First-in-human study of CH5132799, an oral class I PI3K inhibitor, studying toxicity, pharmacokinetics, and pharmacodynamics, in patients with metastatic cancer

Clin Cancer Res. 2014 Dec 1;20(23):5908-17. doi: 10.1158/1078-0432.CCR-14-1315. Epub 2014 Sep 17.


Purpose: This phase I dose-escalation study investigated the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of CH5132799.

Experimental design: Patients with metastatic solid tumors were eligible for the study. CH5132799 was administered orally once daily or twice daily in 28-day cycles.

Results: Thirty-eight patients with solid tumors received CH5132799 at 2 to 96 mg once daily or 48 to 72 mg twice daily. The MTD was 48 mg on the twice-daily schedule but was not reached on the once daily schedule. DLTs were grade 3 elevated liver function tests (LFT), grade 3 fatigue, grade 3 encephalopathy, grade 3 diarrhea, and grade 3 diarrhea with grade 3 stomatitis; all DLTs were reversible. Most drug-related adverse events were grade 1/2. Diarrhea (34%) and nausea (32%) were the most common events. Mean Cmax and AUC0-24 in steady state at MTD were 175 ng/mL and 1,550 ng·h/mL, respectively, consistent with efficacious exposure based on preclinical modeling. Reduction in SUVmax with [(18)F] fluorodeoxyglucose positron emission tomography (FDG-PET) was observed in 5 of 7 patients at MTD. A patient with PIK3CA-mutated clear cell carcinoma of the ovary achieved a partial response by GCIG CA125 criteria and further, a heavily pretreated patient with triple-negative breast cancer had marked improvement in her cutaneous skin lesions lasting six cycles.

Conclusion: CH5132799 is well tolerated at the MTD dose of 48 mg twice daily. At this dose, the drug had a favorable PK and PD profile and preliminary evidence of clinical activity.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use*
  • Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • Class I Phosphatidylinositol 3-Kinases / metabolism
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasm Metastasis
  • Neoplasms / diagnosis
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / pathology*
  • Positron-Emission Tomography
  • Pyrimidines / pharmacology*
  • Pyrimidines / therapeutic use*
  • Sulfonamides / pharmacology*
  • Sulfonamides / therapeutic use*
  • Tomography, X-Ray Computed
  • Treatment Outcome


  • Antineoplastic Agents
  • Pyrimidines
  • Sulfonamides
  • Class I Phosphatidylinositol 3-Kinases
  • CH 5132799