Clinical Trials and Drug Repurposing
ClinicalTrials.gov matches, VICC Meta-Knowledgebase federated evidence, OncoKB actionability, and treatment strategy for five driver mutations.
Clinical Trials
33
21 actively recruiting across 8 European sites
Recruiting Active
21
ClinicalTrials.gov API v2, filtered by patient mutation profile
VICC Evidence
263
From 6 federated databases (CIViC, CGI, JAX, OncoKB, PMKB, MolecularMatch)
OncoKB Level 1 FDA
IDH2 R140Q
Enasidenib: FDA-approved 2017 for R/R AML with IDH2 mutation
Treatment Strategy
Backbone: Venetoclax + azacitidine with enasidenib
for the IDH2 R140Q subclone (VAF 2%). The patient is currently MRD-negative
and in full donor chimerism 28+ months post-allogeneic HSCT. Treatment
considerations are for relapse contingency planning.
Actionable targets: (1) IDH2 R140Q: enasidenib (FDA-approved 2017, OncoKB Level 1). ORR 40.3%, CR 19.3% in R/R AML 21
CONTRAINDICATION: Tazemetostat (EZH2 inhibitor) is CONTRAINDICATED. EZH2 V662A is loss-of-function, not gain-of-function. Tazemetostat inhibits EZH2 catalytic activity, which is already impaired by V662A. Administering tazemetostat would further reduce H3K27me3, potentially accelerating disease 10
Actionable targets: (1) IDH2 R140Q: enasidenib (FDA-approved 2017, OncoKB Level 1). ORR 40.3%, CR 19.3% in R/R AML 21
[21] EM 2017
Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood (2017)
.
NCT03728335 evaluates enasidenib maintenance post-HSCT, directly applicable
to this patient's current status.
(2) PTPN11 E76Q: SHP2 inhibitors (TNO155, RMC-4550)
in Phase I/II trials. Our AutoDock Vina docking: TNO155 = -9.34 kcal/mol,
RMC-4550 = -8.71 kcal/mol against the E76Q mutant structure
23[23] MJ 2020
Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer. J Med Chem (2020)
.
CONTRAINDICATION: Tazemetostat (EZH2 inhibitor) is CONTRAINDICATED. EZH2 V662A is loss-of-function, not gain-of-function. Tazemetostat inhibits EZH2 catalytic activity, which is already impaired by V662A. Administering tazemetostat would further reduce H3K27me3, potentially accelerating disease 10
[10] A 2020
Mutational mechanisms of EZH2 inactivation in myeloid neoplasms. Leukemia (2020)
.
Tazemetostat was withdrawn from the EU market on March 9, 2026, consistent
with the LoF concern in myeloid settings.
IDH2 R140Q FDA
Level 1
Enasidenib (AG-221), approved 2017
PTPN11 E76Q
Phase I/II
TNO155, RMC-4550 (SHP2 inhibitors)
EZH2 V662A Blocked
CONTRA
Tazemetostat: LoF variant, inhibitor CONTRAINDICATED
DNMT3A R882H
HMA
Azacitidine/decitabine (indirect, backbone therapy)
SETBP1 G870S
No Target
PP2A activators (FTY720, DT-061) preclinical only
Drug Landscape
The drug landscape spans FDA-approved agents (enasidenib, venetoclax,
azacitidine), Phase I/II investigational compounds (SHP2 inhibitors),
and preclinical repurposing candidates (PP2A activators for SETBP1).
Of the 5 driver mutations, 2 are directly druggable (IDH2 R140Q, PTPN11 E76Q),
1 has an indirect HMA-based approach (DNMT3A R882H), 1 has only preclinical
candidates (SETBP1 G870S), and 1 requires avoidance of the standard
inhibitor class (EZH2 V662A).
| Target | Drug | Mechanism | Status | Level |
|---|---|---|---|---|
| IDH2 R140Q | Enasidenib (AG-221 / Idhifa) | Selective IDH2 inhibitor — blocks 2-HG production by mutant IDH2, restores norma... | FDA Approved | Approved |
| IDH2 R140Q | Vorasidenib (AG-881) | Dual IDH1/IDH2 inhibitor — brain-penetrant, primarily studied in glioma | FDA Approved | Phase 1 (for AML context — off-label consideration) |
| PTPN11 (SHP2) E76Q | RMC-4550 (Revolution Medicines) | Allosteric SHP2 inhibitor — locks SHP2 in autoinhibited conformation, blocks RAS... | Phase 1/2 | Phase 1/2 |
| PTPN11 (SHP2) E76Q | TNO155 (Novartis) | Allosteric SHP2 inhibitor | Phase 1/2 | Phase 1/2 |
| PTPN11 (SHP2) E76Q | JAB-3312 (Jacobio Pharmaceuticals) | Allosteric SHP2 inhibitor | Phase 1/2 | Phase 1/2 |
| PTPN11 (SHP2) E76Q | RMC-4630 (Revolution Medicines) | Allosteric SHP2 inhibitor — clinical-grade compound from same programme as RMC-4... | Phase 1/2 | Phase 1/2 |
| DNMT3A R882H | Azacitidine (Vidaza) | Hypomethylating agent (HMA) — DNA methyltransferase inhibitor, induces hypomethy... | FDA Approved | Approved |
| DNMT3A R882H | Decitabine (Dacogen) | Hypomethylating agent — similar mechanism to azacitidine but pure deoxynucleosid... | FDA Approved | Approved |
| DNMT3A R882H | Decitabine/Cedazuridine (Inqovi) | Oral HMA — decitabine + CDA inhibitor for oral bioavailability | FDA Approved | Approved |
| SETBP1 G870S | FTY720 (Fingolimod) — PP2A activator | PP2A activating drug (PAD) — disrupts SET-PP2A interaction, reactivates PP2A tum... | FDA Approved | Preclinical (for AML) |
| SETBP1 G870S | OP449 (formerly SET antagonist peptide) | Cell-penetrating peptide that binds SET and releases PP2A from SET-mediated inhi... | Preclinical | Preclinical |
| SETBP1 G870S | DT-061 (SMAP class) | Small molecule activator of PP2A — stabilises active B56alpha-containing PP2A ho... | Preclinical | Preclinical |
| General AML N/A | Venetoclax (Venclexta) | BCL-2 inhibitor — induces apoptosis in AML cells dependent on BCL-2 for survival | FDA Approved | Approved |
| General AML N/A | Midostaurin (Rydapt) | Multi-kinase inhibitor (FLT3, KIT, PDGFR, VEGFR, PKC) | FDA Approved | Not applicable unless FLT3-mutated |
| General AML N/A | Gilteritinib (Xospata) | FLT3 inhibitor (FLT3-ITD and FLT3-TKD) | FDA Approved | Not applicable unless FLT3-mutated |
| Monosomy 7 -7 | No monosomy 7-specific therapies approved | Chromosome 7 loss removes multiple tumour suppressors (EZH2, CUX1, MLL3/KMT2C). ... | Preclinical / early phase | Preclinical |
| Monosomy 7 -7 | EZH2 inhibitors (tazemetostat) — synthetic lethality concept | If monosomy 7 removes one EZH2 allele, remaining allele may be haploinsufficient... | Conceptual / preclinical | Preclinical |
| Monosomy 7 -7 | Allogeneic stem cell transplant | Only curative option for monosomy 7 — replaces malignant clone with donor haemat... | Standard of care | Approved (transplant) |
Table 1.Drug-target landscape for patient mutation profile. Excludes tool compounds and non-applicable agents.
Source: Compiled from DrugBank, OncoKB,
DGIdb, ClinicalTrials.gov, and published literature.
Docking scores from AutoDock Vina (Trott & Olson, 2010).
VICC Meta-Knowledgebase
Total Hits
263
Across 6 federated databases
DNMT3A R882H
55
55 associations across CIViC, JAX, PMKB, CGI, OncoKB
IDH2 R140Q
73
73 associations, highest among patient variants
EZH2 V662A
105
105 associations (mostly gene-level, not variant-specific)
The VICC Meta-Knowledgebase
47
[47] AH 2020
A harmonized meta-knowledgebase of clinical interpretations of somatic genomic variants in cancer. Nat Genet (2020)
federates clinical evidence across
CIViC
36[36] M 2017
CIViC is a community knowledgebase for expert crowdsourcing the clinical interpretation of variants in cancer. Nat Genet (2017)
, CGI, JAX-CKB, OncoKB
35[35] D 2017
OncoKB: A Precision Oncology Knowledge Base. JCO Precis Oncol (2017)
, PMKB, and MolecularMatch.
Querying all 5 patient variants yields 263 total associations
spanning predictive, diagnostic, prognostic, and therapeutic evidence.
IDH2 R140Q has the densest evidence (73 hits) with
Level A (FDA-approved) enasidenib data. SETBP1 G870S
has the sparsest evidence (6 hits), reflecting the limited therapeutic
landscape for this target. EZH2 V662A shows 105 hits,
but these are predominantly gene-level annotations from lymphoma contexts
(GoF mutations), not directly applicable to the myeloid LoF setting.
| Gene | Variant | Total Hits | Top Source | Evidence Levels |
|---|---|---|---|---|
| DNMT3A | R882H | 55 | CIVIC (41) | B:40, A:6, D:5, C:3 |
| IDH2 | R140Q | 73 | jax (35) | A:26, B:21, C:13, D:12 |
| SETBP1 | G870S | 6 | jax (3) | D:2, C:2, A:1, B:1 |
| PTPN11 | E76Q | 24 | jax (20) | D:17, B:5, A:1, C:1 |
| EZH2 | V662A | 105 | jax (76) | D:76, A:13, C:9, B:7 |
Table 2.Per-variant evidence summary from the VICC federated knowledgebase.
Source: VICC Meta-Knowledgebase
(Wagner et al., Nat Genet, 2020). Evidence levels: A (FDA/guidelines),
B (clinical evidence), C (case reports), D (preclinical).
OncoKB Clinical Actionability
OncoKB
35
[35] D 2017
OncoKB: A Precision Oncology Knowledge Base. JCO Precis Oncol (2017)
classifies IDH2 R140Q
as Level 1 (FDA-approved targeted therapy), the highest actionability
designation. The remaining 4 variants are classified as Oncogenic or
Likely Oncogenic but lack Level 1 targeted therapies. PTPN11 E76Q
is Level 4 (biological evidence of investigational SHP2 inhibitors).
All 5 mutations are confirmed oncogenic drivers in the context of myeloid
malignancies, supporting the clinical significance of this quintuple combination.
| Gene | Variant | Oncogenicity | Effect | Highest Level | Drug |
|---|---|---|---|---|---|
| EZH2 | V662A | Likely Oncogenic | Loss-of-function | None | No targeted therapy |
| DNMT3A | R882H | Oncogenic | Loss-of-function | None | No targeted therapy |
| SETBP1 | G870S | Likely Oncogenic | Gain-of-function | None | No targeted therapy |
| PTPN11 | E76Q | Likely Oncogenic | Gain-of-function | None | SHP2 inhibitors (TNO155, RMC-4550, RLY-1971) |
| IDH2 | R140Q | Oncogenic | Gain-of-function | Level 1 | Enasidenib |
Table 3.OncoKB clinical actionability annotations for all 5 patient variants.
Source: OncoKB (Chakravarty et al., JCO PO, 2017).
Tumor type context: Acute Myeloid Leukemia.
Level 1: FDA-approved. Level 4: biological evidence.
Matched Clinical Trials
33 clinical trials matched the patient's mutation profile via the
ClinicalTrials.gov API v2. 21 are actively recruiting.
Trials are scored by eligibility criteria overlap with the patient's
specific mutations, diagnosis (MDS-AML), age (36), and post-HSCT status.
The highest-scored trial is NCT03383575 (azacitidine +
enasidenib for IDH2-mutant MDS, score 100). The most directly relevant
for current status is NCT03728335 (enasidenib maintenance
post-allogeneic HCT in IDH2-mutant patients, score 88).
| NCT ID | Title | Phase | Status | Target | Score |
|---|---|---|---|---|---|
| NCT03383575 | Azacitidine and Enasidenib in Treating Patients With IDH2-Mutant Myelodysplastic... | Ph 2 | Recruiting | IDH2 R140Q | 100 |
| NCT06387069 | A Study to Evaluate HMPL-306 in Patients With IDH1or IDH2-mutated Acute Myeloid ... | Ph 3 | Recruiting | IDH2 R140Q | 99 |
| NCT04603001 | Study of Oral LY3410738 in Patients With Advanced Hematologic Malignancies With ... | Ph 1 | Active | IDH2 R140Q | 96 |
| NCT02632708 | Safety Study of AG-120 or AG-221 in Combination With Induction and Consolidation... | Ph 1 | Active | IDH2 R140Q | 92 |
| NCT03825796 | CPX-351 Plus Enasidenib for Relapsed AML | Ph 2 | Active | IDH2 R140Q | 91 |
| NCT04774393 | Decitabine/Cedazuridine and Venetoclax in Combination With Ivosidenib or Enaside... | Ph 1, PHASE2 | Recruiting | IDH2 R140Q | 91 |
| NCT03728335 | Enasidenib (AG-221) Maintenance Post Allogeneic HCT in Patients With IDH2 Mutati... | Ph 2 | Recruiting | IDH2 R140Q | 88 |
| NCT05010772 | Decitabine Alone or in Combination With Venetoclax, Gilteritinib, Enasidenib, or... | Ph 1 | Recruiting | IDH2 R140Q + combination therapy | 88 |
| NCT06577441 | Testing the Addition of an IDH2 Inhibitor, Enasidenib, to Usual Treatment (Cedaz... | Ph 2 | Recruiting | IDH2 R140Q | 85 |
| NCT05441514 | Enasidenib in Combination With Cobimetinib for the Treatment of Relapsed or Refr... | Ph 1 | Active | IDH2 R140Q | 85 |
| NCT06377579 | OBServatory of Compassionate Use of IVOsidenib in France for Patients With Acute... | Not specified | Recruiting | IDH2 R140Q | 84 |
| NCT06611839 | Venetoclax in Combination With Ivosidenib and Azacitidine for Newly Diagnosed ID... | Ph 1, PHASE2 | Recruiting | IDH2 R140Q | 83 |
Table 4.Top 12 matched clinical trials ranked by eligibility score. NCT IDs link to ClinicalTrials.gov.
Source: ClinicalTrials.gov API v2.
Queried: IDH2 AML, SHP2 myeloid, venetoclax + azacitidine + IDH2,
PTPN11 leukemia, MDS monosomy 7, enasidenib combinations.
Eligibility scores incorporate mutation match, diagnosis, age, and HSCT status.
References
- Stein EM et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood (2017). DOI
- Chase A, Cross NCP. Aberrations of EZH2 in cancer. Leukemia (2020). DOI
- LaMarche MJ et al. Identification of TNO155, an allosteric SHP2 inhibitor for cancer therapy. J Med Chem (2020). DOI
- Chakravarty D et al. OncoKB: A Precision Oncology Knowledge Base. JCO Precis Oncol (2017). DOI
- Wagner AH et al. A harmonized meta-knowledgebase of clinical interpretations of somatic genomic variants in cancer. Nat Genet (2020). DOI
- Griffith M et al. CIViC is a community knowledgebase for expert crowdsourcing the clinical interpretation of variants in cancer. Nat Genet (2017). DOI
- Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function. J Comput Chem (2010). DOI