title: Dose-finding/phase II trial: bevacizumab, immunotherapy, and chemotherapy (BIC) in metastatic renal cell cancer (mRCC). Antitumor effects and variations of circulating T regulatory cells (Treg).
abstract: The aim of this study was to explore the efficacy and toxicities of a combined regimen of bevacizumab plus immunotherapy and chemotherapy (BIC) and the circulating T regulatory cells (Treg) in metastatic renal cell cancer (mRCC). Nephrectomized mRCC patients were enrolled into a multicenter single-arm dose-finding study with five escalated dose levels of chemotherapy with intravenous gemcitabine and 5-fluorouracil associated with fixed intravenous doses of bevacizumab, subcutaneous low doses of interleukin-2, and interferon-α-2a. An expanded cohort (phase II study) was treated at the recommended dose for additional safety and efficacy information according to minimax Simon two-stage design. Blood samples for Treg were collected and evaluated by fluorescence-activated cell sorting (FACS) analysis on cycle 1. Fifty-one patients were entered to receive one of five dose levels. Median age was 58 years (male 67 %, pretreated 49 %): 15 patients were low risk according to Memorial Sloan-Kettering Cancer Center (MSKCC) criteria, while 27 and nine were respectively intermediate- and high-risk patients. More frequent grade 3 and 4 toxicities included nonfebrile neutropenia, thrombocytopenia, and fever. Among patients evaluable for response (49), 29.5 % had partial response and 37 % stable disease. Overall median time to progression and median overall survival were 8.8 and 22.67 months, respectively. We observed a rapid increase in the percentage of Treg after immunotherapy and a reduction after bevacizumab only in patient who obtained a partial response or stable disease. The BIC was feasible, well tolerated, and shown interesting activity. Further studies are needed to explore if Treg could have a role in clinical response in mRCC treated with bevacizumab.
authors.affiliation: Oncology Division, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100, Cremona, Italy, maddalenadonini@gmail.com.
authors.forename: M
authors.initials: M
authors.lastname: Donini
authors.forename: S
authors.initials: S
authors.lastname: Buti
authors.forename: S
authors.initials: S
authors.lastname: Lazzarelli
authors.forename: R
authors.initials: R
authors.lastname: Bozzetti
authors.forename: L
authors.initials: L
authors.lastname: Rivoltini
authors.forename: C
authors.initials: C
authors.lastname: Camisaschi
authors.forename: C
authors.initials: C
authors.lastname: Castelli
authors.forename: A
authors.initials: A
authors.lastname: Bearz
authors.forename: C
authors.initials: C
authors.lastname: Simonelli
authors.forename: G
authors.initials: G
authors.lastname: Lo Re
authors.forename: R
authors.initials: R
authors.lastname: Mattioli
authors.forename: C
authors.initials: C
authors.lastname: Caminiti
authors.forename: R
authors.initials: R
authors.lastname: Passalacqua
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D000068258:Bevacizumab / Q000008:administration & dosage* / Q000009:adverse effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D002469:Cell Separation / Q000379:methods; D017024:Chemotherapy, Adjuvant; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D005434:Flow Cytometry; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects / Q000379:methods*; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage; D007376:Interleukin-2 / Q000008:administration & dosage; D007558:Italy; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009392:Nephrectomy; D011994:Recombinant Proteins / Q000008:administration & dosage; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D013997:Time Factors; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D020533:Angiogenesis Inhibitors; D000964:Antimetabolites, Antineoplastic; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007376:Interleukin-2; D011994:Recombinant Proteins; D003841:Deoxycytidine; D000068258:Bevacizumab; D005472:Fluorouracil; D000093542:Gemcitabine