A randomized, placebo-controlled phase III trial of masitinib plus gemcitabine in the treatment of advanced pancreatic cancer.

BACKGROUND: Masitinib is a selective oral tyrosine-kinase inhibitor. The efficacy and safety of masitinib combined with gemcitabine was compared against single-agent gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: Patients with inoperable, chemotherapy-naïve, PDAC were randomized (1 : 1) to receive gemcitabine (1000 mg/m(2)) in combination with either masitinib (9 mg/kg/day) or a placebo. The primary endpoint was overall survival (OS) in the modified intent-to-treat population. Secondary OS analyses aimed to characterize subgroups with poor survival while receiving single-agent gemcitabine with subsequent evaluation of masitinib therapeutic benefit. These prospectively declared subgroups were based on pharmacogenomic data or a baseline characteristic. RESULTS: Three hundred and fifty-three patients were randomly assigned to receive either masitinib plus gemcitabine (N = 175) or placebo plus gemcitabine (N = 178). Median OS was similar between treatment-arms for the overall population, at respectively, 7.7 and 7.1 months, with a hazard ratio (HR) of 0.89 (95% CI [0.70; 1.13]. Secondary analyses identified two subgroups having a significantly poor survival rate when receiving single-agent gemcitabine; one defined by an overexpression of acyl-CoA oxidase-1 (ACOX1) in blood, and another via a baseline pain intensity threshold (VAS > 20 mm). These subgroups represent a critical unmet medical need as evidenced from median OS of 5.5 months in patients receiving single-agent gemcitabine, and comprise an estimated 63% of patients. A significant treatment effect was observed in these subgroups for masitinib with median OS of 11.7 months in the 'ACOX1' subgroup [HR = 0.23 (0.10; 0.51), P = 0.001], and 8.0 months in the 'pain' subgroup [HR = 0.62 (0.43; 0.89), P = 0.012]. Despite an increased toxicity of the combination as compared with single-agent gemcitabine, side-effects remained manageable. CONCLUSIONS: The present data warrant initiation of a confirmatory study that may support the use of masitinib plus gemcitabine for treatment of PDAC patients with overexpression of ACOX1 or baseline pain (VAS > 20mm). Masitinib's effect in these subgroups is also supported by biological plausibility and evidence of internal clinical validation. TRIAL REGISTRATION: ClinicalTrials.gov:NCT00789633.

Dose escalation to rash for erlotinib plus gemcitabine for metastatic pancreatic cancer: the phase II RACHEL study.

BACKGROUND: This phase II, open-label, randomised study evaluated whether patients with metastatic pancreatic cancer receiving erlotinib/gemcitabine derived survival benefits from increasing the erlotinib dose. METHODS: After a 4-week run-in period (gemcitabine 1000 mg m(-2) once weekly plus erlotinib 100 mg per day), patients with metastatic pancreatic cancer who developed grade 0/1 rash were randomised to receive gemcitabine plus erlotinib dose escalation (150 mg, increasing by 50 mg every 2 weeks (maximum 250 mg); n=71) or gemcitabine plus standard-dose erlotinib (100 mg per day; n=75). The primary end point was to determine whether overall survival (OS) was improved by increasing the erlotinib dose. Secondary end points included progression-free survival (PFS), incidence of grade ⩾2 rash, and safety. RESULTS: Erlotinib dose escalation induced grade ⩾2 rash in 29 out of 71 (41.4%) patients compared with 7 out of 75 (9.3%) patients on standard dose. Efficacy was not significantly different in the dose-escalation arm compared with the standard-dose arm (OS: median 7.0 vs 8.4 months, respectively, hazard ratio (HR), 1.26, 95% confidence interval (CI): 0.88-1.80; P=0.2026; PFS: median 3.5 vs 4.5 months, respectively, HR, 1.09, 95% CI: 0.77-1.54; P=0.6298). Incidence of adverse events was comparable between randomised arms. CONCLUSION: The erlotinib dose-escalation strategy induced rash in some patients; there was no evidence that the higher dose translated into increased benefit.

A randomized controlled phase II trial of a novel composition of paclitaxel embedded into neutral and cationic lipids targeting tumor endothelial cells in advanced triple-negative breast cancer (TNBC).

BACKGROUND: EndoTAG-1, composed of paclitaxel embedded in liposomal membranes targeting tumor endothelial cells, was evaluated for safety and efficacy in advanced triple-negative breast cancer (TNBC). PATIENTS AND METHODS: One hundred and forty patients were treated with weekly EndoTAG-1 (22 mg/m(2)) plus paclitaxel (70 mg/m(2)), twice weekly EndoTAG-1 (2× 44 mg/m(2)), or weekly paclitaxel (90 mg/m(2)) for greater than or equal to four cycles (3-week treatment + 1-week rest) or until progression/toxicity. Primary end point was progression-free survival (PFS) rate evaluated centrally after four cycles of therapy (week 16). The study was not powered for intergroup comparisons. RESULTS: The PFS rate at week 16 was 59.1% [one-sided 95% CI: 45.6, ∞] on combination treatment, 34.2% [21.6, ∞] on EndoTAG-1, and 48.0% [30.5, ∞] on paclitaxel. Median PFS reached 4.2, 3.4, and 3.7 months, respectively. After complete treatment (week 41 analysis), median overall survival (OS) was 13.0, 11.9, and 13.1 months for the modified Intention-to-Treat (ITT) population and 15.1, 12.5, and 8.9 months for the per-protocol population, respectively. The clinical benefit rate was 53%, 31%, and 36% for the treatment groups. Safety analysis revealed known toxicities of the drugs with slight increases of grade 3/4 neutropenia on combination therapy. CONCLUSION: Treatment of advanced TNBC with a combination of EndoTAG-1 and standard paclitaxel [Taxol® (Bristol-Myers Squibb GmbH), or equivalent generic formulation] was well tolerated and showed antitumor efficacy. The positive trend needs to be confirmed in a randomized phase III trial. STUDY REGISTRATION: European Clinical Trials Database: EudraCT number 2006-002221-23. ClinicalTrials.gov identifier: NCT00448305.

A randomized, placebo-controlled phase 2 study of ganitumab or conatumumab in combination with FOLFIRI for second-line treatment of mutant KRAS metastatic colorectal cancer.

BACKGROUND: Targeted agents presently available for mutant KRAS metastatic colorectal cancer (mCRC) are bevacizumab and aflibercept. We evaluated the efficacy and safety of conatumumab (an agonistic monoclonal antibody against human death receptor 5) and ganitumab (a monoclonal antibody against the type 1 insulin-like growth factor receptor) combined with standard FOLFIRI chemotherapy as a second-line treatment in patients with mutant KRAS mCRC. PATIENTS AND METHODS: Patients with mutant KRAS metastatic adenocarcinoma of the colon or rectum refractory to fluoropyrimidine- and oxaliplatin-based chemotherapy were randomized 1 : 1 : 1 to receive intravenous FOLFIRI plus conatumumab 10 mg/kg (Arm A), ganitumab 12 mg/kg (Arm B), or placebo (Arm C) Q2W. The primary end point was progression-free survival (PFS). RESULTS: In total, 155 patients were randomized. Median PFS in Arms A, B, and C was 6.5 months (HR, 0.69; P = 0.147), 4.5 months (HR, 1.01; P = 0.998), and 4.6 months, respectively; median overall survival was 12.3 months (HR, 0.89; P = 0.650), 12.4 months (HR, 1.27; P = 0.357), and 12.0 months; and objective response rate was 14%, 8%, and 2%. The most common grade ≥3 adverse events in Arms A/B/C included neutropenia (30%/25%/18%) and diarrhea (18%/2%/10%). CONCLUSIONS: Conatumumab, but not ganitumab, plus FOLFIRI was associated with a trend toward improved PFS. Both combinations had acceptable toxicity.

Intermediate-dose Ara-C plus G-CSF for stem cell mobilization in patients with lymphoid malignancies, including predicted poor mobilizers.

The optimal protocol for mobilization of hematopoietic stem cells in patients with lymphoid malignancies has not been determined so far. We retrospectively analyzed the efficacy and safety of Ara-C at a dose of 1.6 g/m(2) compared with CY at a dose of 4.0 g/m(2), both combined with filgrastim. Seventy and forty-five patients, respectively, were included, among whom 60% were defined as 'predicted poor mobilizers'. The use of Ara-C was associated with significantly higher peak number of circulating CD34(+) cells compared with CY (P<0.0001). In the Ara-C group, 95% of patients with multiple myeloma (MM) collected at least 5 × 10(6) CD34(+) cells/kg required for tandem transplantation, and 97% of lymphoma patients collected at least 2 × 10(6) CD34(+) cells/kg, needed for a single autologous hematopoietic SCT (autoHSCT), which was achieved with a single leukapheresis in 91% of cases. Results for the CY group were significantly inferior (P<0.0001). No patient mobilized with Ara-C experienced febrile neutropenia, whereas 35% required platelet transfusions. Among patients who proceeded to autoHSCT, the time of both neutrophil and platelet recovery was significantly shorter for those mobilized with Ara-C than CY. We conclude that intermediate-dose Ara-C+filgrastim is a very effective and relatively safe mobilization protocol for patients with lymphoid malignancies.

[Primary non-Hodgkin's lymphoma of the maxillary sinus]. / Pierwotny nieziarniczy chloniak zlosliwy zatoki szczekowej.

The head and neck region is one of the most common sites of extranodal non-Hodgkin's lymphoma, but it is an infrequent tumor at the paranasal sinuses site, representing no more than 5.8-8 percent of the entire malignant tumours in this localization and 0.3-2 percent of all extranodal lymphomas. These rare tumors are characterized by bulky local disease, and a propensity for central nervous system spread. Most of patients with paranasal sinus lymphoma have stage I or IIE disease, but according to the TNM system, more than half have T3-4 disease. Most of these tumors are asymptomatic in the early stages and are diagnosed only after invasion of adjacent structures with local bone destruction. Treatment is basically radiotherapy in combination with aggressive multidrug chemotherapy, also in elderly patients, even at the beginning of the illness. A case of primary extranodal non-Hodgkin's lymphoma arising in maxillary sinus, in 64 year-old man is reported. He was staged IAE by the Ann-Arbor system, and according to the TNM staging T4N0M0. He was treated with irradiation and polychemotherapy and responded complete local regression, but during chemotherapy has been developed extranodal dissemination to central nervous system.

[Non Hodgkin's lymphoma of the breast]. / Nieziarniczy chloniak zlosliwy sutka.

There are described two cases of Non Hodgkin's lymphoma of the breast. The authors pointed to difficulties of histological diagnosis and paid attention that this extranodal localisation may be the first manifestation of malignant lymphoma in its subclinical phase.

[The palatal tonsils as a part of the lymphatic system. Inflow and outflow of newly-formed lymphocytes]. / Die Gaumentonsillen als Teil des lymphatischen Systems. Ein- und Ausstrom neugebildeter Lymphozyten.

Many lymphocytes continuously migrate from one lymphoid organ to another. The tonsils are also included in the migratory stream of long-lived lymphocytes. We investigated the question whether newly formed lymphocytes, for example, those produced in the spleen or mesenteric lymph nodes, also migrate to the tonsils and to which compartment. The spleen and mesenteric lymph nodes of normal young pigs were selectively labelled with the DNA precursor 3H-thymidine and one day later smears and sections of the tonsils were autoradiographed. About 1% of all spleen-derived young lymphocytes and about 0.5% of all emigrated mesenteric lymph node lymphocytes were found in palatine tonsils. These were almost exclusively small to medium sized lymphocytes. These cells were mainly found in the interfollicular area around high endothelial venules. Surprisingly high numbers were also located in the reticular epithelium of the crypts, in the corona and even in follicles. In a second series of experiment palatine tonsils were selectively labelled by multiple minute injections of 3H-thymidine. The follicles showed a very high labelling index but labelled lymphocytes were also identified in other compartments. One day later tonsil-derived lymphocytes were found in the spleen and lymph nodes. There is thus a continuous exchange of newly formed lymphocytes between the tonsils and other lymphoid organs.

The emigration of lymphocytes from palatine tonsils after local labelling.

Lymphocytes in the palatine tonsils of normal young pigs were selectively labelled by minute multiple injections of fluorescein isothiocyanate into the tonsils. One day later the numbers of tonsil-derived lymphocytes were determined in cervical, bronchial and mesenteric lymph nodes, spleen, Peyer's patches, thymus, bone marrow and blood. Although not all tonsillar lymphocytes could be labelled by this technique, a total of approximately 0.6 X 10(9) lymphocytes emigrated from the tonsils. Relatively more lymphocytes were found in lymph nodes than in the spleen and very few in the thymus, Peyer's patches and bone marrow. This organ distribution was different from the results from selectively labelling lymphocytes in lymph nodes, spleen and bone marrow.

Organ distribution and fate of newly formed splenic lymphocytes in the pig.

The production of lymphoid cells in the pig spleen was studied autoradiographically after selective labeling of the spleen using an extracorporeal perfusion circuit. Tritiated thymidine was added as a DNA precursor. One to 4 days after local labeling of the spleen the relative and absolute number of spleen-derived lymphocytes were determined in the following organs: mesenteric, cervical and inguinal lymph nodes, thymus, bone marrow, Peyer's patches, tonsils, three different parts of the gut, lung, liver, and blood. The labeled lymphocytes which migrated to these organs were all small lymphocytes, except for some large cells in the lamina propria. In the bone marrow, however, a considerable number of the spleen-derived immigrants were transformed into plasma cells. The total number of labeled lymphocytes decreased dramatically from Day 1 to Day 4 after labeling, indicating a high percentage of short-lived cells. Within the spleen, plasma cells had the highest labeling index of about 30% at Day 1 but this dropped to only 1.5% on Day 3. The organ distribution of the splenic emigrants changed from Day 1 to Day 4 with a relative increase in lymphocytes found in lymph nodes and a decrease in the lung and intestinal wall. The newly formed splenic lymphocytes migrated to T-and B-cell areas in lymph nodes, Peyer's patches and tonsils. In the intestinal wall labeled lymphocytes were found in the lamina propria and also as intraepithelial lymphocytes. There was no obvious redistribution between organ compartments with time after labeling of the spleen. The spleen produces large numbers of lymphocytes, which show typical organ distribution and homing to areas in lymphoid and nonlymphoid organs.