Gimatecan (DB06721): A Comprehensive Monograph on a Novel Lipophilic Camptothecin Analogue

Executive Summary

Gimatecan is an investigational, orally bioavailable, small molecule drug representing a new generation of camptothecin analogues.[1] Developed as a semi-synthetic, lipophilic derivative of the natural alkaloid camptothecin, it was rationally designed to overcome the pharmacological limitations of earlier agents in its class, such as topotecan and irinotecan. Its primary distinction lies in a strategic chemical modification—a 7-t-butoxyiminomethyl substitution—that confers high lipophilicity, leading to enhanced oral absorption, superior stability of the pharmacologically active lactone ring, and a markedly prolonged biological half-life.[1]

The core mechanism of action for Gimatecan is the potent inhibition of DNA topoisomerase I. By binding to and stabilizing the transient covalent complex formed between the enzyme and DNA, it prevents the re-ligation of single-strand breaks. These persistent lesions are converted into lethal double-strand breaks upon collision with the DNA replication machinery during the S-phase of the cell cycle, ultimately inducing cell cycle arrest and apoptosis.[3] Preclinical studies have consistently demonstrated Gimatecan's remarkable and broad-spectrum antitumor activity. It exhibits superior cytotoxic potency compared to established camptothecins across a wide range of solid tumor models, including those expressing multidrug resistance proteins, a common mechanism of therapeutic failure.[7]

Despite this profound preclinical promise, Gimatecan's journey through clinical development has been met with significant challenges and mixed outcomes. An early Phase II trial in recurrent glioblastoma, an indication for which the drug's properties seemed well-suited, was terminated due to minimal efficacy and dose-limiting toxicities.[10] This setback has prompted a strategic pivot in its development, with current Phase II investigations focused on other solid tumors, notably locally advanced or metastatic pancreatic cancer and platinum-resistant ovarian cancer.[2]

The primary obstacles to Gimatecan's clinical success are rooted in its complex pharmacology. Its very long half-life, while enabling convenient oral dosing, leads to significant drug accumulation and a narrow therapeutic window, with myelosuppression (thrombocytopenia and neutropenia) being a consistent dose-limiting toxicity.[13] Furthermore, its pharmacokinetics are characterized by high inter-patient variability, significantly influenced by plasma levels of alpha1-acid glycoprotein (AGP) and a wide array of potential drug-drug interactions.[1] The future of Gimatecan likely depends on demonstrating a clear clinical benefit in its current target indications and potentially identifying predictive biomarkers or developing pharmacokinetically-guided dosing strategies to manage its challenging safety and variability profile.

Molecular Profile and Synthesis

Chemical Identity and Nomenclature

Gimatecan is a well-defined small molecule with multiple identifiers used across scientific literature, clinical trial registries, and chemical databases. Establishing these identifiers is crucial for accurate data consolidation and cross-referencing.

• Generic Name: Gimatecan [1]
• DrugBank ID: DB06721 [1]
• CAS Number: 292618-32-7 [7]
• Synonyms and Code Names: Throughout its development by various pharmaceutical entities, including Sigma-Tau, Novartis, and Lee's Pharmaceutical, Gimatecan has been known by several code names. These include ST1481, LBQ707, LBQ-707, and CPT-184. Its chemical descriptor is 7-t-butoxyiminomethylcamptothecin.[1]
• Systematic (IUPAC) Name: The unambiguous chemical structure of Gimatecan is defined by its IUPAC name: (4S)-11-[(E)-(tert-butoxyimino)methyl]-4-ethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione.[1]

Physicochemical and Structural Properties

Gimatecan's unique pharmacological profile is a direct result of its specific physicochemical and structural characteristics, which were intentionally engineered to improve upon the parent camptothecin molecule.

• Molecular Formula and Weight: The chemical formula for Gimatecan is C25​H25​N3​O5​. Its average molecular weight is 447.491 Da, with a monoisotopic mass of 447.179420917 Da.[1]
• Structural Class: Gimatecan is classified as a semi-synthetic, lipophilic analogue of camptothecin, placing it within the broader category of quinoline alkaloids.[1] The defining feature of its structure is the substitution of a 7-t-butoxyiminomethyl group on the camptothecin backbone. This modification is the primary determinant of its increased lipophilicity and distinct pharmacological behavior compared to other camptothecins.[20]
• Physical Properties: In its pure form, Gimatecan is a solid powder, typically light yellow to yellow in color.[18] It is soluble in dimethyl sulfoxide (DMSO), which is commonly used for preparing stock solutions for in vitro research.[22] Its predicted boiling point is approximately 780.6°C, and its predicted density is 1.37 g/cm³.[22] For long-term stability, it is typically stored at -20°C.[17]
• Lipophilicity: The development of Gimatecan represents a strategic departure from the design of second-generation camptothecins like topotecan and irinotecan, which were modified to enhance water solubility. Gimatecan was rationally designed to be highly lipophilic. This property was intended to improve its pharmacological profile by enhancing oral absorption, facilitating passive diffusion across cell membranes for increased intracellular accumulation, and stabilizing the critical E-ring lactone, which is prone to hydrolysis to an inactive carboxylate form at physiological pH.[3]

Table 1: Key Physicochemical and Structural Properties of Gimatecan

Property	Value	Source(s)
Generic Name	Gimatecan	1
DrugBank ID	DB06721	1
CAS Number	292618-32-7	7
Synonyms	ST1481, LBQ707, CPT-184	2
Molecular Formula	C25​H25​N3​O5​	1
Average Molecular Weight	447.49 g/mol	1
Monoisotopic Mass	447.1794 Da	1
IUPAC Name	(4S)-11-[(E)-(tert-butoxyimino)methyl]-4-ethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione	1
Appearance	Solid Powder (Light yellow to yellow)	18
Solubility	Soluble in DMSO	22
Predicted Boiling Point	780.6 ± 70.0°C	22
Predicted Density	1.37 ± 0.1 g/cm³	22

Synthesis Pathway

Gimatecan is not a naturally occurring compound but is produced via a multi-step semi-synthetic process starting from the natural product camptothecin.

• Semi-Synthetic Route: The synthesis of Gimatecan involves a three-step chemical modification of the camptothecin scaffold [8]:

1. Step 1: Hydroxymethylation: The process begins with the radical alkylation of the starting material, camptothecin (I). This reaction, typically carried out using hydrogen peroxide (H2​O2​) and ferrous sulfate (FeSO4​), introduces a hydroxymethyl group at the C-7 position of the molecule, yielding the 7-hydroxymethyl derivative (II).
2. Step 2: Oxidation: The resulting alcohol (II) is then oxidized to an aldehyde. This is achieved by heating the compound with acetic acid, which converts the 7-hydroxymethyl group into a 7-formyl group, producing 7-formylcamptothecin (III).
3. Step 3: Condensation: In the final step, the aldehyde (III) undergoes a condensation reaction with O-tert-butylhydroxylamine hydrochloride. This reaction forms an oxime linkage, attaching the tert-butoxyimino group to the C-7 position and yielding the final product, Gimatecan.[8]

• Optimization and Derivatization: The core synthesis of Gimatecan has served as a foundation for further chemical exploration. Research has been conducted to optimize this procedure to increase yields and purity, particularly for producing Gimatecan derivatives on a larger scale for conjugation studies.[26] This work highlights the versatility of the Gimatecan scaffold. Its chemical structure is not merely a final product but a platform that can be further modified, for example, by attaching it to targeting moieties like oligonucleotides or antibodies. This adaptability positions Gimatecan as a potential payload for next-generation targeted therapies, such as antibody-drug conjugates (ADCs), a field of intense interest in modern oncology.[27] This evolution in thinking—from simple analogue to adaptable therapeutic platform—underscores Gimatecan's place as a "third-generation" camptothecin, where the focus has shifted from merely improving systemic pharmacology to enabling precision targeting.

Comprehensive Pharmacological Profile

Mechanism of Action and Pharmacodynamics

Gimatecan's potent antitumor activity stems from its well-defined mechanism as a topoisomerase I poison, augmented by secondary effects on tumor angiogenesis.

• Primary Target: Topoisomerase I (Topo I): The primary molecular target of Gimatecan is DNA topoisomerase I. This enzyme is crucial for normal cellular function, as it resolves topological stress in DNA by creating transient single-strand breaks, allowing the DNA to unwind during replication and transcription before re-ligating the strand.[2]
• Stabilization of the Cleavable Complex: Gimatecan exerts its effect by intercalating at the site of this transient break, binding to the Topo I-DNA complex. This interaction physically obstructs the enzyme, preventing the re-ligation step and trapping the enzyme in a "cleavable complex".[3] This transforms a temporary, harmless enzymatic action into a persistent form of DNA damage.
• Induction of S-Phase Specific Cytotoxicity: The stabilized single-strand breaks are not inherently lethal. Their cytotoxicity arises when the cell enters the S-phase of the cell cycle. The advancing DNA replication machinery collides with the stalled Topo I-DNA complexes, causing the replication fork to collapse and converting the single-strand breaks into permanent, lethal double-strand DNA breaks.[5] This leads to the activation of DNA damage response pathways, cell cycle arrest in the S-phase, and ultimately, the induction of apoptosis (programmed cell death).[5]
• Comparative Potency: A defining feature of Gimatecan is its superior potency compared to clinically approved camptothecins like topotecan and irinotecan. Preclinical studies have shown that Gimatecan induces a more persistent stabilization of the cleavable complex and generates a higher number of DNA breaks for a given concentration.[5] This enhanced on-target activity is reflected in its in vitro cytotoxicity, where it is often 10-fold or more potent than topotecan against various human tumor cell lines.[9] This superior potency is a direct result of its chemical design, which promotes stronger and more durable drug-target interactions.[20]
• Antiangiogenic Activity: In addition to its direct cytotoxic effects, Gimatecan possesses antiangiogenic properties that may contribute significantly to its overall antitumor efficacy, particularly when administered in prolonged, low-dose schedules.[6] This secondary mechanism involves the inhibition of new blood vessel formation within tumors. Evidence for this activity includes the demonstrated ability of Gimatecan to inhibit endothelial cell migration, significantly reduce microvessel density in tumor xenografts, and down-regulate the expression of proangiogenic factors such as basic fibroblast growth factor (bFGF).[3]

Pharmacokinetics (PK) and Metabolism

The pharmacokinetic profile of Gimatecan is distinct from that of earlier camptothecins and is central to both its therapeutic potential and its clinical challenges.

• Absorption and Bioavailability: Gimatecan was specifically designed for oral administration and exhibits high bioavailability through this route.[3] Following oral intake, it is rapidly absorbed, with peak plasma concentrations (Cmax) generally observed within 2 hours.[31]
• Distribution and Half-Life: The drug demonstrates a very long apparent biological half-life, with mean values reported across different studies ranging from approximately 57 to 80 hours.[4] This prolonged persistence in the body is a double-edged sword. While it allows for sustained exposure to the active drug with less frequent dosing, it also leads to significant drug accumulation with repeated administration. Studies have shown that Cmax and the area under the curve (AUC) can increase by a factor of 3 to 6 after multiple doses, a critical consideration for dosing schedule design and toxicity management.[13]
• Lactone Stability: A key pharmacological advantage of Gimatecan is the remarkable stability of its active lactone E-ring. In human plasma, Gimatecan exists predominantly (over 85-87.5%) in this pharmacologically active, intact lactone form.[4] This contrasts sharply with older, more water-soluble camptothecins, which are more susceptible to pH-dependent hydrolysis into an inactive, open-ring carboxylate form, thereby reducing their effective concentration at the tumor site.[8]
• Metabolism: Gimatecan is the primary active species in circulation. Its main metabolite, a hydroxy derivative known as ST1698, is found in plasma at very low levels, with AUC values constituting only 5-15% of the parent drug's exposure.[13]
• Excretion: Gimatecan is identified as a substrate for the organic anion-transporting polypeptide OATP1B1 (encoded by the SLCO1B1 gene), which plays a role in its hepatic uptake and subsequent elimination.[1]

The pharmacokinetic properties that were engineered to make Gimatecan a superior drug—its long half-life and high oral bioavailability—are also the source of its primary clinical liabilities. The goal of achieving sustained exposure to the active lactone form was successful, enabling convenient oral dosing schedules.[33] However, the very long half-life means the drug does not fully clear from the system between doses, leading to progressive accumulation.[13] This accumulation can drive plasma concentrations into a toxic range, causing the severe, dose-limiting myelosuppression observed in clinical trials and forcing dose reductions that may compromise efficacy.[11] This fundamental tension between maintaining therapeutic exposure and avoiding cumulative toxicity is a central challenge in its development. The Phase I study comparing a daily dosing schedule to a twice-weekly (Monday/Thursday) schedule was a direct attempt to mitigate this issue. The goal was to find a regimen that could maintain a similar total drug exposure over a cycle (AUC) while lowering the peak concentrations (Cmax) to improve the therapeutic window, illustrating the delicate balance required to harness Gimatecan's potent but challenging pharmacology.[32]

Table 2: Summary of Gimatecan Pharmacokinetic Parameters in Humans

Parameter	Value (Mean ± SD)	Patient Population	Dosing Schedule	Source(s)
Half-life (t½)	77.1 ± 29.6 h	Advanced Solid Tumors	Daily x 5 days	13
	57 ± 22 h	Malignant Glioma (non-EIASD)	Daily x 5 days	31
	~80 h	Advanced Cancer	Daily x 5 or M/Th	32
	77 ± 37 h	Advanced Solid Tumors	Once weekly x 3	33
Time to Peak (Tmax)	Within 2 h (for 90% of doses)	Malignant Glioma	Daily x 5 days	31
	1 h (median)	Advanced Cancer	Daily x 5 or M/Th	32
Apparent Clearance (CL/f)	1.2 ± 0.9 L/h	Malignant Glioma (non-EIASD)	Daily x 5 days	31
	0.5 ± 0.4 L/h	Advanced Cancer	Daily x 5 or M/Th	32
Accumulation Factor	2.7 ± 0.6 (based on AUC)	Malignant Glioma	Daily x 5 days	31
	3-6 fold (Cmax and AUC)	Advanced Solid Tumors	Multiple Dosing	13
Active Lactone Form in Plasma	>85%	Advanced Solid Tumors	Daily x 5 days	13
	>87.5%	Advanced Cancer	Daily x 5 or M/Th	32
	Almost entirely intact lactone	Advanced Solid Tumors	Once weekly x 3	33

EIASD: Enzyme-Inducing Antiseizure Drugs

Preclinical Antitumor Activity and Efficacy

The preclinical evidence base for Gimatecan is extensive and robust, consistently demonstrating potent and broad-spectrum antitumor activity that surpasses that of established camptothecin analogues.

In Vitro Cytotoxicity and Potency

• Broad-Spectrum Activity: Gimatecan exhibits potent antiproliferative effects across a diverse panel of human cancer cell lines. Studies have documented its activity in models of bladder cancer (HT1376, MCR), pancreatic cancer (Panc-1), esophageal squamous cell carcinoma, gastric cancer, and neuroblastoma, with inhibitory concentrations often in the low nanomolar range.[7] The growth-inhibitory effect is both dose- and time-dependent.[7]
• Superior Potency vs. Comparators: In direct comparative assays, Gimatecan is consistently more potent than both topotecan and irinotecan (and its active metabolite, SN-38). For instance, in gastric cancer cell lines, Gimatecan's IC50 values were orders of magnitude lower than those of irinotecan (e.g., 1.95 nM vs. 3253.71 nM in SNU-1 cells).[35] Similar superior potency was observed in esophageal cancer cell lines, where Gimatecan was effective at nanomolar concentrations while irinotecan required micromolar levels.[29] This heightened potency is attributed to its ability to cause a higher number of DNA breaks and a more persistent stabilization of the Topo I-DNA complex.[20]
• Activity in Drug-Resistant Models: A significant preclinical advantage of Gimatecan is its effectiveness against cancer cells that have developed multidrug resistance (MDR). It has been shown to overcome resistance mediated by efflux pumps such as P-glycoprotein (P-gp170) and Multidrug Resistance-associated Protein (MRP).[9] While it is a moderate substrate for the Breast Cancer Resistance Protein (BCRP), it is affected to a lesser extent than topotecan, allowing it to retain substantial activity in BCRP-overexpressing cells.[38]

In Vivo Efficacy in Human Tumor Xenografts

• Potent Antitumor Effects: When tested in animal models, typically nude mice bearing human tumor xenografts, orally administered Gimatecan demonstrates profound antitumor activity. Treatment results in marked tumor growth inhibition, high rates of complete tumor regression, and significant increases in survival across a wide range of models, including subcutaneous, orthotopic (e.g., brain), and metastatic (e.g., lung, liver) tumor systems.[5]
• Efficacy in Refractory Models: Gimatecan has shown remarkable efficacy in preclinical models of cancers that are notoriously difficult to treat. This includes orthotopic brain tumor models, where its lipophilicity allows it to cross the blood-brain barrier, and pancreatic cancer xenografts (Panc-1), where oral treatment induced complete responses in 5 out of 10 mice.[39]
• Superiority over Standard of Care: In vivo comparative studies have consistently found Gimatecan to be more effective and to possess a wider therapeutic index than topotecan and irinotecan. For example, in a human bladder carcinoma xenograft model, Gimatecan produced a significantly greater inhibition of tumor growth compared to an optimal dose of topotecan.[5]
• Schedule Dependency: The antitumor activity of Gimatecan is highly schedule-dependent. While effective when given on intermittent, high-dose schedules, preclinical studies have shown that prolonged, daily administration of low doses often produces superior efficacy. This "antiangiogenic" schedule not only inhibits tumor growth directly but also significantly reduces tumor vascularization, suggesting that both cytotoxic and antiangiogenic mechanisms contribute to its efficacy.[6]

The strong preclinical data, particularly in intracranial tumor models, built a compelling scientific rationale for investigating Gimatecan in patients with glioblastoma. Its lipophilicity suggested it could effectively penetrate the central nervous system, and its ability to overcome P-glycoprotein-mediated resistance was a key advantage, as this efflux pump is highly expressed at the blood-brain barrier and contributes to the failure of many chemotherapies.[25] However, this preclinical promise did not translate into clinical success. The Phase II trial in recurrent glioblastoma was ultimately terminated for futility, revealing a significant disconnect between the animal models and the human disease state.[11] This failure likely stems from multiple factors. The human blood-brain barrier is far more restrictive than that in xenograft mouse models. More importantly, the trial revealed that the dose required to achieve therapeutic concentrations within the brain could not be safely administered systemically. The onset of grade 4 hematologic toxicities forced a dose reduction from 1.22 mg/m² to 1.0 mg/m², suggesting that the therapeutic window for this indication is vanishingly narrow or non-existent.[11] This outcome serves as a stark reminder of the challenges in translating preclinical efficacy, especially for CNS tumors, into tangible clinical benefit.

Clinical Development and Therapeutic Investigation

The clinical development of Gimatecan has been a multi-stage process involving numerous trials across different cancer types and dosing schedules, reflecting an ongoing effort to identify a viable therapeutic niche for this potent agent.

Phase I Clinical Program

The initial phase of clinical testing was designed to establish the fundamental safety, tolerability, and pharmacokinetic parameters of Gimatecan in humans.

• Objectives: The primary goals of the Phase I program were to determine the maximum tolerated dose (MTD), identify the dose-limiting toxicities (DLTs), and characterize the pharmacokinetic profile of orally administered Gimatecan in patients with advanced solid tumors for whom standard therapies had failed.[9]
• Dosing Schedules Explored: Guided by the preclinical evidence of schedule-dependency, investigators explored a variety of dosing regimens to find an optimal balance between efficacy and safety. These included a daily administration for 5 consecutive days repeated every 28 days [31]; a more intensive daily for 5 days schedule administered for 1, 2, or 3 consecutive weeks out of a 4-week cycle [13]; and a once-weekly schedule for 3 out of 4 weeks.[9]
• Key Findings: Across these studies, a consistent safety profile emerged. Myelosuppression, particularly thrombocytopenia (low platelets) and neutropenia (low white blood cells), was consistently identified as the principal DLT.[11] At higher dose levels, fatigue, nausea, vomiting, and anorexia also became dose-limiting.[4] The MTD for the once-weekly schedule was established at 2.40 mg/m².[33] While objective tumor responses were infrequent in these early-phase trials, a notable number of patients achieved disease stabilization for several months, providing the first signal of clinical antitumor activity.[9] The pharmacokinetic analyses from these trials confirmed Gimatecan's very long half-life and tendency to accumulate, which led to the hypothesis that less frequent dosing, such as a twice-weekly schedule, might offer a better therapeutic window by reducing peak drug concentrations and mitigating cumulative toxicity.[32]

Phase II Clinical Trials by Indication

Following the Phase I program, Gimatecan advanced into Phase II trials to evaluate its efficacy in specific cancer types.

• Recurrent Glioblastoma (NCT00032903): This multicenter, single-arm trial was a critical test of Gimatecan's potential in CNS tumors. The study enrolled adults with recurrent glioblastoma who had progressed after prior treatments and excluded patients taking enzyme-inducing antiseizure drugs (EIASDs) due to the known pharmacokinetic interaction.[11] Patients received Gimatecan orally at an initial dose of 1.22 mg/m²/day for 5 consecutive days every 4 weeks. However, due to severe (grade 4) hematologic toxicity in 4 of the first 10 patients, the dose was reduced to 1.0 mg/m²/day.[11] The trial failed to meet its primary endpoint, with only 12% of patients remaining progression-free at 6 months. The investigators concluded that this regimen had minimal efficacy in this patient population, and development for this indication was discontinued.[10]
• Advanced Pancreatic Cancer (NCT04571489, ChiCTR2100042993): The current development strategy for Gimatecan includes a focus on pancreatic cancer. At least two randomized, controlled Phase II trials have been initiated to evaluate Gimatecan as a second-line therapy for patients with locally advanced or metastatic disease that has progressed after first-line treatment with gemcitabine or fluorouracil-based chemotherapy.[2] In these studies, the experimental arm receives Gimatecan at a dose of 0.8 mg/m² orally on days 1-5 of a 28-day cycle, with comparator arms receiving standard-of-care agents.[45] The status of these trials is varied, with one listed as recruiting and another as unknown, but they represent a key ongoing effort to establish efficacy in a major solid tumor.[2]
• Platinum-Resistant Ovarian, Fallopian Tube, or Peritoneal Cancer (NCT04846842): This single-arm, multi-center Phase II trial was designed to assess the safety and efficacy of Gimatecan in patients with platinum-resistant recurrent disease, a population with a significant unmet medical need.[2] The planned regimen was oral Gimatecan on days 1-5 every 4 weeks.[12] As of the last update, the trial's status was "Not yet recruiting," with an estimated start date in mid-2021.[12]
• Other Solid Tumors: Earlier Phase II investigations included a study in metastatic colorectal cancer, which showed preliminary signs of activity (1 partial response and 3 stable disease in the first 6 patients assessed) but was also complicated by significant toxicity that prompted a dose reduction.[46] Historical reviews also mention that Phase II studies were planned or ongoing in lung cancer, breast cancer, and pediatric tumors, though detailed results from these are not available in the provided materials.[20]

Table 3: Summary of Major Clinical Trials for Gimatecan

Trial ID (NCT)	Phase	Indication	Patient Population	Dosing Regimen	Status	Key Efficacy Outcomes	Key Safety Findings (DLTs)
NCT00032903	I/II	Recurrent Malignant Glioma	Adults with recurrent primary malignant glioma, ≤1 prior regimen for recurrence	1.0 mg/m²/day (reduced from 1.22), PO, days 1-5, q28 days	Completed (Discontinued)	Minimal efficacy; PFS6 of 12%; 1 PR	Grade 4 hematologic toxicity (thrombocytopenia, leukopenia, neutropenia)
NCT00410358	I	Advanced Solid Tumors	Japanese patients with advanced solid tumors, progressed on standard therapy	Dose escalation, PO, days 1-5, q28 days	Completed	Anti-tumor activity assessed by RECIST	Safety assessed by AEs; MTD determination
NCT00420485	I	Advanced Solid Tumors	Adults with advanced or metastatic cancer	Dose escalation, two different schedules (daily x 5 or M/Th)	Completed	N/A (Phase I)	Dose Limiting Toxicity (DLT) determination
NCT04571489	II	Locally Advanced or Metastatic Pancreatic Cancer	Second-line treatment after failure of gemcitabine or fluorouracil	0.8 mg/m², PO, days 1-5, q28 days	Unknown Status	Primary: PFS; Secondary: OS, ORR, DoR	Safety and effect studied
ChiCTR2100042993	II	Locally Advanced or Metastatic Pancreatic Cancer	Second-line treatment	N/A	Recruiting	Effectiveness and safety	N/A
NCT04846842	II	Platinum-Resistant Ovarian, Fallopian Tube, or Peritoneal Cancer	Platinum-resistant recurrent disease, previously treated with Topo I inhibitors excluded	Fixed dose, PO, days 1-5, q28 days	Unknown (Not yet recruiting as of last update)	Primary: PFS; Secondary: DCR	Safety and effect studied

PFS: Progression-Free Survival; PFS6: Progression-Free Survival at 6 months; OS: Overall Survival; ORR: Objective Response Rate; DoR: Duration of Response; DCR: Disease Control Rate; MTD: Maximum Tolerated Dose; AE: Adverse Event; PR: Partial Response

Safety, Tolerability, and Risk Management

The clinical utility of any potent anticancer agent is ultimately defined by its therapeutic index—the balance between its efficacy and its toxicity. For Gimatecan, this balance has proven to be a central and persistent challenge throughout its development.

Clinical Safety and Tolerability Profile

• Dose-Limiting Toxicities (DLTs): The most significant and consistently observed DLT across multiple Phase I clinical trials is myelosuppression.[14] This manifests primarily as severe thrombocytopenia (a critical drop in platelet count) and neutropenia (a drop in a key type of white blood cell), which increase the risks of bleeding and serious infection, respectively.[11] In a Phase II study of patients with ovarian cancer, grade 4 neutropenia and grade 4 thrombocytopenia were observed in 17.4% and 7.2% of patients, respectively.[14] Other DLTs reported, particularly at higher dose levels, include fatigue, anorexia, nausea, and vomiting.[4]
• Common Adverse Events: Beyond the dose-limiting effects, the most common treatment-related adverse events associated with Gimatecan are generally consistent with the camptothecin class. These include anemia, fatigue, neutropenia, nausea, and vomiting.[4] While diarrhea is a hallmark toxicity of irinotecan, severe (grade 4) diarrhea was not observed in the ovarian cancer study, suggesting a potentially more favorable gastrointestinal safety profile.[14] Asthenia and fatigue were common but generally mild to moderate (grade 1-2).[14]
• Cardiotoxicity Profile: An important potential safety advantage for Gimatecan was highlighted in recent preclinical studies. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), Gimatecan did not affect cell viability or induce signs of DNA damage, even at concentrations well above its clinically observed peak levels. This is in stark contrast to other chemotherapeutics like the topoisomerase II inhibitor daunorubicin, which was highly cardiotoxic in the same model.[47] This suggests Gimatecan may have a favorable cardiotoxicity profile, a significant benefit in cancer patients who often have pre-existing cardiac risk factors or receive multiple cardiotoxic agents.

Drug-Drug Interaction Profile

Gimatecan's pharmacokinetics are highly susceptible to alteration by co-administered drugs, creating a significant risk management challenge. This is compounded by the high inter-patient variability in its clearance, which is already influenced by baseline levels of the acute-phase reactant protein alpha1-acid glycoprotein (AGP).[13] The combination of this intrinsic variability with the potential for extrinsic modulation via drug-drug interactions (DDIs) creates a "perfect storm" of pharmacokinetic unpredictability. This makes it exceptionally difficult to ensure that patients receive a dose that is both safe and effective, as standard dosing can lead to either sub-therapeutic exposure or severe toxicity depending on a patient's individual physiology and concomitant medications.

• Pharmacokinetic Interactions: Gimatecan is a substrate for various drug transporters and metabolic pathways, making it vulnerable to a wide range of interactions [1]:
• Inhibitors of Excretion (Increased Gimatecan Exposure): A large number of drugs can decrease the excretion of Gimatecan, leading to higher plasma concentrations and an increased risk of toxicity. These include common medications such as the antibiotic erythromycin, the antifungal ketoconazole, the immunosuppressant cyclosporine, and many others that inhibit efflux transporters like OATP1B1.[1]
• Inducers of Metabolism/Transport (Decreased Gimatecan Exposure): Conversely, certain drugs can increase the clearance of Gimatecan, leading to lower plasma concentrations and potentially compromising its efficacy. The most clinically significant example of this is with enzyme-inducing antiseizure drugs (EIASDs).[1]
• Clinically Significant Interactions from Trials: The interaction with EIASDs was a major finding in the glioblastoma trials. In patients taking these drugs, the apparent clearance of Gimatecan was dramatically increased by a factor of 2 to 10. This necessitated the creation of separate dose-escalation cohorts within the trial to administer much higher doses to these patients in an attempt to achieve plasma levels comparable to those in patients not taking EIASDs.[31] This interaction highlights the profound impact that concomitant medications can have on Gimatecan exposure and underscores the critical need for meticulous medication review before initiating treatment.

Table 4: Clinically Significant Drug-Drug Interactions Affecting Gimatecan

Interacting Drug/Class	Effect on Gimatecan	Proposed Mechanism	Clinical Implication/Recommendation
Enzyme-Inducing Antiseizure Drugs (EIASDs) (e.g., carbamazepine, phenytoin)	Markedly decreased serum concentration (Increased clearance by 2-10x)	Induction of metabolic enzymes (e.g., CYP3A4) and/or transporters	Co-administration should be avoided if possible. If necessary, significantly higher doses of Gimatecan are required to achieve therapeutic exposure.
Strong Inhibitors of OATP1B1/SLCO1B1 (e.g., Cyclosporine, Gemfibrozil)	Increased serum concentration (Decreased excretion)	Inhibition of OATP1B1-mediated hepatic uptake	Potential for increased toxicity. Dose reduction of Gimatecan may be necessary. Monitor closely for adverse events.
Strong CYP3A4 Inhibitors (e.g., Ketoconazole, Clarithromycin)	Increased serum concentration (Decreased excretion)	Inhibition of CYP3A4-mediated metabolism	Increased risk of toxicity. Co-administration should be approached with caution, and patients should be monitored for adverse events.
Strong CYP3A4 Inducers (e.g., Apalutamide, Rifampin)	Decreased serum concentration	Induction of CYP3A4-mediated metabolism	Risk of sub-therapeutic exposure and reduced efficacy. Avoid co-administration if possible.
Other OATP1B1 Substrates/Inhibitors (e.g., Atorvastatin, Digoxin, Erythromycin)	Increased serum concentration (Decreased excretion)	Competitive inhibition of OATP1B1 transport	Potential for increased Gimatecan exposure and toxicity. Monitor for adverse events when co-administered.

This table is not exhaustive but highlights key interaction classes based on available data.[1]

Regulatory Status and Future Outlook

Regulatory Designations and Development History

Gimatecan remains an investigational drug with a complex development history and specific regulatory designations that reflect its target indications.

• Development Pathway: The drug was originally developed by Sigma-Tau and has since been part of the pipelines of Novartis and, more recently, Lee's Pharmaceutical and Zhaoke (Guangzhou) Oncology Pharmaceutical Ltd..[2] This history of changing stewardship is common for investigational assets that face challenges in clinical development.
• Regulatory Status: Gimatecan has not received marketing approval from the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for any indication.[1] It is currently in Phase II of clinical development, its highest achieved stage, for the treatment of solid tumors.[10]
• Orphan Drug Designation: The EMA granted Gimatecan an active orphan designation (EU/3/03/174) for the treatment of Glioma.[10] This designation is granted to drugs intended for rare, life-threatening diseases and provides regulatory and financial incentives to encourage development, such as protocol assistance, reduced fees, and a potential for 10 years of market exclusivity in the EU upon approval. It does not, however, alter the scientific and clinical standards required for marketing authorization. No evidence of an FDA orphan drug designation for Gimatecan was found in the available documentation.[50]

Synthesis and Strategic Analysis

Gimatecan embodies the ongoing effort to optimize the camptothecin scaffold, representing a significant pharmacological advancement with a challenging clinical translation path.

• Summary of Strengths: The clear advantages of Gimatecan lie in its molecular design and preclinical performance. It possesses potent, broad-spectrum antitumor activity, including against MDR models, which is a significant advantage over its predecessors. Its high oral bioavailability, exceptional lactone stability, and long half-life offer the potential for convenient oral dosing with sustained exposure to the active drug form, a profile that is pharmacologically superior to both topotecan and irinotecan.[9]
• Summary of Weaknesses: These strengths are counterbalanced by formidable weaknesses that have emerged in the clinical setting. Its clinical efficacy has been inconsistent and, in the case of glioblastoma, disappointing. The drug is defined by a narrow therapeutic window, with severe myelosuppression as a frequent DLT. Above all, its highly variable and unpredictable pharmacokinetic profile—driven by both patient-specific factors like AGP levels and a high susceptibility to DDIs—makes it an exceptionally difficult drug to dose safely and effectively across a broad patient population.[11]
• Current Strategic Position: The current clinical development strategy, focusing on second-line pancreatic cancer and platinum-resistant ovarian cancer, appears to be a pragmatic pivot away from the challenges of CNS tumors. This approach targets diseases where topoisomerase I inhibitors have established, albeit modest, activity and where the complexities of the blood-brain barrier are not a factor. Success in these indications is now paramount to the drug's future.
• Future Outlook and Unanswered Questions: The path forward for Gimatecan is contingent on addressing several key questions. The most immediate is whether it can demonstrate a clinically meaningful benefit in the ongoing Phase II trials. A positive outcome could justify a pivotal Phase III study, but the high PK variability remains a major threat to achieving consistent results. The development of a predictive biomarker, possibly related to baseline AGP levels or transporter genetics, or the implementation of a therapeutic drug monitoring strategy could be essential to personalize dosing and unlock its therapeutic potential. Furthermore, recent and highly promising preclinical data in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) suggest a completely new and potentially more successful path forward. The reported high potency and remarkable selectivity for leukemia cells over healthy hematopoietic stem cells and cardiomyocytes present a compelling rationale for exploring Gimatecan in this hematologic malignancy.[47]

In conclusion, Gimatecan is a testament to rational drug design, yielding a camptothecin analogue with a truly optimized preclinical pharmacological profile. However, its journey illustrates the profound difficulty of translating such advantages into clinical success when faced with a challenging safety profile and extreme pharmacokinetic variability. Its ultimate fate now rests on the outcomes of its current solid tumor trials and the strategic vision to potentially explore new, perhaps more suitable, therapeutic areas like acute leukemia, where its unique properties might finally find a successful clinical application.

Works cited

1. Gimatecan: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed August 28, 2025, https://go.drugbank.com/drugs/DB06721
2. Gimatecan - Drug Targets, Indications, Patents - Patsnap Synapse, accessed August 28, 2025, https://synapse.patsnap.com/drug/b4cc2fd8f2d14169ba6b064713e2eb1c
3. Definition of gimatecan - NCI Drug Dictionary, accessed August 28, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/gimatecan
4. Pharmacology of Gimatecan; Mechanism of action, Pharmacokinetics, Uses, Effects, accessed August 28, 2025, https://www.youtube.com/watch?v=bzn-Ythoc0A
5. Cellular Basis of Antiproliferative and Antitumor Activity of the Novel Camptothecin Derivative, Gimatecan, in Bladder Carcinoma Models, accessed August 28, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC1501124/
6. Antiangiogenic Effects of the Novel Camptothecin ST1481 (Gimatecan) in Human Tumor Xenografts1 - AACR Journals, accessed August 28, 2025, https://aacrjournals.org/mcr/article/1/12/863/232316/Antiangiogenic-Effects-of-the-Novel-Camptothecin
7. GIMATECAN CAS#: 292618-32-7 - ChemicalBook, accessed August 28, 2025, https://m.chemicalbook.com/ProductChemicalPropertiesCB01011641.htm
8. Gimatecan, accessed August 28, 2025, https://access.portico.org/Portico/show?viewFile=pdf&auId=pjbf78x569b
9. Phase I and Pharmacokinetic Study of Gimatecan Given Orally Once a Week for 3 of 4 Weeks in Patients with Advanced Solid Tumors | Clinical Cancer Research - AACR Journals, accessed August 28, 2025, https://aacrjournals.org/clincancerres/article/15/1/374/73470/Phase-I-and-Pharmacokinetic-Study-of-Gimatecan
10. Lee's Pharmaceutical - Gimatecan - AdisInsight - Springer, accessed August 28, 2025, https://adisinsight.springer.com/drugs/800016903
11. A phase II trial of oral gimatecan for recurrent glioblastoma - PubMed, accessed August 28, 2025, https://pubmed.ncbi.nlm.nih.gov/23232808/
12. A Study of Oral Gimatecan in Platinum-Resistant Epithelial Ovarian, Fallopian Tube or Peritoneal Cancer | ClinicalTrials.gov, accessed August 28, 2025, https://clinicaltrials.gov/study/NCT04846842
13. Clinical pharmacokinetics of the new oral camptothecin gimatecan ..., accessed August 28, 2025, https://pubmed.ncbi.nlm.nih.gov/20007015/
14. Phase II of oral gimatecan in patients with recurrent epithelial ovarian, fallopian tube or peritoneal cancer, previously treated with platinum and taxanes - PMC, accessed August 28, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2844948/
15. GIMATECAN - precisionFDA, accessed August 28, 2025, https://precision.fda.gov/ginas/app/ui/substances/1c925db1-cac3-4e20-ae44-0290b176c9f5
16. Gimatecan|CAS 292618-32-7|DC Chemicals, accessed August 28, 2025, https://www.dcchemicals.com/product_show-Gimatecan.html
17. Gimatecan | CAS 292618-32-7 - InvivoChem, accessed August 28, 2025, https://invivochem.net/gimatecan.html
18. Gimatecan | 292618-32-7 - Sigma-Aldrich, accessed August 28, 2025, https://www.sigmaaldrich.com/US/en/product/ambeedinc/ambh9a7e9ff7?context=bbe
19. GIMATECAN - gsrs, accessed August 28, 2025, https://ginas.ncats.nih.gov/ginas/app/substance/7KKS9R192F
20. Gimatecan, a novel camptothecin with a promising preclinical profile - PubMed, accessed August 28, 2025, https://pubmed.ncbi.nlm.nih.gov/15205595/
21. Camptothecin - Wikipedia, accessed August 28, 2025, https://en.wikipedia.org/wiki/Camptothecin
22. CAS 292618-32-7 Gimatecan - BOC Sciences, accessed August 28, 2025, https://www.bocsci.com/product/gimatecan-cas-292618-32-7-89539.html
23. Gimatecan (ST1481) | Topoisomerase I Inhibitor - MedchemExpress.com, accessed August 28, 2025, https://www.medchemexpress.com/gimatecan.html
24. Gimatecan | CAS NO.:292618-32-7 - GlpBio, accessed August 28, 2025, https://www.glpbio.com/kr/gimatecan.html
25. Efficacy of the Novel Camptothecin Gimatecan against Orthotopic and Metastatic Human Tumor Xenograft Models - AACR Journals, accessed August 28, 2025, https://aacrjournals.org/clincancerres/article/10/21/7357/183520/Efficacy-of-the-Novel-Camptothecin-Gimatecan
26. Optimized Synthesis and Enhanced Efficacy of Novel Triplex ..., accessed August 28, 2025, https://pubs.acs.org/doi/10.1021/bc800494y
27. Optimized synthesis and enhanced efficacy of novel triplex-forming camptothecin derivatives based on gimatecan - PubMed, accessed August 28, 2025, https://pubmed.ncbi.nlm.nih.gov/19309124/
28. Gimatecan, 292618-32-7 - BroadPharm, accessed August 28, 2025, https://broadpharm.com/product/BP-29354
29. (PDF) A novel oral camptothecin analog, gimatecan, exhibits superior antitumor efficacy than irinotecan toward esophageal squamous cell carcinoma in vitro and in vivo - ResearchGate, accessed August 28, 2025, https://www.researchgate.net/publication/325480587_A_novel_oral_camptothecin_analog_gimatecan_exhibits_superior_antitumor_efficacy_than_irinotecan_toward_esophageal_squamous_cell_carcinoma_in_vitro_and_in_vivo
30. The novel lipophilic camptothecin analogue gimatecan is very active in vitro in human neuroblastoma: a comparative study with SN38 and topotecan - PubMed, accessed August 28, 2025, https://pubmed.ncbi.nlm.nih.gov/16139802/
31. Pharmacokinetics of gimatecan, and orally administered camptothecin analogue, in patients with malignant gliomas | Journal of Clinical Oncology - ASCO Publications, accessed August 28, 2025, https://ascopubs.org/doi/10.1200/jco.2004.22.90140.2039
32. Clinical pharmacokinetics (PK) of two oral dosing schedules of gimatecan in a phase I study: Implications for safety and efficacy - ASCO Publications, accessed August 28, 2025, https://ascopubs.org/doi/10.1200/jco.2008.26.15_suppl.2512
33. Phase I and pharmacokinetic study of gimatecan given orally once a week for 3 of 4 weeks in patients with advanced solid tumors - PubMed, accessed August 28, 2025, https://pubmed.ncbi.nlm.nih.gov/19118068/
34. Gimatecan inhibits tumor growth in patient-derived xenograft (PDX)... - ResearchGate, accessed August 28, 2025, https://www.researchgate.net/figure/Gimatecan-inhibits-tumor-growth-in-patient-derived-xenograft-PDX-models-of-esophageal_fig1_325480587
35. Gimatecan exerts potent antitumor activity against gastric cancer in vitro and in vivo via AKT and MAPK signaling pathways, accessed August 28, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5729429/
36. In Vitro and In Vivo Anticancer Activity of Gimatecan against Hepatocellular Carcinoma, accessed August 28, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5454685/
37. Gimatecan exhibits superior antitumor effect than irinotecan in vitro ..., accessed August 28, 2025, https://www.researchgate.net/figure/Gimatecan-exhibits-superior-antitumor-effect-than-irinotecan-in-vitro-and-in-vivo-a-b_fig2_325480587
38. Camptothecin (CPT) and its derivatives are known to target topoisomerase I (Top1) as their mechanism of action: did we miss something in CPT analogue molecular targets for treating human disease such as cancer? - PMC - PubMed Central, accessed August 28, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5752681/
39. High Efficacy of Intravenous Gimatecan on Human Tumor Xenografts - Anticancer Research, accessed August 28, 2025, https://ar.iiarjournals.org/content/38/10/5783
40. High Efficacy of Intravenous Gimatecan on Human Tumor Xenografts - Anticancer Research, accessed August 28, 2025, https://ar.iiarjournals.org/content/anticanres/38/10/5783.full-text.pdf
41. Gimatecan Completed Phase 1 Trials for Advanced Solid Tumors Treatment - DrugBank, accessed August 28, 2025, https://go.drugbank.com/drugs/DB06721/clinical_trials?conditions=DBCOND0030110&phase=1&purpose=treatment&status=completed
42. Study Details | A Dose Escalation of Gimatecan Administered Orally to Japanese Patients With Advanced Solid Tumor. | ClinicalTrials.gov, accessed August 28, 2025, https://www.clinicaltrials.gov/study/NCT00410358
43. Study Details | This is an Early Study to Investigate the Effect of ..., accessed August 28, 2025, https://clinicaltrials.gov/study/NCT00032903
44. Gimatecan Unknown Status Phase 2 Trials for Pancreatic Cancer Treatment - DrugBank, accessed August 28, 2025, https://go.drugbank.com/drugs/DB06721/clinical_trials?conditions=DBCOND0028482&phase=2&purpose=treatment&status=unknown_status
45. A Phase II Study Of Gimatecan (ST1481) In Locally Advanced Or Metastatic Pancreatic Cancer, accessed August 28, 2025, https://www.npcf.us/clinical-trials/a-phase-ii-study-of-gimatecan-st1481-in-locally-advanced-or-metastatic-pancreatic-cancer/
46. A phase II study of the novel oral camptothecin ST1481 in pretreated metastatic colorectal cancer (CRC) - ASCO Publications, accessed August 28, 2025, https://ascopubs.org/doi/10.1200/jco.2004.22.90140.3684
47. The Topoisomerase-I Inhibitor Gimatecan Exhibits Potent and Selective Activities Against B-Cell Precursor Acute Lymphoblastic Leukemia with a Favorable Cardiotoxicity Profile | Blood - ASH Publications, accessed August 28, 2025, https://ashpublications.org/blood/article/142/Supplement%201/4252/499965/The-Topoisomerase-I-Inhibitor-Gimatecan-Exhibits
48. Current Role of Topoisomerase I Inhibitors for the Treatment of Mesenchymal Malignancies and Their Potential Future Use as Payload of Sarcoma-Specific Antibody-Drug Conjugates, accessed August 28, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10860894/
49. Union Register of medicinal products - Public health - European ..., accessed August 28, 2025, https://ec.europa.eu/health/documents/community-register/html/mh1249.htm
50. Search Orphan Drug Designations and Approvals - accessdata.fda.gov, accessed August 28, 2025, https://www.accessdata.fda.gov/scripts/opdlisting/oopd/