Table 2.
FLT3 inhibitors under active clinical investigation either as single agent or in combination.
| TKI | Trial phase | Patient population | Single agent/ combination | Ref./identifier | Status |
|---|---|---|---|---|---|
| Sunitinib | I | Patients with all AML FAB classification types, except AML M3 (n = 29) | Single agent | [115] | Completed |
| I | Patients with primary or secondary AML; relapsed after at least 1 cycle of conventional chemotherapy; refractory to at least 1 cycle of induction chemotherapy; or not candidates for induction chemotherapy; any AML FAB subtype; at least 18 years of age (n = 16) | Single agent | [116] | Completed | |
| I/II | Patients aged 60 years or higher with AML with activating FLT3 mutations (FLT3/ITD, FLT3/ TKD); fit enough for intensive chemotherapy (n = 22) | Combination with standard induction and consolidation therapy | [117] | Completed | |
| Sorafenib | I | Patients with refractory or relapsed AML; median age 61.5 years; median of 2 prior therapies (n = 16) | Single agent | [41] | Completed |
| I | Relapsed, chemotherapy-refractory or frail FLT3/ITD AML patients ineligible for alternative treatments (n = 65) | Single agent | [118] | Completed | |
| I/II | AML patients younger than 65 years (n = 61) | Combination with conventional cytotoxic chemotherapy (AraC, idarubicin) | [64] | Completed | |
| II | Elderly AML patients (n = 197) | Combination with AraC/daunorubicin induction followed by consolidation and sorafenib maintenance | [119] | Completed | |
| I/II | AML by FAB criteria or high-risk MDS defined as IPSS category of intermediate-2 or greater; patients 60 years and older | Combination with low-dose cytarabine | NCT00516828 | Completed | |
| I | FLT3/ITD AML patients who have undergone allogeneic HSCT; age 18 to 75 years | Single agent | NCT01398501 | Recruiting | |
| I | FLT3/ITD AML patients in CR or PR who plan to undergo bone marrow transplantation; age 18 years or older | Single agent | NCT01578109 | Recruiting | |
| I | Relapsed/refractory FLT3/ITD AML; age 18 years and older | Combination with G-CSF and plerixafor/mozobil | NCT00943943 | Ongoing, not recruiting | |
| I | AML patients age 60 years and older and not candidates/refuses standard induction treatment or who have one of the following: poor-risk cytogenetics, AML following antecedent hematologic disorders, or therapy-related AML; patients with relapsed or refractory AML age 18 years are also eligible | Combination with several regimens, including bortezomib and DEC | NCT01861314 | Recruiting | |
| I/II | Patients with newly diagnosed, refractory or relapsed AML, poor-risk or complex cytogenetics, del5, del7 or FLT3/ITD; age 18 years or older | Combination with vorinostat and bortezomib | NCT01534260 | Recruiting | |
| I | Patients with AML or MDS; patients with APL if refractory to ATRA and arsenic trioxide; age 18 years and older | Combination with vorinostat | NCT00875745 | Ongoing, not recruiting | |
| I | Patients with MDS, CMML or AML who have failed prior therapy | Combination with 5-azacitidine | NCT01254890 | Ongoing, but not recruiting | |
| III | Patients with newly diagnosed AML; age up to 29 years | Combination with bortezomib | NCT01371981 | Recruiting | |
| Midostaurin | I | Previously untreated AML patients; age 18 – 60 years (n = 69) | Combination with conventional cytotoxic chemotherapy (daunoru-bicin/cytarabine induction, Ara-C consolidation) | [36] | Completed |
| II | Patients with FLT3 mutated, relapsed/refractory AML or high-grade MDS; not candidates for chemotherapy; median age of 62 years (n = 20) | Single agent | [120] | Completed | |
| I | Patients with relapsed or refractory AML; Patients with secondary AML; age 18 years and older | Combination with bortezomib and conventional chemotherapy | NCT01174888 | Recruiting | |
| II | Patients with suspected diagnosis of AML or related precursor neoplasm, or acute leukemia of ambiguous lineage; age 18 – 70 years | Combination with conventional chemotherapy | NCT01477606 | Ongoing, not recruiting | |
| II | Patients with FLT/ITD-mutated AML who have undergone allogeneic HSCT in CR1; age 18–60 years | Combination with conventional chemotherapy | NCT01883362 | Recruiting | |
| II | Patients with c-KIT or FLT3/ITD mutated t(8;21) AML; age 18 – 65 years | Combination with conventional chemotherapy | NCT01830361 | Recruiting | |
| II | Patients with newly diagnosed AML; except t(15;17); age 60 years and older | Combination with DEC | NCT01846624 | Recruiting | |
| II | Patients with AML, MDS (RAEB-1, −2) or CMML who are either relapsed or refractory to standard therapy, or are considered inappropriate candidates for standard therapy; age 18 years and older | Combination with RAD001 | NCT00819546 | Ongoing, not recruiting | |
| I/II | Patients with MDS, CMML, AML or biphenotypic or bilineage leukemia who have failed prior therapy; patients must have evidence of FLT3-activating mutations; age 18 years and older | Combination with 5-azacitidine | NCT01202877 | Ongoing, not recruiting | |
| I/II | Elderly AML patients (APL excluded); age 60 years and older | Combination with 5-azacitidine | NCT01093573 | Recruiting | |
| III | AML patients with activating FLT3 mutations; patients with antecedent MDS allowed, provided they received no prior cytotoxic therapy (including azacitidine or DEC); age 18–59 years | Combination with standard cytotoxic chemotherapy (daunoru-bicin/cytarabine induction with cytarabine consolidation) | NCT00651261 | Ongoing, not recruiting | |
| Lestaurtinib | I/II | Patients with refractory, relapsed or poor-risk AML; median age 61 years (n = 14) | Single agent | [39] | Completed |
| III | Patients with AML and activating FLT3 mutation (FLT3/ITD or FLT3/ D835); age 18 years and older (n = 224) | Combination with standard cytotoxic chemotherapy | [13] | Completed | |
| III | British MRC trial, AML patients < 60 years considered suitable for intensive chemotherapy (n = 2800) | Combination with standard induction and consolidation regimens | ISRCTN55675535 | Completed | |
| Crenolanib | II | Patients with relapsed/refractory primary AML or AML secondary to antecedent hematologic disorder; age 18 years and older | Single agent | NCT01522469 | Active, not recruiting |
| Patients with primary AML relapsed or refractory after prior therapy; AML secondary to antecedent chemotherapy or radiation therapy, or AML due to prior MDS/MPN with presence of either FLT3/ITD and/or other FLT3 activating mutation; age 18 years and older | Single agent | NCT01657682 | Recruiting | ||
| PLX3397 | I/II | Patients with primary AML, prior-chemotherapy-related AML or AML secondary to an antecedent hematologic disorder; in at least first relapse or refractory AML; positive for FLT3/ITD; age 18 years and older | Single agent | NCT01349049 | Recruiting |
| Quizartinib | I | Patients with primary or secondary AML (excluding APL), refractory to standard chemotherapy, relapsed after one or more cycles of induction chemotherapy or not candidate for standard chemotherapy; age 18 year or older | Single agent | [45] | Completed |
| II (cohort 1) | Elderly AML patients with relapsed/refractory disease; age 60 years and older (n = 134) | Single agent | [68] | Accrual completed | |
| II (cohort 2) | AML patients with relapsed disease or refractory to second-line salvage chemotherapy or relapsed after HSCT; age 18 years and older (n = 137) | Single agent | [47] | Accrual completed | |
| II | Patients with primary AML or AML secondary to MDS; relapsed or refractory after one second-line salvage regimen or after HSCT; FLT/ ITD positive; age 18 years and older | Single agent | NCT01565668 | Ongoing, not recruiting | |
| I | Patients with newly diagnosed AML; age 18–60 years | Combination with standard 7+3 induction, high-dose cytarabine consolidation, and quizartinib maintenance | NCT01390337 | Ongoing, not recruiting | |
| I | AML patients who have received a high dose or a reduced intensity conditioning allogeneic HSCT during first or second remission; age 18 years and older | Single agent | NCT01468467 | Ongoing, not recruiting | |
| I/II | Patients with AML (excluding APL and CML in blast crisis) or high-risk MDS; age 60 years and older | Combination with standard daunorubicin, ara-C and etoposide | NCT01236144 | Completed | |
| I/II | AML, MDS or CMML patients with relapsed/refractory disease; age 18 years and older | Combination with azacitidine or cytarabine | NCT01892371 | Recruiting |
AML: Acute myeloid leukemia; APL: Acute promyelocytic leukemia; ATRA: All trans-retinoic acid; CML: Chronic myeloid leukemia; CR: Complete response; DEC: Decitabine; FLT3: FMS-like tyrosine kinase-3; ITD: Internal tandem duplications; MDS: Myelodysplastic syndrome; PR: Partial response; TKI: Tyrosine kinase inhibitor.