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Phase I clinical trial of temozolomide and methoxyamine (TRC-102), an inhibitor of base excision repair, in patients with advanced solid tumors.
- Source :
-
Investigational new drugs [Invest New Drugs] 2021 Feb; Vol. 39 (1), pp. 142-151. Date of Electronic Publication: 2020 Jun 17. - Publication Year :
- 2021
-
Abstract
- Temozolomide (TMZ) generates DNA adducts that are repaired by direct DNA and base excision repair mechanisms. Methoxyamine (MX, TRC-102) potentiates TMZ activity by binding to apurinic and apyrimidinic (AP) sites after removal of N <superscript>3</superscript> -methyladenine and N <superscript>7</superscript> -methylguanine, inhibiting site recognition of AP endonuclease. We conducted a phase I trial to determine the maximum tolerated dose and dose-limiting toxicities (DLTs) of intravenous MX when given with oral TMZ. Patients with advanced solid tumors and progression on standard treatment were enrolled to a standard 3 + 3 dose escalation trial assessing escalating doses of TMZ and MX. Tumor response was assessed per RECIST and adverse events (AEs) by CTCAEv3. Pharmacokinetics (PK) of MX and COMET assays on peripheral blood mononuclear cells were performed. 38 patients were enrolled-median age 59.5 years (38-76), mean number of cycles 2.9 [1-13]. No DLTs were observed. Cycle 1 grade 3 AEs included fatigue, lymphopenia, anemia, INR, leukopenia, neutropenia, allergic reaction, constipation, psychosis and paranoia. Cycle 2-13 grade 4 AEs included thrombocytopenia and confusion. A partial response was seen in 1 patient with a pancreatic neuroendocrine tumor (PNET) and six additional patients, each with different tumor types, demonstrated prolonged stable disease. MX PK was linear with dose and was not affected by concomitant TMZ. TMZ 200 mg/m <superscript>2</superscript> daily × 5 may be safely administered with MX 150 mg/m <superscript>2</superscript> intravenously once on day 1 with minimal toxicity. Further studies assessing this drug combination in select tumor types where temozolomide has activity may be warranted.
- Subjects :
- Adult
Aged
Antineoplastic Agents, Alkylating administration & dosage
Antineoplastic Agents, Alkylating adverse effects
Antineoplastic Agents, Alkylating pharmacokinetics
Antineoplastic Combined Chemotherapy Protocols pharmacokinetics
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Area Under Curve
DNA Repair drug effects
Dose-Response Relationship, Drug
Drug Synergism
Female
Half-Life
Humans
Hydroxylamines administration & dosage
Hydroxylamines adverse effects
Hydroxylamines pharmacokinetics
Male
Maximum Tolerated Dose
Metabolic Clearance Rate
Middle Aged
Temozolomide adverse effects
Temozolomide pharmacokinetics
Antineoplastic Agents, Alkylating therapeutic use
Hydroxylamines therapeutic use
Neoplasms drug therapy
Temozolomide therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1573-0646
- Volume :
- 39
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Investigational new drugs
- Publication Type :
- Academic Journal
- Accession number :
- 32556884
- Full Text :
- https://doi.org/10.1007/s10637-020-00962-x