Related Experiment Video
Updated: Jan 20, 2026
Author Spotlight: Advancements and Challenges in Surgical Treatments for Postamputation Pain
Published on: March 8, 2024
A randomized phase I and pharmacological trial of sequences of 1,3-bis(2-chloroethyl)-1-nitrosourea and temozolomide
Lisa A Hammond1, John R Eckardt, John G Kuhn
1Cancer Therapy and Research Center, University of San Antonio Health Science Center at San Antonio, San Antonio, Texas, USA.
Purpose:
O(6)-alkylguanine-DNA alkyltransferase (AGAT) is modulated by methylating agents, which, in turn, abrogates nitrosourea resistance in preclinical studies. The feasibility of administering various sequences of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and temozolomide (TEM) in patients with advanced solid neoplasms was evaluated in this Phase I and pharmacological study to assess this premise in the clinical setting. The study also sought to determine the maximum tolerated dose (MTD) levels of BCNU and TEM as a function of Seq, to characterize the pharmacokinetic (PK) behavior of TEM administered both before and after BCNU, assess AGAT fluctuations in peripheral blood mononuclear cells (PBMCs), and seek preliminary evidence of anticancer activity.
Experimental Design:
Sixty-three patients were randomized to receive treatment with oral TEM daily on days 1-5 and BCNU administered i.v., either on day 1 before TEM [Sequence (Seq) B-->T] or day 5 after TEM (Seq T-->B). Treatment was repeated every 6 weeks. Blood sampling for PK studies was performed on both days 1 and 5 of course one. PBMCs were sampled to evaluate major sequence-dependent effects on AGAT levels.
Results:
Neutropenia and thrombocytopenia were the principal dose-limiting toxicities of the BCNU/TEM regimen. These effects were more prominent in patients receiving Seq T-->B, resulting in a much lower MTD of 80/100 mg/m(2)/day compared with 150/110 mg/m(2)/day for Seq B-->T. Notable antitumor activity was observed in patients with glioblastoma multiforme, sarcoma, and ovarian carcinoma. No sequence-dependent PK effects were noted to account for sequence-dependent toxicological effects. At the MTD level, AGAT activity in PBMCs decreased 3-fold, on average, and AGAT fluctuations did not appear to be sequence-dependent.
Conclusions:
The principal toxicities of the BCNU/TEM regimen were neutropenia and thrombocytopenia, which were consistent and predictable, albeit sequence-dependent. Seq T-->B was substantially more myelosuppressive, resulting in disparate MTDs and dose levels recommended for subsequent disease-directed evaluations (150/110 and 80/100 mg/m(2)/day for Seq B-->T and T-->B, respectively). Sequence-dependent differences in TEM PK do not account for this clinically relevant magnitude of sequence-dependent toxicity. The characteristics of the myelosuppressive effects of BCNU/TEM, the paucity of severe nonhematological toxicities, and antitumor activity at tolerable doses warrant disease-directed evaluations on this schedule.
Insights
Administering BCNU before TEM (Seq B-->T) is safer and better tolerated than TEM before BCNU (Seq T-->B) in advanced solid tumors. Seq B-->T allows higher doses, showing promising anticancer activity with manageable toxicity.
Area of Science:
- Pharmacology and Toxicology
- Oncology
- Cancer Therapeutics
Background:
- O(6)-alkylguanine-DNA alkyltransferase (AGAT) modulation by methylating agents affects nitrosourea resistance.
- Preclinical studies suggest sequential administration of BCNU and TEM may overcome resistance.
- Clinical feasibility and optimal sequencing of BCNU and TEM require investigation in advanced solid neoplasms.
Purpose of the Study:
- To evaluate the feasibility of different sequences of BCNU and TEM in patients with advanced solid neoplasms.
- To determine the maximum tolerated dose (MTD) for BCNU and TEM based on administration sequence.
- To characterize the pharmacokinetic (PK) behavior of TEM relative to BCNU and assess AGAT levels in PBMCs.
Main Methods:
- Phase I study involving 63 patients with advanced solid neoplasms.
- Randomization to two sequences: BCNU before TEM (Seq B-->T) or TEM before BCNU (Seq T-->B), repeated every 6 weeks.
- Blood sampling for PK analysis and PBMC sampling for AGAT levels on days 1 and 5 of the first course.
Main Results:
- Neutropenia and thrombocytopenia were the primary dose-limiting toxicities, more severe in Seq T-->B.
- MTD for Seq T-->B was 80/100 mg/m²/day, significantly lower than 150/110 mg/m²/day for Seq B-->T.
- Notable antitumor activity observed in glioblastoma multiforme, sarcoma, and ovarian carcinoma; no sequence-dependent PK effects found.
Conclusions:
- The BCNU/TEM regimen exhibits sequence-dependent myelosuppression, with Seq T-->B being substantially more toxic.
- Seq B-->T demonstrated higher MTDs and is recommended for further evaluation due to manageable toxicity and observed antitumor activity.
- Sequence-dependent PK differences do not explain the observed toxicity variations; further disease-directed evaluations are warranted.
Related Concept Videos
08:36The Adjuvant Efficacy of Angong Niuhuang Pill in the Treatment of Viral Encephalitis: A Meta-Analysis of Randomized Controlled Trials
03:26Targeted Muscle Reinnervation: Surgical Protocol for a Randomized Controlled Trial in Postamputation Pain
09:42Solid Phase Synthesis
Merrifield's solid-phase synthesis is a Nobel Prize winning invention where a reactant molecule is bound on a solid support and undergoes successive chemical reactions to form a desired compound. When the molecules are bound to a solid support, excess reagents and byproducts can be removed by washing away the impurities, while the target compound remains bound to the resin. Specifically, we will...
06:28E-Patient Counseling Trial (E-PACO): Computer Based Education versus Nurse Counseling for Patients to Prepare for Colonoscopy
11:37Protocol for the Solid-phase Synthesis of Oligomers of RNA Containing a 2'-O-thiophenylmethyl Modification and Characterization via Circular Dichroism
11:15Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors