Table 1. Targeted approaches in mantle cell lymphoma.
| Class | Drug | Studies |
|---|---|---|
| CDK inhibitors | ||
| Targeting CDKs induces cell cycle arrest (e.g., CDK4/6) and/or inhibition of translation (e.g., CDK9) |
Flavopiridol (alvocidib) | Ongoing phase II studies using pharmacologically based schedules for relapsed MCL: NCT00445341, NCT00112723 |
| Dinaciclib (SCH 727965) | Phase II in MCL/CLL (Study P04715AM2) (NCT00871546) | |
| P276-00 | Phase II in MCL (NCT00843050) | |
| AT7519 | Phase I/II in combination with bortezomib in MM (NCT01183949); Phase I in solid tumors/NHLs (NCT00390117) |
|
| PD0332991 | Phase I in MCL (NCT00420056); plus bortezomib in MCL (NCT01111188) |
|
| BCR and PI3K/AKT/mTOR inhibitors | ||
| BCR signal transduction inhibitors | ||
| Inhibit signal transduction components downstream of BCR activation |
Fostamatinib (inhibits SYK) |
Phase I/II in B-cell lymphomas including MCL (NCT00446095) |
| Enzastaurin (inhibits PKCβ) |
Phase II in relapsed MCL | |
| PCI-32765 (inhibits BTK) | Phase II (PCYC-1104-CA) in relapsed/refractory MCL (NCT01236391) |
|
| mTOR inhibitors | ||
| Targeting mTOR/TORC1 complex inhibits translation/ribosome biogenesis |
RAD001 (everolimus) | PILLAR-1 and SAKK 36/06 as single-agent in MCL |
| CCI-779 (temsirolimus) | Phase III/IV in relapsed/refractory MCL (NCT00117598/NCT01180049) |
|
| AKT inhibitors | ||
| Targeting Akt kinase inhibits signal transduction |
Perifosine | Completed Phase I in refractory neoplasms testing different loading schedules (NCT00019656) |
| MK2206 | Phase II in relapsed lymphoma (NCT01258998) | |
| Triciribine Phosphate Monohydrate (TCN-PM, VD-0002) |
Phase I in adults with advanced hematologic malignancies (NCT00642031) |
|
| GSK2141795 | Phase I ‘First-Time-In-Human Study’ oral GSK2141795 (NCT00920257) |
|
| PI3K p110 inhibitors | ||
| Targeting p110/PI3K kinase inhibits signal transduction pathway |
CAL-101 | Phase I in select relapsed/refractory hematologic malignancies (NCT00710528) |
| SF1126/LY294002 | Phase I study in B-cell malignancies | |
| Targeting regulators of protein homeostasis | ||
| HSP90 inhibitors | ||
| Targeting HSP90 chaperone impairs stability of various oncoproteins |
17-AAG (tanespimycin) | Completed Phase II in lymphomas/MCL (NCT00117988) |
| IPI-504 and IPI-493 | Phase I in hematologic malignancies (NCT01193491); completed Phase I in relapsed/refractory MM (NCT00113204) |
|
| STA-9090 (ganetespib) | Phase I studies in hematologic malignancies | |
| SNX-5422 and SNX-2112 | 2 Phase I in hematological malignancies (NCT00595686) and lymphomas completed (NCT00647764); Phase I in solid tumor/lymphoma that has not responded to treatment (NCT00644072) |
|
| Inhibitors of small modifier enzymes | ||
| Targeting small modifier enzymes inhibits degradation of select proteins |
MLN4924 | Phase I in adults with lymphoma/MM (NCT00722488) |
| RG7112 | Phase I in relapsed/refractory leukemia (NCT00623870) | |
| Proteasome inhibitors | ||
| Targeting proteasome subunit/s inhibits global protein degradation |
MLN9708/MLN2238 | Phase I in adults with lymphoma (NCT00893464) |
| Carfilzomib (PR171) | Phase I in hematological malignancies (NCT00150462); Phase I in CLL/SLL/PLL (NCT01212380) |
|
| ONX0912 (PR047) | Phase I Study in advanced refractory/recurrent solid tumors (NCT01129349) |
|
| NPI-0052 | Phase I in relapsed/refractory MM (NCT00461045); Phase I in advanced solid tumor malignancies/refractory lymphoma (NCT00396864) |
|
| Bcl-2 family inhibitors | ||
| Targeting antiapoptotic Bcl-2 family members inhibits cell survival |
GX15-070MS (obatoclax mesylate) |
Completed Phase I/II study of GX15-070MS (obatoclax mesylate) plus bortezomib in refractory/relapsed MCL (NCT00407303) |
| AT-101 | Completed Phase II in relapsed/refractory B-cell malignancies/MCL (NCT00275431) |
|
| ABT-737 and ABT-263 | Phase I/II relapsed/refractory lymphoid malignancies (NCT00406809) |
|
| PARP inhibitors | ||
| Targeting PARP inhibits DNA damage repair |
ABT-888 (Veliparib) | Phase I in patients with refractory solid tumors/hematological cancers completed (NCT00387608) |
| MK-4827 | Phase II in relapsed MCL/MCL with inactive ATM (NCT01244009) |
|
| Inhibitors of lysine deacetylases | ||
| Targeting lysine deacetylases impairs gene expression and protein function |
Vorinostat (SAHA, Zolinza) |
Phase I/II studies including MCL in combination regimens |
| Romidepsin (FR901228) | Completed Phase II in relapsed/refractory NHL (NCT00077194) | |
| Belinostat (PXD101) | Completed Phase I plus 17-N-Allylamino-17- Demethoxygeldanamycin in solid tumors/lymphoma (NCT00354185); Phase I plus bortezomib in advanced solid tumors/lymphomas (NCT00348985) |
|
| Panobinostat (LBH589) | Phase II in relapsed/refractory NHL (NCT01261247); Phase I/II plus everolimus in MM/NHL/HL (NCT00918333); Phase II in relapsed/refractory CLL/MCL (NCT01090973) |
|
| Entinostat (MS-275) | Completed Phase I in solid tumors/lymphomas (NCT00020579); plus isotretinoin (NCT00098891) |
|
| JAK/STAT inhibitors | ||
| Targeting JAK kinase inhibits signal transduction |
SB1518 | Phase II in advanced lymphoid malignancies/MCL (NCT01263899) |