Radgocitabine (DB11667): A Comprehensive Profile of an Investigational Nucleoside Analogue for Advanced Colorectal Cancer and Hematologic Malignancies

I. Introduction

Radgocitabine, identified by DrugBank Accession Number DB11667 and CAS Number 135598-68-4, is an investigational small molecule nucleoside analogue.[1] Chemically known as 2'-cyano-2'-deoxy-1-(beta-D-arabinofuranosyl)cytosine, it is also referred to by synonyms such as CNDAC, TAS-109, and DFP-10917.[1] Radgocitabine has been evaluated in clinical trials for the treatment of various malignancies, most notably advanced colorectal cancer and, more recently, acute myeloid leukemia (AML).[1] This report provides a comprehensive overview of Radgocitabine, encompassing its chemical properties, preclinical pharmacology with a focus on its unique mechanism of action, pharmacokinetic profile, clinical development journey including efficacy and safety findings across different indications, drug interaction potential, and current regulatory status. The development of Radgocitabine illustrates a strategic evolution, moving from initial studies in solid tumors to a more focused investigation in hematologic cancers, where it shows considerable promise.

II. Background and Identification

Radgocitabine is classified as an investigational small molecule drug.[1] It belongs to the chemical groups of arabinonucleosides, pyrimidine nucleosides, and more specifically, pyrimidine 2'-deoxyribonucleosides.[1] These are compounds characterized by a pyrimidine base linked to a ribose sugar moiety that lacks a hydroxyl group at the 2' position.[1] Radgocitabine is structurally an analogue of the naturally occurring nucleoside deoxycytidine.[2]

The compound has been investigated under various identifiers. TAS-109 was one of its earlier designations, particularly when studied for solid tumors like advanced colorectal cancer.[1] More recently, in the context of hematologic malignancies, it is often referred to as DFP-10917 or NS-917.[3] CNDAC is a common synonym representing its chemical nature (2'-C-cyano-2'-deoxy-1-β-D-arabino-pentofuranosylcytosine) and is also the active metabolite of the orally bioavailable prodrug sapacitabine.[2] Sapacitabine was designed to improve oral bioavailability, being converted to CNDAC (Radgocitabine) in the body.[6] While sapacitabine has its own development history, this report focuses on Radgocitabine (CNDAC) itself, which is the pharmacologically active entity administered intravenously in many trials.

Key identifiers for Radgocitabine include:

• Generic Name: Radgocitabine [1]
• DrugBank Accession Number: DB11667 [1]
• CAS Number: 135598-68-4 [1]
• Synonyms: 2'-cyano-2'-deoxy-1-(beta-D-arabinofuranosyl)cytosine, CNDAC, TAS-109, TAS 109, DFP-10917, NS-917 [1]
• UNII: 00M634HD2V [1]
• ChEBI ID: CHEBI:145435 [2]
• ChEMBL ID: CHEMBL337450 [2]
• NCI Thesaurus Code: C82697, C116744 [2]

The compound has been primarily studied for its antineoplastic activity, with initial trials focusing on advanced colorectal cancer.[1] However, its development trajectory has significantly shifted towards hematologic malignancies, particularly acute myeloid leukemia (AML), where it is currently in advanced clinical trials.[3]

III. Chemical Structure and Physicochemical Properties

A. Chemical Identifiers and Structure

Radgocitabine, systematically named (2R,3S,4S,5R)-2-(4-amino-2-oxopyrimidin-1-yl)-4-hydroxy-5-(hydroxymethyl)oxolane-3-carbonitrile, possesses a distinct chemical structure that underpins its biological activity.[2]

• SMILES (Simplified Molecular Input Line Entry System): C1=CN(C(=O)N=C1N)[C@H]2[C@H]([C@@H]([C@H](O2)CO)O)C#N [2] or n1(c(nc(cc1)N)=O)[C@H]2[C@H]([C@@H]([C@H](O2)CO)O)C#N [8]
• InChI (International Chemical Identifier): InChI=1S/C10H12N4O4/c11-3-5-8(16)6(4-15)18-9(5)14-2-1-7(12)13-10(14)17/h1-2,5-6,8-9,15-16H,4H2,(H2,12,13,17)/t5-,6+,8-,9+/m0/s1 [1]
• InChIKey: DCYBPMFXJCWXNB-JWIUVKOKSA-N [1]

B. Molecular Formula and Weight

• Chemical Formula: C10​H12​N4​O4​ [1]
• Average Molecular Weight: 252.23 g/mol [1]
• Monoisotopic Molecular Weight: 252.085854882 Da [1] (alternatively reported as 252.0859 Da [10])

C. Physicochemical Properties

The physicochemical properties of Radgocitabine are crucial for its formulation, absorption, distribution, metabolism, excretion (ADME), and interaction with biological targets. Key properties are summarized in Table 1.

Table 1: Key Chemical Identifiers and Physicochemical Properties of Radgocitabine

Property	Value	Source(s)
CAS Number	135598-68-4	1
DrugBank ID	DB11667	1
Molecular Formula	C10​H12​N4​O4​	1
Average Molecular Weight	252.23 g/mol	1
Monoisotopic Molecular Weight	252.085854882 Da	1
IUPAC Name	(2R,3S,4S,5R)-2-(4-amino-2-oxopyrimidin-1-yl)-4-hydroxy-5-(hydroxymethyl)oxolane-3-carbonitrile	2
SMILES	C1=CN(C(=O)N=C1N)[C@H]2[C@H]([C@@H]([C@H](O2)CO)O)C#N	2
InChI	InChI=1S/C10H12N4O4/c11-3-5-8(16)6(4-15)18-9(5)14-2-1-7(12)13-10(14)17/h1-2,5-6,8-9,15-16H,4H2,(H2,12,13,17)/t5-,6+,8-,9+/m0/s1	1
InChIKey	DCYBPMFXJCWXNB-JWIUVKOKSA-N	1
Water Solubility	25.1 mg/mL	ALOGPS 1
LogP (Octanol-Water)	-1.6 (ALOGPS), -2.4 (Chemaxon, XLogP3), -1.78 (ChEMBL AlogP)	1
LogS	-1	ALOGPS 1
pKa (Strongest Acidic)	13.12	Chemaxon 1
pKa (Strongest Basic)	-0.23	Chemaxon 1
Physiological Charge	0	Chemaxon 1
Hydrogen Bond Acceptor Count	7 (Chemaxon) / 8 (ChEMBL)	1
Hydrogen Bond Donor Count	3 (Chemaxon, ChEMBL) / 4 (ChEMBL Lipinski)	1
Polar Surface Area (PSA)	132.17 A˚2 (Chemaxon) / 134.39 A˚2 (ChEMBL)	1
Rotatable Bond Count	2	1
Rule of Five (Lipinski)	Yes / 0 Violations	Chemaxon 1, ChEMBL 10

The physicochemical profile of Radgocitabine, including its good water solubility (25.1 mg/mL [1]) and negative LogP values (e.g., -1.6 to -2.4 [1]), indicates a hydrophilic nature. This is consistent with its structure as a nucleoside analogue and is favorable for intravenous formulation, the primary route of administration for CNDAC. Its pKa values suggest it remains largely neutral at physiological pH.[1] These characteristics influence its behavior in aqueous biological environments, such as blood and interstitial fluid, and its ability to be taken up by cells. Cellular uptake of nucleoside analogs often relies on specific transporter proteins, such as the human equilibrative nucleoside transporter 1 (hENT1), which has been implicated for related compounds.[7] The presence of multiple hydrogen bond donors and acceptors further contributes to its polarity and interactions with biological macromolecules.

Compliance with Lipinski's Rule of Five ("Yes" [1]) generally suggests favorable oral bioavailability characteristics. While this is more directly relevant for its prodrug, sapacitabine (which was designed for oral administration), these intrinsic "drug-like" properties also play a role in the distribution and cellular permeation of intravenously administered CNDAC. Minor variations in computed values for properties like LogP, PSA, and hydrogen bond counts across different sources [1] are common, arising from the different algorithms employed by various prediction software packages. Such variations underscore the importance of experimental validation for parameters critical to drug development. These properties are fundamental to its biological activity and its journey through the body, potentially influencing factors such as differential tumor sensitivity or the development of resistance mechanisms related to cellular uptake.

IV. Preclinical Pharmacology: Mechanism of Action

Radgocitabine (CNDAC) exerts its antineoplastic effects through a distinctive mechanism involving DNA interaction, damage induction, and cell cycle perturbation, setting it apart from other nucleoside analogs.

A. Molecular Target and DNA Incorporation

Radgocitabine is an analogue of the nucleoside deoxycytidine and functions primarily as a DNA synthesis inhibitor.[2] Following administration, it is transported into cells and, after intracellular phosphorylation to its active triphosphate form (CNDAC-TP), becomes a substrate for DNA polymerases.[7] It is subsequently incorporated into newly synthesized DNA strands.[2] While some reports suggest direct inhibition of DNA polymerase activity by Radgocitabine [2], particularly at high concentrations leading to S-phase arrest [11], its most unique and extensively studied mechanism of action occurs after its incorporation into the DNA. One source clarifies that at concentrations relevant for its primary mechanism, DFP-10917 is incorporated into DNA without inhibiting DNA polymerase, and the subsequent strand breaks are key.[11]

B. Induction of DNA Damage: The "Self-Strand-Breaking" Mechanism

The hallmark of Radgocitabine's action is its ability to induce DNA strand breaks through a "self-strand-breaking" mechanism, a feature that distinguishes it from many other nucleoside analogs.6

Upon incorporation into a DNA strand, the CNDAC nucleotide undergoes a β-elimination chemical reaction.11 This process leads to the cleavage of the phosphodiester bond 3' to the incorporated analog. The CNDAC moiety then rearranges to form 2'-C-cyano-2',3'-didehydro-2',3'-dideoxycytidine (CNddC).13 Since CNddC lacks a 3'-hydroxyl group, it acts as a de facto chain terminator at the site of this newly formed single-strand break (SSB).13 The detection of CNddC in cellular DNA is considered indicative of this unique DNA self-strand-breakage event.11

These initially formed SSBs are highly problematic for the cell and can be converted into more cytotoxic double-strand breaks (DSBs) if the cell attempts to replicate its DNA in a subsequent S phase.[6] The formation of these DSBs is therefore replication-dependent and significantly contributes to the drug's lethality.

C. Role of DNA Repair Pathways

Cells possess intricate DNA repair mechanisms to counteract damage. The types of repair pathways engaged by CNDAC-induced lesions are critical to its efficacy and potential for selective tumor targeting.

CNDAC-induced SSBs can be recognized and partially mended by the transcription-coupled nucleotide excision repair (TC-NER) pathway.12 However, the more lethal DSBs, which arise from the SSBs during DNA replication, are primarily repaired by the homologous recombination (HR) pathway.6

Evidence strongly indicates that HR is a major survival mechanism for cells exposed to CNDAC. Cells deficient in key HR components, such as ATM (Ataxia Telangiectasia Mutated), Rad51, Rad51D, Xrcc3, and Brca2, exhibit markedly increased sensitivity to CNDAC, characterized by more extensive chromosomal aberrations and reduced cell viability.6 This heightened sensitivity in HR-deficient cells points to a therapeutic vulnerability that could be exploited.

Conversely, other major repair pathways appear less critical. Neither the non-homologous end-joining (NHEJ) pathway, involving proteins like DNA-PKcs and Ku80, nor the ATR (ATM and Rad3-related) signaling pathway seems to play a significant role in repairing CNDAC-induced damage or promoting cell survival following exposure.13

D. Cell Cycle Perturbations and Apoptosis Induction

The DNA damage inflicted by Radgocitabine triggers significant disturbances in cell cycle progression. A characteristic effect is cell cycle arrest, predominantly in the G2/M phase.2 This G2 arrest is a cellular response to the DNA damage, mediated by the ATR/DNA-PK (but not ATM) and the canonical Chk1-Cdc25C-Cdk1/CyclinB1 signaling pathway.16 Abrogation of this G2 checkpoint, for instance by Chk1 inhibitors, can force cells through mitosis, often leading to a transient G1 arrest before they undergo apoptosis.16

It has also been noted that brief exposure to high concentrations of DFP-10917 (CNDAC) can result in an S-phase arrest, likely due to more direct effects on DNA replication machinery under such conditions.11

Ultimately, the accumulation of unrepaired DNA damage and the sustained cell cycle disruption culminate in DNA fragmentation and the induction of tumor cell apoptosis, which is the desired therapeutic outcome.2

The mechanism of Radgocitabine appears to be schedule-dependent. Preclinical studies suggest that prolonged exposure to low concentrations of DFP-10917 (CNDAC) is optimal for inducing its characteristic DNA fragmentation, G2/M arrest, and apoptosis, leading to superior anti-tumor activity in xenograft models.[11] This contrasts with brief, high-concentration exposures, which tend to cause S-phase arrest via DNA polymerase inhibition.[11] The unique self-strand breaking mechanism, involving incorporation and subsequent β-elimination, is likely favored by sustained exposure, allowing adequate time for these processes to occur. This understanding provides a strong rationale for the continuous infusion schedules (e.g., 7-day or 14-day infusions) employed in clinical trials [11], as these regimens aim to maximize the drug's unique DNA-damaging effects rather than relying solely on general DNA polymerase inhibition. This necessity for prolonged exposure has direct implications for clinical trial design and dosing strategies, favoring continuous or frequent dosing over bolus administration.

The critical dependence on the HR pathway for repairing CNDAC-induced DSBs has significant therapeutic implications. The profound sensitization of HR-deficient cells to CNDAC [6] suggests a potential synthetic lethal interaction. Tumors with inherent defects in HR pathway components (e.g., mutations in BRCA1/2 or other HR-related genes) could be particularly susceptible to Radgocitabine. This opens a promising avenue for personalized medicine, where patients could be selected for Radgocitabine therapy based on the HR status of their tumors. While current clinical development is focused on AML, this principle could be highly relevant in other cancer types known for higher frequencies of HR deficiency, such as certain ovarian, breast, or pancreatic cancers. Future clinical investigations might benefit from stratifying patients based on HR functional status or incorporating relevant biomarkers.

While Radgocitabine is a deoxycytidine analog, sharing this classification with drugs like cytarabine and gemcitabine, its primary mechanism of action—inducing SSBs that convert to DSBs primarily repaired by HR, and its characteristic G2/M arrest—distinguishes it. For example, HR is not considered a major repair mechanism for DNA damage caused by cytarabine or gemcitabine.[6] This mechanistic divergence suggests that Radgocitabine may possess a different spectrum of clinical activity, encounter different resistance mechanisms, and exhibit unique synergistic interactions with other agents compared to more established nucleoside analogs. It could potentially be effective in tumors that have developed resistance to cytarabine or gemcitabine, provided the resistance is not due to shared mechanisms like impaired cellular uptake or deficient initial phosphorylation by deoxycytidine kinase (dCK), which is still required for CNDAC activation.[7]

V. Pharmacokinetics (PK)

The pharmacokinetic profile of Radgocitabine (CNDAC/DFP-10917) describes its absorption, distribution, metabolism, and excretion, which collectively determine the drug's exposure at the target site.

A. Administration and Dosage Forms

In clinical trials, Radgocitabine (as DFP-10917 or TAS-109) is primarily administered via continuous intravenous (IV) infusion.11 Various schedules have been explored, including 7-day or 14-day continuous infusions, typically followed by a rest period to allow for patient recovery.11

It is important to note that Radgocitabine (CNDAC) is also the active metabolite of sapacitabine, an orally bioavailable prodrug designed to enhance gastrointestinal absorption and then convert to CNDAC in the body.6 This report focuses on the PK of Radgocitabine itself, as administered intravenously or formed from its prodrug.

B. Absorption and Distribution

When administered intravenously, absorption is, by definition, 100% and immediate into the systemic circulation. Specific data on the tissue distribution of Radgocitabine from the available research are limited. However, as a nucleoside analogue, it is expected to distribute into various tissues and be taken up by cells. This uptake is likely mediated by nucleoside transporter proteins, such as hENT1, which facilitate the entry of similar nucleosides into cells.[7]

C. Metabolism

The metabolism of Radgocitabine is a critical aspect of its pharmacology:

1. Formation from Prodrug: Radgocitabine (CNDAC) is the active entity derived from the prodrug sapacitabine. Sapacitabine undergoes biotransformation by amidase enzymes present in plasma, the gut, and the liver, which cleave off its N4-palmitoyl group to release CNDAC.[2]
2. Intracellular Activation: Once CNDAC enters the target cells, it requires intracellular phosphorylation to exert its cytotoxic activity. Deoxycytidine kinase (dCK) is the key enzyme responsible for phosphorylating CNDAC to its monophosphate form (CNDAC-MP). Subsequent phosphorylations yield the active CNDAC triphosphate (CNDAC-TP), which is the actual substrate incorporated into DNA.[7]
3. Inactivation: Radgocitabine can be inactivated by the enzyme cytidine deaminase (CDA), which converts it to its corresponding uracil derivative, CNDAU (4-amino-1-(2-cyano-2-deoxy-β-D-arabinofuranosyl)-2(1H)-pyrimidinone).[11] CDA-mediated deamination is a common pathway for the catabolism and inactivation of many cytidine nucleoside analogs and can contribute to drug resistance. CNDAU has been identified and quantified as a primary metabolite of DFP-10917 in pharmacokinetic studies.[11]

D. Excretion

Detailed information on the specific excretion pathways and the extent of renal or biliary clearance for Radgocitabine itself is not extensively covered in the provided materials. For its prodrug, sapacitabine, Phase I clinical data indicated that after oral administration, sapacitabine was not detectable in urine, suggesting that the majority of the prodrug is converted to CNDAC in humans before potential excretion.[7] The excretion characteristics of CNDAC and its metabolites like CNDAU would determine their ultimate elimination from the body.

E. Dose-Proportionality and Key Parameters from Clinical Studies

Pharmacokinetic analyses from Phase 1 studies involving DFP-10917 (CNDAC) administered via continuous IV infusion have demonstrated dose-proportionality. This means that as the administered dose increases, the steady-state plasma concentration (Css) and the total drug exposure, measured by the Area Under the Curve (AUC), increase proportionally for both DFP-10917 and its primary metabolite CNDAU.11 This predictability is important for dose selection and adjustment in clinical settings. Graphical representations of these dose relationships for Css and AUC across 14-day and 7-day infusion schedules have been published.18

Preclinical and early clinical observations suggested that prolonged exposure to DFP-10917 via 14-day continuous infusion at a low concentration might offer an optimal balance of anti-tumor activity and tolerability, potentially being superior to shorter, high-dose administration schedules with respect to myelosuppression.11

Table 2: Summary of Human Pharmacokinetic Parameters of Radgocitabine (DFP-10917) from Phase 1 Studies

Parameter	14-day CIVI (Solid Tumors)	7-day CIVI (Solid Tumors)	14-day CIVI (AML)	Source(s)
Administration Route	Continuous IV Infusion	Continuous IV Infusion	Continuous IV Infusion	11
Dose Range Tested	Up to 4.0 mg/m²/day	Up to 4.0 mg/m²/day	Up to 10 mg/m²/day (Phase 1); 6 mg/m²/day (Phase 2)	11
Dose Proportionality	Yes (Css, AUC for DFP-10917 & CNDAU)	Yes (Css, AUC for DFP-10917 & CNDAU)	Implied by Phase 1 dose escalation logic	11
MTD/RP2D Established	MTD not explicitly stated for 14-day, DLTs at 4.0 mg/m²/day. RP2D for solid tumors: 2.0 mg/m²/day.	MTD: 3.0 mg/m²/day. RP2D for solid tumors: 3.0 mg/m²/day.	MTD from Phase 1: >6 mg/m²/day but <10 mg/m²/day. RP2D for AML: 6 mg/m²/day for 14-day CIVI + 14-day rest.	11
Primary Metabolite(s)	CNDAU	CNDAU	CNDAU	11
Key PK Observations	Dose-proportional Css & AUC.	Dose-proportional Css & AUC.	6 mg/m²/day for 14-day CIVI well-tolerated in Phase 2.	11

The metabolic activation of CNDAC by dCK and its potential inactivation by CDA are critical determinants of its efficacy.[7] Low dCK levels or high CDA activity within tumor cells are well-known mechanisms of resistance to other cytidine nucleoside analogs like cytarabine. Therefore, variability in the expression or activity of these enzymes could significantly influence patient response to Radgocitabine and may contribute to acquired resistance. While sapacitabine (the prodrug) reportedly showed some activity against dCK-deficient cells in preclinical models, possibly due to its palmitoyl moiety facilitating uptake or an alternative activation step for the prodrug itself [7], CNDAC formed from it or administered directly would still likely depend on dCK for its primary intracellular activation. This reliance on specific enzymes opens potential avenues for exploring predictive biomarkers or developing strategies to modulate these enzyme activities, such as co-administering CDA inhibitors, although such combinations were not detailed in the provided materials.

The dose-proportional pharmacokinetics observed with continuous IV infusion [11] provide a predictable relationship between dose and drug exposure, which is advantageous for clinical use. The rationale for continuous infusion is further strengthened by the understanding of its mechanism of action: sustained drug levels achieved through continuous infusion maximize the probability of cancer cells entering the S-phase (DNA synthesis phase) in the presence of the drug. This is crucial for CNDAC's incorporation into DNA and the subsequent multi-step process of strand break formation, which often requires progression through a second S-phase for the conversion of SSBs to lethal DSBs.[6] Consequently, bolus dosing or intermittent schedules might be less effective at leveraging CNDAC's unique DNA self-strand breaking properties. However, continuous infusion regimens can be inconvenient for patients and logistically demanding. The reported development of a PEGylated form of DFP-10917, named DFP-14927, aims to achieve longer circulation and sustained exposure with potentially less frequent administration.[18] If successful, such a formulation could represent a significant improvement in drug delivery and patient convenience.

VI. Clinical Development and Efficacy

Radgocitabine, under various identifiers (TAS-109, DFP-10917, CNDAC), has undergone clinical investigation across different cancer types, with a notable shift in focus over time.

A. Advanced Colorectal Cancer (ACC)

Initial clinical development efforts for Radgocitabine (as TAS-109) included studies in patients with advanced colorectal cancer.1

The most significant trial in this indication was NCT00824161, a Phase II study designed to evaluate TAS-109 in patients with advanced colorectal cancer.3

• Purpose (NCT00824161): The primary objective was to assess progression-free survival (PFS). Secondary objectives included the evaluation of antitumor activity (measured by objective tumor response), duration of clinical benefit, overall survival (OS), and the safety profile of TAS-109.[4]
• Sponsor (NCT00824161): Taiho Pharmaceutical Co., Ltd..[3]
• Status (NCT00824161): This trial was terminated.[3]

The development of Radgocitabine for advanced colorectal adenocarcinoma and refractory colorectal carcinoma reached Phase 2 but was ultimately unsuccessful.[3] Results from the NCT00824161 trial, published in Investigational New Drugs (October 2018), indicated that single-agent DFP-10917 (TAS-109) did not demonstrate meaningful antitumor activity in patients with chemotherapy-refractory advanced CRC.[3] The study analyzed 28 patients, with 26 receiving DFP-10917.[3] Efficacy was limited: only 3 patients (12%) were progression-free at 3 months, the median PFS was a mere 1.3 months, and no complete or partial responses were observed.[15] Consequently, development in this indication was discontinued due to this lack of efficacy.

It is crucial to distinguish Radgocitabine (TAS-109) from TAS-102 (trifluridine/tipiracil). TAS-102 is a different oral antimetabolite combination drug that has shown efficacy and is approved for use in metastatic colorectal cancer.[4] The similar "TAS" prefix can lead to confusion, but TAS-109 (Radgocitabine) did not achieve positive outcomes in ACC.

B. Hematologic Malignancies (Acute Myeloid Leukemia - AML, Acute Lymphoblastic Leukemia - ALL)

Following the disappointing results in solid tumors, the clinical development of Radgocitabine (primarily as DFP-10917 or NS-917) strategically pivoted towards hematologic malignancies, where it has shown more encouraging signals, particularly in AML.[3] This area now represents the major focus of its ongoing development.

Key clinical trials in hematologic malignancies include:

• NCT01702155: A Phase 1/2 study evaluating DFP-10917 administered by continuous infusion in patients with relapsed or refractory acute leukemia (both AML and ALL).[3]
• Sponsor: Delta-Fly Pharma, Inc..[3]
• Status: The trial is completed. While reporting on ClinicalTrials.gov was noted as overdue in May 2025 [29], key results have been published.[15]
• Regimen & RP2D: The study explored 7-day and 14-day continuous IV infusion (CIVI) schedules. The Recommended Phase 2 Dose (RP2D) for AML was established as 6 mg/m²/day administered as a 14-day CIVI, followed by a 14-day rest period.[15]
• Efficacy (Phase 2 AML cohort, N=29): The Overall Response Rate (ORR) was 48.3%, which included Complete Response (CR) in 20.7%, CR with incomplete platelet recovery (CRp) in 3.4%, and CR with incomplete blood count recovery (CRi) in 24.1% of patients.[19] The median OS was reported as 6.9 months, and the median duration of response was 3.5 months.[15] The trial was evaluated as positive.[3]
• NCT03926624: A Phase 3, multicenter, randomized trial comparing DFP-10917 monotherapy against investigator's choice of therapy (either non-intensive reinduction regimens like LoDAC, azacitidine, decitabine, or venetoclax combinations; or intensive reinduction with high/intermediate dose cytarabine regimens) in AML patients in their second, third, or fourth salvage setting.[3]
• Sponsor: Delta-Fly Pharma, Inc..[3]
• Status: Recruiting. As of April 2023, 150 patients had been enrolled, with an interim analysis planned.[30] Updates in December 2024 indicated that data cleaning processes for this interim analysis were underway.[3]
• Experimental Arm Regimen: DFP-10917 at 6 mg/m²/day via 14-day CIVI, followed by a 14-day rest period, per 28-day cycle.[3]
• NCT06382168: A Phase 1/2 study investigating DFP-10917 in combination with Venetoclax for patients with relapsed or refractory AML, typically as second-line therapy.[3]
• Sponsor: Delta-Fly Pharma, Inc..[3]
• Status: Recruiting. As of February/March 2025, the Data Monitoring Committee (DMC) approved the tolerability of the initial dose level in all six patients enrolled in the Phase 1 dose-finding portion. The study is proceeding to the Phase 2 expansion cohort.[3]
• Regimen: DFP-10917 (starting dose of 4 mg/m²/day for 14-day CIVI) administered concurrently with Venetoclax (400 mg daily for 14 days, following an initial ramp-up).[3]
• Early Results (Phase 1): Highly encouraging early data from the first three patients showed good safety and efficacy, with all three achieving CR or CRi, and bone marrow blast counts reducing to zero within four weeks of starting treatment. These responses were observed even in patients who had previously failed venetoclax-based therapies.[3]
• JPRN-jRCT2031210452: A Phase 1 study of NS-917 (Radgocitabine) in Japanese patients with relapsed or refractory AML.[3]
• Sponsor: Nippon Shinyaku Co., Ltd..[3]
• Status: Recruiting, with a start date of February 17, 2022.[3]

The ORR of 48.3% achieved with DFP-10917 monotherapy in a heavily pretreated R/R AML population (NCT01702155 [19]) is a noteworthy finding. Furthermore, the early positive signals from the DFP-10917 plus venetoclax combination trial (NCT06382168 [3]) suggest a promising path forward for this drug in AML.

C. Other Investigated Indications (Solid Tumors - Phase 1)

Initial Phase 1 dose-escalation studies of DFP-10917 included patients with refractory solid tumors, employing both 14-day and 7-day continuous infusion schedules (data published under PMID:29667134, corresponding to [11]). Across these studies, 29 patients with solid tumors were dosed. While the primary aim was to determine MTD and RP2D, some efficacy data were reported: eight patients experienced stable disease for more than 12 weeks. However, no objective responses (complete or partial) were specifically mentioned for the solid tumor cohorts in these early reports. The RP2Ds established from these studies for solid tumors were 2.0 mg/m²/day for the 14-day CIVI schedule and 3.0 mg/m²/day for the 7-day CIVI schedule.[11] It is important to note that the RP2D later established for AML (6 mg/m²/day for 14-day CIVI [19]) was higher, potentially reflecting different tolerability or therapeutic windows between these distinct patient populations.

The clear disparity in outcomes—lack of meaningful activity in advanced CRC versus promising efficacy signals in R/R AML—underpins the significant strategic pivot in Radgocitabine's development. This shift suggests that leukemic cells may exhibit greater sensitivity to CNDAC's unique DNA-damaging mechanism, or that factors such as drug delivery and penetration are more favorable in a systemic disease like AML compared to solid tumors. The rapid proliferation characteristic of AML cells could also render them particularly vulnerable to an agent that disrupts DNA synthesis and integrity. Consequently, Radgocitabine's future clinical utility appears to be predominantly in the realm of hematologic malignancies, with the ongoing Phase 3 trial in AML (NCT03926624) being a critical determinant of its potential role.

The initiation of the combination trial with venetoclax (NCT06382168) and its highly encouraging preliminary results [3] underscore the importance of exploring combination strategies, especially in the challenging R/R AML setting where monotherapy efficacy can be transient. Venetoclax, a BCL-2 inhibitor, has significantly impacted AML treatment, and its combination with a cytotoxic agent like DFP-10917, which has a distinct mechanism of action, offers a rational approach to potentially enhance efficacy and overcome resistance. Success in this combination study could establish a new, effective salvage regimen for AML patients, including those who have relapsed after prior venetoclax-containing therapies.

The difference in RP2Ds established for solid tumors (2-3 mg/m²/day [11]) versus AML (6 mg/m²/day [19]) for similar 14-day CIVI schedules is notable. This could be attributed to various factors, including differing tolerability profiles in distinct patient populations (e.g., solid tumor patients may present with different comorbidities or baseline organ function), different therapeutic indices for the drug in these diseases, or an evolution in the understanding of the drug's activity and safety profile as more clinical data became available. It is plausible that hematologic malignancies can tolerate, or indeed require, higher doses of Radgocitabine to achieve clinically meaningful responses, and this higher dose intensity might contribute to the more favorable outcomes observed in AML compared to solid tumors. This highlights the indication-specific nature of dose optimization, which is crucial for balancing efficacy and toxicity.

Table 3: Summary of Key Clinical Trials with Radgocitabine (CNDAC/TAS-109/DFP-10917)

NCT Identifier	Phase	Indication(s)	Drug Name Used	Sponsor	Key Regimen(s)	Patients (N)	Key Efficacy Outcomes	Clinical Evaluation/Status	Source(s)
NCT00824161	II	Advanced Colorectal Cancer (ACC), Refractory Colorectal Carcinoma	TAS-109/DFP-10917	Taiho Pharmaceutical Co.	DFP-10917 monotherapy	28 (26rx)	Median PFS 1.3 months; No CR/PR; 12% PFS at 3 months.	Negative; Terminated. Did not show meaningful antitumor activity.	3
NCT01702155	I/II	Relapsed/Refractory Acute Leukemia (AML, ALL)	DFP-10917	Delta-Fly Pharma, Inc.	DFP-10917 7-day or 14-day CIVI. RP2D for AML: 6 mg/m²/day for 14-day CIVI + 14-day rest.	29 (AML Ph2)	AML: ORR 48.3% (CR 20.7%, CRp 3.4%, CRi 24.1%); Median OS 6.9 mo; Median DoR 3.5 mo.	Positive for AML; Completed. RP2D established. Results published, reporting on CT.gov overdue.	3
NCT03926624	III	Acute Myelogenous Leukemia (AML) (2nd, 3rd, or 4th salvage)	DFP-10917	Delta-Fly Pharma, Inc.	DFP-10917 6 mg/m²/day 14-day CIVI + 14-day rest vs. Investigator Choice (Non-Intensive or Intensive Reinduction)	150 enrolled	Primary: CR rate. Secondary: OS. Interim analysis planned.	Recruiting. Interim analysis data cleaning underway.	3
NCT06382168	I/II	Relapsed/Refractory Acute Myeloid Leukemia (AML) (second-line therapy)	DFP-10917	Delta-Fly Pharma, Inc.	DFP-10917 (start 4 mg/m²/day 14-day CIVI) + Venetoclax (400 mg daily for 14 days).	6 (Ph1)	Early (first 3 pts): CR/CRi in all 3, marrow blasts 0 within 4 weeks.	Recruiting. Phase 1 tolerability approved by DMC, moving to Phase 2.	3
JPRN-jRCT2031210452	I	Relapsed/Refractory Acute Myeloid Leukemia (AML) (Japanese patients)	NS-917	Nippon Shinyaku Co., Ltd.	NS-917 monotherapy	N/A	Safety, PK, MTD.	Recruiting.	3
PMID:29667134	I	Refractory Solid Tumors	DFP-10917	Not specified in abstract	DFP-10917 14-day CIVI (RP2D: 2.0 mg/m²/day) or 7-day CIVI (RP2D: 3.0 mg/m²/day).	29	8 patients had stable disease >12 weeks. No objective responses mentioned for solid tumors.	Completed. RP2Ds for solid tumors established.	11

CIVI: Continuous Intravenous Infusion; CR: Complete Response; CRp: CR with incomplete platelet recovery; CRi: CR with incomplete blood count recovery; DoR: Duration of Response; MTD: Maximum Tolerated Dose; N/A: Not Available; ORR: Overall Response Rate; OS: Overall Survival; PFS: Progression-Free Survival; Ph: Phase; RP2D: Recommended Phase 2 Dose; rx: received treatment.

VII. Safety and Tolerability Profile

The safety and tolerability of Radgocitabine have been evaluated across its clinical development program, revealing a consistent pattern of adverse events, with myelosuppression being the most prominent.

A. Overview of Adverse Events (AEs) Across Clinical Trials

• Solid Tumors (Phase 1, DFP-10917): In early Phase 1 studies involving patients with refractory solid tumors, common toxicities associated with DFP-10917 (administered via 7-day or 14-day continuous infusions) included nausea, vomiting, diarrhea, neutropenia, and alopecia. Myelosuppression was identified as the principal dose-limiting toxicity.[11]
• Advanced Colorectal Cancer (Phase 2, DFP-10917/TAS-109, NCT00824161): In the Phase 2 trial for advanced colorectal cancer, the most frequently reported medication-related adverse events of Grade 3 or higher were neutropenia (occurring in 38% of patients), fatigue (15%), anemia (12%), and leukopenia (12%). Despite these toxicities, the overall safety profile of DFP-10917 in this patient population was considered tolerable.[15]
• Acute Myeloid Leukemia (Phase 1/2, DFP-10917, NCT01702155): In patients with relapsed or refractory AML, the main drug-related AEs of Grade 3 or higher severity were hematologic: neutropenia (50%), thrombocytopenia (43%), and anemia (37%).[15] Mild to moderate (Grade 1-2) drug-related gastrointestinal adverse events were also frequently observed (in 43% of patients), along with fatigue (13%).[15] Importantly, no patients in the Phase 2 portion of this study discontinued DFP-10917 treatment due to unacceptable drug-related toxicity, indicating that the regimen was manageable in this challenging patient population.[15]

B. Dose-Limiting Toxicities (DLTs)

The determination of DLTs was a key objective in the Phase 1 studies to establish the MTD and RP2D:

• Solid Tumors (14-day CIVI): Dose-limiting toxicities, consisting of febrile neutropenia and thrombocytopenia, occurred at a dose of 4.0 mg/m²/day. At 3.0 mg/m²/day, three patients experienced neutropenia during the second cycle of treatment. A dose of 2.0 mg/m²/day was found to be well tolerated and was recommended for further study in solid tumors.[11]
• Solid Tumors (7-day CIVI): Grade 4 neutropenia was the DLT observed at 4.0 mg/m²/day. The MTD for this schedule was determined to be 3.0 mg/m²/day.[11]
• Acute Myeloid Leukemia (NCT01702155, Phase 1 portion):
• 7-day CIVI (Stage 1): A DLT of Grade 3 diarrhea was reported at a dose of 35 mg/m²/day.[19] This dose is substantially higher than those used in other schedules and may reflect a different initial dosing strategy or context.
• 14-day CIVI (Stage 2): A dose of 10 mg/m²/day resulted in DLTs including prolonged hypocellularity, abdominal pain, diarrhea, and vomiting. The dose of 6 mg/m²/day administered as a 14-day CIVI was found to be well tolerated and was selected as the RP2D for Phase 2 studies in AML.[19]
• Acute Myeloid Leukemia (Combination with Venetoclax, NCT06382168): DLTs are a primary outcome measure and are closely monitored by a Data Monitoring Committee (DMC). The initial dose level of DFP-10917 (4 mg/m²/day for 14 days) in combination with venetoclax (400 mg daily for 14 days) was deemed tolerable in the first six patients enrolled in the Phase 1 portion, allowing the study to proceed to Phase 2 expansion.[3]

C. Management of Toxicities

Specific details on the management protocols for Radgocitabine-induced toxicities are not extensively provided in the research snippets. However, standard supportive care measures would typically be employed. These would include interventions for myelosuppression, such as the administration of granulocyte colony-stimulating factors (G-CSF) for neutropenia, platelet transfusions for thrombocytopenia, and red blood cell transfusions for anemia. Gastrointestinal toxicities like nausea, vomiting, and diarrhea would be managed with appropriate antiemetics and antidiarrheal agents. In one AML trial (NCT06382168), the use of hydroxyurea was permitted to control leukocytosis.[20]

D. Safety in Specific Populations

Information regarding safety in specific subpopulations is primarily gleaned from exclusion criteria in clinical trial protocols. For instance, the DFP-10917 plus venetoclax trial in AML (NCT06382168) excluded patients with: greater than Grade 1 persistent clinically significant toxicities from prior chemotherapy, very high leukemic blast counts (>25 × 109/L), known history of HIV or active hepatitis B or C infection, other concomitant malignancies for which they are receiving active therapy, prior hematopoietic stem cell transplantation (HSCT), malabsorption syndrome, or active uncontrolled systemic infections. Pregnant or lactating women were also excluded, and stringent contraceptive measures were required for female patients of childbearing potential and male patients with partners of childbearing potential.[20] These criteria highlight populations where safety is a particular concern or remains uninvestigated.

Myelosuppression consistently emerges as the most significant and often dose-limiting toxicity of Radgocitabine across different cancer indications (solid tumors, CRC, AML) and administration schedules.[11] This is a characteristic side effect of many nucleoside analogs that interfere with DNA synthesis, as rapidly dividing hematopoietic progenitor cells are highly susceptible to such agents. The drug's mechanism, which involves inducing DNA strand breaks, would likely exacerbate this effect. Effective management of myelosuppression is therefore paramount for the clinical application of Radgocitabine. This involves careful dose selection, adherence to planned cycle schedules with adequate rest periods to allow for bone marrow recovery, prophylactic use of growth factors like G-CSF where appropriate, and vigilant monitoring of blood counts. The severity of myelosuppression could potentially limit its use in heavily pretreated or frail patient populations.

Despite the hematological toxicities, the RP2D of 6 mg/m²/day for a 14-day CIVI was reported as well-tolerated in patients with R/R AML in the NCT01702155 study, with no patients discontinuing treatment due to drug-related toxicity in the Phase 2 component.[15] Similarly, the initial dose level of DFP-10917 in combination with venetoclax appears to be manageable based on early DMC reviews.[3] This suggests that a therapeutic window exists, particularly in the AML population, where antileukemic activity can be achieved with a manageable toxicity profile, especially considering the aggressive nature of R/R AML and the limited therapeutic options. These findings provide a degree of confidence for the ongoing Phase 3 trial of DFP-10917 monotherapy in AML. However, long-term safety and the potential for cumulative toxicities will require continued careful monitoring. The safety profile of the combination with venetoclax will be particularly important to delineate, as venetoclax itself can cause myelosuppression, and overlapping toxicities will need to be managed proactively.

Table 4: Profile of Common and Serious Adverse Events (≥Grade 3) Associated with Radgocitabine (DFP-10917/TAS-109)

Indication	Trial ID / Study Context	Radgocitabine Dose/Schedule	Key Adverse Event (≥Grade 3 unless specified)	Frequency (%) (if available)	Source(s)
Solid Tumors	Phase 1 (PMID:29667134)	14-day CIVI (up to 4 mg/m²/d); 7-day CIVI (up to 4 mg/m²/d)	DLTs: Febrile neutropenia, thrombocytopenia (14-day, 4 mg/m²/d); Grade 4 neutropenia (7-day, 4 mg/m²/d). Common AEs (any grade): Nausea, vomiting, diarrhea, neutropenia, alopecia.	DLTs at specific doses	11
Advanced Colorectal Cancer	NCT00824161 (Phase 2)	DFP-10917 monotherapy	Neutropenia (38%), Fatigue (15%), Anemia (12%), Leukopenia (12%).	As listed	15
Acute Myeloid Leukemia (Monotherapy)	NCT01702155 (Phase 1/2)	DFP-10917 6 mg/m²/day, 14-day CIVI + 14-day rest (Phase 2)	Neutropenia (50%), Thrombocytopenia (43%), Anemia (37%). Common GI AEs (Grade 1-2): 43%. Fatigue (Grade 1-2): 13%. DLTs (Phase 1): Diarrhea (7-day, 35 mg/m²/d); Prolonged hypocellularity, abdominal pain, diarrhea, vomiting (14-day, 10 mg/m²/d).	As listed for Ph2; DLTs specific to Ph1 doses	15
Acute Myeloid Leukemia (Combination w/ VEN)	NCT06382168 (Phase 1)	DFP-10917 4 mg/m²/day, 14-day CIVI + Venetoclax 400 mg daily	DLTs are primary outcome; initial dose deemed tolerable by DMC in first 6 patients. Specific AE frequencies not yet detailed.	N/A (early phase)	3

CIVI: Continuous Intravenous Infusion; DLT: Dose-Limiting Toxicity; VEN: Venetoclax; GI: Gastrointestinal; Ph: Phase.

VIII. Drug Interactions and Combination Strategies

The unique mechanism of action of Radgocitabine (CNDAC), particularly its reliance on specific DNA repair pathways, provides a strong rationale for exploring combination therapies to enhance its antitumor effects or overcome resistance.

A. Preclinical Evidence of Synergism or Additive Effects

Preclinical studies have investigated the interaction of CNDAC with various chemotherapeutic agents, revealing both synergistic and additive effects [14]:

• Synergistic Interactions:
• c-Abl Kinase Inhibitors: The c-Abl kinase inhibitor imatinib demonstrated synergy with CNDAC in HCT116 colon cancer cells, irrespective of their p53 status.[14]
• PARP Inhibitors: Inhibitors of Poly(ADP-ribose) polymerase 1 (PARP1), such as olaparib, veliparib, talazoparib, and rucaparib, which interfere with homologous recombination (HR) repair or base excision repair (BER), showed synergistic cell killing with CNDAC.[14] This is highly relevant given CNDAC's induction of DNA strand breaks that are substrates for these repair pathways.
• BER-Targeting Agents: Agents like temozolomide, which cause DNA damage that is primarily repaired by the BER pathway, also exhibited synergistic effects when combined with CNDAC.[14]
• Additive Interactions:
• DNA Damaging Agents (NER/HR substrates): Nitrogen mustards (e.g., bendamustine, cyclophosphamide/cytoxan) and platinum compounds (e.g., cisplatin, oxaliplatin), which generate DNA adducts repaired by nucleotide excision repair (NER) and HR, resulted in additive toxicity with CNDAC.[14]
• Mitotic Inhibitors: Taxanes, such as paclitaxel and docetaxel, which disrupt microtubule function and affect mitosis, also produced additive cell killing when combined with CNDAC.[14]
• Sapacitabine (Prodrug) Combinations: Preclinical studies with sapacitabine (the prodrug of CNDAC) indicated synergistic effects when combined with gemcitabine, and sequence-specific synergy with doxorubicin and oxaliplatin.[7]

B. Clinically Investigated Combinations

The most prominent clinically investigated combination involving Radgocitabine is:

• DFP-10917 with Venetoclax: This combination is currently under evaluation in the NCT06382168 Phase 1/2 trial for patients with relapsed or refractory AML.[3] As previously noted, early results from the Phase 1 portion have been highly encouraging, with the Data Monitoring Committee approving the tolerability of the initial dose level and reports of complete remissions in the first few patients treated.[3] It is worth noting that the ongoing Phase 3 trial NCT03926624 for DFP-10917 monotherapy in AML includes control arms where patients may receive venetoclax-based combination regimens; however, this is as a comparator treatment, not DFP-10917 in direct combination within that trial design.[3]

C. Potential Pharmacokinetic or Pharmacodynamic Interactions

Specific pharmacokinetic drug-drug interaction studies involving Radgocitabine were not detailed in the provided research materials. The observed synergistic or additive effects in preclinical models are primarily pharmacodynamic in nature, arising from the drugs targeting complementary or interacting cellular pathways, particularly those involved in DNA damage response and cell cycle control.

The metabolism of CNDAC, involving activation by deoxycytidine kinase (dCK) and inactivation by cytidine deaminase (CDA) 7, theoretically suggests that co-administered drugs which induce or inhibit these enzymes could alter CNDAC's pharmacokinetic profile and efficacy. However, no specific interactions of this type were documented in the available snippets.

The robust preclinical data supporting combinations of CNDAC with agents targeting DNA repair pathways, especially PARP inhibitors, offer a compelling rationale for future clinical development. CNDAC induces SSBs and DSBs; if cancer cells rely on HR or BER for survival following this damage, concurrent inhibition of these pathways (e.g., by a PARP inhibitor) could lead to synthetic lethality, significantly enhancing tumor cell kill. This is a well-established therapeutic concept, and its application with CNDAC could be particularly potent in tumors already harboring HR deficiencies, where CNDAC monotherapy is expected to be more active. The observed synergy with imatinib also warrants further investigation, potentially in specific leukemia subtypes where Abl kinase signaling is pertinent.

The ongoing clinical trial combining DFP-10917 with venetoclax (NCT06382168) represents the first significant clinical step in realizing Radgocitabine's combination potential. While preclinical data did not specifically test CNDAC with venetoclax, the latter's mechanism as a BCL-2 inhibitor (promoting apoptosis) is mechanistically complementary to CNDAC's action (inducing DNA damage that ultimately triggers apoptosis). Combining a direct DNA damaging agent with a pro-apoptotic drug that lowers the threshold for cell death is a rational and often effective strategy in oncology. The positive early signals from this trial [3] are therefore highly significant. If this combination proves successful, it could establish a valuable new treatment option for R/R AML and encourage the exploration of other mechanistically sound combinations in hematologic malignancies.

Furthermore, the additive effects observed with standard cytotoxic agents like platinum compounds, nitrogen mustards, and taxanes [14] suggest a broader potential for integrating CNDAC into existing chemotherapy regimens. While additivity is less potent than synergy, it can still provide clinical benefit if toxicities are non-overlapping or manageable. However, careful consideration of cumulative toxicities, particularly myelosuppression, would be essential in designing such combination regimens.

IX. Regulatory Status and Development Outlook

A. Orphan Drug Designations

Radgocitabine has achieved a significant regulatory milestone in the United States:

• FDA (USA): Granted Orphan Drug Designation for the treatment of Acute Myeloid Leukemia (AML) on November 28, 2022. The sponsor for this designation is Delta-Fly Pharma, Inc..[5] It is important to note that while Radgocitabine has this designation, it is not yet FDA approved for this (or any other) orphan indication.[27] Information regarding orphan drug designations by the European Medicines Agency (EMA) was not available in the provided research materials.[28]

B. Status with Major Regulatory Agencies (FDA, EMA)

• FDA: Beyond the Orphan Drug Designation for AML, Radgocitabine (as DFP-10917) is actively being evaluated in clinical trials in the US. A pivotal Phase 3 trial (NCT03926624) in R/R AML is ongoing, with an interim analysis anticipated that could potentially support a New Drug Application (NDA) submission.[3] Additionally, the Phase 1/2 combination trial with venetoclax (NCT06382168) is active in the US.[3]
• EMA: No specific marketing authorizations, scientific advice documents, or other regulatory approvals for Radgocitabine, DFP-10917, or CNDAC from the EMA were identified in the provided materials.[28]

C. Key Developers and Sponsors

Several entities have been involved in the development of Radgocitabine under its various codenames:

• Delta-Fly Pharma, Inc.: Currently appears to be the primary developer driving the clinical program for DFP-10917, particularly in hematologic malignancies (AML) in the United States.[3]
• Nippon Shinyaku Co., Ltd.: Is listed as a developer for NS-917 (Radgocitabine) in Japan, sponsoring a Phase 1 trial in AML (JPRN-jRCT2031210452).[3]
• Taiho Pharmaceutical Co., Ltd.: Was the sponsor for the earlier Phase 2 trial of TAS-109 in advanced colorectal cancer (NCT00824161).[3]

D. Current Highest Phase of Development by Indication

Based on the available information, the highest phases of development for Radgocitabine are:

• Refractory Acute Myeloid Leukemia (AML), Monotherapy: Phase 3 (DFP-10917, NCT03926624, United States).[3]
• Relapsing/Refractory AML, Combination with Venetoclax: Phase 1/2 (DFP-10917, NCT06382168, United States).[3]
• Relapsing/Refractory AML, Monotherapy (Japan): Phase 1 (NS-917, JPRN-jRCT2031210452).[3]
• Acute Leukemia (general) and Acute Lymphoblastic Leukemia (ALL): Previously reached Phase 2 (DFP-10917, as part of NCT01702155, US), but the current development focus appears more specifically targeted towards AML.[3]
• Advanced Colorectal Adenocarcinoma / Refractory Colorectal Carcinoma: Phase 2 (TAS-109, NCT00824161, US). Development in this indication is considered inactive or terminated due to negative clinical trial results.[3]
• Precursor cell lymphoblastic leukaemia-lymphoma: No development reported for this specific indication.[5]

E. Future Perspectives, Unmet Needs, and Potential Challenges

The development of Radgocitabine is now clearly centered on AML, a disease with a significant unmet medical need, particularly in the relapsed or refractory setting where treatment options are limited and outcomes are often poor. The success of the ongoing Phase 3 monotherapy trial (NCT03926624) and the Phase 1/2 venetoclax combination trial (NCT06382168) will be critical in defining its future role.

A significant opportunity lies in the potential for biomarker-driven patient selection. The strong preclinical rationale for heightened sensitivity in HR-deficient cells 6 remains largely unexplored in the clinical setting for Radgocitabine but could substantially refine its therapeutic application.

Challenges in development include the effective management of its primary toxicity, myelosuppression, the potential for emergence of drug resistance mechanisms (e.g., alterations in dCK or CDA activity), and the competitive landscape of novel AML therapies.

The development of a long-acting formulation, such as the PEGylated CNDAC derivative DFP-14927 18, is an interesting prospect. Such a formulation could potentially improve patient convenience by allowing less frequent administration compared to continuous infusion and might alter the therapeutic index, but this is at an early stage of development.

The FDA's granting of Orphan Drug Designation for AML [27] is a significant regulatory acknowledgment that incentivizes continued development for this indication. This, combined with the advanced phase of the ongoing trials, particularly the Phase 3 study (NCT03926624) and the promising early data from the venetoclax combination study (NCT06382168 [3]), signals a concentrated effort by Delta-Fly Pharma to establish DFP-10917 as a therapeutic option in AML. This strategic focus on AML contrasts sharply with the terminated development in colorectal cancer. Radgocitabine's best prospect for regulatory approval and clinical utility in the foreseeable future lies within the R/R AML patient population.

The involvement of multiple pharmaceutical entities in Radgocitabine's development journey—Taiho Pharmaceutical for its early solid tumor exploration, and now Delta-Fly Pharma and Nippon Shinyaku for its hematologic malignancy focus—suggests a common pattern of regional partnerships and licensing agreements in drug development. This can accelerate progress in different geographical regions by leveraging local expertise and market access but also adds layers of complexity to global strategy and data consolidation. Success in one region or by one partner can positively influence regulatory perceptions and further investment by others.

X. Conclusion

Radgocitabine (CNDAC/DFP-10917) is an investigational nucleoside analogue characterized by a unique DNA self-strand breaking mechanism that distinguishes it from other agents in its class. Its incorporation into DNA leads to single-strand breaks which can convert to lethal double-strand breaks, particularly engaging the homologous recombination repair pathway and inducing G2/M cell cycle arrest and apoptosis.

The clinical development of Radgocitabine has been marked by a significant strategic pivot. Initial investigations in advanced colorectal cancer (as TAS-109) did not yield sufficient efficacy, leading to the discontinuation of development in that indication. Subsequently, efforts were refocused on hematologic malignancies, primarily relapsed or refractory acute myeloid leukemia (R/R AML), where Radgocitabine (as DFP-10917) has demonstrated promising signals of activity. As a monotherapy, it achieved a notable overall response rate in R/R AML patients, leading to its advancement into Phase 3 clinical trials. Furthermore, early results from a Phase 1/2 study combining DFP-10917 with venetoclax in R/R AML have been highly encouraging, suggesting potential for synergistic efficacy. This progress has been recognized with an FDA Orphan Drug Designation for AML.

Myelosuppression, particularly neutropenia and thrombocytopenia, stands out as the primary dose-limiting toxicity of Radgocitabine, necessitating careful patient monitoring and management. However, at the recommended Phase 2 dose for AML, the toxicity profile has been considered manageable.

Currently, Radgocitabine's most promising therapeutic niche appears to be in the treatment of R/R AML. The outcomes of the ongoing pivotal Phase 3 monotherapy trial and the combination study with venetoclax will be crucial in determining its future role. Its unique mechanism of action holds potential for overcoming resistance to existing therapies and for effective use in rationally designed combination regimens. The strong preclinical evidence of heightened activity in cells with homologous recombination deficiency also suggests a future avenue for biomarker-guided patient selection, although this has yet to be clinically validated for Radgocitabine.

In conclusion, Radgocitabine represents a noteworthy example of the iterative nature of oncology drug development. Despite initial setbacks in solid tumors, its distinct mechanism and subsequent positive findings in AML have revitalized its clinical prospects. If current advanced-phase trials confirm its efficacy and manageable safety, Radgocitabine could emerge as a valuable new therapeutic option for patients with difficult-to-treat acute myeloid leukemia, addressing a significant unmet medical need. Continued research will be essential to fully delineate its optimal use, including identifying the most effective combination strategies and patient populations likely to derive maximum benefit.

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