Skip to main content
. 2018 Jul 24;8:267. doi: 10.3389/fonc.2018.00267

Table 7.

Toxicity and pharmacokinetics (PK) of NOTCH-targeted therapies in clinical trials where lung cancer patients have been included.

Treatment Toxicity PK Clinical trial ID
NOTCH-based Combination
M PF-03084014 SA Manageable gastrointestinal adverse eventsa T1/2: 22–40 h after-multiple dosing. (178)
RO4929097 SA Serious adverse events in ≥1/5 patients:
  • ▪

    Small intestine obstruction, constipation, nausea

  • ▪

    Lung infection/sepsis, dyspnea

  • ▪

    Cardiac arrest, tachycardia

 UD NCT01 19386; NCT01217411
VEGFR inh cediranib Grade III–IV: diarrhea, headache, hypertension, nausea, hypothyroidism, hypophosphatemia Combination did not affect PK profile (179), PJC-004/NCI 8503
mTOR inh temsirolimus Grade III: rash, mucositis RO4929097 induces CYP3A4: ↑ temsirolimus CL (180)
LY900009 SA Grade III: mucosal inflammation Absorption: 1–4 h
Elimination T1/2: 2–4 h LSN2831047 (GSI metabolite): appearance: 2–6 h, T1/2:5–14 h		 NCT01158404 (181)
SA Weekly dosing was generally well tolerated Slow absorption half-life: 15 h (182)
MK-0752 Dalotuzumab anti-IGFR1 Grade III dehydration, rash, and diarrhea
  • ▪

    MK-0752 1.63–8 μmol/L in plasma

  • ▪

    Dalotuzumab 34–64 μg/mL in serum (at day 8), accumulated in time

 (183)
mAb anti-DLL4 Enoticumab (b) SA Grade III (0.5 mg/kg Q3W): nausea
Grade III (1 mg/kg Q2W): abdominal pain
Severe effects in 4 patients: ventricular dysfunction and pulmonary hypertension		 Nonlinear PK
T1/2: 8–9 days
Dose-independent CL (dose > 1.5 mg/kg) > 2 mg/1 in plasma ∞ max. tumor activity		 (184)
Demcizumab SA Generally well tolerated at doses ≤ 5 mg weekly.
4 patients (10 mg/kg Q2W):
congestive heart failure
Not more than one DLT per dose level		 PK within linear range
CL: 4.17 mL/day/kg
T1/2:15.9 days (>10 μg/mL)		 (185)
MEDI0639 SA No participants with DLT AUC: 7.4–512 μg/day/mL [Conc]Max; in blood: 3.2–81.6 μg/mL
CL: 1.4–0.5 L/day
T1/2: 1.5–8.25 days		 NCT01577745

GSI, gamma-secretase inhibitor; mAb, monoclonal antibody; inh, inhibitor; SA, single agent; ID, identifier; T1/2, half-life; UD, undocumented; CL, clearance; ∞, association; Q3W, once every 3 weeks; Q2W, once every 2 weeks; DLT, dose-limiting toxicity; [Conc]Max, maximum observed concentration; AUC, area under the concentration–time curve; CYP3A4, cytochrome P450 3A4.

aBetter symptoms than those for RO4929097 and MK-0752.

bBetter gastrointestinal toxicity than GSI.