Safety and tolerability of idelalisib, lenalidomide, and rituximab in relapsed and refractory lymphoma: the Alliance for Clinical Trials in Oncology A051201 and A051202 phase 1 trials.
Abstract | BACKGROUND: METHODS: FINDINGS: Between July 9, 2013, and Sept 30, 2014, 11 patients (three with mantle cell lymphoma and eight with follicular lymphoma) were enrolled. Among the first eight patients, four experienced unexpected dose-limiting toxicities: grade 4 sepsis syndrome, grade 4 hypotension with grade 3 rash and fevers, grade 4 aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation with fevers, and grade 3 pulmonary infection with grade 3 maculopapular rash. Symptom onset was 9-20 days after treatment initiation, coinciding with rituximab infusions. Both studies were amended to remove rituximab, but two of three additional patients had grade 3 rashes and one had grade 3 AST elevation. Both trials were permanently closed. The most common grade 3-4 adverse events were ALT elevation (two [67%] of three) and rash (two [67%] of three) for patients with mantle cell lymphoma and neutropenia (five [63%] of eight) and rash (four [50%] of eight) for patients with follicular lymphoma. The primary endpoint of safety and tolerability was not met. INTERPRETATION: The combination of idelalisib, lenalidomide, and rituximab in these trials is excessively toxic, and these trials serve as cautionary notes as new combinations are proposed. Off-target effects, drug-drug interactions, and emerging toxicities should be carefully assessed when investigating biological agents in combination and should never be done outside of a clinical trial setting. FUNDING: National Cancer Institute of the National Institutes of Health.
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Authors | Sonali M Smith, Brandelyn N Pitcher, Sin-Ho Jung, Nancy L Bartlett, Nina Wagner-Johnston, Steven I Park, Kristy L Richards, Amanda F Cashen, Anthony Jaslowski, Scott E Smith, Bruce D Cheson, Eric Hsi, John P Leonard |
Journal | The Lancet. Haematology
(Lancet Haematol)
Vol. 4
Issue 4
Pg. e176-e182
(Apr 2017)
ISSN: 2352-3026 [Electronic] England |
PMID | 28314699
(Publication Type: Clinical Trial, Phase I, Journal Article)
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Copyright | Copyright © 2017 Elsevier Ltd. All rights reserved. |
Chemical References |
- Antineoplastic Agents
- Antineoplastic Agents, Immunological
- Purines
- Quinazolinones
- Rituximab
- Thalidomide
- Lenalidomide
- idelalisib
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Topics |
- Aged
- Antineoplastic Agents
(administration & dosage, adverse effects, therapeutic use)
- Antineoplastic Agents, Immunological
(administration & dosage, adverse effects, therapeutic use)
- Antineoplastic Combined Chemotherapy Protocols
(administration & dosage, adverse effects, therapeutic use)
- Drug Administration Schedule
- Female
- Humans
- Lenalidomide
- Lymphoma, Follicular
(drug therapy)
- Lymphoma, Mantle-Cell
(drug therapy)
- Male
- Maximum Tolerated Dose
- Middle Aged
- Neoplasm Recurrence, Local
(drug therapy)
- Purines
(administration & dosage, adverse effects, therapeutic use)
- Quinazolinones
(administration & dosage, adverse effects, therapeutic use)
- Rituximab
(administration & dosage, adverse effects, therapeutic use)
- Thalidomide
(administration & dosage, adverse effects, analogs & derivatives, therapeutic use)
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