Diana F. Hausman

Phase 1b study of pegylated interferon lambda 1 with or without ribavirin in patients with chronic genotype 1 hepatitis C virus infection.

Interferon lambda 1 (IFN‐λ1) is a type III IFN that produces intracellular responses similar to those of IFN‐α but in fewer cell types because of differences in the receptor distribution pattern, and this could potentially result in an improved safety profile. This was an open‐label three‐part study of patients with chronic hepatitis C virus (HCV) genotype 1 infection. Part 1 evaluated single‐agent pegylated interferon lambda (PEG‐IFN‐λ) at 1.5 or 3.0 μg/kg administered every 2 weeks or weekly for 4 weeks in patients who had relapsed after previous IFN‐α‐based treatment. Part 2 evaluated weekly doses of PEG‐IFN‐λ ranging from 0.5 to 2.25 μg/kg in combination with ribavirin (RBV) for 4 weeks in treatment‐relapse patients. Part 3 evaluated weekly PEG‐IFN‐λ at 1.5 μg/kg in combination with RBV for 4 weeks in treatment‐naive patients. Fifty‐six patients were enrolled: 24 patients in part 1, 25 patients in part 2, and 7 patients in part 3. Antiviral activity was observed at all PEG‐IFN‐λ dose levels (from 0.5 to 3.0 μg/kg). Two of seven treatment‐naive patients (29%) achieved rapid virological response. Treatment was well tolerated with minimal flu‐like symptoms and no significant hematologic changes other than RBV‐associated decreases in hemoglobin. The most common adverse events were fatigue (29%), nausea (12%), and myalgia (11%). Six patients experienced increases in aminotransferases that met protocol‐defined criteria for dose‐limiting toxicity (DLT) or temporarily holding therapy with PEG‐IFN‐λ. Most DLT occurred in patients with high PEG‐IFN‐λ exposure. Conclusion: Weekly PEG‐IFN‐λ with or without daily RBV for 4 weeks is well tolerated with minimal adverse events and hematologic effects and is associated with clear antiviral activity across a broad range of doses in patients with chronic HCV. (HEPATOLOGY 2010;)

A Multicenter Phase I Trial of PX-866, an Oral Irreversible Phosphatidylinositol 3-Kinase Inhibitor, in Patients with Advanced Solid Tumors

Purpose: The objectives of the study were to evaluate the maximum tolerated dose (MTD), safety, pharmacodynamics, pharmacokinetics, and antitumor activity of PX-866 in patients with incurable cancers. Experimental Design: This was a phase I, open-label, dose-escalation study. Drug was administered orally once per day either on an intermittent (arm 1; days 1–5 and 8–12 of a 28-day cycle) or continuous (arm 2; days 1–28 of a 28-day cycle) schedule. Additional patients were treated at the arm 2 MTD in a food effects substudy. Results: Eighty-four patients were treated in the arm 1 (n = 51), arm 2 (n = 20), and food effects (n = 13) cohorts. The most frequent study drug–related adverse events were gastrointestinal disorders (69.0%), with diarrhea being the most common (48.8%). The MTD was 12 and 8 mg for arm 1 and 2, respectively. The dose-limiting toxicities (DLT) consisted of grade III diarrhea (n = 3) and grade III elevated aspartate aminotransferase (AST; n = 1). The pharmacokinetics profile was dose proportional, with no evidence of drug accumulation. PX-866–associated inhibition of platelet pAKTSER473 was observed at the arm 2 MTD. The best response per Response Evaluation Criteria in Solid Tumors (RECIST) was stable disease in 22% of evaluable patients in arm 1, 53% in arm 2, and 11% in the food effects cohort. Eight patients were on study for 4 or more months. Conclusions: This first-in-human study shows that PX-866, an irreversible small-molecule inhibitor of phosphatidylinositol 3-kinase (PI3K), was well tolerated and was associated with prolonged stable disease, particularly when using a continuous dosing schedule. Clin Cancer Res; 18(15); 4173–82. ©2012 AACR.

A patient tumor transplant model of squamous cell cancer identifies PI3K inhibitors as candidate therapeutics in defined molecular bins

Targeted therapy development in head and neck squamous cell carcinoma (HNSCC) is challenging given the rarity of activating mutations. Additionally, HNSCC incidence is increasing related to human papillomavirus (HPV). We sought to develop an in vivo model derived from patients reflecting the evolving HNSCC epidemiologic landscape, and use it to identify new therapies. Primary and relapsed tumors from HNSCC patients, both HPV+ and HPV−, were implanted on mice, giving rise to 25 strains. Resulting xenografts were characterized by detecting key mutations, measuring protein expression by IHC and gene expression/pathway analysis by mRNA‐sequencing. Drug efficacy studies were run with representative xenografts using the approved drug cetuximab as well as the new PI3K inhibitor PX‐866. Tumors maintained their original morphology, genetic profiles and drug susceptibilities through serial passaging. The genetic makeup of these tumors was consistent with known frequencies of TP53, PI3KCA, NOTCH1 and NOTCH2 mutations. Because the EGFR inhibitor cetuximab is a standard HNSCC therapy, we tested its efficacy and observed a wide spectrum of efficacy. Cetuximab‐resistant strains had higher PI3K/Akt pathway gene expression and protein activation than cetuximab‐sensitive strains. The PI3K inhibitor PX‐866 had anti‐tumor efficacy in HNSCC models with PIK3CA alterations. Finally, PI3K inhibition was effective in two cases with NOTCH1 inactivating mutations. In summary, we have developed an HNSCC model covering its clinical spectrum whose major genetic alterations and susceptibility to anticancer agents represent contemporary HNSCC. This model enables to prospectively test therapeutic‐oriented hypotheses leading to personalized medicine.

Interleukin 21: combination strategies for cancer therapy

In the past 20 years researchers have attempted to activate the host immune defence system to kill tumour cells and eradicate cancer. In some cases, the response of patients to immunotherapy has been extremely successful; however, other trials have shown disappointing results, and so there is a clear need for more effective therapies that can effectively adjunct conventional approaches. Interleukin 21 (IL21) is a new immune-stimulating cytokine that has demonstrated antitumour activity in several preclinical models, and has recently undergone Phase I trials in metastatic melanoma and renal cell carcinoma. Here, we provide an overview of the antitumour effects of IL21 and describe strategies to combine IL21 with other drugs for future cancer therapies.

Interferon Lambda as a Potential New Therapeutic for Hepatitis C

Interferon lambdas (IFN‐λ) are Type III interferons with biological activity, including induction of antiviral genes, similar to Type I IFNs, but signal through a distinct receptor complex. The expression pattern for the IFN‐λ receptor is more cell specific than the widely distributed IFN‐α receptor, suggesting in vivo, IFN‐λ may have fewer side effects than IFN‐α, such as less hematologic toxicities. A PEGylated form of IFN‐λ (PEG‐rIL‐29) was well tolerated in animals and did not result in hematologic toxicity. Clinical data from initial studies of PEG‐rIL‐29 has demonstrated antiviral effects in patients with hepatitis C without producing hematologic toxicity. These preclinical and early clinical data support PEG‐rIL‐29 as a potential new therapeutic agent for treatment of patients with hepatitis C.

Phase I Clinical Study of Atacicept in Patients with Relapsed and Refractory B-Cell Non–Hodgkin's Lymphoma

Purpose: B-lymphocyte stimulator and a proliferation-inducing ligand regulate B-cell homeostasis and immunoglobulin production and are overexpressed in B-cell malignancies. Atacicept (TACI-Ig), a recombinant fusion protein that inhibits both B-lymphocyte stimulator and a proliferation-inducing ligand, may be a novel treatment for B-cell malignancies. Experimental Design: A phase 1, open-label, dose-escalation study of atacicept in patients with relapsed or refractory B-cell lymphoma was done. Atacicept was given s.c. weekly for 5 weeks to sequential patient cohorts at doses of 2, 4, 7, or 10 mg/kg. Patients responding or with stable disease were eligible for treatment on an extension study for up to 24 weeks or until disease progression. Results: All patients were heavily pretreated (median number of previous treatments, 5; range, 1-10), and four patients had previously received a stem cell transplant. Four patients were treated at the 2, 4, or 7 mg/kg dose levels, and three patients received 10 mg/kg of atacicept. Atacicept was well tolerated at all doses. Three adverse events with grade 3 severity were reported for one patient, including jaw pain, gastrointestinal hemorrhage, and sepsis; all were considered unrelated to atacicept. Pharmacokinetic results were nonlinear, and treatment with atacicept resulted in dose-dependent decreases in immunoglobulin concentrations. Two patients had stable disease at 8 weeks, entered the extension study, and received additional doses of atacicept with no safety or tolerability concerns. Conclusion: Atacicept at doses of up to 10 mg/kg was well tolerated and showed biological activity by decreasing immunoglobulin concentrations, although tumor responses were not observed.

A randomized, phase 2 trial of docetaxel with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer

INTRODUCTION The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is frequently altered in head and neck squamous cell cancer (HNSCC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. Preclinical models revealed synergy with docetaxel and a phase 1 trial demonstrated tolerability of this combination. This randomized phase 2 study evaluated PX-866 combined with docetaxel in patients with advanced, refractory HNSCC. METHODS Patients with locally advanced, recurrent or metastatic HNSCC who had received at least one and no more than two prior systemic treatment regimens were randomized (1:1) to a combination of docetaxel (75mg/m(2) IV every 21days) with or without PX-866 (8mg PO daily; Arms A and B, respectively). The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (RR), overall survival (OS), toxicity, and correlation of biomarker analyses with efficacy outcomes. RESULTS 85 patients were enrolled. There was a non-significant improvement in response rate in the combination arm (14% vs. 5%; P=0.13). Median PFS was 92days in Arm A and 82days in Arm B (P=0.42). There was no difference in OS between the two arms (263 vs. 195days; P=0.62). Grade 3 or higher adverse events were infrequent, but more common in the combination arm with respect to diarrhea (17% vs. 2%), nausea (7% vs. 0%), and febrile neutropenia (21% vs. 5%); grade 3 or higher anemia was more frequent in arm B (7% vs. 27%). PIK3CA mutations or PTEN loss were infrequently observed. CONCLUSION The addition of PX-866 to docetaxel did not improve PFS, RR, or OS in patients with advanced, refractory HNSCC without molecular pre-selection.

A Randomized, Phase 2 Trial of Docetaxel with or without PX-866, an Irreversible Oral Phosphatidylinositol 3-Kinase Inhibitor, in Patients with Relapsed or Metastatic Non–Small-Cell Lung Cancer

Introduction: The phosphotidylinositol-3 kinase/serine-threonine kinase (AKT)/mammalian target of rapamycin signaling pathway is frequently altered in non–small-cell lung cancer (NSCLC). PX-866 is an oral, irreversible, pan-isoform inhibitor of phosphotidylinositol-3 kinase. Preclinical models revealed synergy with docetaxel and a phase 1 trial demonstrated tolerability of this combination. This randomized phase 2 study evaluated PX-866 combined with docetaxel in patients with advanced, refractory NSCLC. Methods: Patients with locally advanced, recurrent, or metastatic NSCLC who had received at least one and no more than two prior systemic treatment regimens were randomized (1:1) to a combination of docetaxel (75 mg/m2 intravenous every 21 days) with or without PX-866 (8 mg orally daily; arms A and B, respectively). The primary end point was progression-free survival (PFS). Secondary end points included objective response rate, overall survival (OS), toxicity, and correlation of biomarker analyses with efficacy outcomes. Results: A total of 95 patients were enrolled. Median PFS was 2 months in arm A and 2.9 months in arm B (p = 0.65). Objective response rates were 6% and 0% in arms A and B, respectively (p = 0.4). There was no difference in OS between the two arms (7.0 versus 9.2 months; p = 0.9). Grade 3 or higher adverse events were infrequent, but more common in the combination arm with respect to diarrhea (7% versus 2%), nausea (4% versus 0%), and vomiting (7% versus 0%). PIK3CA mutations or PTEN loss were infrequently observed. Conclusion: The addition of PX-866 to docetaxel did not improve PFS, response rate, or OS in patients with advanced, refractory NSCLC without molecular preselection.

Peginterferon Lambda-1a, a New Therapeutic for Hepatitis C Infection, from Bench to Clinic.

Chronic infection with hepatitis C virus (HCV) is estimated to affect approximately 3% of the worlds population and cause 350,000 deaths each year. For a number of years, the standard of care has been combination therapy with recombinant alfa interferons—originally as native proteins but more recently as polyethyleneglycol-modified derivatives—and ribavirin, with the recent addition of an NS3 protease inhibitor for HCV genotype 1. However, therapeutic alfa interferons are associated with a significant burden of treatment-limiting adverse events, including musculoskeletal and influenza-like symptoms, hematologic cytopenias, autoimmune disease, fatigue, and other neurologic events. In 2003, a team at ZymoGenetics (now a fully owned subsidiary of Bristol-Myers Squibb) and a second, independent group simultaneously identified a new class of interferons—the type III lambda interferons—with near-identical activity to the type I alfa interferons in hepatocytes but with an unrelated and less ubiquitous receptor. Subsequent evaluation of the type III interferon system demonstrated antiviral activity against HCV in vitro with limited activity in peripheral blood mononuclear cells and other nonhepatocyte cell types, supporting its development as a potentially better-tolerated therapy for viral hepatitis. Peginterferon lambda-1a (Lambda) is an investigational type III therapeutic agent originally developed at ZymoGenetics that is currently in Phase 3 studies for the treatment of HCV. In this review, we describe the selection of the Lambda molecule and its preclinical and early clinical development, and how the resulting data have helped to establish the differentiated safety profile for Lambda—with fewer influenza-like and musculoskeletal symptoms and less hematologic toxicity than the alfa interferons—that was seen in later studies.

Abstract 652: PI3K inhibition combined with either cetuximab or docetaxel in a direct patient tumor model of HPV-positive and negative head and neck cancers

Purpose: Data suggest that human papilloma virus (HPV)-positive head and neck squamous cell carcinomas (HNSCC) are distinct from HPV negative tumors. We have generated a direct patient tumor xenograft model (DPTM) of HNSCC. DPTM maintain tumor histology better than cell lines and are optimally positioned to investigate in vivo tumor sensitivity and changes in tumor initiating cell (TIC) biology in response to therapy based upon HPV status. Phosphatidyl inositol 3 kinase (PI3K) is a downstream signal of epidermal growth factor receptor (EGFR) that may play a critical role in TIC biology and resistance to chemotherapy or anti-EGFR monoclonal antibodies in HNSCC. PX-866 is an irreversible pan-isoform inhibitor of class 1 PI3K currently in early clinical trials. We aimed to test the in vivo efficacy of PX-866, cetuximab, docetaxel, or a combination of PX-866 and cetuximab or docetaxel. Methods: DPTM were left untreated or exposed to PX-866, docexatel, cetuximab, or a combination of PX-866 plus cetuximab or docetaxel for 25-29 days. Tumor measurements were taken twice weekly during therapy and thereafter until study conclusion. TIC population were determined by flow cytometry. Results: We have treated three DPTM (CUHN015, CUHN022, CUHN027) with PX-866, cetuximab, or PX-866 plus cetuximab, and three DPTM (CUHN004, CUHN011, CUHN015) with PX-866, docetaxel, or the combination of PX-866 plus docetaxel. Neither combination had increased toxicity compared with the single agents. All six untreated DPTM had rapid tumor growth. In two DPTM (CUHN015 and CUHN022) cetuximab was similar to no treatment, whereas single agent PX-866 was slightly more effective than no treatment in CUHN022 and significantly more effective in CUHN015. In CUHN027 both PX-866 and cetuximab arrested growth but the combination caused greater than 50% tumor reduction. The combination of cetuximab and PX-866 was more effective than cetuximab alone in all DPTM. Two xenografts treated with PX-866, docetaxel, or the combination showed decreased tumor growth with PX-866 compared to either docetaxel or no treatment (CUHN004 and CUHN015). In all three DTPM the combination of PX-866 and docetaxel was more effective than either single agent. In the HPV-positive xenograft (CUHN022) cetuximab had no effect. Treatment with chemotherapeutic agents induced TIC accumulation that was partially reversed by combination therapy. Conclusions: PX-866 was equal or superior to cetuximab or docetaxel at slowing tumor growth in 5 of 6 DPTM of HNSCC. The combination of PX-866 plus another agent was superior to single agent therapy in 5 of 6 DPTM. Cetuximab was more effective in HPV-negative cases. Correlations with pathway gene mutations and pharmacodynamic events, including pathway inhibition and TIC subpopulation dynamics, will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 652. doi:10.1158/1538-7445.AM2011-652