A Phase I Trial of TRC102 (Methoxyamine HCl) in Combination With Temozolomide in Patients With Relapsed Solid Tumors and Lymphomas
- Base excision repair (BER) of DNA repair pathway has been implicated in resistance to
both alkylating and antimetabolite chemotherapy.
- TRC102 (methoxyamine HCl) acts through a novel mechanism to inhibit BER and has
demonstrated the ability to potentiate the activity of the alkylating agent
temozolomide (TMZ), in vitro and in vivo.
- We hypothesize that TRC102 can be safely co-administered with TMZ and would potentiate
DNA damage caused by TMZ, resulting in antitumor responses.
- To establish the safety, tolerability, and maximum tolerated dose (MTD) of oral TRC102
in combination with oral TMZ in patients with refractory solid tumors.
- Evaluate the pharmacokinetic (PK) profile of oral TRC102 when administered in
combination with TMZ.
- Determine the effects of the study treatment on the level of histone gammaH2AX in
circulating tumor cells (CTCs) and tumor
- To correlate the gammaH2AX response in tumor and CTCs
- Determine the effects of the study treatment on the levels of cleaved caspase 3 and
Ki-67 in tumor
- Study participants must have histologically confirmed solid tumor that has progressed
on standard therapy known to prolong survival or for which no standard treatment
- No major surgery, radiation, or chemotherapy within 4 weeks prior to entering the study
- Adequate organ function
- This is an open-label Phase I trial; traditional 3+3 design.
- Oral TRC102 and oral TMZ will be administered daily, days 1-5 in 28-day cycles
- Once the MTD is established, 6 additional patients will be enrolled at the MTD to
further evaluate that dose for PK and PD endpoints for evidence of DNA damage and
- During the escalation phase, tumor biopsies will be optional. During the expansion
phase, (once MTD is reached), mandatory paired tumor biopsies will be pursued in the 6
additional patients enrolled to further evaluate PD endpoints.
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Establish safety, tolerability, and maximum tolerated dose of oral TRC102 in combination with oral TMZ in patients with refractory solid tumors.
Shivaani Kummar, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|