TRC102 and Temozolomide in Treating Patients with Relapsed Solid Tumors or Lymphomas
- 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 colorectal adenocarcinoma 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; patients must have measurable disease
- Patients enrolling in the expansion cohorts must have disease amenable to biopsy and be willing to undergo pre-and post-treatment biopsies
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Phase I), =< 1 (Phase II)
- Life expectancy of greater than 3 months
- Absolute neutrophil count >= 1,500/mcL
- Hemoglobin >= 10 g/dL without transfusion within 4 days prior to enrollment
- Platelets >= 100,000/mcL
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal; 5.0 x ULN in cases of liver metastases
- Creatinine =< 1.5 x institutional ULN OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels > 1.5 mg/dL
- The effects of study drug on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and for at least 3 months after dosing with study drugs ceases; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 months after completion of study drug administration
- Patients must have completed any chemotherapy, radiation therapy, or biologic therapy >= 4 weeks (or 5 half-lives, whichever is shorter) prior to entering the study (6 weeks for nitrosoureas or mitomycin C); patients must be >= 2 weeks since any prior administration of a study drug in a phase 0 or equivalent study and >= 1 week from palliative radiation therapy; patients must have recovered to eligibility levels from prior toxicity or adverse events; treatment with bisphosphonates is permitted
- Patients must be able to swallow whole tablets or capsules; nasogastric or gastrostomy tube (G-tube) administration is not allowed
- Ability to understand and the willingness to sign a written informed consent document and to undergo tumor biopsies in the expansion phase
- HEALTHY VOLUNTEER BLOOD DONORS
- Age > 18 years
- Hemoglobin >= 12 g/dL
- No history of bleeding problems; not taking aspirin or any medication that may affect erythrocyte biochemistry
- Willingness to sign the healthy volunteer informed consent form
- Patients who are actively receiving any other investigational agents
- Patients with active brain metastases or carcinomatous meningitis are excluded from this clinical trial; patients with treated brain metastases, whose brain metastatic disease has remained stable for >= 4 weeks without requiring steroid and anti-seizure medications are eligible to participate
- Phase II only: No other prior malignancies are allowed except for the following: * Adequately managed stage 0 (carcinoma in situ), I, or II basal cell or squamous cell carcinoma from which the patient is currently in complete remission * Any other cancer from which the patient has been disease-free for three years * Adequately managed stage I or II well differentiated thyroid or prostate cancer is also eligible, wherein the patient is not required to be in complete remission
- Phase II only: patients with colorectal cancer with known microsatellite instability (MSI)-high disease who have previously been treated with immunotherapy or who have refused treatment with immunotherapy
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to TRC102 or TMZ
- Uncontrolled intercurrent illness including, but not limited to, serious untreated infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- Pregnant women are excluded from this study because the effects of the study drugs on the developing fetus are unknown; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with the study drugs, breastfeeding should be discontinued prior to the first dose of study drug and women should refrain from nursing throughout the treatment period and for 3 months following the last dose of study drug
- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of possible pharmacokinetic (PK) interactions with TRC102
I. To establish the safety, tolerability, and maximum tolerated dose of oral TRC102 (methoxyamine hydrochloride [HCl]) in combination with oral temozolomide (TMZ) in patients with refractory solid tumors.
II. Evaluate the pharmacokinetic (PK) profile of oral TRC102 when administered in combination with TMZ.
III. To explore the response rate of this combination in patients with colon cancer, non-small cell lung cancer (NSCLC), and granulosa cell ovarian cancer.
I. To explore the progression free survival rate of this combination in patients with colon cancer, NSCLC, and granulosa cell ovarian cancer.
I. Investigate tumor genomic and transcriptomic alterations potentially associated with sensitivity and/or the development of resistance to TRC102 and temozolomide.
II. Determine the effects of the study treatment on the level of histone gamma-H2AX in circulating tumor cells (CTCs) and tumor correlate the gamma-H2AX response in tumor and CTCs.
III. Determine the effects of the study treatment on the levels of cleaved caspase 3 and Ki-67 in tumor.
IV. To explore resistance mechanisms to the study drug combination.
V. Determine and characterize the effects of study treatment on erythrocytes.
VI. Characterize the clinical presentation of hemolysis observed in earlier study subjects and explore the possible mechanisms.
OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.
Patients receive methoxyamine hydrochloride orally (PO) once daily (QD) and temozolomide PO QD on days 1-5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Healthy volunteer participants undergo collection of blood samples for research at baseline.
After completion of study treatment, patients are followed up for 30 days.
Trial Phase Phase I/II
Trial Type Treatment
NCI - Center for Cancer Research
A P Chen
- Primary ID 9483
- Secondary IDs NCI-2013-00877, 13-C-0118, P121184, 130118
- Clinicaltrials.gov ID NCT01851369