Methoxyamine (DB06328, TRC-102): A Comprehensive Review of its Pharmacology, Clinical Development, and Therapeutic Potential as a Base Excision Repair Inhibitor

1. Executive Summary

[Methoxyamine, also known by its investigational name TRC-102, is a small molecule compound that has garnered attention for its role as an inhibitor of the Base Excision Repair (BER) pathway, a critical DNA repair mechanism. Its primary mechanism involves the formation of stable adducts at apurinic/apyrimidinic (AP) sites in DNA, thereby blocking their repair and leading to the accumulation of DNA damage, ultimately triggering cell death, particularly in cancer cells. The rationale for Methoxyamine's development, spearheaded by TRACON Pharmaceuticals, centers on its potential to potentiate the efficacy of conventional DNA-damaging cancer therapies, such as chemotherapy and radiotherapy, and to overcome acquired resistance to these treatments.][1]

[Clinical development has explored Methoxyamine (TRC-102) across a spectrum of malignancies, including non-small cell lung cancer (NSCLC), glioblastoma, mesothelioma, and various hematologic cancers, predominantly in combination regimens. While some early-phase trials have shown promising response rates, particularly in NSCLC when combined with chemoradiotherapy, the overall clinical journey has been marked by variable outcomes. For instance, a Phase 2 trial in recurrent glioblastoma did not meet its primary efficacy endpoint, although intriguing biomarker signals emerged in a subset of long-term survivors.][4][ The safety profile of Methoxyamine combinations is generally characterized by manageable hematologic and gastrointestinal toxicities.]

[The development of Methoxyamine underscores a strategy focused on synergy; its utility appears to be primarily as an adjunctive agent enhancing existing therapies rather than as a potent standalone cytotoxic drug. This is supported by its mechanism which largely prevents the repair of damage inflicted by other agents.][1][ Despite a clear mechanistic rationale, translating this into consistent, broad clinical success has proven complex, highlighting the challenges in optimizing its therapeutic window and identifying patient populations most likely to benefit. Methoxyamine holds orphan drug designation for malignant glioma in the US.][2][ Its future therapeutic role will likely depend on the outcomes of ongoing trials and the successful identification of predictive biomarkers to guide patient selection.]

2. Introduction

[Methoxyamine, an investigational anti-cancer agent identified by DrugBank ID DB06328 and CAS number 67-62-9, is more widely recognized in the clinical and research setting by its investigational name, TRC-102.][1][ The development of this small molecule has been primarily advanced by TRACON Pharmaceuticals.][2][ Methoxyamine's therapeutic strategy is rooted in its ability to inhibit the Base Excision Repair (BER) pathway. The BER pathway is a fundamental cellular mechanism responsible for identifying and repairing a wide array of spontaneous and induced DNA base lesions, including those caused by oxidation, alkylation, and deamination, thereby playing a crucial role in maintaining genomic integrity.][3][ In the context of cancer, efficient DNA repair pathways, including BER, can contribute to therapeutic resistance by enabling cancer cells to survive the DNA damage inflicted by cytotoxic chemotherapies and radiotherapy.][3]

[The rationale for developing Methoxyamine (TRC-102) stems from the hypothesis that inhibiting BER can sensitize cancer cells to DNA-damaging agents. By preventing the repair of drug- or radiation-induced DNA lesions, Methoxyamine aims to potentiate the cytotoxic effects of these standard cancer treatments, increase tumor cell kill, and potentially overcome resistance mechanisms linked to upregulated DNA repair capacity.][1][ This approach seeks to address a significant unmet need in oncology: the frequent development of resistance to conventional DNA-damaging therapies, which limits their long-term efficacy. TRACON Pharmaceuticals' development strategy for TRC-102 has notably involved extensive collaboration with academic institutions and government bodies, particularly the National Cancer Institute (NCI). Many of the clinical trials evaluating TRC-102 have been sponsored by or conducted under Cooperative Research and Development Agreements (CRADAs) with the NCI.][2][ This collaborative model has facilitated a broad investigation of TRC-102 across various cancer types and combination regimens, a scope of research that might be challenging for a smaller biopharmaceutical company to undertake independently.]

3. Drug Profile and Chemical Properties

3.1. Identification

[Methoxyamine is the generic name for the compound. It is cataloged in DrugBank under the accession number DB06328.][1][ The Chemical Abstracts Service (CAS) Registry Number for the Methoxyamine base is 67-62-9.][1][ In clinical and research literature, it is frequently referred to by its investigational designation, TRC-102.][2][ Other synonyms include O-Methylhydroxylamine, Methoxylamine, Hydroxylamine methyl ether, MeOX, and O-metilhidroxilamina.][15]

3.2. Chemical Characteristics

[Methoxyamine is a relatively simple organic molecule. Its properties differ slightly depending on whether it is in its base form or as a hydrochloride salt, the latter being commonly used in pharmaceutical preparations for clinical trials.][18][ The small size and high water solubility of Methoxyamine are notable characteristics that generally favor good oral bioavailability and distribution within the body, which is consistent with its administration via oral routes in several clinical studies.][1][ The hydrochloride salt form is likely preferred for clinical development due to its crystalline powder nature, which typically offers better stability and ease of formulation compared to the liquid, odorous base form.][15]

[A summary of the key physicochemical properties for both Methoxyamine base and Methoxyamine Hydrochloride is presented in Table 1.]

Table 1: Physicochemical Properties of Methoxyamine and Methoxyamine Hydrochloride

Property	Methoxyamine (Base)	Methoxyamine Hydrochloride	References
CAS Number	67-62-9	593-56-6	1
Molecular Formula	CH₅NO	CH₅NO·HCl (or CH₆ClNO)	1
Molecular Weight (g/mol)	47.06 (approx. 47.057)	83.52 (approx. 83.515)	1
Percent Composition	C 25.52%, H 10.71%, N 29.76%, O 34.00%	C 14.38%, H 7.24%, O 19.16%, N 16.77%, Cl 42.45%	16
Appearance	Colorless to pale yellow liquid; mobile liquid	Nacreous scales (from alcohol + ether); Crystalline powder	15
Odor	Slightly amine-like; fishy amine odor	Not specified	15
Solubility	600.0 mg/mL in water (ALOGPS); Miscible with water, alcohol, ether	Soluble in water, alcohol	1
Boiling Point (°C)	49-50 (at 760 mmHg)	Decomposes (Melting Point 149-151°C or 300-304°F (decomposes))	16
pKa (Strongest Basic)	4.32 (Chemaxon)	Not specified	1
logP	-0.76 (ALOGPS); -0.36 (Chemaxon)	Not specified	1
Physiological Charge	0 (Chemaxon)	Not specified	1
Polar Surface Area (Ų)	35.25 (Chemaxon)	Not specified	1
Bioavailability (Chemaxon)	1	Not specified	1
Rule of Five (Chemaxon)	Yes	Not specified	1

4. Pharmacology

4.1. Mechanism of Action

[Methoxyamine (TRC-102) exerts its pharmacological effects primarily by inhibiting the Base Excision Repair (BER) pathway, a critical DNA repair system.][1][ The BER pathway is initiated when DNA glycosylases recognize and remove damaged or inappropriate bases (e.g., those modified by alkylating agents or arising from spontaneous depurination), creating an apurinic/apyrimidinic (AP) site.][3][ Methoxyamine's mechanism involves direct interaction with these AP sites. It covalently binds to the aldehyde group present in the open-ring sugar moiety of the AP site, forming a stable Methoxyamine-AP adduct, often referred to as an MX-AP lesion.][1]

[This MX-AP adduct is a crucial intermediate because it is refractory to processing by the next enzyme in the BER pathway, AP endonuclease 1 (APE1).][1][ APE1 normally cleaves the phosphodiester backbone adjacent to the AP site, allowing for subsequent DNA synthesis and ligation to complete the repair. By forming a stable block, Methoxyamine effectively stalls the BER pathway at the AP site stage. This leads to an accumulation of these unrepaired, persistent AP sites, which are themselves cytotoxic lesions. These stalled repair intermediates can obstruct DNA replication forks, leading to replication stress and the formation of more complex and lethal DNA damage, such as DNA double-strand breaks (DSBs), ultimately triggering apoptotic cell death.][1]

[Beyond direct BER inhibition, the MX-AP lesions possess an additional cytotoxic mechanism: they can act as topoisomerase IIα (topo II) poisons.][1][ Topoisomerase IIα is an essential enzyme involved in managing DNA topology during replication, transcription, and chromosome segregation. When topo II encounters these abnormal MX-AP sites, its normal cycle of DNA cleavage and religation can be disrupted, leading to the accumulation of enzyme-linked DNA strand breaks, further contributing to genomic instability and cell death.][1][ This dual action—BER inhibition leading to AP site accumulation and the subsequent topo II poisoning by these adducts—underpins Methoxyamine's ability to synergize with other genotoxic agents.]

[Methoxyamine has also been reported to influence cell cycle progression. It can increase cellular levels of the tumor suppressor proteins p53 and pRb, which are key regulators of cell cycle checkpoints.][1][ This can lead to an arrest of cells in the G1 phase of the cell cycle. Furthermore, Methoxyamine is described as creating a more stringent G1/S checkpoint and an insufficient G2 checkpoint, effectively preventing cells from progressing into the S phase (DNA synthesis) and potentially trapping them before or during mitosis.][1][ This G1 accumulation can be particularly relevant for enhancing the effects of radiotherapy, as cells in the G1 phase are generally more sensitive to ionizing radiation than cells in the S phase.][1][ While G1 arrest might theoretically antagonize S-phase specific chemotherapies if not timed correctly, clinical data with agents like fludarabine and pemetrexed, which have S-phase activity, still demonstrate potentiation by Methoxyamine, suggesting the overwhelming DNA damage from BER inhibition is often the dominant effect or that the scheduling of Methoxyamine administration relative to the S-phase agent is critical for achieving synergy.][3]

[The central therapeutic premise for Methoxyamine is its role as an adjunctive agent to enhance the cytotoxicity of various DNA-damaging treatments. This includes:]

• Alkylating agents[ (e.g., temozolomide): Methoxyamine prevents the BER-mediated repair of alkylation-induced AP sites, thereby increasing the cytotoxic burden of these lesions.][1]
• Antimetabolites[ (e.g., fludarabine, pemetrexed): These drugs can lead to the incorporation of abnormal bases or create imbalances in nucleotide pools that result in lesions repaired by BER. Methoxyamine inhibits the repair of these lesions.][3][ For instance, pemetrexed can lead to uracil incorporation into DNA, which is excised by uracil DNA glycosylase, creating AP sites that become targets for Methoxyamine.][23]
• Radiotherapy[: Ionizing radiation induces a variety of DNA lesions, including base damage and strand breaks, many ofwhich are substrates for BER. Methoxyamine can enhance radiosensitivity by inhibiting the repair of these lesions and by modulating cell cycle distribution towards more radiosensitive phases.][1]

4.2. Pharmacodynamics

[Pharmacodynamic studies have provided evidence of Methoxyamine's target engagement and downstream biological effects. The inhibition of BER by Methoxyamine is expected to lead to an accumulation of DNA damage. Consistent with this, increased markers of DNA double-strand breaks, such as elevated γH2AX expression and increased DNA fragmentation (e.g., Comet tail length), have been observed in cells treated with Methoxyamine in combination with DNA-damaging agents like fludarabine.][3][ Furthermore, in a clinical trial combining TRC102 with temozolomide, induction of nuclear Rad51, a key protein in the homologous recombination repair pathway (which is often activated in response to DSBs), was observed in tumor biopsies from some patients, indicating that the BER inhibition led to damage that cells were attempting to repair via alternative pathways.][22]

[The identification of biomarkers that predict sensitivity or resistance to Methoxyamine is crucial for its clinical development. Preclinical studies suggested that Methoxyamine's potentiation of temozolomide was independent of tumor O⁶-methylguanine-DNA methyltransferase (MGMT) expression, DNA mismatch repair (MMR) status, or p53 mutational status.][7][ This was an encouraging finding, as MGMT expression and MMR deficiency are common mechanisms of resistance to temozolomide. However, clinical findings have suggested a more nuanced biomarker landscape. In the Phase 2 BERT trial of TRC102 with temozolomide in recurrent glioblastoma, two "extended survivors" who experienced prolonged progression-free survival (PFS ≥ 17 months) and overall survival (OS > 32 months) had tumors (at diagnosis) that exhibited significantly enriched gene expression signatures related to DNA Damage Response (DDR), chromosomal instability (CIN70, CIN25), and cellular proliferation (PCNA25).][5][ This suggests that tumors with a pre-existing high level of replicative stress or specific alterations in DDR pathways might be particularly vulnerable to the additional insult of BER inhibition by Methoxyamine when combined with an alkylating agent. Additionally, N-methylpurine DNA glycosylase (MPG) expression, an enzyme that initiates the BER pathway by removing alkylated bases, was associated with prolonged PFS in a Phase 2 trial of TRC102 and temozolomide in recurrent glioblastoma, further supporting a biomarker-driven approach.][26][ These findings imply that while Methoxyamine might act independently of some common resistance markers, certain pre-existing tumor biological characteristics could significantly enhance its therapeutic impact in combination settings, representing a critical area for ongoing research to refine patient selection.]

4.3. Pharmacokinetics

Methoxyamine (TRC-102) has been shown to be orally bioavailable, which is a favorable property for patient convenience and outpatient administration.4 Several Phase 1 clinical trials have characterized its pharmacokinetic (PK) profile.

In a trial combining oral TRC102 with temozolomide, TRC102 exhibited a plasma half-life (t1/2​) of approximately 24 hours, and its plasma concentrations were observed to increase with the administered dose.7 A separate Phase 1 study of oral TRC102 in combination with pemetrexed reported a similar mean t1/2​ of 28 hours, with drug exposure also increasing proportionally to the dose.23

When Methoxyamine was administered intravenously in a Phase 1 trial with oral temozolomide, its PK was found to be linear with dose, and importantly, its PK profile was not significantly affected by the co-administration of temozolomide.28 The relatively long half-life of 24-28 hours observed across studies supports dosing schedules of once daily or even less frequent administration for short durations within a treatment cycle, as has been implemented in various clinical trials.7 Methoxyamine hydrochloride is the salt form typically used in clinical formulations.18

5. Preclinical Development

[The preclinical evaluation of Methoxyamine (TRC-102) provided a robust foundation for its advancement into clinical trials. In vitro studies using various cancer cell lines and in vivo studies employing xenograft models consistently demonstrated Methoxyamine's ability to potentiate the cytotoxic effects of a range of DNA-damaging agents. Specifically, Methoxyamine was shown to enhance the activity of alkylating agents, such as temozolomide, and antimetabolites, including pemetrexed and fludarabine, across diverse cancer types like colon, ovarian, and breast cancer models.][1]

[A key preclinical observation was that TRC102 effectively augmented the anti-tumor effect of temozolomide in human xenograft models, and this enhancement appeared to be independent of common resistance-conferring genetic characteristics of the cell lines, such as O⁶-methylguanine DNA-methyltransferase (MGMT) expression status, mismatch repair (MMR) proficiency, or p53 tumor suppressor gene status.][7][ This suggested a broad potential utility, even in tumors typically resistant to alkylating agents. Similarly, when combined with pemetrexed, TRC102 led to an extended median tumor growth delay in non-small cell lung cancer (NSCLC) xenografts compared to pemetrexed alone.][23]

[Importantly, many preclinical studies indicated that Methoxyamine itself did not exhibit significant direct antineoplastic activity when administered as a monotherapy. Its primary role was consistently observed as a sensitizer, augmenting the anti-tumor effects of its combination partners.][3][ This finding was crucial in guiding the clinical development strategy towards combination therapies from the outset.]

[Mechanistic preclinical studies also corroborated its proposed mode of action. For example, the addition of Methoxyamine to fludarabine resulted in increased markers of DNA double-strand breaks, such as elongated Comet tails and elevated γH2AX expression, in both cancer cell lines and primary chronic lymphocytic leukemia (CLL) cells. This combination also led to the induction of topoisomerase II expression, consistent with the idea that Methoxyamine-stabilized AP sites can act as topoisomerase II poisons.][3][ Furthermore, Methoxyamine demonstrated the ability to potentiate iododeoxyuridine-induced cytotoxicity and radiosensitization, highlighting its potential synergy with radiotherapy.][1][ The consistent preclinical observation of Methoxyamine's broad potentiation of various DNA-damaging agents across different tumor types and genetic backgrounds provided a compelling rationale for its extensive clinical investigation in diverse oncological settings.]

6. Clinical Development of TRC-102 (Methoxyamine)

6.1. Overview of Clinical Program

[The clinical development of Methoxyamine, under the investigational name TRC-102, has been primarily driven by TRACON Pharmaceuticals.][2][ A hallmark of this program has been the significant involvement and support from the National Cancer Institute (NCI), often through Cooperative Research and Development Agreements (CRADAs), which has facilitated numerous clinical trials.][2][ Collaborations with academic institutions such as Case Comprehensive Cancer Center and consortia like the Adult Brain Tumor Consortium (ABTC) have also been instrumental.][2][ The clinical program has been extensive, evaluating TRC-102 in a variety of solid tumors—including non-small cell lung cancer (NSCLC), glioblastoma, and mesothelioma—as well as hematologic malignancies. The overarching strategy has been to assess TRC-102 as a potentiating agent in combination with standard-of-care chemotherapies and/or radiotherapy. This broad exploration, enabled by NCI support, has allowed for data generation across multiple cancer types and therapeutic combinations, which might have been resource-intensive for a single company to achieve alone.]

6.2. Phase 1 Clinical Trials

[Several Phase 1 trials have been conducted to establish the safety, maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D), pharmacokinetics (PK), and preliminary efficacy of TRC-102 in various combinations.]

• Monotherapy (NCT00692159):[ An early Phase 1 trial sponsored by TRACON Pharmaceuticals investigated TRC102 as a monotherapy in patients with neoplasms. This study was completed in June 2008.][17][ Detailed findings from this specific monotherapy trial are limited in the provided information beyond its completion.]
• Combination with Temozolomide (TMZ) (Oral TRC102; NCT01851369, NCI-2013-00877):[ This trial enrolled patients with refractory solid tumors and lymphomas. The MTD was established at TRC102 125 mg orally (PO) once daily (QD) combined with TMZ 150 mg/m² PO QD, both administered on days 1-5 of 28-day cycles.][22][ An earlier report cited the MTD at TRC102 150 mg PO with TMZ 150 mg/m², with hematologic toxicity being dose-limiting at the next dose level.][7][ The combination demonstrated activity, with an initial report of 4 partial responses (PRs) (in NSCLC, ovarian (2), and colon cancer) and 11 stable diseases (SDs) among 37 patients.][7][ A later report on 51 evaluable patients noted 4 PRs and 13 SDs.][22][ Common Grade 3/4 adverse events included anemia, lymphopenia, and neutropenia. TRC102's half-life was approximately 24 hours, with plasma concentrations increasing with dose.][7]
• Combination with Temozolomide (TMZ) (Intravenous Methoxyamine):[ Another Phase 1 study evaluated intravenous (IV) Methoxyamine (MX) with oral TMZ in patients with advanced solid tumors. It was found that TMZ 200 mg/m² daily for 5 days could be safely administered with MX 150 mg/m² IV on day 1, with minimal toxicity. Among 38 patients, 1 PR (pancreatic neuroendocrine tumor) and 6 prolonged SDs were observed. The PK of IV Methoxyamine was linear with dose and was not affected by concomitant TMZ administration.][24]
• Combination with Fludarabine (NCT01633152):[ This trial investigated IV Methoxyamine with fludarabine in patients with advanced hematologic malignancies. Methoxyamine was infused on day 2 in the first cycle and on day 1 in subsequent cycles, prior to fludarabine. TRC102 doses up to 120 mg/m² were explored with standard fludarabine (25 mg/m² IV on days 1-5). No dose-limiting toxicities (DLTs) were observed. The hematologic toxicity profile was comparable to that of single-agent fludarabine. Pharmacodynamic assessments suggested that anti-tumor activity correlated with increased markers of DNA damage (e.g., γH2AX).][3]
• Combination with Pemetrexed and Cisplatin/Carboplatin plus Thoracic Radiotherapy (CRT) (NCT02535325 / NCI-2015-01628):[ This Phase 1 study enrolled patients with Stage III/IV non-squamous NSCLC. The RP2D of TRC102 was determined to be 200 mg when administered with pemetrexed, cisplatin, and radiotherapy.][4][ The regimen was well tolerated, with no DLTs or Grade 5 toxicity reported. The most common adverse events were hematologic and gastrointestinal toxicities. Notably, no clinical radiation pneumonitis was observed. In 15 evaluable patients, a high overall response rate (ORR) of 100% was achieved, including 3 complete responses (CRs, 20%) and 12 PRs (80%). The 6-month progression-free survival (PFS) was 80%, and the 2-year overall survival (OS) was 83%.][1]
• Combination with Pemetrexed (NCT01057791):[ This study evaluated oral TRC102 (daily for 4 days) in combination with standard-dose pemetrexed in patients with advanced solid tumors. The MTD of TRC102 in this combination was 60 mg/m²/day for 4 days. Grade 3 anemia was the DLT at the 100 mg/m²/day dose level. Pharmacodynamic assays confirmed that TRC102 bound to pemetrexed-induced AP sites. Stable disease or better was achieved in 15 out of 25 evaluable patients (60%), including one PR in a patient with oropharyngeal carcinoma.][23]
• Combination with Cisplatin and Pemetrexed (Arm A of NCT02535312 / NCI 9837 / PhI-76):[ This arm of a parallel cohort trial assessed TRC102 with cisplatin (CDDP) and pemetrexed in patients with advanced solid tumors. The RP2D was established as TRC102 100 mg/day PO, CDDP 75 mg/m², and pemetrexed 500 mg/m². No DLTs were reported. Three PRs were observed, all in patients with parotid salivary gland tumors. The median PFS was 7.1 months.][34]

6.3. Phase 2 Clinical Trials

[Building on Phase 1 findings, several Phase 2 trials were initiated to further evaluate the efficacy and safety of TRC-102 in specific indications.]

• Combination with Pemetrexed, Cisplatin/Carboplatin, Radiation, then Durvalumab in NSCLC (NCT05198830 / CASE1522 / NCI-2021-14403):[ Following the highly encouraging results from the Phase 1 NSCLC trial (NCT02535325), this randomized, open-label, two-arm Phase 2 trial was initiated. It is designed to compare TRC102 combined with standard concurrent chemoradiation (pemetrexed, cisplatin or carboplatin, and radiation therapy) followed by consolidative durvalumab, versus standard chemoradiation plus durvalumab alone, in patients with Stage III non-squamous NSCLC. The primary endpoint is PFS. The trial aims to enroll approximately 78 patients, with results anticipated around 2024-2025.][13][ This trial represents the most advanced and potentially pivotal investigation for TRC-102.]
• Combination with Temozolomide in Recurrent Glioblastoma (BERT Trial - NCT02395692 / ABTC-1402):[ This multicenter Phase 2 trial was conducted by the Adult Brain Tumor Consortium. Arm 1 enrolled 19 patients with bevacizumab-naïve glioblastoma at first recurrence, with the primary endpoint being objective response rate. This arm did not meet its primary endpoint, as no objective responses were observed. Consequently, Arm 2 (for bevacizumab-refractory patients) was not opened. For patients in Arm 1, the median OS was 11.1 months, and the median PFS was 1.9 months, with a 6-month PFS rate (PFS6) of 10.5%. Most toxicities were Grade 1 or 2. Notably, two patients were deemed "extended survivors" (PFS ≥ 17 months, OS > 32 months); RNA sequencing of their diagnostic tumor tissue revealed significantly enriched signatures of DNA Damage Response (DDR), chromosomal instability (CIN70, CIN25), and cellular proliferation (PCNA25).][2][ The findings were published in ]Clinical Cancer Research[ in June 2024.]
• Combination with Pemetrexed in Mesothelioma (Arm B of NCT02535312 / NCI 9837 / PhI-76):[ This Phase 2 portion of the trial enrolled patients with malignant mesothelioma refractory to prior platinum and pemetrexed therapy. Patients received TRC102 50 mg/day on days 1-4 with pemetrexed 500 mg/m² every 21 days. Fourteen patients were treated. Two PRs were observed (one confirmed), which met the pre-specified criteria for continued interest in this combination. The median PFS was 4.3 months, and 8 patients achieved stable disease for at least one cycle.][34]
• TRC102 and Temodar in Recurrent Glioblastoma (Earlier Phase 2 Report):[ Data presented at the Society for Neuro-Oncology (SNO) Annual Meeting in 2018 from a Phase 2 trial of TRC102 and Temodar (temozolomide) in recurrent glioblastoma indicated that the combination was tolerable but did not meet the primary efficacy endpoint of ORR in the initial 19 enrolled patients. However, two patients (10.5%) experienced PFS beyond 6 months, and this prolonged benefit was associated with tumor expression of N-methylpurine DNA glycosylase (MPG), an enzyme that initiates the BER pathway.][26][ This appears to be an earlier report or a closely related study to the BERT trial.]

6.4. Overall Safety and Tolerability Profile

[Across the various Phase 1 and Phase 2 clinical trials, Methoxyamine (TRC-102), when used in combination regimens, has generally demonstrated a manageable safety profile, though not without notable toxicities that require careful monitoring and supportive care.]

[The most consistently reported adverse events (AEs) are hematologic and gastrointestinal.]

• Hematologic Toxicities:[ Anemia is a frequent event, sometimes reaching Grade 3 or 4 and requiring blood transfusions or the use of erythropoiesis-stimulating agents. In one Phase 1 study (TRC102 with pemetrexed), Grade 3 anemia was a DLT at the 100 mg/m²/day dose level.][23][ Other common hematologic AEs include neutropenia, lymphopenia, and thrombocytopenia.][3]
• Gastrointestinal Toxicities:[ Nausea, vomiting, diarrhea, and anorexia are commonly observed. Esophagitis has also been reported, particularly in trials involving thoracic radiotherapy, such as the NSCLC study NCT02535325.][4]
• Fatigue:[ This is a frequently reported AE across multiple studies.][4]

[Serious adverse events (SAEs) have generally been infrequent, with Grade 3/4 AEs being predominantly hematologic. Importantly, in several key trials, including the Phase 1 NSCLC study with chemoradiotherapy (NCT02535325), no Grade 5 (fatal) toxicities directly attributed to TRC102 were reported.][4][ A significant positive safety finding from the NCT02535325 trial was the absence of clinical radiation pneumonitis, a serious concern with thoracic chemoradiation, suggesting Methoxyamine did not exacerbate this particular risk in that combination.][4][ This careful management of cumulative and overlapping toxicities is critical when combining Methoxyamine with already intensive treatment regimens.]

6.5. Summary of Efficacy Across Indications

[The clinical efficacy of Methoxyamine (TRC-102) has shown variability depending on the tumor type, the specific combination regimen used, and potentially the underlying tumor biology of individual patients.]

• Non-Small Cell Lung Cancer (Stage III/IV Non-Squamous):[ The most compelling efficacy signals for TRC-102 to date emerged from the Phase 1 trial (NCT02535325). In this study, combining TRC102 with pemetrexed, cisplatin, and thoracic radiotherapy resulted in a 100% ORR (including 20% CRs) in 15 evaluable patients. Furthermore, an 80% 6-month PFS and an 83% 2-year OS were reported.][1][ These highly encouraging results prompted the ongoing randomized Phase 2 trial (NCT05198830) in a similar patient population.]
• Glioblastoma (Recurrent):[ In contrast, the Phase 2 BERT trial (NCT02395692), which combined TRC102 with temozolomide, did not meet its primary endpoint of objective response rate in patients with recurrent glioblastoma. The median OS was 11.1 months, and median PFS was 1.9 months. However, a noteworthy finding was the identification of two "extended survivors" with distinct molecular signatures (enriched DDR, chromosomal instability, and proliferation pathways) who experienced prolonged clinical benefit.][5][ An earlier Phase 2 report also indicated a lack of ORR but noted some prolonged PFS associated with MPG expression.][26]
• Mesothelioma (Refractory):[ In the Phase 2 portion of the NCT02535312 trial, TRC102 combined with pemetrexed demonstrated moderate activity in patients with mesothelioma refractory to prior platinum and pemetrexed. Two PRs were observed in 14 treated patients, with a median PFS of 4.3 months, meeting the pre-specified criteria for continued interest.][34]
• Other Solid Tumors and Lymphomas (Phase 1 settings):
• [With Temozolomide (NCT01851369): PRs were observed in patients with NSCLC, ovarian cancer (two patients), and colon cancer, with additional patients achieving SD.][7]
• [With IV Methoxyamine + Temozolomide: One PR was seen in a patient with a pancreatic neuroendocrine tumor (PNET), and six other patients across different tumor types had prolonged SD.][24]
• [With Pemetrexed (NCT01057791): One PR was noted in a patient with oropharyngeal carcinoma, and SD or better was achieved in 60% of evaluable patients.][23]
• [With Cisplatin + Pemetrexed (NCT02535312 Arm A): Three PRs were observed, all in patients with salivary gland tumors.][34]
• Hematologic Malignancies (Phase 1 with Fludarabine):[ Preliminary activity in this setting appeared to correlate with pharmacodynamic markers of DNA damage.][3]

[This landscape of results indicates that while TRC-102 can contribute to anti-tumor responses in combination, its efficacy is not uniform across all contexts, emphasizing the need for careful selection of combination partners and patient populations.]

Table 2: Summary of Key Clinical Trials of Methoxyamine (TRC-102)

NCT ID	Phase	Patient Population/Indication	Intervention (TRC-102 Dose/Schedule, Combination Agents)	Pts (E/E)	Key Safety Findings	Key Efficacy Results (ORR, PFS, OS)	Status/Ref
NCT02535325	1	Stage III/IV Non-Squamous NSCLC	TRC102 200mg (RP2D) + PEM + Cisplatin + RT	15/15	No DLTs, G5; Hematologic, GI AEs common; No radiation pneumonitis	ORR 100% (20% CR); 6mo PFS 80%; 2yr OS 83%	Completed 4
NCT05198830	2	Stage III Non-Squamous NSCLC	TRC102 + PEM + Cis/Carbo + RT then Durvalumab vs. SOC + Durvalumab	~78 planned	Ongoing	PFS (primary endpoint)	Recruiting 13
NCT02395692 (BERT)	2	Recurrent Glioblastoma (Bevacizumab-naïve, 1st recurrence)	TRC102 + Temozolomide	19/19 (Arm 1)	Most AEs G1/2; 2 G3 lymphopenia, 1 G4 thrombocytopenia	No ORR; mOS 11.1mo; mPFS 1.9mo; PFS6 10.5%; 2 "extended survivors" with DDR signatures	Completed 5
NCT01851369	1	Refractory Solid Tumors/Lymphomas	TRC102 125mg PO QD D1-5 (RP2D) + TMZ 150mg/m² PO QD D1-5	52/51	MTD established; Anemia, lymphopenia, neutropenia common G3/4 AEs	4 PRs (NSCLC, ovarian (2), colon); 13 SDs	Completed 22
NCT01633152	1	Advanced Hematologic Malignancies	TRC102 IV (up to 120mg/m²) + Fludarabine 25mg/m² IV D1-5	N/A	No DLTs; Hematologic AEs comparable to Fludarabine alone	Activity correlated with DNA damage markers	Completed 3
NCT02535312 (Arm B)	2	Mesothelioma (refractory to Platinum + PEM)	TRC102 50mg/day D1-4 + PEM 500mg/m² q21d	14/14	Manageable; 1 G4 neutropenia, 5 G3 AEs	2 PRs (1 confirmed); mPFS 4.3mo; 8 SDs	Completed 34
NCT01057791	1	Advanced Solid Tumors	TRC102 PO (MTD 60mg/m²/d x4) + Pemetrexed	28/25	G3 anemia DLT at 100mg/m²/d	1 PR (oropharyngeal); SD or better in 60%	Completed 23

Pts (E/E): Patients (Enrolled/Evaluable). N/A: Not available in provided snippets. PEM: Pemetrexed. Cis: Cisplatin. Carbo: Carboplatin. RT: Radiotherapy. SOC: Standard of Care.

7. Regulatory Status and Intellectual Property

[Methoxyamine (TRC-102) has achieved a notable regulatory milestone. In 2020, the U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation to TRC102 for the treatment of malignant glioma.][2][ Malignant gliomas, which include glioblastoma, are aggressive brain tumors with limited effective treatment options and poor prognoses. Orphan Drug Designation is intended to encourage the development of drugs for rare diseases or conditions, providing potential benefits such as market exclusivity for a period upon approval, tax credits for clinical research, and FDA assistance in the drug development process. This designation, even with the mixed results from the BERT trial in recurrent glioblastoma, could still offer developmental advantages if TRC-102 is pursued for a specific, perhaps biomarker-defined, subpopulation within malignant gliomas where it might show more pronounced benefit.]

[In TRACON Pharmaceuticals' pipeline, TRC102 (methoxyamine) is listed as a Phase 2 small molecule drug candidate. Its development has focused on indications such as lung cancer, and it has previously been investigated for glioblastoma and mesothelioma.][6][ TRACON Pharmaceuticals has indicated it is actively seeking corporate partnerships for its assets, which may include TRC102, as part of its business strategy.][8]

[Regarding intellectual property, TRACON Pharmaceuticals has stated that it maintains an intellectual property position for its product candidates, and specifically, it retains global rights to develop and commercialize TRC102 in all indications.][14][ Methoxyamine (CAS 67-62-9) and its hydrochloride salt (CAS 593-56-6) are established chemical entities that have been known for some time and are used as chemical reagents.][18][ Consequently, composition of matter patents for Methoxyamine itself are likely expired or not exclusively held by TRACON for the basic molecule. TRACON's intellectual property strategy for TRC-102 is therefore more likely to center on method-of-use patents. These would cover specific applications of TRC-102 in cancer treatment, such as its use in particular combination therapies, specific dosing regimens, or its use in defined patient populations (potentially identified by biomarkers). Such patents are a common way to protect innovations related to new therapeutic applications of known compounds. The provided research material does not detail specific patent numbers held by TRACON for TRC-102 beyond these general assertions of IP rights.]

8. Discussion: Therapeutic Potential and Challenges

[Methoxyamine (TRC-102)'s development is predicated on a sound biological rationale: the inhibition of Base Excision Repair to sensitize cancer cells to DNA-damaging therapies. Its primary therapeutic potential lies in this chemo- and radiosensitization strategy, aiming to improve the efficacy of existing treatments and potentially overcome mechanisms of resistance linked to robust DNA repair capacity in cancer cells.][1][ Strong preclinical evidence across various tumor models and some notable clinical responses, particularly the high overall response rate observed in the Phase 1 trial in non-small cell lung cancer when combined with chemoradiotherapy, underscore this potential.][4]

[However, the clinical journey of Methoxyamine has been characterized by variable efficacy. While the NSCLC Phase 1 results were striking ][4][, and moderate activity was noted in indications like mesothelioma and in other early-phase solid tumor trials ][7][, the Phase 2 BERT trial in recurrent glioblastoma did not achieve its primary objective of improving objective response rates when TRC-102 was added to temozolomide.][5][ This variability suggests that the broad mechanism of BER inhibition does not translate uniformly into clinical benefit across all tumor types or with all combination partners. The efficacy appears highly context-dependent, influenced by the specific DNA-damaging agent used, the tumor type and its microenvironment, and critically, the underlying molecular characteristics of the cancer.]

[Several challenges remain in realizing Methoxyamine's full therapeutic potential. A paramount challenge is ]patient selection and biomarker development[. While initial preclinical studies suggested that TRC-102's activity might be independent of common resistance markers like MGMT or MMR status ][7][, the clinical findings from the BERT trial in glioblastoma are particularly instructive. The "extended survivors" in that trial, who derived significant long-term benefit, had tumors with enriched signatures of DNA Damage Response (DDR) activation, chromosomal instability, and high proliferation at baseline.][5][ Similarly, N-methylpurine DNA glycosylase (MPG) expression showed an association with prolonged PFS in another glioblastoma study.][26][ These findings strongly suggest that tumors already under high replicative stress or possessing certain DDR characteristics might be "primed" and thus more susceptible to the synthetic lethality or enhanced DNA damage induced by BER inhibition in combination with genotoxic agents. The lack of broad objective response in the overall BERT cohort might mask profound effects in a smaller, biomarker-defined subgroup. This underscores an urgent need for robust, validated predictive biomarkers to guide patient selection, which is essential for improving the therapeutic index and demonstrating efficacy in more homogeneous populations.]

[Another challenge lies in ]optimizing combination regimens[. The choice of the DNA-damaging partner, along with the dose and schedule of Methoxyamine, is critical. Synergy is dependent on the specific types of DNA lesions induced by the partner agent and the tumor's reliance on BER for the repair of those particular lesions. The long half-life of Methoxyamine (24-28 hours) must also be factored into scheduling to maximize synergy and manage tolerability.][7]

Toxicity management[ is also a key consideration. While Methoxyamine combinations have generally been reported as tolerable, the prominent hematologic and gastrointestinal toxicities require careful monitoring and proactive supportive care, especially when Methoxyamine is added to already intensive treatments like chemoradiotherapy.][4][ The observation of no clinical radiation pneumonitis in the NSCLC chemoradiation trial (NCT02535325) was a positive safety signal in that specific context, suggesting Methoxyamine might not exacerbate all toxicities of its partners.][4]

[Future directions for Methoxyamine (TRC-102) should logically focus on indications where strong initial signals of efficacy have been observed, such as the ongoing randomized Phase 2 trial in NSCLC (NCT05198830).][13][ A concerted effort in biomarker discovery and validation, building on the insights from trials like BERT, is paramount. This could involve prospectively evaluating markers of DDR pathway activation or high replicative stress. Furthermore, exploring novel combinations, potentially with other DDR inhibitors (given preclinical data suggesting TRC-102 can potentiate PARP inhibitors ][23][) or newer targeted agents where BER might contribute to resistance, could unveil new therapeutic opportunities.]

[In the broader context of BER inhibition, Methoxyamine targets AP sites, a central and ubiquitous intermediate in the BER pathway.][3][ Other BER inhibitors in various stages of development target different enzymatic steps within the pathway. For instance, inhibitors of DNA glycosylases like OGG1 (e.g., TH5487, SU0268) aim to prevent the initial removal of specific damaged bases.][10][ Inhibitors of APE1's endonuclease or redox functions (e.g., CRT0044876, E3330, APX3330) target the enzyme responsible for processing AP sites.][43][ Poly(ADP-ribose) polymerase (PARP) inhibitors (e.g., olaparib, veliparib), while also involved in BER (particularly in single-strand break repair, a process closely linked to BER), have a broader impact on DNA repair, including a critical role in homologous recombination when BER is overwhelmed.][10][ Methoxyamine's distinct mechanism of action—stabilizing the AP site itself—offers a unique approach compared to enzyme-targeted inhibitors. The clinical development of these other BER inhibitors faces similar challenges in defining optimal therapeutic windows and identifying responsive patient populations, underscoring the complexity of targeting this fundamental repair pathway. The success of PARP inhibitors in cancers with BRCA mutations, a classic example of synthetic lethality, serves as a paradigm. The future of Methoxyamine may depend on identifying analogous contexts—specific genetic vulnerabilities or tumor phenotypes—that render cells exquisitely dependent on the BER steps blocked by Methoxyamine, particularly when challenged by a co-administered DNA-damaging agent.]

9. Conclusion

[Methoxyamine (TRC-102) is an investigational small molecule with a well-characterized mechanism of action as an inhibitor of the Base Excision Repair pathway, primarily by forming stable adducts at apurinic/apyrimidinic sites in DNA. Developed by TRACON Pharmaceuticals, its therapeutic strategy has focused on its role as a potentiator of DNA-damaging chemotherapies and radiotherapy, aiming to enhance their efficacy and overcome treatment resistance.][1]

[The clinical development program for Methoxyamine has been extensive, spanning various solid tumors and hematologic malignancies, often in collaboration with the National Cancer Institute. While preclinical studies consistently demonstrated its sensitizing effects, clinical outcomes have been variable. Notable promise has been observed in non-small cell lung cancer when combined with chemoradiotherapy, leading to a high overall response rate in an early Phase 1 trial and progression to a randomized Phase 2 study.][4][ However, in other settings, such as recurrent glioblastoma, Methoxyamine combinations did not meet primary efficacy endpoints in broader patient populations, although intriguing signals of activity in biomarker-defined subgroups have emerged.][5][ The drug holds Orphan Drug Designation from the FDA for malignant glioma.][2]

[The primary therapeutic potential of Methoxyamine continues to reside in its ability to augment established cancer treatments. However, significant challenges remain, chief among them being the identification of predictive biomarkers to guide patient selection and the optimization of combination regimens to maximize synergy while managing toxicity. The journey of Methoxyamine underscores the complexities of translating a clear biological rationale for BER inhibition into widespread oncologic success without refined patient stratification strategies.]

[Ultimately, the future role of Methoxyamine (TRC-102) in cancer therapy will likely be determined by the results of ongoing pivotal trials, such as the randomized Phase 2 study in NSCLC, and by a more profound understanding of the specific tumor contexts and molecular signatures that confer sensitivity to its BER-inhibiting action. A concerted effort to validate and implement predictive biomarkers will be crucial for targeting its use more effectively and potentially unlocking its value in specific patient populations.]

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