Exploring the innovative Phase 1/2 study of CC-90011 combined with venetoclax and azacitidine
Imagine your body's blood production system suddenly turning against you. This is the reality for approximately 20,000 Americans diagnosed each year with acute myeloid leukemia (AML), an aggressive blood cancer where immature white blood cells multiply uncontrollably, crowding out healthy cells in the bone marrow 2 .
For patients like 72-year-old Michael (a composite representative patient), the diagnosis came suddenly—unexplained fatigue, easy bruising, and a blood test showing alarming abnormalities. What followed was the standard treatment: intensive chemotherapy that left him hospitalized for weeks, vulnerable to infections, and with devastating side effects. Unfortunately, like approximately 50% of AML patients who experience relapse after initial treatment, Michael's cancer returned within a year, leaving him with dwindling options and hope 2 .
The prognosis for elderly patients with relapsed AML remains particularly grim, with median survival often measured in mere months 4 . Traditional chemotherapy, developed decades ago, attacks rapidly dividing cells indiscriminately, damaging healthy tissues alongside cancerous ones. The search for more precise, effective, and tolerable treatments has led scientists to investigate the very epigenetic machinery that controls how cancer cells read their DNA instructions. In this article, we explore an innovative triple-drug combination that represents a potential breakthrough: CC-90011, a novel epigenetic therapy, combined with established leukemia drugs venetoclax and azacitidine.
To understand the excitement around CC-90011, we must first explore the fascinating world of epigenetics—the biological system that determines which genes are turned "on" or "off" in different cells without changing the underlying DNA sequence. Think of your DNA as a massive library containing all the instruction manuals for your body, while epigenetic markers are the color-coded tabs and bookmarks that tell each cell which manuals to read deeply and which to ignore.
At the heart of our story lies LSD1 (lysine-specific demethylase 1), an epigenetic "eraser" that was the first histone demethylase discovered in 2004 1 . LSD1's normal function is to remove chemical tags (methyl groups) from histones—the protein spools around which DNA is wound. This demethylation activity helps control which genes are accessible and active. In approximately 60% of AML cases, LSD1 becomes abnormally overexpressed, essentially erasing the "bookmarks" that would normally instruct blood cells to mature properly 2 . The result: immature leukemic cells continue multiplying indefinitely, like a factory producing only incomplete products.
Contains all genetic instructions for the body
Markers that tell cells which genes to activate
Removes epigenetic marks, silencing genes
Overactive LSD1 erases differentiation signals
Research has revealed that LSD1 plays a particularly crucial role in maintaining leukemia stem cells—the resilient, often-dormant cells that can regenerate tumors even after apparent remission and are largely responsible for disease recurrence 2 . This discovery positioned LSD1 as an attractive therapeutic target: if we could inhibit this epigenetic eraser, perhaps we could force leukemia cells to mature and die naturally, while also undermining the cancer-regenerating stem cell population.
The first LSD1 inhibitors were derived from an old antidepressant drug called tranylcypromine (TCP), which was discovered to weakly inhibit LSD1 by forming irreversible covalent bonds with the enzyme 1 . While these early inhibitors proved the therapeutic concept, they lacked selectivity and potency, leading to side effects and limited effectiveness.
CC-90011 represents a next-generation approach to LSD1 inhibition. As a potent, selective, and reversible inhibitor, it temporarily blocks LSD1's activity without permanently binding to it 6 . This reversible mechanism appears to provide a better safety profile than irreversible inhibitors, particularly regarding thrombocytopenia (dangerously low platelet counts), which has been a dose-limiting side effect of earlier LSD1 inhibitors 6 .
Structurally, CC-90011 works by fitting into the same pocket on LSD1 where the enzyme normally interacts with its histone substrates. Detailed X-ray crystallography (PDB ID: 6W4K) reveals that CC-90011 forms hydrogen bonds and hydrophobic interactions with key amino acid residues in the LSD1 binding site, effectively blocking the enzyme's ability to access and demethylate its targets 3 . The consequence of this inhibition is the accumulation of methyl marks on histone proteins, particularly at positions H3K4me1 and H3K4me2, which in turn reactivates genes that promote cellular differentiation and suppress malignant characteristics 5 .
| Feature | First Generation | CC-90011 |
|---|---|---|
| Binding Type | Irreversible | Reversible |
| Selectivity | Low | High |
| Safety Profile | Limited | Improved |
| Thrombocytopenia Risk | High | Reduced |
In preclinical studies, CC-90011 demonstrated impressive antiproliferative activity in various cancer cell lines, including AML and small cell lung cancer 6 . Perhaps more importantly, as a monotherapy in early clinical trials, CC-90011 produced durable responses in some patients with advanced solid tumors and lymphomas, including one patient with relapsed/refractory marginal zone lymphoma who maintained a complete response for over 58 cycles (approximately five years) of treatment 6 .
The innovative approach currently being explored in clinical trials combines CC-90011 with two established leukemia therapies: venetoclax and azacitidine. Each drug attacks leukemia through distinct but potentially complementary mechanisms, creating a multi-pronged assault on the cancer.
| Drug | Mechanism of Action | Role in Combination |
|---|---|---|
| CC-90011 | Reversible LSD1 inhibitor; promotes differentiation by increasing H3K4 methylation | Epigenetic modulator that may sensitize cells to venetoclax and impact leukemia stem cells |
| Venetoclax | BCL-2 inhibitor; triggers mitochondrial apoptosis pathway | Primary apoptosis inducer; directly eliminates leukemia cells |
| Azacitidine | Hypomethylating agent; incorporates into DNA and reduces DNA methylation | Epigenetic primer; may enhance vulnerability to other agents and restore differentiation capacity |
The scientific rationale for this triple combination is rooted in the growing understanding that cancer cells employ multiple survival strategies simultaneously, and effective treatment requires addressing several of these pathways at once. Research has shown that LSD1 inhibition can sensitize AML cells to other therapeutic agents, potentially including venetoclax 2 . Additionally, the combination of venetoclax and azacitidine has already established itself as an important advancement in AML treatment, particularly for older patients unfit for intensive chemotherapy.
In the VIALE-A clinical trial, the venetoclax-azacitidine combination demonstrated significantly improved overall survival (14.7 months versus 9.6 months) compared to azacitidine alone in newly diagnosed AML patients ineligible for intensive chemotherapy 4 . A recent meta-analysis of 19 studies involving 1,615 patients confirmed the efficacy of this combination, showing an overall complete response rate of 57.9% for AML and myelodysplastic syndrome, with particularly strong results in newly diagnosed AML (67.5% response rate) .
The addition of CC-90011 to this backbone represents a logical next step—enhancing an already effective regimen by targeting the epigenetic driver LSD1, which may further improve response rates and durability, particularly in high-risk populations.
The Phase 1/2 clinical trial of CC-90011 combined with venetoclax and azacitidine follows a carefully structured design to systematically evaluate safety, determine optimal dosing, and assess preliminary efficacy.
The trial typically enrolls patients with relapsed or refractory AML—those whose disease has returned after initial treatment or proven resistant to standard therapies. This population represents a critical unmet need, as their options are limited and outcomes are poor. Patients are generally adults with adequate organ function and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory 6 .
The treatment follows a 28-day cycle with specific administration schedules for each drug:
The trial examines multiple endpoints to comprehensively evaluate the treatment's potential:
| Endpoint | Definition | Significance |
|---|---|---|
| Complete Response (CR) | Disappearance of leukemia cells in bone marrow and blood with recovery of normal blood counts | Primary indicator of treatment effectiveness; necessary for long-term remission |
| CR with Incomplete Hematologic Recovery (CRi) | Clearance of leukemia cells without full recovery of platelet or neutrophil counts | Meaningful response despite ongoing blood count issues |
| Overall Survival (OS) | Time from treatment initiation to death from any cause | Most comprehensive measure of clinical benefit |
| Event-Free Survival (EFS) | Time from treatment initiation to treatment failure, relapse, or death | Composite measure capturing both efficacy and durability |
Advancements in drug development, particularly for targeted therapies like LSD1 inhibitors, rely on sophisticated research tools and methodologies. Here we highlight some of the essential components enabling the discovery and evaluation of compounds like CC-90011.
| Tool/Method | Function | Application in CC-90011 Development |
|---|---|---|
| X-ray Crystallography | Determines 3D atomic structure of proteins | Revealed binding mode of CC-90011 to LSD1 (PDB ID: 6W4K) 3 |
| Structure-Based Virtual Screening | Computationally identifies potential drug candidates from chemical libraries | Enabled discovery of novel LSD1 inhibitors through molecular docking 2 |
| Pharmacophore Modeling | Identifies spatial arrangements of chemical features necessary for biological activity | Facilitated screening for compounds with key interactions for LSD1 inhibition 2 |
| Molecular Dynamics Simulation | Models atomic movements over time to study protein-ligand interactions | Assessed stability of LSD1-inhibitor complexes and binding mechanisms 2 |
| Biomarker Assays | Measures biological indicators of drug activity | Evaluated H3K4me1/2 levels, MMD expression, and neuroendocrine peptides 6 |
| Patient-Derived Xenograft Models | Studies drug effects on human tumors grown in immunodeficient mice | Demonstrated CC-90011 efficacy against human AML cells in vivo 6 |
These sophisticated tools have enabled researchers to transition from basic understanding of LSD1 biology to targeted drug design and clinical evaluation. The structural insights gained from crystallography were particularly invaluable in optimizing CC-90011's binding characteristics to achieve both potency and selectivity over related enzymes like MAO-A and MAO-B 3 6 .
The ongoing investigation of CC-90011 combined with venetoclax and azacitidine represents a compelling example of how modern cancer drug development is evolving. Rather than relying on single magic bullets, researchers are increasingly designing rational combinations that attack cancer through multiple complementary mechanisms simultaneously.
This approach is particularly important for a heterogeneous disease like AML, where cancer cells can develop resistance through various escape routes. By simultaneously targeting epigenetic regulation (CC-90011 and azacitidine) and apoptotic pathways (venetoclax), this combination creates a challenging environment for leukemia cells to adapt and survive.
If successful, this triple combination could offer new hope for AML patients with limited options, particularly the elderly and those with relapsed or refractory disease. The once-weekly dosing of CC-90011 and the outpatient administration feasibility of the entire regimen could also significantly improve patients' quality of life compared to conventional intensive chemotherapy 6 .
Beyond AML, the principles demonstrated by this approach—reversible epigenetic modulation in rational combination with other targeted agents—may have broader applications across cancer types. LSD1 overexpression has been observed in various solid tumors, including small cell lung cancer, neuroendocrine tumors, and liver cancer, suggesting potential expansion into these areas 5 6 .
As we await the results of this innovative clinical trial, the story of CC-90011 exemplifies how decades of basic scientific research—from the initial discovery of histone demethylation to the structural biology of enzyme-inhibitor interactions—can gradually translate into potential new therapeutic paradigms for patients in need.
The battle against acute myeloid leukemia represents one of the most challenging fronts in oncology, but also one where scientific advances are steadily transforming the therapeutic landscape. The strategic combination of CC-90011 with venetoclax and azacitidine exemplifies the next wave of cancer therapy: multifaceted, mechanistically-driven, and patient-tailored.
While clinical validation is still underway, the scientific rationale supporting this approach is robust, building upon our growing understanding of cancer epigenetics and apoptosis regulation. As research continues to unravel the complexities of leukemia biology and therapeutic resistance, such innovative combinations offer hope for more effective and tolerable treatments that might ultimately convert this devastating disease from a death sentence to a manageable condition.
For patients like Michael, these developments can't come soon enough. But with each carefully designed clinical trial and each scientific breakthrough, we move closer to a future where a diagnosis of relapsed AML no longer means running out of options, but rather accessing increasingly sophisticated and targeted therapeutic strategies.