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Background: The primary objective of the patient-reported outcomes (PRO) study of E1609 patients (pts) was to compare overall HRQL among pts receiving ipi (ipi10, ipi3) or HDI. We hypothesized that ipi would be superior to HDI in HRQL. Secondary analyses compared HRQL and GI distress between ipi10 and ipi3. Methods: PROs were administered among pts enrolled from NCI Community Oncology Research Program (NCORP) sites at baseline, every 12 weeks (wks) during treatment, and every 24 wks off-treatment for one year. Differences between ipi arms and HDI in overall HRQL at 12 wks (completion of ipi induction) was defined a priori as the primary outcome. HRQL was assessed using the 27-item Functional Assessment of Cancer Therapy -General (FACT-G) total score. GI toxicity was a secondary outcome measured by the 11-item FACIT-Diarrhea (FACIT-D) scale. Two sample t-test was used to compare scores between arms. Results: 548 pts completed PROs at baseline and 334 at 12 wks. Among 322 (59%) pts with PRO data at both time points, mean FACT-G total change scores from baseline to 12 wks were significantly lower (indicating less decline in HRQL) among pts randomized to ipi10 (-4.9

,SD:

14.1) or ipi3 (-3.4 points

,SD:

13.2) vs. HDI (-12.9, SD.:14.1), p < 0.05 for both ipi10 vs. HDI and ipi3 vs. HDI. Mean FACIT-D change scores indicated higher GI distress from baseline to 12 wks among pts randomized to ipi10 (-3.7, SD.:6.9) or ipi3 (-2.2, SD.:5.1) vs HDI (-0.7, SD.:2.7), p < 0.05 for both comparisons. In comparing ipi10 to ipi3, FACT-G total and FACIT-D total change scores from baseline to wk 12 were comparable. Conclusions: Overall decline in HRQL from baseline to completion of ipi induction was less among pts receiving ipi compared to HDI. Pts randomized to ipi reported a greater increase in diarrhea compared to HDI. HRQL and diarrhea were comparable between ipi3 and ipi10. Our findings are based on PRO data, thus increase our confidence in capturing pts' experience with treatment from the pt's perspective.

Aims: BI 2536 is a selective and potent small-molecule inhibitor of polo-like kinase 1. We performed a multi-centre, multi-tumour phase II trial to investigate the efficacy, safety and pharmacokinetics of BI 2536 in five solid tumour types. Patients and methods: Patients with advanced head and neck, breast and ovarian cancer, soft tissue sarcoma and melanoma were selected according to protocol-defined general and tumour-specific criteria. They were ≥18 years old, had a good performance status, adequate bone marrow, renal and liver function, measurable progressive disease and had completed other relevant systemic treatments >4 weeks ago. BI 2536 200-250 mg was given intravenously on day 1 every 3 weeks until intolerance, progression or refusal. The study was based on a Simon two-stage design, with 12 patients entering in stage 1 and additional 25 patients to be entered in case of at least one response in the first stage. The rate of objective responses (RECIST criteria) was chosen as primary end-point. Results: Seventy six patients were included, 71 started treatment and received a median number of two cycles (four in ovarian cancer). Frequent grade 3-4 adverse events were neutropaenia (81.6%), thrombocytopaenia (19.7%), febrile neutropaenia (19.7%), anaemia (15.5%) and pain (9.9%). We did not observe confirmed objective responses. All cohorts were closed after the entry of 14-15 eligible non-responding patients. Pharmacokinetic analyses revealed multi-compartmental behaviour and a rapid distribution of BI 2536. Conclusions: BI 2536 showed limited antitumour activity according to the design of this trial in five different tumour types. Derivatives of BI 2536 with a more favourable pharmacological profile are currently explored further in prospective studies. © 2010 Elsevier Ltd. All rights reserved.

The irradiated, allogeneic, cellular CSF-470 vaccine plus Bacillus Calmette-Guerin (BCG) and recombinant human granulocyte macrophage-colony stimulating factor (rhGM-CSF) is being tested against medium-dose IFN-α2b in stages IIB-III cutaneous melanoma (CM) patients (pts) after surgery in an open, randomized, Phase II/III study. We present the results of the Phase II part of the ongoing CASVAC-0401 study (ClinicalTrials.gov: NCT01729663). Thirty-one pts were randomized to the CSF-470 vaccine (n = 20) or to the IFN-α2b arm (n = 11). During the 2-year treatment, immunized pts should receive 13 vaccinations. On day 1 of each visit, 1.6 × 107 irradiated CSF-470 cells plus 106 colony-forming units BCG plus 100 μg rhGM-CSF were administered intradermally, followed on days 2-4 by 100 μg rhGM-CSF. IFN-α2b pts should receive 10 million units (MU)/day/5 days a week for 4 weeks; then 5 MU thrice weekly for 23 months. Toxicity and quality of life (QOL) were evaluated at each visit. With a mean and a maximum follow-up of 39.4 and 83 months, respectively, a significant benefit in the distant metastasis-free survival (DMFS) for CSF-470 was observed (p = 0.022). Immune monitoring showed an increase in antitumoral cellular and humoral response in vaccinated pts. CSF-470 was well tolerated; 20/20 pts presented grades 1-2 dermic reactions at the vaccination site; 3/20 pts presented grade 3 allergic reactions. Other adverse events (AEs) were grade 1. Pts in the IFN-α2b arm presented grades 2-3 hematological (7/11), hepatic (2/11), and cardiac (1/11) toxicity; AEs in 9/11 pts forced treatment interruptions. QOL was significantly superior in the vaccine arm (p < 0.0001). Our results suggest that CSF-470 vaccine plus BCG plus GM-CSF can significantly prolong, with lower toxicity, the DMFS of high-risk CM pts with respect to medium-dose IFN-α2b. The continuation of a Phase III part of the CASVAC-0401 study is encouraged.

INTERVENTION:

Product Name: Masitinib Product Code: AB1010 Pharmaceutical Form: Coated tablet CAS Number: 790‐299‐79‐5 Current Sponsor code: AB1010 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 100‐ Product Name: Masitinib Product Code: AB1010 Pharmaceutical Form: Coated tablet CAS Number: 790‐299‐79‐5 Current Sponsor code: AB1010 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 200‐ Trade Name: DETICENE Pharmaceutical Form: Powder for infusion* INN or Proposed

INN:

Dacarbazine Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 100‐

CONDITION:

Patients with non‐resectable or metastatic stage 3 or stage 4 melanoma carrying a mutation in the juxta membrane domain of c‐kit ; MedDRA version: 9.1 Level: LLT Classification code 10025670 ; MedDRA version: 9.1 Level: LLT Classification code 10025671

PRIMARY OUTCOME:

Main Objective: The objective is to compare the efficacy and safety of masitinib at 7.5 mg/kg/day to dacarbazine in the treatment of patients with non‐resectable or metastatic stage 3 or stage 4 melanoma carrying a mutation in the juxta membrane domain of c‐kit (c‐kit JM). The primary endpoint is Progression Free Survival (PFS) Primary end point(s): Overall Progression Free Survival (PFS) is defined as the delay between the date of randomization to the date of documented progression (according to m‐RECIST) or any cause of death during the study. Secondary Objective: Secondary objectives are to compare the efficacy and safety of masitinib at 7.5 mg/kg/day to dacarbazine The secondary endpoints are: Efficacy: • Overall Survival (OS) • Survival rate at week 6, 12, 18, 24 and every 12 weeks • PFS rate at week 6, 12, 18, 24 and every 12 weeks • Time To Progression (TTP) and TTP rate at week 6, 12, 18, 24 and every 12 weeks • Best response rate, Objective response rate (CR + PR) and Disease control rate (CR + PR + SD) • Quality of life : assessment at week 6, 12, 18 and 24 and every 12 weeks • ECOG performance status • EORTC QLQ‐C30 • Safety profile using the NCI CTCAE v4.0 classification

INCLUSION CRITERIA:

1.Patient = 18 years old, male or female, weighting more than 40 kg 2.Patient with histologically or cytologically confirmed non‐resectable or metastatic stage III (non‐resectable IIIB or IIIC, AJCC TNM staging system 7th edition) or stage IV melanoma 3.Patient with detectable c‐kit JM mutation confirmed by DNA or RNA sequencing, which is expected to be mainly found after screening of mucosal or acral melanoma or melanoma on skin with chronic sun‐induced damages (defined by a microscopically marked elastosis involving the skin surrounding their primary melanoma) 4.Patient with measurable disease according to RECIST 5.Patient with ECOG = 2 6.Patient with life expectancy = 12 weeks 7.Patient with adequate organ function • Absolute neutrophil count (ANC) = 1.5 x 109/L • Haemoglobin = 10 g/dL • Platelets (PLT) = 100 x 109/L • AST/ALT = 2.5 x ULN (= 5 x ULN in case of liver metastases) • Bilirubin = 1.5 x ULN (= 3 x ULN in case of liver metastases) • C

<b>

PURPOSE:

</b>High-dose interferon (IFN) for 1 year (HDI) is the US Food and Drug Administration-approved adjuvant therapy for patients with high-risk melanoma. Efforts to modify IFN dose and schedule have not improved efficacy. We sought to determine whether a shorter course of biochemotherapy would be more effective.<b>Patients and

METHODS:

</b>S0008 (S0008: Chemotherapy Plus Biological Therapy in Treating Patients With Melanoma) was an Intergroup phase III trial that enrolled high-risk patients (stage IIIA-N2a through IIIC-N3), randomly assigning them to receive either HDI or biochemotherapy consisting of dacarbazine, cisplatin, vinblastine, interleukin-2, IFN alfa-2b (IFN-α-2b) and granulocyte colony-stimulating factor given every 21 days for three cycles. Coprimary end points were relapse-free survival (RFS) and overall survival (OS).<b>

RESULTS:

</b>In all, 432 patients were enrolled. Grade 3 and 4 adverse events occurred in 57% and 7% of HDI patients and 36% and 40% of biochemotherapy patients, respectively. At a median follow-up of 7.2 years, biochemotherapy improved RFS (hazard ratio [HR], 0.75; 95% CI, 0.58 to 0.97; P = .015), with a median RFS of 4.0 years (95% CI, 1.9 years to not reached [NR]) versus 1.9 years for HDI (95% CI, 1.2 to 2.8 years) and a 5-year RFS of 48% versus 39%. Median OS was not different (HR, 0.98; 95% CI, 0.74 to 1.31; P = .55), with a median OS of 9.9 years (95% CI, 4.62 years to NR) for biochemotherapy versus 6.7 years (95% CI, 4.5 years to NR) for HDI and a 5-year OS of 56% for both arms.<b>

CONCLUSION:

</b>Biochemotherapy is a shorter, alternative adjuvant treatment for patients with high-risk melanoma that provides statistically significant improvement in RFS but no difference in OS and more toxicity compared with HDI.

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INTERVENTION:

Product Name: masitinib Product Code: AB1010 Pharmaceutical Form: Coated tablet INN or Proposed

INN:

Masitinib mesylate CAS Number: 790‐299‐79‐5 Current Sponsor code: AB1010 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 100‐ INN or Proposed

INN:

Masitinib mesylate CAS Number: 790‐299‐79‐5 Current Sponsor code: AB1010 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 200‐

CONDITION:

Mélanome métastasé ou non‐opérable stade 3 ou stade 4, ne portant pas de mutation dans le domaine juxta‐membranaire de c‐kit ; MedDRA version: 12.1 Level: LLT Classification code 10025670 Term: Malignant melanoma stage III ; MedDRA version: 12.1 Level: LLT Classification code 10025671 Term: Malignant melanoma stage

IV PRIMARY OUTCOME:

Main Objective: L’objectif est d’évaluer l’efficacité et la tolérance de masitinib à 9 mg/kg/jour en monothérapie et en association avec dacarbazine chez des patients atteints d’un mélanome non opérable ou métastatique de stade 3 ou stade 4, et ne présentant pas de mutation du domaine juxta membranaire du domaine de c‐kit. Primary end point(s): Critère principal :; • Survie sans progression (PFS); ; Critères secondaires : ; ; Survie; • Survie globale (OS); • Taux de survie globale tous les 3 semaines; ; Evaluation de la tumeur : ; • Taux de Survie sans progression toutes les 6 semaines ; • Temps avant progression (TTP); • Taux de progression toutes les 6 semaines; • Durée de la réponse tumorale; • Taux de réponse (CR+PR) toutes les 6 semaines; • Taux de contrôle tumoral (CR+ PR+ SD) toutes les 6 semaines; • Meilleure réponse au cours de l’étude ; ; Evaluation de la qualité de vie toutes les 6 semaines; • Echelle de performances status ECOG; • Questionnaire EORTC QLQ‐C30; ; Evaluation du profil de tolérance selon la classification NCI CTCAE v4.02; ; Pharmacocinétique Secondary Objective: Déterminer l’absorption, la distribution, le métabolisme et l’élimination de masitinib, dacarbazine et de la combinaison masitinib/dacarbazine chez les patients présentant un mélanome non opérable ou métastatique de stade 3 ou stade 4.

INCLUSION CRITERIA:

1. Homme ou femme âgé de plus de 18 ans et avec un BMI > 18 2. Patient avec une confirmation histologique ou cytologique d’un mélanome non opérable ou métastatique de stade 3 (stade IIIB ou IIIC non opérable, selon AJCC TNM staging system 7th edition) ou de stade 4 : mélanome cutané, mélanome muqueux et mélanome dont l’origine n’est pas déterminée sont éligibles. 3. Patient ne présentant pas de mutation du domaine JM de c‐kit confirmé par un séquençage ADN ou ARN 4. Patient ayant des lésions mesurables selon les critères m‐RECIST (version 1.1) 5. Patient avec ECOG = 2 6. Patient ayant une espérance de vie = 12 semaines 7. Patient ayant des fonctions organiques adéquates : • Neutrophiles = 1,5 x 109/L • Hémoglobine = 10 g/dL • Plaquettes = 100 x 109/L • AST/ALT = 2,5x Limites Supérieures Normales (LSN) (= 5 x LSN en cas de métastases au foie) • Bilirubine = 1,5x LSN (= 3 x LSN en cas de métastases au foie) • Gamma GT = 3x LSN

Background: Melanoma is a potentially lethal skin malignancy; patients with stage III/IV resected disease have a recurrence rate of 50-90%. Adjuvant checkpoint inhibitor immunotherapy decreases the risk of recurrence but also causes significant immune-related toxicity. Vaccines are a promising strategy for patients with high risk melanoma. The optimal time to intervene may be in the adjuvant setting after attaining a disease-free state through standard of care therapies. Our strategy uses autologous tumor lysate (TL) in a yeast cell wall particle (YCWP) to load dendritic cells (DC) ex vivo. The tumor lysate particle loaded dendritic cell (TLPLDC) vaccine is then given to prevent melanoma recurrences. An alternate vaccine delivery method that we are evaluating utilizes the tumor lysate particle-only (TLPO) technique, in which tumor lysate is loaded into capped YCWP and injected intradermally, allowing an in vivo uptake by the patient's dendritic cells. Methods: We are performing a prospective, randomized, blinded, placebo-controlled phase IIb trial in patients with resected stage III/IV melanoma who have been rendered disease-free but remain at high risk of recurrence. The study will utilize the TLPLDC strategy vs placebo (2:1) in 120 patients, followed by a bridging study of TLPO vs TLPLDC (2:1) in 60 patients. Both TLPLDC and TLPO inoculations will be monthly x3, followed by boosters at 6, 12, and 18 months. Primary endpoints will be disease free survival (DFS) at 24 months in the TLPLDC arm, and overall safety in the TLPO arm. We have completed enrollment in the phase IIb portion of the study.

INTERVENTION:

Product Name: BMS‐734016 / MDX‐010 / Ipilimumab Pharmaceutical Form: Intravenous infusion INN or Proposed

INN:

Ipilimumab CAS Number: 477202‐00‐9 Current Sponsor code: BMS‐734016 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 5‐ Pharmaceutical form of the placebo: Intravenous infusion Route of administration of the placebo: Intravenous use Trade Name: Dacarbazine Product Name: Dacarbazine Pharmaceutical Form: Powder for solution for infusion INN or Proposed

INN:

Dacarbazine CAS Number: 4342‐03‐4 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 200‐

CONDITION:

Stage III (Unresectable) or IV Melanoma

INCLUSION CRITERIA:

1) Willing and able to give written informed consent; 2) Histologic diagnosis of malignant melanoma; 3) Untreated unresectable Stage III melanoma with N3 macroscopic lymph nodes or in‐transit/satellite metastases or Stage IV melanoma (AJCC 2001) (note that prior adjuvant melanoma therapy is permitted [e.g., IFN therapy]); 4) Measurable/evaluable disease (as per modified WHO criteria), within 28 days of first dose of study drug; 5) Life expectancy of = 16 weeks; 6) ECOG performance status of 0 or 1 (see Protocol Appendix 3); 7) Have the complete set of baseline (i.e., Screening) digital images of lesions and radiographic images, including, but not limited to: brain, chest, abdomen pelvis and bone scans. All images must be of adequate quality; 8) Required values for initial laboratory tests: • WBC = 2500/uL • ANC = 1000/uL • Platelets = 75 x 103/uL • Hemoglobin = 9 g/dL • Creatinine = 2.5x ULN • AST = 3 x ULN for

PRIMARY OUTCOME:

Main Objective: To compare PFS in patients with previously untreated Stage IIIc, N3 (unresectable) or Stage IV melanoma receiving dacarbazine plus 10mg/kg ipilimumab (MDX‐010) vs. dacarbazine with placebo. Primary end point(s): Efficacy Measures: ; Investigator and Independent Review Committee (IRC) tumor evaluations will be based on modified WHO criteria. Throughout the study each respective Investigator will determine disease status of patients at the defined time points and as clinically indicated.; For the purpose of final analysis of study results, an IRC will review all images from all time points for all patients and assess response parameters as specified.; ; Pharmacokinetics: ; Blood draws to assess the serum PK of ipilimumab will be drawn at the time points; listed in section 7.3.5.1. of the protocol. Serum concentration data will be used in conjunction with samples from other studies as part of the population PK assessment. Serum Human Anti‐Human Antibodies (HAHA) will be collected as per Table 7.3.5.1. of the protocol.; ; Safety Measures: ; Safety will be evaluated for all treated patients using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events v3.0 (CTCAE). Safety assessments will be based on medical review of AE reports and the results of vital sign measurements, physical examinations and clinical laboratory tests. The incidence of AEs will be tabulated and reviewed for potential significance and clinical; importance. The reporting period for safety data will be from the date of first on‐study dose to 70 days (5 half‐lives) after the last dose is received.; ; Health‐related quality of life (HRQoL):; will be assessed as measured by the European Organization for Research and Treatment of Cancer Quality of Life questionnaire (EORTC) and will be administered at multiple time‐points throughout the study. Secondary Objective: 1) To compare overall survival (OS) between two arms;; 2) To estimate survival rate at 1 year for each treatment arm;; 3) To compare PFS rate at Week 12 between two arms;; 4) To compare best overall response rate (BORR) between two arms;; 5) To estimate duration of best overall response (BOR) and the proportion of patients with duration of response lasting = 24 weeks for each treatment arm;; 6) To compare disease control rate (proportion with best response of complete response [CR] + partial response [PR] + stable disease [SD]) between two arms;; 7) To estimate time to BOR for each treatment arm;; 8) To evaluate the safety profile for each treatment arm;; 9) To evaluate Health Related Quality of Life (HRQoL) for each treatment arm;; 10) To obtain serum samples for population pharmacokinetics