Table 1 Cellular cytotoxic response to agents in active clinical evaluation in DIPG (excluding biologics).

Drug nameMechanism of
action
Clinical trial
identifier
MPO
score*
CNS
penetrant
JHH-DIPG-1SU-DIPG-XIIISU-DIPG-XVIISU-DIPG-
XXV
DoxorubicinTopo II
inhibitor
NCT02758366§2.79Limited1.048 μM0.934 μM0.235 μM1.176 μM
IrinotecanTopo I inhibitorNCT030866162.94YesI.C.I.C.0.263 μMI.C.
LenalidomideCereblon
inhibitor
NCT01222754#5.42YesI.C.I.C.I.C.I.C.
MebendazoleTub. depol.
inhibitor
NCT01837862**5.09Yes0.468 μM0.417 μM0.093 μM0.331 μM
VincristineTub. pol.
inhibitor
NCT01837862**2.88Limited0.029 μM0.331 μM0.030 μM0.030 μM
AbemaciclibCDK4/6
inhibitor
NCT026444603.11YesI.C.I.C.I.C.I.C.
RibociclibCDK4/6
inhibitor
NCT03355794††4.30YesI.C.I.C.I.C.I.C.
ErlotinibEGFR inhibitorNCT02233049‡‡4.25LimitedI.C.I.C.I.C.I.C.
DasatinibMultikinase
inhibitor
NCT01644773§§3.54YesI.C.I.C.I.C.I.C.
CrizotinibMultikinase
inhibitor
NCT01644773§§3.02Limited0.590 μM0.332 μM0.468 μM0.468 μM
EverolimusmTOR inhibitorNCT03355794††1.94LimitedI.C.I.C.I.C.I.C.
TemsirolimusmTOR inhibitorNCT02420613‖‖2.06YesI.C.I.C.I.C.I.C.
AdavosertibWee1 inhibitorNCT01922076#3.67YesI.C.I.C.I.C.I.C.
ONC-201Multiple
reports
NCT034165305.66UnknownI.C.I.C.I.C.I.C.
Valproic acidHDAC inhibitorNCT00879437¶¶5.62YesI.C.I.C.I.C.I.C.
VorinostatHDAC inhibitorNCT01189266#,##4.82Unknown1.481 μM1.176 μM1.864 μM0.833 μM
PanobinostatHDAC inhibitorNCT02717455***5.25Unknown0.166 μM0.166 μM1.176 μM0.148 μM

*The CNS MPO scores are based on the design algorithm defined by Wager et al. (18).

†Outcome definitions: “Yes” means that published results confirmed CNS exposure in animal or human studies. “Limited” means that published results suggest no or limited CNS exposure in animal or human studies. “Unknown” means that published results were not available to the best of our knowledge.

‡AC50 values are provided for agents with Z-AUC values < −0.85 and are based on the NCATS curve generator and are only provided for agents with a curve class designation of −1.1, −1.2, or −2.1 (otherwise noted as I.C. or “incomplete curve”) [see (43) for curve class definitions].

§NCT02758366 doses doxorubicin using a prolonged infusion alone or in combination with temozolomide or radiation.

‖In NCT02758366, doxorubicin is being dosed using a prolonged, slow infusion, which may increase the CNS exposure.

¶NCT03086616 doses irinotecan using a liposomal formulation administered using convection enhanced delivery.

#NCT01189266, NCT01222754, and NCT01922076 are trials combining the named drug with radiation therapy.

**NCT01837862 examines mebendazole alone or in combination with vincristine, carboplatin, irinotecan, bevacizumab, and/or temozolomide.

††NCT03355794 examines a combination therapy involving ribociclib and everolimus after radiation therapy.

‡‡NCT02233049 examines combinations of erlotinib, dasatinib, and everolimus.

§§NCT01644773 examines a combination therapy involving dasatinib and crizotinib.

‖‖NCT02420613 examines a combination therapy involving temsirolimus and vorinostat.

¶¶NCT00879437 examines a combination therapy involving valproic acid and bevacizumab and radiation.

## Vorinostat is also being explored in NCT02420613.

***NCT03566199 doses panobinostat using a nanoparticle formulation administered using convection enhanced delivery.