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Background: FGFR alterations are reported across various malignancies and might act as oncogenic drivers in multiple histologies. Erdafitinib is an oral, selective pan-FGFR tyrosine kinase inhibitor with activity in FGFR-altered advanced urothelial carcinoma. We aimed to evaluate the safety and activity of erdafitinib in previously treated patients with FGFR-altered advanced solid tumours. Methods: The single-arm, phase 2 RAGNAR study was conducted at 156 investigative centres (hospitals or oncology practices that are qualified oncology study centres) across 15 countries. The study consisted of four cohorts based on tumour histology and patient age; the results reported in this Article are for the primary cohort of the study, defined as the Broad Panel Cohort, which was histology-agnostic. We recruited patients aged 12 years or older with advanced or metastatic tumours of any histology (except urothelial cancer) with predefined FGFR1–4 alterations (mutations or fusions according to local or central testing). Eligible patients had disease progression on at least one previous line of systemic therapy and no alternative standard therapy available to them, and an Eastern Cooperative Oncology Group performance status of 0–1 (or equivalent for adolescents aged 12–17 years). Patients received once-daily oral erdafitinib (8 mg/day with provision for pharmacodynamically guided up-titration to 9 mg/day) on a continuous 21-day cycle until disease progression or intolerable toxicity. The primary endpoint was objective response rate by independent review committee according to Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1, or Response Assessment In Neuro-Oncology (RANO). The primary analysis was conducted on the treated population of the Broad Panel Cohort. This ongoing study is registered with ClinicalTrials.gov, number NCT04083976. Findings: Patients were recruited between Dec 5, 2019, and Feb 15, 2022. Of 217 patients treated with erdafitinib, 97 (45%) pa

Purpose: To assess the safety and tolerability of BMS-986148, a mesothelin-directed antibody-drug conjugate (ADC)+/-nivolumab, in patients with selected tumors. Patients and Methods: In an international phase I/IIa study [NCT02341625 (CA008-002)], patients received BMS-986148 monotherapy (0.1-1.6 mg/kg intravenously (i.v.) every 3 weeks or 0.4 or 0.6 mg/kg i.v. once weekly; n=96) or BMS-986148 0.8 mg/kg nivolumab 360 mg i.v. every 3 weeks (n = 30). The primary endpoint was safety and tolerability. Result(s): In CA008-002, the most common (>= 10%) treatmentrelated adverse events (TRAEs) included increased aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Grade 3/4 TRAEs occurred in 42 patients (49%) receiving BMS-986148 every 3 weeks monotherapy, three (25%) receiving BMS-986148 once-weekly monotherapy, and 10 (33%) receiving BMS-986148 + nivolumab every 3 weeks. Overall, 17 of 126 patients (13%) discontinued because of a TRAE. The MTD of BMS-986148 was 1.2 mg/kg i.v. every 3 weeks. The safety profile of BMS-986148 nivolumab was similar to that of BMS-986148 monotherapy (0.8 mg/kg). Active ADC exposures increased in a dose-proportional manner with both dosing regimens (every 3 weeks and once weekly). Preliminary clinical activity was observed with BMS-986148 +/- nivolumab. No association between mesothelin expression and response was detected. Conclusion(s): BMS-986148 _ nivolumab demonstrated a clinically manageable safety profile and preliminary evidence of clinical activity, supporting additional studies combining directed cytotoxic therapies with checkpoint inhibitors as potential multimodal therapeutic strategies in patients with advanced solid tumors.Copyright © 2022 American Association for Cancer Research Inc.. All rights reserved.

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Background: The anti-CD38 antibody isatuximab is approved for the treatment of relapsed/refractory multiple myeloma, but there are no data on its efficacy in solid tumors. This phase I/II study (NCT03637764) assessed the safety and activity of isatuximab plus atezolizumab (Isa + Atezo), an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with immunotherapy-naive solid tumors: epithelial ovarian cancer (EOC), glioblastoma (GBM), hepatocellular carcinoma (HCC), and squamous cell carcinoma of the head and neck (SCCHN). Patients and methods: Phase I assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and the recommended phase II dose (RP2D) of isatuximab 10 mg/kg intravenously (i.v.) every week for 3 weeks followed by once every 3 weeks + atezolizumab 1200 mg i.v. every 3 weeks. Phase II used a Simon's two-stage design to assess the overall response rate or progression-free survival rate at 6 months (GBM cohort). Interim analysis was carried out at 6 months following first dose of the last enrolled patient in each cohort. Pharmacodynamic biomarkers were tested for CD38, PD-L1, tumor-infiltrating immune cells, and FOXP3+ regulatory T cells (Tregs) in the tumor microenvironment (TME). Results: Overall, 107 patients were treated (EOC, n = 18; GBM, n = 33; HCC, n = 27; SCCHN, n = 29). In phase I, Isa + Atezo showed an acceptable safety profile, no dose-limiting toxicities were observed, and RP2D was confirmed. Most patients experienced ≥1 treatment-emergent adverse event (TEAE), with ≤48.5% being grade ≥3. The most frequent TEAE was infusion reactions. The study did not continue to stage 2 based on prespecified targets. Tumor-infiltrating CD38+ immune cells were reduced and almost cleared after treatment. Isa + Atezo did not significantly modulate Tregs or PD-L1 expression in the TME. Conclusions: Isa + Atezo had acceptable safety and tolerability. Clinical pharmacodynamic evaluation revealed efficient target engagement of isatuximab via treatm

PURPOSE: To assess the safety and tolerability of BMS-986148, a mesothelin-directed antibody-drug conjugate (ADC) {plus minus} nivolumab in patients with selected tumors. EXPERIMENTAL DESIGN: In an international phase 1/2a study (NCT02341625 [CA008-002]), patients received BMS-986148 monotherapy (0.1-1.6 mg/kg IV Q3W or 0.4 or 0.6 mg/kg IV QW; n = 96) or BMS-986148 0.8 mg/kg + nivolumab 360 mg IV Q3W (n = 30). The primary endpoint was safety and tolerability. RESULT(S): In CA008-002, the most common ({greater than or equal to} 10%) treatment-related adverse events (TRAEs) included increased AST, ALT, and ALP. Grade 3/4 TRAEs occurred in 42 patients (49%) receiving BMS-986148 Q3W monotherapy, 3 (25%) receiving BMS-986148 QW monotherapy, and 10 (33%) receiving BMS-986148 + nivolumab Q3W. Overall, 17 of 126 patients (13%) discontinued due to a TRAE. The maximum tolerated dose of BMS-986148 was 1.2 mg/kg IV Q3W.The safety profile of BMS-986148 + nivolumab was similar to that of BMS-986148 monotherapy (0.8 mg/kg). Active ADC exposures increased in a dose-proportional manner with both dosing regimens (Q3W and QW). Preliminary clinical activity was observed with BMS-986148 {plus minus} nivolumab. No association between mesothelin expression and response was detected. CONCLUSION(S): BMS-986148 {plus minus} nivolumab demonstrated a clinically manageable safety profile and preliminary evidence of clinical activity, supporting additional studies combining directed cytotoxic therapies with checkpoint inhibitors as potential multimodal therapeutic strategies in patients with advanced solid tumors.

PURPOSE: To assess the safety and tolerability of BMS-986148, a mesothelin-directed antibody-drug conjugate (ADC) {plus minus} nivolumab in patients with selected tumors. EXPERIMENTAL DESIGN: In an international phase 1/2a study (NCT02341625 [CA008-002]), patients received BMS-986148 monotherapy (0.1-1.6 mg/kg IV Q3W or 0.4 or 0.6 mg/kg IV QW; n = 96) or BMS-986148 0.8 mg/kg + nivolumab 360 mg IV Q3W (n = 30). The primary endpoint was safety and tolerability. RESULT(S): In CA008-002, the most common ({greater than or equal to} 10%) treatment-related adverse events (TRAEs) included increased AST, ALT, and ALP. Grade 3/4 TRAEs occurred in 42 patients (49%) receiving BMS-986148 Q3W monotherapy, 3 (25%) receiving BMS-986148 QW monotherapy, and 10 (33%) receiving BMS-986148 + nivolumab Q3W. Overall, 17 of 126 patients (13%) discontinued due to a TRAE. The maximum tolerated dose of BMS-986148 was 1.2 mg/kg IV Q3W.The safety profile of BMS-986148 + nivolumab was similar to that of BMS-986148 monotherapy (0.8 mg/kg). Active ADC exposures increased in a dose-proportional manner with both dosing regimens (Q3W and QW). Preliminary clinical activity was observed with BMS-986148 {plus minus} nivolumab. No association between mesothelin expression and response was detected. CONCLUSION(S): BMS-986148 {plus minus} nivolumab demonstrated a clinically manageable safety profile and preliminary evidence of clinical activity, supporting additional studies combining directed cytotoxic therapies with checkpoint inhibitors as potential multimodal therapeutic strategies in patients with advanced solid tumors.

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The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of squamous cell carcinoma (SCC) of the oral cavity, larynx, oropharynx and hypopharynx was published in 2020. It was therefore decided by both the ESMO and the Korean Society of Medical Oncology (KSMO) to convene a special, virtual guidelines meeting in July 2021 to adapt the ESMO 2020 guidelines to consider the potential ethnic differences associated with the treatment of SCCs of the head and neck (SCCHN) in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with SCCHN (excluding nasopharyngeal carcinomas) representing the oncological societies of Korea (KSMO), China (CSCO), India (ISMPO), Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug access restrictions in the different Asian countries. The latter was discussed when appropriate. This manuscript provides a series of expert recommendations (Clinical Practice Guidelines) which can be used to provide guidance to health care providers and clinicians for the optimisation of the diagnosis, treatment and management of patients with SCC of the oral cavity, larynx, oropharynx and hypopharynx across Asia.

Immune checkpoint inhibitors have changed the standard of care for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). However, only a minority of patients respond, hence the search for predictive biomarkers. Potential predictive biomarkers for immune checkpoint inhibitors discussed in this chapter include (1) Immune checkpoint ligand expression e.g., PD-L1, (2) biomarkers of a T-cell inflamed tumour microenvironment (TME) such as gene expression profiles of activated T cells, (3) biomarkers of tumour neoepitope burden such as tumour mutation burden (TMB) and (4) multidimensional quantitative techniques. At present only PD-L1 expression has been shown to have clinical utility in head and neck cancer. It enriches for populations more likely to respond, but the false positive predictive value remains high. In the pivotal Keynote−048 trial that established a role for pembrolizumab (anti-PD1) monotherapy and pembrolizumab + chemotherapy as treatment options in first-line R/M HNSCC, primary endpoints included overall survival in defined subgroups based on PD-L1 expression. In this trial the combined positive score (CPS) was used which takes into account PD-L1 expression in tumour and immune cells. Based on this trial regulatory approvals for first-line pembrolizumab in R/M HNSCC require assessment of PD-L1 expression using the CPS. Finally we discuss emerging evidence that locoregionally advanced HPV-associated oropharyngeal cancers that have high expression of CD103 positive CD8 T cells have an excellent prognosis and features that suggest increased probability of responding to anti-PD1/PD-L1, raising the possibility of incorporating these immune therapies as part of a de-escalation trial strategy.

Since the initial reports of activity of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), investigation of the role of immune therapies has been the major focus of clinical trials in R/M HNSCC. Randomised trials initially with nivolumab and later with pembrolizumab established overall survival benefit in patients with R/M HNSCC previously treated with platinum compared to physicians choice of 2nd line therapy, and have led to regulatory approval around the world. More recently the Keynote-048 trial has compared both pembrolizumab monotherapy and pembrolizumab + platinum/5FU to the Extreme regimen of platinum/5FU/cetuximab in the first-line R/M setting. The key findings from this trial are that pembrolizumab monotherapy compared to Extreme improved overall survival in patients with PD-L1 combined positive score (CPS) ≥ 20 and ≥ 1, and that pembro/chemotherapy improved OS in CPS ≥ 20, CPS ≥ 1 and the total population. Relative to Extreme there was less toxicity in the monotherapy arm and comparable toxicity in the pembro/chemo arm. Based on this trial use of pembrolizumab as part of first-line treatment for R/M HNSCC is appropriate for the majority of patients, and represents a new standard of care. The focus has now moved to identifying combinations that may be superior to pembrolizumab monotherapy or to chemotherapy + pembrolizumab. Some of the more promising approaches under investigation in HNSCC are discussed in this chapter. In summary, immune therapies are now the cornerstone of management of R/M HNSCC with the approval of pembrolizumab in the first-line R/M setting.

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Current treatment guidelines for patients with locally advanced head and neck squamous cell carcinoma (HNSCC) recommend multimodal treatment, including chemoradiation therapy (CRT) or surgery followed by radiation, with or without chemotherapy. The immune checkpoint inhibitor pembrolizumab has previously demonstrated antitumor activity in recurrent and/or metastatic HNSCC in large Phase III trials. For patients with locally advanced disease, Phase Ib data on the use of pembrolizumab in combination with chemoradiation have shown the approach to be safe and feasible. We describe here the design and rationale for KEYNOTE-412, a randomized, double-blind, Phase III trial investigating pembrolizumab or placebo administered concurrently with CRT and as maintenance treatment in patients with locally advanced HNSCC.

Background Prostate-specific membrane antigen (PSMA) is a clinically validated target for metastatic castration-resistant prostate cancer (mCRPC). AMG 160 BiTE® immuno-oncology therapy redirects T cells to cancer cells by binding to PSMA on cancer cells and CD3 on T cells, leading to T-cell activation, tumor-cell killing, and T-cell expansion. As the BiTE mode of action leads to an upregulation of immune checkpoints, combining AMG 160 with a PD-1 inhibitor may lead to sustained T cell–dependent killing of tumor cells. Cytokine release syndrome (CRS) is a first-dose effect induced by BiTE molecule-mediated T-cell activation. An approach to mitigate CRS is prophylaxis with an anti-inflammatory agent. Methods The phase 1 study (NCT03792841) has four parts: AMG 160 monotherapy; AMG 160 in combination with pembrolizumab; AMG 160 monotherapy with etanercept prophylaxis; and AMG 160 monotherapy administered in outpatient centers with 24-hour monitoring. Included in the study are men with histologically/cytologically confirmed mCRPC who are refractory to novel androgen receptor signaling inhibitors: abiraterone, enzalutamide, darolutamide, and/or apalutamide and have failed, refused, or are unsuitable for taxanes; and who have ongoing castration with evidence of progressive disease. Patients who received prior PSMA radionuclide therapy are eligible. Patients with CNS metastases, leptomeningeal disease, spinal cord compression, or active autoimmune disease are excluded. Primary objectives are to evaluate safety and tolerability and determine the MTD or RP2D of AMG 160 monotherapy or in combination with pembrolizumab. Secondary objectives are to characterize pharmacokinetics and preliminary antitumor activity. Evaluation of preliminary antitumor activity will be based on RECIST 1.1 with Prostate Cancer Working Group 3 modifications, PSA response, CTC response, progression-free survival (radiographic and PSA), and overall survival. PSMA PET/CT and FDG PET/CT imaging will be us

Background Pembrolizumab alone and in combination with platinum-based chemotherapy have become standard first-line treatment options for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), and there is a growing unmet need for safe and efficacious treatment options for R/M HNSCC that has progressed on or after platinum-based chemotherapy and immunotherapy. Data from Study 111/KEYNOTE-146 showed promising antitumor activity and acceptable safety for the PD-1 inhibitor pembrolizumab given in combination with the multikinase inhibitor lenvatinib in patients with metastatic HNSCC.1 LEAP-009 (NCT04428151), a global, randomized, open-label, phase 2 trial, will assess the efficacy and safety of pembrolizumab in combination with lenvatinib versus SOC chemotherapy, as well as the efficacy and safety of lenvatinib monotherapy, in patients with R/M HNSCC that has progressed after platinum-based chemotherapy and a PD-(L)1 inhibitor. Methods Eligible patients are adults with histologically confirmed, locally incurable R/M HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx, disease progression at any time during or after platinum-containing chemotherapy (with or without cetuximab), disease progression within 12 weeks from the last dose of treatment with ≥2 doses of a PD-(L)1 inhibitor, measurable disease based on RECIST v1.1 as confirmed by BICR, ECOG performance status of 0 or 1, and no major blood vessel invasion/infiltration. Patients will be randomized 3:3:2 to pembrolizumab (200 mg IV Q3W for up to 35 cycles) plus lenvatinib (20 mg orally once daily), investigator’s choice of SOC chemotherapy (docetaxel, paclitaxel, cetuximab, or capecitabine), or lenvatinib monotherapy (24 mg orally once daily). Randomization will be stratified by PD-L1 tumor proportion score (<50% versus ≥50%) and ECOG performance status (0 versus 1). Treatment will continue until centrally verified disease progression, unacceptable toxicity, or decision to withdraw. Patien

We established an international consortium to review and discuss relevant clinical evidence in order to develop expert consensus statements related to cancer management during the severe acute respiratory syndrome coronavirus 2-related disease (COVID-19) pandemic. The steering committee prepared 10 working packages addressing significant clinical questions from diagnosis to surgery. During a virtual consensus meeting of 62 global experts and one patient advocate, led by the European Society for Medical Oncology, statements were discussed, amended and voted upon. When consensus could not be reached, the panel revised statements until a consensus was reached. Overall, the expert panel agreed on 28 consensus statements that can be used to overcome many of the clinical and technical areas of uncertainty ranging from diagnosis to therapeutic planning and treatment during the COVID-19 pandemic.

Vinfunine (VFL) is a novel bifluorinated tubulin-targeted agent of the vinca alkaloids class active in advanced stage breast cancer. We conducted a phase I study combining VFL with doxorubicin (DXR) to define the recommended dose (RD), safety, pharmacokinetic (PK) interaction and efficacy. Two schedules (day 1 every 3weeks; days 1 and 8 every 3weeks) were investigated as first line chemotherapy in metastatic breast cancer patients. Thirty-two patients received a total of 162 cycles of the VFL-DXR combination (median 6). The RDs were VFL 250mg/m2/DXR 40mg/m2 every 3weeks for schedule 1 and VFL 120mg/m2/DXR 25mg/m2 days 1 and 8 every 3weeks for schedule 2. The main dose-limiting toxicity was neutropenia. The most frequent non-hematological adverse events were nausea, fatigue, constipation, vomiting, anorexia, stomatitis and dyspnea. Objective response rate was reached in 47.1% of the patients. No PK interaction was observed. VFL-DXR combination is feasible with manageable toxicity. The antitumor activity was promising and supports further evaluation

BackgroundIn the phase III LUX-Head & Neck 1 (LUX-H&N1) trial, second-line afatinib significantly improved progression-free survival (PFS) versus methotrexate in patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Here, we evaluated association of prespecified biomarkers with efficacy outcomes in LUX-H&N1.Patients and methodsRandomized patients with R/M HNSCC and progression following ≥2 cycles of platinum therapy received afatinib (40 mg/day) or methotrexate (40 mg/m2/week). Tumor/serum samples were collected at study entry for patients who volunteered for inclusion in biomarker analyses. Tumor biomarkers, including p16 (prespecified subgroup; all tumor subsites), EGFR, HER2, HER3, c-MET and PTEN, were assessed using tissue microarray cores and slides; serum protein was evaluated using the VeriStrat® test. Biomarkers were correlated with efficacy outcomes.ResultsOf 483 randomized patients, 326 (67%) were included in the biomarker analyses; baseline characteristics were consistent with the overall study population. Median PFS favored afatinib over methotrexate in patients with p16-negative [2.7 versus 1.6 months; HR 0.70 (95% CI 0.50-0.97)], EGFR-amplified [2.8 versus 1.5 months; HR 0.53 (0.33-0.85)], HER3-low [2.8 versus 1.8 months; HR 0.57 (0.37-0.88)], and PTEN-high [1.6 versus 1.4 months; HR 0.55 (0.29-1.05)] tumors. Afatinib also improved PFS in combined subsets of patients with p16-negative and EGFR-amplified tumors [2.7 versus 1.5 months; HR 0.47 (0.28-0.80)], and patients with p16-negative tumors who were EGFR therapy-naïve [4.0 versus 2.4 months; HR 0.55 (0.31-0.98)]. PFS was improved in afatinib-treated patients who were VeriStrat 'Good' versus 'Poor' [2.7 versus 1.5 months; HR 0.71 (0.49-0.94)], but no treatment interaction was observed. Afatinib improved tumor response versus methotrexate in all subsets analyzed except for those with p16-positive disease (n = 35).ConclusionsSubgroups of HNSCC patients who may

BackgroundIn the phase III LUX-Head & Neck 1 (LUX-H&N1) trial, second-line afatinib significantly improved progression-free survival (PFS) versus methotrexate in patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Here, we evaluated association of prespecified biomarkers with efficacy outcomes in LUX-H&N1.Patients and methodsRandomized patients with R/M HNSCC and progression following ≥2 cycles of platinum therapy received afatinib (40 mg/day) or methotrexate (40 mg/m2/week). Tumor/serum samples were collected at study entry for patients who volunteered for inclusion in biomarker analyses. Tumor biomarkers, including p16 (prespecified subgroup; all tumor subsites), EGFR, HER2, HER3, c-MET and PTEN, were assessed using tissue microarray cores and slides; serum protein was evaluated using the VeriStrat® test. Biomarkers were correlated with efficacy outcomes.ResultsOf 483 randomized patients, 326 (67%) were included in the biomarker analyses; baseline characteristics were consistent with the overall study population. Median PFS favored afatinib over methotrexate in patients with p16-negative [2.7 versus 1.6 months; HR 0.70 (95% CI 0.50-0.97)], EGFR-amplified [2.8 versus 1.5 months; HR 0.53 (0.33-0.85)], HER3-low [2.8 versus 1.8 months; HR 0.57 (0.37-0.88)], and PTEN-high [1.6 versus 1.4 months; HR 0.55 (0.29-1.05)] tumors. Afatinib also improved PFS in combined subsets of patients with p16-negative and EGFR-amplified tumors [2.7 versus 1.5 months; HR 0.47 (0.28-0.80)], and patients with p16-negative tumors who were EGFR therapy-naïve [4.0 versus 2.4 months; HR 0.55 (0.31-0.98)]. PFS was improved in afatinib-treated patients who were VeriStrat 'Good' versus 'Poor' [2.7 versus 1.5 months; HR 0.71 (0.49-0.94)], but no treatment interaction was observed. Afatinib improved tumor response versus methotrexate in all subsets analyzed except for those with p16-positive disease (n = 35).ConclusionsSubgroups of HNSCC patients who may

Purpose: Limited data are available on cabazitaxel pharmacokinetics in patients with renal impairment. This open-label, multicenter study assessed cabazitaxel in patients with advanced solid tumors and normal or impaired renal function. Methods: Cohorts A (normal renal function: creatinine clearance [CrCL] >80 mL/min/1.73 m2), B (moderate renal impairment: CrCL 30 to <50 mL/min/1.73 m2) and C (severe impairment: CrCL <30 mL/min/1.73 m2) received cabazitaxel 25 mg/m2 (A, B) or 20 mg/m2 (C, co

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An increased understanding of the molecular genetic and biology of cancer has enabled the development of novel drugs that are collectively referred to as molecular targeted cancer therapies. Unlike the agents used in conventional anti-cancer chemotherapy, these drugs are designed to block the growth and spread of cancer by interfering with specific molecules responsible for the malignant phenotype. They include drugs that interfere with cell growth signaling or tumor blood vessel development, promote the cancer cell apoptosis, stimulate the immune system to destroy specific cancer cells and deliver toxic drugs to cancer cells. The convergence of cancer genome biology, technology and targeted therapeutics paves the way to the advent of personalized cancer medicine.

We have prepared antigen-antibody complexes from grass pollen allergens and autologous specific antibodies isolated by immunoadsorption from the serum of allergic patients. These complexes were inoculated into patients in a double-blind trial to evaluate their effect on grass pollen-related rhinitis and bronchial asthma. Thirty-eight grass pollen-hypersensitive patients were allocated to three groups; patients in the first two groups were treated with antigen-antibody complexes at different ratios and dosages and were compared with the third group who received the placebo carrier buffer alone. In addition, we treated a fourth group who had already received antigen-antibody complex inoculation during the previous pollen season. Injections were given every 2 weeks during the pollen season, starting 5 weeks prior to it. Tolerance was excellent with no signs of local or systemic side effects. The treatment prevented nasal symptoms while enabling the patients to reduce antihistamine intake. Bronchial asthma was virtually absent in the treated groups even though no bronchodilators or corticosteroids had to be taken. Specific IgE antibodies did not increase during the pollen season nor did IgG "blocking" antibodies. Inoculation of allergen-antibody complexes could provide a valuable alternative for the treatment of immediate hypersensitivity to airborne allergens as it appears to be safe and rapidly efficacious. This treatment offers several advantages compared to conventional hyposensitization and is characterized by the absence of an increase in specific IgG antibodies.

Vinfunine (VFL) is a novel bifluorinated tubulin-targeted agent of the vinca alkaloids class active in advanced stage breast cancer. We conducted a phase I study combining VFL with doxorubicin (DXR) to define the recommended dose (RD), safety, pharmacokinetic (PK) interaction and efficacy. Two schedules (day 1 every 3weeks; days 1 and 8 every 3weeks) were investigated as first line chemotherapy in metastatic breast cancer patients. Thirty-two patients received a total of 162 cycles of the VFL-DXR combination (median 6). The RDs were VFL 250mg/m2/DXR 40mg/m2 every 3weeks for schedule 1 and VFL 120mg/m2/DXR 25mg/m2 days 1 and 8 every 3weeks for schedule 2. The main dose-limiting toxicity was neutropenia. The most frequent non-hematological adverse events were nausea, fatigue, constipation, vomiting, anorexia, stomatitis and dyspnea. Objective response rate was reached in 47.1% of the patients. No PK interaction was observed. VFL-DXR combination is feasible with manageable toxicity. The antitumor activity was promising and supports further evaluation