Volasertib (BI 6727): A Comprehensive Profile of a Polo-Like Kinase 1 Inhibitor from Clinical Promise to Precision-Guided Revival

Executive Summary

Volasertib (BI 6727) is an investigational, first-in-class, small-molecule inhibitor of Polo-like kinase 1 (PLK1), a critical regulator of mitosis. Developed by Boehringer Ingelheim, the compound demonstrated high potency against its target, inducing a characteristic "Polo arrest" that leads to cell cycle disruption and apoptosis, preferentially in malignant cells. Preclinical data showed broad antitumor activity across a range of solid and hematological malignancies, with the strongest rationale emerging for the treatment of acute myeloid leukemia (AML).

The clinical development of volasertib was characterized by a trajectory of significant promise followed by a profound setback. A randomized Phase II study in elderly AML patients unfit for intensive chemotherapy showed that the combination of volasertib with low-dose cytarabine (LDAC) more than doubled the objective response rate and significantly improved both event-free and overall survival compared to LDAC alone. These compelling results led to the U.S. Food and Drug Administration (FDA) granting Breakthrough Therapy and Orphan Drug designations and prompted the initiation of a large, pivotal Phase III trial, POLO-AML-2.

However, the POLO-AML-2 trial failed to meet its primary endpoint of a statistically significant improvement in objective response rate. More critically, the combination therapy was associated with a substantially higher rate of fatal adverse events, driven primarily by severe and prolonged myelosuppression leading to fatal infections. This negative risk-benefit profile resulted in the discontinuation of the program by Boehringer Ingelheim in 2016. The drug's pharmacokinetic profile, featuring a long terminal half-life and extensive tissue distribution, likely contributed to the prolonged duration of its myelosuppressive effects, exacerbating toxicity in this vulnerable patient population.

Despite this failure, the underlying clinical activity of volasertib remained evident. The asset has since been out-licensed and is now under development by Notable Labs for relapsed/refractory AML. This revival is predicated on a modern, precision oncology strategy. A new Phase II trial aims to mitigate the historical toxicity through optimized, body-surface-area-based dosing and enhanced supportive care. Crucially, it will employ a proprietary ex vivo functional diagnostic platform to prospectively identify patients predicted to be highly sensitive to volasertib. This biomarker-driven approach seeks to enrich the trial population with likely responders, fundamentally altering the drug's risk-benefit calculus. The story of volasertib thus serves as a compelling case study in drug development, illustrating the challenges of translating preclinical promise to clinical success and representing a test case for the potential of functional precision medicine to salvage potent but toxic agents that have failed in unselected populations.

---

1.0 Volasertib: Molecular Profile and Physicochemical Characteristics

A comprehensive understanding of any therapeutic agent begins with a precise definition of its molecular identity and physical properties. These foundational characteristics govern its interaction with biological systems, influence its pharmacokinetic behavior, and provide the basis for its mechanism of action.

1.1 Nomenclature and Key Identifiers

Volasertib is an investigational small molecule that has been assigned multiple identifiers across various chemical, pharmacological, and regulatory databases, ensuring its unambiguous tracking and cross-referencing in scientific literature and clinical trial registries.[1]

• Primary Name: Volasertib [2]
• Synonyms and Code Names: The most common code name, used throughout its development by Boehringer Ingelheim, is BI 6727. Variations such as BI-6727 are also frequently used. Other identifiers include NBL-001 and the descriptive name "Polo-like kinase 1 inhibitor BI 6727".[4]
• DrugBank ID: DB12062 [1]
• CAS Number: The Chemical Abstracts Service (CAS) registry number for the free base form of the molecule is 755038-65-4.[4] Related CAS numbers for salt forms, such as the hydrochloride salt (946161-17-7), have also been registered.[3]
• Other Key Identifiers: To facilitate comprehensive data retrieval, volasertib is also cataloged under several other major systems, including:
• UNII: 6EM57086EA [2]
• KEGG: D10182 [2]
• ChEBI: CHEBI:231358 [7]
• ChEMBL: CHEMBL1233528 [8]
• IUPHAR/BPS: 7947 [2]

1.2 Structural Analysis and Physicochemical Properties

Volasertib is classified as a dihydropteridinone derivative, the second in this novel class of compounds to be developed as a therapeutic agent.[2] Its complex structure is responsible for its high-potency binding to its target kinase.

• Molecular Formula and Weight: The correct molecular formula for volasertib is C34​H50​N8​O3​.[3] This corresponds to an average molecular weight of approximately 618.81-618.83 g/mol and a monoisotopic mass of 618.4006 Da.[1] It is critical to note that some commercial supplier databases have reported an erroneous molecular formula ( C15​H27​N5​O5​), underscoring the importance of relying on curated scientific and regulatory databases for foundational chemical data.[9]
• IUPAC Name: The systematic IUPAC name for the molecule is N-((1S,4S)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-4-(((R)-7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-3-methoxybenzamide.[2]
• Structural Identifiers: For computational and database purposes, the structure is unambiguously represented by the following identifiers:
• SMILES: CC[C@@H]1C(=O)N(C2=CN=C(N=C2N1C(C)C)NC3=C(C=C(C=C3)C(=O)NC4CCC(CC4)N5CCN(CC5)CC6CC6)OC)C [7]
• InChIKey: SXNJFOWDRLKDSF-STROYTFGSA-N [10]
• Physicochemical Properties: Analysis of volasertib's structure reveals key properties that predict its drug-like behavior. These parameters, largely consistent with Lipinski's Rule of Five but with some violations, suggest a molecule optimized for cell permeability but with potential liabilities. The high molecular weight and number of hydrogen bond acceptors exceed the typical Lipinski guidelines, which is not uncommon for modern targeted therapies that require complex structures for specific binding.[8]

Table 1: Key Identifiers and Physicochemical Properties of Volasertib

Property	Value	Source(s)
DrugBank ID	DB12062	1
CAS Number	755038-65-4 (free base)	4
Molecular Formula	C34​H50​N8​O3​	3
Average Molecular Weight	618.81 g/mol	3
IUPAC Name	N-((1S,4S)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-4-(((R)-7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-3-methoxybenzamide	2
InChIKey	SXNJFOWDRLKDSF-STROYTFGSA-N	10
Drug Class	Small Molecule; Dihydropteridinone Derivative	1
AlogP / XLogP	4.2 - 4.27	8
Topological Polar Surface Area	106.17 A˚2	8
# Hydrogen Bond Donors	2	8
# Hydrogen Bond Acceptors	9 - 11	8
# Lipinski RO5 Violations	2	8

---

2.0 Pharmacodynamics: The Mechanism of PLK1 Inhibition

The therapeutic rationale for volasertib is rooted in its highly specific and potent inhibition of the Polo-like kinase (PLK) family, particularly PLK1. This enzyme is a master regulator of cell division, and its dysregulation is a hallmark of many cancers, making it a compelling therapeutic target.

2.1 Targeting the Polo-Like Kinase Family: Potency and Selectivity

Volasertib was engineered to be a potent inhibitor of PLK1, a serine/threonine kinase that plays a pivotal role in multiple stages of mitosis, including the G2/M checkpoint, mitotic entry, spindle assembly, and cytokinesis.[2] Overexpression of PLK1 is observed in up to 80% of human malignancies and is frequently associated with increased aggressiveness and poor prognosis, providing a strong justification for its therapeutic targeting.[2]

• Potency: In cell-free enzymatic assays, volasertib exhibits exceptionally high potency against its primary target, PLK1, with a half-maximal inhibitory concentration (IC50​) of 0.87 nM.[4] This potent enzymatic inhibition translates into effective anti-proliferative activity in cellular models, where it demonstrates half-maximal effective concentrations ( EC50​) in the low nanomolar range (11–37 nM) across various cancer cell lines.[3]
• Selectivity: While volasertib is most potent against PLK1, it also inhibits other members of the PLK family, albeit at higher concentrations. The reported IC50​ values for the closely related isoforms PLK2 and PLK3 are 5 nM and 56 nM, respectively.[3] This profile indicates a 6-fold selectivity for PLK1 over PLK2 and a 65-fold selectivity over PLK3.[4] Importantly, when screened against a broad panel of over 50 other kinases, volasertib showed no significant inhibitory activity at clinically relevant concentrations (up to 10 µM), confirming its high degree of specificity for the PLK family.[15]

The drug's activity against PLK2 and PLK3, though weaker, introduces a layer of complexity to its pharmacological profile. While often described simply as a "PLK1 inhibitor," its effects at therapeutic concentrations are likely a composite of inhibiting all three isoforms. Some evidence suggests that PLK2 and PLK3 can function as tumor suppressors within the p53 signaling network.[13] Consequently, their inhibition could represent a clinically relevant off-target effect, potentially contributing to dose-related toxicities or even counteracting some of the on-target benefits, thereby narrowing the drug's therapeutic window.

Table 2: Summary of Volasertib Potency (IC50​) Against PLK Isoforms

Kinase Target	IC50​ (nM)	Selectivity Ratio (vs. PLK1)	Source(s)
PLK1	0.87	1x	3
PLK2	5	~6x	3
PLK3	56	~65x	3

2.2 The Molecular Cascade of "Polo Arrest": Induction of Mitotic Catastrophe and Apoptosis

Volasertib exerts its antineoplastic effect by disrupting the fundamental process of cell division. It functions as an ATP-competitive inhibitor, binding reversibly to the ATP-binding pocket within the kinase domain of PLK1.[2] This direct competition prevents the natural substrate, ATP, from binding and blocks the kinase's ability to phosphorylate its downstream targets, which are essential for mitotic progression.

The cellular consequence of this inhibition is a profound disruption of the mitotic machinery. Cells are unable to form a proper bipolar mitotic spindle, leading to a distinct cellular phenotype characterized by aberrant, monopolar spindles.[15] This failure to complete mitosis triggers the mitotic checkpoint, causing cells to arrest in the G2/M phase of the cell cycle.[3] This specific state of mitotic arrest induced by PLK inhibition is often referred to as

"Polo arrest".[15] If this arrest is prolonged, the cell ultimately undergoes mitotic catastrophe and is eliminated through programmed cell death, or apoptosis.[4] This process can be observed experimentally as an increase in the sub-G1 cell population in flow cytometry analysis and the activation of executioner caspases like caspase-3.[19]

2.3 Downstream Effects on Tumor Suppressor Pathways, including p53 and p21

The cellular response to volasertib extends beyond simple mitotic arrest and involves the activation of key tumor suppressor pathways. Clinical and preclinical studies have shown that treatment with volasertib leads to a significant induction of p53 protein expression and the expression of its downstream transcriptional target, the cyclin-dependent kinase inhibitor p21.[19]

The functional status of the p53 pathway appears to be a critical determinant of the cellular fate following PLK1 inhibition, though the relationship is nuanced. Studies in non-small cell lung cancer (NSCLC) cell lines revealed that cells with wild-type p53 exhibited a less pronounced G2/M arrest compared to cells with non-functional p53.[3] However, these p53 wild-type cells were ultimately more sensitive to volasertib, as they were more prone to undergo apoptosis and cellular senescence following the mitotic disruption.[24] This complex interplay suggests that p53 status could be a predictive biomarker for volasertib sensitivity. However, a successful biomarker strategy would need to measure the ultimate outcome of cell death rather than relying on an intermediate mechanistic marker like the degree of G2/M arrest, which could be misleading.

2.4 Differential Cytotoxicity: Malignant vs. Non-Malignant Cells

A key feature of volasertib's therapeutic potential is its differential effect on cancerous versus normal cells, which provides a basis for its therapeutic window. Although volasertib inhibits PLK1 in all dividing cells, the ultimate outcome differs significantly.[2] In cancer cells, the induced "Polo arrest" is typically irreversible and leads to apoptosis.[3] In contrast, normal, non-malignant cells respond to PLK1 inhibition with a temporary and reversible arrest in the G1 and G2 phases of the cell cycle, without committing to apoptosis.[2] This specificity for inducing cell death in cancer cells is thought to enhance the drug's efficacy while minimizing toxicity to healthy tissues.[25]

---

3.0 Clinical Pharmacology: Human Pharmacokinetics and Metabolism (ADME)

The clinical utility of a drug is determined not only by its pharmacodynamics but also by its pharmacokinetic profile—the way it is absorbed, distributed, metabolized, and excreted (ADME) by the body. Volasertib possesses a distinct pharmacokinetic profile characterized by extensive distribution and slow elimination, which has profound implications for both its efficacy and its toxicity.

3.1 Absorption, Distribution, and Tissue Penetration

Volasertib has been formulated for both intravenous (IV) and oral administration, though clinical development has focused primarily on the IV route.[2] Following administration, the drug exhibits multi-compartmental pharmacokinetic behavior, meaning it distributes from the central circulation into various tissue compartments at different rates.[20]

A defining characteristic of volasertib is its exceptionally large volume of distribution at steady state (Vss​), which has been consistently reported in human studies to be greater than 4000 L, with specific values of 4150 L and 4500 L cited.[20] This large

Vss​ value, far exceeding total body water, indicates extensive partitioning from the plasma into peripheral tissues and suggests good tissue penetration.[15] While beneficial for reaching tumor sites, preclinical data indicates that exposure in the central nervous system (CNS) is significantly lower than in other organs and does not exceed plasma levels.[15]

3.2 Metabolic Pathways and Elimination Profile

A human ADME study using radiolabeled (14C) volasertib provided key insights into its fate in the body.[27]

• Metabolism: The parent drug, volasertib, is the primary circulating species, accounting for approximately 71.6% of the total drug-related radioactivity in plasma up to 8 hours after infusion. A metabolite, designated CD 10899, was identified, but it constitutes only a minor fraction (1.5%) of the total plasma radioactivity. A notable portion (~27%) of plasma radioactivity could not be attributed to either volasertib or CD 10899, and analysis of urine suggests the presence of additional, unidentified metabolites.[27]
• Elimination and Half-Life: Volasertib is characterized by a long terminal elimination half-life (t1/2​), consistently reported to be approximately 107–111 hours in clinical studies.[20] The primary metabolite, CD 10899, is eliminated even more slowly, with an apparent terminal half-life of 136 hours.[27]
• Excretion: The drug is cleared from the body via both renal and fecal routes. Approximately half of the administered radioactive dose is excreted within the first week, with elimination continuing at a slower rate thereafter. Renal excretion of unchanged volasertib is a minor pathway, accounting for just under 10% of the total administered dose.[27]

The combination of a very large volume of distribution and a long elimination half-life is a critical aspect of volasertib's profile. While these properties ensure prolonged target engagement and were considered an improvement over its predecessor compound, BI 2536, they also create a significant clinical liability.[15] The drug's persistence in the body means that its primary on-target toxicity—myelosuppression—is also sustained for a long period. This prolonged window of bone marrow suppression likely prevents timely hematopoietic recovery, leaving patients vulnerable to opportunistic infections. This direct link between the drug's pharmacokinetic properties and its safety profile is crucial for understanding the high rate of fatal infections observed in the pivotal POLO-AML-2 trial, especially within its frail, elderly patient population.

3.3 Key Pharmacokinetic Parameters from Human Studies

Quantitative analysis from clinical trials has defined several key parameters for volasertib.

• Clearance: Volasertib is described as a moderate clearance drug, with total plasma clearance values reported in the range of 792–807 mL/min.[20]
• Dose Proportionality: A population pharmacokinetic analysis of 501 patients demonstrated that the drug's kinetics are dose-independent, or linear, across a dose range of 150 mg to 550 mg.[31] This predictability simplifies dosing.
• Covariates: The same population analysis identified body surface area and ethnicity as significant factors influencing drug exposure. Notably, Japanese patients were found to have higher exposure, although this conclusion is tempered by the small proportion of Japanese patients (7%) in the dataset.[31]

3.4 Assessment of Drug-Drug Interaction Potential

Understanding a drug's potential to interact with other medications is essential for its safe clinical use.

• Interaction with Cytarabine: In studies combining volasertib with low-dose cytarabine (LDAC), population pharmacokinetic analyses found no evidence of a mutual pharmacokinetic interaction; neither drug appeared to alter the clearance or exposure of the other.[26]
• CYP3A4-Mediated Metabolism: A clinical trial (NCT01772563) was specifically designed to investigate the interaction between volasertib and itraconazole, a potent inhibitor of the cytochrome P450 enzyme CYP3A4.[32] The existence of this study suggests that CYP3A4-mediated metabolism is a relevant clearance pathway for volasertib, and co-administration with strong CYP3A4 inhibitors or inducers could alter its exposure.
• Other Potential Interactions: Pharmacodynamic interactions have also been noted. DrugBank lists a potential for an increased risk of methemoglobinemia when volasertib is combined with various local anesthetics (e.g., lidocaine, benzocaine) and an increased risk of thrombosis when used with erythropoiesis-stimulating agents.[1]

Table 3: Summary of Human Pharmacokinetic Parameters of Volasertib

Parameter	Value	Unit	Source(s)
Terminal Half-Life (t1/2​)	~111	hours	28
Volume of Distribution (Vss​)	>4000	L	26
Clearance (CL)	~800	mL/min	20
Major Metabolite(s)	CD 10899 (minor)	-	27
Route of Excretion	Urine and Feces	-	27
Renal Excretion (Unchanged)	~9.9	% of dose	27

---

4.0 Preclinical Development: Establishing the Therapeutic Rationale

Before advancing into human trials, volasertib underwent extensive preclinical evaluation to establish its mechanism of action, demonstrate its antineoplastic activity, and define its initial safety profile. These studies provided a strong and broad rationale for its clinical development, particularly in hematological malignancies.

4.1 In Vitro Antineoplastic Activity Across Diverse Malignancies

In cell culture experiments, volasertib demonstrated potent cytotoxic and anti-proliferative effects across a wide spectrum of human cancer cell lines. This activity was not confined to a single tumor type, suggesting a broad potential applicability based on the ubiquitous role of PLK1 in cell division.

• Broad-Spectrum Activity: Potent activity, characterized by inhibition of cell proliferation and induction of apoptosis, was confirmed in cell lines derived from colon cancer, non-small cell lung cancer (NSCLC), melanoma, and glioma stem cells.[2]
• Hematological Malignancies: The drug showed particularly strong efficacy in models of hematological cancers. Robust activity was observed in multiple AML cell lines and, critically, in primary bone marrow cells isolated directly from AML patients, providing direct evidence of its potential in this disease.[11]
• Pediatric Cancers: Preclinical studies also highlighted its potential in highly proliferative pediatric malignancies, with significant activity seen in rhabdomyosarcoma and neuroblastoma cell lines.[12]
• Overcoming Chemoresistance: A key finding from these in vitro studies was volasertib's ability to induce cell death in cancer cells that had acquired resistance to conventional anti-mitotic chemotherapies, such as taxanes and vinca alkaloids.[2] This suggested a distinct mechanism of action and positioned volasertib as a potential option for patients who had failed prior lines of therapy.

4.2 Efficacy and Tolerability in In Vivo Xenograft Models

The promising in vitro results were subsequently validated in animal models, primarily using human tumor xenografts implanted in immunodeficient mice. These studies confirmed that volasertib could achieve therapeutic concentrations in vivo, leading to significant antitumor effects with acceptable tolerability.

• Solid Tumor Models: In mice bearing xenografts of human colon cancer, NSCLC, melanoma, and glioma, systemic administration of volasertib resulted in marked antitumor activity, including significant tumor growth delay and, in some cases, complete tumor regression.[2]
• AML Models: The strong signal in AML was reinforced in vivo. In both subcutaneous and disseminated xenograft models of AML, volasertib treatment was highly efficacious, leading to marked tumor regression while being well-tolerated by the animals.[11]
• Combination Synergy: The potential for combination therapy was explored preclinically, revealing synergistic or additive effects. Co-administration of volasertib with standard-of-care agents like cytarabine and emerging therapies like hypomethylating agents (azacitidine, decitabine) enhanced its antitumor activity in AML models.[11] Synergy was also observed with vincristine in pediatric cancer models.[12]

Despite the broad and compelling preclinical activity observed across numerous solid tumor models, the clinical activity later seen in Phase I and II trials in patients with solid tumors was relatively modest. This common "preclinical-to-clinical translation gap" highlights the limitations of xenograft models in predicting human efficacy. While PLK1 remains a valid biological target, its inhibition as a monotherapy may not be sufficient to overcome the complex resistance mechanisms present in established, heavily pretreated solid tumors in patients. This translational disconnect likely informed the strategic decision by Boehringer Ingelheim to pivot and concentrate its development efforts on AML, where the preclinical rationale was not only strong but was also supported by more encouraging early clinical signals.

---

5.0 Clinical Development in Acute Myeloid Leukemia (AML)

The clinical development program for volasertib ultimately focused on acute myeloid leukemia (AML), a disease characterized by high proliferative rates and where its target, PLK1, is highly expressed. The journey in AML was a dramatic arc, beginning with strong early-phase data that generated significant optimism, followed by a definitive late-stage failure that halted its development under its original sponsor.

Table 4: Overview of Major Clinical Trials Investigating Volasertib

Trial ID (NCT)	Phase	Indication(s)	Status	Intervention(s)	Key Findings/Purpose
NCT01721876	3	Acute Myeloid Leukemia (AML)	Completed	Volasertib + Cytarabine	Pivotal trial in elderly AML; failed to meet primary endpoint due to toxicity 34
NCT00804856	2	Acute Myeloid Leukemia (AML)	Completed	Volasertib + Cytarabine	Randomized trial in elderly AML; showed significant improvement in ORR, EFS, and OS 17
NCT01662505	1	Acute Myeloid Leukemia (AML)	Completed	Volasertib	Dose-finding and safety study in Japanese patients with AML 36
NCT00969553	1	Advanced Solid Cancers	Completed	Volasertib	First-in-human dose-finding and safety study 28
NCT01022853	1/2	Advanced Solid Tumors	Completed	Volasertib + Nintedanib	Combination therapy safety and efficacy study 32
NCT01145885	1	Advanced Solid Tumors	Completed	Volasertib	Human ADME (Absorption, Distribution, Metabolism, Excretion) study 32

5.1 Early Phase Trials: Dose-Finding and Initial Signals of Efficacy

The initial clinical studies for volasertib established its safety profile, defined tolerable doses, and provided the first indications of its antileukemic activity in humans.

• First-in-Human Study: The first clinical trial was a Phase I dose-escalation study in 65 patients with a variety of advanced solid tumors (NCT00969553).[28] This study established a manageable safety profile, with myelosuppression being the primary dose-limiting toxicity. It determined a maximum tolerated dose (MTD) of 400 mg administered as a single IV infusion every 3 weeks, with a recommended Phase II dose (RP2D) of 300 mg based on overall tolerability.[28]
• Phase I in AML: A dedicated Phase I trial (NCT01662505) was conducted in Japanese patients with relapsed/refractory or untreated AML to establish the MTD and safety in this specific population and disease context.[36]
• Phase I/II Combination with LDAC: The most critical early study in AML was a Phase I/II trial (part of NCT00804856) that evaluated volasertib in combination with low-dose cytarabine (LDAC). The dose-finding portion of this study established the MTD for the combination regimen as 350 mg of volasertib (IV on days 1 and 15 of a 28-day cycle).[17] In a cohort of 32 heavily pretreated patients, this combination demonstrated significant antileukemic activity, with 7 patients (22%) achieving a complete remission (CR) or CR with incomplete blood count recovery (CRi). This was the first strong clinical evidence supporting the combination's potential in AML and provided the rationale to proceed to a randomized evaluation.[26]

5.2 The Randomized Phase II Study (NCT00804856): A Foundation of Promise in Elderly AML

Building on the encouraging Phase I data, a randomized, open-label Phase II study was conducted that would become the cornerstone of volasertib's development program. This trial was designed to evaluate the efficacy and safety of the volasertib-LDAC combination against LDAC monotherapy in a population with a high unmet medical need: elderly patients (median age 75) with previously untreated AML who were deemed ineligible for intensive induction chemotherapy.[17]

The results of this 87-patient trial were highly promising and generated considerable excitement. The combination of volasertib and LDAC demonstrated superiority over LDAC alone across all key efficacy endpoints [39]:

• Objective Response Rate (ORR): The primary endpoint of ORR (CR + CRi) was more than doubled in the combination arm, reaching 31.0% compared to 13.3% for LDAC alone. While this difference narrowly missed conventional statistical significance (p=0.052), the magnitude of the benefit was clinically compelling.[17]
• Event-Free Survival (EFS): Patients in the combination arm experienced a significantly longer median EFS of 5.6 months, compared to 2.3 months for those on LDAC alone (Hazard Ratio 0.57; p=0.021).[17]
• Overall Survival (OS): Most importantly, the combination therapy translated into a statistically significant improvement in overall survival. The median OS was 8.0 months for the volasertib arm versus 5.2 months for the control arm (HR 0.63; p=0.047).[17]

The strength of these results, particularly the survival benefit in a difficult-to-treat population, led the FDA to grant volasertib a Breakthrough Therapy designation in 2013.[38] This designation, along with subsequent Orphan Drug status, underscored the drug's perceived potential and paved the way for an expedited late-stage development program, culminating in the design of the pivotal POLO-AML-2 trial.[29]

5.3 The POLO-AML-2 Trial (NCT01721876): A Post-Mortem of Phase III Failure

The POLO-AML-2 trial was designed as the definitive, confirmatory study to validate the promising findings of the Phase II trial and support global regulatory approval. However, the trial failed to replicate the earlier success and ultimately led to the termination of the development program.

5.3.1 Trial Design, Patient Population, and Endpoints

POLO-AML-2 was a large-scale, multicenter, randomized, double-blind, placebo-controlled Phase III trial. It enrolled 666 patients aged 65 or older with previously untreated AML who were ineligible for intensive therapy—the same population as the preceding Phase II study.[34] Patients were randomized 2:1 to receive either volasertib plus LDAC or a placebo plus LDAC.[43] The primary endpoint was the objective response rate (ORR).[34]

5.3.2 Analysis of Efficacy Outcomes: Why the Primary Endpoint Was Not Met

The trial did not meet its primary endpoint. While the ORR was numerically higher in the volasertib arm (25.2%) compared to the placebo arm (16.8%), the difference was not statistically significant (Odds Ratio 1.66; p=0.071).[34] This result failed to confirm the magnitude of benefit observed in the smaller, open-label Phase II study and was insufficient to demonstrate clinical superiority. This discrepancy is a classic example of the "Phase II to Phase III translation problem," where promising signals from smaller, less rigorously controlled studies are not borne out in larger, blinded, confirmatory trials. The initial benefit may have been an overestimation due to statistical chance or unconscious biases inherent in an open-label design.

5.3.3 Deconstructing the Safety Profile: The Critical Impact of Fatal Infections

While the efficacy results were disappointing, the safety findings were the decisive factor in the trial's failure. The addition of volasertib to LDAC led to a dramatic increase in severe and fatal toxicity.

• Increased Fatal Adverse Events: The rate of fatal adverse events was substantially higher in the volasertib arm, occurring in 31.2% of patients compared to 18.0% in the placebo arm.[34]
• Excess Fatal Infections: The primary driver of this increased mortality was a nearly threefold increase in the frequency of fatal infections. These occurred in 16.6% to 17.1% of patients receiving volasertib, compared to only 5.1% to 6.3% of those receiving placebo.[34]
• Negative Impact on Overall Survival: This severe toxicity completely negated any modest efficacy benefit. At the time of the primary analysis, there was a negative trend in overall survival for the volasertib arm (median OS: 4.8 vs. 6.5 months).[43] The final analysis confirmed this, showing no survival advantage (median OS: 5.6 vs. 6.5 months; HR 0.97).[34]

The clear negative risk-benefit profile, driven by an unacceptable rate of fatal infections, led to the unblinding of the study and the subsequent discontinuation of volasertib's development by Boehringer Ingelheim.[45] The failure mode was a direct and foreseeable consequence of applying a highly myelosuppressive agent with a long pharmacokinetic half-life to a frail, elderly population without adequate toxicity mitigation strategies in place.

Table 5: Comparative Efficacy Outcomes from Phase II (NCT00804856) and Phase III (POLO-AML-2) Trials

Endpoint	Phase II (V+LDAC)	Phase II (LDAC Alone)	Phase III (V+LDAC)	Phase III (P+LDAC)
Objective Response Rate (ORR)	31.0%	13.3%	25.2%	16.8%
Median Event-Free Survival (EFS)	5.6 months	2.3 months	Not Reported	Not Reported
Median Overall Survival (OS)	8.0 months	5.2 months	5.6 months	6.5 months
Sources	17	17	34	34

---

6.0 Clinical Investigation in Solid Tumors

While the primary focus of volasertib's development was on AML, it was also evaluated in a range of solid tumors, consistent with the broad overexpression of its target, PLK1. However, the clinical activity observed in these indications was generally modest.

6.1 Summary of Phase I/II Trials and Observed Antitumor Activity

The initial clinical evaluation of volasertib was in patients with advanced solid malignancies.

• First-in-Human Phase I Study: The foundational Phase I dose-escalation trial (NCT00969553) enrolled 65 patients with various refractory solid tumors. This study demonstrated that the drug was safe to administer and stable in the bloodstream. It also provided preliminary evidence of antitumor activity, with three patients (5%) achieving a confirmed partial response (PR), 48% achieving stable disease (SD), and six patients remaining progression-free for over six months.[2]
• Urothelial Cancer: One of the more encouraging signals in solid tumors came from a Phase II trial (part of NCT01022853) of single-agent volasertib as a second-line treatment for advanced urothelial cancer. An interim analysis of 31 patients showed a PR rate of 19% and an SD rate of 23%. This level of activity was sufficient to meet the prespecified criteria for continuing the trial to its second stage.[32]
• Combination Studies: Several Phase I trials were conducted to explore volasertib in combination with standard chemotherapies and other targeted agents. These included studies combining volasertib with cisplatin or carboplatin (NCT00969761), the EGFR inhibitor afatinib (NCT01206816), and the multi-kinase angiogenesis inhibitor nintedanib (NCT01022853).[32]
• Overall Assessment: Despite these exploratory efforts and some early signs of activity, particularly in urothelial cancer, the overall efficacy of volasertib in unselected solid tumor populations was deemed insufficient to warrant late-stage development.[24] The clinical program subsequently pivoted to focus almost exclusively on AML, where the biological rationale was stronger and the clinical signals were more compelling.

---

7.0 Comprehensive Safety and Tolerability Profile

The clinical utility of any antineoplastic agent is defined by the balance between its efficacy and its toxicity. For volasertib, a potent inhibitor of a fundamental cellular process, the safety and tolerability profile proved to be the ultimate determinant of its clinical fate.

7.1 Dose-Limiting Toxicities and Determination of the Maximum Tolerated Dose (MTD)

Early-phase dose-escalation studies are designed to identify the highest dose of a new drug that can be given safely. For volasertib, these trials consistently identified myelosuppression as the principal dose-limiting toxicity (DLT).

• Primary DLTs: Across Phase I trials in both solid tumors and AML, the most common DLTs were reversible hematological events, including Grade 3/4 thrombocytopenia (low platelet count), neutropenia (low neutrophil count), and febrile neutropenia (neutropenia accompanied by fever, a medical emergency).[2] At higher dose levels, non-hematological DLTs such as Grade 3 mucositis (inflammation of mucous membranes) and Grade 4 pneumonia were also observed.[26]
• Maximum Tolerated Dose (MTD): Based on the DLTs observed, the following MTDs were established:
• Monotherapy (every 3 weeks): The MTD was determined to be 400 mg, although a dose of 300 mg was selected as the recommended Phase II dose for further development based on a better overall tolerability profile.[28]
• Combination with LDAC (days 1 & 15): In combination with low-dose cytarabine, the MTD for volasertib was established at 350 mg per dose.[26]

7.2 Profile of Adverse Events from Monotherapy and Combination Therapy Trials

The overall pattern of adverse events (AEs) seen with volasertib is consistent with its mechanism as a potent anti-mitotic agent.

• Most Common AEs: The most frequently reported drug-related AEs across all studies were hematological toxicities (anemia, neutropenia, thrombocytopenia) and constitutional symptoms such as fatigue, decreased appetite, and nausea.[2]
• Adverse Events in AML Trials: The safety profile in the pivotal AML trials highlighted the significant toxicity of the combination therapy.
• In the Phase II trial (NCT00804856), the volasertib plus LDAC arm experienced a substantially higher frequency of Grade 3 or higher AEs compared to the LDAC alone arm. The most pronounced differences were seen for febrile neutropenia (38% vs. 7%), infections (38% vs. 7%), and gastrointestinal AEs (21% vs. 7%).[40]
• In the Phase III POLO-AML-2 trial (NCT01721876), this toxicity was even more apparent. The most common AEs in the volasertib arm were infections and infestations (occurring in 81.3% of patients vs. 63.5% with placebo) and febrile neutropenia (60.4% vs. 29.3%).[34] The high incidence of fatal infections (17.1% vs. 6.3%) was the primary safety concern that led to the trial's failure.[34]

Table 6: Profile of Key Grade ≥3 Adverse Events in AML Combination Trials

Adverse Event	Phase II (V+LDAC)	Phase II (LDAC Alone)	POLO-AML-2 (V+LDAC)	POLO-AML-2 (P+LDAC)
Febrile Neutropenia	38%	7%	60.4%	29.3%
Infections (All)	38%	7%	81.3% (All Grades)	63.5% (All Grades)
Fatal Infections	Not specified	Not specified	17.1%	6.3%
Thrombocytopenia	Not specified	Not specified	Not specified	Not specified
Anemia	Not specified	Not specified	Not specified	Not specified
Sources	40	40	34	34

---

8.0 Regulatory Trajectory and Development History

The regulatory and corporate history of volasertib mirrors its clinical journey, marked by initial enthusiasm and special designations, followed by discontinuation and a subsequent effort at repurposing.

8.1 FDA and EMA Special Designations: A Timeline of Promise and Revocation

Based on the highly encouraging results from the randomized Phase II trial in elderly AML, volasertib was granted several special designations by regulatory authorities in the United States and Europe, intended to facilitate and expedite its development.

• FDA Breakthrough Therapy Designation: In September 2013, the U.S. FDA granted Breakthrough Therapy designation to volasertib for use in combination with LDAC for the treatment of elderly patients with previously untreated AML.[38] This designation is reserved for drugs that may demonstrate substantial improvement over existing therapies for serious conditions and allows for more intensive FDA guidance and a potentially accelerated review.
• FDA Orphan Drug Designation: On April 14, 2014, the FDA granted Orphan Drug designation for the treatment of AML, a status given to drugs intended for rare diseases (affecting fewer than 200,000 people in the U.S.).[47] This provides incentives such as tax credits and potential market exclusivity. However, following the failure of the Phase III trial and discontinuation of the program, this designation was officially withdrawn or revoked on June 19, 2019.[47] This regulatory action served as the formal closure of the drug's initial development chapter.
• EMA Orphan Designation: Similarly, the European Medicines Agency (EMA) granted orphan designation (EU/3/14/1255) for the treatment of AML on March 26, 2014.[49] The associated Paediatric Investigation Plan (PIP) for the drug was later officially discontinued, reflecting the halt in its overall development.[50]

8.2 Discontinuation by Boehringer Ingelheim and Subsequent Repurposing

The failure of the POLO-AML-2 trial to meet its primary efficacy endpoint, combined with the unacceptable level of fatal toxicity, led to a pivotal strategic shift by the original developer.

• Discontinuation of Development: In December 2016, Boehringer Ingelheim officially announced the discontinuation of the global clinical development of volasertib for strategic reasons, directly stemming from the negative outcome of the Phase III trial.[45]
• Out-Licensing and Repurposing: The volasertib asset was not permanently shelved. In September 2019, shortly after the FDA orphan designation was formally withdrawn, Boehringer Ingelheim signed a worldwide, exclusive licensing agreement with Oncoheroes Biosciences.[53] The new focus for Oncoheroes was to repurpose volasertib for pediatric cancer indications, such as rhabdomyosarcoma, where strong independent academic data had emerged supporting its potential.[51]
• Partnership for Precision Medicine: The drug's journey took another turn in November 2021, when Oncoheroes partnered with Notable Labs to continue its development in AML.[45] Notable Labs acquired the exclusive worldwide rights to develop and commercialize volasertib for most indications, leveraging its unique predictive biomarker platform to guide a new clinical strategy.[55] This transition marked the beginning of volasertib's second life, shifting from a broad population approach to a targeted, precision medicine paradigm.

---

9.0 The Revival of Volasertib: A New Paradigm in Precision Oncology

The story of volasertib did not end with the failure of the POLO-AML-2 trial. Its demonstrated antileukemic activity made it a candidate for revival, contingent on a new strategy that could overcome the toxicity that led to its initial downfall. This new approach, spearheaded by Notable Labs, is a case study in modern, biomarker-driven drug development.

9.1 Rationale and Design of the Notable Labs Phase II Trial in Relapsed/Refractory AML

The new clinical trial for volasertib is designed to address the specific shortcomings of the original Phase III study while targeting a population with an even greater unmet medical need.

• New Patient Population: The trial will focus on patients with relapsed/refractory (R/R) AML, including those whose disease has progressed after treatment with modern standards of care like venetoclax-based regimens.[45] This is a population with very poor prognosis and limited therapeutic options.
• New Combination Partner: Instead of low-dose cytarabine, the new study will evaluate volasertib in combination with the hypomethylating agent decitabine.[45] Preclinical data had previously shown synergistic activity between volasertib and hypomethylating agents.[11]
• Toxicity Mitigation Strategies: The trial design directly incorporates lessons learned from the POLO-AML-2 failure. To improve the safety profile, the protocol includes:

1. Body-Surface Area (BSA)-Based Dosing: Moving away from the "one-size-fits-all" flat dose used previously, BSA-based dosing will be implemented to better tailor the drug exposure to individual patients, potentially reducing the risk of severe toxicity.[55]
2. Enhanced Supportive Care: The protocol standardizes the use of best supportive care, including prophylactic antibiotic treatment, to proactively manage and reduce the risk of the severe infections that were fatal in the prior trial.[55]

9.2 The Role of the Predictive Precision Medicine Platform (PPMP) in Patient Selection

The most innovative aspect of volasertib's revival is the central role of a functional diagnostic platform to guide patient enrollment. This strategy aims to fundamentally change the drug's risk-benefit equation by treating only those patients who are most likely to benefit.

• Biomarker-Driven Enrollment: The core of the strategy is the use of Notable Labs' proprietary Predictive Precision Medicine Platform (PPMP). This platform involves treating a patient's own cancer cells (ex vivo from a blood or bone marrow sample) with volasertib to functionally determine their sensitivity to the drug before they are enrolled in the trial.[57]
• Companion Diagnostic Development: The clinical program is designed in two parts. An initial dose-optimization phase will enroll a small cohort of "all-comers" to confirm the safety of the new regimen. The main part of the trial (Phase 2b) will then exclusively enroll patients who are predicted to be responders based on the PPMP assay. This approach simultaneously evaluates the drug and co-develops a companion diagnostic test to identify the appropriate patient population.[55]
• Central Hypothesis: The fundamental hypothesis is that the therapeutic index of volasertib is too narrow for an unselected population but may be highly favorable in a pre-selected, sensitive sub-population. By enriching the trial with predicted responders, the goal is to achieve a much higher clinical response rate than the 25-30% observed previously. A significantly higher efficacy rate could justify the inherent safety risks, even with improved management. This approach represents a shift from trying to make the drug safer to finding the patients in whom the drug is most effective.

9.3 Future Perspectives and Unanswered Questions

The new Phase II trial was planned to initiate in the second quarter of 2024, with initial data from the dose-optimization prelude anticipated in the fourth quarter of 2024 and the first efficacy results from the PPMP-selected cohort expected in the first half of 2025.[55]

The ultimate success of this revival hinges on one critical question: can a patient selection strategy overcome a drug's inherent toxicity? The future of volasertib depends entirely on the ability of the PPMP to identify a patient population in which the magnitude of clinical benefit is so profound that it clearly outweighs the significant, albeit better-managed, safety risks. If successful, this approach would not only salvage a potent antileukemic agent but also provide a powerful validation for functional precision medicine as a tool to de-risk and resurrect other promising but challenging oncology assets.

---

10.0 Expert Analysis and Strategic Outlook

The trajectory of volasertib offers a compelling and instructive narrative in modern oncology drug development. Its journey from a promising first-in-class agent to a failed Phase III asset, and now to a candidate for precision-guided revival, encapsulates many of the key challenges and emerging strategies in the field.

10.1 Synthesis of Volasertib's Strengths and Weaknesses

A balanced assessment of volasertib reveals a profile of clear strengths counterbalanced by significant, historically fatal, weaknesses.

• Strengths:
• Potent and Well-Characterized Mechanism: Volasertib is an exceptionally potent inhibitor of PLK1, a clinically validated and rational target in highly proliferative cancers like AML.
• Demonstrated Clinical Activity: Despite its Phase III failure, the drug has repeatedly demonstrated single-agent and combination antileukemic activity in AML patients, achieving complete remissions even in refractory settings.
• Favorable Pharmacokinetics for Target Engagement: Its long half-life and extensive distribution ensure prolonged and widespread target inhibition, which is theoretically advantageous for efficacy.
• Weaknesses:
• Narrow Therapeutic Index: The dose required for efficacy is very close to the dose that causes severe and life-threatening toxicity.
• Severe Myelosuppression: Its on-target mechanism of mitotic arrest inevitably leads to profound myelosuppression, which is the primary source of its dose-limiting and fatal toxicities.
• Problematic Pharmacokinetics for Safety: The same long half-life that aids target engagement becomes a major liability by prolonging the period of neutropenia and vulnerability to infection.
• Historical Failure: The drug carries the stigma of a large, well-conducted Phase III trial failure, which creates a high bar for any revival effort.

10.2 Critical Assessment of the Biomarker-Driven Revival Strategy

The strategy employed by Notable Labs is both logical and ambitious. It directly addresses the central reason for the POLO-AML-2 failure: an unfavorable risk-benefit ratio in an unselected population. By seeking to enrich the treated population for responders, the strategy aims to dramatically improve the benefit side of the equation.

The success of this approach is contingent on several factors. First, the PPMP assay must be robust, reproducible, and truly predictive of clinical response. Preliminary ex vivo data presented by the company suggests that it can identify a subset of AML samples (~25-33%) that are highly sensitive.[57] Second, the toxicity mitigation strategies, including BSA-based dosing and enhanced supportive care, must be effective in reducing the incidence of fatal infections. Finally, and most critically, the magnitude of clinical benefit in the PPMP-selected population must be overwhelmingly positive. A modest improvement in response rate will likely be insufficient to justify the drug's risks. The trial will need to demonstrate not just statistically significant, but clinically profound and durable responses in the selected patients.

This revival represents a microcosm of a major trend in oncology: the shift toward functional precision medicine. Rather than relying solely on genomic biomarkers, this approach assesses the functional response of a patient's tumor to a drug ex vivo. If successful, the volasertib program could serve as a powerful proof-of-concept for this strategy, potentially creating a blueprint for re-evaluating other potent oncology drugs that have failed due to toxicity in broad populations.

10.3 Potential Future Positioning in the Oncology Armamentarium

Should the biomarker-guided revival prove successful, volasertib will not re-emerge as a broad-use agent for AML. Instead, it would be positioned as a highly specialized, niche therapy for a biomarker-defined subset of patients with relapsed/refractory AML. Its use would be inextricably linked to its companion diagnostic test.

The ultimate impact of volasertib may extend beyond its own clinical use. A successful revival would send a powerful message to the pharmaceutical industry about the value locked away in pipelines of "failed" drugs. It would demonstrate that some assets are not inherently flawed but were simply tested in the wrong patient population in an era before advanced predictive diagnostics were available. The journey of volasertib, therefore, is more than just the story of a single molecule; it is a test of a new philosophy in drug development, where the key to unlocking a drug's potential lies not in changing the drug itself, but in precisely defining the patient for whom it is intended.

Works cited

1. Volasertib: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed September 11, 2025, https://go.drugbank.com/drugs/DB12062
2. Volasertib - Wikipedia, accessed September 11, 2025, https://en.wikipedia.org/wiki/Volasertib
3. Volasertib | BI-6727 | CAS#755038-65-4 | PLK1 Inhibitor - MedKoo Biosciences, accessed September 11, 2025, https://www.medkoo.com/products/5951
4. Volasertib | PLK inhibitor | 99.78%(HPLC) | In Stock - Selleck Chemicals, accessed September 11, 2025, https://www.selleckchem.com/products/BI6727-Volasertib.html
5. Definition of volasertib - NCI Drug Dictionary, accessed September 11, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/volasertib
6. Volasertib - Oncoheroes Biosciences/Notable Labs - AdisInsight - Springer, accessed September 11, 2025, https://adisinsight.springer.com/drugs/800026979
7. Volasertib | C34H50N8O3 | CID 10461508 - PubChem, accessed September 11, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/10461508
8. Compound: VOLASERTIB (CHEMBL1233528) - ChEMBL - EMBL-EBI, accessed September 11, 2025, https://www.ebi.ac.uk/chembl/explore/compound/CHEMBL1233528
9. Volasertib (5mg) from selleckchem - SmallMolecules.com, accessed September 11, 2025, https://smallmolecules.com/product/755038-65-4-selleckchem-volasertib-bi-6727-5mg/
10. volasertib | Ligand page - IUPHAR/BPS Guide to PHARMACOLOGY, accessed September 11, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7947
11. Efficacy and mechanism of action of volasertib, a potent and ..., accessed September 11, 2025, https://pubmed.ncbi.nlm.nih.gov/25576074/
12. Polo-like Kinase Inhibitor Volasertib Exhibits Antitumor Activity and Synergy with Vincristine in Pediatric Malignancies - Anticancer Research, accessed September 11, 2025, https://ar.iiarjournals.org/content/anticanres/36/2/599.full.pdf
13. Structure-Based Discovery of a Highly Selective, Oral Polo-Like Kinase 1 Inhibitor with Potent Antileukemic Activity | Journal of Medicinal Chemistry - ACS Publications, accessed September 11, 2025, https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c02422
14. Volasertib (BI 6727) | PLK1 Inhibitor | MedChemExpress, accessed September 11, 2025, https://www.medchemexpress.com/Volasertib.html
15. Discovery and development of the Polo-like kinase inhibitor volasertib in cancer therapy - CORE, accessed September 11, 2025, https://core.ac.uk/download/pdf/30850517.pdf
16. Identification of volasertib-resistant mechanism and evaluation of combination effects with volasertib and other agents on acute myeloid leukemia - PMC, accessed September 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5667974/
17. Randomized, phase 2 trial of low-dose cytarabine with or without volasertib in AML patients not suitable for induction therapy | Blood - ASH Publications, accessed September 11, 2025, https://ashpublications.org/blood/article/124/9/1426/73070/Randomized-phase-2-trial-of-low-dose-cytarabine
18. en.wikipedia.org, accessed September 11, 2025, https://en.wikipedia.org/wiki/Volasertib#:~:text=4%20References-,Mechanism%20of%20action,pocket%20of%20the%20PLK1%20protein.
19. Small molecule inhibition of polo-like kinase 1 by volasertib (BI 6727) causes significant melanoma growth delay and regression in vivo - PubMed, accessed September 11, 2025, https://pubmed.ncbi.nlm.nih.gov/27793694/
20. A phase I dose escalation study of the polo-like kinase 1 inhibitor volasertib (BI 6727) with two different dosing schedules in patients with advanced solid malignancies. - ASCO, accessed September 11, 2025, https://www.asco.org/abstracts-presentations/ABSTRACT77872
21. volasertib - My Cancer Genome, accessed September 11, 2025, https://www.mycancergenome.org/content/drugs/volasertib/
22. (PDF) Efficacy and Mechanism of Action of Volasertib, a Potent and Selective Inhibitor of Polo-Like Kinases, in Preclinical Models of Acute Myeloid Leukemia - ResearchGate, accessed September 11, 2025, https://www.researchgate.net/publication/270705576_Efficacy_and_Mechanism_of_Action_of_Volasertib_a_Potent_and_Selective_Inhibitor_of_Polo-Like_Kinases_in_Preclinical_Models_of_Acute_Myeloid_Leukemia
23. Small molecule inhibition of polo-like kinase 1 by volasertib (BI 6727 ..., accessed September 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5171235/
24. In vitro study of the Polo‐like kinase 1 inhibitor volasertib in non‐small‐cell lung cancer reveals a role for the tumor suppressor p53 - PMC, accessed September 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6487694/
25. fda – Page 21 - New Drug Approvals, accessed September 11, 2025, https://newdrugapprovals.org/tag/fda/page/21/?iframe=true&preview=true%2Ffeed%2F
26. Phase I/II Study of Volasertib (BI 6727), An Intravenous Polo-Like Kinase (Plk) Inhibitor, in Patients with Acute Myeloid Leukemia (AML) - ResearchGate, accessed September 11, 2025, https://www.researchgate.net/publication/336477193_Phase_III_Study_of_Volasertib_BI_6727_An_Intravenous_Polo-Like_Kinase_Plk_Inhibitor_in_Patients_with_Acute_Myeloid_Leukemia_AML_Updated_Results_of_the_Dose_Finding_Phase_I_Part_for_Volasertib_in_Combi
27. Trial synopsis 1230.23_DR - Boehringer Ingelheim, accessed September 11, 2025, https://content.boehringer-ingelheim.com/DAM/0c566781-33d5-4821-bd4c-ac760188dab5/1230-0023_synopsis.pdf
28. A phase I, dose-escalation study of the novel Polo-like kinase inhibitor volasertib (BI 6727) in patients with advanced solid tumours - PubMed, accessed September 11, 2025, https://pubmed.ncbi.nlm.nih.gov/22119200/
29. Volasertib for the Treatment of Acute Myeloid Leukemia: A Review of Preclinical and Clinical Development | Request PDF - ResearchGate, accessed September 11, 2025, https://www.researchgate.net/publication/263296418_Volasertib_for_the_Treatment_of_Acute_Myeloid_Leukemia_A_Review_of_Preclinical_and_Clinical_Development
30. Discovery and development of the Polo-like kinase inhibitor volasertib in cancer therapy, accessed September 11, 2025, https://www.researchgate.net/publication/263972081_Discovery_and_development_of_the_Polo-like_kinase_inhibitor_volasertib_in_cancer_therapy
31. Population Pharmacokinetics of Volasertib Administered in Patients ..., accessed September 11, 2025, https://www.researchgate.net/publication/317778105_Population_Pharmacokinetics_of_Volasertib_Administered_in_Patients_with_Acute_Myeloid_Leukaemia_as_a_Single_Agent_or_in_Combination_with_Cytarabine
32. Volasertib Completed Phase 1 Trials for Neoplasms Treatment | DrugBank Online, accessed September 11, 2025, https://go.drugbank.com/drugs/DB12062/clinical_trials?conditions=DBCOND0027948&phase=1&purpose=treatment&status=completed
33. The polo-like kinase 1 inhibitor volasertib synergistically increases radiation efficacy in glioma stem cells | Oncotarget, accessed September 11, 2025, https://www.oncotarget.com/article/24041/text/
34. Adjunctive Volasertib in Patients With Acute Myeloid Leukemia not ..., accessed September 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8328241/
35. Volasertib Completed Phase 3 Trials for Acute Myeloid Leukemia Treatment - DrugBank, accessed September 11, 2025, https://go.drugbank.com/drugs/DB12062/clinical_trials?conditions=DBCOND0029883&phase=3&purpose=treatment&status=completed
36. ANLL Completed Phase 1 Trials for Volasertib (DB12062) | DrugBank Online, accessed September 11, 2025, https://go.drugbank.com/indications/DBCOND0042650/clinical_trials/DB12062?phase=1&status=completed
37. Study Results | NCT01145885 | BI 6727 (Volasertib) Human ADME, accessed September 11, 2025, https://www.clinicaltrials.gov/study/NCT01145885?term=BI%206727&rank=4&tab=results
38. Volasertib Given Breakthrough Therapy Designation - American Journal of Managed Care, accessed September 11, 2025, https://www.ajmc.com/view/volasertib-given-breakthrough-therapy-designation
39. Boehringer Ingelheim's volasertib showed in a Phase II study an improvement in overall survival in older AML patients | Fierce Biotech, accessed September 11, 2025, https://www.fiercebiotech.com/biotech/boehringer-ingelheim-s-volasertib-showed-a-phase-ii-study-an-improvement-overall-survival
40. Boehringer Ingelheim's volasertib Phase II data including new overall survival results in older patients with acute myeloid leukemia published in Blood - PR Newswire, accessed September 11, 2025, https://www.prnewswire.com/news-releases/boehringer-ingelheims-volasertib-phase-ii-data-including-new-overall-survival-results-in-older-patients-with-acute-myeloid-leukemia-published-in-blood-266190861.html
41. Volasertib – Knowledge and References - Taylor & Francis, accessed September 11, 2025, https://taylorandfrancis.com/knowledge/Medicine_and_healthcare/Pharmaceutical_medicine/Volasertib/
42. Boehringer Ingelheim's investigational volasertib receives FDA Breakthrough Therapy designation - PR Newswire, accessed September 11, 2025, https://www.prnewswire.com/news-releases/boehringer-ingelheims-investigational-volasertib-receives-fda-breakthrough-therapy-designation-224041091.html
43. PHASE III RANDOMIZED TRIAL OF VOLASERTIB PLUS LOW-DOSE CYTARABINE... by Prof. Dr. Hartmut Döhner - EHA Library, accessed September 11, 2025, https://library.ehaweb.org/eha/2016/21st/135257/hartmut.dhner.phase.iii.randomized.trial.of.volasertib.plus.low-dose.html
44. Results of Phase III study of volasertib for the treatment of acute myeloid leukaemia presented - 1stOncology, accessed September 11, 2025, https://www.1stoncology.com/blog/results-of-phase-iii-study-of-volasertib-for-the-treatment-of-acute-myeloid-leukaemia-presented1234535646/
45. Notable Labs hopes for success with Boehringer's failed AML drug - Clinical Trials Arena, accessed September 11, 2025, https://www.clinicaltrialsarena.com/news/notable-labs-launch-trial-with-failed-volasertib/
46. Phase II study of single-agent volasertib (BI 6727) for second-line treatment of urothelial cancer (UC). - ASCO, accessed September 11, 2025, https://www.asco.org/abstracts-presentations/ABSTRACT72206
47. Search Orphan Drug Designations and Approvals - FDA, accessed September 11, 2025, https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=415913
48. Volasertib Granted Orphan Drug Designation for Acute Myeloid Leukemia - The ASCO Post, accessed September 11, 2025, https://ascopost.com/issues/may-15-2014/volasertib-granted-orphan-drug-designation-for-acute-myeloid-leukemia/
49. EU/3/14/1255 - orphan designation for treatment of acute myeloid leukaemia | European Medicines Agency (EMA), accessed September 11, 2025, https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-14-1255
50. EMEA-000674-PIP02-11-M01 - paediatric investigation plan - European Medicines Agency, accessed September 11, 2025, https://www.ema.europa.eu/en/medicines/human/paediatric-investigation-plans/emea-000674-pip02-11-m01
51. Ricardo Garcia: The Power of Repurposing - NFCR, accessed September 11, 2025, https://www.nfcr.org/blog/ricardo-garcia-the-power-of-repurposing/
52. Volasertib as a monotherapy or in combination with azacitidine in patients with myelodysplastic syndrome, chronic myelomonocytic leukemia, or acute myeloid leukemia: summary of three phase I studies - PMC, accessed September 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9124414/
53. Oncoheroes Biosciences Inc. and Boehringer Ingelheim International GmbH sign exclusive licensing agreement for volasertib, accessed September 11, 2025, https://oncoheroes.com/press-releases-content/2019/9/11/oncoheroes-biosciences-inc-and-boehringer-ingelheim-international-gmbh-sign-exclusive-licensing-agreement-for-volasertib
54. Volasertib, a potential new treatment for rhabdomyosarcoma, receives Orphan Drug Designation from the U.S. FDA - Oncoheroes Biosciences, accessed September 11, 2025, https://oncoheroes.com/press-releases-content/2020/10/14/volasertib-a-potential-new-treatment-for-rhabdomyosarcoma-receives-orphan-drug-designation-from-the-us-fda
55. Notable Labs Gets FDA Nod for Volasertib Phase 2 Study - Patsnap Synapse, accessed September 11, 2025, https://synapse.patsnap.com/article/notable-labs-gets-fda-nod-for-volasertib-phase-2-study
56. Notable Labs advances Phase 2 AML treatment study - Investing.com, accessed September 11, 2025, https://www.investing.com/news/company-news/notable-labs-advances-phase-2-aml-treatment-study-93CH-3533462
57. Abstract 5178: Guided by a predictive ex vivo test: Bringing the PLK1 inhibitor volasertib back into the clinic for venetoclax-HMA relapsed/refractory acute myeloid leukemia patients | Cancer Research - AACR Journals, accessed September 11, 2025, https://aacrjournals.org/cancerres/article/84/6_Supplement/5178/738628/Abstract-5178-Guided-by-a-predictive-ex-vivo-test
58. Notable Advances Volasertib Phase 2 Program Utilizing ... - SEC.gov, accessed September 11, 2025, https://www.sec.gov/Archives/edgar/data/1603207/000149315224007502/ex99-1.htm
59. Notable Labs Presents the Design Plan for the PPMP-Enabled Phase 2 Trial with Volasertib for Relapsed/Refractory AML at AACR 2024 - FirstWord Pharma, accessed September 11, 2025, https://firstwordpharma.com/story/5845423