Increased Moxifloxacin Dosing among MDR-TB Patients with Low-Level Resistance to Moxifloxacin did not Improve Treatment Outcomes in a Tertiary Care Center in Mumbai, India

Background Mycobacterium tuberculosis (Mtb) strains resistant to isoniazid and rifampin (MDR-TB) are increasingly reported worldwide, requiring renewed focus on the nuances of drug resistance. Patients with low-level moxifloxacin resistance may benefit from higher doses, but limited clinical data on this strategy are available . Methods We conducted a 5-year observational cohort study of MDR-TB patients at a tertiary care center in India. Participants with Mtb isolates resistant to isoniazid, rifampin, and moxifloxacin (at the 0.5µg/mL threshold) were analyzed according to receipt of high-dose moxifloxacin (600mg daily) as part of a susceptibility-guided treatment regimen. Univariable and multivariable cox proportional hazard models assessed the relationship between high-dose moxifloxacin and unfavorable treatment outcomes. Results Of 354 participants with MDR-TB resistant to moxifloxacin, 291 (82.2%) received high-dose moxifloxacin. The majority experienced good treatment outcomes (200, 56.5%), which was similar between groups (56.7% vs. 54.0%, p=0.74). Unfavorable outcomes were associated with greater extent of radiographic disease, lower initial body mass index, and concurrent treatment with fewer drugs with confirmed phenotypic susceptibility. Treatment with high-dose moxifloxacin was not associated with improved outcomes in either unadjusted [hazard ratio (HR) 1.2, 95% confidence interval (CI): 0.6–2.4] or adjusted models (HR 0.8, 95% CI: 0.5–1.4) or but was associated with joint pain (HR 3.2, 95% CI: 1.2–8.8). Conclusion In a large observational cohort, adding high-dose (600mg) moxifloxacin to a DST-based treatment regimen for MDR-TB was associated with increased treatment-associated side effects without improving overall outcomes and should be avoided for empiric treatment of moxifloxacin resistant MDR-TB.

Maximal Tolerated Dose Determined for Venetoclax in Combination with Liposomal Vincristine in Patients with Relapsed or Refractory Ph-Negative T-Cell or B-Cell Acute Lymphoblastic Leukemia: Results of Phase 1 Portion of ECOG-ACRIN EA9152

Background: Relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) remain a therapeutic challenge, especially in elderly patients(pts) or those with T-cell immunophenotype. Inhibition of apoptosis is an increasingly recognized mechanism for resistance to conventional chemotherapy. Recently, the oral bcl-2 inhibitor venetoclax (VEN) has shown remarkable activity in a variety of hematologic malignancies. Preclinical data in both B- and T-ALL suggests synergy of VEN with vincristine(VCR). Liposomal VCR (L-VCR) is FDA approved for relapsed ALL having progressed following 2 or more antileukemia therapies. We designed a phase I/II trial (EA9152) of the combination of L-VCR and VEN for pts with r/r B-or T-cell ALL or LL. Here, we report for the first time the safety and efficacy outcomes of the phase I portion of this trial (NCT03504644). Methods: This open-label phase I/II study enrolled pts age>=18 with ALL or LL who were R/R to multiagent chemotherapy. Subjects could have received prior VCR or VEN . In a standard 3 + 3 dose escalation design, subjects were given a two week lead-in phase of single agent VEN in the following schedule: dose level 1 - 20, 50, 100, 200 mg on days 1, 2, 3, 4 and 400 mg on days 5 ‒ 42; dose level 2 - 50, 100, 200, 400 mg on days 1, 2, 3, 4 and 600 mg on days 5 ‒ 42; and dose level 3 ‒ 100, 200, 400, 600 mg on days 1, 2, 3, 4 and 800 mg on days 5 ‒ 42. Weekly L-VCR 2.25mg/m 2 IV was started on D15 of cycle 1, and starting day 1 for subsequent cycles (cycle 2+ = 28 days). For cycle 2 and beyond, VEN 400mg, 600mg, or 800mg based on dose level was given starting on day 1 of the cycle. Primary objective of the phase I portion was to determine the maximum tolerated dose (MTD) of VEN in combination with L-VCR. Secondary objectives included determining preliminary response rates. Results: EA9152 was activated on April 26, 2018 and the phase I portion closed to accrual on March 2, 2021. Among the 18 pts in dose escalation (Table 1), the median age was 42 years (22-77). The majority of pts were male (56%), white (80%), and with a performance status (PS) of 1 (78%). Among 13 pts with disease diagnosis reported, 9 had ALL and 4 had LL. Seventeen of 18 (94%) reported previous chemotherapy, two of which had previous stem cell transplant. Median treatment cycles received is 1 (range 1-11). One patient, having received 11 cycles, remains on study at the time of data analysis. Grade >=3 treatment-related adverse events were reported in 89% of treated pts, with neutrophil count decreased (67%), white blood cell decreased (56%), and anemia (50%) as the most common. One pt experienced grade 3 tumor lysis syndrome. Twelve pts were considered evaluable for MTD determination. Six pts were considered not evaluable for toxicity analysis on account of withdraw of consent for treatment (n=4) or rapid disease progression (n=2). Two pts (2 of 3) at dose level 3 experienced DLTs, one each of hypokalemia and heart failure. Therefore, the MTD of the combination was determined to be dose level 2 - VEN 50, 100, 200, 400 mg on days 1, 2, 3, 4 and 600 mg on days 5 ‒ 42 and for subsequent cycles, with L-VCR 2.25mg/m2 IV weekly. In regards to best overall responses observed (Table 2) 4 of 18 pts (22%) achieved complete response (CR), 4 patients (22%) had stable disease, and 7 (39%) had progressive disease. Two patients in CR were found to be measurable residual disease (MRD) negative as well. Conclusions: In the phase 1 portion of this study, the combination of VEN and L-VCR was found to be safe for patients with ALL and LL. The MTD of the combination was found to be VEN 600mg daily with encouraging preliminary efficacy seen including MRD negative responses. The phase 2 portion of this trial is actively enrolling with VEN 600mg daily starting C1D1. Figure 1 Figure 1. Disclosures Palmisiano: Takeda: Consultancy; Genentech: Research Funding; Foundation One: Consultancy; AbbVie: Consultancy, Research Funding. Claxton: Astellas: Other: Clinical Trial; Novartis: Research Funding; Astex: Research Funding; Cyclacel: Research Funding; Daiichi Sankyo: Research Funding; Incyte: Research Funding. Park: BMS: Consultancy; Amgen: Consultancy; Autolus: Consultancy; Novartis: Consultancy; Minerva: Consultancy; PrecisionBio: Consultancy; Curocel: Consultancy; Artiva: Consultancy; Kite Pharma: Consultancy; Kura Oncology: Consultancy; Affyimmune: Consultancy; Servier: Consultancy; Innate Pharma: Consultancy; Intellia: Consultancy. Podoltsev: Novartis: Honoraria; Incyte: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Blueprint Medicines: Honoraria; Bristol-Myers Squib: Honoraria; PharmaEssentia: Honoraria; CTI BioPharma: Honoraria. Atallah: Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Honoraria, Speakers Bureau; Takeda: Consultancy, Research Funding; Abbvie: Consultancy, Speakers Bureau; Amgen: Consultancy. Dinner: Kite/Gilead: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Webster: AmGen: Consultancy; Pfizer: Consultancy. Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Litzow: AbbVie: Research Funding; Astellas: Research Funding; Amgen: Research Funding; Actinium: Research Funding; Pluristem: Research Funding; Jazz: Other: Advisory Board; Omeros: Other: Advisory Board; Biosight: Other: Data monitoring committee. OffLabel Disclosure: Venetoclax, a BCL-2 inihibitor, is not FDA-approved for use in ALL.

ACTH Producing Mediastinal Tumor - Multidisciplinary Approach

Introduction: Ectopic ACTH syndrome is rare but is frequently a severe condition because of the intensity of the hypercortisolism. Patient management is complex and demands both strategies: the diagnosis and treatment of Cushing syndrome, and the specific management of neuroendocrine tumors. Therefore, management should be performed ideally by experienced endocrinology teams in collaboration with surgeons, oncologists, nuclear medicine, specialized hormonal laboratory and modern imaging platforms. Clinical Case: Female patient, born in 2000, at the age of 15 was diagnosed with Cushing’s syndrome secondary to ACTH secretion by mediastinal tumor. At diagnosis, ACTH 1152pg/ml was found (reference value <46pg/ml). Turkish seat resonance was normal, and chest tomography described a 4.5x3.6x3.8cm mediastinal lesion. Underwent a mediastinal surgical approach in 2015, with clinical and laboratory remission of hypercortisolism. The analysis of the lesion revealed a well-differentiated neuroendocrine carcinoma, with Ki67 5%. Progression of the mediastinal lesion was observed, without an exuberant clinic or laboratory, and a new surgery was performed in 2017, with a remaining macroscopic tumor, due to technical difficulties in resection due to contact with vascular structures. The immunohistochemistry of the resected lesion in this approach showed Ki67 30%, which reflects loss of differentiation. Octreoscan was performed, with no uptake. She evolved without exuberant Cushing’s syndrome until May 2019, when the clinical condition decompensated due to hypercortisolism, and was submitted to a new hospitalization. She was assisted by the thoracic surgery and oncology teams. From this moment a follow-up with endocrinology team started. Ketoconazole was introduced and PET-DOTATOC was requested. She underwent chemotherapy with Oxaliplatin and Capecitabine. In March 2020, DOTATOC uptake was checked and a somatostatin analogue was started. She showed considerable clinical and laboratory improvement. The patient remains clinically stable, with control of hypercortisolism using Ketoconazole 600mg daily and Octreotide 30mg every 28 days. The patient remains under clinical and laboratory surveillance. Awaiting PET-FDG. Mediastinal radiotherapy, lutetium, new mediastinal surgical approach, and bilateral adrenalectomy are also considered as possible therapeutic alternatives. Clinical Lesson: The reported case shows a rare location of an ACTH-producing tumor, emphasizing the severity of the presentation, the evolution of tumor de-differentiation, the different results identified in octreoscan and PET-DOTATOC, and the importance of multidisciplinary management.

Anabolic Steroids in Myelodysplastic Syndromes: A Systematic Review

Background Anabolic steroids, such as danazol, have been used for years in the treatment of myelodysplastic syndromes (MDS). Their successful use has been documented in aplastic anemia, hypoplastic MDS, and immune thrombocytopenia, among other hematologic conditions. In patients with low-risk MDS, available treatment options are limited. Danazol is frequently used to improve symptoms and modify the disease course; however, its efficacy and optimal dosing schedule are unclear. Methods We conducted a systematic review of the literature to identify studies that used anabolic steroids, including danazol, in the treatment of MDS. In accordance to guidelines, our systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) under ID CRD42019121467. We included case series with more than 15 patients, observational studies (cohorts and case control), and randomized trials where anabolic steroids were used to treat MDS. Following PRISMA guidelines, 2 independent reviewers assessed the studies obtained through the search strategy. Discrepancies were resolved by a third reviewer. Due to the heterogeneity of the findings, no meta-analysis was performed. Results A total of 1000 studies were identified through our search. After removing duplicates and undergoing Level 1 screening by 2 reviewers, 69 full text articles were assessed. Thirteen studies were included in the final review as the other studies did not meet inclusion criteria. Of these, 3 were retrospective cohorts, 8 prospective cohorts, and 2 randomized trials. A total of 366 patients with MDS were exposed to anabolic steroids throughout the studies with diverse outcomes reported. FAB classification was used by most of the studies to categorize MDS, with one exception that used the 2008 WHO classification. Diagnoses included refractory anemia, refractory anemia with ring sideroblasts, refractory anemia with excess blasts (RAEB), RAEB in transformation, and chronic myelomonocytic leukemia. All but 2 studies used danazol as their intervention, with the exceptions using other anabolic steroids as well as danazol. Dosage varied across studies with the majority aiming for a dose of danazol 600mg daily. Patient characteristics and interventions are summarized in Table 1. The intervention was sustained for at least 1 month and up to 12 months across studies. Outcomes reported are diverse with positive and negative studies identified. Unfortunately, outcomes are not comparable due to the presence of different response definitions with different hematologic improvement cutoffs. Reports of response were highly variable, with studies showing 5 - 75% response rates depending on their study response definitions. Multiple studies reported a trend in platelet count improvement. Response duration was not specified by all studies and was highly variable across the reports. Response definitions and outcomes are shown in Table 2. No significant adverse effects to danazol were reported in any of the studies reviewed. No specific analysis of benefit throughout the different MDS groups was reported in any of the studies. Conclusion Our systematic review highlights the significant lack of data and irregular results across studies. The heterogeneity of included populations, MDS classification, response criteria, and interventions, do not allow for evidence based recommendations regarding the use of danazol or anabolic steroids in MDS patients. Given the limited treatment options for low-risk MDS patients, particularly in low and middle income countries, further well designed studies are needed. Disclosures No relevant conflicts of interest to declare.

Antihypertensive Drugs (АCE- Inhibitors/ Beta- Blockers) and Chronic Infections as Potential Triggers for the Spontaneously Development of Small Plaque Parapsoriasis ?!

Background: There are different literature data according to which small plaque parapsoriasis (SPP) and guttate parapsoriasis could be considered as part of the various clinical forms of MF. However, there are no literature data that compare different control groups of patients (receiving/ not taking antihypertensive medication) and the two important possibilities deriving from it, namely: 1) that certain drug forms could be inducers of parapsoriasis and 2) that other drug forms could potentiate the transformation of existing parapsoriasis into T-cell lymphoma. We describe a case of possible infectious and / or drug-induced SPP by discussing an important, albeit currently hypothetical link to the drug mediated cancerogenesis. Case report: We present a 39-year-old man with a disseminated eruptive erythemo-papulo-squamous rash, localized on the skin of the trunk and extremities. According to anamnestic data, skin symptoms date back to about 1 month when the patient was hospitalized in the ENT compartment for severe throat pain. Primary empirical antibiotic therapy with clindamycin 4x 600mg/ daily i.v was performed on a regimen and partial remission was achieved. Immediately afterwards there was a resumption of symptoms and the additional occurrence of skin lesions. From the conducted tests, the presence of acute tonsillopharyngitis, focal infection of dental origin and elevated antistreptolysin titer was found. In parallel, the patient receives antihypertensive therapy (ACE inhibitor and beta blocker) on the occasion of arterial hypertension. There was a suspicion for infectious and / or drug-triggered psoriasis gutata, as the subsequent histological study showed evidence of small plaque parapsoriasis. Conclusion: Although there are a number of literature data on the relationship between antihypertensive drugs and their pro-or anticancerogenic action against various types of tumors, there is currently no data available to compare the existing risk of developing T- cell lymphoma in patients with SPP and concomitant cardiac therapy with ACE inhibitors and beta blockers. We present a patient with triple histologically verified small plaque parapsoriasis and we are discussing a completely new pathogenetic element: triggering in the framework a possible chronic infection and systemic antihypertensive therapy. The selected retrospective or prospective analysis of wider groups of patients with chronic infections / systemic antihypertensive medication as well as proven T cell lymphomas could provide clarity with respect to the shared by us observations in single patients. Keywords: Small plaque parapsoriasis; antihypertensive drugs; chronic infections; triggers; drug mediated cancerogenesis;

Phase ιι (window) preoperative study of olaparib with cisplatin or with durvalumab or alone or no treatment in patients with histologically proven head and neck squamous cell carcinoma who are candidates for surgery (OPHELIA).

TPS6096 Background: Novel agents are often investigated in unselected end-stage cancer patients and their efficacy is evaluated by the classical RECIST criteria making unlikely to fully exploit the antitumor potential of these targeted agents. Olaparib (O) is a potent inhibitor of PARP especially active in tumors that have homologous recombination DNA repair pathway deficiencies. Durvalumab (D) is a selective, high-affinity human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80, overcoming PD-L1-mediated inhibition of T-cell activation. There is substantial evidence that tumor cells use PARP to repair platinum-induced DNA damage and thus escape apoptosis. In addition, O may complement the antitumor activity of D by increasing DNA damage through repair inhibition. Methods: OPHELIA is an open-label randomized multicenter phase II (window) trial in patients (pts) with head and neck squamous cell carcinoma (HNSCC). Treatment-naive HNSCC pts selected for primary curative study are randomized 3:3:3:1 in 4 neoadjuvant treatment groups: D 1500 mg on day 1 followed by O 600mg daily for 21-28 days (12 pts), cisplatin 60 mg/m2 on day 1 followed by O 75mg daily for 5 days (12 pts), monotherapy with O 600mg daily for 21-28 days (12 pts) and no treatment (5 pts). Preoperative therapy is discontinued 24 to 36 hours before surgery. Tumor biopsies, CT scans, PET and blood specimens are obtained at diagnosis and at surgery. Primary endpoint is the change in the tumor Ki-67 before and after treatment. Secondary endpoints are objective response rate according to RECIST 1.1 criteria, pathologic complete response rate and metabolic response rate assessed by FDG-PET/CT scan. Exploratory endpoints will include tumor and blood biomarkers. Translational correlates will be tested in tumor tissue, plasma and germline DNA and will include mutations in genes associated with DNA repair assessed by next generation sequencing and circulating tumor cells (CTCs) evaluated for DNA repair biomarkers and PD-L1. Trial is open to enrollment. Clinical trial information: NCT02882308.

A single-arm biomarker-based phase II trial of savolitinib in patients with advanced papillary renal cell cancer (PRCC).

436 Background: Savolitinib (HMPL504/Volitinib, AZD6094) is a potent, selective MET inhibitor (IC50 of 4nM). MET and its ligand, HGF, are known to play an important role in the molecular events underlying oncogenesis in PRCC, a disease without a clear standard of care and marked by alterations of chromosome 7 (containing both MET and HGF genes) in a majority of patients as well as gene amplification or MET kinase domain mutations (Albiges et al. 2014, Linehan et al., 2015). Methods: This study evaluates savolitinib in PRCC patients dosed at 600mg daily until disease progression. ORR is the primary endpoint. PFS & DoR are secondary endpoints. PRO & HRQoL questionnaires are exploratory endpoints. Eligibility includes naive and previously treated metastatic PRCC, ECOG PS 0 or 1. Archival tumor was used to centrally confirm PRCC pathology post hoc and to determine MET status using Next Generation Sequencing (Foundation Medicine Inc, USA). Results: As of 27 June 2016, 109 pts were dosed. Best response was PR n=8, SD n=43, PD n=48 and 10 patients were not evaluable for response. 44 pts are MET-driven (MET/HGF gene copy number gain or kinase domain mutations), 46 pts were MET-negative, 19 pts are status unknown. MET-driven pts included Papillary Type I & II histologies. All 8 responders were in the MET-driven group, 18% RR in this subset. Median PFS in the MET-driven group was 6.2 months (95% CI: 4.1–7.0) vs. 1.4 months (95% CI: 1.4–2.7) in the MET-negative group (p = 0.002). Overall 10/109 pts had AEs leading to discontinuation. 23/109 pts had ≥ Grade 3 toxicity related to savolitinib. The most common AEs (all grades) includes: nausea (39%), fatigue (27%), edema (18%), and abnormal LFTs (17%). One death from hepatic encephalopathy was considered related to savolitinib. PRO & HRQoL data was not statistically analysed, descriptive data support main efficacy findings. Conclusions: In the largest biomarker-profiled trial dedicated to PRCC, savolitinib was generally well tolerated with anti-tumor activity in MET-driven patients. These findings warrant further clinical investigation of savolitinib in MET-driven PRCC. Clinical trial information: NCT02127710.

Feasibility Of Pegylated-Asparaginase (PEG-ASP) During Induction In Adults With Acute Lymphoblastic Leukaemia (ALL): Results From The UK Phase 3 Multicentre Trial UKALL 14

L- asparaginase treatment improves clinical outcomes in childhood ALL and Pegylated asparaginase (PEG-ASP) ) has become the standard of care for this patient group. By contrast, safety and efficacy data on PEG-ASP in adult ALL is limited. A key question is the impact of asparaginase associated toxicity on the delivery of multiagent chemotherapy in adult treatment regimes. UKALL14 prospectively evaluated the tolerability of PEG-ASP as part of a 5 drug induction regimen in adults with ALL between 25-65 yrs. The primary-end point of the PEG-ASP evaluation was toxicity. Here, we report on the toxicity of PEG-ASP in the first 91 subjects, after which the trial protocol was amended due to safety concerns. UKALL 14 Induction Phase 1 consisted of intravenous PEG-ASP (1000 IU/m2) on days (d) 4 and 18, Daunorubicin 60mg/m2 and Vincristine 1.4mg/m2 (2mg max) on d1,8,15 and 22, Dexamethasone 10mg/m2 d1,-4, 8-11,15-18 and a single intrathecal (IT) Methotrexate 12.5mg on d14. Patients with pre-B lineage ALL were randomized to receive Rituximab or not. Patients with Philadelphia chromosome (Ph) positive disease received continuous Imatinib 400mg escalating to 600mg daily throughout induction. Phase 2 induction comprised of cyclophosphamide 1000mg/m2 d1+ 15, Ara-C 75mg/m2 d2-5, 9-12, 16-19 + 23-26, mercaptopurine 60mg/m2 throughout and IT methotrexate d1,8,15,22. Results The median age was 47 years (25-65yrs). Overall, 80.2% (73/91) patients completed phase 1 induction. Of these 60 achieved CR, 9 did not, and 4 had missing CR data. Thirteen of the 18 patients who did not complete phase 1 induction suffered early death. The overall induction mortality was 19.8% (18/91). Sixteen deaths occurred pre phase 2 induction and 2 deaths post phase 2. The most common cause of induction death was sepsis in combination with hepatotoxicity (55.6%,10/18) followed by sepsis alone (16.7%, n= 3). Additional causes of death were bowel ischaemia in combination with hepatotoxicity (n=2), acute coronary syndrome (n=1), haemorrhage (n=1) and pancreatitis + bowel perforation (n=1). Ten of the 12 hepatotoxicity associated induction deaths had NCI Grades 3-4 hyperbilirubinaemia. The median time from last dose of PEG-ASP to induction death was 14.5 days (6-71). Taking into account the multiple risk factors contributing to hepatoxicity associated morbidity (concomitant administration of hepatotoxic drugs and sepsis itself), a PEG-ASP related cause of death was “definitely or probably” implicated in 11/18 induction deaths. Logistic regression showed that age and Ph status were independent variables predicting induction death<40yrs vs ≥40yrs, odds ratio (OR) 5.27 (95% CI 1.13-24.7), p =0.035; age <55yrs vs ≥55yrs OR 4.47 (1.51-13.18), p =0.007 and Ph pos vs Ph neg disease, OR 6.08 (2.01 – 18.34), p =0.001. The trial steering committee confirmed that there was no relationship to Rituximab randomization. The incidence of non-fatal PEG-ASP toxicity during induction was 36.7% (n=33).The most common toxicity was abnormal liver function test (24.5%,n=22) followed by coagulopathy (7.7%,n=7) and thrombosis (5.6%,n=5). Grade 3-4 PEG-ASP related liver dysfunction was significantly associated with older age (<40 vs >40, p= 0.031). Enzyme activity, assessed by MAAT, after the first PEG-ASP dose in phase 1 induction was available for a subset of patients (n=27). Nearly all patients (88.9%) achieved a therapeutic level of enzyme activity of >100IU/ml 14 days after the first PEG-ASP. Conclusion Significant levels of treatment associated mortality occurred in adults treated with a PEG-ASP containing induction regimen on UKALL 14 which was strongly associated with older age and Ph pos disease. As a consequence of the toxicity the protocol was amended to omit d4 PEG-ASP for those over 40yrs. PEG-ASP was completely removed from induction treatment for Ph positive patients. Furthermore, due to the high level of sepsis related to profound myelosuppression, the daunorubicin dose was halved to 30mg /m2 on d1,8,15 and 22. One year following the amendment 123 further patients have been recruited and 8 (6.5%) induction deaths recorded. Our data indicate that whilst PEG-ASP achieves effective asparagine depletion in adult patients it is difficult to deliver safely to those over the age of 40yrs with particularly pronounced toxicity in the over 55s, and should not be started early during induction. Caution should be exercised in co-administration with Imatinib. Disclosures: Fielding: Medac: Research Funding.

Final results of a phase I study evaluating the combination of linsitinib, a dual inhibitor of insulin-like growth factor-1 receptor (IGF-1R), and insulin receptor (IR) with weekly paclitaxel (PAC) in patients (Pts) with advanced solid tumors.

e13502 Background: Linsitinib (OSI-906) is an oral inhibitor of IGF-1R and IR. Increased IGF-1R and IR activity is observed in human cancers and implicated in resistance to chemotherapy. In preclinical studies, linsitinib blocked IGF-1R/IR-AKT pathway activity evoked by PAC treatment. This study combines linsitinib + a cytotoxic agent. Methods: Pts with advanced solid tumors received weekly IV PAC (80mg/m2) in 21-day cycles with intermittent linsitinib (Arm A, d1-3q7d) or continuous linsitinib (Arm B, B2 and B3, twice daily (BID) d1-21). The primary objective was to determine the maximum tolerated dose (MTD) of linsitinib + PAC using a standard 3+3 phase I design. Results: 58 pts were treated (49F:9M, median age 58 yrs). Linsitinib doses of 300mg to 600mg daily (QD) d1-3q7d in Arm A and 75mg to 150 mg BID in Arm B were evaluated. Dose limiting toxicities in Arm A (n=27) were grade G3 neutropenia, G2 neuropathy and G3 deep vein thrombosis (DVT), and in Arm B (n=31) were G3 hyperglycemia, G3 fatigue (n=2) and G4 pulmonary embolism (PE). DVT and PE were reported as unrelated to linsitinib. MTD: Arm A = 600mg QD d1-3q7d Arm B = 150mg BID. Most common drug-related toxicities in ≥20%were (any grade; G3): fatigue (60%; 15.5%), nausea (48%; 0%), alopecia (48%; 0%), diarrhea (36%; 5%), drug eruption (21%; 2%), neuropathy (26%; 2%) and dysgeusia (24%; 0%). The median duration of exposure (days) for Arm A was 64.5, 91.0, 132.0 and 159.5 for the 300mg, 400mg, 450mg and 600mg doses, respectively. In Arm B, median duration of exposure (days) was 232.0 and 87.5 for the 75mg and 150mg doses, respectively. Partial response was achieved in 6 pts (10%)-3 ovarian, 1 primary peritoneal, 1 endometrial, and 1 esophageal. Stable disease was achieved in 25 pts (43%) - 10 ovarian, 2 primary peritoneal, 1 endometrial, and 12 pts in other tumor types. Pharmacokinetic (PK) results suggested no substantial PK interaction when linsitinib was administered 2 hours prior to PAC. Conclusions: Linsitinib + PAC did not show any unexpected safety concerns given the known mechanism of action, at doses up to the single agent MTDs. Clinical trial information: NCT00889382.