhance clinical benefit. IMMU-Target was set-up as a prospective, open-label, phase I/II trial, with a safety phase I part followed by a randomized phase II part, to study the tolerability and clinical activity of PEM, ENC and BIN triplet therapy. Methods: Treatment naïve adult patients (pts) with stage IIIB-IV (AJCC 2017), BRAF V600 mutant melanoma with measurable disease but no active brain metastasis were eligible. The dose finding part used a 3+3 design, starting with a dose level (DL) 0 applying the clinically recommended doses of PEM (200 mg Q3W), ENC (450 mg QD) and BIN (45 mg BID). In case of ≥2 dose-limiting toxicities (DLT), a reduction of the ENC and BIN doses (300 mg QD and 30 mg BID at DL-1, 200 mg QD and 30 mg BID at DL -2) was foreseen. Primary endpoints of the phase I part were safety and tolerability. Results: From April 2018 until May 2020, 14 pts with BRAF V600 mutations were enrolled. 2 of 3 pts at DL 0 developed DLT (creatine phosphokinase (CPK) elevations grade 3 plus cytokine release syndrome grade 4; gamma glutamyl transferase (GGT) elevations grade 3), and had to stop therapy early. Therefore, 3+3 further pts at DL -1 were included with no DLT observed in these 6 pts. One (isolated GGT elevations grade 3) of the 2 DLT observed in the 3 pts of DL 0 enrolled initially was questionable as DLT, as the patient had further episodes of isolated GGT elevations without therapy. As a result, further 5 pts were enrolled at DL 0: here no DLT-matching treatment-related adverse event (TRAE) occurred. In total, 12 out of 14 pts (86%) experienced a TRAE and 7 (50%) experienced a grade ≥3 TRAE; there were no fatal AE or TRAE-related deaths. Increases in alanine and in aspartate aminotransferases, GGT and CPK elevations (6 of 14 pts) were the most common grade 3-4 TRAE. In median, pts at DL 0 (n=8) received triplet therapy for 18 weeks (IQR 7.5-29), at DL-1 (n=6) for 46 weeks (IQR 27-102). The overall response rate was 64% (95% CI=35-87). At a median follow-up of 10.0 months at DL 0 and 27.0 months at DL-1, progression-free survival at 12 months was 37.5% (95% CI 9- 67) and 60% (95% CI 13-88), respectively. Conclusions: Triplet therapy was feasible and safe at both dose levels leading to clinically meaningful disease control. The phase II part was not initiated, since the clinical efficacy of PEM plus ENC and BIN is currently investigated in STARBOARD ( NCT04657991 ), a prospective, randomized, placebo-controlled (PEM mono), double-blinded phase III trial. Clinical trial information: NCT02902042.

Trastuzumab deruxtecan (T-DXd) combinations in patients with HER2-positive advanced or metastatic breast cancer: A phase 1b/2, open-label, multicenter, dose-finding and dose-expansion study (DESTINY-Breast07).

TPS1096 Background: HER2-targeted therapies have improved survival in patients (pts) with HER2+ advanced/metastatic breast cancer (mBC) but challenges remain, including resistance to current HER2-targeted therapies. Also, additional treatment options are needed in pts with brain metastases (BM). In the phase 2 DESTINY-Breast01 trial, T-DXd demonstrated efficacy, with an objective response rate (ORR) of 61.4% and median progression-free survival (mPFS) of 19.4 mo in pts with previously treated HER2+ advanced/mBC (Modi SABCS 2020); data from an earlier cutoff of this trial supported approval of T-DXd in the US, Europe, and Japan. In a subgroup analysis of 24 pts with stable BM, T-DXd showed preliminary efficacy, with mPFS of 18.1 mo (Jerusalem ESMO Breast Cancer 2020). Here, we describe a phase 1b/2 trial evaluating the safety and preliminary antitumor activity of T-DXd monotherapy and combinations in pts with HER2+ advanced/mBC, including pts with stable and active BM. Methods: DESTINY-Breast07 (NCT04538742) is a global, multicenter, open-label, phase 1b/2 trial designed to evaluate the safety, tolerability, and preliminary antitumor activity of T-DXd monotherapy and combinations in pts with HER2+ advanced/mBC. This study consists of a T-DXd monotherapy module (module 0) and 5 combination modules of T-DXd plus (1) durvalumab, (2) pertuzumab, (3) paclitaxel, (4) durvalumab + paclitaxel, or (5) tucatinib, all in pts with no or stable BM. Two additional modules consisting of (6) T-DXd + tucatinib and (7) T-DXd monotherapy will include pts with untreated BM not requiring local therapy or previously treated BM that have progressed since local therapy (active BM). The need for chronic steroids or local therapy to manage BM symptoms is exclusionary. Modules 2 to 5 will each consist of 2 parts: dose finding (part 1) and dose expansion (part 2). Modules 0, 1, 6, and 7 will include part 2 only. Part 1 of individual modules will enroll pts who have had disease progression while receiving ≥1 prior line of therapy in the metastatic setting. In part 2, pts who have received no prior therapy (modules 0 to 5) or ≤1 prior therapy (modules 6 to 7) for metastatic disease will be randomized to receive a T-DXd combination regimen or monotherapy. The primary endpoints are determination of the recommended phase 2 doses (part 1 only) and safety and tolerability of T-DXd and combinations (parts 1 and 2). Secondary endpoints include ORR, PFS, PFS2, duration of response (DoR), and overall survival (all assessed in part 2 only) and pharmacokinetics and immunogenicity (parts 1 and 2). To assess central nervous system (CNS) activity, exploratory endpoints were added, including CNS-ORR, CNS-DoR, and CNS-PFS (by RECIST version 1.1 and RANO-BM criteria) as well as cognitive and symptom assessment using CANTAB, MDASI-BT, and NANO. Clinical trial information: NCT04538742 .

HERIZON: A phase 1B/2 open-label study of imu-131 HER2/neu peptide vaccine PLUS standard of care chemotherapy with randomization in phase 2 in patients with HER2/neu overexpressing metastatic or advanced adenocarcinoma of the stomach or gastroesophageal junction.

e16065 Background: The phase 2 part of the study hypothesizes HER-Vaxx (IMU-131) will provide treatment benefits consistent with traditional monoclonal antibodies that target HER2 in patients with confirmed Her2+ advanced or metastatic gastric cancer with a corresponding adaptive immune response without added toxicity. In the phase 1b dose finding part of the study tumor response of patients who received 50ug dose strongly correlated with antibody levels with 50ug selected as the phase 2 dose (Wiedermann et. al., 2019). Phase 2 is a randomized two arm study of either HER-Vaxx plus standard chemotherapy or standard chemotherapy alone. The primary endpoint is overall survival, with progression-free survival, safety and immune related changes in humoral and cellular immunogenicity secondary endpoints. Methods: Patients received SOC chemotherapy for a maximum of 6 cycles with the HER-Vaxx group also receiving 50ug dose of IMU-131 at Baseline/Day 0, Day 14, Day 35, Day 77 and then every 63 days until disease progression. The per protocol pre-planned first interim analysis (OS, PFS and safety) in a total of 27 patients after 15 progression events was reviewed by the independent data monitoring committee (IDMC). Results: Within ITT analysis, 8 of 27 patients died on the control arm and 4 on the HER-Vaxx plus SOC chemotherapy arm with an overall survival HR of 0.418 (2 sided 80% CI: 0.186, 0.942) and a 1-sided p-value of 0.083. Out of 27 patients, 9 patients progressed on the control arm while 6 patients progressed on the HER-Vaxx plus SOC chemotherapy arm with a HR of 0.532 (2 sided 80% CI: 0.267, 1.060) and a 1-sided p-value of 0.086. A robust HER2 specific antibody response developed in the HER-Vaxx arm compared to the control arm whereas there was no difference in safety between the two treatment arms. Conclusions: The IDMC confirmed that the safety of the study was favorable with no added toxicity of HER-Vaxx and SOC chemotherapy with a favorable risk-benefit for the combination. The study has completed enrollment and final data is expected in late 2021. Clinical trial information: NCT02795988.

Abstract OT-03-04: Trastuzumab deruxtecan (T-DXd; DS-8201) combinations in patients with HER2-positive advanced or metastatic breast cancer: A phase 1b/2 open-label, multicenter, dose-finding and dose-expansion study (DESTINY-Breast07)

Abstract Background HER2-targeted therapies have substantially improved survival in patients with HER2-positive (immunohistochemistry [IHC] 3+ or IHC2+/in situ hybridization-positive) advanced or metastatic breast cancer. Despite significant advancements, patients ultimately develop resistance to standard-of-care HER2-targeted therapies. Therefore, a need remains for regimens that prolong disease control and survival in these patients. T-DXd is a HER2-targeted antibody-drug conjugate containing a linker selectively cleaved in tumor cells and a topoisomerase I inhibitor payload with high cell-membrane permeability. T-DXd has been approved by the FDA for use in adult patients with unresectable or metastatic HER2-positive breast cancer who have received ≥ 2 prior anti-HER2-based regimens in the metastatic setting and by Japan’s Ministry of Health, Labour and Welfare for use in patients with HER2-positive unresectable or recurrent breast cancer after prior chemotherapy (use limited to patients refractory to or intolerant of standard treatments). Results from the phase 2 DESTINY-Breast01 trial demonstrated an objective response rate (ORR) of 60.9% per independent central review and a median progression-free survival (PFS) of 16.4 months in a heavily pretreated population (median of 6 prior lines of therapy) of patients with HER2-positive advanced or metastatic breast cancer treated with T-DXd (Modi S, et al. N Engl J Med. 2020;382:610-621). Here, we describe a phase 1b/2 trial evaluating the safety and preliminary antitumor activity of T-DXd combinations in patients with HER2-positive advanced or metastatic breast cancer. Study Description DESTINY-Breast07 is a global, multicenter, open-label, phase 1b/2 dose-finding and dose-expansion trial designed to evaluate the safety, tolerability, and preliminary antitumor activity of T-DXd in combination with other therapies in patients with HER2-positive advanced or metastatic breast cancer. Patients will be enrolled globally at ≈ 110 sites in ≈ 10 countries. The study will initially consist of 4 combination modules, each with 2 parts: dose finding (part 1) and dose expansion (part 2), and a T-DXd monotherapy module (part 2 only). The 4 combination modules will enroll patients for treatment with (1) T-DXd + durvalumab, (2) T-DXd + pertuzumab, (3) T-DXd + paclitaxel, or (4) T-DXd + durvalumab + paclitaxel. New combination treatment modules may be added via protocol amendment. Part 1 of each combination module will enroll patients who have had disease progression on ≥ 1 prior line of therapy in the metastatic setting. In part 2, patients who have received no prior therapy for metastatic disease will be randomized to receive a combination regimen or T-DXd monotherapy. Antitumor activity will be evaluated based on investigator assessment according to RECIST 1.1. The primary endpoint is to assess the safety and tolerability of T-DXd combinations and determine the recommended phase 2 doses. Secondary endpoints include ORR, PFS, duration of response, overall survival, pharmacokinetics, and immunogenicity. Citation Format: Fabrice Andre, Erika Hamilton, Sherene Loi, Peter Schmid, Tinghui Yu, Shiyao Lu, Sarice Boston, Celina D'Cruz, Pia Herbolsheimer, Komal Jhaveri. Trastuzumab deruxtecan (T-DXd; DS-8201) combinations in patients with HER2-positive advanced or metastatic breast cancer: A phase 1b/2 open-label, multicenter, dose-finding and dose-expansion study (DESTINY-Breast07) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-03-04.

A new radio-enhancer, PEP503 (NBTXR3), in combination with concurrent chemoradiation in locally advanced or unresectable rectal cancer: The dose-finding part of a phase I/II trial.

66 Background: PEP503 (as known as NBTXR3) is a novel radio-enhancer composed of functionalized hafnium oxide nanoparticles for a higher energy deposit by radiotherapy comparing to radiotherapy alone without it. A prior phase 3 study for soft tissue sarcoma has demonstrated the clinical benefit. The phase 1b part of the study aimed to test the feasibility of PEP503 intra-tumor injection and examine the safety profile of various dose levels of PEP503 in combination with concurrent chemo-radiation (CCRT) for locally advanced rectal cancers. Methods: Patients who had rectal adenocarcinoma of T3-4 or locally unresectable disease suitable for neoadjuvant CCRT were eligible. A single administration of PEP503 intra-tumor injection with multiple needle punctures was applied 24 to 72 hours before the start of IMRT or IMAT at 50 Gy in 25 fractions in combination with capecitabine or infusion 5-FU over 5~6 weeks. Dose escalation of 4 levels of PEP503 injected volume was based on 5%, 10%, 15%, and 22% of the baseline tumor volume by MRI. Intra-tumor dispersion of nanoparticles was inspected by CT-scan and the body kinetics evaluation was performed. The total mesorectal excision was planned around 8~12 weeks later after the completion of CCRT. Preliminary efficacy including tumor response after CCRT and the pathological response with tumor regression grade (TRG) after surgery was collected. Results: Twenty patients were enrolled, with 7, 4, 3, and 6 patients at 5%, 10%, 15%, and 22% dose levels, respectively. An injection procedure-related dose-limiting toxicity of urinary tract infection with sepsis was reported in the first treated patient at 5%. There was no adverse event (AE) or serious AE directly caused by PEP503. The most frequently reported AEs related to CCRT across all dose levels were diarrhea (~45%), WBC decreased (~40%), and dermatitis (~25%), but all were grade 1 or 2. The safety profile of CCRT with PEP503 was similar to it of CCRT without PEP503 for rectal cancer patients. The CT scans, before and after CCRT, displayed the dispersion of PEP503 among different tumor shapes and contours without leakage to the surrounding healthy tissues. In most patients, hafnium was not detected in the circulation in 60 minutes after PEP503 injection and not found in urine. Around 70% of patients showed tumor response after the CCRT and half of the patients receiving surgery achieved good tumor regression (AJCC TRG 0 or TRG 1). In the small phase 1b dose-escalation part of the trial, the dose-dependency of the efficacy endpoints could not be assessed. Conclusions: Intra-tumor injection of PEP503/NBTXR3 with CCRT is feasible without additional toxicities for rectal cancer patients. The extension phase 2 of the trial to investigate the clinical benefits of PEP503 at 22% of tumor volume is ongoing in Taiwan. Clinical trial information: NCT02465593.

Increased Detection of KIT D816V Mutation in Peripheral Blood Samples from Patients with Indolent Systemic Mastocytosis (ISM) in the Phase 2 Pioneer Study Using a High Sensitivity Droplet Digital (dd) PCR Assay Compared with Next Generation Sequencing (NGS)

Introduction: Systemic mastocytosis (SM) is a rare, clonal, hematopoietic neoplasm characterized by excessive proliferation and hyperactivation of abnormal mast cells (MCs). Approximately 95% of patients with SM harbor the KIT D816V mutation within the KIT receptor tyrosine kinase, which results in constitutive activation of the KIT receptor. Abnormal activation of KIT leads to increased proliferation, survival, and hyperactivation of MCs, which can cause debilitating constitutional symptoms such as pruritus, flushing, headaches, bone pain, nausea, vomiting, diarrhea, and life-threatening anaphylaxis, across all SM subtypes.Polymerase chain reaction (PCR)-based detectionof the KIT D816V mutation in bone marrow (BM) aspirates or other extracutaneous tissues is an important tool to confirm clinical and pathological diagnosis. In addition, genomic determination of the KIT D816V variant allelic fraction (VAF) in peripheral blood (PB) or BM can serve as a potential prognostic tool and may also be used to monitor treatment efficacy over time. However, low numbers of neoplastic MCs in BM or PB samples, especially from patients with non-advanced forms of the disease (ISM and smoldering SM) can result in misdiagnosis and underestimation of disease burden. Here, we report on the performance of an adapted ddPCR assay compared with NGS for measuring the KIT D816V VAF in PB samples from patients with moderate to severe ISM and symptoms inadequately controlled with best supportive care enrolled in part 1 (randomized dose finding part to determine recommended dose) of the ongoing, randomized, double-blind, placebo-controlled phase 2 PIONEER clinical study (NCT03731260) of avapritinib, a potent and selective inhibitor of KIT D816V mutant kinases. Methods : Part 1 of PIONEER included 39 patients (3 cohorts with 10 patients at 25, 50 and 100 mg of avapritinib, and a placebo cohort of 9 patients) with a confirmed diagnosis of ISM based on World Health Organization criteria and moderate-to-severe symptoms based on Total Symptom Score as measured on the ISM-System Assessment Form (ISM-SAF). Samples of PB were collected at screening for all enrolled patients in part 1 and were evaluated by local quantitative and qualitative KIT testing, central ddPCR assay for detection of KIT D816V, and central NGS (TruSight™ Myeloid Panel) for KIT D816V and other co-mutations (central assays performed by MolecularMD, Portland, OR). Results were expressed as the percentage of patient PB samples testing positive for KIT D816V mutation (all genomic assays) and the log percent of VAF as measured by both central assay methods. Correlations of KIT D816V VAF to objective measure of MC burden, including serum tryptase levels and BM MC numbers, were performed. KIT D816V VAF was also evaluated serially in each patient over the treatment period. Results: The central ddPCR assay method detected the KIT D816V mutation in 37/39 (95%) of PB samples compared with 11/39 (28%) assayed by NGS and 30/39 (80%) of PB samples assayed locally (Table). ddPCR also demonstrated ~30-fold greater sensitivity over NGS for measuring VAF: median percent VAF (range) by ddPCR was 0.36 (0.02-30) and by NGS was 11 (1.9-31) (Figure). The lower limit of detection of VAF by ddPCR on PB samples was 95-fold lower than that of NGS (0.02% and 1.9%, respectively). In addition, ddPCR provided greater diagnostic sensitivity for ISM compared with serum tryptase >20 ng/mL (30/39, 77%) and presence of BM MC aggregates (35/39, 90%). Conclusions: The high-sensitivity ddPCR assay method detected the KIT D816V mutation in 95% of PB samples from patients with previously confirmed ISM, which provided greater sensitivity for detection of KIT D816V mutation than either NGS or local assessments, greater sensitivity over NGS for KIT D816V VAF in PB samples, and higher diagnostic sensitivity than clinical assessments of serum tryptase and BM MC aggregates. These results have implications for assay sensitivity in the diagnosis of SM and suggest that higher sensitivity testing for KIT D816V mutation using a minimally invasive PB ddPCR assay could be used as a screening tool to facilitate identification of ISM patients, including those with variable disease characteristics or low MC burden. Disclosures George: Blueprint Medicines Corporation: Consultancy, Other: I have received no funding for this research. ARUP Laboratories, owned by the University of Utah, has received funding; Allakos: Consultancy; Celgene: Consultancy; Deciphera: Other: consultancy, but has received no financial compensation for the past 12 months. Hoehn:Blueprint Medicines Corporation: Current Employment, Current equity holder in publicly-traded company. Lin:Blueprint Medicines Corporation: Current Employment, Current equity holder in publicly-traded company. Miller:Blueprint Medicines Corporation: Current Employment, Current equity holder in publicly-traded company. Akin:Novartis: Consultancy; Blueprint Medicines Corporation: Consultancy, Research Funding.

Hepcidin Mimetic (PTG-300) Reverses Iron Deficiency While Controlling Hematocrit in Polycythemia Vera Patients

Background. The majority of PV patients are iron deficient at diagnosis [Ginzburg Leukemia 2018]. PV patients are treated with periodic therapeutic phlebotomy (TP) in order to maintain hematocrit levels <45% in an effort to reduce the incidence of thrombotic events [Marchioli NEJM 2013]. Symptomatic iron deficiency represents a challenge in PV as it is commonly present at diagnosis and TP worsens iron deficiency and PV patients can be severely symptomatic from their iron deficiency [Krayenbuehl Blood 2011]. Iron deficiency is defined as insufficient iron stores to meet the needs of cellular homeostasis. We hypothesized that both iron deficiency and expanded erythropoiesis in PV lead to suppression of hepcidin, the body's main negative regulator of iron metabolism, and that hepcidin suppression enhances iron absorption and iron availability for enhanced erythropoiesis in TP-requiring PV patients. We previously demonstrated that PTG-300, a hepcidin-mimetic, caused dose-related anemia in pre-clinical studies. In healthy volunteers PTG-300 decreases serum iron and transferrin saturation (TSAT) by >70% within 12 hours and the effect persists for 3-7 days. In a phase 2 trial in β-thalassemia, PTG-300 also decreased serum iron and TSAT but did not demonstrate off-target effects. The current study aims to compare the iron status in frequent TP-requiring PV patients before, during, and after treatment with PTG-300. Methods. Polycythemia patients who met 2016 WHO criteria for diagnosis were enrolled in the 28-week dose finding part of a Phase 2 trial. All patients required ≥3 phlebotomies with or without concurrent cytoreductive therapy over 6 months prior to enrollment. Patients were given PTG-300 doses of 10, 20, 40, 60 and 80 mg administered subcutaneously weekly in individualized adjustment to maintain hematocrit <45%. Body iron status was quantified by monitoring serum ferritin, serum iron, transferrin saturation (TSAT), mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH). Results. Thirteen subjects were enrolled to date: 7/13 with low risk, mean age 57.4 years (range 31-74). Six receiving TP alone, 6 on concurrent hydroxyurea, 1 on concurrent interferon; TP in the 24 weeks prior to enrollment = 3-9; median time between TP = 42 days. All subjects-maintained hematocrit <45% after appropriate dose adjustment. Mean baseline values were serum ferritin = 14.2 ng/mL (5, 37); serum iron = 33.0 ug/dL (16.8, 107.8); and TSAT = 7.6% (4, 30). During treatment with PTG-300, serum ferritin levels increased progressively toward normal (Figure 1a) reflecting increase in iron stores. TSAT (Figure 1b) and serum iron values increased modestly but remained below normal ranges, reflecting PTG-300's pharmacodynamic effect of inhibiting iron release from intracellular stores. This was associated with increased MCV (Figure 1c) and MCH (Figure 1d) and decreased hematocrit and erythrocyte counts, together suggesting a normalization of iron distribution. Conclusions. The current results indicate that PTG-300 is an effective agent for the controlling hematocrit and reversing iron deficiency. The effect of PTG-300 on PV-related symptoms and those of iron deficiency, are also being evaluated. Continued patient enrollment will enable more definitive conclusions regarding the efficacy and safety of hepcidin mimetic PTG-300 in PV patients with high TP requirements. Disclosures Kremyanskaya: Incyte Corporation: Research Funding; Bristol Myers Squibb: Research Funding; Astex Pharmaceuticals: Research Funding; Constellation Pharmaceuticals: Research Funding; Protagonist Therapeutics: Consultancy, Research Funding. Kuykendall:Novartis: Research Funding; Blueprint Medicines: Research Funding; BMS: Research Funding; Incyte: Research Funding. Yacoub:Agios: Honoraria, Speakers Bureau; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara Therapeutics: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Dynavax: Current equity holder in publicly-traded company; Novartis: Speakers Bureau; Roche: Other: Support of parent study and funding of editorial support. Yang:AROG: Research Funding; AstraZeneca: Research Funding; Protagonist: Research Funding; Jannsen: Research Funding. Gupta:Protagonist: Current Employment. Valone:Protagonist: Current Employment. Khanna:Protagonist: Current Employment, Current equity holder in publicly-traded company. Hoffman:Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Dompe: Research Funding; Forbius: Consultancy; Protagonist: Consultancy. Verstovsek:Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; ItalPharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; Protagonist Therapeutics: Research Funding; NS Pharma: Research Funding; CTI Biopharma Corp: Research Funding; Blueprint Medicines Corp: Research Funding; Genentech: Research Funding; PharmaEssentia: Research Funding; Roche: Research Funding; AstraZeneca: Research Funding.

Safety and preliminary antitumor activity of the transforming growth factor beta (TGF-β) receptor I kinase inhibitor, vactosertib, in combination with paclitaxel in patients with metastatic gastric adenocarcinoma.

e16505 Background: Recent studies demonstrated that TGF-β signaling attenuation in combination with paclitaxel inhibits epithelial-to-mesenchymal transition and cancer stem-like cells features, especially in diffuse type. We are reporting dose finding part in phase 1b study evaluating the combination of vactosertib, a highly selective and potent TGF-β inhibitor, with paclitaxel as a second line treatment in patients with metastatic gastric adenocarcinoma (GA). Methods: Eligible patients (pts) are ≥19 years old, have ECOG status ≤1, and have progressed on the first line treatment of metastatic GA treated with the combination therapy of fluoropyrimidine and platinum, or trastuzumab containing combination therapy in HER2-positive GA. The primary objective is to assess the safety and recommended phase 2 dose (RP2D) of vactosertib given 5 days on/2 days off in combination with weekly paclitaxel 80 mg/m2. Three dose levels of vactosertib (100, 200, and 300 mg BID) were tested. Results: As of Jan. 25, 2020, 12 pts were enrolled to the study (6, 3, and 3 pts in 100, 200, and 300 mg BID, respectively) and finished the safety evaluation. Median age was 50 (range, 39-65), 50% were male, and 75% had gastrectomy (4 pts with subtotal gastrectomy; 5 pts with total gastrectomy). At all cohorts, no dose limiting toxicity was observed. The most frequently reported treatment related adverse events (AEs) were anemia (50.0%), anorexia (41.6%), fatigue (33.3%), and urticaria (33.3%). AEs were mostly grade 1 or 2 and manageable. One case of grade 3 anorexia was reported as a treatment-related severe adverse event. Among 6 evaluable patients in 200/300 mg BID cohorts, the best responses to treatment were partial response in 1 patient; 57% decrease from baseline, 16.7% of overall response rate, and 83.3% of disease control rate at 12 weeks. Median progression free survival of the RP2D cohort has not been reached yet. Updated safety, PK, efficacy and biomarker data will be presented at the meeting. Conclusions: The combination of vactosertib plus paclitaxel has been well tolerated. The anti-tumor activity of this combination in patients with metastatic GA is now under exploration in the phase 2a part of the study. Clinical trial information: NCT03698825 .

TAS-116, an oral HSP90 inhibitor, in combination with nivolumab in patients with colorectal cancer and other solid tumors: An open-label, dose-finding, and expansion phase Ib trial (EPOC1704).

4044 Background: Regulatory T cells (Tregs) potentially induce the resistance of anti-PD1/PD-L1 inhibitors (A-PD1). TAS-116, a novel HSP90 inhibitor, enhanced antitumor immunity via reducing Tregs in vitro and in vivo. Combination of TAS-116 plus A-PD1 showed a superior tumor growth suppression compared with either treatment alone in vivo. Based on the above, we investigated safety and efficacy of TAS-116 in combination with nivolumab in patients with solid tumors. Methods: Enrolled patients received TAS-116 plus nivolumab in a dose-finding part to estimate the maximum tolerated dose and the recommended phase 2 dose (RP2D). Additional patients were enrolled in a dose-expansion part. TAS-116 monotherapy (orally once daily, 80mg on level 1, 120mg on level 2, and 160mg on level 3) was administrated for 2 weeks followed by the combination with nivolumab (intravenously every 2 weeks, 3 mg/kg). The primary endpoint was dose-limiting toxicities (DLTs) during the first cycle (4 weeks). PD-L1 combined positive score (CPS) and tumor mutation burden (TMB) were assessed. We also conducted biomarker research using paired samples from repeated tumor biopsies and blood collections. Results: A total of 44 patients with colorectal cancer (CRC, n = 29), gastric cancer (GC, n = 8), sarcoma (n = 5), non-small cell lung cancer (NSCLC, n = 1) and melanoma (n = 1) after standard of cares were enrolled. One patient had MSI-H CRC, but all other patients had MSS tumors. No DLTs were observed at all levels and TAS-116 160 mg was determined as RP2D. The common grade 3 or worse treatment-related adverse included AST/ALT increased (7%), creatinine increased (5%) and platelet count decreased (5%). Objective tumor response was observed in 6 patients including 4 MSS CRC, 1 MSI-H CRC and 1 sarcoma, resulting in objective response rate (ORR) of 16% in MSS CRC without prior A-PD-1. PD-L1 CPS and TMB could be evaluated in 18 and 17 MSS CRC without prior A-PD-1, respectively. ORR was 27% in patients with CPS ≥1 and 0% in patients with CPS < 1. ORR was 33% with TMB-high (median as the cut-off) and 12% with TMB-low. Analysis of tumor-infiltrating lymphocytes before treatment and after TAS-116 monotherapy demonstrated reduction of FoxP3hiCD45RA−Tregs fraction in the tumor microenvironment. Conclusions: The combination of TAS-116 160mg plus nivolumab had manageable safety profiles and anti-tumor activity especially for MSS CRC patients, which warrants further investigations in a large cohort. Clinical trial information: UMIN000032801 .

Tumour-specific fluorescence-guided surgery for pancreatic cancer using panitumumab-IRDye800CW: a phase 1 single-centre, open-label, single-arm, dose-escalation study

Complete surgical resection remains the primary curative option for pancreatic ductal adenocarcinoma, with positive margins in 30-70% of patients. In this study, we aimed to evaluate the use of intraoperative tumour-specific imaging to enhance a surgeon's ability to detect visually occult cancer in real time. In this single-centre, open-label, single-arm study, done in the USA, we enrolled patients who had clinically suspicious or biopsy-confirmed pancreatic ductal adenocarcinomas and were scheduled for curative surgery. Eligible patients were 19 years of age or older with a life expectancy of more than 12 weeks and a Karnofsky performance status of at least 70% or an Eastern Cooperative Oncology Group or Zubrod level of one or lower, who were scheduled to undergo curative surgery. Patients were sequentially enrolled into each dosing group and 2-5 days before surgery, patients were intravenously infused with 100 mg of unlabelled panitumumab followed by 25 mg, 50 mg, or 75 mg of the near-infrared fluorescently labelled antibody (panitumumab-IRDye800CW). The primary endpoint was to determine the optimal dose of panitumumab-IRDye800CW in identifying pancreatic ductal adenocarcinomas as measured by tumour-to-background ratio in all patients. The tumour-to-background ratio was defined as the fluorescence signal of the tumour divided by the fluorescence signal of the surrounding healthy tissue. The dose-finding part of this study has been completed. This study is registered with ClinicalTrials.gov, NCT03384238. Between April, 2018, and July, 2019, 16 patients were screened for enrolment onto the study. Of the 16 screened patients, two (12%) patients withdrew from the study and three (19%) were not eligible; 11 (69%) patients completed the trial, all of whom were clinically diagnosed with pancreatic ductal adenocarcinoma. The mean tumour-to-background ratio of primary tumours was 3·0 (SD 0·5) in the 25 mg group, 4·0 (SD 0·6) in the 50 mg group, and 3·7 (SD 0·4) in the 75 mg group; the optimal dose was identified as 50 mg. Intraoperatively, near-infrared fluorescence imaging provided enhanced visualisation of the primary tumours, metastatic lymph nodes, and small (<2 mm) peritoneal metastasis. Intravenous administration of panitumumab-IRDye800CW at the doses of 25 mg, 50 mg, and 75 mg did not result in any grade 3 or higher adverse events. There were no serious adverse events attributed to panitumumab-IRDye800CW, although four possibly related adverse events (grade 1 and 2) were reported in four patients. To our knowledge, this study presents the first clinical use of panitumumab-IRDye800CW for detecting pancreatic ductal adenocarcinomas and shows that panitumumab-IRDye800CW is safe and feasible to use during pancreatic cancer surgery. Tumour-specific intraoperative imaging might have added value for treatment of patients with pancreatic ductal adenocarcinomas through improved patient selection and enhanced visualisation of surgical margins, metastatic lymph nodes, and distant metastasis. National Institutes of Health and the Netherlands Organization for Scientific Research.

First-in-human study of the cancer peptide vaccine, TAS0313, in patients with advanced solid tumors: Phase I dose-finding part results.

73 Background: TAS0313 is a cancer vaccine cocktail containing three long peptides, with a total of 12 cytotoxic T lymphocyte (CTL) epitope peptides. These peptides were derived from eight cancer-associated antigens that are highly expressed in various cancers. We report the results of a phase I part examining the tolerability, safety, potential efficacy, and immunological responses of 9 and 27 mg TAS0313 in patients (pts) with advanced solid tumors. Methods: The enrolled pts had at least one of the following HLA types: HLA-A*02:01, -A*02:06, -A*02:07, -A*11:01, -A*24:02, -A*31:01, or -A*33:03. TAS0313 was subcutaneously administered on Days 1, 8, and 15 of Cycles 1 and 2 and on Day 1 of Cycle 3 or later in 21-day cycles until disease progression, or unacceptable toxicity. Tolerability was assessed in at least six pts during the first cycle. Tumor response was evaluated using RECIST v1.1. The antigen specific CTL and IgG were analyzed post treatment by blood samples. Optional serial tumor biopsies were performed for tumor infiltrating leukocyte (TIL) analysis. CTL, IgG, and TIL were measured by ELISPOT assay, Luminex assay, and IHC (CD8 positive), respectively. Results: Seventeen pts were enrolled in 9mg (n = 10) and 27mg (n = 7) groups. There was no serious adverse drug reaction (ADR) in any patient. All ADRs were of grade 1 or 2, with the most frequent being dermatological injection site reaction, in 7/10 (70%) and 6/7 (86%) pts and pyrexia, in 1/10 (10%) and 2/7 (29%) for the 9 and 27mg groups, respectively. The best overall response was stable disease, in 2/10 (20%) and 2/7 (28%) pts. One patient with cancer of unknown origin received prolonged administration (over 10 months) of the 9mg dose. Increment of CTL and IgG by treatment were detected in 9 and 27mg groups. TIL counts were increased in 2/3(67%) and 3/4(75%) in 9 and 27mg groups compared with pre-treatment samples, respectively. Conclusions: TAS0313 demonstrated safety, tolerability, and immunological responses in pts with advanced solid tumors in the 9 and 27mg groups. A phase II part, evaluating the efficacy of combination therapy with pembrolizumab in pts with urothelial carcinoma and monotherapy in glioblastoma pts, is currently underway. Clinical trial information: JapicCTI-183824.

Romiplostim in patients with refractory aplastic anaemia previously treated with immunosuppressive therapy: a dose-finding and long-term treatment phase 2 trial

Aplastic anaemia is a rare, life-threatening condition, characterised by pancytopenia with hypocellular bone marrow. Haematopoietic stem cells and most progenitor cells express thrombopoietin receptor (c-MPL). Romiplostim is a peptibody with c-MPL agonist activity that stimulates endogenous thrombopoietin production and leads to promoting the proliferation and differentiation of megakaryocytes in the bone marrow. In this phase 2 trial we aimed to assess the activity and safety of romiplostim in patients with aplastic anaemia who were previously treated with immunosuppressive therapy. We did an open-label, phase 2 study including a randomised, parallel, dose-finding part followed by an extension part to evaluate long-term treatment at two clinical centres in Seoul, South Korea. Eligible patients were aged 19 years or older, and had aplastic anaemia confirmed by bone marrow and cytogenetic studies and thrombocytopenia (platelet count ≤30 × 109/L), an Eastern Cooperative Oncology Group performance status score of 2 or lower, and were previously treated with immunosuppressive therapy, including at least one course of antithymocyte globulin plus cyclosporin. In the dose-finding part, patients were randomly assigned to fixed dose cohorts (1, 3, 6, or 10 μg/kg) of subcutaneous romiplostim once weekly for 8 weeks, according to a static allocation procedure after stratification by platelet count. In the extension part of the study, patients continued romiplostim titrated every 4 weeks in single steps (1, 3, 6, 10, 13, 16, and 20 μg/kg once weekly), depending on platelet response and safety up to 1 year (weeks 9-52). Patients who had a platelet response during weeks 46-53 continued dose titration in single steps (3, 6, 10, 13, 16, and 20 μg/kg once weekly) for an additional 2 years (weeks 53-156). The primary endpoint was the proportion of patients achieving a platelet response at week 9 (after completion of the dose-finding part). Activity was assessed per-protocol in all patients evaluable for response at week 9 and safety was assessed in all patients who received at least one dose of romiplostim. This trial is registered with ClinicalTrials.gov, NCT02094417. Between April 14 and Nov 24, 2014, 35 patients were enrolled and randomly assigned to one of four dose cohorts: romiplostim 1 μg/kg (n=7), 3 μg/kg (n=9), 6 μg/kg (n=9), and 10 μg/kg (n=10). Data cutoff for this final analysis was on April 14, 2018. The median duration of treatment for all patients was 53 weeks (IQR 35-155). Ten (30%) of 33 evaluable patients achieved a platelet response at week 9, including seven (70%) of ten patients in the 10 μg/kg cohort, three (33%) of nine patients in the 6 μg/kg cohort, and no patients in both the 3 μg/kg and 1 μg/kg cohorts. During the extension study, 18 (55%) of 33 evaluable patients had a platelet response during weeks 46-53 and were eligible for continued treatment. Ten (30%) patients maintained a platelet response at 2 and 3 years, of whom nine had an erythroid response and five a neutrophil response, and completed protocol treatment. Treatment-related adverse events occurred in three (9%) of 35 patients, including grade 1 or 2 myalgia, fatigue, and dizziness. 17 (49%) of 35 patients had adverse events of grade 3 or higher; seven (20%) had serious adverse events (one event of febrile neutropenia, cataract, retinal detachment, macular fibrosis, inguinal hernia, appendicitis, cellulitis, tendon injury, and transfusion reaction); and one patient died from sepsis during treatment; none of these events were related to treatment. No patients developed clonal evolution. Romiplostim seems to be active and has a favourable safety profile in patients with refractory aplastic anaemia. 10 μg/kg once weekly might be used as a recommended starting dose in future studies. These findings warrant further investigation. Kyowa Hakko Kirin Korea.

First-in-human (FIH) phase 1 (Ph1) study of MORAb-202 in patients (pts) with advanced folate receptor alpha (FRA)-positive solid tumors.

5544 Background: MORAb-202 is an antibody drug conjugate consisting of farletuzumab (a humanized monoclonal antibody that binds to FRA) paired with a cathepsin B-cleavable linker to eribulin mesylate (a microtubule dynamics inhibitor). We report preliminary results from a FIH Ph1 study of MORAb-202 in pts with FRA-positive solid tumors. Methods: This open-label, ongoing, FIH study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, maximum tolerated dose, and/or the recommended dose of MORAb-202 (Part 1: Dose finding part with accelerated modified toxicity probability interval design; Part 2: Expansion part). Eligible pts had FRA-positive solid tumors who failed standard therapy and an ECOG PS of ≤1. MORAb-202 was administered by intravenous injection once every 3 weeks and dose-limiting toxicities (DLTs) were assessed during the first 21-day cycle. Efficacy endpoints were assessed with RECIST v1.1 by investigator assessment. Results: As of Nov 16, 2018, 16 pts with confirmed FRA-positive tumors were enrolled and treated with MORAb-202 across 4 dose levels in Part 1 (0.3mg/kg: n = 3 [2 endometrial and 1 ovarian], 0.45mg/kg: n = 3 [3 ovarian], 0.68mg/kg: n = 3 [1 NSCLC, 1 ovarian, and 1 TNBC], 0.9mg/kg: n = 7 [4 ovarian, 1 endometrial, 1 NSCLC, and 1 TNBC]); all completed &gt; 1 cycle. One pt in the 0.9mg/kg cohort experienced DLTs of alanine aminotransferase increased (grade 3) and gamma-glutamyl transferase increased (grade 3). Treatment-emergent adverse events (TEAEs) occurred in 15 pts (93.8%). The most common TEAEs were leukopenia and neutropenia (50% each). The objective response rate based on RECIST v1.1 was 37.5% (6/16 pts) in Part 1 with 1 complete response (ovarian) at 0.9mg/kg and 5 partial responses including 2 pts (both ovarian) at 0.9mg/kg, 1 pt (endometrial) at 0.3mg/kg, and 2 pts (1 TNBC and 1 NSCLC) at 0.68mg/kg. The disease control rate was 75% (12/16 pts). Exposure to MORAb-202 was dose proportional across the dose range investigated. Conclusions: MORAb-202 escalation to 0.9mg/kg was manageable with encouraging initial antitumor activity in pts with FRA-positive solid tumors. Clinical trial information: NCT03386942.

PHASE I/II STUDY OF BRENTUXIMAB VEDOTIN IN REFRACTORY/RELAPSED HODGKIN LYMPHOMA PATIENTS TREATED BY CHEMOTHERAPY (ICE) IN SECOND LINE BEFORE AUTOLOGOUS TRANSPLANTATION.

Introduction: About 10–15% of patients with localized and 25–30% with disseminated classical HL failed to respond or relapse after primary conventional treatment. Autologous stem cell transplantation (ASCT) is a standard of care after salvage chemotherapy leading to an increased disease free survival (DFS). With this strategy approximately 60% to 80% of patients proved to be chemo sensitive become eligible for ASCT. As the disease status before ASCT appears to be the most important factor predicting outcome, second line chemotherapy has to be more efficient. Brentuximab-Vedotin (BV), a CD30-directed antibody conjugated to the highly potent anti-microtubule agent monomethyl auristatin E (MMAE), has shown significant activity in a phase II single arm, open label, multicenter pivotal study (SG035-0003) in patients with relapsed or refractory HL, of whom 71% had primarily refractory disease. Given the above, it seems to be logical and feasible to use BV in patients treated with ICE before auto SCT to induce a significantly higher (metabolic) CR rate, as judged by FDG-PET negativity. Otherwise, Moskowitz et al. have reported that negativity of FDG-PET improves EFS (>80% compared with 28.9% for those patients with improvement of CT but with persistent PET positivity). Methods: In order to increase the complete response (CR) rate judged by FDG-PET in patients with primary refractory or first relapse cHL, we added Brentuximab Vedotin to ICE (Ifosfamide, carboplatine, and etoposide) chemotherapy (ICE-BV). In the first dose-finding part of the study (phase I), the optimal dose of BV with ICE (3 cycles) will be established. In the second part the efficacy of BV with ICE will be assessed at the fixed optimal dose level of both BV and ICE. Results: Phase I study was activated in 5 centers of the LYSA group and 10 patients have already been enrolled. Patients received 3 cycles of ICE-BV and one cycle of BV before ASCT. Three patients were enrolled in the first cohort, BV: 1.2 mg/kg and 7 patients in cohort two (BV: 1.8 mg/kg). Clinical characteristics at inclusion were median age: 29.5 years (range: 22–55), sex ratio (M/F): 6/4, and status of the disease: refractory: 3 patients and relapse: 7 patients. Efficacy and toxicity are currently analyzed. Conclusion: The first part of ICE-BV before ASCT in R/R HL patients has been completed. Phase II will start after the validation of BV dose by the Independent Data Monitoring Committee (IDMC). Keywords: brentuximab vedotin; classical Hodgkin lymphoma (cHL); ICE.

Phase I/II study of durvalumab (anti–PD-L1 antibody) as monotherapy and in combination in patients with lymphoma or chronic lymphocytic leukemia.

TPS7574 Background: The PD-1/PD-L1 pathway is an important immune checkpoint used by tumor cells to evade immune cell detection and inhibit antitumor responses. PD-1/PD-L1 expression in multiple hematologic malignancies may provide an effective target for enhancing anticancer immune response. Durvalumab (MEDI4736) is a high-affinity human IgG1 monoclonal Ab that selectively blocks PD-L1 binding to PD-1 and CD80, and has shown preliminary evidence of antitumor activity across multiple tumor types. Study objectives are to evaluate durvalumab monotherapy and combinations to determine dose and safety, as well as identify histologies and combinations that show the best complementary antitumor signals for future study. Methods: This is a phase I/II open-label, global, multicenter study of durvalumab as a monotherapy and in combination in relapsed/refractory B-cell lymphoma or CLL (MEDI4736-NHL-001; EUDRA CT 2015-003516-21; NCT02733042). Patients must have histologically-confirmed FL, MCL, splenic or nodal MZL, T-cell/histiocyte rich BCL, PMBCL, ALK+ large BCL, transformed large BCL, Richter’s transformation, DLBCL (NOS), CLL/SLL, or classical HL during the dose-finding part. Inclusion criteria are ECOG PS 0-2, and ≥1 prior antilymphoma therapy. Up to 253 patients may enroll in 4 treatment arms, which include fixed-dose durvalumab 1500 mg Q4W monotherapy or combinations with lenalidomide/rituximab, ibrutinib, or bendamustine/rituximab. The study has 3 parts: dose finding, dose confirmation, and dose expansion. The monotherapy arm does not have a dose finding or expansion part; upon progression, patients may receive combination therapy or involved-field radiation to a single nodal site (evaluating for systemic abscopal antitumor effect). Primary endpoints are safety, identification of recommended phase II dose (phase I, 3+3 design), and overall response rate (ORR; phase II); secondary endpoints include DOR, PFS, and PK/PD. ORR is measured by 2014 IWG criteria for lymphoma or modified 2008 iwCLL criteria for CLL; safety is assessed per NCI CTCAE v4.03 criteria. Recruitment is ongoing, with a target enrollment of 253 patients across 60-80 centers globally. Clinical trial information: NCT02733042.

Single-agent dose-finding cohort of a phase 1/2 study of lenvatinib (LEN) in children and adolescents with refractory or relapsed solid tumors.

10544 Background: LEN is an inhibitor of vascular endothelial growth factor (VEGF) receptors 1‒3, fibroblast growth factor receptors 1‒4, platelet-derived growth factor receptor α, RET, and KIT. LEN is approved in adults for radioiodine-refractory differentiated thyroid cancer (DTC) and in combination with everolimus in patients (pts) with advanced renal cell carcinoma. We show results from the single-agent LEN dose-finding part of a phase 1/2 study in children and adolescents with solid tumors. Methods: Pts had any relapsed or refractory solid tumor, evaluable or measurable disease, were aged 2 to ≤18 years, had &lt; 2 prior VEGF-targeted therapies, and adequate organ function. A starting dose of LEN 11 mg/m2was escalated with a time-to-event continual reassessment method. The primary endpoint was to determine the LEN recommended dose (RD). Secondary objectives included best overall response (BOR), objective response rate, safety, and pharmacokinetics (PK). Results: 23 pts enrolled (11 mg/m2: n = 5, 14 mg/m2: n = 11, 17 mg/m2: n = 7). The most common tumors were rhabdomyosarcoma (n = 5), Ewing sarcoma (n = 4), and neuroblastoma (n = 3). 3 Dose-limiting toxicities occurred in cycle 1 at 14 mg/m2 (increased alanine aminotransferase: 1; hypertension: 2). All pts had any-grade treatment-emergent adverse events (TEAEs; grade 3/4: 65%). Most common any-grade TEAEs were vomiting (52%), abdominal pain (48%), decreased appetite (48%), diarrhea (44%), and hypothyroidism (44%). 1 Pt discontinued LEN due to a LEN-related TEAE (hypertension). BOR was stable disease (n = 10). Effect of age on oral clearance and central volume of distribution was not significant. Exposure was similar to that in adults. LEN 14 mg/m2/day was therefore identified as the RD. Updated cohort 1 data will be shown. Conclusions: The LEN RD in children and adolescents was similar to the adult dose and showed a reasonable safety profile. PK in these pts did not differ significantly from that in adults. The phase 1b dose-finding study of LEN in combination with chemotherapy in osteosarcoma (OS) and phase 2 LEN monotherapy (RD 14 mg/m2) parts in DTC and OS are ongoing. Clinical trial information: NCT02432274.

A first in human phase I study of AZD8186, a potent and selective inhibitor of PI3K in patients with advanced solid tumours as monotherapy and in combination with the dual mTORC1/2 inhibitor vistusertib (AZD2014) or abiraterone acetate.

2570 Background: Loss of PTEN function leads to increased PI3Kβ signalling. AZD8186 (AZD) exhibits significant anti-tumour activity in PTEN-deficient preclinical models, particularly when combined with anti-androgens or the dual mTORC1/2 inhibitor vistusertib (AZD2014). Here we report on the dose-finding part of this Phase 1 study. Methods: AZD single agent was administered twice daily (BD) in 3 different schedules (5 days on/ 2 days off, 2 days on/ 5 days off and continuous). Escalating doses of AZD were evaluated in cohorts of 3-6 patients treated until progression, unacceptable toxicity, or consent withdrawal. Accrual is ongoing in the combination arms with vistusertib or abiraterone acetate. Results: As of 16 Jan 2017, 87 patients have received AZD at doses of 30–360 mg BD, with 28 confirmed as PTEN deficient (IHC). The selected RP2D for the 5 days on/2 days off monotherapy schedule is 60 mg BD. PK parameters show that systemic exposures to AZD and its major active metabolite increase in a dose proportional manner. 69 serious adverse events (SAEs) were reported in 31 patients on AZD monotherapy with 23 SAEs considered possibly related to AZD. In the 5/2 schedule: 5 dose limiting toxicities (G3 rash with ≥G2 fever and/or chills) were observed in 5 patients at doses of 120-360mg. Adverse events ≥G1 in &gt; 20% included diarrhoea, nausea, fatigue, LFT elevations and decreased appetite. 20 patients remained on study for &gt; 100 days. Dose-dependent target inhibition has been demonstrated in surrogate tissue (platelets). Evaluation of direct tumour target engagement in paired biopsies is currently ongoing. Preliminary efficacy: Confirmed PRs seen in a CRPC patient (BRCA2 and androgen receptor mutant) treated in combination with vistusertib (on study for 411 days) and in one ongoing monotherapy PTEN-deficient colorectal cancer patient (on study &gt; 329 days). Updated data will be presented. Conclusions: AZD has potential for treatment of PTEN-deficient tumours. Investigation of the safety/tolerability and preliminary efficacy in combination with vistusertib or abiraterone acetate is continuing. Clinical trial information: NCT01884285.

SC05.02 Novel Cytotoxic Drugs in Lung Cancer

Even in the era of precision medicine and immunotherapy, cytotoxic chemotherapies remain an essential component of lung cancer treatment, both in resectable disease as well as in advanced/metastatic lung cancer. We have chosen to focus on 2 new cytotoxic compounds, which are likely to emerge as new players in the field of lung cancer management. One (named PM1183) has activity in small-cell lung cancer (SCLC), the other TAS-114 has activity in non-small cell lung cancer (NSCLC). PM1183 is a DNA-binding chemotherapy with a new mechanism of action. PM1183 acts as an inhibitor of transcription. Binding of PM1183 to CG-rich motifs, triggers sequential phosphorylation of Pol II and stalling of elongating Pol II. This leads to recruitment of the ubiquitin-proteasome machinery, RNA Pol II degradation, and recruitment of XPF, generation of DNA breaks and induction of apoptosis. PM1183 has been tested in a phase IB trial in combination with doxorubicine. In the dose-finding part: recommended dose (RD) was defined at PM1183 4.0 mg flat dose (FD) or 2.0 mg/m2 + DOX 50 mg/m2 both on day (D)1 every three weeks (q3w). Myelosuppression was dose-limiting (DLT). Compelling activity was observed during escalation phase. It was especially remarkable as 2nd line in SCLC patients: 5 of 7 evaluable pts (71%) had objective partial response (PR) as per RECIST v.1.1. In an expansion cohort of 20 patients, PM1183 and DOX showed outstanding clinical activity: 67% response rate, including 10% of CRs, as 2nd line treatment in SCLC patients. A randomized phase III trial testing PM1183 + DOX is planned and will compare this combination with topotecan or CAV. TAS-114 is a first-in-class oral deoxyuridine triphosphatase (dUTPase) inhibitor that acts as a modulator of the pyrimidine nucleotide metabolic pathway by blocking the conversion of 2’-deoxyuridine-5’-triphosphate (dUTP; FdUTP) into 2’-deoxyuridine-5’-monophophate (dUMP; FdUMP) through reversible inhibition of dUTPase (gatekeeper protein), resulting in the enhanced incorporation of both uracil and fluorouracil into DNA. The activity of TAS-114, administered in combination with thymidine synthase (TS) inhibitors, 5-FU, S-1 or capecitabine, has been studied pre-clinically in various cancer cell lines and animal models. TAS-114 selectively inhibited dUTPase and showed a higher affinity than the substrates of dUTPase, dUTP and FdUTP, inhibition constant values of TAS-114 were 0.13 μM and 0.10 μM, respectively. The antitumor effect of TAS-114 combined with S-1 as compared to that of S-1 alone was investigated in vivo using a xenograft mouse model with NCI-H2228 (human NSCLC). Both regimens were administered orally (TAS-114: 600 mg/kg/day and S-1: 8.3 mg/kg/day vs S-1: 8.3 mg/kg/day through day 1 to 28) and resulted in relative tumor volumes of 1.61% vs 3.04%, p<0.01, inhibition rates of 52.7% vs 10.8%, and body weight changes of 6.8% vs 3.3%, respectively. A phase 1 clinical study of TAS-114 and S-1 combination treatment is currently ongoing to investigate the safety and to determine the maximum-tolerated dose (MTD) and recommended dose (RD) in patients (pts) with advanced refractory solid tumors. TAS-114 and S-1 are administrated orally twice a day for 14 days followed by 7 days resting period for a 21-days cycle at the starting dosage of 5 mg/m2 with the fixed dosage of 25 mg/m2, respectively. To date, a total of 96 pts were enrolled with 37 pts in the dose escalation and 59 pts in the MTD expansion stages. TAS-114 and S-1 were escalated up to 240 mg/m2 and 36 mg/m2, respectively, with 2 DLTs observed at the highest dose level (1 patient with G3 rash and 1 patient with G2 rash/G2 HFS), therefore TAS-114 at 240 mg/m2 and S-1 at 30 mg/m2 was determined to be the MTD and RD. The most common treatment related adverse events were anemia and rash. There were 4 confirmed partial responses observed in 2 non-small cell lung (NSCLC) pts, 1 pancreas pt and 1 colorectal cancer patient to date. Amongst 6 evaluable NSCLC pts to date, there was an overall response rate of 33% (2/6) with 2 confirmed PR and a disease control rate of 100% (6/6). Pharmacodynamics analysis performed on patient tumor specimens treated at MTD indicated TAS-114 target engagement by reductions in the amount of intra-tumoral dUMP, a “surrogate” metabolite indicative of dUTPase inhibition, following TAS-114/S-1 combination as compared to S-1 alone administration. When TAS-114 is administered in combination with S-1, an additional cytocidal antitumor effect to TTP depletion by TS inhibition is expected as TAS-114 inhibits a gatekeeper protein, thereby allowing increased DNA incorporation of both uracil and 5-FU resulting in DNA damage. new cytotoxics, small-cell lung cancer, non-small cell lung cancer

Bortezomib (Velcade), Thalidomide, Dexamethasone and Panobinostat (VTD-P) Is a Safe, Well Tolerated and Efficacious Regimen for Patients with Relapsed Multiple Myeloma: Preliminary Results of the Muk-Six Trial

Introduction: VTD is an effective regimen for patients with multiple myeloma and forms a backbone for the addition of novel agents. The MUK-six trial aimed to improve the efficacy by adding Panobinostat, a now FDA approved pan-histone deacetylase inhibitor that demonstrated synergy with proteasome inhibition and immunomodulatory agents in pre-clinical models. We have previously reported the phase 1 dose finding part which determined the MTD of panobinostat with VTD to be 20mg. Here we present the efficacy results from the recommended dose (RD) expansion phase (primary end point) and safety, tolerability data for all patients during the induction phase of the study.Methods: MUK-six was a multi-centre UK Phase I/IIa trial for patients with relapsed and relapsed/ refractory myeloma who had received between 1 and 4 prior lines of therapy. Subjects received VTD-P (bortezomib 1.3mg/2sc days 1 and 8, thalidomide 100mg daily (50mg if pre-existing neuropathy), dexamethasone 20mg days 1, 2, 8, 9 and panobinostat 20mg days 1, 3, 5, 8, 10, 12) every 3 weeks for up to 16 cycles (induction) followed by 1 year of panobinostat maintenance. Those planned for autologous stem cell transplantation (ASCT) received a minimum of 6 cycles of VTD-P. All patients treated with VTD-P received venous thrombosis prophylaxis as per institutional practice. Responses were assessed using modified IWG uniform response criteria and toxicity graded by CTCAE V4.0.Results: 46 patients were treated at the RD and were of a median age of 60 years (41-76). 80.4% had received one prior line of therapy (range 1-4), 71.7% had prior bortezomib and 39.2% prior thalidomide. Most patients were ISS 1 (60.9%), 45.7% had adverse FISH lesions at baseline, 8.7% had 17p deletion. 6 patients remain on treatment at the time of this abstract. 51.3% of patients came off study to proceed to ASCT.The overall response rate (≥PR) for patients receiving at least one dose of panobinostat was 91.3%, ≥VGPR 45.7% (CR 6.5%, VGPR 39.1%, PR 45.7%). The ≥VGPR rate for those with standard FISH was 52.1% vs 42.9% for adverse FISH. Those treated at first relapse had higher overall responses to those treated later in their disease course (≥PR 94.6% vs 77.8%). Responses were independent of prior bortezomib exposure (≥PR 90.9%, ≥VGPR 45.5% vs PR≥92.3%, ≥VGPR 46.2%).Treatment was generally well tolerated, with a mean panobinostat dose of 17.4mg (86.8% of the RD) delivered across all cycles. 32.1% of those starting at 50mg thalidomide stopped the drug due to toxicity, and 52.6% of those starting at 100mg required dose reductions/stopping. 46 serious adverse events were reported in 27 patients which were mainly infections (17/46, 37.0%). The commonest grade 3-4 toxicities reported for all 57 patients were: neutropenia (14, 24.6%), hypophosphatemia (11, 19.3%), thrombocytopenia (8, 14.1%) and diarrhoea (6, 10.5%). Of note there were no reports of ≥ grade 3 neuropathy. The most frequent grade 1-2 toxicities were fatigue (50, 87.7%), neuropathy (43, 75.5%), constipation (35, 61.4%), diarrhoea (35, 61.4%), bone pain (33, 57.9%), and nausea (27, 47.4%). 2 patients withdrew consent due to toxicity.Conclusions: This study demonstrated that panobinostat can be safely given in combination with VTD and appears highly effective with a response rate of 91.3%, ≥VGPR 45.6% despite 72% having previous bortezomib. This regimen was well tolerated, in particular the incidence of diarrhoea, neuropathy and asthenia/fatigue appeared lower than that observed in the PANORAMA 2 trial (San Miguel et al., 2014). It is possible that the incorporation of a low intensity subcutaneous bortezomib schedule (2 doses every 3 weeks) contributed to the lesser toxicity.Acknowledgments: This trial was part of the Myeloma UK Clinical Trial Network, ISRCTN: 59395590. DisclosuresPopat:Janssen: Honoraria. Off Label Use: Panobinostat: use outside of FDA licence, not yet EU approved. Kishore:Celgene: Other: Conference Sponsorship; Jazz pharma: Other: Conference Sponsorship. Oakervee:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Yong:Janssen: Honoraria; Autolous: Consultancy; Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Novartis: Consultancy. Cook:Sanofi: Consultancy, Honoraria, Speakers Bureau; Jazz Pharma: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Chugai: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cavenagh:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

A phase I study of BI 853520, an inhibitor of focal adhesion kinase (FAK), in patients with advanced or metastatic solid tumors.

2541 Background: BI 853520 is a potent and highly selective inhibitor of FAK. In the dose-finding part of this study in patients (pts) with advanced or metastatic solid tumors, the maximum tolerate...