Idelalisib

證據等級: L5

預測適應症: 10 個

Idelalisib: From B-Cell Lymphoid Malignancies to Mantle Cell Lymphoma

One-Sentence Summary

Idelalisib is an oral PI3Kδ (phosphatidylinositol 3-kinase delta) inhibitor originally developed for relapsed chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and small lymphocytic lymphoma (SLL) — all B-cell malignancies driven by B-cell receptor (BCR) signalling. The TxGNN model predicts it may also be effective for Mantle Cell Lymphoma (MCL), another BCR/PI3Kδ-dependent B-cell neoplasm, with 9 clinical trials and 20 publications currently supporting this direction — including a completed Phase 1 trial reporting direct clinical activity in MCL.

Quick Overview

Item	Content
Original Indication	Not on file in the Norway regulatory registry (no license record). Per the literature evidence in this pack (e.g., PMID 25187123, 25637459), idelalisib was originally approved elsewhere for relapsed CLL, relapsed follicular lymphoma, and relapsed SLL
Predicted New Indication	Mantle Cell Lymphoma (MCL)
TxGNN Prediction Score	99.84%
Evidence Level	L3
Norway Market Status	✗ Not Marketed (未上市)
Number of Authorizations	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

Currently, detailed mechanism of action data is not available in this Evidence Pack (drug-level MOA field is a data gap). Based on known information drawn from the literature evidence collected here, idelalisib is a first-in-class, selective inhibitor of the delta isoform of phosphatidylinositol 3-kinase (PI3Kδ), a lipid kinase expressed almost exclusively in hematopoietic cells and constitutively active downstream of the B-cell receptor (BCR) in B-cell malignancies (PMID 30069634, 28295729).

Its efficacy in relapsed CLL, follicular lymphoma, and SLL is well established in the literature (PMID 25637459, 25187123), and mechanistically this rationale extends naturally to mantle cell lymphoma. MCL is likewise a mature B-cell neoplasm characterized by the t(11;14) translocation and constitutive BCR/PI3K/AKT pathway activation, which drives survival and proliferation of the malignant clone (PMID 22361516, 24273091). Because idelalisib blocks the same upstream signalling node exploited by MCL cells, it is biologically plausible that the drug retains activity in this related lymphoma subtype.

This is not purely theoretical: a dedicated Phase 1 clinical trial (PMID 24615778, published in Blood) directly tested idelalisib in relapsed/refractory MCL and reported measurable clinical activity, later summarized in a companion report titled "Idelalisib has activity in mantle cell lymphoma" (PMID 24795031). However, subsequent mechanistic work also identified intrinsic and acquired resistance pathways in MCL (e.g., CBX5 loss, PMID 40466505; p300/CBP-mediated resistance, PMID 33850273), indicating that while the mechanistic rationale is sound, clinical benefit in MCL is not uniform and combination strategies may be needed.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT01838434	Phase 1	Completed	106	Idelalisib + lenalidomide in relapsed/refractory MCL
NCT01088048	Phase 1	Completed	241	Idelalisib combined with chemo/immunomodulatory/anti-CD20 agents in relapsed/refractory iNHL, MCL, or CLL
NCT02603445	Phase 1	Completed	20	BCL201 + idelalisib combination in follicular lymphoma and MCL
NCT03740529	Phase 1/2	Completed	803	Pirtobrutinib in CLL/SLL/NHL patients who failed standard of care (idelalisib-experienced population)
NCT02824159	N/A	Completed	121	Real-world pharmacokinetic/side-effect correlation study of ibrutinib and idelalisib; notes EMA approval of idelalisib specifically for MCL
NCT01796470	Phase 2	Terminated	66	Entospletinib + idelalisib in relapsed/refractory hematologic malignancies including MCL, CLL, DLBCL, iNHL
NCT02457598	Phase 1	Terminated	203	Tirabrutinib combined with targeted anti-cancer therapies in B-cell malignancies
NCT03151057	Phase 1	Terminated	16	Idelalisib as post-allogeneic HSCT maintenance in B-cell malignancies
NCT04985214	N/A	Unknown	464	Quality-of-life assessment in lymphoma patients (incl. MCL) treated with oral therapies including idelalisib

Literature Evidence

PMID	Year	Type	Journal	Key Findings
24615778	2014	Phase 1 Trial	Blood	Phase 1 study of PI3Kδ inhibitor idelalisib in 40 patients with relapsed/refractory MCL; safety, PK, and response data
24795031	2014	Clinical Report	Cancer Discovery	Idelalisib effective in heavily pretreated MCL patients
27342398	2017	Mechanistic/Clinical	Clinical Cancer Research	Idelalisib impacts MCL cell growth via translation-regulatory mechanism disruption
33850273	2022	Preclinical	Acta Pharmacologica Sinica	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-tumor effect of palbociclib via PLK1 in B-cell lymphoma (incl. MCL)
24974852	2014	Review	British Journal of Haematology	Overview of current regimens and novel agents for MCL
26360791	2015	Review	Expert Opinion on Pharmacotherapy	Treatment options for MCL, including PI3K-pathway agents
23512567	2013	Review	Current Treatment Options in Oncology	Current and emerging therapies in MCL by patient fitness/age
28775119	2017	Review	Haematologica	Practical approach to incidence and management of ibrutinib/idelalisib toxicity

Norway Market Information

Idelalisib is currently not marketed in Norway (未上市) and holds 0 authorizations on file — no license records are available to summarize.

Cytotoxicity

This section applies because idelalisib is an antineoplastic agent (targeted small-molecule kinase inhibitor used across B-cell hematologic malignancies).

Item	Content
Cytotoxicity Classification	Targeted therapy (PI3Kδ inhibitor, oral small-molecule kinase inhibitor; not a conventional cytotoxic chemotherapy agent)
Myelosuppression Risk	Low to moderate — neutropenia has been reported in idelalisib trials, but the dominant safety signals described in the literature are non-hematologic (hepatotoxicity, colitis, pneumonitis) (PMID 28775119, 30069634)
Emetogenicity Classification	Low — oral targeted kinase inhibitor, not among conventionally high-emetogenic agents
Monitoring Items	Liver function tests (baseline and frequent early monitoring), CBC with differential, respiratory symptom/imaging surveillance (pneumonitis risk), GI symptom monitoring (colitis/diarrhea), infection surveillance
Handling Protection	Standard oral hazardous-drug handling precautions per institutional policy for targeted oncology agents; not classified under conventional cytotoxic reconstitution/handling regulations

Safety Considerations

Please refer to the package insert for safety information. (No structured warnings, contraindications, or drug-interaction data are currently on file in this Evidence Pack — see Data Gap DG001, blocking severity.)

Conclusion and Next Steps

Decision: Hold

Rationale: While mechanistic rationale is sound and a completed Phase 1 trial plus multiple early-phase combination studies show clinical activity of idelalisib in MCL, there is no confirmatory Phase 2/3 RCT specific to this indication, and the drug is not currently marketed in Norway. Critically, official label safety data (warnings/contraindications) is a Blocking data gap (DG001), which prevents this candidate from entering the S1 safety pre-assessment stage.

To proceed, the following is needed:

Official package insert / TFDA-equivalent label with warnings and contraindications (resolves DG001, Blocking)
Confirmed mechanism-of-action documentation from DrugBank (resolves DG002)
Regulatory pathway assessment for Norway market entry, given current "Not Marketed" status
If development continues, a confirmatory Phase 2 (ideally randomized) trial specifically in MCL patients to move beyond the existing Phase 1 activity signal
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.