TRC102 and Temozolomide for Relapsed Solid Tumors and Lymphomas

Summary

Participation Requirements

Description

Background: -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 a...

Background: -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. -Based on responses measured during the Phase I portion of the trial, we will further explore the efficacy of this combination in patients with metastatic colon carcinoma, nonsmall cell lung cancer (NSCLC), and granulosa cell ovarian cancer Primary Objective: -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. -To explore the response rate of this combination in patients with colon cancer, NSCLC, and granulosa cell ovarian cancer Secondary Objective: To explore the progression free survival rate of this combination in patients with colon cancer, NSCLC, and granulosa cell ovarian cancer Exploratory Objectives: Investigate tumor genomic and transcriptomic alterations potentially associated with sensitivity and/or the development of resistance to TRC102 and temozolomide. Determine the effects of the study treatment on the level of histone gamma-H2AX in circulating tumor cells (CTCs) and tumor and correlate the gamma-H2AX response in tumor and CTCs Determine the effects of the study treatment on the levels of cleaved caspase 3, epithelial- mesenchymal transition, and APE in tumor and CTCs Determine and characterize the effects of study treatment on erythrocytes Characterize the clinical presentation of hemolysis observed in earlier study subjects and explore the possible mechanisms Eligibility: -Phase I: histologically confirmed solid tumors that have progressed on standard therapy known to prolong survival or for which no standard treatment options exist -Phase II: histologically confirmed adenocarcinoma of the colon post at least two lines of therapy, NSCLC post at least two lines of therapy, or granulosa cell ovarian cancer post at least one line of therapy No major surgery, radiation, or chemotherapy within 4 weeks prior to entering the study Adequate organ function Healthy adult volunteers greater than or equal to 18 years of age will be consented to donate research blood Please note: healthy adult volunteers will no longer be recruited to provide blood for this study as we will no longer perform the hemolysis analysis. Study Design: Phase I 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, up to 15 additional patients will be enrolled at the MTD to further evaluate that dose for PK and PD endpoints for evidence of DNA damage and apoptosis. -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 15 additional patients enrolled to further evaluate PD endpoints. Phase II -This is a 3-arm Simon 2-stage design trial evaluating independently the response rate of patients with colon, NSCLC, and granulosa cell ovarian cancer. Patients with a body surface area (BSA) of greater than or equal to 1.6 m(2) will receive 125 mg of TRC 102 and 150 mg/m2 of TMZ PO qday x 5 every 28 days (DL6). Patients with a BSA of <1.6 m(2) will receive 100 mg of TRC 102 and 150 mg/m2 of TMZ PO qday x 5 every 28 days (DL5).. Each cycle will be 28 days. The accrual ceiling for the Phase II portion is 75 patients. Mandatory paired tumor biopsies will be pursued to further evaluate PD endpoints.

Tracking Information