Ronan J. Kelly

Phase I Clinical Trial of the Chimeric Anti-Mesothelin Monoclonal Antibody MORAb-009 in Patients with Mesothelin Expressing Cancers

Purpose: MORAb-009 is a chimeric monoclonal antibody that targets mesothelin, a tumor differentiation antigen overexpressed in pancreatic cancer, ovarian cancer, mesothelioma, and other malignancies. We conducted a phase I clinical trial of MORAb-009 in patients with advanced mesothelin-expressing cancers to determine its safety, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD). Methods: Cohorts consisting of 3 to 6 subjects each received MORAb-009 intravenously on days 1, 8, 15, and 22 at progressively increasing doses ranging from 12.5 to 400 mg/m2. Disease evaluation with computed tomography occurred on day 35. Subjects with responding or stable disease could receive additional cycles of MORAb-009. Results: A total of 24 subjects were treated including 13 mesothelioma, 7 pancreatic cancer, and 4 ovarian cancer patients. The median number of MORAb-009 infusions was 4 (range 1–24 infusions). At the 400 mg/m2 dose level, 2 subjects experienced DLT (grade 4 transaminitis and a grade 3 serum sickness). Thus, although there were other contributing causes of these adverse events, 200 mg/m2 was considered the MTD. Other adverse events at least possibly related to MORAb-009 included 7 drug hypersensitivity events (all grade 1 or 2) and a thromboembolic event (grade 4). Eleven subjects had stable disease. There was a dose-dependent increase in serum MORAb-009 concentration. Conclusion: MORAb-009 is well tolerated and the MTD when administered weekly is conservatively set at 200 mg/m2. In this group of previously treated patients, 11 subjects had stable disease. Phase II studies of MORAb-009 in different mesothelin-expressing cancers are ongoing.

Molecular Profiling and Targeted Therapy for Advanced Thoracic Malignancies: A Biomarker-Derived, Multiarm, Multihistology Phase II Basket Trial

PURPOSE We conducted a basket clinical trial to assess the feasibility of such a design strategy and to independently evaluate the effects of multiple targeted agents against specific molecular aberrations in multiple histologic subtypes concurrently. PATIENTS AND METHODS We enrolled patients with advanced non-small-cell lung cancer (NSCLC), small-cell lung cancer, and thymic malignancies who underwent genomic characterization of oncogenic drivers. Patients were enrolled onto a not-otherwise-specified arm and treated with standard-of-care therapies or one of the following five biomarker-matched treatment groups: erlotinib for EGFR mutations; selumetinib for KRAS, NRAS, HRAS, or BRAF mutations; MK2206 for PIK3CA, AKT, or PTEN mutations; lapatinib for ERBB2 mutations or amplifications; and sunitinib for KIT or PDGFRA mutations or amplification. RESULTS Six hundred forty-seven patients were enrolled, and 88% had their tumors tested for at least one gene. EGFR mutation frequency was 22.1% in NSCLC, and erlotinib achieved a response rate of 60% (95% CI, 32.3% to 83.7%). KRAS mutation frequency was 24.9% in NSCLC, and selumetinib failed to achieve its primary end point, with a response rate of 11% (95% CI, 0% to 48%). Completion of accrual to all other arms was not feasible. In NSCLC, patients with EGFR mutations had the longest median survival (3.51 years; 95% CI, 2.89 to 5.5 years), followed by those with ALK rearrangements (2.94 years; 95% CI, 1.66 to 4.61 years), those with KRAS mutations (2.3 years; 95% CI, 2.3 to 2.17 years), those with other genetic abnormalities (2.17 years; 95% CI, 1.3 to 2.74 years), and those without an actionable mutation (1.85 years; 95% CI, 1.61 to 2.13 years). CONCLUSION This basket trial design was not feasible for many of the arms with rare mutations, but it allowed the study of the genetics of less common malignancies.

Impacting tumor cell-fate by targeting the inhibitor of apoptosis protein survivin

Survivin (BIRC5), a member of the inhibitor of apoptosis protein (IAP) family that inhibits caspases and blocks cell death is highly expressed in cancer and is associated with a poorer clinical outcome. Functioning simultaneously during cell division and apoptosis inhibition, survivin plays a pivotal role in determining cell survival. Survivin has consistently been identified by molecular profiling analysis to be associated with higher tumor grade, more advanced disease, abbreviated survival, accelerated rates of recurrence, and chemotherapy and radiation resistance. Survivins differential expression in cancer compared to normal tissue and its role as a nodal protein in a number of cellular pathways make it a highly flexible therapeutic target, suitable for small-molecule inhibitiors, molecular antagonists, and vaccination-based therapies. By targeting survivin it is hoped that multiple tumor signaling circuitries may be simultaneously disabled. This effect may be applicable to many tumor histologies irrespective of specific genetic makeup. To date, survivin inhibitors have shown modest activity as single agents, but it is anticipated that when given in combination with cytotoxic chemotherapy or monoclonal antibodies they may exhibit enhanced efficacy. This review discusses the complex circuitry of survivin in human cancers and highlights clinical trials involving novel agents that target this important protein.

A Phase I Combination Study of Olaparib with Cisplatin and Gemcitabine in Adults with Solid Tumors

Purpose: To determine the safety and tolerability of olaparib with cisplatin and gemcitabine, establish the maximum tolerated dose (MTD), and evaluate the pharmacodynamic and pharmacokinetic profile of the combination. Experimental Design: We conducted a phase I study of olaparib with cisplatin and gemcitabine in patients with advanced solid tumors. Treatment at dose level 1 (DL1) consisted of olaparib 100 mg orally every 12 hours on days 1 to 4, gemcitabine 500 mg/m2 on days 3 and 10, and cisplatin 60 mg/m2 on day 3. PAR levels were measured in peripheral blood mononuclear cells (PBMC). Results: Dose-limiting toxicities (DLT) in two of three patients at DL1 included thrombocytopenia and febrile neutropenia. The protocol was amended to enroll patients treated with ≤2 prior severely myelosuppressive chemotherapy regimens and treated with olaparib 100 mg once daily on days 1 to 4 (DL−1). No DLTs were seen in six patients at DL−1. Because of persistent thrombocytopenia and neutropenia following a return to DL1, patients received 100 mg olaparib every 12 hours on day 1 only. No hematologic DLTs were observed; nonhematologic DLTs included gastrointestinal bleed, syncope, and hypoxia. Of 21 patients evaluable for response, two had partial response. Olaparib inhibited PARP in PBMCs and tumor tissue, although PAR levels were less effectively inhibited when olaparib was used for a short duration. Conclusions: Olaparib in combination with cisplatin and gemcitabine is associated with myelosuppression even at relatively low doses. Modified schedules of olaparib in chemotherapy naive patients will have to be explored with standard doses of chemotherapy. Clin Cancer Res; 18(8); 2344–51. ©2012 AACR.

Phase II Study of Belinostat in Patients With Recurrent or Refractory Advanced Thymic Epithelial Tumors

PURPOSE Thymic epithelial tumors are rare malignancies, and there is no standard treatment for patients with advanced disease in whom chemotherapy has failed. Antitumor activity of histone deacetylase (HDAC) inhibitors in this disease has been documented, including one patient with thymoma treated with the pan-HDAC inhibitor belinostat. PATIENTS AND METHODS Patients with advanced thymic epithelial malignancies in whom at least one line of platinum-containing chemotherapy had failed were eligible for this study. Other eligibility criteria included adequate organ function and good performance status. Belinostat was administered intravenously at 1 g/m(2) on days 1 to 5 of a 21-day cycle until disease progression or development of intolerance. The primary objective was response rate in patients with thymoma. RESULTS Of the 41 patients enrolled, 25 had thymoma, and 16 had thymic carcinoma; patients had a median of two previous systemic regimens (range, one to 10 regimens). Treatment was well tolerated, with nausea, vomiting, and fatigue being the most frequent adverse effects. Two patients achieved partial response (both had thymoma; response rate, 8%; 95% CI, 2.2% to 25%), 25 had stable disease, and 13 had progressive disease; there were no responses among patients with thymic carcinoma. Median times to progression and survival were 5.8 and 19.1 months, respectively. Survival of patients with thymoma was significantly longer than that of patients with thymic carcinoma (median not reached v 12.4 months; P = .001). Protein acetylation, regulatory T-cell numbers, and circulating angiogenic factors did not predict outcome. CONCLUSION Belinostat has modest antitumor activity in this group of heavily pretreated thymic malignancies. However, the duration of response and disease stabilization is intriguing, and additional testing of belinostat in this disease is warranted.

Dabrafenib in patients with BRAFV600E-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial

BACKGROUND Activating BRAF(V600E) (Val600Glu) mutations are found in about 1-2% of lung adenocarcinomas, which might provide an opportunity for targeted treatment in these patients. Dabrafenib is an oral selective inhibitor of BRAF kinase. We did a trial to assess the clinical activity of dabrafenib in patients with advanced non-small-cell lung cancer (NSCLC) positive for the BRAF(V600E) mutation. METHODS In this phase 2, multicentre, non-randomised, open-label study, we enrolled previously treated and untreated patients with stage IV metastatic BRAF(V600E)-positive NSCLC. Patients received oral dabrafenib 150 mg twice daily. The primary endpoint was investigator-assessed overall response, which was assessed in patients who had received at least one dose of dabrafenib; safety was also assessed in this population. The study is ongoing but not enrolling patients in this cohort. This trial is registered with ClinicalTrials.gov, number NCT01336634. FINDINGS Between Aug 3, 2011, and Feb 25, 2014, 84 patients were enrolled, six of whom had not previously received systemic treatment for NSCLC. 26 of the 78 previously treated patients achieved an investigator-assessed overall response (33% [95% CI 23-45]). Four of the six previously untreated patients had an objective response. One patient died from an intracranial haemorrhage that was judged by the investigator to be due to the study drug. Serious adverse events were reported in 35 (42%) of 84 patients. The most frequent grade 3 or worse adverse events were cutaneous squamous-cell carcinoma in ten (12%), asthenia in four (5%), and basal-cell carcinoma in four (5%). INTERPRETATION Dabrafenib showed clinical activity in BRAF(V600E)-positive NSCLC. Our findings suggest that dabrafenib could represent a treatment option for a population of patients with limited therapeutic options. FUNDING GlaxoSmithKline.

A Phase I Study of PF-04929113 (SNX-5422), an Orally Bioavailable Heat Shock Protein 90 Inhibitor, in Patients with Refractory Solid Tumor Malignancies and Lymphomas

Purpose: To determine the maximum tolerated dose (MTD), toxicities, and pharmacokinetic/pharmacodynamic profile of the Hsp90 inhibitor PF-04929113 (SNX-5422) in patients with advanced solid tumors and lymphomas. Methods: This was a single-institution, phase I, dose-escalation study of PF-04929113 administered twice weekly. Endpoints included determination of dose-limiting toxicities (DLT), MTD, the safety profile of PF-04929113, pharmacodynamic assessment of PF-04929113 on Hsp70 induction, pharmacokinetic analysis of PF-04928473 (SNX-2112) and its prodrug PF-04929113, and assessment of response. Results: Thirty-three patients with advanced malignancies were treated. Dose escalation was continued up to 177 mg/m2 administered orally twice a week. One DLT (nonseptic arthritis) was noted. No grade 4 drug-related adverse events were seen; grade 3 adverse events included diarrhea (9%), nonseptic arthritis (3%), aspartate aminotransferase elevation (3%), and thrombocytopenia (3%). No objective responses were seen in 32 evaluable patients. Fifteen patients (47%) had stable disease; 17 patients (53%) had progressive disease. Pharmacokinetic data revealed rapid absorption, hepatic, and extrahepatic clearance, extensive tissue binding, and almost linear pharmacokinetics of the active drug PF-04928473. Pharmacodynamic studies confirmed inhibition of Hsp90 and a linear correlation between pharmacokinetic parameters and Hsp70 induction. Conclusions: PF-04929113 administered orally twice a week is well tolerated and inhibits its intended target Hsp90. No objective responses were seen, but long-lasting stabilizations were obtained. Although no clinically significant drug-related ocular toxicity was seen in this study, the development of PF-04929113 has been discontinued because of ocular toxicity seen in animal models and in a separate phase I study. Clin Cancer Res; 17(21); 6831–9. ©2011 AACR.

Patterns of PD-L1 expression and CD8 T cell infiltration in gastric adenocarcinomas and associated immune stroma

Objective Recent data supports a significant role for immune checkpoint inhibitors in the treatment of solid tumours. Here, we evaluate gastric and gastro-oesophageal junction (G/GEJ) adenocarcinomas for their expression of programmed death-ligand 1 (PD-L1), infiltration by CD8+ T cells and the relationship of both factors to patient survival. Design Thirty-four resections of primary invasive G/GEJ were stained by immunohistochemistry for PD-L1 and CD8 and by DNA in situ hybridisation for Epstein–Barr virus (EBV). CD8+ T cell densities both within tumours and at the tumour–stromal interface were analysed using whole slide digital imaging. Patient survival was evaluated according to PD-L1 status and CD8 density. Results 12% of resections showed tumour cell membranous PD-L1 expression and 44% showed expression within the immune stroma. Two cases (6%) were EBV positive, with one showing membranous PD-L1 positivity. Increasing CD8+ densities both within tumours and immune stroma was associated with increasing percentage of tumour (p=0.027) and stromal (p=0.005) PD-L1 expression. Both tumour and immune stromal PD-L1 expression and high intratumoral or stromal CD8+ T cell density (>500/mm2) were associated with worse progression-free survival (PFS) and overall survival (OS). Conclusions PD-L1 is expressed on both tumour cells and in the immune stroma across all stages and histologies of G/GEJ. Surprisingly, we demonstrate that increasing CD8 infiltration is correlated with impaired PFS and OS. Patients with higher CD8+ T cell densities also have higher PD-L1 expression, indicating an adaptive immune resistance mechanism may be occurring. Further characterisation of the G/GEJ immune microenvironment may highlight targets for immune-based therapy.

Thymic Malignancies: From Clinical Management to Targeted Therapies

PURPOSE A key challenge in the treatment of thymoma and thymic carcinoma (TC) is in improving our understanding of the molecular biology of these relatively rare tumors. In recent years, significant efforts have been made to dissect the molecular pathways involved in their carcinogenesis. Here we discuss the results of large-scale genomic analyses conducted to date and review the most active chemotherapies and targeted treatments. METHODS We reviewed the literature for chemotherapeutic trials in the last 20 years and trials involving targeted therapies between 1999 and 2010. The search was supplemented by a review of abstracts presented at the annual meetings of the American Society of Clinical Oncology (from 1999 to 2010), at the first International Conference on Thymic Malignancies in 2009, and at a follow-up meeting of the newly formed International Thymic Malignancies Interest Group in 2010. RESULTS Surgery remains the treatment of choice for operable tumors, whereas chemotherapy is standard in locally advanced and metastatic disease. Thus far, targeted therapies have been developed empirically. Histone deacetylase inhibitors have shown some activity in thymoma whereas sunitinib may be active in TC. There are no data to support the use of HER2- or EGFR-targeted therapies in thymic malignancies. CONCLUSION Drug development for the treatment of thymic malignancies is difficult because of the rarity of these tumors. Ethnic differences are becoming apparent, with aggressive subtypes being observed in Asians and African Americans. Incremental improvements in our understanding of tumor biology suggest that molecular profiling-directed therapies may be the preferred route of investigation in the future.

Mesothelin-targeted agents in clinical trials and in preclinical development.

Mesothelin is a tumor differentiation antigen that is highly expressed in several malignant diseases in humans, including malignant mesothelioma and pancreatic, ovarian, and lung adenocarcinomas. The limited expression of mesothelin on normal human tissues and its high expression in many common cancers make it an attractive candidate for cancer therapy. Several agents, including an immunotoxin, monoclonal antibody, antibody drug conjugate, and tumor vaccine, are in various stages of development to treat patients with mesothelin-expressing tumors. This review highlights ongoing clinical trials, as well as other approaches to exploit mesothelin for cancer therapy, that are in preclinical development. Mol Cancer Ther; 11(3); 517–25. ©2012 AACR.