Reference Detail

Ref Type

Journal Article

PMID

(32556884)

Authors

Eads JR, Krishnamurthi SS, Saltzman J, Bokar JA, Savvides P, Meropol NJ, Gibbons J, Koon H, Sharma N, Rogers L, Pink JJ, Xu Y, Beumer JH, Riendeau J, Fu P, Gerson SL, Dowlati A

Title

Phase I clinical trial of temozolomide and methoxyamine (TRC-102), an inhibitor of base excision repair, in patients with advanced solid tumors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Investigational new drugs			2020 Jun 17	142-151	Invest New Drugs

URL

Abstract Text

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 N3-methyladenine and N7-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/m2 daily × 5 may be safely administered with MX 150 mg/m2 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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
TRC102	TRC102	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
TRC102		Methoxyamine\|TRC-102		TRC102 (Methoxyamine) inhibits the base excision repair pathway, potentially resulting in increased sensitivity to chemotherapeutic agents and anti-tumor activity (J Clin Oncol 34, 2016 (suppl; abstr 2556), PMID: 23054206, PMID: 32556884).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References