Idelalisib
| 證據等級: L5 | 預測適應症: 10 個 |
目錄
Idelalisib: From B-Cell Malignancies to Mantle Cell Lymphoma
One-Sentence Summary
Idelalisib is a PI3Kδ-selective kinase inhibitor used internationally for relapsed chronic lymphocytic leukaemia (CLL), follicular lymphoma and small lymphocytic lymphoma (SLL), though it is not currently registered or marketed in Australia. The TxGNN model predicts it may also be effective for Mantle Cell Lymphoma (MCL), with 9 clinical trials and 20 publications currently identified in this evidence pack supporting the direction, including two clinical reports specifically in relapsed/refractory MCL.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Chronic lymphocytic leukaemia (CLL), follicular lymphoma (FL), small lymphocytic lymphoma (SLL) — per literature evidence in this pack; drug is not TGA-registered |
| Predicted New Indication | Mantle Cell Lymphoma |
| TxGNN Prediction Score | 99.84% |
| Evidence Level | L3 |
| Australia Market Status | Not marketed |
| Number of ARTG Entries | 0 |
| Recommended Decision | Hold (evidence pack labels this a “Research Question”, decision stage S2) |
Why is This Prediction Reasonable?
Detailed mechanism-of-action data was not returned from DrugBank for this drug record (flagged as a data gap in the evidence pack). However, the literature evidence collected here consistently and independently describes idelalisib as a first-in-class, orally administered phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor. PI3Kδ is expressed almost exclusively in haematopoietic cells and is a key node in B-cell receptor (BCR) signalling, which drives survival and proliferation across multiple B-cell malignancies.
Idelalisib’s established/approved use has been in CLL, follicular lymphoma and SLL — all B-cell neoplasms that, like mantle cell lymphoma, depend on constitutive BCR/PI3Kδ pathway activation. Mantle cell lymphoma is itself a B-cell non-Hodgkin lymphoma subtype in which the PI3K/AKT pathway is recognised as a contributor to pathogenesis, providing a plausible mechanistic bridge from the approved indications to MCL.
That said, one preclinical paper in this pack (PMID 33850273) specifically notes that idelalisib shows intrinsic resistance in MCL treatment unless combined with a p300/CBP inhibitor, and a second (PMID 40466505) describes CBX5-loss-driven resistance mechanisms. This tempers the mechanistic rationale — MCL response to idelalisib monotherapy appears less reliable than in CLL/FL/SLL, which is consistent with the modest (Phase 1) clinical evidence available below rather than confirmatory Phase 3 data.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrolment | Key Findings |
|---|---|---|---|---|
| NCT01088048 | Phase 1 | Completed | 241 | Safety of idelalisib combined with anti-CD20 mAb, chemotherapy, mTOR/immunomodulatory agents in relapsed/refractory iNHL, MCL or CLL |
| NCT01838434 | Phase 1/2 | Completed | 106 | Idelalisib + lenalidomide vs lenalidomide alone in relapsed/refractory MCL |
| NCT02603445 | Phase 1b | Completed | 20 | BCL201 + idelalisib dose-escalation in FL and MCL; safety/tolerability endpoint |
| NCT01796470 | Phase 2 | Terminated | 66 | Entospletinib (GS-9973) + idelalisib in relapsed/refractory heme malignancies including MCL, DLBCL, CLL, iNHL |
| NCT03151057 | Phase 1 | Terminated | 16 | Idelalisib as post-allogeneic HSCT maintenance in B-cell malignancies; safety/cytopenia/GVHD focus |
| NCT02457598 | Phase 1 | Terminated | 203 | Tirabrutinib + other targeted agents (incl. idelalisib) in B-cell malignancies |
| NCT02824159 | N/A | Completed | 121 | Real-world plasma concentration vs side-effect correlation for ibrutinib and idelalisib (idelalisib EMA-approved for MCL noted) |
| NCT04985214 | N/A | Unknown | 464 | Quality-of-life study of oral therapies (incl. idelalisib) used in CLL, FL, Waldenström’s and MCL |
| NCT03740529 | Phase 1/2 | Completed | 803 | Pirtobrutinib (LOXO-305) study in CLL/SLL/NHL; idelalisib not the study intervention — low direct relevance |
No ANZCTR (Australian) trial registrations were found for this indication.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 24795031 | 2014 | Clinical Trial Report | Cancer Discovery | PI3Kδ inhibitor idelalisib was effective in heavily pretreated patients with mantle cell lymphoma |
| 24615778 | 2014 | Phase 1 Trial Report | Blood | 48-week Phase 1 study (n=40) of idelalisib in relapsed/refractory MCL; primary outcome safety/DLT, secondary ORR/PFS/DOR |
| 27342398 | 2017 | Preclinical/Mechanistic | Clin Cancer Res | Idelalisib impacts MCL cell growth via inhibition of translation-regulatory mechanisms |
| 33850273 | 2022 | Preclinical | Acta Pharmacol Sin | P300/CBP inhibitor A-485 overcomes intrinsic idelalisib resistance in MCL in vitro/in vivo |
| 40466505 | 2025 | Preclinical | Phytomedicine | CBX5 loss drives PI3Kδ inhibitor resistance in MCL; propolis restores sensitivity via ferroptosis |
| 38815797 | 2024 | Preclinical | Cancer Letters | Idelalisib enhances anti-tumour effect of palbociclib via PLK1 in relapsed/refractory DLBCL and MCL |
| 28775119 | 2017 | Review | Haematologica | Practical approach to incidence and management of toxicity with ibrutinib and idelalisib in indolent B-cell malignancies including MCL |
| 26841011 | 2016 | Review | Cancer Journal | Idelalisib targeting the PI3K pathway in non-Hodgkin lymphoma |
| 24974852 | 2014 | Review | Br J Haematol | Current regimens and novel agents for mantle cell lymphoma (context review) |
Australia Market Information
Idelalisib currently has no ARTG entries and is not marketed in Australia (0 licences on record). No TGA-approved product information is available for this drug.
Cytotoxicity
Idelalisib is an antineoplastic agent (approved oncology indications; PI3Kδ-targeted small-molecule kinase inhibitor).
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy (PI3Kδ-selective small-molecule kinase inhibitor) |
| Myelosuppression Risk | Please refer to the Product Information (PI) warnings and precautions |
| Emetogenicity Classification | Please refer to the Product Information (PI) warnings and precautions |
| Monitoring Items | Please refer to the Product Information (PI) warnings and precautions |
| Handling Protection | Please refer to the Product Information (PI) warnings and precautions |
Safety Considerations
No key warnings, contraindications, or drug interaction data were returned for idelalisib in this evidence pack, and the drug is not TGA-registered. Please refer to the TGA-approved Product Information (PI) for safety information once/if this drug becomes available in Australia; in the interim, refer to the US FDA or EMA product labelling.
Conclusion and Next Steps
Decision: Hold
Rationale: Evidence for idelalisib in MCL is limited to Phase 1/2 studies (best single trial: Phase 1, n=40, direct MCL population) plus two preclinical resistance-mechanism papers, without a confirmatory Phase 3 RCT — consistent with the evidence pack’s own L3/”Research Question” scoring. The drug is also not currently registered or marketed in Australia, and core safety/MOA data are unavailable, so no regulatory pathway assessment can be made at this time.
To proceed, the following is needed:
- TGA product information / regulatory pathway assessment, given the drug currently has no Australian market presence
- Confirmed mechanism-of-action data from DrugBank (currently a data gap)
- Formal safety/DDI profile (key warnings, contraindications, interactions — currently not found)
- A confirmatory Phase 2/3 trial specifically in MCL, given noted intrinsic-resistance mechanisms reported in preclinical literature
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.