A phase I study of pulse high-dose vorinostat (V) plus rituximab (R), ifosphamide, carboplatin, and etoposide (ICE) in patients with relapsed lymphoma.
Given the poor outcomes of relapsed aggressive lymphomas and preclinical data suggesting that ≥2·5 μmol/l concentrations of vorinostat synergize with both etoposide and platinums, we hypothesized that pulse high-dose vorinostat could safely augment the anti-tumour activity of (R)ICE [(rituximab), ifosphamide, carboplatin, etoposide] chemotherapy. We conducted a phase I dose escalation study using a schedule with oral vorinostat ranging from 400 mg/d to 700 mg bid for 5 d in combination with the standard (R)ICE regimen (days 3, 4 and 5). Twenty-nine patients [median age 56 years, median 2 prior therapies, 14 chemoresistant (of 27 evaluable), 2 prior transplants] were enrolled and treated. The maximally tolerated vorinostat dose was defined as 500 mg twice daily × 5 d. Common dose limiting toxicities included infection (n = 2), hypokalaemia (n = 2), and transaminitis (n = 2). Grade 3 related gastrointestinal toxicity was seen in 9 patients. The median vorinostat concentration on day 3 was 4·5 μmol/l (range 4·2-6·0 μmol/l) and in vitro data confirmed the augmented antitumour and histone acetylation activity at these levels. Responses were observed in 19 of 27 evaluable patients (70%) including 8 complete response/unconfirmed complete response. High-dose vorinostat can be delivered safely with (R)ICE, achieves potentially synergistic drug levels, and warrants further study, although adequate gastrointestinal prophylaxis is warranted.
Clinical Research Dvision, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Lihua E
LE
Budde
Michelle M
MM
Zhang
Andrei R
AR
Shustov
John M
JM
Pagel
Ted A
TA
Gooley
George R
GR
Oliveira
Tara L
TL
Chen
Nancy L
NL
Knudsen
Jennifer E
JE
Roden
Britt E
BE
Kammerer
Shani L
SL
Frayo
Thomas A
TA
Warr
Thomas E
TE
Boyd
Oliver W
OW
Press
Ajay K
AK
Gopal
D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D004357:Drug Synergism; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000009:adverse effects; D007069:Ifosfamide / Q000008:administration & dosage / Q000009:adverse effects; D008223:Lymphoma / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D000069283:Rituximab; D000077337:Vorinostat
D058846:Antibodies, Monoclonal, Murine-Derived; D006877:Hydroxamic Acids; D000069283:Rituximab; D000077337:Vorinostat; D005047:Etoposide; D016190:Carboplatin; D007069:Ifosfamide