Gefitinib plus interleukin-2 in advanced non-small cell lung cancer patients previously treated with chemotherapy

The activation of lymphocytes by gefitinib treatment has been described. In this phase II pilot trial, we explored the possible synergism between IL-2 and gefitinib for non-small cell lung cancer (NSCLC) treatment. From September, 2003, to November, 2006, 70 consecutive patients with advanced, progressive NSCLC, previously treated with chemotherapy, received oral gefitinib 250 mg daily. The first 39 patients received gefitinib alone (G group). The other 31 also received subcutaneous IL-2 (GIL-2 group): 1 MIU/m2 (Million International Unit/m2)twice a day on Days 1 and 2, once a day on Days 3, 4, 5 every week for four consecutive weeks with a four-week rest period. Median follow-up was 25.2 months. Grade 3–4 toxicity of gefitinib was represented by skin rash (7%), asthenia/anorexia (6%) and diarrhea (7%); patients treated with IL-2 showed grade 2–3 fever (46%), fatigue (21%) and arthralgia (13%). In the GIL-2 group and G-group, we respectively observed: an overall response rate of 16.1% (6.4% complete response) and 5.1% (only partial response); a disease control rate of 41.9% and 41%; a median time to progression of 3.5 (CI 95% = 3.2–3.8) and 4.1 (CI 95% = 2.6–5.7) months; a median overall survival of 20.1 (CI 95% = 5.1–35.1) and 6.9 (CI 95% = 4.9–8.9) months (p = 0.002); and an actuarial one-year survival rate of 54% and 30%. Skin toxicity (p < 0.001; HR = 0.29; CI 95% = 0.16–0.54) and use of IL-2 (p < 0.001; HR = 0.33; CI 95% = 0.18–0.60) were independently associated with improvement of survival. In this consecutive, non-randomized, series of advanced NSCLC patients, the use of IL-2 increased the efficacy of gefitinib

A Tethered Bilayer Assembled on Top of Immobilized Calmodulin to Mimic Cellular Compartmentalization

International audienceBACKGROUND: Biomimetic membrane models tethered on solid supports are important tools for membrane protein biochemistry and biotechnology. The supported membrane systems described up to now are composed of a lipid bilayer tethered or not to a surface separating two compartments: a "trans" side, one to a few nanometer thick, located between the supporting surface and the membrane; and a "cis" side, above the synthetic membrane, exposed to the bulk medium. We describe here a novel biomimetic design composed of a tethered bilayer membrane that is assembled over a surface derivatized with a specific intracellular protein marker. This multilayered biomimetic assembly exhibits the fundamental characteristics of an authentic biological membrane in creating a continuous yet fluid phospholipidic barrier between two distinct compartments: a "cis" side corresponding to the extracellular milieu and a "trans" side marked by a key cytosolic signaling protein, calmodulin. METHODOLOGY/PRINCIPAL FINDINGS: We established and validated the experimental conditions to construct a multilayered structure consisting in a planar tethered bilayer assembled over a surface derivatized with calmodulin. We demonstrated the following: (i) the grafted calmodulin molecules (in trans side) were fully functional in binding and activating a calmodulin-dependent enzyme, the adenylate cyclase from Bordetella pertussis; and (ii) the assembled bilayer formed a continuous, protein-impermeable boundary that fully separated the underlying calmodulin (trans side) from the above medium (cis side). CONCLUSIONS: The simplicity and robustness of the tethered bilayer structure described here should facilitate the elaboration of biomimetic membrane models incorporating membrane embedded proteins and key cytoplasmic constituents. Such biomimetic structures will also be an attractive tool to study translocation across biological membranes of proteins or other macromolecules

A new modified schedule of sunitinib for metastatic renal cell carcinoma: A retrospective analysis

Background and aim of the work: Sunitinib 50 mg/day given for 4 weeks followed by 2 weeks off treatment (4+2 schedule) is a standard treatment for metastatic renal cell carcinoma, but several patients are forced to reduce the doses and/or had to discontinue therapy permanently due to toxicity. Recent data showed that increased exposure to sunitinib is associated with improved clinical outcome underlining the key role of dose-intensity in the efficacy/toxicity balance. We investigated the tolerability and efficacy of a modified schedule. Patients and methods: This is a retrospective analysis which assessed consecutive non-progressive metastatic renal cell carcinoma patients admitted to our hospital who had at least a grade 2 toxicity during sunitinib therapy, and then switched to a modified schedule maintaining the same dose-intensity of 4+2 schedule: starting on Monday, 1 tablet/day for 5 consecutive days a week (days 6 and 7 off therapy) for 5 weeks and 1 tablet/day on days 1, 3 and 5 in the sixth week (days 2, 4, 6 and 7 off therapy) until disease progression. Primary end points were toxicity changes assessment and schedule feasibility. Results: Complete data from eight nephrectomized patients were collected: 6 males; median age 61; 3 pretreated patient. Median time from start therapy to switch was 7.4 months. After switch, treatment delays and dose reductions decreased from 50% to 25% and from 37% to 12% of patients respectively. Toxicity was reduced. Conclusions: Even though no conclusions can be drawn about the actual effectiveness and toxicity of our schedule compared to the standard dosing schedule, it seems to be well tolerated and able to maintain a high adherence to therapy, resulting in maintenance of antitumour activity. © Mattioli 1885

Combination of Bevacizumab plus low-doses Immunotherapy plus Chemotherapy (BIC regimen) in metastatic renal cell cancer: antitumor effects and variations of T-regulatory cells (Treg) during the treatment. A multicentre study of the Italian Oncology Group for Clinical Research (GOIRC)

Background: Bevacizumab (B) is effective in metastatic Renal Cell Cancer (mRCC) and has a synergistic effect with Chemotherapy (Ch) in many tumors. The activity of B plus immunotherapy (It) with interleukin- 2 (IL-2) and interferon-α (IFN-α) has not been studied. Our previous dose-finding study showed the feasibility of the combination B+It+Ch (BIC regimen) [JCO Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 15586]. Aim of this study is to explore the efficacy of BIC and to correlate its efficacy with the variations in circulating T regulatory lymphocytes (Treg). Methods: Patients (pts) with histological diagnosis of mRCC, previous nephrectomy, PS 0-1, adequate organ function, no untreated CNS metastases and 0-2 previous systemic regimens were treated with B (10 mg/kg days 1 and 15) plus Ch (Gemcitabine: 1,000 mg/m2 i.v. in 1 hour followed by 5-fluorouracil 600 mg/m2 iv bolus days 1 and 8 every 28) plus It (IL-2: 1 MUI/m2 bid sc days 8, 9, 15, 16 and 1 MUI/m2/die sc from day 10 to 12 and from 17 to 19; and IFN-α: 3 MUI sc on days 10, 12, 17, 19). This phase II study was conducted according to two stages Minimax Simon design. CT was repeated for a maximum of 6 cycles followed by maintenance with B and It until progressive disease (PD). In 30 pts, blood samples for Treg were evaluated on days: 1, 8, 15, 22, 29 of cycle 1 and at the disease progression (PD). Recist criteria and ITT analysis were applied. Results: 45 pts were included: male 66%; median age 59 years; 47% pre-treated; 18% PS ≥ 1; 43 pts were evaluable for response (2 too early) and we observed 33% partial response (PR), 31% stable disease (SD) and 31% PD for an overall disease control rate (DCR) of 64%. Median PR/SD duration was 7.3 months (mths). Median TTP was 8.2 mths (95% CI: 6.9-9.4). In 24 not pre-treated pts DCR was 79%. In MSKCC poor risk group (13%) we observed 33% PR and a DCR of 83% with a TTP of 8.7 mths. Treatment was well tolerated, grade 3-4 toxicity included neutropenia non-febrile 36%, febrile 2%, thrombocytopenia 27%, flu-like syndrome 19%, hypertension 7%. Data show overall increased percentage of Treg, identified by FACS analysis as CD4+/CD25high/FoxP3+ in PBMCs, after the first week of It (day 15) and a overall decrease after the treatment with B (day 22); but from day 15 to 22 in PR/SD pts Treg decrease, while PD pts Treg increase. Conclusions: BIC combination is effective in all subgroups of mRCC and is well tolerated. Variation in Treg during first cycle seems to be correlated with the response to treatmen

Dose-finding/phase II trial with a combination of bevacizumab (B) plus immunotherapy plus chemotherapy (BIC) in patients with metastatic renal cell cancer (mRCC): A GOIRC multicentre study

Introduction: Therapy (tp) with IL-2 and IFN-α is considered as an effective immunotp (IT) for mRCC. Bevacizumab (B) proved to have efficacy with different mechanism as regards as IT and had at least an additive effect with chemotherapy (Ch) in many tumors. We searched for a synergism between B, IT and Ch (BIC). Methods: This is a multicenter dose- finding (DF)/phase II study aimed at to investigate: 1) safety and maximum tolerated dose (MTD) of the BIC tp; 2) antitumor activity. DF study comprised 5 escalation dose levels of Ch: Gemcitabine (G) (initial dose [id] 600 mg/m2 to 1,000 mg/m2) followed by 5FU bolus (id 400 mg/m2 to 600 mg/m2) each one on days (d) 1 and 8 every 28 d, associated with fixed doses of B (10 mg/kg on d 1 and 15), IL-2 (1 MUI/m2 bid sc on d 8, 9, 15, 16 and 1 MUI/m2/d sc from d 10 to 12 and from 17 to 19) and IFN-α (3 MUI sc on d 10, 12, 17, 19). DF study was conducted according to Fibonacci statistical method. Phase II study used the reached MTD and was conducted according to two stage Minimax Simon design. Tp was repeated for a maximum of 6 cycles followed by a maintenance with B and IT until progressive disease (PD). Results: 41 pts were enrolled (male 66%); median age 58 yrs; all were assessable for toxicity and 49% were pre-treated. According to MSKCC risk, 27%, 59% and 14% were at low, intermediate and high risk, respectively. Tp was generally well tolerated and MTD was not reached; phase II used the 5° dose level of Ch. Main grade 3-4 toxicity during all cycles: neutropenia non febrile (23/41) and 1 febrile, thrombocytopenia in 11 pts, fever in 7. At present analysis 37 pts are assessable for response: 12 (32%) partial responses (PR), 13 (35%) stable disease and 12 PD for an overall disease control rate (DCR) of 68%; median (med) duration of response was 8.2 mths. In not pre-treated there was a DCR of 78%. Major activity was observed in young pts (< 58 yrs) with a RR of 53% and interesting activity in high MSKCC risk: RR 20% and DCR 80% with a med time to progression (TTP) of 8.7 mths. Overall med TTP was 8.2 mths (CI 95% 6.9-9.4). Conclusions: This is the first study that explored the BIC tp in mRCC and it was generally well tolerated and showed promising activity

Sequential chemotherapy with dose-dense docetaxel, cisplatin, folinic acid and 5-fluorouracil (TCF-dd) followed by combination of oxaliplatin, folinic acid, 5-fluorouracil and irinotecan (COFFI) in metastatic gastric cancer: Results of a phase II trial

Purpose: To evaluate a new strategy of two sequential, intensified chemotherapy regimens in metastatic gastric cancer. Patients and methods: Chemo-naïve patients with metastatic gastric cancer were enrolled to receive 4 cycles of TCF-dd (docetaxel initially 85 mg/m2 and cisplatin initially 75 mg/m2 on day 1 [later modified due to toxicity: 70 and 60 mg/m2 respectively], l-folinic acid 100 mg/m 2 on days 1 and 2, 5-fluorouracil 400 mg/m2 bolus and then 600 mg/m2 as a 22 h continuous infusion on day 1 and 2, every 14 days). Subsequently, patients with CR, PR or SD received 4 cycles of COFFI (oxaliplatin 85 mg/m2, irinotecan 140 mg/m2, l-folinic acid 200 mg/m2, 5-fluorouracil bolus 400 mg/m2 on day 1 followed by 2,400 mg/m2 as a 48 h continuous infusion, every 14 days). In both regimens pegfilgrastim 6 mg subcutaneously on day 3 was included. Results: Forty consecutive patients were enrolled. TCF-dd regimen achieved an ORR of 55% (95% CI, 40-70). Twenty-three patients proceeded to COFFI. After this regimen the ORR was then increased to 60% (95% CI, 45-75). Among the 21 patients treated with TCF-dd after the protocol amendments, main grade 3-4 toxicities were: neutropenia (29%), thrombocytopenia (19%), asthenia (24%) and diarrhea (14%). COFFI caused grade 3-4 neutropenia (all not febrile) and diarrhea in 35% and 17% of patients respectively. Conclusions: A sequential strategy with TCF-dd followed by COFFI is very active and may be of special interest in selected patients. © 2010 Springer-Verlag