Phase I and pharmacokinetic study of docetaxel combined with melphalan and carboplatin, with autologous hematopoietic progenitor cell support, in patients with advanced refractory malignancies.

The purpose of this study was to define the maximal tolerated dose (MTD), extramedullary toxicities, and pharmacokinetics of docetaxel combined with high-dose melphalan and carboplatin with autologous hematopoietic progenitor cell support. Fifty-nine patients with advanced refractory malignancy (32 breast cancer, 10 non-Hodgkin lymphoma, 6 germ cell tumors, 4 Hodgkin disease, 4 ovarian cancer, 2 sarcoma, and 1 unknown primary adenocarcinoma) with a median of 3 prior chemotherapy regimens and a median of 3 organs involved were enrolled. Treatment included docetaxel (150-550 mg/m2 infused over 2 hours on day -6), melphalan (150-165 mg/m2 infused over 15 minutes from day -5 to -3), and carboplatin (1000-1300 mg/m2 as a 72-hour continuous infusion from day -5). Five patients died from direct regimen-related organ toxicity (2 capillary leak syndrome, 2 enterocolitis, and 1 hepatic toxicity), and 1 additional patient died from pulmonary aspergillosis. The docetaxel MTD was defined as 400 mg/m 2 , combined with melphalan (150 mg/m2 ) and carboplatin (1000 mg/m2 ). The MTD cohort was expanded to enroll a total of 26 patients, 1 of whom died from toxic enterocolitis. The remaining 25 patients presented the following extramedullary toxicity profile, which was manageable and largely reversible: stomatitis, myoarthralgias, peripheral neuropathy, gastrointestinal and cutaneous toxicities, and syndrome of inappropriate antidiuretic hormone secretion. Docetaxel exhibited linear pharmacokinetics in the dose range tested (150-550 mg/m2 ). Pharmacodynamic correlations were noted between the docetaxel area under the curve and peripheral neuropathy or stomatitis. The response rate among 38 patients with measurable disease was 95%, with 47% complete responses. At a median follow-up of 26 months (range, 7-72 months), the 3-year event-free survival and overall survival were 26% and 36%, respectively. In conclusion, a 4-fold dose escalation of docetaxel, combined with melphalan and carboplatin, is feasible with autologous hematopoietic progenitor cell support. The notable activity of this regimen in treatment-refractory patients warrants its further evaluation.     

Amifostine and autologous hematopoietic stem cell support of escalating-dose melphalan: a phase I study.

This study was conducted to define a new maximum tolerated dose and the dose-limiting toxicity (DLT) of melphalan and autologous hematopoietic stem cell transplantation (AHSCT) when used with the cytoprotective agent amifostine. Fifty-eight patients with various types of malignancy who were ineligible for higher-priority AHSCT protocols were entered on a phase I study of escalating doses of melphalan beginning at 220 mg/m(2) and advancing by 20 mg/m(2) increments in planned cohorts of 4 to 8 patients until severe regimen-related toxicity (RRT) was encountered. In all patients, amifostine 740 mg/m(2) was given on 2 occasions before the first melphalan dose (ie, 24 hours before and again 15 minutes before). AHSCT was given 24 hours after the first melphalan dose. Melphalan was given in doses up to and including 300 mg/m(2). Hematologic depression was profound, although it was rapidly and equally reversible at all melphalan doses. Although mucosal RRT was substantial, it was not the DLT, and some patients given the highest melphalan doses (ie, 300 mg/m(2)) did not develop mucosal RRT. The DLT was not clearly defined. Cardiac toxicity in the form of atrial fibrillation occurred in 3 of 36 patients treated with melphalan doses >/=280 mg/m(2) and was deemed fatal in 1 patient given melphalan 300 mg/m(2). (Another patient with a known cardiomyopathy was given melphalan 220 mg/m(2) and died as a result of heart failure but did not have atrial fibrillation.) Another patient given melphalan 300 mg/m(2) died of hepatic necrosis. The maximum tolerated dose of melphalan in this setting was thus considered to be 280 mg/m(2), and 27 patients were given this dose without severe RRT. Moreover, 38 patients were evaluable for delayed toxicity related to RRT; none was noted. Tumor responses have been noted at all melphalan doses and in all diagnostic groups, and 21 patients are alive at median day +1121 (range, day +136 to day +1923), including 16 without evidence of disease progression at median day +1075 (range, day +509 to day +1638). Amifostine and AHSCT permit the safe use of melphalan 280 mg/m(2), an apparent increase over the dose of melphalan that can be safely administered with AHSCT but without amifostine. Further studies are needed not only to confirm these findings, but also to define the antitumor efficacy of this regimen. Finally, it may be possible to evaluate additional methods of further dose escalation of melphalan in this setting.     

A Phase II study of capecitabine combined with gemcitabine in patients with advanced gallbladder carcinoma

Capecitabine and gemcitabine are used in the treatment of a variety of solid tumors including pancreatic and biliary tract carcinomas. The authors evaluated survival, response, and toxicity associated with using a combination of capecitabine and gemcitabine to treat patients with unresectable or metastatic gallbladder adenocarcinoma (GBC). Eligible patients had histologically- or cytologically-confirmed GBC, no prior systemic therapy with capecitabine or gemcitabine, Karnofsky Performance Status 70%, serum total bilirubin up to three times normal, and measurable disease. Treatment consisted of gemcitabine 1000 mg/m2 IV on Days 1 and 8 concurrent with administration of capecitabine 1000 mg/m2 PO BID on Days 1 through 14, on a 3-week cycle. Tumor response was assessed by the response evaluation criteria in solid tumors (RECIST criteria) and survival was calculated from initiation of CapGem therapy. A total of 24 patients were enrolled. Median age at the time of diagnosis was 62 years (range, 41-78 years). Fourteen patients had undergone prior surgery. Results showed that eight patients achieved partial response (33%) with an additional 10 patients achieving stable disease (42%). The overall median time to disease progression was 6.0 months (95% CI, 3.8-8.1 months) and overall survival was 16 months (95% CI, 13.8-18.3 months). The one-year survival rate was 58%. No Grade 4 toxicity was seen. Transient Grade 3 neutropenia/ thrombocytopenia and manageable nausea, hand-foot syndrome and anorexia were the most common toxicities. Our study shows that CapGem is an active and well-tolerated chemotherapy regimen in patients with advanced GBC.     

Short communication: the efficacy of fixed dose rate infusion of gemcitabine combined with IFN-alpha2a in patients with advanced refractory renal cell carcinoma.

The fixed dose rate (FDR) infusion of gemcitabine is based on pharmacokinetic studies demonstrating an increased peak concentration of gemcitabine-active metabolites inside the cell. In this prospective study, for the first time we investigated gemcitabine FDR infusion together with interferon-alpha2a (IFN-alpha) in pretreated patients with advanced renal cell carcinoma (RCC). Twelve patients received 800 mg/m2 gemcitabine (i.v. infusion of 10 mg/m2/min) on days 1 and 8 every 3 weeks, combined with 3.0 x 10(6) U s.c. IFN-alpha on days 1, 3, and 5 of each week. Median age of patients was 64 years, and the Eastern Cooperative Oncology Group performance status (ECOG PS) was 0-1 in 10 patients. All patients were pretreated, 5 with > or =2 lines of chemoimmunotherapy. A median number of five cycles of gemcitabine per patient were given, with a mean weekly dose intensity of 72% of that planned. Among 11 evaluable patients, 2 (18%) partial responses and 5 (46%) stable diseases (median duration of 9.3 months) were observed. Median time to progression (TTP) and overall survival were 7.1 months and 13.0 months, respectively. The most frequently occurring grade 3 or 4 adverse events were leukoneutropenia (25%), thrombocytopenia (17%), and diffuse edema (25%). One patient developed a cerebrovascular accident potentially related to treatment. These promising results with the combination of gemcitabine infused at FDR and IFN-alpha deserve further investigation.     

An expanded phase I/II trial of cyclophosphamide, etoposide, and carboplatin plus total body irradiation with autologous marrow or stem cell support for patients with hematologic malignancies.

The major cause for failure of autologous stem cell transplantation for hematologic malignancies is the risk of recurrent disease. As a result, new treatment regimens that include novel agents or combinations of agents and approaches are needed. The current report describes a large Phase I/II, single-center trial that includes 60 patients with a variety of hematologic malignancies. These patients received a fixed dose of carboplatin (1 g/m(2)/d x 72 hours by CI) etoposide (600 mg/m(2)/d x 3 days) and cyclophosphamide (2 g/m(2)/d x 3 days), plus escalating doses of total body irradiation (TBI) (at 1000, 1200, and 1295 cGy) over 3 days. Eleven patients received infusion of autologous marrow, 32 received peripheral blood stem cells, and 17 patients received both. The maximum tolerated dose of this regimen was a radiation dose of 1200 cGy given in 200-cGy fractions BID x 3 days. The dose-limiting toxicity was mucositis, with 97% of patients requiring narcotic analgesia for mouth pain. Overall treatment-related mortality was 6.7%, with 2 of the 4 deaths occurring in a group of 9 patients aged 60 and older. Responses were seen in all patient groups, but the most encouraging outcomes were seen in 12 patients with high-risk or advanced acute myelocytic lymphoma (AML), 7 of whom remain alive and free of disease beyond 5 years. This regimen is intensive and causes considerable mucositis but is otherwise well tolerated and has demonstrated activity in a number of hematologic malignancies, especially AML.     

Phase I/II study of immunotherapy using autologous tumor lysate-pulsed dendritic cells in patients with metastatic renal cell carcinoma

This phase I/II study was conducted to evaluate the feasibility, safety and efficacy of immunotherapy using tumor lysate (TL)-pulsed dendritic cells (DC) in patients with metastatic renal cell carcinoma (RCC). DC were generated by culturing peripheral blood mononuclear cells in the presence of GM-CSF and IL-4 and were pulsed with autologous TL and keyhole limpet hemocyanin (KLH). Maturation of DC was induced by a combined treatment of CD40 ligand, IFN and monocyte-conditioned medium. The patients were administered two cycles of TL-pulsed DCs vaccination, each of which comprised of four doses injected subcutaneously at biweekly intervals. Nine patients were included. The immunotherapy was well tolerated without severe side effects. One patient achieved an objective partial response (PR). Five patients showed stable disease (SD), and the remaining three had progressive disease (PD). With a median follow-up of 17.5 months, the median time to progression was 5.2 months and the median overall survival was 29 months. In the antigen-specific lymphocyte proliferation assay, eight patients showed a proliferative response, which tended to be stronger in patients with SD or PR than in patients with PD. The ELISPOT assay was performed in two patients and indicated that one patient with PR showed a much stronger response than another with PD. Our results suggest that TL-pulsed DC immunotherapy in combination with nephrectomy affect the natural course of RCC and are associated with clinical benefits for patients with metastatic diseases.     

Prognostic significance of occult tumor cells in the apheresis products of patients with advanced breast cancer receiving high-dose chemotherapy and autologous hematopoietic progenitor cell support.

We prospectively evaluated the prognostic significance of occult tumor cells (OTCs) contaminating the peripheral blood progenitor cell apheresis products of patients with advanced breast cancer receiving high-dose chemotherapy. Immunocytochemistry of peripheral blood progenitor cells was performed in 242 patients with high-risk primary breast cancer (HRPBC) and in 111 patients with metastatic breast cancer (MBC). OTCs were detected in 6.6% of HRPBC patients and in 16.2% of MBC patients (P = .005). In HRPBC, OTCs correlated with worse prognostic scores and larger tumor sizes, but not with axillary nodal status, hormone receptors, or HER2. In the MBC group, OTCs correlated with bone marrow involvement and with disease status at transplantation. The number of apheresis procedures was not associated with the risk of contamination. In HRPBC patients, at a median follow-up of 7 years (range, 1.5-11 years), the presence of OTCs correlated with worse event-free survival (P = .007) and overall survival (P = .002). In the MBC group, OTCs correlated with worse event-free survival (P = .04), but not overall survival (P = .2). In multivariate analyses, the presence of OTCs had an independent adverse effect on outcome in HRPBC, but not MBC. Our observations imply a direct role of OTCs in posttransplantation relapse in HRPBC.     

Phase I clinical study of anti-apoptosis protein, survivin-derived peptide vaccine therapy for patients with advanced or recurrent colorectal cancer

Survivin is a member of the inhibitor of apoptosis protein (IAP) family containing a single baculovirus IAP repeat domain. It is expressed during fetal development but becomes undetectable in terminally differentiated normal adult tissues. We previously reported that survivin and its splicing variant survivin-2B was expressed abundantly in various types of tumor tissues as well as tumor cell lines and was suitable as a target antigen for active-specific anti-cancer immunization. Subsequently, we identified an HLA-A24-restricted antigenic peptide, survivin-2B80-88 (AYACNTSTL) recognized by CD8+ cytotoxic T lymphocytes (CTLs). We, therefore, started a phase I clinical study assessing the efficacy of survivin-2B peptide vaccination in patients with advanced or recurrent colorectal cancer expressing survivin. Vaccinations with survivin-2B peptide were given subcutaneously six times at 14-day intervals. Of 15 patients who finished receiving the vaccination schedule, three suffered slight toxicities, including anemia (grade 2), general malaise (grade 1), and fever (grade 1). No severe adverse events were observed in any patient. In 6 patients, tumor marker levels (CEA and CA19-9) decreased transiently during the period of vaccination. Slight reduction of the tumor volume was observed in one patient, which was considered a minor responder. No changes were noted in three patients while the remaining eleven patients experienced tumor progression. Analysis of peripheral blood lymphocytes of one patient using HLA-A24/peptide tetramers revealed an increase in peptide-specific CTL frequency from 0.09% to 0.35% of CD8+ T cells after 4 vaccinations. This phase I clinical study indicates that survivin-2B peptide-based vaccination is safe and should be further considered for potential immune and clinical efficacy in HLA-A24-expression patients with colorectal cancer.     

A phase I study of PRO131921, a novel anti-CD20 monoclonal antibody in patients with relapsed/refractory CD20 + indolent NHL: Correlation between clinical responses and AUC pharmacokinetics

PRO131921 is a third-generation, humanized anti-CD20 monoclonal antibody with increased antibody-dependent cytotoxicity and complement-dependent cytotoxicity compared to rituximab. In this phase I study, PRO131921 was administered as a single agent to patients with CD20 +, relapsed or refractory, indolent non-Hodgkin lymphoma (NHL) who had been treated with a prior rituximab-containing regimen. The primary aim of this study was safety and tolerability of PRO131921. The secondary aim of the study, and focus of this report, was to determine the pharmacokinetics (PK) profile of PRO131921 and establish a correlation between drug exposure and clinical efficacy. Patients were treated with PRO131921 by intravenous infusion weekly for 4 weeks and the dose was escalated based on safety in a 3 + 3 design. Twenty-four patients were treated with PRO131921 at doses from 25 mg/m² to 800 mg/m². Analysis of PK data demonstrated a correlation between higher normalized drug exposure (normalized AUC) and tumor shrinkage (p = .0035). Also, normalized AUC levels were higher among responders and subjects displaying tumor shrinkage versus subjects progressing or showing no regression (p = 0.030). In conclusion, PRO131921 demonstrated clinical activity in rituximab-relapsed and refractory indolent NHL patients. The observation that higher normalized AUC may be associated with improved clinical responses has potential implications in future trials of monoclonal antibody-based therapies, and emphasizes the importance of early PK studies to optimize antibody efficacy.     

Association of the I148M/PNPLA3 (rs738409) polymorphism with premature coronary artery disease,fatty liver,and insulin resistance in type 2 diabetic patients and healthy controls. The GEA study

The aim of this study was to evaluate the potential use of the I148M/PNPLA3 (rs738409) gene polymorphism as a susceptibility marker for premature coronary artery disease (pCAD) and/or cardiovascular risk factors in Mexican type 2 diabetes mellitus patients (T2DM). The polymorphism was genotyped by 5′ exonuclease TaqMan assays in a group of 2572 subjects (1103 with pCAD and 1469 healthy controls) belonging to the Genetics of Atherosclerotic Disease (GEA) Mexican Study. Anthropometric and biochemical measurements were performed in all individuals. The association between the I148M/PNPLA3 (rs738409) gene polymorphism with pCAD and other metabolic and cardiovascular risk factors was evaluated using logistic regression analysis under different statistical approaches including dominant, recessive, heterozygous, additive, and co-dominant models. The polymorphism was not associated with pCAD in the whole group of participants, however, when patients and controls were divided into those with and without T2DM, under additive model, the polymorphism was associated with the presence of pCAD only in patients with T2DM (OR = 1.20, 95% CI: 1.01–1.42, P_add = 0.042). On the other hand, under several models adjusted for age, gender, body mass index and T2DM, the polymorphism was associated with increased risk of fatty liver and elevated levels of alanine transaminase (ALT) in the whole group of pCAD patients and controls. In the control group, the polymorphism was associated with insulin resistance and coronary artery calcification (CAC) score ≥ 10 under several models. The results suggest that the I148M/PNPLA3 (rs738409) polymorphism is associated with the presence of pCAD in T2DM patients and with some cardiometabolic parameters. The association detected with CAC in the control group indicates that this polymorphism could be a marker for subclinical atherosclerosis.     

A study in the Ivory Coast (1985-1987) of the efficacy and tolerance of ivermectin (Mectizan) in human onchocerciasis. I. A comparative double-blind study of 220 patients with onchocerciasis treated with a single oral dose of 100, 150 or 200 mcg/kg

Two hundred and twenty adult males living in endemic onchocerciasis areas in Ivory Coast, with a mean of 59 to 64 mf/mg of skin microfilariae, having or not ocular lesions, were divided into 4 homogeneous groups and treated by placebo or by a single oral dose of 100, 150 or 200 mcg/kg of ivermectin. Parasitological, clinical, ophthalmological, biological data were gathered before treatment (J less than 1) and at day 4 and 3, 6, 12 months post treatment. The doses of 150 to 200 mcg/kg gave the best results with a reduction of microfilariae of 75 to 79% at day 4 and of 97 to 99% at 3 months. A slight increase appears at six months reaching to 10% of the initial level, at 12 months. These posologies reduce also the number of ocular microfilariae 12 months after treatment. The percentage of patients presenting microfilariae in the cornea varies from 4 to 14% according to the given dose whereas it was initially between 26 and 33%, and in the anterior chamber from 22 to 16% instead of 62 to 67%. In patients who were still positive after treatment the detected number of ocular microfilariae was very small. Side effects starting 12 to 24 hours after treatment are similar to those appearing during the normal evolution of onchocerciasis. They were observed in 36% of subjects receiving a placebo and 56 to 65% of treated subjects. Statistically they are neither correlated with the intensity of parasitism nor to the given posology and disappear spontaneously few days later or after administration of aspirin and/or antihistaminic. Ivermectin given at a single oral dosage of 150 to 200 mcg/kg is a powerful microfilaricidal drug with a rapid and prolonged action and without major side effects.