title: A phase I-II study of 9-cis retinoic acid and interferon-alpha2b in patients with advanced renal-cell carcinoma: an NCIC Clinical Trials Group study.
abstract: Although advanced renal-cell carcinoma (RCC) responds poorly to standard therapies, phase I-II trials have shown activity for combinations of interferon-alpha2b (IFN) with a retinoid. Alitretinoin (9-cis RA) is an endogenous retinoid with high binding affinity for both RAR and RXR receptor families. This phase I-II study enrolled 38 patients with RCC in a dose-escalation study of tolerability, pharmacokinetics (PK), and efficacy of twice daily oral 9-cis RA with subcutaneous IFN. In contrast to studies with similar doses of daily 9-cis RA, PK studies found a consistent reduction in 9-cis RA concentrations of about 50% after multiple b.i.d. doses of 30 or 50 mg/m2, independent of cotreatment with IFN. In the phase I portion, toxicities included systemic symptoms typical of IFN and biochemical abnormalities previously associated with retinoids. Two patients experienced dose-limiting toxicity at 50 mg/m2 b.i.d. of 9-cis RA, thus the recommended phase II dose was 30 mg/m2 b.i.d. One of twenty-six evaluable patients achieved a durable objective partial remission, and repeated dosing with this regimen was poorly tolerated. This combination of retinoid and interferon is not recommended for further study in RCC.
authors.affiliation: Department of Oncology, McGill University, Montreal, PQ, Canada. wmiller@ldi.jgh.mcgill.ca
authors.forename: W H
authors.initials: WH
authors.lastname: Miller
authors.forename: L M
authors.initials: LM
authors.lastname: Reyno
authors.forename: G R
authors.initials: GR
authors.lastname: Loewen
authors.forename: S
authors.initials: S
authors.lastname: Huan
authors.forename: E
authors.initials: E
authors.lastname: Winquist
authors.forename: M
authors.initials: M
authors.lastname: Moore
authors.forename: A
authors.initials: A
authors.lastname: Cato
authors.forename: D
authors.initials: D
authors.lastname: Jaunakais
authors.forename: J A
authors.initials: JA
authors.lastname: Truglia
authors.forename: S
authors.initials: S
authors.lastname: Matthews
authors.forename: J
authors.initials: J
authors.lastname: Dancey
authors.forename: E
authors.initials: E
authors.lastname: Eisenhauer
mesh_terms: D000328:Adult; D000368:Aged; D000077556:Alitretinoin; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005334:Fever / Q000139:chemically induced; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009392:Nephrectomy; D010146:Pain / Q000139:chemically induced; D011994:Recombinant Proteins; D012074:Remission Induction; D017211:Treatment Failure; D014212:Tretinoin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D007155:Immunologic Factors; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D000077556:Alitretinoin; D014212:Tretinoin