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


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Lymphomas, Solid Tumors

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Trial Information

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


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.

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.

Secondary Objectives:

- 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

Eligibility:

- Study participants must have histologically confirmed solid tumor that has progressed
on standard therapy known to prolong survival or for which no standard treatment
options exist.

- No major surgery, radiation, or chemotherapy within 4 weeks prior to entering the study

- Adequate organ function

Study Design:

- 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
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 6
additional patients enrolled to further evaluate PD endpoints.

Inclusion Criteria


- INCLUSION CRITERIA:

- Patients must have histologically confirmed solid tumors that has progressed on
standard therapy known to prolong survival or for which no standard treatment options
exist.

- Age greater than or equal to 18 years. Because no dosing or adverse event data are
currently available on the use of TRC102 in combination with TMZ in patients less
than 18 years of age, children are excluded from this study.

- Patients enrolling in the expansion cohorts must have disease amenable to biopsy and
be willing to undergo pre-and post-treatment biopsies.

- ECOG performance status less than or equal to 2.

- Life expectancy of greater than 3 months

- Patients must have normal organ and marrow function as defined below:

- Absolute neutrophil count greater than or equal to 1,500/mcL

- Hemoglobin greater than or equal to 9 g/dL without transfusion within 1 week
prior to enrollment

- Platelets greater than or equal to 100,000/mcL

- Total bilirubin less than or equal to 1.5 X institutional ULN

---AST(SGOT)/ALT(SGPT) less than or equal to 3 X upper limit of normal; 5.0 X
ULN in cases of liver metastases

- creatinine less than or equal to 1.5 X institutional ULN

OR

? creatinine clearance greater than or equal to 60 mL/min/1.73 m2 for patients with
creatinine levels greater than 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
greater than or equal to 4 weeks prior to entering the study (6 weeks for
nitrosoureas or mitomycin C). Patients must be greater than or equal to 2 weeks since
any prior administration of a study drug in a phase 0 or equivalent study. 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 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.

EXCLUSION CRITERIA:

- Patients who are 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 greater than or equal to 4 weeks without requiring
steroid and anti-seizure medications are eligible to participate.

- History of allergic reactions attributed to compounds of similar chemical or biologic

- 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.

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
possible PK interactions with TRC102.

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Establish safety, tolerability, and maximum tolerated dose of oral TRC102 in combination with oral TMZ in patients with refractory solid tumors.

Outcome Time Frame:

1 year

Safety Issue:

Yes

Principal Investigator

Shivaani Kummar, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

130118

NCT ID:

NCT01851369

Start Date:

April 2013

Completion Date:

February 2015

Related Keywords:

  • Lymphomas
  • Solid Tumors
  • Solid Tumors
  • Lymphomas
  • DNA Damage
  • Pharmacodynamics
  • Pharmacokinetics
  • Lymphoma
  • Neoplasms

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892