Pilot trial of the hu14.18-IL2 immunocytokine in patients with completely resectable recurrent stage III or stage IV melanoma.

Phase I testing of the hu14.18-IL2 immunocytokine (IC) in melanoma patients showed immune activation, reversible toxicities, and a maximal tolerated dose of 7.5 mg/m2/day. Preclinical data in IC-treated tumor-bearing mice with low tumor burden documented striking antitumor effects. Patients with completely resectable recurrent stage III or stage IV melanoma were scheduled to receive 3 courses of IC at 6 mg/m2/day i.v. on days 1, 2 and 3 of each 28-day course. Patients were randomized to complete surgical resection either following neoadjuvant (Group A) or prior to adjuvant (Group B) IC course 1. Primary objectives were to: (1) evaluate histological evidence of anti-tumor activity and (2) evaluate recurrence-free survival (RFS) and OS. Twenty melanoma patients were randomized to Group A (11 patients) or B (9 patients). Two Group B patients did not receive IC due to persistent disease following surgery. Six of 18 IC-treated patients remained free of recurrence, with a median RFS of 5.7 months (95% confidence interval (CI) 1.8-not reached). The 24-month RFS rate was 38.9% (95% CI 17.5-60.0%). The median follow-up of surviving patients was 50.0 months (range: 31.8-70.4). The 24-month OS rate was 65.0% (95% CI 40.3-81.5%). Toxicities were similar to those previously reported. Exploratory tumor-infiltrating lymphocyte (TIL) analyses suggest prognostic value of TILs from Group A patients. Prolonged tumor-free survival was seen in some melanoma patients at high risk for recurrence who were treated with IC.

VcR-CVAD Induction Chemotherapy Followed by Maintenance Rituximab Produces Durable Remissions in Mantle Cell Lymphoma: A Wisconsin Oncology Network Study.

INTRODUCTION: VcR-CVAD was developed as an intermediate-intensity induction regimen with maintenance rituximab (MR) to improve remission durations after first-line therapy for mantle cell lymphoma (MCL) in older and younger patients with MCL. PATIENTS AND METHODS: Patients with previously untreated MCL received VcR-CVAD induction chemotherapy for 6 cycles (21-day cycles). Patients achieving at least a partial response received rituximab consolidation (375 mg/m2 × 4 weekly doses) and MR (375 mg/m2 every 12 weeks × 20 doses). The primary endpoints were overall and complete response (CR), and the secondary endpoints were progression-free survival (PFS) and overall survival (OS). Thirty patients were enrolled, with a median age of 61 years. There was an even distribution of patients < 60 years and ≥ 60 years. Mantle cell lymphoma international prognostic index medium- or high-risk disease was present in 60%. The overall response rate observed was 90% (77% CR/unconfirmed CR). After a median follow-up of 7.8 years, the 6-year PFS and OS were 53% and 70%, respectively. There was no difference in 6-year PFS or OS between the younger (age < 60 years) and older (age ≥ 60 years) subgroups. In a univariate analysis, lactate dehydrogenase, when analyzed for interaction with age, had a significant effect on PFS outcomes at 6 years. There were no pretreatment variables determined to have a significant effect on OS outcomes at 6 years. CONCLUSIONS: Long-term outcomes with VcR-CVAD are comparable with more intensive inductions and consolidation approaches. MCL is biologically heterogeneous, and durable remission can be achieved with intermediate intensity therapy. MR appears to contribute to these excellent outcomes.

Phase I study to evaluate toxicity and feasibility of intratumoral injection of α-gal glycolipids in patients with advanced melanoma.

Effective uptake of tumor cell-derived antigens by antigen-presenting cells is achieved pre-clinically by in situ labeling of tumor with α-gal glycolipids that bind the naturally occurring anti-Gal antibody. We evaluated toxicity and feasibility of intratumoral injections of α-gal glycolipids as an autologous tumor antigen-targeted immunotherapy in melanoma patients (pts). Pts with unresectable metastatic melanoma, at least one cutaneous, subcutaneous, or palpable lymph node metastasis, and serum anti-Gal titer ≥1:50 were eligible for two intratumoral α-gal glycolipid injections given 4 weeks apart (cohort I: 0.1 mg/injection; cohort II: 1.0 mg/injection; cohort III: 10 mg/injection). Monitoring included blood for clinical, autoimmune, and immunological analyses and core tumor biopsies. Treatment outcome was determined 8 weeks after the first α-gal glycolipid injection. Nine pts received two intratumoral injections of α-gal glycolipids (3 pts/cohort). Injection-site toxicity was mild, and no systemic toxicity or autoimmunity could be attributed to the therapy. Two pts had stable disease by RECIST lasting 8 and 7 months. Tumor nodule biopsies revealed minimal to no change in inflammatory infiltrate between pre- and post-treatment biopsies except for 1 pt (cohort III) with a post-treatment inflammatory infiltrate. Two and four weeks post-injection, treated nodules in 5 of 9 pts exhibited tumor cell necrosis without neutrophilic or lymphocytic inflammatory response. Non-treated tumor nodules in 2 of 4 evaluable pts also showed necrosis. Repeated intratumoral injections of α-gal glycolipids are well tolerated, and tumor necrosis was seen in some tumor nodule biopsies after tumor injection with α-gal glycolipids.

Characterization of class II ß chain major histocompatibility complex genes in a family of Hawaiian honeycreepers: 'amakihi (Hemignathus virens).

Hawaiian honeycreepers (Drepanidinae) have evolved in the absence of mosquitoes for over five million years. Through human activity, mosquitoes were introduced to the Hawaiian archipelago less than 200 years ago. Mosquito-vectored diseases such as avian malaria caused by Plasmodium relictum and Avipoxviruses have greatly impacted these vulnerable species. Susceptibility to these diseases is variable among and within species. Due to their function in adaptive immunity, the role of major histocompatibility complex genes (Mhc) in disease susceptibility is under investigation. In this study, we evaluate gene organization and levels of diversity of Mhc class II ß chain genes (exon 2) in a captive-reared family of Hawaii 'amakihi (Hemignathus virens). A total of 233 sequences (173 bp) were obtained by PCR+1 amplification and cloning, and 5720 sequences were generated by Roche 454 pyrosequencing. We report a total of 17 alleles originating from a minimum of 14 distinct loci. We detected three linkage groups that appear to represent three distinct haplotypes. Phylogenetic analysis revealed one variable cluster resembling classical Mhc sequences (DAB) and one highly conserved, low variability cluster resembling non-classical Mhc sequences (DBB). High net evolutionary divergence values between DAB and DBB resemble that seen between chicken BLB system and YLB system genes. High amino acid identity among non-classical alleles from 12 species of passerines (DBB) and four species of Galliformes (YLB) was found, suggesting that these non-classical passerine sequences may be related to the Galliforme YLB sequences.

Clinical Activity of Pazopanib in Metastatic Extraosseous Ewing Sarcoma.

We report a response to pazopanib in a 69-year-old man with heavily pre-treated metastatic extraosseous Ewing sarcoma in addition to molecular profiling of his tumor. To our knowledge, this case is the earliest to demonstrate activity of an oral multi-targeted kinase inhibitor in Ewing sarcoma. This case provides rationale for adding a Ewing sarcoma arm to SARC024, a phase II study of regorafenib, another multi-targeted kinase inhibitor, in patients with liposarcoma, osteosarcoma and Ewing and Ewing-like sarcomas (NCT02048371). This national multi-institutional study is ongoing.

A phase 1/1b study of satraplatin (JM-216) in combination with docetaxel in patients with advanced solid tumors and metastatic castrate-resistant prostate cancer.

BACKGROUND: Satraplatin is an oral platinum with potential advantages over other platinum agents. This study investigated the combination of satraplatin and docetaxel in a phase 1 study of patients with advanced solid tumor malignancies followed by a phase 1b study in men with chemotherapy naïve metastatic castrate-resistant prostate cancer (CRPC). METHODS: In this single institution phase 1/1b study, patients received docetaxel on day 1 and satraplatin on days 1-5 of a 21-day cycle ± granulocyte colony stimulating factor (GCSF). For phase 1b, prednisone 10 mg daily was added. RESULTS: Twenty-nine patients received treatment. Based on 3 dose limiting toxicities (DLT) (grade 4 neutropenia) in 13 patients at dose levels 1 and -1 (docetaxel 60 mg/m(2) plus satraplatin 40 mg/m(2) and docetaxel 60 mg/m(2) plus satraplatin 50 mg/m(2)) GCSF was administered with subsequent cohorts. A dose level of docetaxel 60 mg/m(2) plus satraplatin 50 mg/m(2) with GCSF was the starting dose level for phase 1b. At the highest dose in the phase 1b (docetaxel 75 mg/m(2) plus satraplatin 50 mg/m(2)) there were no DLTs. CONCLUSION: The combination of satraplatin and docetaxel is feasible in solid tumor malignancies. In advanced malignancies, the recommended phase 2 dose is docetaxel 60 mg/m(2) IV day 1 with satraplatin 40 mg/m(2)/d PO days 1-5, without G-CSF, and Docetaxel 70 mg/m(2) IV day 1 with Satraplatin 50 mg/m(2)/day PO days 1-5, with G-CSF support, repeated in 3-week cycles. For patients with CRPC the recommended phase 2 dose is docetaxel 75 mg/m(2) IV day 1 with satraplatin 50 mg/m(2)/d PO days 1--5, with G-CSF and prednisone 10 mg daily, repeated in 3-week cycles.

Maintenance rituximab following induction chemo-immunotherapy for mantle cell lymphoma: long-term follow-up of a pilot study from the Wisconsin Oncology Network.

Mantle cell lymphoma (MCL) is challenging to manage, with a median survival of 3-5 years. While intensive strategies are often appropriate for younger patients, these approaches are often not appropriate for older patients. In 2006, we reported our initial results using modified R-hyperCVAD (rituximab with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) with maintenance rituximab. The complete response rate was 64%, and median progression-free survival (PFS) 37 months. Herein, we update our results, now with a median follow-up of 62 months. The median PFS is unchanged and the median overall survival (OS) is 70 months. The proportion of patients surviving at 5 years is 62%, comparable to studies using intensive strategies in similar patient populations. No late toxicities were noted in our cohort. These long-term results suggest that the modified R-hyperCVAD regimen with maintenance rituximab is an excellent option for older patients with newly diagnosed mantle cell lymphoma.

VcR-CVAD induction chemotherapy followed by maintenance rituximab in mantle cell lymphoma: a Wisconsin Oncology Network study.

Intensive chemotherapy regimens are not feasible in many adults with mantle cell lymphoma (MCL). We sought to build upon our previous experience with a non-intensive regimen, modified R-hyperCVAD chemotherapy (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone) with maintenance rituximab (MR), by the incorporation of bortezomib (VcR-CVAD) and the extension of MR beyond 2 years. Patients with previously untreated MCL received VcR-CVAD chemotherapy every 21 d for six cycles. Patients achieving at least a partial response to induction chemotherapy received rituximab consolidation (375 mg/m(2) × 4 weekly doses) and MR (375 mg/m(2) every 12 weeks × 20 doses). The primary end points were overall and complete response (CR), and secondary endpoints were progression-free (PFS) and overall survival (OS). Thirty patients were enrolled, with a median age of 61 years. All patients had advanced stage disease, and 60% had medium/high MCL International Prognostic Index risk factors. A CR or unconfirmed CR was achieved in 77% of patients. After a median follow-up of 42 months, the 3-year PFS and OS were 63% and 86%, respectively. The observed 3-year PFS and OS with VcR-CVAD in MCL were comparable to reported outcomes with more intensive regimens. A cooperative group trial (E1405) is attempting to replicate these promising results.

Dose-escalation study of fixed-dose rate gemcitabine combined with capecitabine in advanced solid malignancies.

PURPOSE: To define dose limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of capecitabine with fixed-dose rate (FDR) gemcitabine. METHODS: Eligible adults (advanced solid tumor; performance status or=3 toxicity was myelosuppression, particularly neutropenia. At dose level 4 (1,000 mg/m(2) gemcitabine), two out of five evaluable patients had a DLT (grade 4 neutropenia >or=7 days). At dose level 3 (800 mg/m(2) gemcitabine), one patient had a DLT (grade 3 neutropenia >or=7 days) among six evaluable patients. Therefore, the MTD and recommended phase II dose was designated as capecitabine 500 mg/m(2) PO BID days 1-14 with 800 mg/m(2) FDR gemcitabine days 1 and 8 infused at 10 mg/m(2) per min on a 21-day cycle. Partial responses occurred in pretreated patients with esophageal, renal cell and bladder carcinomas. CONCLUSIONS: This regimen was well tolerated and may deserve evaluation in advanced gastrointestinal and genitourinary carcinomas.

A phase II trial of gemcitabine, 5-fluorouracil and leucovorin in advanced esophageal carcinoma.

BACKGROUND: The aim of this study was to evaluate the overall response rate, toxicity and overall survival in patients with locally advanced or metastatic esophageal cancer treated with gemcitabine, 5-fluorouracil (5-FU) and leucovorin. PATIENTS AND METHODS: Patients with either adenocarcinoma or squamous cell carcinoma of the esophagus could enroll; however, patients could not have received prior chemotherapy for metastatic disease. Treatment cycles consisted of infusions of all three agents at days 1, 8 and 15, repeated every 28 days. Patients received gemcitabine 1,000, leucovorin 25 and 5-FU 600 mg/m(2). Tumor assessment was performed every 2 cycles. Responses were assessed using the Eastern Cooperative Oncology Group solid tumor response criteria. RESULTS: Thirty-five patients with metastatic or locally advanced esophageal cancer enrolled. One complete response and ten partial responses were observed for an overall response rate of 31.4%. An additional 11 patients had stable disease as their best response. The median survival was 9.8 months with a 1-year survival rate of 37.1%. Toxicity was predominately hematologic, with 58% of patients experiencing grade 3 or 4 neutropenia. CONCLUSION: The combination of gemcitabine, 5-FU and leucovorin had activity in advanced esophageal cancer. Patients tolerated the regimen well, with myelosuppression occurring most commonly. The combination merits further investigation as a treatment for esophageal cancer.