Anti-Angiogenesis Small Molecules

Neha Vapiwala, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: September 27, 2005

Vatalanib (PTK 787/ZK 222584)

  • Vatalanib is an oral drug that selectively inhibits all three types of VEGFR, as well as platelet-derived growth factor receptor (PDGFR) and c-KIT. (Note: c-KIT is a tyrosine kinase receptor pathway that is important for tumor growth and progression in several cancers, including gastrointestinal stromal tumor, acute myeloid leukemia, small cell lung carcinoma, and Ewing sarcoma.)
  • Phase I trials found maximally tolerated dose (MTD) of 750 mg twice daily and dose-limiting toxicity (DLT) of sudden lightheadedness.
  • CONFIRM I is a multinational, randomized phase III study of over 1,000 patients with previously untreated metastatic CRC, testing FOLFOX (a combination of oxaliplatin, fluorouracil (5-FU), and leucovorin) with either PTK 787 or placebo.
    • Preliminary results presented at ASCO 2005 show no difference to date in either RR or PFS.
  • CONFIRM II is also a multinational, randomized phase III trial evaluating PTK787 in patients with metastatic CRC who are refractory to irinotecan/5-FU therapy.

AZD 2171

  • AZD 2171 is an oral drug that potently inhibits all three types of VEGFR as well as PDGFR.
  • No MTD was reached in phase I studies, and the most common toxicities seen were fatigue, nausea, and vomiting.
  • Several clinical trials of AZD 2171 are currently accruing for the following diseases: liver metastases, acute myelogenous leukemia, and prostate cancer.
  • Preliminary results on tumor response appear promising.

GW 786034

  • GW 786034 is an oral drug that selectively inhibits all three types of VEGFR.
  • Currently in phase I dose escalation trials, with 800 mg/daily as a potential dose for phase II trials.
  • Most common side effects were hypertension, diarrhea, nausea, vomiting, and fatigue.
  • Minor responses seen in renal cell carcinoma and leiomyosarcoma.

Sunitinib (SU11248)

  • SU 11248 is an oral drug that inhibits VEGFR-2, PDGFR, KIT, and FLT3.
  • Phase I trials found DLT of fatigue, and recommended a phase II dose of 50 mg daily x 4 weeks with a 2-week break.
  • Two phase II trials are studying the use of sunitinib as second-line therapy for metastatic renal cell carcinoma.
    • Overall response rate of ~40% in both studies, almost entirely partial responses.
    • Stable disease for > 3 months in ~25% of patients.