Belinostat
| Evidence Level: L5 | Predicted Indications: 3 |
Table of Contents
Belinostat: From T-Cell Lymphoma to Myeloid Leukemia
One-Sentence Summary
Belinostat is an intravenous histone deacetylase (HDAC) inhibitor. Published literature describes it as approved for T-cell lymphomas. The TxGNN model predicts it may be effective for myeloid leukemia, and 6 clinical trials and 20 publications are linked to this prediction. Most of that evidence is early-phase combination studies and preclinical work, so efficacy is not yet established.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | T-cell lymphomas (per literature; the US license record supplied has no indication text) |
| Predicted New Indication | Myeloid leukemia |
| TxGNN Prediction Score | 99.53% |
| Evidence Level | L2 (as assigned in the Evidence Pack; the one completed Phase 2 study is single-arm, not randomized) |
| US Market Status | ✓ Marketed |
| Number of NDAs | 1 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the Evidence Pack. From general knowledge, belinostat is a pan-HDAC inhibitor. HDAC inhibition can reactivate silenced tumor suppressor genes and promote apoptosis and differentiation in cancer cells. Its efficacy in T-cell lymphoma is established, and mechanistically it may also apply to myeloid leukemia.
Both T-cell lymphoma and acute myeloid leukemia (AML) are blood cancers with abnormal epigenetic regulation. Preclinical work supports this: belinostat has anti-leukemic activity in acute promyelocytic leukemia cells and primary AML cells.
The data also suggest that combinations are more promising than monotherapy. Published studies show synergy with:
- proteasome inhibition (bortezomib)
- NEDD8 inhibition (pevonedistat)
- WEE1 inhibition (adavosertib)
Consistent with this, PMID 39821392 notes that belinostat and pevonedistat each showed only limited single-agent activity in blood cancers.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00357032 | Phase 2 | Completed | 12 | Belinostat (PXD101) alone in relapsed/refractory AML, or newly diagnosed AML in patients over 60. Highest-phase direct evidence, but efficacy outcomes are not in the provided data. |
| NCT00878722 | Phase 1/2 | Completed | 41 | Belinostat plus idarubicin in AML patients unsuitable for standard intensive therapy. Two schedules tested for safety and early efficacy. |
| NCT01075425 | Phase 1 | Completed | 41 | Belinostat plus bortezomib in relapsed/refractory acute leukemia or MDS. Dose finding and safety. |
| NCT00351975 | Phase 1 | Completed | 56 | Belinostat plus azacitidine in advanced hematologic malignancies. Broader population, so the match to myeloid leukemia is partial. |
| NCT03772925 | Phase 1 | Terminated | 18 | Pevonedistat plus belinostat in relapsed/refractory AML or MDS. Early termination limits interpretation. |
| NCT02381548 | Phase 1 | Terminated | 20 | Adavosertib plus belinostat in relapsed/refractory myeloid malignancies. Early termination limits interpretation. |
No Phase 3 trials exist.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 24369094 | 2014 | Phase 2 trial | Leuk Lymphoma | Belinostat 1000 mg/m² IV on days 1-5 of a 21-day cycle in relapsed/refractory AML or newly diagnosed AML over age 60. Primary endpoint was complete response rate. Results are not in the excerpt provided. |
| 39821392 | 2025 | Phase 1 trial | Cancer Chemother Pharmacol | Belinostat plus pevonedistat in relapsed/refractory AML or high-risk MDS, following preclinical synergy data. |
| 36864346 | 2023 | Phase 1 trial | Cancer Chemother Pharmacol | Belinostat plus adavosertib in relapsed/refractory myeloid malignancies. Preclinical synergy was shown in AML lines and xenografts. |
| 33356689 | 2021 | Phase 1 trial | Leuk Lymphoma | Belinostat plus bortezomib in 38 patients. QTc prolongation was the only dose-limiting toxicity. Recommended Phase 2 doses were bortezomib 1.3 mg/m² and belinostat 1000 mg/m². |
| 26851293 | 2016 | Preclinical | Blood | Pevonedistat plus belinostat synergistically induced AML cell apoptosis, including cells with p53 deficiency or FLT3-ITD, by disrupting the DNA damage response. |
| 21375523 | 2011 | Preclinical | Br J Haematol | Belinostat plus bortezomib sharply increased apoptosis in AML and ALL cell lines and primary blasts, linked to NF-κB and Bim changes. |
| 24800886 | 2014 | Preclinical | Anti-Cancer Drugs | Characterizes belinostat’s epigenetic and molecular effects in acute promyelocytic leukemia cells, alone and combined with all-trans retinoic acid. |
| 25864732 | 2015 | Preclinical | J Cell Mol Med | Belinostat has anti-leukemic effects in acute promyelocytic leukemia cells via chromatin remodelling. |
| 17982680 | 2007 | Preclinical | Int J Oncol | HDAC inhibitors including PXD101 inhibited proliferation and increased apoptosis in primary cells from 59 AML patients. Patient subgroups differed in susceptibility. |
| 26447190 | 2015 | Preclinical | Blood | Genetic and pharmacological dissection of HDAC dependencies in mouse lymphoid and myeloid leukemias. |
US Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| NDA206256 | Beleodaq (Acrotech Biopharma Inc) | Lyophilized powder for injection | Indication text not included in the provided record |
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted/epigenetic therapy (HDAC inhibitor), used within cytotoxic combination regimens |
| Myelosuppression Risk | Medium (general knowledge for HDAC inhibitors; confirm against the package insert) |
| Emetogenicity Classification | Low to medium (general knowledge; confirm against the package insert) |
| Monitoring Items | CBC with differential, liver and renal function, electrolytes, ECG/QTc (QTc prolongation was the only dose-limiting toxicity in the belinostat plus bortezomib Phase 1) |
| Handling Protection | Follow institutional cytotoxic drug handling regulations. Please refer to the package insert warnings and precautions. |
Safety Considerations
- QTc prolongation: it was the only dose-limiting toxicity in the belinostat plus bortezomib Phase 1 study (PMID 33356689). Cardiac monitoring is therefore relevant in combination regimens.
Please refer to the package insert for other safety information.
Conclusion and Next Steps
Decision: Hold
Rationale: The predicted score is high and there is a plausible mechanism and preclinical synergy. However, the clinical evidence is limited to small Phase 1 and Phase 2 studies, and half of the combination trials were terminated early. There is no randomized or Phase 3 evidence, and efficacy outcomes are missing from the provided data. The package insert warnings and contraindications are also missing, which the pack marks as a blocking gap for safety screening.
To proceed, the following is needed:
- Package insert warnings and contraindications (blocking gap DG001)
- Efficacy results (response rates) from the published NCT00357032 and NCT00878722 studies (PMIDs 24369094 and others)
- Confirmed mechanism of action from DrugBank (DG002)
- US indication text for NDA206256, to confirm the original indication
- A randomized or controlled trial design, most likely a combination regimen rather than monotherapy
Other predicted indications: plasma cell myeloma (score 99.27%) has only two small Phase 2 trials, one terminated after 4 patients and the other enrolling 25, with no efficacy data. Indolent plasma cell myeloma (99.08%) has no trials or literature and is on Hold.
This report is for research reference only and does not constitute medical advice. Drug repurposing candidates require clinical validation before any clinical use.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.