Pazopanib
| 證據等級: L5 | 預測適應症: 10 個 |
目錄
Pazopanib: Toward Liposarcoma — A Multi-Indication Repurposing Screen
One-Sentence Summary
Pazopanib is a multi-target tyrosine kinase inhibitor (VEGFR-1/2/3, PDGFR-α/β, c-KIT) with an established anti-angiogenic profile in oncology; this evidence pack screened it against 10 candidate indications, most of them rare renal and soft-tissue sarcoma subtypes. The TxGNN model’s most actionable prediction is Liposarcoma, supported by 9 clinical trials (including a randomized Phase 2 trial) and 20 publications, making it the only candidate in this pack to reach decision stage S3 (“Proceed with Guardrails”). The other 9 candidates range from moderately supported (unclassified RCC, dermatofibrosarcoma protuberans, fibroblastic neoplasms) to purely model-driven with no corroborating evidence (e.g., RCC with Xp11.2/TFE3 fusion, ovarian myxoid liposarcoma).
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not recorded as a structured field in this evidence pack (drug not currently marketed in the evaluated jurisdiction); literature evidence within the pack repeatedly describes pazopanib as an established therapy for clear-cell renal cell carcinoma and non-adipocytic soft tissue sarcoma |
| Predicted New Indication | Liposarcoma |
| TxGNN Prediction Score | 99.59% |
| Evidence Level | L2 |
| US Market Status | Not Marketed |
| Number of NDAs | 0 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
The formal original_moa field for this drug is a documented data gap (DG002). However, the evidence pack’s own literature and clinical-trial rationale text consistently describe pazopanib as a multi-target tyrosine kinase inhibitor, blocking VEGFR-1/2/3, PDGFR-α/β, and c-KIT — an anti-angiogenic, anti-proliferative mechanism that underlies its established role in vascularized solid tumors such as clear-cell renal cell carcinoma and non-adipocytic soft tissue sarcoma.
Liposarcoma is mechanistically adjacent to this established use: it belongs to the same broad soft-tissue sarcoma family, and several subtypes (dedifferentiated and pleomorphic liposarcoma in particular) show PDGFR pathway activation and angiogenesis dependency. A patient-derived orthotopic xenograft study (PMID 30060824) demonstrated that PDGFRA-amplified pleomorphic liposarcoma regressed under pazopanib, and a separate xenograft study (PMID 25500074) showed tumor growth suppression via anti-angiogenic activity in dedifferentiated liposarcoma models — direct preclinical support for the mechanistic link.
Notably, the pivotal PALETTE trial that established pazopanib for soft tissue sarcoma originally excluded adipocytic (liposarcoma) tumors due to uncertain sensitivity. The clinical trials identified here (two dedicated Phase 2 studies, NCT01506596 and NCT01692496, plus a randomized Phase 2 trial combining pazopanib with gemcitabine, NCT01532687) represent the subsequent, indication-specific evidence base that closes that gap — making liposarcoma a logical “label-expansion” candidate rather than a purely speculative one.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT01506596 | Phase 2 | Completed | 42 | Single-arm study of pazopanib monotherapy in unresectable or metastatic liposarcoma |
| NCT01692496 | Phase 2 | Completed | 52 | Pazopanib activity/tolerability in advanced/metastatic liposarcoma relapsed after standard therapy |
| NCT01532687 | Phase 2 | Completed | 54 | Randomized, double-blind: gemcitabine ± pazopanib for refractory soft tissue sarcoma (includes liposarcoma) |
| NCT02357810 | Phase 2 | Completed | 178 | Pazopanib + oral topotecan in metastatic/unresectable soft tissue and bone sarcomas |
| NCT02048371 | Phase 2 | Completed | 131 | Oral regorafenib in selected sarcoma subtypes; cites pazopanib activity precedent in soft tissue sarcoma |
| NCT01900743 | Phase 2 | Completed | 219 | Regorafenib vs. placebo in metastatic soft tissue sarcoma post-anthracycline, including a liposarcoma cohort |
| NCT02180867 | Phase 2/3 | Active, not recruiting | 140 | Neoadjuvant chemoradiation ± pazopanib in non-rhabdomyosarcoma soft tissue sarcoma |
| NCT06263231 | Phase 3 | Active, not recruiting | 333 | INT230-6 (intratumoral) vs. US standard of care in liposarcoma/UPS/leiomyosarcoma |
| NCT06239272 | Phase 1/2 | Recruiting | 139 | Risk-adapted study of maintenance pazopanib, dose-escalated radiotherapy, and selinexor in non-rhabdomyosarcoma soft tissue sarcoma |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 28844815 | 2017 | Phase 2 Trial | The Lancet. Oncology | Pazopanib for advanced liposarcoma |
| 31010343 | 2019 | Phase 2 Trial | Expert Opin Investig Drugs | Pazopanib activity in advanced intermediate/high-grade liposarcoma |
| 34050255 | 2021 | Phase 2 Trial | British Journal of Cancer | Pazopanib with oral topotecan prolongs PFS in refractory soft tissue sarcoma |
| 33355646 | 2021 | Randomized Trial (PAPAGEMO) | JAMA Oncology | Pazopanib ± gemcitabine in anthracycline/ifosfamide-refractory soft tissue sarcoma |
| 34356494 | 2021 | Translational Cohort (GISG-04/NOPASS) | Biology | Molecular/pathological profiling of high-risk soft tissue sarcoma before/after neoadjuvant pazopanib |
| 30060824 | 2018 | Case Report / PDX Model | Tissue & Cell | PDGFRA-amplified pleomorphic liposarcoma regressed by pazopanib in a patient-derived xenograft |
| 25500074 | 2014 | Preclinical | Translational Oncology | Pazopanib suppresses tumor growth via angiogenesis inhibition in dedifferentiated liposarcoma xenografts |
| 35609512 | 2022 | Review | Oncology Research and Treatment | Established and experimental systemic treatment options for advanced liposarcoma |
| 32026050 | 2020 | Review | Current Treatment Options in Oncology | Systemic therapy options for dedifferentiated liposarcoma |
| 37298520 | 2023 | Review | Int J Molecular Sciences | Treatment of dedifferentiated liposarcoma in the era of immunotherapy |
US Market Information
Pazopanib is currently recorded as Not Marketed in this evidence pack (total_licenses: 0, no license records available). No NDA/authorization data could be extracted for this candidate.
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy (multi-target tyrosine kinase inhibitor: VEGFR-1/2/3, PDGFR-α/β, c-KIT) |
| Myelosuppression Risk | Typically low-to-moderate for anti-angiogenic TKIs as a class; no drug-specific toxicity data available in this evidence pack — please refer to the package insert |
| Emetogenicity Classification | Typically low for oral TKIs as a class; please refer to the package insert for drug-specific data |
| Monitoring Items | Blood pressure, liver function tests, urinalysis (proteinuria), and CBC are generally relevant given the VEGFR/PDGFR mechanism; please refer to the package insert for definitive monitoring requirements |
| Handling Protection | No drug-specific handling data available in this evidence pack — please refer to the package insert and institutional hazardous oral oncolytic handling protocols |
Safety Considerations
Please refer to the package insert for safety information. (TFDA warnings, contraindications, and DDI data are flagged as a Blocking data gap — DG001 — in this evidence pack and could not be retrieved.)
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: Liposarcoma is the only one of the 10 screened indications to reach decision stage S3, backed by two indication-specific Phase 2 trials and a randomized Phase 2 trial, plus preclinical mechanistic support (PDGFR pathway activation) — a reasonable evidentiary base for cautious advancement, but not yet sufficient for an unconditional “Go.”
To proceed, the following is needed:
- TFDA/label safety data (warnings, contraindications, DDI) — currently a Blocking gap (DG001)
- Formal, structured mechanism-of-action documentation (DG002)
- Taiwan/US regulatory and licensing status confirmation (currently 0 licenses on record)
- A dedicated randomized Phase 3 trial in liposarcoma to move beyond the current single-arm/small-RCT evidence base
Appendix: Other Predicted Indications Screened (Same Drug)
For context, this evidence pack scored pazopanib against 9 additional candidate indications. None reached the evidence maturity of liposarcoma; two others reached “Research Question” status:
| Rank | Disease | TxGNN Score | Evidence Level | Decision Stage | Recommendation | |——|———|——|——|——|——| | 1 | RCC w/ Xp11.2/TFE3 fusion | 99.63% | L5 | S0 | Hold | | 2 | RCC associated with neuroblastoma | 99.63% | L5 | S0 | Hold | | 3 | Unclassified renal cell carcinoma | 99.63% | L2 | S2 | Research Question | | 5 | Childhood kidney cell carcinoma | 99.54% | L4 | S1 | Hold | | 6 | Ovarian myxoid liposarcoma | 99.51% | L5 | S0 | Hold | | 7 | Heart fibrosarcoma | 99.37% | L4 | S0 | Hold | | 8 | Fibroblastic neoplasm (incl. desmoid tumor, SFT) | 99.35% | L2 | S2 | Research Question | | 9 | Kidney fibrosarcoma | 99.33% | L5 | S0 | Hold | | 10 | Dermatofibrosarcoma protuberans | 99.29% | L2 | S2 | Research Question |
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.