Eganelisib, a First-in-Class PI3Kγ Inhibitor, in Patients with Advanced Solid Tumors: Results of the Phase 1/1b MARIO-1 Trial.

PURPOSE: Eganelisib (IPI-549) is a first-in-class, orally administered, highly selective PI3Kγ inhibitor with antitumor activity alone and in combination with programmed cell death protein 1/ligand 1 (PD-1/PD-L1) inhibitors in preclinical studies. This phase 1/1b first-in-human, MAcrophage Reprogramming in Immuno-Oncology-1 (NCT02637531) study evaluated the safety and tolerability of once-daily eganelisib as monotherapy and in combination with nivolumab in patients with solid tumors. PATIENTS AND METHODS: Dose-escalation cohorts received eganelisib 10-60 mg as monotherapy (n = 39) and 20-40 mg when combined with nivolumab (n = 180). Primary endpoints included incidence of dose-limiting toxicities (DLT) and adverse events (AE). RESULTS: The most common treatment-related grade ≥3 toxicities with monotherapy were increased alanine aminotransferase (ALT; 18%), aspartate aminotransferase (AST; 18%), and alkaline phosphatase (5%). No DLTs occurred in the first 28 days; however, toxicities meeting DLT criteria (mostly grade 3 reversible hepatic enzyme elevations) occurred with eganelisib 60 mg in later treatment cycles. In combination, the most common treatment-related grade ≥3 toxicities were increased AST (13%) and increased ALT and rash (10%). Treatment-related serious AEs occurred in 5% of monotherapy patients (grade 4 bilirubin and hepatic enzyme increases in one patient each) and 13% in combination (pyrexia, rash, cytokine release syndrome, and infusion-related reaction in ≥2 patients each). Antitumor activity was observed in combination, including patients who had progressed on PD-1/PD-L1 inhibitors. CONCLUSIONS: On the basis of the observed safety profile, eganelisib doses of 30 and 40 mg once daily in combination with PD-1/PD-L1 inhibitors were chosen for phase 2 study.

ACCELERATE and European Medicines Agency Paediatric Strategy Forum for medicinal product development of checkpoint inhibitors for use in combination therapy in paediatric patients.

The third multistakeholder Paediatric Strategy Forum organised by ACCELERATE and the European Medicines Agency focused on immune checkpoint inhibitors for use in combination therapy in children and adolescents. As immune checkpoint inhibitors, both as monotherapy and in combinations have shown impressive success in some adult malignancies and early phase trials in children of single agent checkpoint inhibitors have now been completed, it seemed an appropriate time to consider opportunities for paediatric studies of checkpoint inhibitors used in combination. Among paediatric patients, early clinical studies of checkpoint inhibitors used as monotherapy have demonstrated a high rate of activity, including complete responses, in Hodgkin lymphoma and hypermutant paediatric tumours. Activity has been very limited, however, in more common malignancies of childhood and adolescence. Furthermore, apart from tumour mutational burden, no other predictive biomarker for monotherapy activity in paediatric tumours has been identified. Based on these observations, there is collective agreement that there is no scientific rationale for children to be enrolled in new monotherapy trials of additional checkpoint inhibitors with the same mechanism of action of agents already studied (e.g. anti-PD1, anti-PDL1 anti-CTLA-4) unless additional scientific knowledge supporting a different approach becomes available. This shared perspective, based on scientific evidence and supported by paediatric oncology cooperative groups, should inform companies on whether a paediatric development plan is justified. This could then be proposed to regulators through the available regulatory tools. Generally, an academic-industry consensus on the scientific merits of a proposal before submission of a paediatric investigational plan would be of great benefit to determine which studies have the highest probability of generating new insights. There is already a rationale for the evaluation of combinations of checkpoint inhibitors with other agents in paediatric Hodgkin lymphoma and hypermutated tumours in view of the activity shown as single agents. In paediatric tumours where no single agent activity has been observed in multiple clinical trials of anti-PD1, anti-PDL1 and anti-CTLA-4 agents as monotherapy, combinations of checkpoint inhibitors with other treatment modalities should be explored when a scientific rationale indicates that they could be efficacious in paediatric cancers and not because these combinations are being evaluated in adults. Immunotherapy in the form of engineered proteins (e.g. monoclonal antibodies and T cell engaging agents) and cellular products (e.g. CAR T cells) has great therapeutic potential for benefit in paediatric cancer. The major challenge for developing checkpoint inhibitors for paediatric cancers is the lack of neoantigens (based on mutations) and corresponding antigen-specific T cells. Progress critically depends on understanding the immune macroenvironment and microenvironment and the ability of the adaptive immune system to recognise paediatric cancers in the absence of high neoantigen burden. Future clinical studies of checkpoint inhibitors in children need to build upon strong biological hypotheses that take into account the distinctive immunobiology of childhood cancers in comparison to that of checkpoint inhibitor responsive adult cancers.

Exposure-response relationship of olaratumab for survival outcomes and safety when combined with doxorubicin in patients with soft tissue sarcoma.

PURPOSE: Olaratumab is a recombinant human IgG1 monoclonal antibody against PGDFRα. Olaratumab plus doxorubicin improved survivalversus doxorubicin in an open-label, randomised phase 2 soft tissue sarcoma (STS) trial. We characterised the olaratumab exposure-response relationship for progression-free survival (PFS), overall survival (OS), and safety. METHODS: PFS and OS data from the 133 patients enrolled in the phase 2 study were analysed using time-to-event modelling. The effect of olaratumab on PFS/OS was explored using the trough serum concentration after cycle 1 (Cmin1) and the average concentration throughout treatment (Cavg). The rate of treatment-emergent adverse events (TEAEs) was compared across olaratumab exposure quartiles. RESULTS: PFS and OS were described by models with an exponential hazard function and inhibitory EMAX functions to describe the effect of olaratumab, regardless of the PK endpoint. The olaratumab EC50s for PFS (ECmin150 = 82.0 µg/mL, ECavg50 = 179 µg/mL) and OS (ECmin150 = 66.1 µg/mL, ECavg50 = 134 µg/mL) corresponded to the median and 25th percentile of Cmin1/Cavg in the study, respectively. Maximum predicted improvement in the hazard ratio for OS and PFS was approximately 75% and 60%, respectively. There was no change in the rate of TEAEs with increasing olaratumab serum levels. CONCLUSIONS: PFS/OS benefits occurred without a rate change in TEAEs across quartiles. Maximum benefit in OS was achieved in the upper three quartiles and a potential of early disease progression in the lower quartile of olaratumab serum exposure. These results prompted a loading dose strategy in the ongoing phase 3 STS trial.

Randomised phase II study of second-line olaratumab with mitoxantrone/prednisone versus mitoxantrone/prednisone alone in metastatic castration-resistant prostate cancer.

INTRODUCTION: Platelet-derived growth factor receptor-α (PDGFRα) is expressed in primary prostate adenocarcinoma and in associated skeletal metastases. Olaratumab is a fully human monoclonal antibody that binds PDGFRα and blocks downstream signalling. This phase II study assessed the efficacy and safety of olaratumab in combination with mitoxantrone and prednisone (M/P) versus M/P alone in patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed after docetaxel. METHODS: Patients were randomised to receive 21-d cycles of olaratumab (15 mg/kg, Days 1 and 8) plus mitoxantrone (12 mg/m2, Day 1) and prednisone (5 mg, twice daily) or M/P alone. Progression-free survival (PFS) was the primary end-point. Secondary end-points included overall survival (OS), safety, and circulating tumour cell (CTC) counts. RESULTS: A total of 123 patients were randomised, 63 to olaratumab + M/P and 60 to M/P. Median PFS was 2.3 months for olaratumab + M/P and 2.4 months for M/P (hazard ratio [HR] = 1.29; 95% confidence interval [CI] = 0.87-1.90). Median OS was 14.2 months for olaratumab + M/P and 12.8 months for M/P (HR = 1.08; 95% CI = 0.72-1.61). Both treatment arms had similar toxicity profiles; neutropenia (24% versus 15%), anaemia (13% versus 14%) and fatigue (11% versus 9%) (olaratumab + M/P versus M/P, respectively) were the most common grade ≥3 events. High CTC count was associated with poorer OS in both arms. Patients with very high cell counts (>37 cells/7.5 ml) exhibited improved OS with olaratumab + M/P (interaction P = 0.043). CONCLUSIONS: Olaratumab + M/P had an acceptable safety profile but did not improve the efficacy of M/P chemotherapy. Further study with selected patient populations and earlier in the disease course might be considered.

Randomized phase II study of the PDGFRα antibody olaratumab plus liposomal doxorubicin versus liposomal doxorubicin alone in patients with platinum-refractory or platinum-resistant advanced ovarian cancer.

BACKGROUND: Olaratumab is a platelet-derived growth factor receptor-α (PDGFRα)-targeting monoclonal antibody blocking PDGFRα signaling. PDGFRα expression is associated with a more aggressive phenotype and poor ovarian cancer outcomes. This randomized, open label phase II study evaluated olaratumab plus liposomal doxorubicin compared with liposomal doxorubicin alone in advanced ovarian cancer patients. METHODS: Patients with platinum-refractory or platinum-resistant advanced ovarian cancer were randomized 1:1 to receive liposomal doxorubicin (40 mg/m2, intravenous infusion) administered every 4 weeks with or without olaratumab (20 mg/kg, IV infusion) every 2 weeks. Patients were stratified based on prior response to platinum therapy (refractory vs resistant). The primary efficacy endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate, duration of response, and safety. RESULTS: A total of 123 patients were treated (62 olaratumab+liposomal doxorubicin; 61 liposomal doxorubicin). Median PFS was 4.2 months for olaratumab+liposomal doxorubicin and 4.0 months for liposomal doxorubicin (stratified hazard ratio [HR] = 1.043; 95% confidence interval [CI] 0.698-1.558; p = 0.837). Median OS was 16.6 months and 16.2 months in the olaratumab+liposomal doxorubicin and liposomal doxorubicin arms, respectively (HR = 1.098; 95% CI 0.71-1.71). In the platinum-refractory subgroup, median PFS was 5.5 months (95% CI 1.6-9.2) and 3.7 months (95% CI 1.9-9.2) in the olaratumab+liposomal doxorubicin (n = 15) and liposomal doxorubicin arms (n = 16), respectively (HR = 0.85; 95% CI 0.38-1.91). Overall, 59.7% (olaratumab+liposomal doxorubicin) and 65.6% (liposomal doxorubicin) of patients reported grade ≥ 3 adverse events regardless of causality. The most common treatment-emergent adverse events (all grades) regardless of causality were fatigue related (61%), nausea (57%), and constipation (52%) with olaratumab+liposomal doxorubicin and nausea (64%), fatigue related (62%), and mucositis (46%) with liposomal doxorubicin. CONCLUSIONS: The addition of olaratumab to liposomal doxorubicin did not result in significant prolongation of PFS or OS in platinum-resistant or platinum-refractory ovarian cancer. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00913835 ; registered June 2, 2009.

Population Pharmacokinetic Modeling of Olaratumab, an Anti-PDGFRα Human Monoclonal Antibody, in Patients with Advanced and/or Metastatic Cancer.

BACKGROUND AND OBJECTIVES: Olaratumab is a recombinant human monoclonal antibody that binds to platelet-derived growth factor receptor-α (PDGFRα). In a randomized phase II study, olaratumab plus doxorubicin met its predefined primary endpoint for progression-free survival and achieved a highly significant improvement in overall survival versus doxorubicin alone in patients with advanced or metastatic soft tissue sarcoma (STS). In this study, we characterize the pharmacokinetics (PKs) of olaratumab in a cancer patient population. METHODS: Olaratumab was tested at 15 or 20 mg/kg in four phase II studies (in patients with nonsmall cell lung cancer, glioblastoma multiforme, STS, and gastrointestinal stromal tumors) as a single agent or in combination with chemotherapy. PK sampling was performed to measure olaratumab serum levels. PK data were analyzed by nonlinear mixed-effect modeling techniques using NONMEM®. RESULTS: The PKs of olaratumab were best described by a two-compartment PK model with linear clearance (CL). Patient body weight was found to have a significant effect on both CL and central volume of distribution (V 1), whereas tumor size significantly affected CL. A small subset of patients developed treatment-emergent anti-drug antibodies (TE-ADAs); however, TE-ADAs did not have any effect on CL or PK time course of olaratumab. There was no difference in the PKs of olaratumab between patients who received olaratumab as a single agent or in combination with chemotherapy. CONCLUSION: The PKs of olaratumab were best described by a model with linear disposition. Patient body weight and tumor size were found to be significant covariates. The PKs of olaratumab were not affected by immunogenicity or chemotherapeutic agents.

Phase II study of olaratumab with paclitaxel/carboplatin (P/C) or P/C alone in previously untreated advanced NSCLC.

BACKGROUND: In non-small cell lung cancer (NSCLC), platelet-derived growth factor receptor (PDGFR) mediates angiogenesis, tissue invasion, and tumor interstitial pressure. Olaratumab (IMC-3G3) is a fully human anti-PDGFRα monoclonal antibody. This Phase II study assessed safety and efficacy of olaratumab+paclitaxel/carboplatin (P/C) versus P/C alone for previously untreated advanced NSCLC. MATERIALS AND METHODS: Patients received up to six 21-day cycles of P 200mg/m2 and C AUC 6 (day 1)±olaratumab 15mg/kg (days 1 and 8). Primary endpoint was PFS. Olaratumab was continued in the olaratumab+P/C arm until disease progression. RESULTS: 131 patients were: 67 with olaratumab+P/C and 64 with P/C; 74% had nonsquamous NSCLC. Median PFS was similar between olaratumab+P/C and P/C (4.4 months each) (HR 1.29; 95% CI [0.86-1.93]; p=0.21). Median OS was similar between olaratumab+P/C (11.8 months) and P/C (11.5 months) (HR 1.04; 95% CI [0.68-1.57]; p=0.87). Both arms had similar toxicity profiles. All evaluable cases were PDGFR-negative by immunohistochemistry. Tumor stroma PDGFR expression was evaluable in 23/131 patients, of which 78% were positive. CONCLUSIONS: The addition of olaratumab to P/C did not result in significant prolongation of PFS or OS in advanced NSCLC. Olaratumab studies in other patient populations, including soft tissue sarcoma (NCT02783599), pancreatic cancer (NCT03086369), and pediatric malignancies (NCT02677116) are underway.

A first-in-human phase 1 study of a hepcidin monoclonal antibody, LY2787106, in cancer-associated anemia.

BACKGROUND: Hepcidin plays a central role in iron homeostasis and erythropoiesis. Neutralizing hepcidin with a monoclonal antibody (mAb) may prevent ferroportin internalization, restore iron efflux from cells, and allow transferrin-mediated iron transport to the bone marrow. This multicenter, phase 1 study evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of a fully humanized mAb (LY2787106) with high affinity for hepcidin in cancer patients with anemia. METHODS: Thirty-three patients with hepcidin levels ≥5 ng/mL received LY2787106 either every 3 weeks (19 patients, dose range 0.3-10 mg/kg) (part A) or weekly (14 patients, dose 10 mg/kg) (part B). LY2787106 PK/PD markers of iron and hematology biology were measured. RESULTS: LY2787106 clearance (32 mL/h) and volume of distribution (7.7 L) were independent of dose and time, leading to a dose-proportional increase in concentration with dose. Consistent dose-dependent increases in serum iron, and transferrin saturation were seen at the 3 and 10 mg/kg dose levels, typically peaking within 24 h after LY2787106 administration and returning to baseline by day 8. CONCLUSIONS: Our findings indicate that LY2787106 was well tolerated in cancer patients with anemia and that targeting the hepcidin-ferroportin pathway by neutralizing hepcidin resulted in transient iron mobilization, thus supporting the role of hepcidin in iron regulation. TRIAL REGISTRATION: ClinicalTrial.gov, NCT01340976.

Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial.

BACKGROUND: Treatment with doxorubicin is a present standard of care for patients with metastatic soft-tissue sarcoma and median overall survival for those treated is 12-16 months, but few, if any, novel treatments or chemotherapy combinations have been able to improve these poor outcomes. Olaratumab is a human antiplatelet-derived growth factor receptor α monoclonal antibody that has antitumour activity in human sarcoma xenografts. We aimed to assess the efficacy of olaratumab plus doxorubicin in patients with advanced or metastatic soft-tissue sarcoma. METHODS: We did an open-label phase 1b and randomised phase 2 study of doxorubicin plus olaratumab treatment in patients with unresectable or metastatic soft-tissue sarcoma at 16 clinical sites in the USA. For both the phase 1b and phase 2 parts of the study, eligible patients were aged 18 years or older and had a histologically confirmed diagnosis of locally advanced or metastatic soft-tissue sarcoma not previously treated with an anthracycline, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and available tumour tissue to determine PDGFRα expression by immunohistochemistry. In the phase 2 part of the study, patients were randomly assigned in a 1:1 ratio to receive either olaratumab (15 mg/kg) intravenously on day 1 and day 8 plus doxorubicin (75 mg/m(2)) or doxorubicin alone (75 mg/m(2)) on day 1 of each 21-day cycle for up to eight cycles. Randomisation was dynamic and used the minimisation randomisation technique. The phase 1b primary endpoint was safety and the phase 2 primary endpoint was progression-free survival using a two-sided α level of 0.2 and statistical power of 0.8. This study was registered with ClinicalTrials.gov, number NCT01185964. FINDINGS: 15 patients were enrolled and treated with olaratumab plus doxorubicin in the phase 1b study, and 133 patients were randomised (66 to olaratumab plus doxorubicin; 67 to doxorubicin alone) in the phase 2 trial, 129 (97%) of whom received at least one dose of study treatment (64 received olaratumab plus doxorubicin, 65 received doxorubicin). Median progression-free survival in phase 2 was 6.6 months (95% CI 4.1-8.3) with olaratumab plus doxorubicin and 4.1 months (2.8-5.4) with doxorubicin (stratified hazard ratio [HR] 0.67; 0.44-1.02, p=0.0615). Median overall survival was 26.5 months (20.9-31.7) with olaratumab plus doxorubicin and 14.7 months (9.2-17.1) with doxorubicin (stratified HR 0.46, 0.30-0.71, p=0.0003). The objective response rate was 18.2% (9.8-29.6) with olaratumab plus doxorubicin and 11.9% (5.3-22.2) with doxorubicin (p=0.3421). Steady state olaratumab serum concentrations were reached during cycle 3 with mean maximum and trough concentrations ranging from 419 µg/mL (geometric coefficient of variation in percentage [CV%] 26.2) to 487 µg/mL (CV% 33.0) and from 123 µg/mL (CV% 31.2) to 156 µg/mL (CV% 38.0), respectively. Adverse events that were more frequent with olaratumab plus doxorubicin versus doxorubicin alone included neutropenia (37 [58%] vs 23 [35%]), mucositis (34 [53%] vs 23 [35%]), nausea (47 [73%] vs 34 [52%]), vomiting (29 [45%] vs 12 [18%]), and diarrhoea (22 [34%] vs 15 [23%]). Febrile neutropenia of grade 3 or higher was similar in both groups (olaratumab plus doxorubicin: eight [13%] of 64 patients vs doxorubicin: nine [14%] of 65 patients). INTERPRETATION: This study of olaratumab with doxorubicin in patients with advanced soft-tissue sarcoma met its predefined primary endpoint for progression-free survival and achieved a highly significant improvement of 11.8 months in median overall survival, suggesting a potential shift in the treatment of soft-tissue sarcoma. FUNDING: Eli Lilly and Company.

An innovative, multi-arm, complete phase 1b study of the novel anti-cancer agent tasisulam in patients with advanced solid tumors.

BACKGROUND: This phase Ib study used a parallel, multi-arm design to examine tasisulam-sodium (hereafter tasisulam), a drug with complex pharmacology, combined with standard chemotherapies in patients with advanced solid tumors, with the ultimate goal of accelerating drug development. METHODS: Patients received escalating doses of tasisulam (3 + 3 schema; target Cmax 300-400 µg/mL) every 28 days plus 1,000 mg/m(2) gemcitabine HCl (days 1 and 15), 60 mg/m(2) docetaxel, 200 mg/m(2)/day temozolomide, 75 mg/m(2) cisplatin, or 150 mg/day erlotinib. Following dose-escalation, patients were enrolled into specific tumor subtype arms, chosen based on the established activity of the standard agent. Because tasisulam is highly albumin-bound, patients in the tumor-specific confirmation arms were dosed targeting specific albumin-corrected exposure ranges (AUCalb) identified during dose-escalation (3,500 h*µg/mL [75th percentile] for docetaxel, temozolomide, and cisplatin; 4,000 h*µg/mL for gemcitabine and erlotinib). RESULTS: A total of 234 patients were enrolled. The safety profile of tasisulam with standard chemotherapies was sufficient to allow enrollment into the dose-confirmation phase in all arms. The primary dose-limiting toxicities were hematologic (thrombocytopenia and neutropenia). The most common grade ≥3 drug-related treatment-emergent adverse event was neutropenia, with the highest incidence in the docetaxel arm. CONCLUSIONS: The multi-arm design allowed the efficient determination of the maximum tolerated dose of tasisulam across multiple combinations, and a preliminary characterization of pharmacokinetics, safety, and potential efficacy. Although enrollment into all planned groups was not completed due to termination of compound development, these data support the feasibility of this approach for accelerated cancer drug development, even for drugs with complex pharmacology.

A randomized, open-label clinical trial of tasisulam sodium versus paclitaxel as second-line treatment in patients with metastatic melanoma.

BACKGROUND: Tasisulam sodium (hereafter referred to as tasisulam) is a novel, highly albumin-bound agent that demonstrated activity in a phase 2 melanoma study. METHODS: In this open-label phase 3 study, patients with AJCC stage IV melanoma received tasisulam (targeting an albumin-corrected exposure of 1200-6400 h (hour).µg/mL on day 1) or paclitaxel (80 mg/m(2) on days 1, 8, and 15) every 28 days as second-line treatment. RESULTS: The study was placed on clinical hold after randomization of 336 patients when a safety review indicated an imbalance of possibly drug-related deaths in the tasisulam arm. Efficacy results for tasisulam versus paclitaxel revealed a response rate of 3.0% versus 4.8%, a median progression-free survival of 1.94 months versus 2.14 months (P = .048), and a median overall survival of 6.77 months versus 9.36 months (P = .121). The most common drug-related grade ≥3 laboratory toxicities (graded according to Common Terminology for Adverse Events [version 3.0]) were thrombocytopenia (18.9%) for patients treated with tasisulam and neutropenia/leukopenia (8.7%) among those receiving paclitaxel. There were 13 possibly related deaths reported to occur on the study, with the majority occurring during cycle 2 in the setting of grade 4 myelosuppression, all in the tasisulam arm. Investigation of the unexpectedly high rate of hematologic toxicity revealed a subset of patients with low tasisulam clearance, leading to drug accumulation and high albumin-corrected exposure in cycle 2. CONCLUSIONS: Although the study was stopped early because of safety issues in the tasisulam arm, tasisulam was considered unlikely to be superior to paclitaxel, and paclitaxel activity in the second-line treatment of melanoma was much lower than expected. The toxicity imbalance was attributed to an unexpectedly low tasisulam clearance in a subset of patients, underscoring the importance of pharmacokinetic monitoring of compounds with complex dosing, even in late-phase studies.

A phase I study of tasisulam sodium using an albumin-tailored dose in Japanese patients with advanced solid tumors.

PURPOSE: This phase I study was designed to determine the maximum tolerated dose (MTD) and the dose to be recommended for a future phase II study of tasisulam sodium in Japanese patients with advanced, refractory solid tumors. Safety, pharmacokinetics and preliminary anti-tumor activities were assessed. Due to high-affinity albumin binding, an albumin-tailored dose to reduce the variability in tasisulam exposure was also studied. METHODS: A dose escalation scheme of tasisulam was used over 4 dose levels. Dose levels 1-3 targeted the maximum plasma concentration (C max) of 300, 340, and 360 µg/mL. Dose level 4 used an albumin-tailored range of C max-targeted doses to achieve an albumin-corrected exposure (AUCalb) of 1,200-6,400 µg h/mL, the range chosen for global tasisulam studies. Tasisulam was administered intravenously on day 1 of each 21-day (dose levels 1 and 2) or 28-day (dose levels 3 and 4) cycle. RESULTS: The major adverse events were related to bone marrow suppression, particularly neutropenia and thrombocytopenia. Dose-limiting toxicities (DLTs) were not observed until dose level 4, where 3 out of 6 patients experienced DLT, despite a tendency toward lower AUCalb variability (CV %) in the albumin-tailored dose group (38 %) compared with the targeted C max groups (50-236 %). CONCLUSIONS: Tasisulam in doses up to dose level 3 (target C max 360 µg/mL) was well tolerated. Although albumin-tailored dosing provided less AUCalb variability, a MTD that aligns with other global tasisulam studies was not identified. A lower AUCalb range may be required for the Japan population.

A phase II study of tasisulam sodium (LY573636 sodium) as second-line or third-line treatment for patients with unresectable or metastatic soft tissue sarcoma.

BACKGROUND: Tasisulam sodium (hereafter tasisulam), a novel anticancer agent, is being studied in a broad range of tumors. The primary objective of this phase II study was to determine progression-free survival (PFS) in patients with 1 or 2 prior chemotherapy regimens for unresectable/metastatic soft tissue sarcoma (STS). Secondary objectives included objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS), pharmacokinetics, and safety. METHODS: Tasisulam was administered intravenously on day 1 of 21-day cycles according to a lean body weight-based dosing algorithm targeting a peak plasma concentration (C(max)) of 420 µg/mL; a 360-µg/mL dose level was also explored. RESULTS: The median age of patients treated at 420 µg/mL was 58.3 years (range, 18.6-80.4; n = 63). Median PFS was 2.64 months (90 % CI, 1.41-3.38), with a 6-month PFS rate of 11 % (90 % CI, 4-17). Median OS was 8.71 months (90 % CI, 7.39-16.23); ORR, 3.2 %; and CBR, 46.0 % (stable disease, n = 27; partial response/confirmed, n = 2 [angiosarcoma and leiomyosarcoma]; partial response/unconfirmed, n = 1 [desmoplastic small round cell tumor]). The most frequent drug-related grade 3/4 toxicities in patients treated at 420 µg/mL were thrombocytopenia (27.0 %) and neutropenia (22.2 %). Incidences of grade 4 thrombocytopenia and/or neutropenia were 20.6 % in patients treated at 420 µg/mL and 15.8 % in those treated at 360 µg/mL (n = 38). CONCLUSIONS: Tasisulam at a target C(max) of 420 µg/mL on day 1 of 21-day cycles demonstrated modest activity as second-/third-line treatment in patients with STS. Grade 4 hematologic toxicity posed some challenges in these heavily pre-treated patients. Tasisulam dosing continues to be refined.

A phase I study of tasisulam sodium (LY573636 sodium), a novel anticancer compound, administered as a 24-h continuous infusion in patients with advanced solid tumors.

PURPOSE: To determine the recommended/maximum tolerated dose (MTD), pharmacokinetics (PK), and safety profile of tasisulam sodium (hereafter tasisulam), a novel anticancer agent. METHODS: In this phase I study, tasisulam was administered as a 24-h continuous intravenous infusion on day 1, every 28 days, to patients with advanced solid tumors. A flat-dosing schema was planned for four cohorts of 3-6 patients: 600, 1,200, 2,000, and 2,500 mg. RESULTS: Twenty-six patients were enrolled. No dose-limiting toxicities (DLTs) were observed until cohort 3 (grade 3 hyperbilirubinemia). Interim PK analyses of this and another ongoing phase I study suggested that a lower dose after cycle 1 was necessary for doses ≥2,500 mg because of the long half-life of tasisulam (~14 days). Therefore, a loading dose of 2,500 mg followed by a chronic dose of 1,750 mg was implemented for cohort 4; one patient developed DLT (grade 4 neutropenia), and another developed grade 3 thrombocytopenia in cycles 2 and 3. These findings, together with PK data, which indicated a disproportionate increase in free drug relative to total tasisulam concentrations at doses >2,500 mg, led to the determination of the 2,500-/1,750-mg regimen as the MTD. Eight patients had stable disease, and two patients unconfirmed partial responses. CONCLUSIONS: When administered as a flat-dose, 24-h infusion, the MTD of tasisulam was a loading dose of 2,500 mg followed by a chronic dose of 1,750 mg, every 28 days. Consistent with the profile of the 2-h infusion in clinical development, bone marrow suppression was the major DLT.

Tasisulam sodium (LY573636 sodium) as third-line treatment in patients with unresectable, metastatic non-small-cell lung cancer: a phase-II study.

INTRODUCTION: Tasisulam sodium (hereafter referred to as tasisulam) is a novel anticancer compound that induces apoptosis and exhibits antiangiogenesis activity in a broad range of cancer models, including non-small-cell lung cancer (NSCLC). METHODS: Tasisulam was administered as a 2-hour infusion every 21 days as third-line treatment in patients with advanced (stage IIIB/IV) NSCLC. RESULTS: Thirty-two patients received a Cmax target dose of 420 µg/ml. Median time to progression was 3.12 months, median progression-free survival was 2.69 months, and median overall survival was 8.48 months. There were no objective responses; 43.8% of patients achieved stable disease. A high rate of grade-4 hematologic toxicity in the first 30 patients led to exploration of a lower Cmax target dose of 380 µg/ml. The rate of grade-4 hematologic toxicity (thrombocytopenia and/or neutropenia) at the 380-µg/ml dose (n = 20) was 20% versus 34% at the 420-µg/ml dose. CONCLUSIONS: Tasisulam has only modest activity as a third-line treatment of patients with unresectable/metastatic NSCLC. The high rate of grade-4 hematologic toxicity observed with this highly albumin- bound compound in this patient population provided challenges for fixed Cmax-based dosing. Alternative dosing methods, including varying the Cmax target dose by predose albumin, are under investigation in other studies.

Tasisulam sodium, an antitumor agent that inhibits mitotic progression and induces vascular normalization.

LY573636-sodium (tasisulam) is a small molecule antitumor agent with a novel mechanism of action currently being investigated in a variety of human cancers. In vitro, tasisulam induced apoptosis via the intrinsic pathway, resulting in cytochrome c release and caspase-dependent cell death. Using high content cellular imaging and subpopulation analysis of a wide range of in vitro and in vivo cancer models, tasisulam increased the proportion of cells with 4N DNA content and phospho-histone H3 expression, leading to G(2)-M accumulation and subsequent apoptosis. Tasisulam also blocked VEGF, epidermal growth factor, and fibroblast growth factor-induced endothelial cell cord formation but did not block acute growth factor receptor signaling (unlike sunitinib, which blocks VEGF-driven angiogenesis at the receptor kinase level) or induce apoptosis in primary endothelial cells. Importantly, in vivo phenocopying of in vitro effects were observed in multiple human tumor xenografts. Tasisulam was as effective as sunitinib at inhibiting neovascularization in a Matrigel plug angiogenesis assay in vivo and also caused reversible, non G(2)-M-dependent growth arrest in primary endothelial cells. Tasisulam also induced vascular normalization in vivo. Interestingly, the combination of tasisulam and sunitinib significantly delayed growth of the Caki-1 renal cell carcinoma model, whereas neither agent was active alone. These data show that tasisulam has a unique, dual-faceted mechanism of action involving mitotic catastrophe and antiangiogenesis, a phenotype distinct from conventional chemotherapies and published anticancer agents.

A phase 2 study of tasisulam sodium (LY573636 sodium) as second-line treatment for patients with unresectable or metastatic melanoma.

BACKGROUND: Tasisulam sodium (hereafter, tasisulam) is a novel anticancer agent that induces apoptosis through the intrinsic pathway and has antiangiogenic activity in preclinical models. Tasisulam demonstrated activity across a broad range of tumors, including melanoma. The primary objective of this phase 2 study was to determine the objective response rate (ORR) in patients who had received 1 previous systemic chemotherapy for unresectable/metastatic melanoma; secondary objectives were to evaluate the clinical response rate (CRR), progression-free survival (PFS), overall survival (OS), duration of response, safety, and pharmacokinetics. METHODS: Tasisulam was administered intravenously on Day 1 of 21-day cycles according to a lean body weight-based dosing algorithm targeting a peak plasma concentration (C(max)) of 420 µg/mL. RESULTS: In 68 enrolled patients, the median age was 59 years (range, 26-83 years). No patients had a complete response (CR), 8 patients had a partial response (PR), and 24 patients had stable disease (SD); the ORR (CR + PR) was 11.8%, and the CRR (CR + PR + SD) was 47.1%. The median PFS was 2.6 months, and the median OS was 9.6 months. The predominant treatment-related grade 3/4 toxicity was thrombocytopenia (20.6% of patients). Tasisulam exhibited a biexponential disposition with a predicted distribution half-life of 0.3 hours to 2.8 hours and a median terminal elimination half-life of 10 days (consistent with the turnover of albumin), suggesting that tasisulam is very tightly bound to albumin. CONCLUSIONS: Tasisulam administered at a targeted C(max) of 420 µg/mL on Day 1 of 21-day cycles demonstrated activity and tolerable toxicity as second-line treatment in malignant melanoma. These results led to a registration trial in metastatic melanoma.

A phase I study of tasisulam sodium (LY573636 sodium), a novel anticancer compound in patients with refractory solid tumors.

PURPOSE: This phase I study was carried out to determine the phase II recommended dose of tasisulam sodium (hereafter, tasisulam), a novel anticancer agent with a unique mechanism of action. METHODS: Tasisulam was administered intravenously, every 21 days, in patients with refractory solid tumors using a three-plus-three dose-escalation schema. RESULTS: Fifty-three patients were enrolled; the first 34 were treated with a flat dose of tasisulam of up to 2,400 mg, the dose level at which all three patients had dose-limiting toxicity (DLT). Controlling for C(max) proved important to reduce the risk of toxicity; therefore, we initially focused on identifying which parameters explained C(max) (end-of-infusion concentration) variability. Pharmacokinetic analysis indicated that C(max) negatively correlates with lean body weight (LBW). Thus, the dosing regimen was revised using a LBW-based algorithm targeting a specific C(max). A loading/chronic dose paradigm was then implemented as pharmacokinetic results revealed a long terminal half-life of tasisulam, likely because of its high-affinity albumin binding. C(max)-based dose escalation was stopped at the 420-µg/mL cohort, in which one of the 16 patients had DLT (transient hepatic transaminase elevation); grade 3/4 hematologic toxicity was noted in later cycles in three patients. Although response was not a primary objective, 33% of heavily pretreated patients with post-dose radiological assessments had stable disease. CONCLUSION: Implementation of a novel targeted C(max)-based dosing regimen allowed for the recommendation of a phase II tasisulam dose (loading dose of 420 µg/mL targeted C(max) with all subsequent doses administered at 65% of chronic dose given every 21 days) despite pharmacological challenges posed by high albumin binding.

Novel acyl sulfonamide LY573636-sodium: effect on hematopoietic malignant cells.

LY573636-sodium is a promising anti-tumor agent, which causes growth arrest and apoptosis of a variety of human solid tumors in vitro and in vivo. Moreover, studies have shown that the compound is selectively toxic towards tumor cells over their normal counterparts. This targeted effect makes LY573636 a candidate for combined therapy regimens in patients with advanced or resistant cancers. We studied for the first time, the anti-tumor properties of LY573636 against a variety of human hematopoietic malignancies, including AML, B-ALL, large B-cell and mantle cell lymphoma cell lines. Cells were treated with the compound in vitro and its effect on cell proliferation, apoptosis and differentiation was determined. The cell lines underwent growth arrest in response to treatment with LY573636 in a dose-dependent manner. This antiproliferative activity was associated with the induction of apoptosis, loss of mitochondrial membrane potential and induction of reactive oxygen species. Furthermore, we showed that LY573636 was able to induce granulocytic/monocytic differentiation of HL60 and U937 cells. LY573636, as shown before in solid tumors, is effective in hematopoietic cell lines as well. These data suggest the use of LY573636 alone or in combination with conventional chemotherapeutic regimens in hematopoietic malignancies.

Imatinib mesylate inhibits antigen-specific memory CD8 T cell responses in vivo.

Imatinib mesylate (IM) is effective at inducing complete cytogenetic remission in patients with chronic myelogenous leukemia. Because its influence on CD8 T cell responsiveness in vivo is unknown, we investigated the effects of IM by analyzing the response of OT-1 CD8 T cells to Listeria monocytogenes (LM) that express the cognate epitope OVA(257-264) (LM-OVA). In vitro, IM had no effect on Ag-specific expansion, cell division, cell cycle progression, or IFN-gamma expression in naive or memory OT-1 T cells. However, IM induced apoptosis of naive and memory OT-1 T cells at doses of >5 microM. At 15 microM IM, OT-1 T cells did not survive in in vitro cultures. The primary response of OT-1 T cells in vivo to LM-OVA infection was unaltered. In contrast, continuous IM treatment resulted in a diminished memory OT-1 response. The expression of IL-7Ralpha, a receptor required for memory cell survival, was lower (on OT-1 cells) in animals receiving IM. These results indicate that IM treatment affects the ability of the CD8 memory pool to respond to Ag and has the potential to increase susceptibility to infection.