Clinical Activity In Solid Tumors Research Articles

ARC-9: A randomized study to evaluate etrumadenant based treatment combinations in previously treated metastatic colorectal cancer (mCRC).

3508 Background: Adenosine mediated signaling via A2a and A2b receptors impairs activation, proliferation, and cytotoxic activity of effector T cells resulting in inhibition of antitumor activity. Adenosine receptor blockade may therefore enhance therapeutic efficacy of chemo/immunotherapy regimens. Etrumadenant (E) is an orally bioavailable, selective, A2a and A2b receptor antagonist that has demonstrated safety and clinical activity in solid tumors when combined with chemo/immunotherapy. ARC-9 (NCT04660812), a Phase Ib/II trial evaluating the safety and efficacy of E combined with zimberelimab (Z) (anti-PD-1 antibody), and FOLFOX/bevacizumab (bev) regimens or novel therapies in 3 cohorts of patients (pts) with mCRC. While FOLFOX rechallenge is frequently used in the management of mCRC, no prospective trials have been performed to date. Methods: Cohort B enrolled pts who previously progressed on both oxaliplatin and irinotecan containing regimens.Pts were randomized 2:1 to EZFB: E (150 mg orally [PO] once daily [QD]) + Z (240 mg intravenous [IV] once every 2 weeks [Q2W]) + mFOLFOX-6 + bev (5 mg/kg IV Q2W), or regorafenib (rego) (160 mg PO QD [days 1-21 every 4 weeks]). Pts who progressed on rego were allowed to crossover to EZFB. The primary endpoint is progression-free survival (PFS) per RECIST 1.1 and overall survival (OS) is a key secondary endpoint. Results: In Cohort B, 112 pts were randomized. Baseline characteristics are comparable between arms. As of 13 Nov 2023, with median follow-up of 20.4 months (mo), EZFB demonstrated statistically significant improvement in PFS (HR 0.27, 95% CI 0.17-0.43, p < 0.0001) and OS (HR 0.37, 95% CI 0.22-0.63, p = 0.0003) vs rego (Table). EZFB had an acceptable safety profile, consistent with the known FOLFOX/bev toxicity profile with no deaths related to study treatment in either arm. Conclusions: In this randomized phase II clinical trial, EZFBsignificantlyimproved efficacy outcomes compared to rego in refractory mCRC pts previously treated with 5-FU, oxaliplatin and irinotecan regimens with no unexpected toxicities. Further investigation of this promising regimen is warranted given the clinically meaningful PFS and OS improvement. Table Clinical trial information: NCT04660812 . [Table: see text]

Enhancing anti-AML activity of venetoclax by isoflavone ME-344 through suppression of OXPHOS and/or purine biosynthesis in vitro

Venetoclax (VEN), in combination with low dose cytarabine (AraC) or a hypomethylating agent, is FDA approved to treat acute myeloid leukemia (AML) in patients who are over the age of 75 or cannot tolerate standard chemotherapy. Despite high response rates to these therapies, most patients succumb to the disease due to relapse and/or drug resistance, providing an unmet clinical need for novel therapies to improve AML patient survival. ME-344 is a potent isoflavone with demonstrated inhibitory activity toward oxidative phosphorylation (OXPHOS) and clinical activity in solid tumors. Given that OXPHOS inhibition enhances VEN antileukemic activity against AML, we hypothesized that ME-344 could enhance the anti-AML activity of VEN. Here we report that ME-344 enhanced VEN to target AML cell lines and primary patient samples while sparing normal hematopoietic cells. Cooperative suppression of OXPHOS was detected in a subset of AML cell lines and primary patient samples. Metabolomics analysis revealed a significant reduction of purine biosynthesis metabolites by ME-344. Further, lometrexol, a purine biosynthesis inhibitor, synergistically enhanced VEN-induced apoptosis in AML cell lines. Interestingly, AML cells with acquired AraC resistance showed significantly increased purine biosynthesis metabolites and sensitivities to ME-344. Furthermore, synergy between ME-344 and VEN was preserved in these AraC-resistant AML cells. In vivo studies revealed significantly prolonged survival upon combination therapy of ME-344 and VEN in NSGS mice bearing parental or AraC-resistant MV4-11 leukemia compared to the vehicle control. This study demonstrates that ME-344 enhances VEN antileukemic activity against preclinical models of AML by suppressing OXPHOS and/or purine biosynthesis.

Human epidermal growth factor receptor 2/3 (HER2/HER3) expression in higher-grade meningioma.

e14063 Background: Meningiomas are the most frequently diagnosed primary central nervous system (CNS) tumors in adults. Although most meningiomas can be cured by resection, higher-grade lesions (CNS WHO grades 2 & 3) tend to recur, with limited systemic treatment options after exhaustion of local therapies. Antibody drug conjugates (ADCs) targeting human epidermal growth factor receptors 2 and 3 HER2/HER3) have shown remarkable clinical activity in solid tumors including breast cancer brain metastases and are under investigation in various malignancies. Methods: 64 patients with WHO grade 2 (atypical) and 3 (anaplastic) meningioma have been included. DNA methylation analysis has been performed using Illumina EPIC methylation arrays. Panel sequencing for NF2, PIK3CA, SMO, ARID1A, ARID1B, KLF4, SUFU, TERT promotor, and TRAF7 has been executed applying the Illumina NextSeq 500 platform. HER2 and HER3 expression was evaluated by immunohistochemical analysis using PATHWAY HER2 (4B5, Roche) and HER3 #12708 (Cell Signaling) antibodies on a Ventana Benchmark Ultra staining system. Results: In total, 44/64 (68.8%) patients with WHO grade 2 and 20/64 (31.2%) patients with WHO grade 3 meningioma were included. Median age at surgery was 60 years (range: 19-83), and 37/64 (57.8%) patients were female. DNA methylation classes according to the Molecular Neuropathology classifier were benign-1 in 10 (15.6%), benign-2 in 10 (15.6%), benign-3 in 4 (6.3%), intermediate-A in 26 (40.6%), intermediate-B in 4 (6.3%), and malignant in 10 (15.6%) out of 64 tumors. Weak membranous HER2 expression was observed in 1/64 (1.6%) tumor, which was categorized as WHO grade 3/intermediate-B meningioma characterized by infiltration of adjacent bone and fat tissue as well as positive Ki-67 staining of up to 39% of cells. Similarly, only one sample (1.6%) was HER3-positive which was diagnosed as WHO grade 2 tumor of methylation class benign-2, showing meningothelial morphology with elevated mitotic activity and a mutation in TRAF7. The single HER2+ as well as the HER3+ sample were from two distinct female patients. Conclusions: In our cohort, HER2 and HER3 were only infrequently expressed in a small subset of samples of different WHO grade, methylation class, and genetic background. Exploration of further targets of ADCs which are approved or under investigation in other tumors is currently ongoing.

Abstract A018: Mitazalimab (CD40 agonist) in combination with mFOLFIRINOX in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): Safety data and recommended dose for phase 2 (RP2D) from OPTIMIZE-1, a phase 1b/2 study

Abstract Mitazalimab is a human CD40 agonistic IgG1antibody being developed as cancer immunotherapy. Targeting CD40 kickstarts the cancer immunity cycle by licensing DCs leading to tumor-specific T cell priming and activation. Furthermore, in PDAC, CD40 agonism activates myeloid cells and promotes the degradation of the desmoplastic tumor stroma, improving the influx of T cells and chemotherapeutic agents into the tumor. Mitazalimab has shown to be safe and well tolerated (at doses up to 1200 μg/kg) with signs of clinical activity in solid tumors in a Phase I study (NCT02829099). Most drug related adverse events (AE) were grade 1 or 2. OPTIMIZE-1 (NCT04888312) is a phase 1b/2, open-label, multicenter study designed to evaluate safety, tolerability, and efficacy of mitazalimab in combination with mFOLFIRINOX in adults diagnosed with previously untreated mPDAC. The objective of the first (phase 1b) part of the study was to determine the RP2D of mitazalimab + mFOLFIRINOX. Mitazalimab was escalated from 450 µg/kg to 900 µg/kg following a Bayesian optimal interval design with at least 3 patients enrolled per dose level. In the first 21-day treatment cycle (Dose Limiting Toxicity assessment period), mitazalimab is administered intravenously on day 1 and 10 and mFOLFIRINOX starts on day 8. In the second and subsequent cycles, treatment follows a 14-day cycle schedule where mitazalimab is administered 2 days after mFOLFIRINOX. In part 2 of the study (phase 2), mitazalimab at the RP2D will be administered in combination with mFOLFIRINOX. Primary endpoint is RECIST-defined overall response rate. Progression-free survival and overall survival will be assessed as secondary endpoints. We report data from phase 1b (dose escalation) part of this study. As of March 9, 2022, 11 patients were treated with mitazalimab: 5 at 450 µg/kg and 6 at 900 µg/kg mitazalimab doses. One patient in the 900 µg/kg dose cohort withdrew from the trial for administrative reasons after the first mitazalimab infusion, prior to receiving mFOLFIRINOX and was not included in RP2D determination. Key baseline characteristics included: 7 female, 4 male; median age 63 (range 57-70); ECOG 0-1; median time since mPDAC diagnosis, 25 days. Mitazalimab related AEs were reported in 9/11 patients. Treatment related AEs occurring in >1 patient were fever (60%), muscle pain (50%) and fatigue (20%). At the 450 µg/kg dose, all mitazalimab related AEs were grade 1-2. At the 900 µg/kg dose, 4 patients (67%) experienced grade 1-2 mitazalimab related AEs. One patient in the 900 µg/kg dose experienced mitazalimab related grade 3 fatigue and grade 3 headache that led to treatment discontinuation after the first cycle. There were no mitazalimab related grade 4 or 5 AEs. 1/10 patients required mFOLFIRINOX dose reduction and, at the cutoff date, the range of treatment length was 1-14 weeks. Mitazalimab combined with mFOLFIRINOX is safe and well tolerated. The 900 µg/kg dose of mitazalimab was selected as the RP2D. Phase 2 of the OPTIMIZE-1 trial is currently enrolling patients. Citation Format: Jean-Luc Van Laethem, Ivan Borbath, Hans Prenen, Aurélien Lambert, Karen Geboes, Jean-Frédéric Blanc, Yago Pico de Coaña, Karin Enell-Smith, Lena Schultz, Karin Nordbladh, Peter Ellmark, Sumeet Ambarkhane, Malin Carlsson, Philippe Cassier. Mitazalimab (CD40 agonist) in combination with mFOLFIRINOX in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): Safety data and recommended dose for phase 2 (RP2D) from OPTIMIZE-1, a phase 1b/2 study [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A018.

First-in-human phase 1/1b study to evaluate sitravatinib in patients with advanced solid tumors

Sitravatinib (MGCD516), a spectrum-selective receptor tyrosine kinase inhibitor targeting TAM (TYRO3, AXL, MERTK) and split kinase family receptors, has demonstrated preclinical anti-tumor activity and modulation of tumor microenvironment. This first-in-human phase 1/1b study included sitravatinib dose exploration and anti-tumor activity evaluation in selected patients with advanced solid tumors. Primary objectives included assessment of safety, pharmacokinetics and clinical activity of sitravatinib. Secondary objectives included identifying doses for further investigation and exploring molecular markers for patient selection. In phase 1, 32 patients received 10–200 mg, while phase 1b dose expansion comprised 161 patients (150 mg n = 99, 120 mg n = 62). Maximum tolerated dose was determined as 150 mg daily. Dose-limiting toxicity was reported in 4/28 evaluable phase 1 patients (three at 200 mg, one at 80 mg). In phase 1b, 120 mg was defined as the recommended dose due to tolerability. Treatment-related adverse events (TRAEs) were experienced by 174/193 patients (90.2%); grade ≥ 3 TRAEs in 103 patients (53.4%). Most common TRAEs were diarrhea, fatigue, hypertension and nausea; TRAEs led to treatment discontinuation in 26 patients (13.5%) and death in one patient. Sitravatinib was steadily absorbed and declined from plasma with a terminal elimination half-life of 42.1–51.5 h following oral administration. Overall objective response rate was 11.8% in phase 1b, 13.2% in patients with non-small cell lung cancer (NSCLC) and 4.2% in patients with NSCLC with prior checkpoint inhibitor experience. Sitravatinib demonstrated manageable safety and modest clinical activity in solid tumors. NCT02219711 (first posted August 14, 2014).

Abstract CT248: Design and rationale of a first in human (FIH) phase 1/1b study evaluating KIN-2787, a potent and highly selective pan-RAF inhibitor, in adult patients with BRAF- and NRAS-mutation positive solid tumors

Abstract Background: BRAFV600 alterations (BRAF Class (Cl) I alterations) encode a highly active monomeric oncogenic kinase that can be targeted by approved RAF kinase inhibitors (RAFi) in patients (pts) with melanoma (MEL), NSCLC, colorectal & anaplastic thyroid cancers. Cl II and III represent molecularly distinct BRAF alterations driving dimer-dependent signaling. Cl II alterations include single nucleotide variants (SNVs), indels and gene fusions that induce BRAF homodimer formation, leading to oncogenic kinase activation. Cl III alterations, typically SNVs, are low activity alterations that promote RAF dimerization and RAS-dependent oncogenic MAPK pathway signaling. Approved BRAFi have limited clinical activity in solid tumors driven by BRAF Cl II or III alterations, highlighting the urgency to develop effective targeted therapies for these patients. Combinations of a RAFi and a MEK inhibitor (MEKi) show promising results in early clinical trials. KIN-2787 is a potent, highly selective type II pan-RAFi designed to target both monomeric & dimeric forms of the altered BRAF kinase and minimize paradoxical activation, a liability often observed with other RAFi that can adversely impact tolerability & require addition of a MEKi to suppress pathway activation. KIN-2787 has favorable pharmaceutical properties, achieves substantial systemic exposures in pre-clinical toxicology studies, & induces regressions in human cancer xenograft models driven by BRAF Cl I, II, or III alterations. Combinations of KIN-2787 with a MEKi show promising activity in preclinical models. Methods: This is a FIH, multicenter, non-randomized Ph1 study (NCT04913285) of KIN-2787 in adult pts with BRAF mutant advanced & metastatic solid tumors (AMST). KIN-2787 will be given orally bid continuously in 28-day cycles until drug intolerance or disease progression. Planned sample size is approx. 155 pts in 2 parts: Part A is a dose-escalation to MTD open to pts with AMST driven by either BRAF genomic alterations (Cl I, II or III ) or by NRAS. Part A1 assesses single agent KIN-2787; Part A2 assesses KIN-2787 in combination w/binimetinib. Part B will evaluate a selected dose of KIN-2787 in 3 cohorts of pts (MEL, NSCLC, or other AMST), each driven by BRAF Cl II or III alterations. Standard Ph1 enrollment criteria are required (ECOG PS 0-2, normal organ function, prior receipt of standard treatment or medical judgment that such is not appropriate). Pts may have measurable or evaluable disease. Key exclusion criteria include known active brain metastases, prior BRAF-, MEK-, or MAPK inhibitor therapy (unless for FDA approved indications), HBV/HCV seropositivity. Primary endpoints are safety/tolerability (Part A), and preliminary antitumor activity: objective response rate, disease control rate, duration of response, & duration of stable disease (Part B). Secondary objectives include pharmacokinetic and pharmacodynamic assessments including measures of MAPK signaling inhibition. Enrollment began in August 2022. Trial is open globally. Citation Format: Meredith McKean, Cesar A. Perez, Shumei Kato, Alexander I. Spira, Yan Xing, Hao Xie, Michael Millward, Anthony Olszanski, Ken Kobayashi, Nichol Miller, Paul Severson, Betty Tam, Caro Unger. Design and rationale of a first in human (FIH) phase 1/1b study evaluating KIN-2787, a potent and highly selective pan-RAF inhibitor, in adult patients with BRAF- and NRAS-mutation positive solid 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 CT248.

Mitazalimab in combination with mFOLFIRINOX in patients with metastatic pancreatic ductal adenocarcinoma (PDAC): Safety data from part of the OPTIMIZE-1 study.

e16237 Background: Mitazalimab is a human CD40 agonistic IgG1antibody being developed for cancer immunotherapy. Targeting CD40 kickstarts the cancer immunity cycle by licensing DCs leading to tumor-specific T cell priming and activation. Furthermore, in PDAC CD40 agonists on myeloid cells promote degradation of the desmoplastic tumor stroma, improving influx of T cells and chemotherapeutic agents into the tumor. Mitazalimab has shown to be safe and well tolerated (at doses up to 1200 μg/kg), with signs of clinical activity in solid tumors in a Phase I study (NCT02829099). Most drug related adverse events (AE) were grade 1 or 2. Methods: OPTIMIZE-1 (NCT04888312) is a Phase 1b/2, open-label, multicenter study designed to evaluate safety, tolerability, and efficacy of mitazalimab in combination with mFOLFIRINOX in adults diagnosed with previously untreated metastatic PDAC. In the first 21-day treatment cycle (Dose Limiting Toxicity (DLT) assessment period), mitazalimab is administered intravenously on day 1 and 10 and mFOLFIRINOX infusion starts on day 8. In the second and subsequent cycles, treatment follows a 14-day cycle schedule where mitazalimab is administered 2 days after mFOLFIRINOX. The primary objective of the first part of the study (Phase 1b) is to determine the recommended Phase 2 Dose (RP2D) of mitazalimab in combination with mFOLFIRINOX. Mitazalimab will be escalated from 450 µg/kg to 900 µg/kg following a Bayesian optimal interval design with at least 3 patients enrolled per dose level. A minimum of 6 patients will be evaluated at the RP2D. In Part 2 of the study, mitazalimab at the RP2D will be administered in combination with mFOLFIRINOX. The primary endpoint is RECIST-defined overall response rate. Progression-free survival and overall survival will be assessed as secondary endpoints. Here we report data from the Phase 1b (dose escalation) part of this study. Results: Five patients with histologically confirmed, previously untreated metastatic PDAC were treated at the 450 µg/kg dose level. Key baseline characteristics included: 2 female, 3 male; median age 65 (range 60-68); ECOG score of 0 or 1; median time since primary diagnosis 13 days (range 7-82). Treatment related AEs were only grade 1 or 2 (reported in 4 of 5 patients). Treatment related AEs occurring in > 1 patient were fever, muscle pain and nausea. No DLTs were reported. No patients required dose interruption/reduction with mitazalimab or mFOLFIRINOX. Two patients discontinued treatment due to disease progression and three remain on study. The study continues and patients are currently being enrolled at the 900 µg/kg mitazalimab dose in combination with mFOLFIRINOX. Conclusions: Mitazalimab at 450 µg/kg dose combined with mFOLFIRINOX is safe and well tolerated. Enrollment at the 900 µg/kg dose is ongoing for this Phase 1b/2 study. Updated data from part 1 of the study will be presented. Clinical trial information: NCT04888312.

Abstract 1533: Vδ1γδ T-cells: A unique tissue-derived, allogeneic cell therapy platform for the treatment of cancer

Abstract The treatment of cancer with adoptive cell therapy is largely limited to platforms based on circulating, patient-derived, engineered autologous αβ T cells. Although successful in some hematological malignancies, this approach comes with challenges including associated toxicities, high production costs and a requirement to gene edit cells to avoid graft vs host disease if used in an allogeneic setting. While engineered αβ T cells have shown therapeutic activity in haematological malignancies, clinical activity in solid tumors has been challenging. In contrast to αβ T cells, Vδ1 γδ T cells are a subset of innate T cells defined by expression of T cell receptors composed of a γ chain paired to a Vδ1 chain. In mice, Vδ1 γδ T cells are predominantly tissue resident where they are highly protective against a broad spectrum of carcinomas by mediating anti-tumor responses via pattern and natural cytotoxicity receptor recognition. Similarly, in humans, Vδ1 γδ T-cell predominantly reside within epithelial tissues, mediate target cell recognition that is not MHC restricted and are not allo-HLA reactive. HLA matching of patients is therefore not required for γδ T-cell adoptive cell therapies. The innate Vδ1 γδ T-cell biology which enables antigen independent tumour recognition, lack of necessity for HLA matching, and inherent migration to and residence in human tissues makes Vδ1 γδ T-cells an attractive platform for cellular therapy. We have developed a good manufacturing practice (GMP) compliant, scalable processes to isolate tissue-resident Vδ1 γδ T-cells from healthy human skin tissue. Using organotypic culture methods, the process generates a mixture of tissue resident lymphocytes that is easily cryopreservable. This frozen intermediate (termed ‘DermaPack') serves as qualified starting material for expansion and highly efficient transduction of γδ T cells to generate allogeneic ‘off-the-shelf' CAR γδ T-cell therapies for the treatment of solid tumors. CAR Vδ1 γδ T-cells show excellent recoverability and viability post cryopreservation, an activated innate phenotype and produce high levels of IFNγ and chemokines which can attract and stimulate activation of other immune effector cells like APCs and αβ T cells. Vδ1 CAR-T cells show potent cytotoxic activity against solid tumor cell lines in vitro. These data demonstrate a novel method for a unique, off the shelf CAR-T cell platform for targeting solid tumor that combines the specificity of a CAR with the innate features of tissue resident Vδ1 γδ T cells. Citation Format: Andrew Hutton, Shristi Bhandari, Mahdieh Hassanjani, Daniel Adams, Madeline Dalziel, Peter Mitchell, Ines Sa Pereira, Sean O'Farrell, Rebecca Alade, Istvan Kovacs, Michael Koslowski, Alice C. Brown, Oliver Nussbaumer. Vδ1γδ T-cells: A unique tissue-derived, allogeneic cell therapy platform for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1533.

Abstract CT034: Phase I study of WNT974 + spartalizumab in patients (pts) with advanced solid tumors

Abstract Background: WNT974, a Porcupine inhibitor, has shown evidence of Wnt pathway inhibition in clinical trials. Dysregulated Wnt signaling has been linked to immunotherapy resistance, suggesting WNT974 may act synergistically with checkpoint inhibitors. Spartalizumab is an αPD-1 mAb with demonstrated clinical activity in solid tumors. Methods: In this Phase I, open-label trial (NCT01351103) adult pts received WNT974 ± spartalizumab; here we report on the dose escalation of the combination. Eligible pts had melanoma (including uveal), lung SCC, HNSCC, esophageal SCC, cervical SCC, or TNBC. Pts with melanoma, lung SCC, or HNSCC must have had a best response of progressive disease (primary refractory) to prior αPD-1 therapy; other pts were naïve or primary refractory to prior αPD-1. WNT974 was dosed orally QD in 28-day cycles (2.5-10 mg, Days 1-8 or 1-15 of Cycles 1 or 1-4); spartalizumab was dosed IV at 400 mg Q4W. Objectives were to determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE), safety, pharmacokinetics (PK), pharmacodynamics, and activity of WNT974 + spartalizumab. Pre- and on-treatment pt samples were collected: skin samples for RT-PCR analysis of AXIN2, a marker of Wnt pathway activity; tumor samples for RNAseq of AXIN2 and immune cell markers. Results: As of Sept 2, 2019, 27 pts were enrolled: 24 discontinued (18 due to disease progression; 67%), 3 were ongoing. Most common tumor types were non-uveal melanoma (n=8), TNBC (n=7), and uveal melanoma (n=5); 63% had received prior αPD-1. PK parameters for WNT974 + spartalizumab were consistent with prior single agent data. Dose-limiting toxicities were reported in 2 pts: Grade (G) 2 spinal compression fracture that occurred in the setting of trauma and G3 arthralgia. 78% of pts experienced a treatment-related AE, the most common being hypothyroidism (19%); 4 pts (15%) had 7 suspected-related G3/4 AEs (arthralgia, atrial fibrillation, diabetes mellitus, diabetic ketoacidosis, hyperglycemia, hyponatremia, and maculopapular rash). One pt (4%) with TNBC had a partial response, 11 pts (41%) had stable disease (SD), 13 pts (48%) had progressive disease; response was unknown in 2 pts. SD was reported in 9/17 pts (53%) who were primary refractory to prior αPD-1; 4 remained on study >24 wks. All pts with uveal melanoma (n=5) had SD. Evidence of Porcupine inhibition, assessed by skin AXIN2 suppression, was detected at all dose levels studied. Pts with the largest reductions in tumor size had on-treatment increases in immune marker mRNA in tumor samples, including a pt with αPD-1 primary refractory melanoma with high baseline AXIN2 expression and 42% reduction in the sum of target lesion diameters; this pt remained on study at 48 wks at the cutoff date. Conclusions: WNT974 + spartalizumab was well tolerated; MTD/RDE have not been determined. Preliminary data suggest blocking Wnt signaling may enable response to checkpoint inhibition in some pts. Citation Format: Filip Janku, Filip de Vos, Maria de Miguel, Patrick Forde, Antoni Ribas, Misako Nagasaka, Guillem Argiles, Ana Maria Arance, Aitano Calvo, Marios Giannakis, Maritza Melendez, Jiachang Gong, Sebastian Szpakowski, Rebecca Kan, Susan E. Moody, Maja De Jonge. Phase I study of WNT974 + spartalizumab in patients (pts) with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT034.

Proteasome Inhibition Increases Interleukin‐8 Expression in Triple Negative Breast Cancer Cells, Resulting in Their Increased Survival, Proliferation, and Migration

Interleukin‐8 (IL‐8, CXCL8) is a pro‐inflammatory and pro‐angiogenic chemokine that stimulates cancer progression by inducing tumor cell proliferation, survival, and migration. IL‐8 expression is increased in many types of advanced cancers, including triple negative breast cancer (TNBC), and correlates with poor prognosis. Because no targeted therapies are currently available, and majority of TNBC patients initially responding to cytotoxic chemotherapy become drug‐resistant, development of novel therapeutic strategies is essential. Proteasome inhibition by Bortezomib (BZ; Velcade; PS‐341) and Carfilzomib (CZ), developed for its ability to inhibit transcription of NFκB‐dependent anti‐apoptotic genes, has been effective in treating hematological malignancies. By contrast, as single agents, proteasome inhibitors (PI) have failed to show a significant clinical activity in solid tumors, including TNBC, but the mechanisms are not fully understood. Here, we demonstrate that proteasome inhibition increases expression of IL‐8, resulting in increased survival, proliferation, and migration of TNBC cells. The induced IL‐8 expression is mediated by IkB kinase (IKK), and associated with an increased nuclear accumulation of p65 NFκB, and IKK‐dependent p65 recruitment to IL‐8 promoter. Inhibition of IKK activity significantly decreases proliferation, migration, and invasion of BZ‐treated TNBC cells. These results are the first to show that proteasome inhibition increases IL‐8 signaling in TNBC cells, suggesting that targeting IKK activity might increase PI effectiveness in TNBC treatment.Support or Funding InformationSponsor: Dr. Ivana Vancurova (ASBMB member ID: 32743) Funding : NIH CA202775 grant (to Dr. Ivana Vancurova)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Abstract CT009: Results of a dose- and regimen-finding Phase Ib study of HDM201 in combination with ribociclib in patients with locally advanced or metastatic liposarcoma

Abstract Background: Well-differentiated/dedifferentiated liposarcoma (WDLPS/DDLPS) is characterized by a consistent coamplification of human double minute 2 homolog (HDM2) and cyclin-dependent kinase 4 (CDK4) which inactivates the tumor suppressor pathways p53 and Rb, respectively. HDM201 is a selective inhibitor of the p53-HDM2 interaction and ribociclib is a CDK4/6 inhibitor. Preclinical studies suggested a synergy in in vitro and in vivo models of WDLPS/DDLPS and both agents have demonstrated single-agent clinical activity in solid tumors. We aim to determine the optimal dose and regimen of HDM201 + ribociclib and to assess the preliminary antitumor activity of this combination in patients (pts) with liposarcoma. Methods: In this multicenter, open-label, Phase Ib ongoing study, pts with locally advanced or metastatic liposarcoma that had unequivocally progressed on, or despite prior systemic therapy were treated orally with HDM201 + ribociclib. Three treatment regimens were explored: Regimen (Reg) 1 (HDM201 + ribociclib daily for the first 2 wks [QD 1st 2 wks] in a 4-wk cycle), Reg 4 (HDM201 every 3 wks + ribociclib QD 1st 2 wks in a 3-wk cycle), and Reg 5 (HDM201 every 4 wks + ribociclib QD 1st 2 wks in a 4-wk cycle). Results: As of Nov 21, 2017, 74 pts received HDM201 + ribociclib (Reg 1 n=26; Reg 4 n=29; Reg 5 n=19); 12 pts (6 each in Reg 4 and 5) were still receiving treatment. Ten pts (Reg 1 n=3; Reg 4 n=6; Reg 5 n=1) discontinued treatment due to adverse events (AEs) and 2 pts (1 each in Reg 4 and 5) died. The most common AE of any grade, regardless of cause, reported across regimens (Reg 1; Reg 4; Reg 5) was nausea (81%; 76%; 63%) which was mainly Grade 1/2 and not dose limiting. Common Grade 3/4 AEs regardless of cause included neutropenia (39%; 52%; 42%), thrombocytopenia (35%; 45%; 42%), anemia (27%; 17%; 21%), leukopenia (27%; 28%; 37%), and lymphopenia (15%; 14%; 21%). Dose-limiting toxicities were reported in 16 pts (2; 9; 5) and all except 1 (prolonged QT) were hematologic (including neutropenia [n=5], thrombocytopenia [n=4], febrile neutropenia, and anemia [n=2 each]). Partial responses were observed in 3 (4%) pts (2 in Reg 4; 1 in Reg 5). Stable disease was achieved by 36 (49%) pts (11 in Reg 1; 16 in Reg 4; 9 in Reg 5). The median progression-free survival (PFS) was 2.7 mo (95% confidence interval [CI]: 1.9-8.2 mo) in Reg 1, 4.8 mo (95% CI: 3.9 mo-not reached) in Reg 4, and 2.1 mo (95% CI: 1.4 mo-not reached) in Reg 5. Conclusions: HDM201 + ribociclib demonstrated a manageable safety profile and preliminary efficacy in pts with locally advanced or metastatic WDLPS/DDLPS, with hematologic toxicities being dose limiting. The median PFS in Reg 4 compares favorably with single-agent CDK4 inhibitors and, alongside a tolerable safety profile, suggests further exploration of this regimen may be warranted in Phase II studies of HDM201 + ribociclib in this patient population. Citation Format: Albiruni Abdul Razak, Sebastian Bauer, Jean-Yves Blay, Richard Quek, Cristina Suárez, Chia-Chi Lin, Marie L. Hütter-Krönke, Ricardo Cubedo, Stephane Ferretti, Christophe Meille, Ensar Halilovic, Giorgia Clementi, Maria Santos-Rosa, Nelson Guerreiro, Astrid Jullion, Claire Fabre, Antoine Italiano. Results of a dose- and regimen-finding Phase Ib study of HDM201 in combination with ribociclib in patients with locally advanced or metastatic liposarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT009.

A Phase II Study Evaluating the Combination of Nivolumab (Nivo) or Ipilimumab (Ipi) with Azacitidine in Pts with Previously Treated or Untreated Myelodysplastic Syndromes (MDS)

A Phase II Study Evaluating the Combination of Nivolumab (Nivo) or Ipilimumab (Ipi) with Azacitidine in Pts with Previously Treated or Untreated Myelodysplastic Syndromes (MDS)

Abstract 3506: Carfilzomib demonstrates antiproliferative and proapoptotic activities in preclinical triple-negative breast cancer models

Abstract BACKGROUND: The proteosome is clinically validated as a target for cancer therapeutics. Carfilzomib (CFZ) is a proteasome inhibitor that selectively and irreversibly binds to its target and has been approved in the US for treatment of relapsed and refractory multiple myeloma. Phase 1/2 studies of CFZ reported signals of clinical activity in solid tumors. The aim of this study was to investigate the activity of CFZ in triple negative breast cancer models. METHODS: A diverse panel of human triple negative breast cancer cell lines was used to investigate the anti-tumor activity of CFZ. Cell viability following CFZ treatment was assessed using MTT assay. Proliferation was monitored both with IncuCyte Zoom real-time imaging system and 3D-ON-TOP clonogenic assay. Annexin-V flow cytometry was used to measure apoptosis. Apoptotic protein levels were measured with Western blot and proteome profiler array. MCL1 and Ki67 expression were also assessed using immunocytochemistry. RESULTS: CFZ had marked anti-proliferative activity in MDA-MD231, MDA-MB468, BT20, and SUM149 TNBC cell lines, with IC50 values following 96-hour exposure from 8 nM to 25 nM by MTT assay. The anti-proliferative activity of CFZ was observed by 3D-ON-TOP clonogenic assay. The anti-proliferative activity of CFZ was also demonstrated with IncuCyte proliferation assay. Proliferation was inhibited by low nanomolar concentrations in both MDA-MB468 and BT20 cells. Western blot analysis of CFZ-treated BT20, MDA-MB231 and MDA-MB468 cells showed cleavage of poly ADP ribose polymerase (PARP) and CASPASE-3, indicative of apoptosis, and induction of microtubule-associated protein-1 light chain-3B (LC3B), indicative of autophagy. However, expression level of anti-apoptotic protein MCL1 was increased in RAS-RAF mutated cells (MDA-MB231) but not in PTEN-null MDA-MD468 cells following the treatment of CFZ. Double immune-fluorescence staining of MDA-MB231 cells following the treatment of CFZ showed higher expression of MCL1 but no change in Ki67 expression. Interestingly, a combination of CFZ and TOR kinase inhibitor (MLN0128) enhanced cleaved CASPASE3 and BIM expression with a concomitant increased induction of apoptosis (annexinV expression) in MDA-MB231 cells. CONCLUSIONS: CFZ demonstrated anti-proliferative activity in TNBC cell lines in vitro. Flow cytometric analysis of annexin V-positive cells and Western blot expression of cleaved CASPASE 3, cleaved PARP and BIM indicated that CRZ -induced TNBC cell death through an apoptosis-dependent manner. Citation Format: Mathew Larson, Jennifer H. Carlson, Yuliang Sun, Tonia Bucholz, Casey Williams, Nandini Dey, Brian Leyland-Jones, Pradip De. Carfilzomib demonstrates antiproliferative and proapoptotic activities in preclinical triple-negative breast cancer models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3506.

An Open-Label Phase II Study of Buparlisib (BKM120) in Patients with Relapsed and Refractory Diffuse Large B-Cell Lymphoma (DLBCL), Mantle Cell Lymphoma (MCL) and Follicular Lymphoma (FL)

Background: Patients (pts) with relapsed or refractory (R/R) non-Hodgkin's lymphoma (NHL), including DLBCL, MCL, and FL, have poor outcomes and few therapy options. Activation of the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway plays an important role in NHL pathogenesis. The relative expression of aberrant PI3K isoforms can change over the course of disease: for example in MCL, PI3Kd (frequently overexpressed in B-cell malignancies) is more common initially, while PI3Kα plays a more significant role in disease progression and has been identified as an escape mechanism to selective PI3Kd inhibition (Iyengar et al. 2013). Therefore, an agent that targets multiple PI3K isoforms might elicit more durable responses, particularly in later stages of disease. The oral pan-class I PI3K inhibitor buparlisib (BKM120) showed activity in DLBCL cells in vitro (decreased phosphorylation of downstream PI3K signaling effectors, reduced cell proliferation and survival (Zang et al. 2014)) and has shown clinical activity in solid tumors. This study evaluated the safety and efficacy of buparlisib in pts with R/R NHL.Methods: In this multicenter, parallel-arm, open-label, global Phase II study (NCT01693614), pts with DLBCL, MCL, or FL received buparlisib (100 mg QD) continuously until progression, intolerance, or withdrawal of consent. Key inclusion criteria were R/R disease following ≥1 prior therapy, ≥1 measurable lesion per local assessment using standard criteria (Cheson et al. 2007), and Eastern Cooperative Oncology Group (ECOG) performance status ≤2. Pts with DLBCL were eligible if they had received or were ineligible for autologous stem cell transplant (ASCT). The primary endpoint was overall response rate (ORR). Secondary endpoints were progression-free survival (PFS), duration of response, overall survival, safety, and tolerability. PI3K pathway activation status, an exploratory endpoint, was assessed by mutation analysis (PIK3CA, PTEN) and immunohistochemistry (PTEN loss) in archival tumor tissue samples. Results for the 6-month primary efficacy and safety analysis of buparlisib in pts with DLBCL and FL were previously presented (Younes et al. ASH 2014). Here, we report results for pts enrolled in the MCL cohort.Results: At this 6-month primary analysis (data cut-off, February 25, 2015), 22 pts with MCL were enrolled. The median age was 68.5 years (range 47-79 years). The median number of prior therapies was 2 (range 1-6), which included intensive combination chemoimmunotherapy regimens, radiotherapy, and/or ASCT.The median duration of exposure was 20.6 weeks (range 1.7-54.1 weeks). Overall, 17 (77.3%) pts discontinued study treatment for the following reasons: 9 (40.9%) adverse events (AEs); 5 (22.7%) disease progressions, 2 (9.1%) protocol deviations, and 1 (4.5%) physician decision. Four pts died during the study: 1 due general deterioration and 3 due to underlying disease (with 1 on-treatment death due to disease progression). The most common AEs regardless of causality were hyperglycemia (n=10 [45.5%]), and fatigue, anxiety, depression, and weight decrease (n=7 [31.8%] each). The most frequent grade 3/4 AEs were asthenia, confusional state, leukopenia, and febrile neutropenia (n=2 [9.1%] each). Abnormal laboratory values grade 3/4 included elevated levels of fasting glucose (18.2%), aspartate transaminase and alanine transaminase (4.5% each), and neutropenia (18.2%).ORR was 22.7% (95% CI, 7.8-45.4), with 1 (4.5%) complete response and 4 (18.2%) partial responses (Figure 1). Thirteen (59.1%) pts had stable disease. The disease control rate was 81.8% (95% CI, 59.7-94.8). With 7 PFS events, the median PFS was 11.3 months (95% CI, 3.8-not estimable).The estimated PFS rate at 6 months was 68.6% (95% CI, 39.8-85.7). Of the 11 pts with evaluable samples, none showed PI3K pathway activation at baseline.Conclusions: Buparlisib treatment was moderately well tolerated, had an acceptable safety profile, and elicited sustained reduction in tumor burden in pts with R/R MCL with a median PFS of 11.3 months. Despite the limited ORR (22.7%), the observed disease control with targeted inhibition of all 4 PI3K isoforms in this cohort of pts with MCL is encouraging, and warrants further exploration of buparlisib in pts with NHL. Updated results for the DLBCL and FL cohorts will be presented at this meeting. [Display omitted] DisclosuresYounes:Celgene: Honoraria; Sanofi-Aventis: Honoraria; Bayer: Honoraria; Bristol Meyer Squibb: Honoraria; Curis: Research Funding; Novartis: Research Funding; Incyte: Honoraria; Janssen: Honoraria; Takeda Millenium: Honoraria; Seattle Genetics: Honoraria, Research Funding; Johnson and Johnson: Research Funding. Salles:Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Gerecitano:AbbVie: Consultancy, Other: Advisory Board; Genentech: Consultancy, Other: Advisory Board. Herbst:Novartis: Employment. Williams:Novartis: Employment. Mukherjee:Novartis: Employment. Tavorath:Novartis: Employment, Equity Ownership.

Clinical Response to Idasanutlin (RG7388) in Acute Myeloid Leukemia Patients Is Associated with Pre-Treatment MDM2 Protein Expression in Leukemic Blasts and Leukemic Stem Cells

Introduction. Despite years of translational research and discovery, outcomes in Acute Myeloid Leukemia remain poor. The MDM2 antagonist idasanutlin has shown promising clinical activity in solid tumors and acute leukemias. Idasanutlin enhances the activity of the tumor suppressor, p53, through antagonism of MDM2:p53 interaction. Such protein:protein disruption abolishes MDM2 targeting of p53 for ubiquitination and degradation. Subsequent stabilization of the p53 protein allows it to exert tumor suppressor transcriptional regulation and induction of apoptotic pathways. Identification of patients in whom functional p53 activation drives efficacy may translate into improved outcomes for patients treated with idasanutlin.Patients and Methods. Trial NP28679 (NCT01773408) is a Phase 1/1b study evaluating idasanutlin (as monotherapy or in combination with cytarabine) in relapsed or refractory AML patients, with clinical response as the primary endpoint. To identify biomarkers of response, patients' pre-treatment peripheral blood specimens were evaluated for MDM2 protein expression levels in leukemic blasts and leukemic stem cells. Association of MDM2 percent cell positivity with clinical outcomes was evaluated using intracellular flow cytometry gated on CD45dim leukemic blasts and CD45dim/CD117+/CD34+ leukemic stem cells.Results. We observed in a proof-of-principle training data set that MDM2 expression in leukemic blasts was associated with patients more likely to exhibit Complete Remission (CR, CRp, CRi) versus Progressive Disease (PD, HI, PR) [n=61; Wilcoxon p = .0041 (AUC = .74; 95%CI[.57, .91])] TP53 mutational status alone was not tightly associated with patient response (Fisher's Exact Test p = .19 [AUC = .60; 95%CI [.52,.67.])] When MDM2 protein expression and TP53 mutational status were analyzed as co-variates, an enhanced association with patient CR was observed (AUC = .76; 95% CI [.59, .93.]) A separate group of patients treated with an optimized idasanutlin formulation was utilized as a validation set. Association of CR with MDM2 expression in blasts was also shown in this separate patient population [n=24; Wilcoxon p = .0052 (AUC = .82; 95% CI [.64, 1.00.]) Comparable results were observed for proof-of-principle and validation set analyses of response association with MDM2 protein expression in AML patients CD45dim/CD117+/CD34+ stem cell subpopulations.Conclusions. In summary, training and validation sets reveal that MDM2 protein expression in leukemic blasts and stem cells are associated with idasanutlin-induced CR in patients with AML. We will continue to monitor this potentially predictive biomarker in future randomized clinical studies of idasanutlin. On a broader level, the data presented here support the concept that leukemic blasts may be "oncogene-addicted" to MDM2 in AML, i.e. that AML tumor cells may rely on a dominant oncogene for growth and survival, such that inhibition of the function of this specific oncogene is sufficient to halt the neoplastic phenotype. Thus, the concept of oncogene addiction may apply not only to mutated kinases but also to ubiquitin ligases such as MDM2. DisclosuresReis:Roche Pharma: Employment, Equity Ownership. Jukofsky:Roche Pharma: Employment, Equity Ownership. Chen:Roche Pharma: Employment, Equity Ownership. Martinelli:BMS: Speakers Bureau; MSD: Consultancy; Roche: Consultancy; ARIAD: Consultancy; Novartis: Speakers Bureau; Pfizer: Consultancy. Zhong:Roche Pharma: Employment, Equity Ownership. So:Roche Pharma: Employment, Equity Ownership. Drummond:Baxalta: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees. Assouline:Pfizer: Consultancy; BMS: Consultancy; Novartis: Consultancy. Hashemyan:Roche Pharma: Employment, Equity Ownership. Theron:Roche Pharma: Employment, Equity Ownership. Blotner:Roche Pharma: Employment, Equity Ownership. Rueger:Roche Pharma: Employment, Equity Ownership. Middleton:Roche Pharma: Employment, Equity Ownership. Vey:Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria. Nichols:Roche Pharma: Employment, Equity Ownership. Chen:Roche Pharma: Employment, Equity Ownership. Pierceall:Roche Pharma: Employment, Equity Ownership.

Carfilzomib demonstrates broad anti-tumor activity in pre-clinical non-small cell and small cell lung cancer models.

BackgroundCarfilzomib (CFZ) is a proteasome inhibitor that selectively and irreversibly binds to its target and has been approved in the US for treatment of relapsed and refractory multiple myeloma. Phase 1B studies of CFZ reported signals of clinical activity in solid tumors, including small cell lung cancer (SCLC). The aim of this study was to investigate the activity of CFZ in lung cancer models.MethodsA diverse panel of human lung cancer cell lines and a SHP77 small cell lung cancer xenograft model were used to investigate the anti-tumor activity of CFZ.ResultsCFZ treatment inhibited both the constitutive proteasome and the immunoproteasome in lung cancer cell lines. CFZ had marked anti-proliferative activity in A549, H1993, H520, H460, and H1299 non-small cell lung cancer (NSCLC) cell lines, with IC50 values after 96 hour exposure from <1.0 nM to 36 nM. CFZ had more variable effects in the SHP77 and DMS114 SCLC cell lines, with IC50 values at 96 hours from <1 nM to 203 nM. Western blot analysis of CFZ-treated H1993 and SHP77 cells showed cleavage of poly ADP ribose polymerase (PARP) and caspase-3, indicative of apoptosis, and induction of microtubule-associated protein-1 light chain-3B (LC3B), indicative of autophagy. In SHP77 flank xenograft tumors, CFZ monotherapy inhibited tumor growth and prolonged survival, while no additive or synergistic anti-tumor efficacy was observed for CFZ + cisplatin (CDDP).ConclusionsCFZ demonstrated anti-proliferative activity in lung cancer cell lines in vitro and resulted in a significant survival advantage in mice with SHP77 SCLC xenografts, supporting further pre-clinical and clinical investigations of CFZ in NSCLC and SCLC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-014-0111-8) contains supplementary material, which is available to authorized users.

A Phase I/II, Multiple-Dose, Dose-Escalation Study of Siltuximab, an Anti-Interleukin-6 Monoclonal Antibody, in Patients with Advanced Solid Tumors

This phase I/II study evaluated safety, efficacy, and pharmacokinetics of escalating, multiple doses of siltuximab, a chimeric anti-interleukin (IL)-6 monoclonal antibody derived from a new Chinese hamster ovary (CHO) cell line in patients with advanced/refractory solid tumors. In the phase I dose-escalation cohorts, 20 patients with advanced/refractory solid tumors received siltuximab 2.8 or 5.5 mg/kg every 2 weeks or 11 or 15 mg/kg every 3 weeks intravenously (i.v.). In the phase I expansion (n = 24) and phase II cohorts (n = 40), patients with Kirsten rat sarcoma-2 (KRAS)-mutant tumors, ovarian, pancreatic, or anti-EGF receptor (EGFR) refractory/resistant non-small cell lung cancer (NSCLC), colorectal, or H&N cancer received 15 mg/kg every 3 weeks. The phase II primary efficacy endpoint was complete response, partial response, or stable disease >6 weeks. Eighty-four patients (35 colorectal, 29 ovarian, 9 pancreatic, and 11 other) received a median of three (range, 1-45) cycles. One dose-limiting toxicity occurred at 5.5 mg/kg. Common grade ≥3 adverse events were hepatic function abnormalities (15%), physical health deterioration (12%), and fatigue (11%). Ten percent of patients had siltuximab-related grade ≥3 adverse events. Neutropenia (4%) was the only possibly related adverse event grade ≥3 reported in >1 patient. Serious adverse events were reported in 42%; most were related to underlying disease. The pharmacokinetic profile of CHO-derived siltuximab appears similar to the previous cell line. No objective responses occurred; 5 of 84 patients had stable disease >6 weeks. Hemoglobin increased ≥1.5 g/dL in 33 of 47 patients. At 11 and 15 mg/kg, completely sustained C-reactive protein suppression was observed. Siltuximab monotherapy appears to be well tolerated but without clinical activity in solid tumors, including ovarian and KRAS-mutant cancers. The recommended phase II doses were 11 and 15 mg/kg every 3 weeks.

569P - Somore Trial: Combining Sorafenib (SOR) with Capecitabine (CAP) Yields Highly Encouraging Survival Results and Elevated Metabolic Response Rate in Chemorefractory Metastatic Colorectal Cancer (MCRC)

ABSTRACT Background Several phases I and II trials including mCRC and metastatic breast cancer patients have suggested an interesting clinical activity in solid tumors with a SOR-CAP combination. SoMore's aim is to assess its potential benefit in chemorefractory mCRC and the predictive value of early metabolic response (MR) on survival. Methods SoMore (EUDRACT 2010-023695-91) is a multicentric phase II in PS 0-1 chemorefractory mCRC pts. Two co-primary objectives were defined 1) to demonstrate that overall survival (OS) at 6 months is > 30% (67 pts needed to have 90% power to detect a true rate of 50% at 1-sided level 2.5%); 2) to compare OS between early PET responders and non responders (62 deaths required before analysis -on pts assessable for MR- to detect a true HR 2.5 liver uptake; size > 15 mm). Results Between February and October 2011, 92 eligible pts were recruited in 6 centers: 50 male pts (54%), ECOG PS 0/1 : 51 (55%)/41 (45%), median age of 61 years. A median of 5 treatment cycles were given (0-18 + , treatment ongoing in 11 pts). No toxic death was observed. Grade III-IV toxic reactions were reported in 53% of the pts, mainly fatigue (17%), hand-foot skin reaction (13%), diarrhea (13%). 3/81 pts stopped their treatment due to toxicity. OS rate at 6 months was 65/92 (71%, 95% CI : 61%-79%), significantly higher than 50% (p Conclusions SoMore largely met one of its primary objectives with an observed 71% OS at 6 months for this heavily pretreated mCRC population with manageable toxicity. Data about PET assessment according to mOS and PFS will likely be mature at the time of the meeting and presented if available. Disclosure All authors have declared no conflicts of interest.

Abstract 1782: Human tumor explants are better predictors of clinical trial outcome than cell line xenografts for the KSP inhibitor ARRY-520

Abstract Historically, human tumor cell line cultures and xenografts have served as standard models for identifying and optimizing anticancer drugs. Despite wide use, cell line models are poor predictors of clinical activity of drugs, particularly cytotoxics. Primary human tumor explant models have significant potential to inform clinical direction. These models have not undergone genetic drift or selection for growth in culture. Furthermore, low-passage explants retain the morphology and aspects of the tumor microenvironment reflecting the primary cancer in patients. These models further represent patients who have been treated with current chemotherapeutics. ARRY-520 is a novel kinesin spindle protein inhibitor which has been investigated in clinical studies in both solid and hematological cancers. In cell line xenografts, ARRY-520 has significant activity in solid tumors and even greater activity in hematological cell lines both in vitro and in vivo. In clinical studies, while ARRY-520 has demonstrated significant single-agent activity in multiple myeloma, activity in solid tumors has been modest. Thus, while preclinical data in hematological models has correlated with clinical activity in myeloma, the impressive solid tumor data has not translated to clinical activity in solid tumors. To probe the disparity of preclinical and clinical activity in solid tumors, we have investigated the ability of preclinical models to inform clinical success by retrospective analysis of the activity of ARRY-520 in solid tumor cell line and explant models, as compared to clinical data of this molecule in these indications. ARRY-520 shows potent activity in human tumor cell lines both in vitro, (IC50 0.5-14nM) and in vivo (50% tumor regression in 4/5 cell line xenografts CRC and PaCa including 100% regression in 2 models). By contrast, in 6 primary CRC and PaCa explants, ARRY-520 showed minimal activity (transient stable disease in 1/6 models and progressive disease in 5/6 models). Phase 1 solid tumor data on ARRY-520 was reported at ASCO 2010. In this study, 30 patients with solid tumors, treated at or above the MTD, were evaluable for response with best response of SD&amp;gt;12 weeks in 2 patients (7%). Within this study, there were 4 CRC and 3 PaCa patients, all of whom experienced progressive disease within 12 weeks of initiation. Further investigation of ARRY-520 in solid tumor explants is ongoing. Analysis of responsive and non-responsive models will be used to identify solid tumor types for further clinical development. In summary, in this study, human solid tumor explant xenografts more accurately predicted the actual clinical results from a Phase 1 solid tumor trial. These data suggest that solid tumor explant models may have significant utility in informing clinical decisions. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1782. doi:1538-7445.AM2012-1782

An open‐label, phase 2 trial of RPI.4610 (angiozyme) in the treatment of metastatic breast cancer

Serum and plasma levels of vascular endothelial growth factor (VEGF) correlate with prognosis in patients with metastatic breast cancer (MBC). VEGF binds to 2 receptors on endothelial cells, VEGFR-1 and VEGFR-2. RPI.4610 (Angiozyme0) is an antiangiogenic ribozyme targeting the VEGFR-1 mRNA. Preclinical and phase 1 studies suggested that RPI.4610 is a well-tolerated agent with clinical activity in solid tumors. The authors' trial evaluated the efficacy of RPI.4610 in the treatment of patients with progressive MBC. This phase 2, multicenter, single-arm study was designed to assess the objective response rate of RPI.4610 in patients with MBC who had experienced disease progression with at least 1 course of chemotherapy for MBC. Patients received daily subcutaneous injections of RPI.4610 100 mg/m(2) for 12 weeks. Most patients (93%) had received at least 2 lines of chemotherapy previously; 69% of patients had received at least 3 lines of chemotherapy. Median follow-up was 2.76 months (range, 0.89-36.6 months). No partial responses nor complete responses were found. Median progression-free survival was 1.41 months (95% confidence interval [CI], 1.35-1.45). The median overall survival from start of treatment was 11.89 months (95% CI, 4.11-23.66). Treatment-related adverse events (AEs) were primarily grade 1 to 2 in intensity. Most common AEs were: injection site reactions, abdominal pain, anorexia, chromaturia, constipation, dyspnea, fatigue, headache, pain at the injection site, nausea, vomiting, and fever. Although RPI.4610 demonstrated a well-tolerated safety profile, its lack of clinical efficacy precludes this drug from further development.