TRC102 and Temozolomide for Relapsed Solid Tumors and Lymphomas

• ClinicalTrials.gov Identifier: NCT01851369
• Recruitment Status: Recruiting
• First Posted: May 10, 2013
• Last Update Posted: October 12, 2020
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Tracking Information

• First Submitted Date: May 8, 2013
• First Posted Date: May 10, 2013
• Last Update Posted Date: October 12, 2020
• Actual Study Start Date: July 12, 2013
• Estimated Primary Completion Date: February 1, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 8, 2019)

• Evaluate the pharmacokinetic (PK) profile of oral TRC102 when administered in combination with TMZ [ Time Frame: First 5 days ]
  Blood and urine pharmacokinetics will be assessed in the phase Iportion of the study.
• To establish the safety, tolerability, and maximum tolerated dose (MTD) of oral TRC102 in combination with oral TMZ in patients with refractory solid tumors. [ Time Frame: DLT determined first cycle (28 days) ]
  Adverse events will be characterized using the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
• To explore the response rate of this combination in patients with colon cancer, NSCLC, and granulosa cell ovarian cancer [ Time Frame: Response rate one year ]
  Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1).

Original Primary Outcome Measures (submitted: May 8, 2013)

• Establish safety, tolerability, and maximum tolerated dose of oral TRC102 in combination with oral TMZ in patients with refractory solid tumors. [ Time Frame: 1 year ]
• Evaluate the pharmacokinetic (PK) profile of oral TRC102 when administered in combination with TMZ. [ Time Frame: 1 year ]

Current Secondary Outcome Measures (submitted: July 9, 2020)

To explore the progression free survival rate of this combination in patients with colon cancer, NSCLC, and granulosa cell ovarian cancer [ Time Frame: Duration on study ]

To explore the progression free survival rate of this combination in patients with colon cancer, NSCLC, and granulosa cell ovarian cancer

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

Brief Summary

Background:

- TRC102 is a new cancer treatment drug that may help improve the results of chemotherapy. It blocks tumor cells' attempts to repair damaged 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.

Detailed 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 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.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

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

Intervention

Drug: TRC 102

TRC102 has been shown to potentiate the activity of temozolomide by preventing BER and allowing cleavage of TRC102 bound DNA, which will cause DNA strand breaks in cancer cells. We hypothesize that oral TRC102 can be safely co-administered with TMZ and would potentiate DNA damage caused by TMZ resulting in antitumor responses.

Study Arms

Experimental: 1

combination treatment with oral TRC102 and oral TMZ for days 1-5 of 28-day cycles

Intervention: Drug: TRC 102

Publications *

• Liu L, Nakatsuru Y, Gerson SL. Base excision repair as a therapeutic target in colon cancer. Clin Cancer Res. 2002 Sep;8(9):2985-91.
• Yan L, Bulgar A, Miao Y, Mahajan V, Donze JR, Gerson SL, Liu L. Combined treatment with temozolomide and methoxyamine: blocking apurininc/pyrimidinic site repair coupled with targeting topoisomerase IIalpha. Clin Cancer Res. 2007 Mar 1;13(5):1532-9.
• Kinders RJ, Hollingshead M, Lawrence S, Ji J, Tabb B, Bonner WM, Pommier Y, Rubinstein L, Evrard YA, Parchment RE, Tomaszewski J, Doroshow JH; National Cancer Institute Phase 0 Clinical Trials Team. Development of a validated immunofluorescence assay for γH2AX as a pharmacodynamic marker of topoisomerase I inhibitor activity. Clin Cancer Res. 2010 Nov 15;16(22):5447-57. doi: 10.1158/1078-0432.CCR-09-3076. Epub 2010 Oct 5.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 26, 2018): 140
• Original Estimated Enrollment (submitted: May 8, 2013): 40
• Estimated Study Completion Date: February 1, 2022
• Estimated Primary Completion Date: February 1, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

• Eligibility Criteria (Patients)
• 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.
• Age greater than18 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 2 (Phase I), less than or equal to 1(Phase II).
• Life expectancy of greater than 3 months
• Patients must have normal organ and marrow function as defined below:
• Absolute neutrophil count greater than 1,500/mcL
• Hemoglobin greater than or equal to 10 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 to1.5 X institutional ULN

AST(SGOT)/ALT(SGPT) less than or equal to 3 X institutional 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 (or 5 half-lives, whichever is shorter) 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 and greater than or equal to 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 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)

• 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 greater than or equal to 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 MSI-high disease who have not 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.
• HIV-positive patients on combination antiretroviral therapy are ineligible because of possible PK interactions with TRC102.

(Healthy volunteer blood donors)

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.

• Age greater than 18 years; hemoglobin greater than or equal to 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Jennifer H Zlott; (240) 760-6046; zlottjh@mail.nih.gov

Contact: Alice P Chen, M.D.; (240) 781-3320; chenali@mail.nih.gov

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01851369
• Other Study ID Numbers: 130118; 13-C-0118
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
• Study Sponsor: National Cancer Institute (NCI)
• Collaborators: Not Provided

Investigators

• Principal Investigator: Alice P Chen, M.D.; National Cancer Institute (NCI)

• PRS Account: National Institutes of Health Clinical Center (CC)
• Verification Date: October 7, 2020