Fimepinostat (CUDC-907): A Comprehensive Report on Development and Clinical Evaluation

I. Fimepinostat (CUDC-907): Overview and Background

A. Identification and Chemical Properties

Fimepinostat, also known by its code name CUDC-907, is an investigational small molecule drug developed for the treatment of various cancers.[1] Identified by the DrugBank Accession Number DB11891 and CAS Number 1339928-25-4, Fimepinostat is classified chemically as a thienopyrimidine derivative.[3] It is formulated as an orally available agent, typically appearing as a solid powder soluble in dimethyl sulfoxide (DMSO). While specific details on its exact chemical formula and molecular weight are not consistently provided across the source materials, its identity as CUDC-907/Fimepinostat with the specified CAS number is well-established.[3]

B. Developer and Development History

Fimepinostat was developed internally by Curis, Inc., a biotechnology company focused on oncology therapeutics.[1] Clinical development commenced in 2013 with the initiation of a Phase 1 trial (NCT01742988) evaluating the drug in patients with relapsed or refractory (R/R) lymphomas and multiple myeloma.[7] Based on encouraging preliminary results, particularly in Diffuse Large B-cell Lymphoma (DLBCL), Curis advanced Fimepinostat into Phase 2 development in the first quarter of 2016 (NCT02674750).[7]

The potential of Fimepinostat, especially in MYC-altered DLBCL, was recognized through regulatory designations. The U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation for DLBCL in April 2015 and Fast Track Designation in May 2018 for adult patients with R/R DLBCL after two or more lines of systemic therapy.[7] These designations underscored the significant unmet medical need in this patient population and acknowledged the promising early clinical data suggesting durable responses.[7] Following these designations, Curis announced plans to initiate a pivotal study in 2018.[8]

However, subsequent developments indicated challenges. A Phase 1 combination study arm evaluating Fimepinostat with the BCL2 inhibitor venetoclax (within NCT01742988), initiated in July 2019, was discontinued in March 2020 due to a lack of efficacy.[7] Furthermore, a Phase 2 trial in thyroid cancer (NCT03002623) was terminated.[27] While Phase 1 trials in pediatric/young adult populations with CNS cancers, solid tumors, and lymphomas (NCT02909777, NCT03893487) were reported as ongoing but not recruiting as of March 2024 [21], Curis's recent corporate updates and pipeline presentations have largely focused on other assets like Emavusertib (CA-4948).[19] Fimepinostat is typically listed under assets with demonstrated "Clinical Activity" but not highlighted as undergoing active pivotal development.[23] This suggests that despite early promise and regulatory support, Fimepinostat development for its primary target indications, such as R/R DLBCL, has likely been deprioritized or halted by Curis.

C. Regulatory Designations

• FDA Orphan Drug Designation (April 2015): Granted for the treatment of DLBCL.[7] This designation is intended to encourage the development of drugs for rare diseases or conditions.
• FDA Fast Track Designation (May 2018): Granted for the development of Fimepinostat in adult patients with R/R DLBCL after two or more lines of systemic therapy.[7] This designation facilitates development and expedites the review process for drugs addressing serious conditions with unmet medical needs, offering benefits such as more frequent FDA interactions and eligibility for Accelerated Approval and Priority Review if criteria are met.[8]
• NUT Midline Carcinoma Orphan Drug Designation: FDA granted orphan drug designation (FDA ORPHAN DRUG 482415) for the treatment of nuclear protein in testis (NUT) midline carcinoma.[31] The date of this designation is not specified in the snippet.

The granting of these designations, particularly for DLBCL, reflected the significant unmet need for effective therapies in the relapsed/refractory setting, especially for patients with high-risk features like MYC alterations, and the potential clinical benefit suggested by early Fimepinostat data showing durable responses.[7]

II. Mechanism of Action: Dual PI3K and HDAC Inhibition

Fimepinostat (CUDC-907) was rationally designed as a first-in-class, oral, dual inhibitor targeting two critical oncogenic signaling pathways: phosphoinositide 3-kinase (PI3K) and histone deacetylases (HDACs).[1] This dual-targeting strategy aimed to overcome drug resistance by simultaneously suppressing interconnected networks involved in cancer cell proliferation, survival, and epigenetic regulation.[2]

A. Rationale for Dual Targeting

The PI3K/AKT/mTOR pathway and HDAC-mediated epigenetic regulation are frequently dysregulated in various malignancies, contributing to uncontrolled cell growth, survival, and resistance to therapy.[32] Aberrant PI3K signaling promotes cell survival and proliferation [41], while altered HDAC activity leads to aberrant gene expression, silencing tumor suppressors and activating oncogenes.[49]

A key rationale for combining PI3K and HDAC inhibition stems from their convergent roles in regulating the MYC oncogene, a critical driver in many lymphomas and solid tumors.[1] PI3K pathway activity influences MYC protein stability, with inhibition promoting its degradation via ubiquitination.[14] Concurrently, HDACs regulate chromatin structure around the MYC gene promoter, and their inhibition leads to transcriptional repression of MYC.[14] By targeting both mechanisms, Fimepinostat was designed to achieve potent and potentially synergistic suppression of MYC activity, offering a therapeutic advantage in MYC-dependent cancers.[1] This dual attack on MYC provided a strong preclinical basis for investigating Fimepinostat in MYC-altered lymphomas, where MYC deregulation is a known driver of aggressive disease and poor prognosis.[1]

B. PI3K Inhibition

The PI3K/AKT/mTOR pathway is a central regulator of cellular processes essential for cancer development and progression, including cell growth, survival, proliferation, and metabolism.[41] Class I PI3Ks, activated by receptor tyrosine kinases or G protein-coupled receptors, phosphorylate PIP2 to generate PIP3, a crucial second messenger that recruits and activates downstream kinases like PDK1 and AKT.[42] Activated AKT, in turn, phosphorylates numerous substrates, promoting cell survival (e.g., by inhibiting pro-apoptotic proteins like Bad) and stimulating cell growth and proliferation, often through the mTOR complex.[41] Aberrant activation of this pathway, through mutations or amplifications of components like PIK3CA or AKT, or loss of the negative regulator PTEN, is common in cancer and contributes to therapeutic resistance.[41]

Fimepinostat specifically targets the Class I PI3K isoforms α, β, and δ, with reported IC50 values of 19 nM, 54 nM, and 39 nM, respectively.[2] Some data also suggest inhibition of the γ isoform, albeit at higher concentrations (IC50 311 nM).[3] Inhibition of these PI3K isoforms blocks the generation of PIP3, leading to reduced activation of downstream effectors. This is evidenced by decreased phosphorylation of AKT (pAKT) observed in preclinical models treated with Fimepinostat.[32] The consequent suppression of PI3K/AKT/mTOR signaling contributes to the drug's anti-proliferative and pro-apoptotic effects and facilitates MYC protein degradation.[34]

C. HDAC Inhibition

Histone deacetylases (HDACs) are epigenetic regulators that remove acetyl groups from lysine residues on histone tails and various non-histone proteins.[49] Histone deacetylation generally leads to a more condensed chromatin structure, restricting access for transcription factors and resulting in gene silencing.[50] HDACs play critical roles in regulating gene expression programs involved in cell cycle control, differentiation, apoptosis, and immune responses.[51] Aberrant HDAC activity or expression is frequently observed in cancer, contributing to the silencing of tumor suppressor genes and the activation of oncogenes.[49] Mammalian HDACs are grouped into classes; Class I (HDAC1, 2, 3, 8) are primarily nuclear enzymes, while Class II (HDAC4, 5, 6, 7, 9, 10) shuttle between the nucleus and cytoplasm.[51]

Fimepinostat inhibits enzymes belonging to both Class I (HDAC1, HDAC2, HDAC3) and Class II (HDAC10).[1] It exhibits potent inhibition with reported IC50 values of 1.7 nM, 5.0 nM, 1.8 nM, and 2.8 nM for HDAC1, HDAC2, HDAC3, and HDAC10, respectively.[3] Inhibition of these HDACs leads to the accumulation of acetylated histones (e.g., increased H3 acetylation, H3K9Ac) and non-histone proteins (e.g., acetylated tubulin), altering chromatin structure and protein function.[32] Key downstream consequences relevant to its anti-cancer activity include the transcriptional repression of oncogenes like MYC [14], upregulation of cell cycle inhibitors like p21 and p27 [40], induction of apoptosis through modulation of death receptors and caspase activation [32], and effects on DNA damage response pathways.[30]

D. Combined Effects and Synergy

The simultaneous inhibition of PI3K and HDAC pathways by Fimepinostat results in multifaceted anti-cancer effects observed across numerous preclinical models. The dual action leads to potent induction of apoptosis and cell cycle arrest (typically G2/M phase) in cell lines derived from diverse cancers including lymphoma, leukemia, multiple myeloma, breast, thyroid, pancreatic, liver, neuroblastoma, and schwannoma.[4]

A central aspect of its activity, particularly relevant for hematologic malignancies, is the robust suppression of MYC oncogene expression and protein levels.[1] In specific contexts like NF2-deficient schwannoma models, Fimepinostat also demonstrated inhibition of YAP, another oncogenic driver downstream of merlin loss.[36]

Furthermore, preclinical studies explored the potential for synergy between Fimepinostat and other anti-cancer agents. Combination with the BCL2 inhibitor venetoclax showed synergistic killing in AML and double-hit lymphoma models.[14] Additive or synergistic effects were also suggested with PARP inhibitors in small cell lung cancer models.[37] Fimepinostat was also investigated for its potential to reverse HIV-1 latency ex vivo, showing potent activity comparable to established HDAC inhibitors but without inducing T cell activation.[33]

III. Clinical Development Program

Fimepinostat underwent evaluation in multiple Phase 1 and Phase 2 clinical trials, primarily focusing on hematologic malignancies and solid tumors.[1] The development program was largely driven by encouraging preclinical data and early clinical signals in R/R DLBCL, especially in patients with MYC alterations.[1]

A. Phase 1 Monotherapy Trials (NCT01742988, NCT02307240)

Two key Phase 1 studies established the initial safety, tolerability, pharmacokinetics (PK), and recommended dose of Fimepinostat.

• NCT01742988 (Lymphoma/Multiple Myeloma): This multi-center, open-label study, initiated in 2013, enrolled patients with R/R lymphomas or multiple myeloma who had received at least two prior lines of therapy.[1] The dose-escalation phase explored various schedules (daily, twice weekly, thrice weekly, 5 days on/2 days off) and doses (30-150 mg).[1] Expansion cohorts evaluated the recommended Phase 2 dose (RP2D) of 60 mg (5 days on/2 days off) alone or briefly in combination with rituximab in R/R DLBCL patients.[1] A later amendment added a dose-finding arm combining Fimepinostat with venetoclax for R/R DLBCL/HGBL patients, including those with MYC/BCL2 alterations.[14] The overall study is marked as completed, but the venetoclax combination arm was discontinued prematurely in March 2020 due to lack of efficacy.[7] This trial established the RP2D of 60 mg (5 days on/2 days off) and demonstrated preliminary efficacy signals in DLBCL.[1]
• NCT02307240 (Solid Tumors): This Phase 1, open-label, multi-center study evaluated the safety, tolerability, and PK of orally administered Fimepinostat in patients (≥18 years) with advanced/relapsed solid tumors that had progressed on standard therapy or for which no standard therapy existed.[6] Specific expansion cohorts targeted patients with triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC).[6] Notably, patients aged ≥16 years with NUT midline carcinoma (NMC) were also eligible for enrollment.[6] This study is listed as completed.[6] Specific efficacy outcomes or the RP2D determined from this solid tumor study are not detailed in the provided materials.

B. Phase 2 Monotherapy Trial (NCT02674750)

Based on Phase 1 findings, particularly the responses in MYC-altered DLBCL, Curis initiated this Phase 2 study in Q1 2016.[1]

• Design: An open-label, multi-center trial evaluating Fimepinostat monotherapy at the RP2D (60 mg, 5 days on/2 days off).[1] The study enrolled patients with R/R DLBCL or High-Grade B-cell Lymphoma (HGBL) after 2-4 prior therapies.[57] Central testing for MYC alterations (translocation by FISH, copy number gain by FISH, or protein expression ≥40% by IHC) was required, and patients were stratified accordingly.[15] Patients with MYC-negative disease were also eligible.[57] A total of 66 eligible patients were treated.[15]
• Primary Objective: To assess the Objective Response Rate (ORR) in patients with MYC protein expression ≥40% by IHC (n=46).[1]
• Status: Completed.[27]

C. Other Trials and Discontinued Development

• Thyroid Cancer (NCT03002623): A Phase 2 trial investigating Fimepinostat in metastatic and locally advanced thyroid cancer was initiated but subsequently terminated.[27] The specific reason for termination was not provided in the available sources, though common reasons include slow accrual, strategic shifts, or emerging safety/efficacy concerns.[63]
• Pediatric Trials (NCT02909777, NCT03893487): Ongoing Phase 1 trials are evaluating Fimepinostat in children and young adults with R/R solid tumors, CNS tumors (including DIPG, HGG, medulloblastoma), or lymphoma.[21] As of March 2024, these trials were reported as active but not recruiting.[21]
• Venetoclax Combination (NCT01742988 arm): Despite strong preclinical rationale for combining PI3K/HDAC inhibition with BCL2 inhibition in MYC/BCL2 co-altered lymphomas [14], the Phase 1b dose-finding arm was discontinued in March 2020 due to a lack of efficacy.[7] Dose-limiting toxicities were observed at the higher Fimepinostat dose level (60 mg) combined with venetoclax 400 mg.[18]

The pattern of trial completions, terminations (NCT03002623), and the explicit discontinuation of the venetoclax combination due to lack of efficacy [7], combined with Curis's recent pipeline focus [19], strongly indicates that Fimepinostat's development path for its initial lead indications faced significant obstacles. While early Phase 1 results in DLBCL were encouraging [1], the Phase 2 ORR was modest [15], and attempts to enhance efficacy through combination (venetoclax) or expand into other indications (thyroid cancer) were unsuccessful or halted. The drug's potential may now be limited to specific niche populations, such as those being explored in the ongoing pediatric trials.

Table 1: Summary of Key Fimepinostat Clinical Trials

NCT ID	Phase	Title Snippet / Key Indication(s)	Status (Final)	Fimepinostat Arm(s)	Key Outcome/Note	Snippet Ref(s)
NCT01742988	Ib/II	Safety/Tolerability/PK in Lymphoma/MM	Completed	Monotherapy (various schedules); + Rituximab (expansion); + Venetoclax (dose-finding arm)	Established RP2D (60mg 5on/2off); Venetoclax arm discontinued (lack of efficacy)	1
NCT02307240	I	Safety/Tolerability/PK in Advanced/Relapsed Solid Tumors	Completed	Monotherapy (dose escalation)	Included TNBC, HGSOC, NUT Midline Carcinoma patients; Assessed safety/PK.	6
NCT02674750	II	Efficacy/Safety in R/R DLBCL/HGBL (incl. MYC Alterations)	Completed	Monotherapy (60mg 5on/2off)	Primary endpoint ORR 15% in MYC-IHC≥40% population. Pooled analysis with Ph1 showed ORR ~22% in MYC-altered. Some durable responses noted.	1
NCT03002623	II	CUDC-907 in Metastatic/Locally Advanced Thyroid Cancer	Terminated	Monotherapy	Terminated early; reason not specified in snippets.	27
NCT02909777	I	CUDC-907 in Children/Young Adults (Solid/CNS Tumors/Lymphoma)	Active, not recruiting	Monotherapy (dose escalation)	Pediatric/Young Adult population focus.	21
NCT03893487	I	Fimepinostat in Children/Young Adults (Brain Tumors - PNOC016)	Active, not recruiting	Monotherapy (dose escalation)	Pediatric/Young Adult population focus (DIPG, HGG, etc.).	21

RP2D: Recommended Phase 2 Dose; R/R: Relapsed/Refractory; DLBCL: Diffuse Large B-cell Lymphoma; HGBL: High-Grade B-cell Lymphoma; MM: Multiple Myeloma; TNBC: Triple-Negative Breast Cancer; HGSOC: High-Grade Serous Ovarian Cancer; NMC: NUT Midline Carcinoma; CNS: Central Nervous System; DIPG: Diffuse Intrinsic Pontine Glioma; HGG: High-Grade Glioma.

Status as per latest available snippet information.

IV. Clinical Efficacy

The clinical efficacy of Fimepinostat has been evaluated primarily in patients with R/R lymphomas, with additional investigations in solid tumors.

A. Relapsed/Refractory DLBCL/HGBL

The most robust efficacy data for Fimepinostat comes from studies in patients with R/R DLBCL and HGBL, particularly those harboring MYC alterations.

• Phase 1 Results (NCT01742988): Initial results from the Phase 1 dose-escalation and expansion study showed promising activity. Among 21 response-evaluable patients with R/R DLBCL, 9 objective responses were observed (3 Complete Responses, 6 Partial Responses), translating to an ORR of approximately 43% in this subset.[7] A key finding from a retrospective analysis was that 5 of these 9 responders had confirmed MYC oncogene alterations, providing early support for the MYC-targeting hypothesis.[7]
• Phase 2 Results (NCT02674750): The subsequent Phase 2 trial focused on patients with R/R DLBCL/HGBL, specifically aiming to evaluate efficacy in MYC-altered populations. The primary endpoint analysis, focused on patients with MYC protein expression ≥40% by IHC (n=46), yielded an ORR of 15%.[15]
• Pooled Analyses (Phase 1 & 2): To gain a broader understanding, exploratory pooled analyses combining data from both Phase 1 and Phase 2 trials were conducted, focusing on patients defined as having MYC-altered disease (based on IHC, FISH, or other methods). In a cohort of 63 such patients, the ORR was reported as 22%.[15] Other analyses of pooled data reported similar ORRs, around 23% in MYC-altered patients.[1] The slight variations in reported ORRs (15%, 22%, 23%) likely reflect differences in the specific patient populations included (e.g., Phase 2 primary analysis set vs. various pooled MYC-altered definitions) and whether intent-to-treat or evaluable patient sets were used.[1] The consistency around 22-23% ORR in pooled MYC-altered groups provides a reasonable estimate of single-agent activity in this targeted population.
• Duration of Response (DOR): A significant finding across studies was the durability of responses observed in some patients. The median DOR was reported to be over one year [8], and specifically 13.6 months in one analysis.[14] The pooled analysis highlighted seven responding patients with MYC-altered disease who remained on treatment for approximately two years or longer.[15] This durability, observed in a patient population with typically poor prognosis [8], was a key factor supporting the drug's potential and its Fast Track designation, even with a modest ORR below 30%.
• Progression-Free Survival (PFS) and Overall Survival (OS): While listed as secondary endpoints in trial protocols [57], specific median PFS or OS data from the Fimepinostat DLBCL trials are not detailed in the provided source materials.[2]
• Biomarkers: MYC alterations (detected by IHC or genetics) were associated with response, forming the basis for enrichment strategies in the Phase 2 trial.[1] Additionally, the VIPER (Virtual Inference of Protein activity by Enriched Regulon) analysis identified a potential three-protein biomarker signature that demonstrated high positive and negative predictive values (≥85%) in the pooled cohort, suggesting a possible avenue for improved patient selection beyond MYC status alone.[15]

B. Solid Tumors

Fimepinostat was evaluated in a Phase 1 trial (NCT02307240) involving patients with various advanced/relapsed solid tumors.[6]

• NUT Midline Carcinoma (NMC): Patients aged ≥16 years with NMC were eligible for enrollment in NCT02307240.[6] However, no specific efficacy data (such as ORR or DOR) for patients with NMC treated in this trial are reported in the available source materials.[3] Given the rarity and aggressiveness of NMC [71] and the nature of Phase 1 solid tumor "basket" trials, the absence of reported results likely indicates that either too few NMC patients were enrolled to draw conclusions, or no significant clinical activity was observed in this specific subgroup. Fimepinostat did receive FDA Orphan Drug Designation for NMC.[31]
• Thyroid Cancer: Preclinical studies showed Fimepinostat inhibited thyroid cancer cell proliferation, induced apoptosis, decreased migration/invasion, and inhibited tumor growth and metastases in mouse models.[40] However, the subsequent Phase 2 clinical trial (NCT03002623) in metastatic/locally advanced thyroid cancer was terminated early.[27]
• Other Solid Tumors: The Phase 1 trial NCT02307240 included expansion cohorts for TNBC and HGSOC.[6] Preclinical activity was also demonstrated in models of hepatocellular carcinoma [34] and neuroblastoma.[32] However, specific clinical efficacy results for these solid tumor types are not available in the provided snippets.

C. Other Malignancies

• Multiple Myeloma (MM): Patients with R/R MM were eligible for the initial Phase 1 trial (NCT01742988).[1] Preclinical studies showed activity.[25] No clinical efficacy data for MM patients treated with Fimepinostat are reported in the source materials.
• Acute Myeloid Leukemia (AML): Preclinical studies suggested synergy with venetoclax.[30] However, Fimepinostat has not been reported in clinical development for AML.[21]

Table 2: Summary of Fimepinostat Efficacy in R/R DLBCL/HGBL

Indication / Population	Trial (NCT ID / Analysis)	N (Evaluable/ITT)	ORR (%)	CR (%)	Median DOR (months)	PFS/OS	Key Notes	Snippet Ref(s)
R/R DLBCL	Phase 1 (NCT01742988)	21 / 25	~43	~14	Not Specified	Not Specified	5/9 responders had MYC alterations.	7
R/R DLBCL/HGBL (MYC-IHC ≥40%)	Phase 2 (NCT02674750)	46 / 66	15	Not Specified	Not Specified	Not Specified	Primary endpoint analysis.	15
R/R DLBCL/HGBL (MYC-Altered Pool)	Pooled Ph 1/2	63 / --	22	Not Specified	>12 (7 pts ≥ ~24)	Not Specified	Exploratory analysis; durable responses noted. VIPER biomarker identified.	8
R/R DLBCL (MYC-Altered Pool Alt. 1)	Pooled Ph 1/2	14 / 37	23	Not Specified	Not Specified	Not Specified	Specific pooled analysis subset.	1
R/R DLBCL (MYC-Altered Pool Alt. 2)	Pooled Ph 1/2	-- / --	23 (ITT) / 29 (Eval)	Not Specified	13.6	Not Specified	Specific pooled analysis subset; median DOR reported.	14

ORR: Objective Response Rate; CR: Complete Response; DOR: Duration of Response; PFS: Progression-Free Survival; OS: Overall Survival; R/R: Relapsed/Refractory; DLBCL: Diffuse Large B-cell Lymphoma; HGBL: High-Grade B-cell Lymphoma; ITT: Intent-to-Treat; IHC: Immunohistochemistry; VIPER: Virtual Inference of Protein activity by Enriched Regulon.

Note: ORR variations likely due to different patient populations and analysis methods across reports.

V. Safety and Tolerability

The safety profile of Fimepinostat monotherapy was characterized in Phase 1 and Phase 2 clinical trials.

A. Overall Profile

Fimepinostat was generally reported as well-tolerated when administered at the RP2D (60 mg orally, 5 days on/2 days off schedule) in patients with R/R lymphoma.[1] The safety profile was considered manageable.[1]

B. Common Adverse Events (Grade 1/2)

The most frequently reported drug-related adverse events (AEs) were generally low grade (Grade 1 or 2) and included diarrhea, fatigue, and nausea.[1] A pooled analysis of Phase 1/2 data also listed thrombocytopenia, neutropenia, anemia, vomiting, decreased appetite, dysgeusia, constipation, weight decrease, hyperglycemia, hypokalemia, and hypophosphatemia as common AEs occurring in >10% of patients.[1]

C. Serious Adverse Events (Grade 3/4)

Hematologic toxicities were among the common Grade 3/4 AEs, including thrombocytopenia and neutropenia.[1] Common non-hematologic Grade 3/4 AEs reported in 3 or more patients in the Phase 1 study included diarrhea, hyperglycemia, and fatigue.[7] Grade 3/4 hypokalemia and hypophosphatemia were also noted in the pooled analysis.[1]

D. Dose-Limiting Toxicities (DLTs)

During the Phase 1 dose-escalation phase (NCT01742988), diarrhea and hyperglycemia were identified as DLTs at higher doses or different schedules.[7] Importantly, no DLTs were reported at the established RP2D of 60 mg administered on the 5 days on/2 days off schedule.[7] In the subsequent combination arm with venetoclax, DLTs were encountered at the 60 mg Fimepinostat dose level when combined with 400 mg venetoclax, but the lower 30 mg Fimepinostat dose combined with 400 mg venetoclax was tolerated.[18]

E. Discontinuations

Information regarding AE-related discontinuation rates in the monotherapy trials is limited in the provided sources. The venetoclax combination arm was discontinued due to lack of efficacy, not primarily due to toxicity, although DLTs were observed at the higher dose level tested.[7]

F. Specific Safety Considerations

• Hyperglycemia: The emergence of hyperglycemia as both a Grade 3/4 AE and a DLT is noteworthy.[7] This is mechanistically plausible given the inhibition of the PI3K/AKT pathway, which plays a significant role in glucose metabolism and insulin signaling.[41] Disruption of this pathway can impair glucose homeostasis, leading to elevated blood sugar levels.
• Diarrhea: Diarrhea was a prominent AE, occurring frequently as a low-grade event and also identified as a DLT.[1] Gastrointestinal toxicities, including diarrhea, are known class effects associated with HDAC inhibitors.[49] This AE likely reflects the HDAC inhibitory component of Fimepinostat's dual mechanism.

Table 3: Summary of Common and Serious Adverse Events (Fimepinostat Monotherapy in R/R Lymphoma)

Adverse Event	Grade 1/2 Frequency	Grade 3/4 Frequency	Trial Context / Notes	Snippet Ref(s)
Diarrhea	Common (>10%)	Yes (≥3 pts in Ph1); DLT	Most common low-grade AE; Also dose-limiting.	1
Fatigue	Common (>10%)	Yes (≥3 pts in Ph1)	Most common low-grade AE.	1
Nausea	Common (>10%)	Not specified	Most common low-grade AE.	1
Thrombocytopenia	Common (>10%)	Yes (≥3 pts in Ph1)	Common hematologic AE.	1
Neutropenia	Common (>10%)	Yes (≥3 pts in Ph1)	Common hematologic AE (Neutrophil decrease).	1
Anemia	Common (>10%)	Not specified	Common hematologic AE.	1
Hyperglycemia	Common (>10%)	Yes (≥3 pts in Ph1); DLT	Also dose-limiting. Mechanistically linked to PI3K inhib.	1
Vomiting	Common (>10%)	Not specified		1
Decreased Appetite	Common (>10%)	Not specified		1
Dysgeusia	Common (>10%)	Not specified		1
Constipation	Common (>10%)	Not specified		1
Weight Decreased	Common (>10%)	Not specified		1
Hypokalemia	Common (>10%)	Yes		1
Hypophosphatemia	Common (>10%)	Yes		1

Frequencies based primarily on Phase 1 data and pooled analyses where specified.[1] DLT: Dose-Limiting Toxicity. Ph1: Phase 1.

VI. Development Status and Conclusion

A. Summary of Development Trajectory

Fimepinostat (CUDC-907) emerged from Curis, Inc. as a rationally designed, first-in-class oral dual inhibitor of PI3K and HDAC enzymes.[1] Its development was underpinned by a strong preclinical rationale, particularly its ability to suppress the MYC oncogene through complementary mechanisms.[1] Phase 1 studies initiated in 2013 successfully established an RP2D (60 mg, 5 days on/2 days off) and demonstrated preliminary anti-cancer activity, most notably in patients with R/R DLBCL harboring MYC alterations.[1] These promising early signals led to the granting of FDA Orphan Drug and Fast Track designations for R/R DLBCL, paving the way for Phase 2 evaluation (NCT02674750) and plans for pivotal studies.[1] Fimepinostat was also investigated in solid tumors (including NMC, TNBC, HGSOC in NCT02307240; thyroid cancer in NCT03002623) and in combination with venetoclax for DLBCL/HGBL (NCT01742988 arm).[6]

B. Current Status

Despite the initial promise and regulatory support, the clinical development program for Fimepinostat appears to have stalled for its major target indications. The Phase 2 trial in R/R DLBCL (NCT02674750) completed, but the reported ORR of 15% in the primary endpoint population (MYC-IHC ≥40%) and ~22% in pooled MYC-altered patients, while showing durability in some responders, may have fallen short of thresholds required for a single-agent pivotal path in this challenging setting.[15] Attempts to broaden its application or enhance efficacy through combination were unsuccessful; the Phase 2 thyroid cancer trial (NCT03002623) was terminated [27], and the Phase 1b combination with venetoclax (NCT01742988 arm) was discontinued due to lack of efficacy.[7] Recent corporate communications and pipeline updates from Curis heavily emphasize other drug candidates, particularly Emavusertib, with Fimepinostat relegated to a non-priority status or listed only under historical "Clinical Activity".[19] While Phase 1 pediatric trials (NCT02909777, NCT03893487) remain listed as active but not recruiting as of early 2024 [21], there is no indication of active late-stage development for Fimepinostat in its initial target indications.

C. Concluding Remarks

Fimepinostat (CUDC-907) represents an innovative therapeutic concept targeting the interconnected PI3K and HDAC pathways, with a strong mechanistic rationale for activity in MYC-driven cancers like DLBCL. Early clinical studies provided proof-of-concept, demonstrating durable objective responses in a subset of heavily pretreated patients with MYC-altered R/R DLBCL/HGBL, a population with significant unmet need. However, the overall response rates observed in Phase 2 may not have been sufficient to support single-agent registration, and efforts to enhance efficacy through combination (venetoclax) or expand into other indications (thyroid cancer) did not yield positive results, leading to the apparent discontinuation or deprioritization of its development by Curis for these indications. Challenges in achieving broader efficacy or navigating the therapeutic window, potentially related to toxicities associated with dual pathway inhibition (e.g., hyperglycemia, diarrhea), may have contributed to these outcomes. While Fimepinostat demonstrated biological activity and durable responses in some patients, its future clinical potential seems limited based on the available data and current development status, possibly restricted to niche applications or requiring novel biomarker strategies or combination partners yet to be identified.

Works cited

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