Dataset Information

A phase I study of pulse high-dose vorinostat (V) plus rituximab (R), ifosphamide, carboplatin, and etoposide (ICE) in patients with relapsed lymphoma.

ABSTRACT: Given the poor outcomes of relapsed aggressive lymphomas and preclinical data suggesting that ?2·5 ?mol/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 ?mol/l (range 4·2-6·0 ?mol/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.

SUBMITTER: Budde LE

PROVIDER: S-EPMC3618618 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A phase I study of pulse high-dose vorinostat (V) plus rituximab (R), ifosphamide, carboplatin, and etoposide (ICE) in patients with relapsed lymphoma.

Budde Lihua E LE Zhang Michelle M MM Shustov Andrei R AR Pagel John M JM Gooley Ted A TA Oliveira George R GR Chen Tara L TL Knudsen Nancy L NL Roden Jennifer E JE Kammerer Britt E BE Frayo Shani L SL Warr Thomas A TA Boyd Thomas E TE Press Oliver W OW Gopal Ajay K AK

British journal of haematology 20130129 2

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 ...[more]

PMID: 23356514

Similar Datasets

Project description:BackgroundIn the clinical use of third-line treatment of non-Hodgkin lymphoma (NHL), the combination treatment is increasingly used due to problems such as drug resistance, and while their efficacy has been proven, whether they are economical has become a new issue. A recent trial showed copanlisib plus rituximab combination therapy (CRCT) had better efficacy in the treatment of relapsed indolent NHL (iNHL) compared to rituximab monotherapy (RM). However, the long-term cost and effectiveness of this regimen is not known. We are the first to evaluate the cost effectiveness of CRCT in third-line treatment of relapsed iNHL from the perspective of US payers.MethodsWe used a Markov model to evaluate cost and quality-adjusted life years (QALYs) which included a population from CHRONOS-3 with mean age of 62.5 years and total cycle length of 16.3 years. The cycle length was 1 month, adverse reaction rates were from CHRONOS-3, mean body surface area was referenced from published literature, cost values are referenced from published literature and Drugbank, utility values were referenced from the published literature, and the primary endpoint was the incremental cost-effectiveness ratio (ICER). The willingness to pay (WTP) threshold was set at $150,000 per QALYs, and one-way sensitivity analysis and probabilistic sensitivity analysis were used to verify the robustness of the model. All costs are expressed in 2021 dollars and costs and utilities have been calculated at a discount rate of 3% per year.ResultsCRCT and RM obtained 6.53 QALYs and 5.15 QALYs, respectively, and the ICER of CRCT vs. RM was $358,895.2/QALYs. Parameters having the greatest impact on the robustness of the model were the drug cost of copanlisib and the utility value of the progression-free survival (PFS) state. When the WTP threshold was $150,000, the probability of CRCT and RM being the most cost effective was 0.4% and 99.6% respectively.ConclusionsFrom a US payer perspective, CRCT is not cost-effective in treating relapsed iNHL at current prices compared to RM. But given its positive clinical efficacy, appropriate price discounts or assistance programs should be considered to make CRCT more affordable to patients with relapsed iNHL.

Project description:The randomized phase 3 LYM3001 trial in relapsed follicular lymphoma (FL) demonstrated higher overall (ORR) and complete response (CR) rates and prolonged progression-free survival (PFS) with bortezomib-rituximab versus rituximab. We report findings in high-risk patients (FL International Prognostic Index [FLIPI] score ?3, and high tumor burden by modified Groupe d'Etude des Lymphomas Folliculaires [GELF] criteria).Patients aged ?18 years with grade 1/2 FL, ?1 measurable lesion, and documented relapse or progression following prior therapy, rituximab-naïve or rituximab-sensitive, were enrolled at 164 centers in 29 countries across Europe, the Americas, and Asia-Pacific. Patients were randomized (1:1) to five 5-week cycles of bortezomib-rituximab (bortezomib 1.6 mg/m2, days 1, 8, 15, and 22, all cycles; rituximab 375 mg/m2, days 1, 8, 15, and 22, cycle 1, and day 1, cycles 2-5; N=336) or rituximab alone (N=340). Randomization was stratified by FLIPI score, prior rituximab, time since last dose of anti-lymphoma therapy, and geographical region. The primary endpoint of the study was PFS.103 bortezomib-rituximab and 98 rituximab patients had high-risk FL. The ORR was 59% versus 37% (p=0.002), the CR/CRu rate was 13% versus 6% (p=0.145), and the durable response rate was 45% versus 26% (p=0.008) with bortezomib-rituximab versus rituximab. Median PFS was 9.5 versus 6.7 months (hazard ratio [HR] 0.667, p=0.012) with bortezomib-rituximab versus rituximab; median time to progression was 10.9 versus 6.8 months (HR 0.656, p=0.009); median time to next anti-lymphoma treatment was 14.8 versus 9.1 months (HR 0.762, p=0.103); and the 1-year Overall Survival rate was 83.1% versus 76.6%. Overall, 51% of bortezomib-rituximab and 32% of rituximab patients reported grade ?3 adverse events, including neutropenia (18%, 6%), anemia (4%, 5%), diarrhea (8%, 0%), thrombocytopenia (5%, 2%), and sensory neuropathy (1%, 0%).High-risk FL patients treated with bortezomib-rituximab had significantly higher ORR and longer PFS than patients receiving rituximab alone, with greater clinical benefit than in the overall study population; additional toxicity was acceptable and did not affect treatment feasibility.The phase 3 LYM3001 trial is registered with ClinicalTrials.gov, with the identifier NCT00312845.

Dataset Information

A phase I study of pulse high-dose vorinostat (V) plus rituximab (R), ifosphamide, carboplatin, and etoposide (ICE) in patients with relapsed lymphoma.

Publications

A phase I study of pulse high-dose vorinostat (V) plus rituximab (R), ifosphamide, carboplatin, and etoposide (ICE) in patients with relapsed lymphoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets