Table 2.
Summary of in vitro and in vivo data of given compounds and related clinical trials.
| Drug | Target | Mechanism of action | In vivo and in vivo efficacya | Clinical trial (ClinicalTrials.gov Identifier) | Phase; Patients; Recruitment Status | Combination therapies | Clinical outcome in NPM1-mut AML pts (CR/CRi) |
|---|---|---|---|---|---|---|---|
| Leptomycin B (LMB) | XPO1 inhibitor natural compound (irreversible) | NPM1 export inhibition | OCI-AML2, OCI-AML3, HL-60, KG1, MV4-11; RPMI-8226 and NCI-H929 (MM cell lines). | / | / | / | / |
| CBS9106 | XPO1 degradation (reversible) | NPM1 export inhibition | MM.1R, MM.1S, RPMI-8226, and ARH-77 (MM cell lines). RPMI-8226 xenograft mice. | / | / | / | / |
| KPT-185 | XPO1 inhibitors (reversible) SINE, 1st generation | NPM1 export inhibition | HL-60, Kasumi-1, KG1a, MOLM13, MV4-11, OCI-AML3, and THP-1 cell lines; NCI-H929 and RPMI-8226 (MM cell lines). AML primary patient samples with NPM1 and FLT3 -ITD mutations. Primary CLL cells. | / | / | / | / |
| KPT-249 | HL-60; APL cell lines; NCI-H929 and RPMI-8226 (MM cell lines). | / | / | / | / | ||
| KPT-251 | Primary CLL cells; MV4-11 xenograft mice. | / | / | / | / | ||
| KPT-276 | HL-60, MV4-11; NCI-H929 and RPMI-8226 (MM cell lines). MV4-11 xenograft mice. | / | / | / | / | ||
| KPT-330 (Selinexor) | HL-60, K562, KG-1, IMS-M2, MOLM13, MOLM16, MOLT-4, MV4-11, NB4, OCI-AML3, OCI-AML5, THP-1 and U937 cell lines; NCI-H929 and RPMI-8226 (MM cell lines). MV4-11 xenograft mice and others AML-derived xenografts (including CN and FLT3 -ITD). | NCT02093403 | Phase 1; 25 patients; Enrollment completed | Decitabine | Evaluating efficacy | ||
| NCT02249091 | Phase 2; 42 patients; Enrollment completed | Ara-C and Idarubicin | Evaluating efficacy | ||||
| NCT02088541 | Phase 2; 317 patients; Enrollment completed | Hydroxyurea and Ara-C | Evaluating efficacy | ||||
| NCT01607892 | Phase 1; 286 patients (95 AML patients); Enrollment completed | / | Evaluating efficacy | ||||
| NCT03955783 | Phase 1b; 78 patients; Recruiting | Venetoclax | Evaluating efficacy | ||||
| KPT-335 | Jurkat (T-cell leukemia); OCI-Ly3 and OCI-Ly10 (B-cell lymphoma) cell lines; CLBL1 (canine lymphoma) cell line; primary DLBCL cells. | / | / | / | Evaluating efficacy | ||
| KPT-8602 (eltanexor) | XPO1 inhibitors (reversible) SINE, 2nd generation | NPM1 export inhibition | K562, Kasumi-1, KG1, MOLM13, MOLM16, Mono-Mac-1, MV4-11, NB4, OCI-AML2, OCI-AML3, SKM1, and U937. MV4-11 xenograft mice. | NCT02649790 | Phase 1/2; 119 patients;Recruiting | ASTX727 and Dexamethasone | Evaluating efficacy |
| VTX (Venetoclax) | BCL-2 inhibitor | Apoptosis | GDM1, HL-60, KG1, K562, ME1, ML2, MOLM13, MOLM16, Mono-Mac-6, MV4-11, OCI-AML2, OCI-AML3, OCI-M1, NB4, NOMO1, THP-1 and U937. AML primary patient samples with NPM1, FLT3-ITD mutations. MV4-11 xenograft mice and others AML-PDX models harboring different mutations including NPM1, DNMT3A, FLT3, IDH1, PML-RARα, CEBPA. | NCT04867928 | Phase 2; 35 patients; Recruiting | Azacitidine | Evaluating efficacy |
| NCT02203773 | Phase 1b; 212 patient Active, not recruiting | Azacitidine or Decitabine |
91.5% (N = 23, 21/23) |
||||
| NCT02993523 | Phase 3; 400 patients; Active, not recruiting | Azacitidine |
66.7% (N = 27, 18/27) |
||||
| NCT02287233 | Phase 1/2; 94 patients; Enrollment completed | LDAC |
89% (N = 9, 8/9) |
||||
| NCT03069352 | Phase 3; 211 patients; Active, not recruiting | LDAC |
78% (N = 18, 14/18) |
||||
| ACTRN12616000445471b | Phase 1b; 48 patients; Recruiting | 5 + 2 (cytarabine + idarubicin) |
80% (N = 10, 8/10) |
||||
| NCT03214562 | Phase 1b/2; 116 patients; Recruiting | FLAG + IDA |
100% (N = 8, 8/8) |
||||
| MI-2-2 | MLL-Menin protein–protein interaction inhibition | HOX genes and MEIS1 downregulation | HL-60, KOPN-8, ML-2, MOLM13, MV4-11 and OCI-AML3 cell lines; MLL-AF9, MLL-AF6 and MLL-AF1p. OCI-AML3 xenograft mice. | / | / | / | / |
| MI-503 | MV4-11 and OCI-AML3 cell lines. MLL-AF9 BMCs from patients. MOLM13, MV4-11 and OCI-AML3 xenograft mice. | / | / | / | / | ||
| MI-3454 | K562, KOPN-8, MOLM13, MV4-11, SET2 and U937. RS4-11 and SEM (B-cell leukemia) cell lines. AML primary patient samples with NPM1 mutations or MLL1 translocations. MOLM13 and MV4-11 xenograft mice. | / | / | / | / | ||
| KO-539 | MOLM13, MV4-11, OCI-AML3 cell lines. AML primary patient samples with NPM1, KMT2A and FLT3-TKD mutations. PDX models with MLL-FP or NPM1 mutations. | NCT04067336 (KOMET-1) | Phase 1/2; 60 patients; Recruiting | FLT3 inhibitors | Evaluating efficacy | ||
| VTP-50469 | MLL-Menin protein–protein interaction inhibition | HOX genes and MEIS1 downregulation | HL-60, K562, ML2, MOLM13, MV4-11, NOMO1, OCI-AML3, THP1 cell lines. RS4-11, KOPN-8 and HB11-19 (B-cell leukemia) cell lines. Mouse MOZ-TIF2 cells and MLL-AF9 cells. MV4-11 xenograft mice and others AML-PDX models harboring different mutations including NPM1, FLT3, DNMT3A and IDH1. | / | / | / | / |
| SNDX-5613 | MOLM13, MV4-11 and OCI-AML3. MOLM13 xenograft mice and others AML-PDX models harboring different mutations including NPM1, DNMT3A, FLT3, IDH1, WT1, KMT2C. | NCT04065399 (AUGMENT-101) | Phase 1/2; 186 patients; Recruiting | / |
30% (N = 10, 3/10) |
||
| JNJ-75276617 | AML cell lines (not specified). AML patient samples with NPM1 and KMT2Ar mutations. | NCT04811560 | Phase 1; 110 patients; Recruiting | FLT3 inhibitors | Evaluating efficacy | ||
| DS-1594b | Menin inhibitor | HOX genes and MEIS1 downregulation | AML and ALL cells with MLLr (not specified). | NCT04752163 | Phase 1/2; 122 patients; Recruiting | Azacitidine, Venetoclax, or mini-HCVD | Evaluating efficacy |
| BMF-219 | Menin inhibitor (irreversible) | HOX genes and MEIS1 downregulation | MOLM13 cell line. CLL and MM cell lines (not specified). AML patient samples with NPM1 and MLLr mutations. | NCT05153330 (COVALENT-101) | Phase 1; 100 patients; Recruiting | / | Evaluating efficacy |
CR complete response, CRi complete response with incomplete count recovery, CN cytogenetically normal, SINE selective inhibitor of nuclear export, MM Multiple myeloma, DLBCL diffuse large B-cell lymphoma, HMAs hypomethylating agents, LDAC Low-Dose Cytarabine, mini-HCVD mini–hyper fractionated cyclophosphamide, vincristine and dexamethasone, FLAG-IDA fludarabine, cytarabine, granulocyte colony-stimulating factor (G-CSF) and idarubicin.
aData from the most important studies in AML cells are reported, unless otherwise indicated.
bAustralian Clinical Trials.