Vorinostat
| 證據等級: L5 | 預測適應症: 2 個 |
目錄
- Vorinostat
- Vorinostat: From Cutaneous T-Cell Lymphoma to Primary Cutaneous B-Cell Lymphoma
- Additional Predicted Indication: Sézary Syndrome (Stronger Evidence — L1)
Vorinostat: From Cutaneous T-Cell Lymphoma to Primary Cutaneous B-Cell Lymphoma
One-Sentence Summary
Vorinostat is an oral HDAC (histone deacetylase) inhibitor originally developed for cutaneous T-cell lymphoma (CTCL); no confirmed original-indication text is on file in this evidence pack. The TxGNN model’s top prediction is primary cutaneous B-cell lymphoma (PCBCL), currently supported by 8 clinical trials (none disease-specific) and 1 mechanistic publication. A second, substantially stronger candidate — Sézary syndrome — is also flagged in this pack, backed by a completed Phase 3 RCT (MAVORIC, n=372) and 20 publications; it is reported separately below because its evidence tier (L1) differs markedly from the primary prediction (L4).
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not on file in this pack (data gap). Literature context indicates vorinostat is marketed as Zolinza® for cutaneous T-cell lymphoma (CTCL). |
| Predicted New Indication | Primary Cutaneous B-Cell Lymphoma (PCBCL) |
| TxGNN Prediction Score | 99.21% |
| Evidence Level | L4 |
| US Market Status | Not Marketed (0 licenses on file — see note below) |
| Number of NDAs | 0 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Currently, detailed mechanism of action data is not available in the structured drug record (original_moa = Data Gap). Based on evidence collected from the linked trials and literature, vorinostat is a histone deacetylase (HDAC) inhibitor that induces chromatin remodeling in malignant lymphocytes, leading to cell-cycle arrest (p21 induction) and apoptosis via caspase activation. It is an approved oral therapy for cutaneous T-cell lymphoma (CTCL).
The mechanistic rationale for PCBCL is that HDAC inhibition could theoretically induce apoptosis in malignant B-cells through epigenetic reprogramming, analogous to its established effect in T-cell lymphoma. However, the only mechanistic literature identified (PMID 21652541) demonstrates this effect in mantle cell lymphoma — a nodal/systemic B-cell neoplasm — not in primary cutaneous B-cell lymphoma. These two entities differ substantially in clinical course and tumor microenvironment, so the mechanistic extrapolation from mantle cell lymphoma to PCBCL is indirect and currently unproven in disease-specific models or trials.
No clinical trial in this pack directly enrolled PCBCL patients; the eight trials listed are either off-target populations (solid tumors, GVHD, mixed lymphoid malignancies) or use a different investigational drug. This is consistent with the L4 evidence tier (mechanism/preclinical only, no disease-specific clinical data).
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT01567709 | Phase 1 | Completed | 34 | Alisertib + vorinostat combination in relapsed lymphoid malignancies (Hodgkin, B-NHL, PTCL); not PCBCL-specific |
| NCT00499811 | Phase 1 | Completed | 15 | PK study of vorinostat in solid tumors/lymphoma with hepatic dysfunction |
| NCT00045006 | Phase 1 | Completed | N/A | Early oral SAHA (vorinostat) dose-finding in advanced solid tumors and hematologic malignancies |
| NCT01789255 | Phase 2 | Completed | 12 | Vorinostat + tacrolimus + methotrexate for GVHD prevention — indication unrelated to PCBCL |
| NCT00007345 | Phase 2 | Completed | 131 | Depsipeptide (not vorinostat) in CTCL/PTCL — drug mismatch |
| NCT01500538 | Phase 2 | Terminated | 1 | Vorinostat + eltrombopag in lymphoma; terminated, no statistical power |
| NCT00005634 | Phase 1 | Completed | N/A | Early SAHA pharmacology study in advanced solid tumors |
| NCT02943642 | Phase 2 | Unknown | 162 | Resimmune vs. oral vorinostat in mycosis fungoides — different drug and disease |
No trial in this pack specifically enrolled or reported outcomes for primary cutaneous B-cell lymphoma.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 21652541 | 2011 | Mechanistic (in vitro) | Clinical Cancer Research | Vorinostat induces apoptosis in mantle cell lymphoma via acetylation of proapoptotic BH3-only gene promoters; mechanism study, not PCBCL-specific |
US Market Information
No marketing authorization records are present in this evidence pack (0 licenses, market_status = “Not Marketed”). Vorinostat is internationally known as Zolinza® (approved for CTCL in some jurisdictions); the absence of license records here should be treated as a data gap pending regulatory-source verification, not confirmation of non-approval.
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy (HDAC inhibitor); classified within antineoplastic agents |
| Myelosuppression Risk | Moderate — trial-level evidence (NCT01500538) notes thrombocytopenia (low platelet counts) commonly observed early in treatment |
| Emetogenicity Classification | Low to moderate (class-based; no drug-specific toxicity data in this pack) |
| Monitoring Items | CBC with differential and platelets, electrolytes, renal and hepatic function, ECG (QT interval) |
| Handling Protection | Please refer to the package insert warnings and precautions; no drug-specific handling protocol available in this pack |
Safety Considerations
Please refer to the package insert for safety information. All structured safety fields (key warnings, contraindications, drug interactions) are marked as data gaps in this evidence pack.
Conclusion and Next Steps (Primary Cutaneous B-Cell Lymphoma)
Decision: Hold
Rationale: No PCBCL-specific clinical trials exist, and the only supporting literature is a mechanistic study in a different B-cell neoplasm (mantle cell lymphoma). Evidence level L4 does not support progression beyond hypothesis stage.
To proceed, the following is needed:
- Confirmed original MOA and original indication documentation
- PCBCL-specific preclinical or case-series data
- TFDA/regulatory label data (currently a Blocking data gap per meta.data_gaps)
- Vorinostat safety/DDI profile from an authoritative source
Additional Predicted Indication: Sézary Syndrome (Stronger Evidence — L1)
This evidence pack also identifies Sézary syndrome as a TxGNN candidate with substantially stronger clinical support than the primary prediction above, and is reported here for decision completeness.
Quick Overview
| Item | Content |
|---|---|
| Predicted New Indication | Sézary Syndrome |
| TxGNN Prediction Score | 99.07% |
| Evidence Level | L1 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Sézary syndrome is the leukemic, aggressive variant of cutaneous T-cell lymphoma (CTCL). Vorinostat’s original approved indication (CTCL) and Sézary syndrome sit on the same disease spectrum rather than representing a mechanistic extrapolation — the HDAC-inhibition mechanism (chromatin remodeling, cell-cycle arrest, apoptosis in malignant T-lymphocytes) is directly applicable, and vorinostat has in fact been used clinically as an active comparator in Sézary syndrome trials.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT01728805 | Phase 3 | Completed | 372 | MAVORIC trial — mogamulizumab vs. vorinostat in relapsed/refractory CTCL (including Sézary syndrome); vorinostat used as active comparator, direct disease-specific RCT data |
| NCT00091559 | Phase 2b | Completed | 74 | Multicenter trial of oral SAHA (vorinostat) in advanced CTCL, stage IB+, post-progression on ≥2 prior therapies |
| NCT01567709 | Phase 1 | Completed | 34 | Alisertib + vorinostat in relapsed lymphoid malignancies including CTCL-related entities |
| NCT00601718 | Phase 1/2 | Completed | 29 | Vorinostat + rituximab/ifosfamide/carboplatin/etoposide in relapsed lymphoid malignancies |
| NCT00499811 | Phase 1 | Completed | 15 | PK study of vorinostat in solid tumors/lymphoma with hepatic dysfunction |
| NCT00045006 | Phase 1 | Completed | N/A | Early oral SAHA dose-finding in advanced solid tumors/hematologic malignancies |
| NCT00005634 | Phase 1 | Completed | N/A | Early SAHA pharmacology study in advanced solid tumors |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 30100375 | 2018 | RCT | Lancet Oncology | MAVORIC Phase 3 RCT: mogamulizumab vs. vorinostat in previously treated CTCL/Sézary syndrome; establishes vorinostat efficacy/safety benchmark in this population |
| 31366601 | 2019 | Regulatory Summary | Clinical Cancer Research | FDA approval summary for mogamulizumab, detailing MAVORIC trial design with vorinostat as comparator arm (n=372) |
| 40072489 | 2025 | Review | J Cutaneous Medicine and Surgery | Oral systemic therapies for MF/Sézary syndrome, including vorinostat |
| 35444765 | 2022 | Review | Mediterranean J Hematology and Infectious Diseases | Treatment of advanced-stage MF/Sézary syndrome, hematologist’s perspective |
| 31192214 | 2019 | Review | Frontiers in Medicine | Novel and future therapeutic drugs for advanced MF/Sézary syndrome |
| 39315857 | 2025 | Post-hoc analysis (Phase 3) | J European Academy of Dermatology and Venereology | Post-hoc HRQL analysis of MAVORIC Phase 3 trial in MF/Sézary syndrome |
| 35993803 | 2023 | Post-hoc analysis (Phase 3) | J European Academy of Dermatology and Venereology | Blood involvement impact on efficacy/time-to-response in MAVORIC (mogamulizumab vs. vorinostat) |
| 35678206 | 2022 | Post-hoc analysis | J Comparative Effectiveness Research | Crossover-adjusted overall survival analysis of MAVORIC trial |
| 33618592 | 2021 | Subgroup analysis (Phase 3) | Leukemia & Lymphoma | MAVORIC subgroup analysis in Black patients with MF/Sézary syndrome |
| 21455551 | 2011 | Clinical study | J Drugs in Dermatology | Vorinostat + IFN-alpha + extracorporeal photopheresis combination in late-stage MF and Sézary syndrome |
Cytotoxicity
Same class-level profile as above (HDAC inhibitor, targeted therapy). Note: PMID 38170178 (mechanistic study) reports that S. aureus infection can induce HDAC-inhibitor drug resistance in Sézary syndrome malignant T-cells — relevant for monitoring infection status during treatment.
Conclusion and Next Steps (Sézary Syndrome)
Decision: Proceed with Guardrails
Rationale: Vorinostat has completed Phase 3 RCT data (MAVORIC, n=372) directly in the Sézary syndrome/CTCL population as an active comparator, supported by regulatory documentation and multiple post-hoc/subgroup analyses. This meets the L1 evidence bar (≥1 completed Phase 3 RCT with disease-specific data), but vorinostat itself was the inferior arm in MAVORIC (vs. mogamulizumab), so guardrails on expected efficacy and sequencing after other therapies are warranted.
To proceed, the following is needed:
- Confirmed regulatory/label status (market_status currently shows “Not Marketed” — verify against authoritative source)
- Drug-drug interaction and contraindication data (currently data gaps)
- Positioning guidance relative to mogamulizumab and other approved CTCL therapies, given vorinostat’s inferior PFS in the MAVORIC comparator arm
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.