Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma.

Evofosfamide (TH-302) is a clinical-stage hypoxia-activated prodrug of a DNA-crosslinking nitrogen mustard that has potential utility for human papillomavirus (HPV) negative head and neck squamous cell carcinoma (HNSCC), in which tumor hypoxia limits treatment outcome. We report the preclinical efficacy, target engagement, preliminary predictive biomarkers and initial clinical activity of evofosfamide for HPV-negative HNSCC. Evofosfamide was assessed in 22 genomically characterized cell lines and 7 cell line-derived xenograft (CDX), patient-derived xenograft (PDX), orthotopic, and syngeneic tumor models. Biomarker analysis used RNA sequencing, whole-exome sequencing, and whole-genome CRISPR knockout screens. Five advanced/metastatic HNSCC patients received evofosfamide monotherapy (480 mg/m2 qw × 3 each month) in a phase 2 study. Evofosfamide was potent and highly selective for hypoxic HNSCC cells. Proliferative rate was a predominant evofosfamide sensitivity determinant and a proliferation metagene correlated with activity in CDX models. Evofosfamide showed efficacy as monotherapy and with radiotherapy in PDX models, augmented CTLA-4 blockade in syngeneic tumors, and reduced hypoxia in nodes disseminated from an orthotopic model. Of 5 advanced HNSCC patients treated with evofosfamide, 2 showed partial responses while 3 had stable disease. In conclusion, evofosfamide shows promising efficacy in aggressive HPV-negative HNSCC, with predictive biomarkers in development to support further clinical evaluation in this indication.

Systemic versus local responses in melanoma patients treated with talimogene laherparepvec from a multi-institutional phase II study.

BACKGROUND: We previously reported that talimogene laherparepvec, an oncolytic herpes virus encoding granulocyte-macrophage colony-stimulating factor (GM-CSF), resulted in an objective response rate of 26 % in patients with advanced melanoma in a phase II clinical trial. The response of individual lesions, however, was not reported. Since talimogene laherparepvec is thought to mediate anti-tumor activity through both direct tumor cytolysis and induction of systemic tumor-specific immunity, we sought to determine the independent response rate in virus-injected and non-injected lesions. METHODS: Fifty patients with stage IIIC or IV melanoma were treated with talimogene laherparepvec in a multi-institutional single-arm open-label phase II clinical trial. In this study patients were treated until a complete response was achieved, all accessible tumors disappeared, clinically significant disease progression, or unacceptable toxicity. This report is a post hoc analysis of the systemic effects of talimogene laherparepvec in injected lesions and two types of uninjected lesions-non-visceral lesions and visceral lesions. RESULTS: Eleven of 23 patients (47.8 %) had a ≥ 30 % reduction in the total burden of uninjected non-visceral lesions, and 2 of 12 patients (16.7 %) had a ≥ 30 % reduction in the total burden of visceral lesions. Among 128 evaluable lesions directly injected with talimogene laherparepvec, 86 (67.2 %) decreased in size by ≥ 30 % and 59 (46.1 %) completely resolved. Of 146 uninjected non-visceral lesions, 60 (41.1 %) decreased in size by ≥ 30 %, the majority of which (44 [30.1 %]) completely resolved. Of 32 visceral lesions, 4 (12.5 %) decreased in size by ≥ 30 %, and 3 (9.4 %) completely resolved. The median time to lesion response was shortest for lesions that were directly injected (18.4 weeks), followed by uninjected non-visceral lesions (23.1 weeks) and visceral lesions (51.3 weeks), consistent with initiation of a delayed regional and systemic anti-tumor immune response to talimogene laherparepvec. CONCLUSIONS: These results support a regional and systemic effect of talimogene laherparepvec immunotherapy in patients with advanced melanoma.

Phase I study of intravenously administered ATI-1123, a liposomal docetaxel formulation in patients with advanced solid tumors.

PURPOSE: ATI-1123 is a liposomal formulation of docetaxel and may be administered without the premedications and hypersensitivity reactions. This Phase I study examines the safety, tolerability, pharmacokinetics (PKs), and antitumor activity of ATI-1123. METHODS: Patients with advanced solid malignancies received escalating doses of ATI-1123 intravenously over 1-h every 3 weeks. The dosing commenced using an accelerated titration design and was followed by a modified 3 + 3 Fibonacci schema to determine maximally tolerated dose (MTD). Plasma was analyzed for encapsulated/non-encapsulated docetaxel; PK analyses were performed using model independent method. Response was assessed using RECIST criteria. RESULTS: In total, 29 patients received doses ranging from 15 to 110 mg/m(2). At 110 mg/m(2), two of six patients experienced dose-limiting toxicities including grade 3 stomatitis and febrile neutropenia. The 90 mg/m(2) cohort was expanded to ten patients and identified as the MTD. The most common adverse events were fatigue, nausea, neutropenia, anemia, anorexia, and diarrhea. ATI-1123 exhibited linear and dose proportional PKs. One patient with lung cancer had confirmed partial response, and stable disease was observed in 75 % patients. CONCLUSIONS: ATI-1123 demonstrated an acceptable tolerability and favorable PK profile in patients with solid tumors. Our results provide support for Phase II trials to determine the antitumor activity of this drug.

Phase 1 study of N(1),N(11)­diethylnorspermine (DENSPM) in patients with advanced hepatocellular carcinoma.

PURPOSE: N(1),N(11)-diethylnorspermine (DENSPM), a synthetic analog of the naturally occurring polyamine spermine, can induce polyamine depletion and inhibit tumor cell growth. The objectives of this phase I study were to assess the safety, maximum-tolerated dose (MTD), pharmacokinetics, and preliminary antitumor activity of DENSPM in advanced HCC. METHODS: Patients with measurable advanced HCC, Child-Pugh A or B cirrhosis, CLIP score ≤3, and Karnofsky score ≥60 % were eligible. DENSPM was given as a short intravenous infusion on days 1, 3, 5, 8, 10, and 12 of each 28-day cycle. The starting dose of 30 mg/m(2) was escalated at a fixed increment of 15 mg/m(2) until the MTD was identified. The plasma pharmacokinetics of DENSPM for the first and last doses given in cycle 1 was characterized. RESULTS: Thirty-eight patients (male 79 %; median age 61 years; Child-Pugh A 84 %; ≥1 prior systemic therapy 45 %) were enrolled and treated. The most common adverse events (AEs) ≥grade 1 were fatigue (53 %), nausea (34 %), diarrhea (32 %), vomiting (32 %), anemia (29 %), and elevated AST (29 %). The most common grade 3-4 AEs were fatigue/asthenia (13 %), elevated AST (13 %), hyperbilirubinemia (11 %), renal failure (8 %), and hyperglycemia (8 %). The MTD was 75 mg/m(2). There were no objective responses, although 7/38 (18 %) patients achieved stable disease for ≥16 weeks. The overall mean (±SD) total body clearance for the initial dose, 66.3 ± 35.9 L/h/m(2) (n = 16), was comparable to the clearance in patients with normal to near normal hepatic function. Drug levels in plasma decayed rapidly immediately after the infusion but remained above 10 nM for several days after dosing at the MTD. CONCLUSIONS: N(1),N(11)-diethylnorspermine treatment at the MTD of 75 mg/m(2), given intravenously every other weekday for two consecutive weeks of each 28-day cycle, was relatively well tolerated in patients with advanced HCC including those with mild-to-moderate liver dysfunction. This administration schedule provided prolonged systemic exposure to potentially effective concentrations of the drug. Stable disease was seen in 18 % of patients receiving DENSPM treatment. Further evaluation of DENSPM monotherapy for advanced HCC does not appear to be justified because of insufficient evidence of clinical benefit in the patients evaluated in this study.

Phase I clinical study of Seneca Valley Virus (SVV-001), a replication-competent picornavirus, in advanced solid tumors with neuroendocrine features.

PURPOSE: Seneca Valley Virus (SVV-001) is a novel naturally occurring replication-competent picornavirus with potent and selective tropism for neuroendocrine cancer cell types, including small cell lung cancer. We conducted a first-in-human, first-in-class phase I clinical trial of this agent in patients with cancers with neuroendocrine features, including small cell lung cancer. EXPERIMENTAL DESIGN: Clinical evaluation of single intravenous doses in patients with cancers with neuroendocrine features was performed across five log-increments from 10(7) to 10(11) vp/kg. Toxicity, viral titers and clearance, neutralizing antibody development, and tumor response were assessed. RESULTS: A total of 30 patients were treated with SVV-001, including six with small cell carcinoma at the lowest dose of 10(7) vp/kg. SVV-001 was well tolerated, with no dose-limiting toxicities observed in any dose cohort. Viral clearance was documented in all subjects and correlated temporally with development of antiviral antibodies. Evidence of in vivo intratumoral viral replication was observed among patients with small cell carcinoma, with peak viral titers estimated to be >10(3)-fold higher than the administered dose. One patient with previously progressive chemorefractory small cell lung cancer remained progression-free for 10 months after SVV-001 administration, and is alive over 3 years after treatment. CONCLUSIONS: Intravenous SVV-001 administration in patients is well tolerated at doses up to 10(11) vp/kg, with predictable viral clearance kinetics, intratumoral viral replication, and evidence of antitumor activity in patients with small cell lung cancer. Phase II clinical evaluation in small cell lung cancer is warranted, and has been initiated.

Activity of IPI-504, a novel heat-shock protein 90 inhibitor, in patients with molecularly defined non-small-cell lung cancer.

PURPOSE: IPI-504 is a novel, water-soluble, potent inhibitor of heat-shock protein 90 (Hsp90). Its potential anticancer activity has been validated in preclinical in vitro and in vivo models. We studied the activity of IPI-504 after epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy in patients with advanced, molecularly defined non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with advanced NSCLC, prior treatment with EGFR TKIs, and tumor tissue available for molecular genotyping were enrolled in this prospective, nonrandomized, multicenter, phase II study of IPI-504 monotherapy. The primary outcome was objective response rate (ORR). Secondary aims included safety, progression-free survival (PFS), and analysis of activity by molecular subtypes. RESULTS: Seventy-six patients were enrolled between December 2007 and May 2009 from 10 United States cancer centers. An ORR of 7% (five of 76) was observed in the overall study population, 10% (four of 40) in patients who were EGFR wild-type, and 4% (one of 28) in those with EGFR mutations. Although both EGFR groups were below the target ORR of 20%, among the three patients with an ALK gene rearrangement, two had partial responses and the third had prolonged stable disease (7.2 months, 24% reduction in tumor size). The most common adverse events included grades 1 and 2 fatigue, nausea, and diarrhea. Grade 3 or higher liver function abnormalities were observed in nine patients (11.8%). CONCLUSION: IPI-504 has clinical activity in patients with NSCLC, particularly among patients with ALK rearrangements.

Phase III multicenter trial of doxorubicin plus cyclophosphamide followed by paclitaxel compared with doxorubicin plus paclitaxel followed by weekly paclitaxel as adjuvant therapy for women with high-risk breast cancer.

PURPOSE: This study compared disease-free survival (DFS) obtained with two different regimens of adjuvant therapy in high-risk breast cancer. METHODS: Women (who had performance status [PS] of 0 to 1) with operable, histologically confirmed, stage I to III adenocarcinoma of the breast were eligible. Patients had undergone primary surgery with no residual tumor. Treatments were as follows: arm 1 was doxorubicin 60 mg/m(2) plus cyclophosphamide 600 mg/m(2) every 3 weeks for four cycles followed by paclitaxel 175 mg/m(2) every 3 weeks for four cycles (ie, AC-P); and arm 2 was doxorubicin 50 mg/m(2) plus paclitaxel 200 mg/m(2) every 3 weeks for four cycles followed by paclitaxel 80 mg/m(2) weekly for 12 weeks. RESULTS: Overall, 1,830 patients were enrolled and 1,801 were treated: arm 1 (n = 906; AC-->P) and arm 2 (n = 895; AP-WP). Overall, patients had a PS of 0 (88%), had estrogen receptor and progesterone receptor-positive disease (52%), had one to three positive nodes (46%), and were postmenopausal (57%); the median age was 52 years. Currently, 1,640 patients (90%) are alive. The 6-year DFS was 79% to 80% in both groups. Disease relapse was the cause of death for 83 patients in arm 1 and in 66 patients of arm 2. Overall 6-year survival rates were 82% and 87% in arms 1 and 2, respectively. Reasons for patients being taken off study treatment included toxicity (13% in arm 1 v 20% in arm 2), progressive disease or recurrence (7% v 5%), and consent withdrawn (9% v 8%), respectively. The most frequent toxicities were hematologic, including neutropenia and leukopenia followed by neuropathy, myalgia, nausea, fatigue, headache, arthralgia, and vomiting. CONCLUSION: The results indicate that the AP-WP regimen is an equally effective and tolerable option for the adjuvant treatment of patients with high-risk breast cancer. The substitution of paclitaxel for cyclophosphamide results in comparable effectiveness of the regimen.

Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second-generation oncolytic herpesvirus in patients with unresectable metastatic melanoma.

PURPOSE: Treatment options for metastatic melanoma are limited. We conducted this phase II trial to assess the efficacy of JS1/34.5-/47-/granulocyte-macrophage colony-stimulating factor (GM-CSF) in stages IIIc and IV disease. PATIENTS AND METHODS: Treatment involved intratumoral injection of up to 4 mL of 10(6) pfu/mL of JS1/34.5-/47-/GM-CSF followed 3 weeks later by up to 4 mL of 10(8) pfu/mL every 2 weeks for up to 24 treatments. Clinical activity (by RECIST [Response Evaluation Criteria in Solid Tumors]), survival, and safety parameters were monitored. RESULTS: Fifty patients (stages IIIc, n = 10; IVM1a, n = 16; IVM1b, n = 4; IVM1c, n = 20) received a median of six injection sets; 74% of patients had received one or more nonsurgical prior therapies for active disease, including dacarbazine/temozolomide or interleukin-2 (IL-2). Adverse effects were limited primarily to transient flu-like symptoms. The overall response rate by RECIST was 26% (complete response [CR], n = 8; partial response [PR], n = 5), and regression of both injected and distant (including visceral) lesions occurred. Ninety-two percent of the responses had been maintained for 7 to 31 months. Ten additional patients had stable disease (SD) for greater than 3 months, and two additional patients had surgical CR. On an extension protocol, two patients subsequently achieved CR by 24 months (one previously PR, one previously SD), and one achieved surgical CR (previously PR). Overall survival was 58% at 1 year and 52% at 24 months. CONCLUSION: The 26% response rate, with durability in both injected and uninjected lesions including visceral sites, together with the survival rates, are evidence of systemic effectiveness. This effectiveness, combined with a limited toxicity profile, warrants additional evaluation of JS1/34.5-/47-/GM-CSF in metastatic melanoma. A US Food and Drug Administration-approved phase III investigation is underway.

Phase II assessment of talabostat and cisplatin in second-line stage IV melanoma.

BACKGROUND: Metastatic melanoma is an incurable disease with an average survival of less than one year. Talabostat is a novel dipeptidyl peptidase inhibitor with immunostimulatory properties. METHODS: This phase II, open label, single arm study was conducted to evaluate the safety and efficacy of 75-100 mg/m2 cisplatin combined with 300-400 mcg talabostat bid for 6, 21-day cycles. The primary endpoint was overall response. The rate of complete responses, duration of overall objective response, progression-free survival (PFS), and overall survival were the secondary endpoints. RESULTS: Six objective partial responses were recorded in the 74 patients (8.1%) in the intention-to-treat population. Five of these responses involved the 40 evaluable patients (12.5%). Thirty-one percent of patients reported SAEs to the combination of talabostat and cisplatin. CONCLUSION: Acceptable tolerability was observed in the intention-to-treat population and antitumor activity was observed in 12.5% of evaluable patients, which is not greater than historical expectation with cisplatin alone.

Emerging technologies for the genomic analysis of cancer.

Cancer-cell survival, growth and metastatic potential are directed by dominant molecular signalling patterns, the components of which have been shown to be qualitatively different from their normal tissue counterparts. These signalling patterns can now be further distinguished by quantitative assessment, either at a single point in time or at intervals. This commentary will focus on the emergence of proteomic analysis which, in conjunction with the genomic expression data, is an evolving technology that one day will enable personalized therapeutic strategies that are differentially targeted against cancer.

Chemo-inducible gene therapy.

Chemo-inducible cancer gene therapy is a potential new treatment for solid tumors that may in part enhance the anti-tumor effects of chemotherapy while minimizing toxicity. This approach combines viral vectors expressing cytotoxic transgenes that can be transcriptionally activated by DNA-damaging agents. The development of chemo-inducible gene therapy has numerous implications for the treatment of both localized and metastatic disease in patients with solid tumors.

Phase I trial of irinotecan, infusional 5-fluorouracil, and leucovorin (FOLFIRI) with erlotinib (OSI-774): early termination due to increased toxicities.

PURPOSE: This phase I study was conducted to establish the dose-limiting toxicities and maximum-tolerated dose of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in combination with FOLFIRI, a standard regimen of irinotecan, leucovorin, and infusional 5-fluorouracil (5-FU) in patients with advanced colorectal cancer. EXPERIMENTAL DESIGN: The trial used a dose-escalation design beginning with 100 mg/day erlotinib continuously and dose-reduced FOLFIRI (150 mg/m2 i.v. day 1 irinotecan, 200 mg/m2 i.v. leucovorin, 320 mg/m2 i.v. bolus days 1 to 2 5-FU, and 480 mg/m2 i.v. 5-FU infusion over 22 hours, days 1 to 2) administered in 6-week cycles (three FOLFIRI treatments). Plasma sampling was performed for irinotecan, erlotinib, and 5-FU for pharmacokinetic analysis during cycle 1. RESULTS: The study was halted after six patients at the lowest dose level due to unexpectedly severe toxicities, including disfiguring grade 2 rash (three patients), grade 3 diarrhea (three patients), and grade > or = 3 neutropenia (three patients). All patients required some dose interruption or reduction of either erlotinib or FOLFIRI, and only one patient completed two 6-week cycles of therapy. Five patients had stable disease after one cycle, and one patient had a partial response. No plasma pharmacokinetic interaction was observed that could explain the observed increased toxicity. CONCLUSIONS: FOLFIRI combined with erlotinib causes excessive toxicity at reduced doses. These findings contrast with available data regarding the optimal safety profile of trials combining small molecule epidermal growth factor receptor inhibitors with other conventional chemotherapy and highlight the need to perform safety-oriented studies of such combinations.

Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck.

PURPOSE: To determine the efficacy and safety profiles of erlotinib in patients with advanced recurrent and/or metastatic squamous cell cancer of the head and neck (HNSCC). PATIENTS AND METHODS: Patients with locally recurrent and/or metastatic HNSCC, regardless of their HER1/EGFR status, were treated with erlotinib at an initial dose of 150 mg daily. Dose reductions or escalations were allowed based on tolerability of erlotinib. RESULTS: One-hundred fifteen patients were enrolled onto this study. Forty-seven percent of patients received erlotinib at 150 mg daily throughout the entire study, 6% had dose escalations, and 46% required dose reductions and/or interruptions. Five patients achieved partial responses on study, for an overall objective response rate of 4.3% (95% CI, 1.4% to 9.9%). Disease stabilization was maintained in 44 patients (38.3%) for a median duration of 16.1 weeks. The median progression-free survival was 9.6 weeks (95% CI, 8.1 to 12.1 weeks), and the median overall survival was 6.0 months (95% CI, 4.8 to 7.0 months). Subgroup analyses revealed a significant difference in overall survival favoring patients who developed at least grade 2 skin rashes versus those who did not (P =.045), whereas no difference was detected based on HER1/EGFR expression. Rash and diarrhea were the most common drug-related toxicities, encountered in 79% and 37% of patients, respectively, though the severity was mild to moderate in most cases. CONCLUSION: Erlotinib was well tolerated in this heavily pretreated HNSCC population and produced prolonged disease stabilization; hence, further evaluation of its role in this tumor type is warranted.