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Purpose: The aim of the study was to determine safety, antitumor activity, and pharmacodynamic profile of mogamulizumab, an anti-CCR4 monoclonal antibody targeting effector regulatory T cells (Treg) in combination with the checkpoint inhibitor nivolumab in patients with locally advanced or metastatic solid tumors. Patients and Methods: This was a multicenter, dose-finding (phase I), and dose expansion (phase II) study (NCT02705105) in patients with locally advanced or metastatic solid tumors. There were no dose-limiting toxicities in phase I with mogamulizumab 1 mg/kg every week for cycle 1 followed by 1 mg/kg every 2 weeks plus nivolumab 240 mg every 2 weeks intravenously, and cohort expansion occurred at this dose level. Results: All 114 patients treated with mogamulizumab 1 mg/kg plus nivolumab 240 mg in phases I (n = 4) and II (n = 110) were assessed for safety and efficacy. Mogamulizumab plus nivolumab showed acceptable safety and tolerability. Objective response rate was 10.5% [95% confidence interval (CI), 5.6–17.7; 3 complete and 9 partial responses]. Disease control rate was 36.8%. Median duration of response was 14.4 months. Median progression-free survival was 2.6 (95% CI, 2.3–3.1) months, and median overall survival was 9.5 (95% CI, 5.9–13.5) months. Conclusions: Combination of mogamulizumab with nivolumab for treatment of patients with locally advanced or metastatic solid tumors did not result in enhanced efficacy. Tolerability of mogamulizumab 1 mg/kg plus nivolumab 240 mg was acceptable.

BackgroundThe indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that, in cancer, is exploited by tumors to evade antitumor immunity. Indoximod is a small-molecule IDO pathway inhibitor that reverses the immunosuppressive effects of low tryptophan (Trp) and high kynurenine (Kyn) that result from IDO activity. In this study, indoximod was used in combination with a checkpoint inhibitor (CPI) pembrolizumab for the treatment for advanced melanoma.MethodsPatients with advanced melanoma were enrolled in a single-arm phase II clinical trial evaluating the addition of indoximod to standard of care CPI approved for melanoma. Investigators administered their choice of CPI including pembrolizumab (P), nivolumab (N), or ipilimumab (I). Indoximod was administered continuously (1200 mg orally two times per day), with concurrent CPI dosed per US Food and Drug Administration (FDA)-approved label.ResultsBetween July 2014 and July 2017, 131 patients were enrolled. (P) was used more frequently (n=114, 87%) per investigator’s choice. The efficacy evaluable population consisted of 89 patients from the phase II cohort with non-ocular melanoma who received indoximod combined with (P).The objective response rate (ORR) for the evaluable population was 51% with confirmed complete response of 20% and disease control rate of 70%. Median progression-free survival was 12.4 months (95% CI 6.4 to 24.9). The ORR for Programmed Death-Ligand 1 (PD-L1)-positive patients was 70% compared with 46% for PD-L1-negative patients. The combination was well tolerated, and side effects were similar to what was expected from single agent (P).ConclusionIn this study, the combination of indoximod and (P) was well tolerated and showed antitumor efficacy that is worth further evaluation in selected patients with advanced melanoma.

Background IDO-1 inhibitors have shown antitumor activity in combination with immunotherapeutic agents in multiple cancers. KHK2455 is a novel and selective oral IDO-1 inhibitor. KHK2455 inhibits IDO-1 apo-enzyme, with long-lasting and potent activity. Mogamulizumab is an anti-C-C chemokine receptor 4 (CCR4) monoclonal antibody that has shown synergy with KHK2455 in preclinical models. Mogamulizumab is approved in the US and EU for treatment of mycosis fungoides and Sezary syndrome. Methods In this first-in-human study, patients with advanced solid tumors received escalating oral doses of KHK2455 alone (0.3, 1, 3, 10, 30 and 100 mg once daily) for 4 weeks (Cycle 0), followed by combination with 1 mg/kg weekly of IV mogamulizumab for 4 weeks (Cycle 1), and then on Days 1 and 15 (from Cycle 2 onward) in a standard 3+3 Phase I design. Safety, tolerability, pharmacokinetics and IDO activity (kynurenine [Kyn] and tryptophan [Trp] levels and ex vivo Kyn production) were evaluated. Results Thirty-six patients were enrolled across all cohorts. One patient with lower esophageal cancer in the 100 mg cohort exhibited dose-limiting toxicity (Grade 3 gastrointestinal necrosis). The most frequent (≥10%) treatment-emergent adverse events (TEAEs) are presented in table 1. Overall numbers of TEAEs, ≥Grade 3 TEAEs, and serious TEAEs related to KHK2455 and mogamulizumab are presented in table 2. Serious KHK2455-related TEAEs included gastrointestinal necrosis (KHK2455 monotherapy), and nausea and drug eruption (combination therapy). In addition, five drug-related TEAEs in combination therapy led to discontinuation; there were no fatal outcomes related to either study drug. Plasma KHK2455 concentrations reached steady state by Day 8 (Cycle 0) and increased dose-dependently. Potent dose-dependent inhibition of IDO activity was demonstrated by plasma Kyn concentration and Kyn/Trp ratio (median inhibition 70.5% and 70.8%, respectively, at 100 mg dose on Day 15, compared to baseline) and ex vivo Kyn production (>95% inhibition at ≥10 mg KHK2455), confirming target modulation. Six of 26 evaluable patients from all dosing groups achieved durable disease stabilization (≥6 months, RECIST 1.1), and one patient with bevacizumab-resistant glioblastoma demonstrated confirmed partial response (43.5% tumor reduction over a 2-year observation period). Median overall survival was 13.4 months, with 30% of subjects surviving for 2 years or longer (figure 1). Conclusions KHK2455 in combination with mogamulizumab was well-tolerated and manageable at all doses tested, suppressed Kyn production in a dose-dependent and sustained manner, and demonstrated signals of antitumor activity. These data support the continued development of this combination. Acknowledgements Medical writing assistance was provided by Susan E. Johnson, PhD, S.E. Johnson Consulting, LLC, New Hope, PA, USA. Trial Registration NCT02867007 (www.clinicaltrials.gov) Ethics Approval This study was approved by Ethics Committees at all participating study institutions.

Background PF-06840003 is a highly selective indoleamine 2, 3-dioxygenase (IDO1) inhibitor with antitumor effects in preclinical models. This first-in-human phase 1 study evaluated safety, pharmacokinetics/pharmacodynamics, and preliminary efficacy in recurrent malignant glioma to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Methods Patients (N = 17) received oral PF-06840003 in four dose-escalation groups: 125 mg once-daily (QD; n = 2); 250 mg QD (n = 4); 250 mg twice-daily (BID; n = 3); 500 mg BID (n = 8). A modified toxicity probability interval method determined the MTD. Results Four patients experienced serious adverse events (SAEs); one with treatment-related SAEs (grade 4 alanine and aspartate aminotransferase elevations). The dose-limiting toxicity (DLT) rate at 500 mg BID was 12.5% (n = 1/8); the MTD was not reached. Following PF-06840003 dosing, median time to maximum plasma concentration for the active enantiomer PF-06840002 was 1.5–3.0 hr and mean elimination half-life was 2 to 4 hr (Cycle 1 Day 1). Urinary recovery of PF-06840002 was low (

Fedratinib, an oral selective kinase inhibitor with activity against both wild type and mutationally activated Janus kinase 2, has been approved for the treatment of adult patients with intermediate-2 or high-risk myelofibrosis by the US Food and Drug Administration. In vitro studies indicated that fedratinib was an inhibitor of several cytochrome P450 (CYP) enzymes. The primary objective of this study was to evaluate the effects of repeated doses of fedratinib on the activity of CYP2D6, CYP2C19, and CYP3A4 in patients with solid tumors using a CYP probe cocktail. An open-label, one-sequence, two-period, two-treatment crossover study was conducted. Patients were administered a single oral dose cocktail of metoprolol (100 mg), omeprazole (20 mg), and midazolam (2 mg) used as probe substrates for CYP2D6, CYP2C19, and CYP3A4 enzyme activities, respectively, without fedratinib on Day -1 or with fedratinib on Day 15. Coadministration of 500 mg once-daily doses of fedratinib for 15 days increased the mean area under the plasma concentration–time curve from time zero to infinity following a single-dose cocktail containing metoprolol (CYP2D6 substrate), omeprazole (CYP2C19 substrate), and midazolam (CYP3A4 substrate) by 1.77-fold (90% confidence interval [CI] 1.27–2.47) for metoprolol, 2.82-fold (90% CI 2.26–3.53) for omeprazole, and 3.84-fold (90% CI 2.62–5.63) for midazolam, respectively. The mean plasma Day 14/Day 1 ratio of 4β-hydroxycholesterol, an endogenous biomarker of CYP3A4 activity, was 0.59 (90% CI 0.54-0.66), suggesting a net inhibition of CYP3A4 by fedratinib. Fedratinib is a weak inhibitor of CYP2D6, and a moderate inhibitor of CYP2C19 and CYP3A4. These results serve as the basis for dose modifications of these CYP substrate drugs when co-administered with fedratinib.

Alpha-emitters are radionuclides that decay through the emission of high linear energy transfer α-particles and possess favorable pharmacologic profiles for cancer treatment. When coupled with monoclonal antibodies, peptides, small molecules, or nanoparticles, the excellent cytotoxic capability of α-particle emissions has generated a strong interest in exploring targeted α-therapy in the pre-clinical setting and more recently in clinical trials in oncology. Multiple obstacles have been overcome by researchers and clinicians to accelerate the development of targeted α-therapies, especially with the recent improvement in isotope production and purification, but also with the development of innovative strategies for optimized targeting. Numerous studies have demonstrated the in vitro and in vivo efficacy of the targeted α-therapy. Radium-223 (223Ra) dichloride (Xofigo®) is the first α-emitter to have received FDA approval for the treatment of prostate cancer with metastatic bone lesions. There is a significant increase in the number of clinical trials in oncology using several radionuclides such as Actinium-225 (225Ac), Bismuth-213 (213Bi), Lead-212 (212Pb), Astatine (211At) or Radium-223 (223Ra) assessing their safety and preliminary activity. This review will cover their therapeutic application as well as summarize the investigations that provide the foundation for further clinical development.

BACKGROUND Optimal management of progressive high-grade gliomas (HGG) is not fully defined and outcomes are poor. Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme which converts tryptophan to kynurenines, which contribute to the immunosuppresive tumor microenvironment (TME). Targeting the TME by inhibiting IDO1 is a strategy for potential improvement in survival in HGG. METHODS A phase 1/2 trial using the IDO1 inhibitor indoximod was conducted in progressive grade 3 and 4 gliomas. The phase 1 cmponent used a 3 + 3 design escalating indoximod from 600mg po BID to 1200mg po BID in conjunction with temozolomide (150 mg/m2, 5/28 days). The phase 2 component consisted of 3 cohorts: A) indoximod+temozolomide B) indoximod+temozolomide+bevacizumab (patients already on bevacizumab) C) indoximod+temozolomide+stereotactic radiosurgery (SRS). Patients were treated until progression or toxicity. RESULTS 33.3% of patients developed indoximod TEAEs. There were no dose limiting toxicities in the phase 1 component (n=12). 1200 mg BID was established as the phase 2 dose of indoximod. In the phase 2 component (n=148) PFS6 was 74% (A), 93% (B), 70% (C). Median OS was 289 days [10.3 months](A), 159 days [5.7 months](B), 285 days [10.2 months](C). Correlative study results will be available for meeting presentation. CONCLUSIONS The IDO1 inhibitor indoximod proved safe and tolerable in conjunction with temozolomide, bevacizumab, and SRS in patients with progressive HGG. There was a trend toward better survival outcomes when indoximod was combined with temozolomide alone or temozolomide+SRS.

The clinical development of cancer drugs is rapidly moving from empirical "one drug fits all" or development-by-tumor-type approaches towards more personalized treatment models. A deeper understanding of cancer and the immune system, novel technologies, and powerful analytics have fueled an increase in precision oncology approaches integrating the molecular profiles of the tumor with the clinical profile of the patient. While this approach has been successful for targeted therapies, the complex mode of action of immunotherapies will likely require integration of clinical profiling with more comprehensive profiling of the tumor, of the tumor microenvironment, and of the immune system of the patient. Integration of precision oncology into clinical research for immunotherapies is viewed as a means to better select patients in the early clinical phase of drug development to (1) maximize the benefit-to-risk ratio for the patient, (2) generate early proof of concept and proof of relevance for the investigational drug, and (3) inform on how to best combine or sequence the therapeutic with other drugs. Here we discuss the upsides and challenges of incorporating precision immuno-oncology into early-phase clinical trials.

Background: RGX-104 is a small-molecule LXR agonist that modulates innate immunity via transcriptional activation of the ApoE gene. Binding of ApoE to its receptor LRP8 robustly inhibits angiogenesis and depletes myeloid derived suppressor cells (MDSC), thereby activating cytotoxic T-lymphocytes. MDSCs are associated with resistance to both checkpoint inhibitors (CPI) and chemotherapy, providing a rationale for combination therapy with RGX-104. We previously reported results of the RGX-104 monotherapy dose escalation for which 26 patients with refractory solid tumors were treated in 5 dose cohorts. On-target AEs included hyperlipidemia and neutropenia. Flow-cytometry demonstrated MDSC depletion with associated T cell activation, which correlated with clinical benefit. A 40% disease control rate (DCR; SD+PR) was observed with a confirmed partial response (PR) by irRC (>79% reduction in index lesions) in a patient with platinum-refractory small cell lung cancer (SCLC). Methods: Here, we present the safety, biomarker and efficacy results of the docetaxel combination arm of the RGX-104 trial. Cohort 1- RGX-104 80 mg BID, and docetaxel at 35 mg/m2 days 1, 8, and 15 of a 28-day cycle; Cohort 2- RGX-104 80 mg BID, 5 days-on/2 days-off (5/2), and docetaxel at 28 mg/m2 on above schedule. Cohort 3- RGX-104 100 mg BID (5/2), and docetaxel as per cohort 2. Results: As of February 7, 2020, 11 patients with refractory solid tumors have been treated in 3 dose escalation cohorts with RGX-104 plus docetaxel. AEs were consistent with the individual toxicity profiles of docetaxel and RGX-104, with neutropenia being the most common AE and dose-limiting in cohort 1. The 5/2 dosing regimen in cohorts 2 and 3 resulted in significantly fewer episodes of neutropenia and no DLTs, while maintaining pharmacodynamic effects including >50% sustained MDSC depletion. A 66% DCR was observed in 9 evaluable patients including 2 patients in cohort 2 with PRs, a CPI-refractory SCCHN patient and a CPI-refractory melanoma patient, who remains on treatment at 36 weeks. A patient with melanoma in Cohort 3 had an initial assessment of SD and continues on study at 14 weeks. Clinical responses were associated with increases in T cell activation markers exceeding that generally observed with RGX-104 alone (up to a 5-fold increase in total CD8 T cells, a 7-fold increase in LAG-3+ CD8 T cells, and a 75-fold induction of serum IFNγ). Conclusion: The safety profile and marked pharmacodynamic and clinical activity of the RGX-104/docetaxel combination in CPI-refractory patients supports further development of this regimen. Consequently, the RGX-104/docetaxel regimen will be evaluated in a Phase 1b/2 expansion cohort in patients with relapsed/refractory ES-SCLC/high grade-neuroendocrine tumors. Citation Format: Emerson Lim, Erika P. Hamilton, Rebecca Redman, Michael A. Postow, Russell J. Schilder, Monica M. Mita, Alain C. Mita, Bartosz Chmielowski, James Strauss, Angela Jain, Shubham Pant, Olivier Rixe, Tomislav Dragovich, R. Donald Harvey, Igor Puzanov, Kevin B. Kim, Eric K. Rowinsky, Michael Szarek, Foster Gonsalves, Isabel Kurth, Celia Andreu, Robert W. Busby, David Darst, Masoud Tavazoie, Syed Raza, Narayan Lebaka16, Robert Wasserman, Gerald Falchook. RGX-104, a first-in-class immunotherapy targeting the liver-X receptor (LXR): Initial results from the phase 1b RGX-104 plus docetaxel combination dose escalation cohorts [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 CT146.

CD40 is a co-stimulatory receptor of the TNF receptor superfamily expressed on antigen presenting cells (APCs). Antibodies targeting CD40 may have therapeutic benefit via multiple mechanisms including innate immune activation that can support generation of antigen-specific, antitumor T cell responses, and binding to CD40-expressing cancer cells leading to antibody-mediated target cell killing. Multiple CD40-directed antibodies are in clinical development and differ by immunoglobulin isotype, affinity to CD40, and selectivity for FcγR-binding. These alterations could lead to differences in pharmacodynamic and antitumor activity. SEA-CD40 is an agonistic non-fucosylated, humanized IgG1 monoclonal antibody directed against CD40. SEA-CD40 has enhanced FcγRIIIa binding (~10x greater than parent IgG1 antibody) that drives increased effector function, resulting in more potent immune stimulatory activity than antibodies with muted or selective FcγR binding. The enhanced effector function of SEA-CD40 may confer greater immune stimulation and antitumor activity relative to other CD40-directed therapeutics. Preclinically, SEA-CD40 exposure results in a distinct signature of responses including activation of APCs, CD8+ and CD4+ T cells and NK cells, and targeted depletion of CD40+ B cells. SEA-CD40 demonstrates superior activity compared to other CD40-targeted antibodies in vitro and in vivo, suggesting that the enhanced effector function is critical for optimal immune cell agonism. For example, SEA-CD40 drove in vitro ADCC activity 100-fold above the parent antibody and exhibited robust ADCC with the low and high affinity FcγRIIIA genotype. At matched dose levels in cynomolgus monkeys, SEA-CD40 induced circulating cytokines and sustained B cell depletion that were up to 50-fold above that induced with the parent antibody. The SEA-CD40 signature of activation translates to increased antitumor activity as a single agent and in combination with standard of care treatments in preclinical models, suggesting the potential for beneficial combination therapy in the clinic. The SEA-CD40 immune signature was confirmed by pharmacodynamic changes in an ongoing phase 1 clinical trial in patients with relapsed/refractory metastatic solid tumors (NCT02376699). SEA-CD40 treatment induced dose-dependent increases in circulating cytokines and chemokines associated with myeloid and lymphoid immune activation and trafficking. SEA-CD40 treatment also resulted in activation of CD4+ and CD8+ T cells and CD40-targeted B cell depletion in the periphery. These findings support continued clinical evaluation of SEA-CD40. The ongoing phase 1 clinical trial is actively enrolling and includes a cohort in pancreatic cancer assessing the combination of SEA-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab. Citation Format: Haley Neff-LaFord, Juneko E. Grilley-Olson, David C. Smith, Brendan Curti, Sanjay Goel, Timothy M. Kuzel, Svetomir N. Markovic, Olivier Rixe, David L. Bajor, Thomas F. Gajewski, Martin Gutierrez, Elisabeth I. Heath, John Thompson, Sahar Ansari, Shyra Gardai, Celine Jacquemont, Michael Schmitt, Andrew L. Coveler. SEA-CD40 is a non-fucosylated anti-CD40 antibody with potent pharmacodynamic activity in preclinical models and patients 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 5535.

3505 Background: BXQ-350 is a first-in-class agent comprised of Saposin C (SapC) and dioleoyl phosphatidylserine (DOPS). SapC, a multifunctional lysosomal-activator glycoprotein that preferentially interacts with tumor cell phospholipids, has demonstrated anti-tumor effects in both in vitro and in vivo preclinical models. The tolerability and preliminary efficacy of BXQ-350 in the first-in-human study are summarized here. Methods: Eighty-six refractory solid tumor (ST) or high-grade glioma (HGG) patients age ≥18 (36F:50M, age 24-81) were enrolled in a 3-part first-in-human trial (NCT02859857) from 2016-2019 and received at least one dose of BXQ-350. Doses were administered via intravenous infusion during 28-day cycles until disease progression occurred. The previously reported part 1 dose escalation portion of the study (9 HGG, 9 ST patients) established the highest planned dose of 2.4mg/kg as safe but did not identify a maximum tolerated dose. The part 2 expansion cohort treated 37 patients (18 HGG and 19 ST) and an additional part 3 cohort treated 31 ST gastrointestinal (GI) patients, both at the 2.4 mg/kg dose level. Preliminary antitumor activity was evaluated (RECISTv1.1 or RANO). Results: There were no BXQ-350-related serious adverse events, dose limiting toxicities or withdrawals with the exception of 1 allergic type reaction. Three patients (Glioblastoma, Ependymoma, Appendiceal) demonstrated a partial response per RECIST/RANO. Two HGG patients with progressive radiologic enhancement were seen to have treatment effect at surgery, and hence considered to have stable disease. Seven patients (2 HGG, 3 GI, 2 other ST) remain on study and have received treatment for 9+ to 41+ months, with 5 patients treated for > 1 year. A continuing treatment protocol is planned in order to allow these patients to remain on BXQ-350 treatment. Conclusions: BXQ-350 was well tolerated with no significant dose-limiting toxicities at the highest planed dose level. Preliminary results indicate this novel agent demonstrated possible anti-tumor activity in refractory solid tumors and HGG. Clinical trial information: NCT03967093) .

BACKGROUND: Ependymomas are rare primary nervous system tumors accounting for about 3% of adult brain tumors in the United States. The current standard of care includes surgical resection and radiation therapy, with more than half experiencing relapse and poor outcomes. Saposin C and dioleylphosphatidylserine (SapC-DOPS) nanovesicles are a novel investigational treatment agent that can cross the blood-brain barrier and selectively target externalized phosphatidylserine that is expressed on tumor cell surfaces. METHODS: We examined a rare complex ependymoma case enrolled in the ongoing Phase 1b study of SapC-DOPS cancer-targeting agent BXQ-350 (NCT02859857). The patient received cycle 1 (BXQ-350 2.4 mg/kg IV infusion at Day 1–5, 8, 10, 12, 15, 22) and 3 additional cycles (1x28 days), and was followed until death for safety, response, RANO, and ECOG. RESULTS: A 67-year old white male with recurrent Grade III anaplastic ependymoma diagnosed 3 years before enrollment and with a history of surgical intervention exhibited measurable extra-axial (6.4x3.2 cm) and inferolateral intracranial components on MRI, accompanied by palpable skull mass. At baseline, the lesion was 6.4 x 3.2 cm with stable disease per RANO and ECOG of 1. After 2 cycles, minor decrease in size of intracranial enhancing components was reported (overall stable disease per RANO). The patient received 4 total cycles of BQX-350 without related adverse events or toxicities, and cycle 5 was withheld due to volume progression on MRI. He died 6 months post-enrollment. Post-mortem histology and gross anatomy showed extensive tumor necrosis with chondroid differentiation and gross signs of metastatic disease in the lungs, thoracic, and lumbar spine on microscopy. CONCLUSIONS: While further study of cancer-targeting SapC-DOPS nanovesicle efficacy in adult patients with ependymoma is needed, good tolerability in rare aggressive tumors was observed. The role of extensive necrosis and possibly treatment-related intracranial mass reduction supports additional investigations in this indication.

BACKGROUND: Saposin C-dioleylphosphatidylserine (SapC-DOPS) is a novel blood-brain barrier penetrant nanoliposomal agent that targets externalized phosphatidylserine overexpressed on tumor cell membranes. A recent Phase 1a BXQ-350 trial (NCT02859857) reported SapC-DOPS was well tolerated in both solid tumor and high-grade glioma (HGG) patients with potential for treating clinically challenging gliomas, including their diffuse infiltrative components. METHODS: We evaluated the HGG subset of the ongoing Phase 1 study of IV BXQ-350 administered on Days 1–5, 8, 10, 12, 15, 22 (cycle 1) and each 28 day cycles thereafter. MRI neuroimaging (e.g. Axial T1-post-contrast Ax SE T1 POST-FC and medically necessary views) at Days 29, 57, 113, and 171 (or withdrawal) were completed. RANO assessment, functional neurological deficits, ECOG Performance Status, and safety were assessed. RESULTS: The HGG patients (9/17) were dosed at 0.7 (N = 1), 1.1 (N = 1), 1.4 (N = 2), 1.8 (N = 2), or 2.4 (N = 3) mg/kg, with 8/9 completing a full cycle before withdrawal (7 due to progression, 1 voluntary withdrawal). BXQ-350 was not linked to dose limiting toxicities or severe adverse reactions. Functional neurological deficits and ECOG decline were proportional to radiological progression, with ECOG scores declining from a baseline 0–1 in 2/9 (22%) to 3. One patient completing 6 cycles (>12 months) of BXQ-350 therapy (0.7 mg/kg) exhibited stable disease, -7% lesion size, and no significant progressive functional neurological deficits. Three patients underwent surgery for progression while on treatment. CONCLUSIONS: BXQ-350 was well tolerated by GBM patients with promising best response apparent in neuroimaging, suggesting therapeutic benefit warranting further trials. Updates from the ongoing trial will be presented.

Supplemental Digital Content is available in the text., Taxane–gemcitabine combinations have demonstrated antitumor activity. This phase I study (NCT01001221) aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel plus gemcitabine and to assess the preliminary efficacy of this combination. The patients included had metastatic or unresectable solid tumors and had exhausted standard treatment. Cohorts of three to six patients received cabazitaxel (15–20 mg/m2) before (part 1a) or after (part 1b) gemcitabine (700–1000 mg/m2) on Day 1 and gemcitabine alone on Day 8. Prophylactic growth factors were not allowed in cycle 1. In part 1a (n=12), five patients received 20 mg/m2 cabazitaxel plus 1000 mg/m2 gemcitabine (20/1000), five received 15/900, two received 15/700. In part 1b, all six patients received the lowest dose (700/15). At all doses, two or more patients experienced a DLT, regardless of administration sequence, including febrile neutropenia (n=4), grade 4 neutropenia (n=2), grade 4 thrombocytopenia (n=2), and grade 3 aspartate transaminase increase (n=1). The MTD was not established as all cohorts exceeded the MTD by definition. All patients experienced an adverse event; the most frequent all-grade nonhematologic events were fatigue (66.7%), decreased appetite (50.0%), and diarrhea (44.4%). The most frequent grade 3–4 hematologic abnormalities were neutropenia (83.3%), leukopenia (77.8%), and lymphopenia (72.2%). Toxicity was sequence-independent but appeared worse with gemcitabine followed by cabazitaxel. Durable partial responses were observed in three patients (prostate cancer, appendiceal cancer, and melanoma). The unacceptable DLTs with cabazitaxel plus gemcitabine, at doses reduced more than 25% from single-agent doses, preclude further investigation.

Introduction: Based on extensive preclinical data and abundant evidence for clinical activity, vascular endothelial growth factor receptor (VEGFR) inhibitors are currently standard of care for metastatic renal cell carcinoma (mRCC). Axitinib is one of the most selective molecules in the class of anti-angiogenic agents, which confers an optimal profile between its safety and anti-cancer activity spectrum.Area covered: In this review, the authors discuss the different stages that lead to the approval of axitinib in the clinic as well as the current perspectives for its clinical use with other promising therapies in mRCC such as immune checkpoint inhibitors and vaccines.Expert opinion: In 2015, axitinib has emerged as one of the major agents used in mRCC. Based on robust preclinical data, this highly specific VEGFR inhibitor continues to be evaluated in different indications, including the adjuvant setting but also sequential administration with other molecularly targeted agents or combinations with immune t...

Cabazitaxel is primarily metabolized by CYP3A. This study evaluated the impact of moderate/strong CYP3A inhibitors [aprepitant (Study Part 2); ketoconazole (Study Part 3)] or strong CYP3A inducers [rifampin (Study Part 4)] on the pharmacokinetics of cabazitaxel.Adult patients received IV cabazitaxel/cisplatin 15/75 mg/m(2) on Day 1 of 3-week cycles (5/75 mg/m(2) in Cycles 1 and 2 of Part 3 to allow a safety margin to the cabazitaxel MTD). Patients received repeated oral doses of aprepitant, ketoconazole or rifampin before/during Cycle 2. Cabazitaxel clearance was the primary endpoint; clearance and area under the plasma concentration-time curve (AUC) were normalized to body surface area and dose, respectively.The PK population included 13 (Part 2), 23 (Part 3) and 21 patients (Part 4). Repeated aprepitant administration did not affect cabazitaxel clearance [geometric mean ratio (GMR) 0.98; 90 % confidence interval (CI) 0.80-1.19]. Repeated ketoconazole administration resulted in 20 % decrease in cabazitaxel clearance (GMR 0.80; 90 % CI 0.55-1.15), associated with 25 % increase in AUC (GMR 1.25; 90 % CI 0.86-1.81). Repeated rifampin administration resulted in 21 % increase in cabazitaxel clearance (GMR 1.21; 90 % CI 0.95-1.53), associated with 17 % decrease in AUC (GMR 0.83; 90 % CI 0.65-1.05). The GMR of AUC0-24 with rifampin administration was 1.09 (90 % CI 0.9-1.33), suggesting that rifampin had a low impact during the initial phases of cabazitaxel elimination. Safety findings were consistent with previous results.Cabazitaxel pharmacokinetics are modified by drugs strongly affecting CYP3A. Co-administration of cabazitaxel with strong CYP3A inhibitors or inducers should be avoided.

Background Whether patients with good prognosis and intermediate/poor prognosis advanced seminoma should be treated differently has not been defined. Objective To assess a risk-adapted chemotherapy regimen in patients with advanced seminoma. Design, setting, and participants A total of 132 patients were included in this prospective study. Patients with a good prognosis according to the International Germ Cell Cancer Collaboration Group (IGGCCG) were treated with four cycles of cisplatin-etoposide (EP). Patients with an intermediate prognosis according to the IGCCCG (or a poor prognosis according to the Medical Research Council classification) were treated with four cycles of VIP (EP and ifosfamide) and granulocyte colony-stimulating factor (G-CSF). Outcome measurements and statistical analysis Survival curves were estimated using the Kaplan-Meier method. Results and limitations The median follow-up was 4.5 yr (range: 0.4–11.6 yr). Among 108 patients (82%) with a good prognosis who received EP, grade 3–4 toxicity included neutropenia (47%) and neutropenic fever (12%). Among the 24 patients (18%) with an intermediate/poor prognosis who received VIP plus G-CSF, toxicity included grade 3–4 neutropenia (36%), neutropenic fever (23%), thrombocytopenia (23%), anemia (23%), and a toxicity-related death ( n =1; 4%). The 3-yr progression-free survival (PFS) rate was 93% (range: 85–97%) in the good prognosis group and 83% (range: 63–93%) in the intermediate/poor prognosis group ( p =0.03 for PFS). The 3-yr overall survival (OS) rate was 99% (range: 92–100%) and 87% (range: 67–95%), respectively ( p Conclusions A risk-adapted chemotherapy policy for advanced seminoma yielded an excellent outcome with a 3-yr OS rate of 96%.

e14141 Background: Pre clinical studies have demonstrated the effect of gut microbiome in the efficacy of immune check point inhibitors. The effect of antibiotic exposure to patients receiving PD-1/CTLA-4 inhibitor therapy has not been extensively studied, especially in metastatic melanoma. In this study, we demonstrate the effect of antibiotic exposure to metastatic melanoma patients receiving PD-1/CTLA-4 inhibitor therapy. Methods: We performed a retrospective analysis of 108 patients with stage 4 metastatic melanoma who received immunotherapy with PD-1 inhibitors or CTLA-4 inhibitors or combination of both between Nov 2010 and Oct 2017. Patients were divided into Abx(+) and Abx(-) groups that were defined as patients exposed or not exposed to antibiotics respectively. The time frame for antibiotic exposure was taken from 6 months prior to 1 month after initiation of immunotherapy. We compared progression free survival (PFS), overall survival (OS) and response rate (RR) between the two groups. RR was calculated based on the entire length of follow-up. PFS and OS were assessed using Kaplan-Meier estimates. Cox proportional hazards were used to calculate hazard ratios. Results: Out of 108 patients, 66 (61.1%) were men, with a mean age 64.6 ± 15.1 years. 46 (42.6%) patients were exposed to antibiotics of varied classes. Median PFS in abx(+) group [88 days (95%CI: 70, 104)] was shorter as compared to abx(-) group [322 days (95%CI: 191, 410), p < 0.0001)]. Patients in abx(-) group had a 68% (95%CI: 45, 82) reduced risk of progression within 200 days of immunotherapy initiation adjusting for sex, age and number of immunotherapy cycles (p < 0.0001) . Median OS in ab(+) group [294 days (95%CI: 198, 345)] was shorter as compared to abx(-) group [573 days (95%CI: 453, 677)], p < 0.0001. Response rate defined as percentage of patients whose cancer was stable or entered remission was 12.9% (95%CI: 5.7, 23.9) in abx(-) group as compared to 8.7% (95%CI: 2.4, 20.8) ab(+) group. Patients in abx(-) group had a 52% (95% CI: 24, 69) reduced risk of death adjusting for sex, age and number of immunotherapy cycles (p = 0.002). Conclusions: Antibiotic exposure is associated with poorer outcomes in patients with advanced metastatic melanoma being treated with PD-1/CTLA-4 inhibitors which is likely related to alteration of gut microbiome. Antibiotics should be prescribed with caution in patients undergoing treatment with immune check point inhibitors. These data should be validated in a larger patient population.

e13531 Background: BXQ-350 is composed of the multifunctional, lysosomal-activator protein Saposin C and phosphatidylserine lipid with demonstrated antitumor effects in vitro and in vivo. In this abstract we update the safety and pharmacokinetic (PK) profile based on an ongoing Phase 1 trial. Methods: BXQ-350 was administered in a Phase 1a dose-escalation trial (NCT02859857), and an ongoing Phase 1b trial (data cut off at max of 6 cycles, 01DEC2018) to refractory solid tumor/high-grade glioma patients (pts). In Phase 1a, pts received escalating IV BXQ-350 doses of 0.7, 1.1, 1.4, 1.8, or 2.4 mg/kg on days 1, 2, 3, 4, 5, 8, 10, 12, 15, 22 (cycle 1), 29 (cycle 2), and thereafter 28-day cycles. PK was assessed over a 24-hr period following the first dose. The Saposin C level was analyzed by ELISA and PK parameters were calculated using noncompartmental methods. Results: The 1a cohort of 18 pts (age 24-69) had a median of 3 cycles and 1b cohort of 20 pts (age 31-80) had median of 2 cycles with no treatment-related serious adverse events to date. Moderately severe related adverse events (AEs, n case, n events) are reported with serious non-related events. The most common treatment-related AE was fatigue (2 at dose 1.1, 2 at 1.8, 1 at 2.4mg/kg and 3 in 1b), at 2.4 mg/kg, 1 pt had moderate blood pressure elevation. Exposures in the 1.4 and 1.8 mg/kg cohorts were less than dose-proportional, likely due to higher clearance in those groups. The overall mean clearance and half-live values were 66.8 (mL/kg/h) and 4.03 h, respectively. Conclusions: BXQ-350 has had no serious related AEs during dose-escalation or in the on-going trial supporting a tolerable safety profile at 2.4 mg/kg. Clinical trial information: NCT02859857. [Table: see text]

Glioblastoma multiforme (GBM) is the most aggressive brain tumor in adults and remains incurable despite multimodal intensive treatment regimens including surgical resection, radiation and chemotherapy. EGFRvIII is a truncated extracellular mutant of the EGF receptor (EGFR) found in about a third of GBMs. It confers enhanced tumorigenic behavior and is associated with chemo- and radio-resistance. GBM patients testing positive for EGFRvIII have a bleaker prognosis than those who do not. Targeting EGFRvIII positive tumors via vaccines or antibody-drug-conjugates represents a new challenging therapeutic avenue with potential great clinical benefits. In this study, we developed a strategy to detect EGFRvIII deletion in the circulating tumor DNA. The overall goal is to identify a simple and robust biomarker in the peripheral blood of patients diagnosed with GBM in order to follow their disease status while on treatment. Thirteen patients were included in this study, three of which were found to carry the EGFRvIII deletion. The circulating DNA status for EGFRvIII correlates with the analysis performed on the respective tumor samples, and its level seems to correlate with the extent of the tumor resection. This semi-quantitative blood biomarker may represent a strategy to (1) screen patients for an anti-EGFRvIII therapy and (2) monitor the patients' response to treatment.

Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, approved for second-line therapy for advanced renal cell carcinoma (RCC). Axitinib population pharmacokinetic and pharmacokinetic/pharmacodynamic relationships were evaluated. Using nonlinear mixed effects modeling with pooled data from 383 healthy volunteers, 181 patients with metastatic RCC, and 26 patients with other solid tumors in 17 trials, the disposition of axitinib was best described by a 2-compartment model with first-order absorption and a lag time, with estimated mean systemic clearance (CL) of 14.6 L/h and central volume of distribution (V(c)) of 47.3 L. Of 12 covariates tested, age over 60 years and Japanese ethnicity were associated with decreased CL, whereas V(c) increased with body weight. However, the magnitude of predicted changes in exposure based on these covariates does not warrant dose adjustments. Multivariate Cox proportional hazard regression and logistic regression analyses showed that higher exposure and diastolic blood pressure were independently associated with longer progression-free and overall survivals and higher probability of partial response in metastatic RCC patients. These findings support axitinib dose titration to increase plasma exposure in patients who tolerate axitinib, and also demonstrate diastolic blood pressure as a potential marker of efficacy.

Background To determine dose-limiting toxicities (DLTs), recommended phase II trial dose (RPTD), safety, preliminary antitumour activity and pharmacokinetics of intravenous aflibercept with irinotecan, 5-fluorouracil and leucovorin (LV5FU2). Patients and methods In this open-label study, 38 patients with advanced solid tumours received aflibercept 2, 4, 5, or 6 mg/kg on day 1, then irinotecan and LV5FU2 on days 1 and 2 every 2 weeks. Results Two grade 3/4 aflibercept-associated DLTs occurred with 4 mg/kg: proteinuria lasting >2 weeks and acute nephrotic syndrome with thrombotic microangiopathy. Two DLTs with 5 mg/kg (grade 3 stomatitis and grade 3 oesophagitis reflux) and three with 6 mg/kg (febrile neutropenia, grade 3 stomatitis and grade 3 abdominal pain) were considered related to concurrent chemotherapy and underlying disease. The most common grade 3/4 adverse events were neutropenia, hypertension and diarrhoea. Nine patients had partial responses, five with 4 mg/kg. Twenty-two patients had stable disease (five with 4 mg/kg), lasting >3 months in 17 patients. No anti-aflibercept antibodies were detected. Free aflibercept was in excess of bound in most patients on 4 mg/kg. Conclusion Based on pharmacokinetics, acceptable safety and encouraging antitumour activity, aflibercept 4 mg/kg was selected as the RPTD with irinotecan and LV5FU2 every 2 weeks.

Purpose Cabazitaxel has not been studied in patients with hepatic impairment (HI). This phase I study assessed cabazitaxel safety and pharmacokinetics in patients with HI. Methods Patients with advanced, non-hematologic cancer, and normal hepatic function (Cohort 1: C-1), or mild (C-2), moderate (C-3), severe (C-4) HI received cabazitaxel starting doses of 25, 20, 10, and 10 mg/m2, respectively. Doses were escalated in patients with HI based on Cycle 1 dose-limiting toxicities (DLTs). Adverse events and the cabazitaxel pharmacokinetic profile were assessed. Results In C-2, three patients receiving cabazitaxel 25 mg/m2 experienced DLTs; maximum tolerated dose (MTD) was 20 mg/m2. In C-3, two patients receiving 20 mg/m2 experienced DLTs; MTD was 15 mg/m2. C-4 was discontinued early due to DLTs. The most frequent cabazitaxel-related, grade 3–4 toxicity was neutropenia (42%). Cabazitaxel clearance normalized to body surface area (CL/BSA) was lower in C-1 (geometric mean [GM] 13.4 L/h/m2) than expected (26.4 L/h/m2), but similar in C-2 (23.5 L/h/m2) and C-3 (27.9 L/h/m2). CL/BSA in C-4 was 18.1 L/h/m2. Compared with C-2, CL/BSA increased 19% in C-3 (GM ratio 1.19; 90% CI 0.74–1.91), but decreased 23% in C-4 (0.77; 0.39–1.53). Cabazitaxel free fraction was unaltered. No significant correlation was found between grade 3–4 toxicities and pharmacokinetic parameters. Conclusions Mild–moderate HI did not cause substantial decline in cabazitaxel clearance. Cabazitaxel dose reductions in patients with mild–moderate HI, and a contraindication in patients with severe HI, are justified based on safety data.

Axitinib, an inhibitor of vascular endothelial growth factor (VEGF) receptors, is approved as second-line treatment for advanced renal cell carcinoma (RCC). Agents targeting the VEGF pathway may induce renal toxicities, which may be influenced by pre-existing renal dysfunction. The objective was to characterize axitinib pharmacokinetics and safety in patients with renal impairment. Effect of renal function (baseline creatinine clearance [CrCL]) on axitinib clearance was evaluated in a population pharmacokinetic model in 207 patients with advanced solid tumors who received a standard axitinib starting dose, and in 383 healthy volunteers. Axitinib safety according to baseline CrCL was assessed in previously treated patients with RCC (n = 350) who received axitinib in the phase 3 AXIS study. Median axitinib clearance was 14.0, 10.7, 12.3, 7.81, and 12.6 L/h, respectively, in individuals with normal renal function (≥90 ml/min; n = 381), mild renal impairment (60–89 ml/min; n = 139), moderate renal impairment (30–59 ml/min; n = 64), severe renal impairment (15–29 ml/min; n = 5), and end-stage renal disease (

Purpose Axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3, is under investigation for treatment of various solid tumors. The safety and pharmacokinetics of axitinib in combination with gemcitabine in patients with advanced pancreatic cancer was evaluated in the phase I portion of this trial. The randomized phase II portion was reported separately. Patients and methods Patients with advanced pancreatic cancer who had received no prior chemotherapy were eligible for this study. Pharmacokinetic profiles of the drugs were obtained on cycle (C) 1 day (D) 1 (gemcitabine alone 1,000 mg/m2), C1D14 (steady state, axitinib alone 5 mg twice daily [BID]), and C1D15 (gemcitabine plus steady-state axitinib). Adverse events were monitored weekly at the clinic. Results Eight patients participated in the phase IB portion of the trial. Patients received gemcitabine on D1, D8, and D15 and continuous axitinib in a 28 day-cycle beginning C1D3. There was no dose-limiting toxicity. Common treatment-related adverse events included fatigue, diarrhea, dysphonia, and hypertension. Myelosuppression was similar to gemcitabine monotherapy. No apparent major pharmacokinetic interactions between gemcitabine and axitinib were observed. Of six patients evaluable for efficacy, three had confirmed partial responses. Conclusions Axitinib (5 mg BID) and gemcitabine (1,000 mg/m2) were well tolerated when administered together, without any pharmacokinetic interactions, and showed encouraging antitumor activity.

Purpose: To evaluate if diastolic blood pressure (dBP) ≥90 mm Hg during axitinib treatment is a marker of efficacy. Experimental Design: The relationship between dBP ≥90 mm Hg and efficacy was retrospectively explored across 5 phase II studies of single-agent axitinib for the treatment of 4 different tumor types. All patients had baseline BP ≤140/90 mm Hg and were stratified into 2 groups based on in-clinic BP measurements after initiating therapy: those with dBP Results: Two-hundred thirty patients were evaluated. Patients with dBP ≥90 mm Hg had a significantly lower relative risk of death than those with dBP Conclusions: Axitinib efficacy correlated with dBP ≥90 mm Hg. Further investigation of dBP as a predictive biomarker of efficacy in patients receiving axitinib is warranted. Clin Cancer Res; 17(11); 3841–9. ©2011 AACR.

Background: The aim of our study was to determine whether the presence of bone metastases affects outcomes in patients with metastatic clear-cell renal cell carcinoma (m-ccRCC) receiving sunitinib. Patients and methods: We reviewed the charts of all patients in four academic centers in Belgium and France who started first-line sunitinib (50 mg/day; 4 weeks on and 2 weeks off) between January 2005 and December 2008. Data were collected on known prognostic factors for metastatic renal cell carcinoma and metastatic sites. Response and progression were evaluated by computed tomography scan (according to RECIST). Results: Two hundred twenty-three patients were identified. With a median follow-up of 40 months, median progression-free survival (PFS) and median overall survival (OS) were significantly shorter in patients with bone metastases than in those without: respectively, 8.2 versus 19.1 months (P < 0.0001) and 19.5 versus 38.5 months (P < 0.0001). On multivariate analysis, taking on account platelet count, Eastern Cooperative Oncology Group performance status, number of metastatic sites, neutrophil count, corrected serum calcium, time from diagnosis to systemic treatment, and the presence of bone metastases, bone metastasis was the independent variable most significantly associated with poor PFS (P < 0.0001) and OS (P = 0.001). Conclusion: The presence of bone metastases in m-ccRCC patients has a significant and clinically relevant negative impact on outcome on sunitinib.

e14537Background: Interspecies allometric scaling is used to extrapolate pharmacokinetics (PK) from preclinical data to human PK and dosing. Efficacy of BXQ-350, a novel Saposin C phosphatidylserin...

e14533Background: Saposin C is a lysosomal activator protein that can be combined with a phosphatidylserine lipid to create a nanovesicle that targets cancer cells. Similar lipid nanovesicle prepar...

3040Background: IDO-1 inhibitors have shown antitumor activity in combination with immunotherapeutic agents in multiple cancers. KHK2455 is a novel and selective oral IDO-1 inhibitor. Unlike other ...

2517Background: BXQ-350 is a novel agent composed of the multifunctional, lysosomal activator protein Saposin C and phosphatidylserine. BXQ-350 demonstrated antitumor effects in vitro and in vivo, ...

9512Background: The indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that, in cancer, is exploited by tumors to prevent and evade anti-tumor immunity. Inhibitors of t...

3093Background: SEA-CD40 is a non-fucosylated, humanized IgG1 monoclonal antibody which binds CD40, an immune-activating TNF receptor. Binding to antigen presenting cells and crosslinking via FcγRI...

New medical strategies have emerged over the past decade for the treatment of advanced renal cell carcinoma based on the discovery of specific molecular abnormalities. However, molecular targeted therapeutics including anti-angiogenics have demonstrated significant limits (limited impact on overall survival, development of potential severe toxicities). We review the future directions for drug development based on specific interaction with cellular and extra-cellular pathways. Both von Hippel-Lindau alterations and high immunogenicity profile represent two remarkable characteristics identified in clear cell carcinoma. The new generation of anti-angiogenics (including HIF, Notch, or angiopoietin inhibitors) and recent developments in immunotherapy also provide opportunities to modify the prognosis of advanced renal cell carcinoma.

Hepatocellular carcinoma (HCC) is a highly aggressive cancer. For patients who are diagnosed with advanced stage disease that are not surgical candidates, the disease is universally lethal. Advance has been made to extend survival with molecular target therapy, but durable complete responses are extremely rare. We report an unusual case where a 74-year-old patient with unresectable HCC received eight months of reduced-dose of sorafenib, a tyrosine kinase inhibitor, and achieved a durable complete remission. At the most recent follow up, he remains in remission 16 months after cessation of treatment, without clinical or imaging evidence of disease recurrence.

An improved understanding of the molecular biology involved in many solid tumors has led to the development of novel targeted agents. Axitinib is a potent and selective inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases 1, 2, and 3. This review presents preclinical and clinical data available for axitinib, including findings from key phase II clinical trials in a wide variety of tumors including melanomas and renal, pancreatic, thyroid, breast, lung, and colorectal carcinomas. The differences between axitinib and other VEGFR inhibitors are explored and details of the possible use of blood pressure elevation and erythropoietin blood levels as predictive markers of VEGF/VEGFR pathway inhibition are outlined. Ongoing Phase III studies in pancreatic and metastatic renal cell carcinoma should help to determine the optimum utilization of these agents at the appropriate stage of disease.

The use of molecular targeted therapies for the treatment of cancer has increased over the last decade. The benefits of these compounds in terms of efficacy are often relatively modest and counter balanced by the occurrence of significant toxicities. Many of these newer agents used in clinical practice lack specificity and selectivity and have a propensity to inhibit multiple targets. The biological consequences of multi-kinase activity are poorly defined and numerous class-specific toxicities have been described. The kidney is an organ where most of these targeted pathways are expressed. Preclinical data and human renal biopsies have generated an understanding of the mechanisms involved in how targeted agents can cause renal toxicity. This review article discusses the observed nephrotoxicity with this burgeoning class of therapeutics and reviews both the biological reasons for its occurrence and possible ways to prevent significant renal damage.

Angiogenesis or new blood vessel formation is a complex and fundamental event in the process of tumor growth and metastatic dissemination. Actually, most of antiangiogenic agents target the VEGF considered like the most potent proangiogenic factor. These molecules directly inhibit VEGF or the kinase activity of its receptor (VEGFR) and represent a significant therapeutic progress in several solid tumors types. First clinical studies of antiangiogenic agents in thoracic and laryngopharyngeal carcinomas have shown promise mainly in combination with other therapies (chemotherapy, other targeted therapies or radiotherapy). Besides common antiangiogenic therapies-induced adverse events, risks of bleeding caused by tumor necrosis mainly in squamous cell lung carcinomas have been observed during early clinical trials. Assessment of surrogate markers of target inhibition could allow a better selection of patients able to benefit from antiangiogenic treatments eventually combined with chemotherapy or molecules targeting others metabolic pathways.

The role of biomarkers in drug discovery and development has gained precedence over the years. As biomarkers become integrated into drug development and clinical trials, quality assurance and, in particular, assay validation become essential with the need to establish standardized guidelines for analytic methods used in biomarker measurements. New biomarkers can revolutionize both the development and use of therapeutics but are contingent on the establishment of a concrete validation process that addresses technology integration and method validation as well as regulatory pathways for efficient biomarker development. This perspective focuses on the general principles of the biomarker validation process with an emphasis on assay validation and the collaborative efforts undertaken by various sectors to promote the standardization of this procedure for efficient biomarker development.

Summary Background Axitinib (AG-013736) is an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3. We aimed to assess the activity and safety of axitinib in patients with metastatic renal-cell cancer who had failed on previous cytokine-based treatment. Methods Between Oct 3, 2003, and April 7, 2004, 52 patients were enrolled. All patients who had at least one measurable target lesion received axitinib orally (starting dose 5 mg twice daily). The primary endpoint was objective response (ie, percentage of patients with confirmed complete response or partial response by use of Response Evaluation Criteria In Solid Tumors [RECIST] criteria. Secondary endpoints were duration of response, time to progression, overall survival, safety, pharmacokinetics, and patient-reported health-related quality of life. This trial is registered on the clinical trials site of the US National Cancer Institute website http://www.clinicaltrials.gov/ct/show/NCT00076011. Findings In an intention-to-treat analysis, two complete and 21 partial responses were noted, for an objective response rate of 44·2% (95% CI 30·5–58·7). Median response duration was 23·0 months (20·9–not estimable; range 4·2–29·8). However, 12 of 23 initial responders progressed with response duration ranging from 4·2 months to 26·5 months. Additionally, 22 patients showed stable disease for longer than 8 weeks, including 13 patients with stable disease for 24 weeks or longer. Four patients had early disease progression. Three patients had missing response data. Median time to progression was 15·7 months (8·4–23·4, range 0·03–31·5) and median overall survival was 29·9 months (20·3–not estimable; range 2·4–35·8). Treatment-related adverse events included diarrhoea, hypertension, fatigue, nausea, and hoarseness. Treatment-related hypertension occurred in 30 patients and resolved with antihypertensive treatment in all but eight patients, of whom seven patients had a history of hypertension at baseline. Interpretation Axitinib shows clinical activity in patients with cytokine-refractory metastatic renal-cell cancer. Although 28 patients had grade 3 or grade 4 treatment-related adverse events, these adverse events were generally manageable and controlled by dose modification or supportive care, or both. Further studies are needed to confirm these findings.

Abdominal CT is considered the imaging method of choice for the staging and treatment monitoring of Gastrointestinal Stromal Tumors (GIST). The role of Whole-body FDG-PET seems limited for staging because of the low rate of extra-abdominal tumoral involvement and lower sensitivity than CT. However, PET provides assessment of therapeutic response to imatinib as early as 8 days after treatment is begun. The decrease in the metabolic tumor activity is often marked and intense and it is easier to evaluate than changes in tumor shrinkage and density measured on CT. PET may also be useful when morphological findings are unclear, treatment efficacy uncertain or when progression is identified on CT scan, especially when these findings do not agree with clinical data. PET and CT are complementary and hybrid PET/CT systems have been shown to be useful in GIST. PET may be proposed for the assessment of treatment response in prospective studies with imatinib or other molecules. In patients with GIST, FDG-PET should be performed based on a pluridisciplinary decision.

Background Since sunitinib malate has shown activity in two uncontrolled studies in patients with metastatic renal-cell carcinoma, a comparison of the drug with interferon alfa in a phase 3 trial is warranted. Methods We enrolled 750 patients with previously untreated, metastatic renal-cell carcinoma in a multicenter, randomized, phase 3 trial to receive either repeated 6-week cycles of sunitinib (at a dose of 50 mg given orally once daily for 4 weeks, followed by 2 weeks without treatment) or interferon alfa (at a dose of 9 MU given subcutaneously three times weekly). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, patient-reported outcomes, and safety. Results The median progression-free survival was significantly longer in the sunitinib group (11 months) than in the interferon alfa group (5 months), corresponding to a hazard ratio of 0.42 (95% confidence interval, 0.32 to 0.54; P

BACKGROUND: Indoleamine 2, 3-dioxygenase (IDO) is a key immune-modulatory enzyme within the IDO Pathway that inhibits CD8+ T cells and enhances the suppressor activity of Tregs. IDO is expressed in 50 to 90% of glioblastoma (GBM), and this high expression correlates with poor prognosis. IDO pathway inhibitors such as indoximod can improve anti-tumor T cell response slowing the tumor growth in vivo. We have demonstrated a synergistic effect of indoximod when combined with temozolomide (TMZ) and radiation in a syngeneic orthotopic brain tumor model. The purpose of this study is to determine the safety and preliminary efficacy of indoximod in combination with TMZ in recurrent refractory malignant brain tumors. METHODS: After progression on TMZ, patients are treated with indoximod (1200 mg BID orally) combined with a standard fixed dose of TMZ (150mg/m2x5 days). In the phase 2 expansion, patients are enrolled into 3 cohorts: 2a: indoximod with TMZ, 2b: indoximod with TMZ and bevacizumab (after progression on bevacizumab), 2c: indoximod with TMZ in conjunction with stereotactic radiosurgery in selected patients. Indoximod is administered for 28 days of each treatment cycle. RESULTS: 30 patients of a planned 105 are enrolled of which 12 patients completed the phase 1b cohort with no DLTs. The ready for phase 2 dose was 1200mg BID. 4 patients in phase 1b remain on study, the longest for 15 months. Best responses to date in the phase 1b component include one patient demonstrating an ongoing PR at 15 months per RANO criteria and SD in 4 patients lasting between 4 and 11 months. No severe AEs or change in TMZ dosing due to indoximod addition were documented. CONCLUSIONS: The phase 1b part has been successfully concluded with encouraging preliminary observations. Enrollment into the phase 2 portion is ongoing. Updates will be presented at the meeting. NCT02052648.

Purpose: We hypothesized that lymphoid-selective host conditioning and subsequent adoptive transfer of sirolimus-resistant allogeneic T cells (T-Rapa), when combined with high-dose sirolimus drug therapy in vivo, would safely achieve antitumor effects while avoiding GVHD. Experimental Design: Patients (n = 10) with metastatic renal cell carcinoma (RCC) were accrued because this disease is relatively refractory to high-dose conditioning yet may respond to high-dose sirolimus. A 21-day outpatient regimen of weekly pentostatin (P; 4 mg/m2/dose) combined with daily, dose-adjusted cyclophosphamide (C; ≤200 mg/d) was designed to deplete and suppress host T cells. After PC conditioning, patients received matched sibling, T-cell–replete peripheral blood stem cell allografts, and high-dose sirolimus (serum trough target, 20–30 ng/mL). To augment graft-versus-tumor (GVT) effects, multiple T-Rapa donor lymphocyte infusions (DLI) were administered (days 0, 14, and 45 posttransplant), and sirolimus was discontinued early (day 60 posttransplant). Results: PC conditioning depleted host T cells without neutropenia or infection and facilitated donor engraftment (10 of 10 cases). High-dose sirolimus therapy inhibited multiple T-Rapa DLI, as evidenced by stable mixed donor/host chimerism. No antitumor responses were detected by RECIST criteria and no significant classical acute GVHD was observed. Conclusions: Immune-selective PC conditioning represents a new approach to safely achieve alloengraftment without neutropenia. However, allogeneic T cells generated ex vivo in sirolimus are not resistant to the tolerance-inducing effects of in vivo sirolimus drug therapy, thereby cautioning against use of this intervention in patients with refractory cancer. Clin Cancer Res; 21(19); 4312–20. ©2015 AACR.

Researchers have recently demonstrated a significant activity in the use of antiangiogenic compounds for the treatment of clear-cell metastatic renal cell carcinoma (RCC). The pVHL protein plays an important role in angiogenesis. Germline or somatic alterations of the VHL gene result in an abnormal accumulation of hypoxia inducible factor (HIF) inducing the upregulation of proangiogenic downstream genes. From a cohort of 13 patients with RCC included in a phase II study testing the activity of AG-013736 (axitinib), a multi-target receptor tyrosine kinase inhibitor (including VEGFR-1 and -2, PDGFR-β), we investigated the correlation between the presence of VHL somatic mutations and the activity of axitinib. Tumor samples collected were formalin-fixed paraffin-embedded tissues. DNA extracted from these samples were PCR-amplified and directly sequenced for the VHL gene. Among the 13 tumor DNA samples studied, 12 were successfully sequenced. There was an objective response in six patients. Two patients who experienced an objective response had evidence of VHL sequence variants. No VHL mutation was detected among the other patients. In conclusion, no correlation was observed between the somatic mutational status of the VHL gene and the objective response to axitinib in our series.

Thrombotic microangiopathy (TMA) is a microvascular occlusive disorder characterized by predominantly platelet thrombi in the renal and/or systemic circulations. Haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are the clinical entities comprising TMA, with predominantly renal manifestations in the former, while the latter more often presents with systemic and neurological findings. In some cases, TMA includes de novo hypertension and pulmonary or central nervous system symptoms. TMA is a rare condition, which is severe and may be fatal. Globally, two biological abnormalities explain TMA, namely: ADAMTS13 (A Disintegrin-like And Metalloprotease with ThromboSpondin type 1 repeats) deficiency and various complement component deficiencies. Studies aimed at determining these deficiencies in cases of chemotherapy-induced TMA were not systematically available in the articles reviewed. Gemcitabine was approved by the US Food and Drug Administration (FDA) in 1996 for the treatment of patients with metastatic pancreatic cancer and is currently used for the treatment of a wide range of malignancies, including lymphoma, lung, bladder and breast cancer. Casper et al. [1] first linked TMA to gemcitabine therapy in 1994, during a phase II trial of pancreatic cancer patients receiving this agent. The reported incidence of gemcitabine-associated TMA in the literature is very low, with a manufacturer’s estimate of 0.015% (range 0.008–0.078%) according to adverse event reports in 1997 [2], contrasting with the apparent frequency of patients with gemcitabineassociated TMA at local institutions [3,4]. Since most gemcitabine-treated patients presenting with TMA have far advanced disease and some have received other agents known to be associated with TMA, the exact role of the underlying disease and chemotherapeutic agents is not easily delineated. Although microangiopathy caused by disseminated cancer and chemotherapy-associated TMA may represent two distinct syndromes, and distinguishing clinical and histological features have been identified for these two conditions, there may be more similarities than differences. Nevertheless, clinical improvement after gemcitabine withdrawal in some cases and the result from re-exposure to the drug strongly suggest gemcitabine to be causative for TMA. We report three patients who developed gemcitabine-associated TMA from January 2001 to December 2005, and we undertook a retrospective review to investigate the clinical manifestations and outcomes associated with this condition in case reports and Phase II/III trials.