TRC102 and Temozolomide for Relapsed Solid Tumors and Lymphomas

NCT01851369 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 13011813-C-0118
• Study Type: interventional
• Target: 93
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

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

Keywords

Solid Tumors; Lymphomas; DNA Damage; Pharmacodynamics; Pharmacokinetics

Outcome Measures

Primary Outcomes (6)

• Phase 2: Response Rate of This Combination in Participants With Colon Cancer, Non-small Cell Lung Cancer (NSCLC), and Granulosa Cell Ovarian Cancer

  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). Response was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Complete response (CR) is disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on-study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progressions.

  Response rate at one year

• The Number of Dose Limiting Toxicities Observed in Participants Receiving Oral TRC102 in Combination With Oral TMZ

  Dose-limiting toxicities (DLTs) are defined as toxicities occurring within the first cycle of treatment felt to be possibly, probably, or definitely related to administration of study drugs and fulfilling one of the following criteria: Grade 4 neutropenia, febrile neutropenia, neutropenic infection: Grade ≥ 3 neutropenia with grade ≥ 3 infection, Grade ≥ 3 thrombocytopenia, a drop in hemoglobin (Hgb) ≥3.0 g/dL over one week, and all Grade ≥ 3 non-hematologic toxicity other than: non-bloody diarrhea Grade 3 that is corrected to Grade ≤ 2 within 24 hours, nausea and vomiting Grade 3 that is corrected to Grade ≤ 1 within 24 hours, creatinine Grade 3 corrected to Grade ≤ 1 within 48 hours, and Grade 3 electrolyte abnormalities. Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. And Grade 5 is death related to adverse event.

  At dose-limiting toxicity (DLT) determined in the first cycle; approximately 28 days

• Phase 1 Pharmacokinetic (PK) Profile of Oral TRC102 When Administered in Combination With Temozolomide (TMZ) as Measured by Maximum Plasma Concentration (Cmax) of TRC102: Mean (Standard Deviation)

  Blood samples will be collected, and pharmacokinetics will be assessed in the phase I portion of the study. Samples will be analyzed using a validated LC-MS or LC-MS/MS method in human plasma. The maximum observed analyte concentration in plasma was reported.

  First 5 days of treatment

• Phase 1 Pharmacokinetic (PK) Profile: the Percentage of TRC102 Dose Recovered From Participant Urine in Participants Treated With Oral TRC102 in Combination With Temozolomide (TMZ)

  Urine samples will be collected, and pharmacokinetics will be assessed in phase I portion of the study. Samples will be analyzed using a validated liquid chromatography-mass spectrometry (LC-MS) or liquid chromatography with tandem mass spectrometry (LC-MS-MS) method.

  First day of treatment

• Phase 1 Maximum Tolerated Dose (MTD) of Oral TRC102 in Participants With Refractory Solid Tumors.

  The MTD or recommended Phase II dose is the dose level at which no more than 1 of 6 participants experience dose-limiting toxicity (DLT) during the first cycle of treatment, and the dose below that at which at least 2 (of ≤ 6) participants have DLT as a result of the drug. DLTs are defined as toxicities occurring within the first cycle of treatment felt to be possibly, probably, or definitely related to administration of study drugs and fulfilling one of the following criteria: Grade 4 neutropenia, febrile neutropenia, neutropenic infection: Grade ≥ 3 neutropenia with grade ≥ 3 infection, Grade ≥ 3 thrombocytopenia, a drop in hemoglobin (Hgb) ≥3.0 g/dL over one week, and all Grade ≥ 3 non-hematologic toxicities other than: non-bloody diarrhea Grade 3 that is corrected to Grade ≤ 2 within 24 hours, nausea and vomiting Grade 3 that is corrected to Grade ≤ 1 within 24 hours, creatinine Grade 3 corrected to Grade ≤ 1 within 48 hours, and Grade 3 electrolyte abnormalities.

  First cycle of treatment; approximately 28 days

• Phase 1 Maximum Tolerated Dose (MTD) of Oral Temozolomide (TMZ) in Participants With Refractory Solid Tumors.

  The MTD or recommended Phase II dose is the dose level at which no more than 1 of 6 participants experience dose-limiting toxicity (DLT) during the first cycle of treatment, and the dose below that at which at least 2 (of ≤ 6) participants have DLT as a result of the drug. DLTs will be defined as toxicities occurring within the first cycle of treatment and is felt to be possibly, probably, or definitely related to administration of study drugs and fulfills one of the following criteria: hematologic toxicities - Grade 4 neutropenia, febrile neutropenia, neutropenic infection: Grade ≥ 3 neutropenia with grade ≥ 3 infection, Grade ≥ 3 thrombocytopenia, a drop in hemoglobin (Hgb) ≥3.0 g/dL over one week, any degree of lymphopenia, or leukopenia in the absence of grade 4 neutropenia will not be considered dose limiting, and Grade ≥ 3 non-hematologic toxicity. Grade ≥ 3 electrolyte abnormalities will not be considered dose limiting.

  First cycle of treatment; approximately 28 days

Secondary Outcomes (1)

• Phase 2: Progression Free Survival Rate of This Combination in Participants With Colon Cancer, Non-small Cell Lung Cancer (NSCLC), and Granulosa Cell Ovarian Cancer

  Duration on study, an average of 130 days

Other Outcomes (1)

• Phase 1 and Phase 2: Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)

  Date treatment consent signed to date off study, an average of 115 days.

Study Arms (1)

Combination Treatment with Oral methoxyamine hydrochloride (TRC102) and oral Temozolomide (TMZ)

EXPERIMENTAL

Combination treatment with oral methoxyamine hydrochloride (TRC102) and oral Temozolomide (TMZ) for days 1-5 of 28-day cycles.

Drug: TRC102; Diagnostic Test: CT scan; Other: Lomotil; Other: Prochlorperazine; Other: Metoclopramide; Other: 5-HT3 antagonist; Other: Aprepitant; Procedure: Biopsy

Interventions

TRC102 DRUG

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

Also known as: Methoxyamine hydrochloride

Combination Treatment with Oral methoxyamine hydrochloride (TRC102) and oral Temozolomide (TMZ)

CT scan DIAGNOSTIC_TEST

CT scans will be performed at baseline, and repeat scans will be performed every 2 cycles (every 3 cycles for participants on study more than one year).

Also known as: Computed tomography

Combination Treatment with Oral methoxyamine hydrochloride (TRC102) and oral Temozolomide (TMZ)

Lomotil OTHER

If diarrhea develops and does not have an identifiable cause other than study drug administration, anti-diarrheal's such as Lomotil (diphenoxylate hydrochloride (HCl) 2.5 mg + atropine sulfate 0.025 mg/tablet) dosed according to package insert or loperamide 4 mg by mouth (po) after the first unformed stool with 2 mg po every 2 hours as long as unformed stools continue (4 mg every 4 hours while asleep). No more than 16 mg of loperamide should be taken in during a 24-hour period.

Also known as: Diphenoxylate hydrocholoride

Combination Treatment with Oral methoxyamine hydrochloride (TRC102) and oral Temozolomide (TMZ)

Prochlorperazine OTHER

If a participant develops nausea/vomiting, an anti-emetic such as prochlorperazine may be given.

Also known as: Compro

Combination Treatment with Oral methoxyamine hydrochloride (TRC102) and oral Temozolomide (TMZ)

Metoclopramide OTHER

If a participant develops nausea/vomiting, an anti-emetic such as metoclopramide may be given.

Also known as: Reglan

Combination Treatment with Oral methoxyamine hydrochloride (TRC102) and oral Temozolomide (TMZ)

5-HT3 antagonist OTHER

If a participant develops nausea/vomiting, an anti-emetic such as 5-HT3 antagonist may be given.

Also known as: 5-hydroxytryptamine

Combination Treatment with Oral methoxyamine hydrochloride (TRC102) and oral Temozolomide (TMZ)

Aprepitant OTHER

If a participant develops nausea/vomiting, an anti-emetic such as aprepitant may be given.

Also known as: Emend

Combination Treatment with Oral methoxyamine hydrochloride (TRC102) and oral Temozolomide (TMZ)

Biopsy PROCEDURE

Tumor biopsies will be optional during the escalation phase.

Combination Treatment with Oral methoxyamine hydrochloride (TRC102) and oral Temozolomide (TMZ)

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• 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 pharmacokinetic (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.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• 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.

  PMID: 12231545 BACKGROUND

• 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. doi: 10.1158/1078-0432.CCR-06-1595.

  PMID: 17332299 BACKGROUND

• 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 gammaH2AX 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.

  PMID: 20924131 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Lymphoma; Colonic Neoplasms

Interventions

methoxyamine; Tomography, X-Ray Computed; atropine sulfate-diphenoxylate hydrochloride drug combination; Prochlorperazine; Metoclopramide; Serotonin 5-HT3 Receptor Antagonists; Serotonin; Aprepitant; Biopsy

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases

Intervention Hierarchy (Ancestors)

Image Interpretation, Computer-Assisted; Diagnostic Imaging; Diagnostic Techniques and Procedures; Diagnosis; Radiographic Image Enhancement; Image Enhancement; Photography; Radiography; Tomography, X-Ray; Tomography; Phenothiazines; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Benzamides; Amides; para-Aminobenzoates; Aminobenzoates; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Chlorobenzoates; Hydroxybenzoate Ethers; Hydroxybenzoates; Hydroxy Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Phenyl Ethers; Phenols; Serotonin Antagonists; Serotonin Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Physiological Effects of Drugs; Tryptamines; Biogenic Monoamines; Biogenic Amines; Amines; Indoles; Heterocyclic Compounds, 2-Ring; Autacoids; Inflammation Mediators; Biological Factors; Morpholines; Oxazines; Heterocyclic Compounds, 1-Ring; Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Specimen Handling; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Investigative Techniques

Results Point of Contact

• Title: Dr. Alice P.Chen
• Organization: National Cancer Institute

chenali@mail.nih.gov

2407813320

Study Officials

• Alice P Chen, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: May 8, 2013
• First Posted: May 10, 2013
• Study Start: July 12, 2013
• Primary Completion: August 1, 2023
• Study Completion: August 1, 2023
• Last Updated: May 8, 2024
• Results First Posted: May 8, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely.
• Access Criteria: Requests for all collected individual participant data (IPD) data from clinical trials, conducted under a binding collaborative agreement between National Cancer Institute (NCI/Division of Cancer Treatment and Diagnosis (DCTD) and a pharmaceutical/biotechnology company, that are not under data safety monitoring board (DSMB) monitoring must be in compliance with the terms of the binding collaborative agreement and must be approved by NCI/DCTD and the Pharmaceutical Collaborator (i.e., the NCI Experimental Therapeutics Clinical Trials Network (ETCTN) Director in conjunction with the NCI/DCTD Regulatory Affairs Branch).

Locations

US (1)