TRC102 and Temozolomide for Relapsed Solid Tumors and Lymphomas

Solid Tumors Clinical Trial

Official title: A Phase I/II Trial of TRC102 (Methoxyamine HCl) in Combination With Temozolomide in Patients With Relapsed Solid Tumors and Lymphomas

Status Completed

Clinical Trial Summary

Background:

• Methoxyamine hydrochloride (TRC102) is a new cancer treatment drug that may help improve the results of chemotherapy. It blocks tumor cells' attempts to repair damaged deoxyribonucleic acid (DNA), which may allow chemotherapy to kill the cells more easily. Researchers want to see how well it works with temozolomide, a chemotherapy drug that is designed to damage tumor cell DNA. These drugs will be given to people who have advanced solid tumors or lymphomas that have not responded to earlier treatments.

Objectives:

• To test the safety and effectiveness of TRC102 and temozolomide for advanced solid tumors and lymphomas.

Eligibility:

• Individuals at least 18 years of age who have advanced solid tumors or lymphomas that have not responded to earlier treatments.

Design:

• Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Tumor samples may also be collected. The size and location of the tumors will be determined with imaging studies.

• Participants will take TRC102 and temozolomide for 28-day cycles of treatment. They will take temozolomide and TRC 102 by mouth once a day on days 1-5. Participants will keep a diary to record doses and any side effects.

• Treatment will be monitored with frequent blood tests and imaging studies. Tumor samples will also be collected.

• Participants will continue their treatment as long as the cancer does not grow and there are no severe side effects.

Clinical Trial Description

Background:

• Base excision repair (BER) of deoxyribonucleic acid (DNA) repair pathway has been implicated in resistance to both alkylating and antimetabolite chemotherapy.

• TRC102 (methoxyamine hydrochloride (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, non-small 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-H2A histone family member X (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 abdominoperineal excision (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 pharmacodynamic (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 progressive disease (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/m(2) 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/m(2) of TMZ by mouth (PO) every (q)day x 5 every 28 days (Dose Level (DL)5). 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. ;

Related Conditions & MeSH terms

• Granulosa Cell Ovarian Cancer
• Lymphoma
• Lymphomas
• Metastatic Colon Carcinoma
• NSCLC
• Solid Tumors

• NCT number: NCT01851369
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: July 12, 2013
• Completion date: August 1, 2023