LXR/ApoE Activation Restricts Innate Immune Suppression in Cancer.

Therapeutic harnessing of adaptive immunity via checkpoint inhibition has transformed the treatment of many cancers. Despite unprecedented long-term responses, most patients do not respond to these therapies. Immunotherapy non-responders often harbor high levels of circulating myeloid-derived suppressor cells (MDSCs)-an immunosuppressive innate cell population. Through genetic and pharmacological approaches, we uncovered a pathway governing MDSC abundance in multiple cancer types. Therapeutic liver-X nuclear receptor (LXR) agonism reduced MDSC abundance in murine models and in patients treated in a first-in-human dose escalation phase 1 trial. MDSC depletion was associated with activation of cytotoxic T lymphocyte (CTL) responses in mice and patients. The LXR transcriptional target ApoE mediated these effects in mice, where LXR/ApoE activation therapy elicited robust anti-tumor responses and also enhanced T cell activation during various immune-based therapies. We implicate the LXR/ApoE axis in the regulation of innate immune suppression and as a target for enhancing the efficacy of cancer immunotherapy in patients.

LOAd703, an oncolytic virus-based immunostimulatory gene therapy, combined with chemotherapy for unresectable or metastatic pancreatic cancer (LOKON001): results from arm 1 of a non-randomised, single-centre, phase 1/2 study.

BACKGROUND: Pancreatic ductal adenocarcinoma is characterised by low immunogenicity and an immunosuppressive tumour microenvironment. LOAd703, an oncolytic adenovirus with transgenes encoding TMZ-CD40L and 4-1BBL, lyses cancer cells selectively, activates cytotoxic T cells, and induces tumour regression in preclinical models. The aim of this study was to evaluate the safety and feasibility of combining LOAd703 with chemotherapy for advanced pancreatic ductal adenocarcinoma. METHODS: LOKON001 was a non-randomised, phase 1/2 study conducted at the Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA, and consisted of two arms conducted sequentially; the results of arm 1 are presented here. In arm 1, patients 18 years or older with previously treated or treatment-naive unresectable or metastatic pancreatic ductal adenocarcinoma were treated with standard 28-day cycles of intravenous nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 (up to 12 cycles) and intratumoural injections of LOAd703 every 2 weeks. Patients were assigned using Bayesian optimal interval design to receive 500 µL of LOAd703 at 5 × 1010 (dose 1), 1 × 1011 (dose 2), or 5 × 1011 (dose 3) viral particles per injection, injected endoscopically or percutaneously into the pancreatic tumour or a metastasis for six injections. The primary endpoints were safety and treatment-emergent immune response in patients who received at least one dose of LOAd703, and antitumour activity was a secondary endpoint. This study was registered with ClinicalTrials.gov, NCT02705196, arm 2 is ongoing and open to new participants. FINDINGS: Between Dec 2, 2016, and Oct 17, 2019, 23 patients were assessed for eligibility, leading to 22 patients being enrolled. One patient withdrew consent, resulting in 21 patients (13 [62%] men and eight [38%] women) assigned to a dose group (three to dose 1, four to dose 2, and 14 to dose 3). 21 patients were evaluable for safety. Median follow-up time was 6 months (IQR 4-10), and data cutoff was Jan 5, 2023. The most common treatment-emergent adverse events overall were anaemia (96 [8%] of 1237 events), lymphopenia (86 [7%] events), hyperglycaemia (70 [6%] events), leukopenia (63 [5%] events), hypertension (62 [5%] events), and hypoalbuminaemia (61 [5%] events). The most common adverse events attributed to LOAd703 were fever (14 [67%] of 21 patients), fatigue (eight [38%]), chills (seven [33%]), and elevated liver enzymes (alanine aminotransferase in five [24%], alkaline phosphatase in four [19%], and aspartate aminotransferase in four [19%]), all of which were grade 1-2, except for a transient grade 3 aminotransferase elevation occurring at dose 3. A maximum tolerated dose was not reached, thereby establishing dose 3 as the highest-evaluated safe dose when combined with nab-paclitaxel plus gemcitabine. Proportions of CD8+ effector memory cells and adenovirus-specific T cells increased after LOAd703 injections in 15 (94%) of 16 patients for whom T-cell assays could be performed. Eight (44%, 95% CI 25-66) of 18 patients evaluable for activity had an objective response. INTERPRETATION: Combining LOAd703 with nab-paclitaxel plus gemcitabine in patients with advanced pancreatic ductal adenocarcinoma was feasible and safe. To build upon this novel chemoimmunotherapeutic approach, arm 2 of LOKON001, which combines LOAd703, nab-paclitaxel plus gemcitabine, and atezolizumab, is ongoing. FUNDING: Lokon Pharma, the Swedish Cancer Society, and the Swedish Research Council.

Phase 1 study of the protein deubiquitinase inhibitor VLX1570 in patients with relapsed and/or refractory multiple myeloma.

This phase 1 study sought to characterize the safety, tolerability, and pharmacokinetic behavior of VLX1570, a small molecule inhibitor of the deubiquitinases (DUBs) that remove sterically bulky ubiquitin chains from proteins during processing in the19S regulatory subunit of the proteasome, in patients with relapsed and refractory multiple myeloma (MM). Fourteen patients were treated with escalating doses of VLX1570 ranging from 0.05 to 1.2 mg/kg as a brief intravenous (IV) infusion on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Due to its poor aqueous solubility, VLX1570 was formulated in polyethylene glycol, polyoxyethylated castor oil, and polysorbate 80 and administered as a brief intravenous (IV) infusion via a central venous catheter. Anti-myeloma effects were noted at doses at or above 0.6 mg/kg, however, two patients treated at the 1.2 mg/kg dose level experienced severe, abrupt, and progressive respiratory insufficiency, which was associated with diffuse pulmonary infiltrates on imaging studies, similar to those rarely noted with bortezomib and other inhibitors of the 20S proteasome, culminating in death. Although the contribution of VLX1570's formulation to the pulmonary toxicity could not be ruled out, the severity and precipitous nature of the toxicity and the steep relationship between dose and toxicity, the study was discontinued. Despite the severe pulmonary toxicity noted with VLX1570, efforts directed at identifying DUB inhibitors with greater therapeutic indices appear warranted based on the unique mechanism of action, robustness of preclinical antitumor activity, and activity of the DUB inhibitors in MM resistant to PIs targeting the 20S proteasome subunit.

A Phase 1 Trial of CNDO-109-Activated Natural Killer Cells in Patients with High-Risk Acute Myeloid Leukemia.

Natural killer (NK) cells are an emerging immunotherapy approach to acute myeloid leukemia (AML); however, the optimal approach to activate NK cells before adoptive transfer remains unclear. Human NK cells that are primed with the CTV-1 leukemia cell line lysate CNDO-109 exhibit enhanced cytotoxicity against NK cell-resistant cell lines. To translate this finding to the clinic, CNDO-109-activated NK cells (CNDO-109-NK cells) isolated from related HLA-haploidentical donors were evaluated in a phase 1 dose-escalation trial at doses of 3 × 105 (n = 3), 1 × 106 (n = 3), and 3 × 106 (n = 6) cells/kg in patients with AML in first complete remission (CR1) at high risk for recurrence. Before CNDO-109-NK cell administration, patients were treated with lymphodepleting fludarabine/cyclophosphamide. CNDO-109-NK cells were well tolerated, and no dose-limiting toxicities were observed at the highest tested dose. The median relapse-free survival (RFS) by dose level was 105 (3 × 105), 156 (1 × 106), and 337 (3 × 106) days. Two patients remained relapse-free in post-trial follow-up, with RFS durations exceeding 42.5 months. Donor NK cell microchimerism was detected on day 7 in 10 of 12 patients, with 3 patients having evidence of donor cells on day 14 or later. This trial establishes that CNDO-109-NK cells generated from related HLA haploidentical donors, cryopreserved, and then safely administered to AML patients with transient persistence without exogenous cytokine support. Three durable complete remissions of 32.6 to 47.6+ months were observed, suggesting additional clinical investigation of CNDO-109-NK cells for patients with myeloid malignancies, alone or in combination with additional immunotherapy strategies, is warranted.

Activity of SL-401, a targeted therapy directed to interleukin-3 receptor, in blastic plasmacytoid dendritic cell neoplasm patients.

This is the first prospective study of treatment of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive hematologic malignancy derived from plasmacytoid dendritic cells that typically involves the skin and rapidly progresses to a leukemia phase. Despite being initially responsive to intensive combination chemotherapy, most patients relapse and succumb to their disease. Because BPDCN blasts overexpress the interleukin-3 receptor (IL3R), the activity of SL-401, diptheria toxin (DT)388IL3 composed of the catalytic and translocation domains of DT fused to IL3, was evaluated in BPDCN patients in a phase 1-2 study. Eleven patients were treated with a single course of SL-401 at 12.5 µg/kg intravenously over 15 minutes daily for up to 5 doses; 3 patients who had initial responses to SL-401 received a second course in relapse. The most common adverse events including fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia were transient. Seven of 9 evaluable (78%) BPDCN patients had major responses including 5 complete responses and 2 partial responses after a single course of SL-401. The median duration of responses was 5 months (range, 1-20+ months). Further studies of SL-401 in BPDCN including those involving multiple sequential courses, alternate schedules, and combinations with other therapeutics are warranted. This trial is registered at clinicaltrials.gov as #NCT00397579.

In vivo and in vitro sensitivity of blastic plasmacytoid dendritic cell neoplasm to SL-401, an interleukin-3 receptor targeted biologic agent.

Blastic plasmacytoid dendritic cell neoplasm is an aggressive malignancy derived from plasmacytoid dendritic cells. There is currently no accepted standard of care for treating this neoplasm, and therapeutic strategies have never been prospectively evaluated. Since blastic plasmacytoid dendritic cell neoplasm cells express high levels of interleukin-3 receptor α chain (IL3-Rα or CD123), antitumor effects of the interleukin-3 receptor-targeted drug SL-401 against blastic plasmacytoid dendritic cell neoplasm were evaluated in vitro and in vivo. The cytotoxicity of SL-401 was assessed in patient-derived blastic plasmacytoid dendritic cell neoplasm cell lines (CAL-1 and GEN2.2) and in primary blastic plasmacytoid dendritic cell neoplasm cells isolated from 12 patients using flow cytometry and an in vitro cytotoxicity assay. The cytotoxic effects of SL-401 were compared to those of several relevant cytotoxic agents. SL-401 exhibited a robust cytotoxicity against blastic plasmacytoid dendritic cell neoplasm cells in a dose-dependent manner. Additionally, the cytotoxic effects of SL-401 were observed at substantially lower concentrations than those achieved in clinical trials to date. Survival of mice inoculated with a blastic plasmacytoid dendritic cell neoplasm cell line and treated with a single cycle of SL-401 was significantly longer than that of untreated controls (median survival, 58 versus 17 days, P<0.001). These findings indicate that blastic plasmacytoid dendritic cell neoplasm cells are highly sensitive to SL-401, and support further evaluation of SL-401 in patients suffering from blastic plasmacytoid dendritic cell neoplasm.

SL-401 and SL-501, targeted therapeutics directed at the interleukin-3 receptor, inhibit the growth of leukaemic cells and stem cells in advanced phase chronic myeloid leukaemia.

While imatinib and other tyrosine kinase inhibitors (TKIs) are highly efficacious in the treatment of chronic myeloid leukaemia (CML), some patients become refractory to these therapies. After confirming that interleukin-3 receptor (IL3R, CD123) is highly expressed on CD34(+) /CD38(-) BCR-ABL1(+) CML stem cells, we investigated whether targeting IL3R with diphtheria toxin (DT)-IL3 fusion proteins SL-401 (DT388 -IL3) and SL-501 (DT388 -IL3[K116W]) could eradicate these stem cells. SL-401 and SL-501 inhibited cell growth and induced apoptosis in the KBM5 cell line and its TKI-resistant KBM5-STI subline. Combinations of imatinib with these agents increased apoptosis in KBM5 and in primary CML cells. In six primary CML samples, including CML cells harbouring the ABL1 T315I mutation, SL-401 and SL-501 decreased the absolute numbers of viable CD34(+) /CD38(-) /CD123(+) CML progenitor cells by inducing apoptosis. IL3-targeting agents reduced clonogenic growth and diminished the fraction of primitive long-term culture-initiating cells in samples from patients with advanced phase CML that were resistant to TKIs or harboured an ABL1 mutation. Survival was also extended in a mouse model of primary TKI-resistant CML blast crisis. These data suggest that the DT-IL3 fusion proteins, SL-401 and SL-501, deplete CML stem cells and may increase the effectiveness of current CML treatment, which principally targets tumour bulk.

Safety, pharmacokinetics, and pharmacodynamics in healthy Chinese volunteers treated with SC0062, a highly selective endothelin-A receptor antagonist.

This study evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and food effects (FE) of SC0062, a highly active endothelin-A (ETA ) receptor antagonist, in healthy subjects. The primary objectives of this first-in-human phase I study, comprised of single-ascending-dose, multiple-ascending-dose, and FE parts, were to characterize the safety and tolerability of SC0062, and FE. The secondary objectives were to determine the PK behavior of SC0062 and its major active metabolite M18, whereas exploratory objectives focused on PD effects, principally effects on endothelin-1 (ET-1) and total bile acids (TBA). Single doses of 10 to 100 mg and multiple daily doses of 20 and 50 mg for 6 days were well tolerated. SC0062 was rapidly absorbed and plasma exposure of SC0062 and M18 increased disproportionately with dose, achieving steady state by day 3, with accumulation ratios of 1.22 and 1.89 on day 6 for SC0062 and M18, respectively. The geometric mean (geometric standard deviation) terminal elimination half-life (t1/2 ) values of SC0062 and M18 were 7.25 (1.70) h and 13.73 (1.32) h, respectively. Plasma ET-1 concentrations were dose-proportional, whereas plasma TBA concentrations behaved erratically. Following a single 50 mg dose of SC0062 after a high-fat meal, Cmax values for SC0062 and M18 increased by 41% and 32%, respectively, and median Tmax values for SC0062 were 3 h longer than fasting values; exposure was unaffected. These favorable safety, PK, and PD results provide a foundation for further studies of SC0062 in pulmonary arterial hypertension, chronic kidney disease, and other relevant indications.

A phase II randomized study of cetuximab and bevacizumab alone or in combination with gemcitabine as first-line therapy for metastatic pancreatic adenocarcinoma.

The purpose of this study was to assess the efficacy and safety of bevacizumab plus cetuximab with or without gemcitabine in patients with advanced pancreatic adenocarcinoma. Patients with locally advanced or metastatic pancreatic adenocarcinoma, previously untreated, were randomized to bevacizumab (10 mg/kg q2w) plus cetuximab (400/250 mg/m(2) initial/weekly), either with (Arm A) or without (Arm B) gemcitabine (1000 mg/m(2) weekly × 3 of 4 weeks). Tumor assessments were performed q8w. Primary study endpoint was progression-free survival (PFS). Sixty-one patients were randomized to Arm A (n = 30) or Arm B (n = 31). Median treatment duration was 9 weeks in Arm A and 8 weeks in Arm B (range, 2.0-40.4). Patients in Arm A had median PFS and overall survival values of 3.55 months and 5.41 months, respectively, compared to 1.91 months and 4.17 months in Arm B. The study closed early due to lack of sufficient efficacy in both treatment arms. Although both regimens were well tolerated, patients treated with gemcitabine experienced more grade 3-4 toxicities, including proteinuria and thromboembolic events. The combination of cetuximab and bevacizumab did not result in promising activity with or without gemcitabine, suggesting that a strategy of dual EGFR/VEGF inhibition in pancreatic cancer does not warrant further development. To our knowledge, this is one of the first trials to evaluate a completely noncytotoxic regimen in the first-line treatment of advanced pancreatic cancer. (ClinicalTrials.gov number, NCT00326911).

Phase I and pharmacokinetic study of 3'-C-ethynylcytidine (TAS-106), an inhibitor of RNA polymerase I, II and III,in patients with advanced solid malignancies.

BACKGROUND: TAS-106 is a novel nucleoside analog that inhibits RNA polymerases I, II and II and has demonstrated robust antitumor activity in a wide range of models of human cancer in preclinical studies. This study was performed to principally evaluate the feasibility of administering TAS-106 as a bolus intravenous (IV) infusion every 3 weeks. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of TAS-106 as a single bolus IV infusion every 3 weeks. Plasma and urine sampling were performed during the first course to characterize the pharmacokinetic profile of TAS-106 and assess pharmacodynamic relationships. RESULTS: Thirty patients were treated with 66 courses of TAS-106 at eight dose levels ranging from 0.67-9.46 mg/m(2). A cumulative sensory peripheral neuropathy was the principal dose-limiting toxicity (DLT) of TAS-106 at the 6.31 mg/m(2) dose level, which was determined to be the maximum tolerated dose (MTD). Other mild-moderate drug-related toxicities include asthenia, anorexia, nausea, vomiting, myelosuppression, and dermatologic effects. Major objective antitumor responses were not observed. The pharmacokinetics of TAS-106 were dose-proportional. The terminal elimination half-life (t(1/2)) averaged 11.3 ± 3.3 h. Approximately 71% of TAS-106 was excreted in the urine as unchanged drug. Pharmacodynamic relationships were observed between neuropathy and: C(5min;) AUC(0-inf;) and dermatologic toxicity. CONCLUSIONS: The recommended phase II dose of TAS-106 is 4.21 mg/m(2). However, due to a cumulative drug-related peripheral sensory neuropathy that proved to be dose-limiting, further evaluation of this bolus every 21 day infusion schedule will not be pursued and instead, an alternate dosing schedule of TAS-106 administered as a continuous 24-hour infusion will be explored to decrease C(max) in efforts to minimize peripheral neuropathy and maximize antitumor activity.

A phase II, multicenter study of cetuximab monotherapy in patients with refractory, metastatic colorectal carcinoma with absent epidermal growth factor receptor immunostaining.

PURPOSE: To determine antitumor activity of cetuximab monotherapy in patients with refractory metastatic colorectal carcinoma (mCRC) with lack of specific membrane immunostaining for the epidermal growth factor receptor (EGFR). PATIENTS AND METHODS: Patients had immunohistochemical (IHC)-determined mCRC with absent EGFR immunostaining that progressed after receiving at least one standard, fluoropyrimidine-containing chemotherapeutic regimen. Absent EGFR immunostaining was defined as the IHC absence of specific membrane staining in ≥500 cancer cells examined in well-preserved tissue. The study was performed prior to results of studies linking cetuximab sensitivity to K-ras mutation status. Patients received 400 mg/m(2) of intravenous (i.v.) cetuximab followed by once-weekly i.v. cetuximab 250 mg/m(2) until disease progression or unacceptable toxicity. Patients were evaluated for objective response at least every 6 weeks. Kaplan-Meier estimates were calculated for duration of response, time to progression (TTP), and overall survival (OS). RESULTS: Seven (8.2%) of 85 mCRC patients whose tumors lacked EGFR immunostaining had major responses following cetuximab treatment. The median duration of response was 5.1 months. Median TTP and OS were 2.5 months and 10.0 months, respectively; the 1-year survival rate was 39.6%. The most frequently reported cetuximab-related adverse events were acneiform dermatitis, fatigue, headache, and dry skin. CONCLUSION: Cetuximab monotherapy produces objective antitumor activity in patients with mCRC that does not express EGFR as determined by IHC. The activity and safety profiles of cetuximab monotherapy in mCRC lacking EGFR immunostaining are similar to previous observations in EGFR IHC-positive disease that was not selected based on K-ras mutation status.

A phase 2 study of SP1049C, doxorubicin in P-glycoprotein-targeting pluronics, in patients with advanced adenocarcinoma of the esophagus and gastroesophageal junction.

PURPOSE: To evaluate the antitumor activity of SP1049C, a novel P-glycoprotein targeting micellar formulation of doxorubicin, consisting of doxorubicin and two non-ionic block copolymers (pluronics), in patients with advanced adenocarcinoma of the esophagus and gastroesophageal junction (GEJ). PATIENTS AND METHODS: Patients with metastatic or locally advanced unresectable adenocarcinoma of the esophagus or GEJ who had not previously received systemic chemotherapy and had measurable disease were treated with SP1049C 75 mg/m(2) (doxorubicin equivalents) as a brief intravenous infusion every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate in patients who had received a least one course of SP1049C and had undergone tumor assessment, whereas, secondary endpoints included the objective response rate, progression-free survival (PFS), overall survival, and safety in the intent-to-treat (ITT) population. A review of scans was also conducted post-hoc by a blinded panel of radiologists. RESULTS: Twenty-one patients, of which 19 were evaluable for response, were treated with at least one dose of SP1049C. Nine patients had a partial response (PR) and eight patients had either a minor response or stable disease as their best response. The objective response rate was 47% (95% CI: 24.4-71) in the evaluable patient population, whereas the objective response rate was 43% (95% CI: 21.8-65.9) in the ITT population. The post-hoc radiological review confirmed that all nine responders had a PR; seven of the nine had a PR that was confirmed by a subsequent scan, whilst two patients had unconfirmed PRs. The median overall survival and PFS were 10.0 months (95%CI: 4.8-11.2) and 6.6 months (95% CI: 4.5-7.6), respectively. Neutropenia was the principal toxicity of SP1049C. Four patients developed an absolute percentage decrement of at least 15% in their left ventricular ejection fraction, none of which decreased to below 45% nor were symptomatic. CONCLUSION: SP1049C has a notable single-agent activity in patients with adenocarcinoma of the esophagus and GEJ, as well as an acceptable safety profile. These results, in addition to the results of preclinical studies demonstrating superior antitumor activity of SP1049C compared with doxorubicin in a standard formulation, indicate that further evaluations of SP1049C alone or combined with other relevant therapeutics in this disease setting are warranted.

Efficacy and safety of sorafenib in a subset of patients with advanced soft tissue sarcoma from a Phase II randomized discontinuation trial.

AIM: Phase II multi-disease randomized discontinuation trial to assess the safety and efficacy of sorafenib including patients with advanced soft tissue sarcoma (STS). METHODS: Sorafenib (400 mg twice daily) was initially administered for 12 weeks. Patients with: ≥25% tumour shrinkage continued sorafenib; ≥25% tumour growth discontinued; other patients were randomized and received sorafenib or placebo. RESULTS: Twenty-six patients (median age 55 years) were enrolled. Common drug-related adverse events, including fatigue, hand-foot skin reaction, rash or gastrointestinal disturbances, were manageable, reversible and generally low grade. Fatigue, skin toxicity, nausea, diarrhoea and hypertension occurred at grade ≥3 in 19% of patients. After 12 weeks eight (31%) patients had not progressed. Three patients who experienced tumour shrinkage and continued on sorafenib, and five (19%) were randomized either to continue sorafenib or to receive placebo. Of the three patients randomized to sorafenib, one achieved a partial response and two had SD. Overall one patient achieved a partial response and three further patients achieved minor responses. CONCLUSIONS: There was evidence of disease activity in STS as defined by tumor regressions including one objective partial response. Further investigation in STS is warranted.

Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival.

BACKGROUND: Previous results from our phase 3 randomised trial showed that adding cetuximab to primary radiotherapy increased overall survival in patients with locoregionally advanced squamous-cell carcinoma of the head and neck (LASCCHN) at 3 years. Here we report the 5-year survival data, and investigate the relation between cetuximab-induced rash and survival. METHODS: Patients with LASCCHN of the oropharynx, hypopharynx, or larynx with measurable disease were randomly allocated in a 1:1 ratio to receive either comprehensive head and neck radiotherapy alone for 6-7 weeks or radiotherapy plus weekly doses of cetuximab: 400 mg/m(2) initial dose, followed by seven weekly doses at 250 mg/m(2). Randomisation was done with an adaptive minimisation technique to balance assignments across stratification factors of Karnofsky performance score, T stage, N stage, and radiation fractionation. The trial was un-blinded. The primary endpoint was locoregional control, with a secondary endpoint of survival. Following discussions with the US Food and Drug Administration, the dataset was locked, except for queries to the sites about overall survival, before our previous report in 2006, so that an independent review could be done. Analyses were done on an intention-to-treat basis. Following completion of treatment, patients underwent physical examination and radiographic imaging every 4 months for 2 years, and then every 6 months thereafter. The trial is registered at www.ClinicalTrials.gov, number NCT00004227. FINDINGS: Patients were randomly assigned to receive radiotherapy with (n=211) or without (n=213) cetuximab, and all patients were followed for survival. Updated median overall survival for patients treated with cetuximab and radiotherapy was 49.0 months (95% CI 32.8-69.5) versus 29.3 months (20.6-41.4) in the radiotherapy-alone group (hazard ratio [HR] 0.73, 95% CI 0.56-0.95; p=0.018). 5-year overall survival was 45.6% in the cetuximab-plus-radiotherapy group and 36.4% in the radiotherapy-alone group. Additionally, for the patients treated with cetuximab, overall survival was significantly improved in those who experienced an acneiform rash of at least grade 2 severity compared with patients with no rash or grade 1 rash (HR 0.49, 0.34-0.72; p=0.002). INTERPRETATION: For patients with LASCCHN, cetuximab plus radiotherapy significantly improves overall survival at 5 years compared with radiotherapy alone, confirming cetuximab plus radiotherapy as an important treatment option in this group of patients. Cetuximab-treated patients with prominent cetuximab-induced rash (grade 2 or above) have better survival than patients with no or grade 1 rash. FUNDING: ImClone Systems, Merck KGaA, and Bristol-Myers Squibb.

Phase I, pharmacokinetic study of temsirolimus administered orally to patients with advanced cancer.

An oral formulation of temsirolimus (Torisel), an inhibitor of the mammalian target of rapamycin, was evaluated on an intermittent schedule (once daily for 5 days every 2 weeks) in patients with advanced cancer. The maximum tolerated dose was determined to be 75 mg after dose-limiting toxicities of grade 3 elevated aminotransferases (1 patient) and grade 3 rash (1 patient) occurred with a 100-mg dose. The most common temsirolimus-related adverse events were mucositis, rash/maculopapular rash, and asthenia. Six of 12 patients who received the 75-mg dose required dose reductions due to temsirolimus-related adverse events. Two patients who received 75-mg temsirolimus and did not have dose reductions had minor tumor responses. Relative exposure from contributions of both temsirolimus and sirolimus, the principal metabolite, was 17.9% of the 75-mg dose. Thus, oral temsirolimus, 75 mg administered once daily for 5 days every 2 weeks, was further evaluated in patients with metastatic breast cancer.

Phase I and pharmacokinetic study of XRP6258 (RPR 116258A), a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid tumors.

PURPOSE: To assess the feasibility of administering XRP6258, a new taxane with a low affinity for the multidrug resistance 1 protein, as a 1-hour i.v. infusion every 3 weeks. The study also sought to determine the maximum tolerated dose and the recommended dose, to describe the pharmacokinetic (PK) behavior of the compound, and to seek preliminary evidence of anticancer activity. EXPERIMENTAL DESIGN: Twenty-five patients with advanced solid malignancies were treated with 102 courses of XRP6258 at four dose levels ranging from 10 to 25 mg/m(2). Dose escalation was based on the occurrence of dose-limiting toxicity (DLT) at each dose level, provided that PK variables were favorable. The maximum tolerated dose was defined as the dose at which at least two patients developed a DLT at the first course. RESULTS: Neutropenia was the principal DLT, with one patient experiencing febrile neutropenia and two others showing prolonged grade 4 neutropenia at the 25 mg/m(2) dose level. Nonhematologic toxicities, including nausea, vomiting, diarrhea, neurotoxicity, and fatigue, were generally mild to moderate in severity. XRP6258 exhibited dose-proportional PK, a triphasic elimination profile, a long terminal half-life (77.3 hours), a high clearance (mean CL, 53.5 L/h), and a large volume of distribution (mean V(ss), 2,034 L/m(2)). Objective antitumor activity included partial responses in two patients with metastatic prostate carcinoma, one unconfirmed partial response, and two minor responses. CONCLUSION: The recommended phase II dose of XRP6258 on this schedule is 20 mg/m(2). The general tolerability and encouraging antitumor activity in taxane-refractory patients warrant further evaluations of XRP6258.

Phase I and pharmacokinetic study of trabectedin as a 1- or 3-hour infusion weekly in patients with advanced solid malignancies.

PURPOSE: This study was designed to determine the safety, tolerability, and pharmacokinetics, and to seek preliminary evidence of anticancer activity of trabectedin, a novel marine-derived DNA minor grove binder, when administered as a 1-hour or 3-hour i.v. infusion for 3 consecutive weeks every 4 weeks in patients with advanced solid malignancies. The study also sought to determine the maximum tolerated dose (MTD) levels of trabectedin on these schedules, as well as to recommend doses for disease-directed studies. EXPERIMENTAL DESIGN: A total of 32 and 31 patients were treated in sequential cohorts with trabectedin on the 1-hour schedule (doses ranging from 0.46 to 0.80 mg/m(2)) and on the 3-hour schedule (doses ranging from 0.30 to 0.65 mg/m(2)). RESULTS: Neutropenia, transient elevations in hepatic transaminases and creatine phosphokinase, and fatigue precluded dose escalation above 0.70 mg/m(2) (1-hour schedule) and 0.65 mg/m(2) (3-hour schedule), which were determined to be the MTD levels, respectively. The pharmacokinetics of trabectedin on both schedules were characterized by a high clearance rate, a long terminal half-life, and a large volume of distribution. A patient with soft tissue sarcoma had partial response, and several soft tissue sarcoma patients had prolonged (> or =6 months) stable disease. CONCLUSIONS: The MTD levels of trabectedin given weekly for 3 weeks every 4 weeks is 0.61 mg/m(2) as a 1-hour infusion and 0.58 mg/m(2) as a 3-hour infusion. The manageable toxicities at the MTDs, preliminary evidence of antitumor activity, pharmacokinetic profile, and the unique mechanistic aspects of trabectedin warrant further disease-directed evaluations on weekly schedules.

Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck.

BACKGROUND: We conducted a multinational, randomized study to compare radiotherapy alone with radiotherapy plus cetuximab, a monoclonal antibody against the epidermal growth factor receptor, in the treatment of locoregionally advanced squamous-cell carcinoma of the head and neck. METHODS: Patients with locoregionally advanced head and neck cancer were randomly assigned to treatment with high-dose radiotherapy alone (213 patients) or high-dose radiotherapy plus weekly cetuximab (211 patients) at an initial dose of 400 mg per square meter of body-surface area, followed by 250 mg per square meter weekly for the duration of radiotherapy. The primary end point was the duration of control of locoregional disease; secondary end points were overall survival, progression-free survival, the response rate, and safety. RESULTS: The median duration of locoregional control was 24.4 months among patients treated with cetuximab plus radiotherapy and 14.9 months among those given radiotherapy alone (hazard ratio for locoregional progression or death, 0.68; P=0.005). With a median follow-up of 54.0 months, the median duration of overall survival was 49.0 months among patients treated with combined therapy and 29.3 months among those treated with radiotherapy alone (hazard ratio for death, 0.74; P=0.03). Radiotherapy plus cetuximab significantly prolonged progression-free survival (hazard ratio for disease progression or death, 0.70; P=0.006). With the exception of acneiform rash and infusion reactions, the incidence of grade 3 or greater toxic effects, including mucositis, did not differ significantly between the two groups. CONCLUSIONS: Treatment of locoregionally advanced head and neck cancer with concomitant high-dose radiotherapy plus cetuximab improves locoregional control and reduces mortality without increasing the common toxic effects associated with radiotherapy to the head and neck. (ClinicalTrials.gov number, NCT00004227.)

A phase I and pharmacokinetic study of lapatinib in combination with letrozole in patients with advanced cancer.

PURPOSE: The main objectives of this phase I and pharmacokinetic, open-label study were to determine the optimally tolerated regimen (OTR), safety, pharmacokinetics, and clinical activity of lapatinib in combination with letrozole in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: Patients with advanced breast cancer with immunohistochemically detectable estrogen or progesterone receptors or other cancers were eligible. Doses of lapatinib were escalated in cohorts of three subjects from 1,250 to a maximum of 1,500 mg/d based on dose-limiting toxicities in the first treatment cycle. The letrozole dose was fixed at 2.5 mg/d. Additional patients were enrolled at the OTR dose level to further evaluate safety and for pharmacokinetic analyses. RESULTS: Thirty-nine patients were enrolled in the study: 12 in the dose-escalation group, 7 in the OTR safety group, and 20 in the pharmacokinetic group. The OTR dose level was identified as 1,500 mg/d lapatinib and 2.5 mg/d letrozole. The most common (>25% of patients) drug-related adverse events were diarrhea (77%), rash (62%), nausea (46%), and fatigue (26%). No significant differences were observed in the pharmacokinetic variables (C(max) and AUC) of lapatinib and letrozole when coadministered compared with single-agent administration. One patient with endometrial cancer had a confirmed partial response. CONCLUSIONS: Clinically relevant doses of lapatinib in combination with letrozole were well tolerated and did not result in a pharmacokinetic interaction, and clinical antitumor activity was observed.

Polymorphisms in cyclooxygenase-2 and epidermal growth factor receptor are associated with progression-free survival independent of K-ras in metastatic colorectal cancer patients treated with single-agent cetuximab.

PURPOSE: Recently, an objective response rate of 12% was reported in a phase II study of cetuximab in patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer (mCRC) refractory to fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy (IMC-0144). In this large molecular correlates study, we tested whether K-ras mutation status and polymorphisms in genes involved in the EGFR-signaling pathway were associated with clinical outcome in IMC-0144. EXPERIMENTAL DESIGN: We analyzed all available tissue samples from 130 of 346 mCRC patients enrolled in the IMC-0144 phase II clinical trial of cetuximab. Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor tissues, and K-ras mutation status and the genotypes were analyzed using PCR-RFLP, direct DNA-sequencing, and 5'-end [gamma-33P] ATP-labeled PCR-protocols. RESULTS: The PFS of patients with cyclooxygenase-2 (COX-2) -765 G>C [C/C; risk ratio (RR), 0.31; 95% confidence interval (95% CI), 0.12-0.84; P = 0.032], COX-2 +8473 T>C (C/C; RR, 0.67; 95% CI, 0.40-1.13; P = 0.003), EGF +61 A>G (G/G; RR, 0.57; 95% CI, 0.34-0.95; P = 0.042), and EGFR +497 G>A (A/G; RR, 0.82; 95% CI, 0.56-1.20; P = 0.017) genotypes was significantly longer compared with those with other genotypes. In addition, patients whose tumors did not have K-ras mutations showed better RR, PFS, and overall survival than patients with K-ras mutations. In multivariable analysis, COX-2 +8473 T>C (adjusted P = 0.013) and EGFR +497 G>A (adjusted P = 0.010) remained significantly associated with progression-free survival, independent of skin rash toxicity, K-ras mutation status, and Eastern Cooperative Group performance status. CONCLUSIONS: Polymorphisms in COX-2 and EGFR may be useful independent molecular markers to predict clinical outcome in patients with mCRC treated with single-agent cetuximab, independent of skin rash toxicity, K-ras mutation, and Eastern Cooperative Oncology Group performance status.