Phase 1/2 clinical trial of interferon alpha2b and weekly liposome-encapsulated all-trans retinoic acid in patients with advanced renal cell carcinoma.
To evaluate the feasibility, efficacy, and biologic effects of weekly liposome-encapsulated all-trans retinoic acid (ATRA-IV) plus interferon alpha2b (IFN) in patients with advanced renal cell carcinoma (RCC). Twenty-six patients with metastatic RCC were treated on a phase 1/2 trial with weekly ATRA-IV and IFN SQ daily 5 d/wk. Twelve patients received ATRA-IV at three dose levels (60, 75, and 90 mg/m2) according to phase 1 methodology, and 14 additional patients received 90 mg/m2. Response was assessed according to an intention-to-treat analysis. Serum retinoic acid (RA) concentrations were assayed and peripheral blood mononuclear cell mRNA expression of RA and IFN-inducible genes (RARalpha, RARbeta2, IRF1, CRABP2, and TRAIL) were examined. No dose limiting toxicities occurred at 60 mg/m2; grade 3 leukopenia affected 1/6 patients at 75 mg/m2, whereas 3 patients received 90 mg/m2 without a dose limiting toxicities. Fourteen additional patients received 90 mg/m2 ATRA-IV without grade 3/4 toxicity. Five of 26 (19%) patients achieved a major response, with a median duration of 14 months (range 9 to 23); 9 additional patients (41%) demonstrated stable disease or minor response lasting > or =4 months. No significant differences in serum (RA) after ATRA infusion were detected between weeks 1 and 8 of treatment. Peripheral blood mononuclear cell mRNA expression did not correlate with clinical response. The addition of weekly ATRA-IV to IFN therapy is feasible and well tolerated, resulting in sustainable increased serum (RA). This regimen demonstrates antitumor activity in metastatic RCC, and suggests ATRA-IV augments IFN therapy.
Department of Urology, the Division of Hematology and Medical Oncology, Weill Medical College of Cornell University, New York, NY 10021, USA.
Stephen A
SA
Boorjian
Matthew I
MI
Milowsky
Jodi
J
Kaplan
Martin
M
Albert
Marta Vallee
MV
Cobham
Deirdre M
DM
Coll
Nigel P
NP
Mongan
Gary
G
Shelton
Daniel
D
Petrylak
Lorraine J
LJ
Gudas
David M
DM
Nanus
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D004334:Drug Administration Schedule; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D008081:Liposomes; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins; D014212:Tretinoin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D008081:Liposomes; D011994:Recombinant Proteins; D014212:Tretinoin