Open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of intravenously administered CNF1010 (17-(allylamino)-17-demethoxygeldanamycin [17-AAG]) in patients with solid tumors

• Published in: Cancer chemotherapy and pharmacology 2013-05, Vol.71 (5), p.1345-1355
• Main Authors: Saif, M. W., Erlichman, C., Dragovich, T., Mendelson, D., Toft, D., Burrows, F., Storgard, C., Von Hoff, D.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacology; Benzoquinones - administration & dosage; Benzoquinones - adverse effects; Benzoquinones - pharmacology; Biological and medical sciences; Biomarkers - metabolism; Cancer Research; Dose-Response Relationship, Drug; Emulsions; Female; HSP70 Heat-Shock Proteins - metabolism; HSP90 Heat-Shock Proteins - antagonists & inhibitors; Humans; Infusions, Intravenous; Lactams, Macrocyclic - administration & dosage; Lactams, Macrocyclic - adverse effects; Lactams, Macrocyclic - pharmacology; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - metabolism; Male; Maximum Tolerated Dose; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Nanoparticles; Neoplasms - drug therapy; Neoplasms - pathology; Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Receptor, ErbB-2 - blood; Tumors
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-013-2134-9

Background 17-(Allylamino)-17-demethoxygeldanamycin (17-AAG) is a benzoquinone ansamycin that binds to and inhibits the Hsp90 family of molecular chaperones leading to the proteasomal degradation of client proteins critical in malignant cell proliferation and survival. We have undertaken a Phase 1 trial of CNF1010, an oil-in-water nanoemulsion of 17-AAG. Methods Patients with advanced solid tumors and adequate organ functions received CNF1010 by 1-h intravenous (IV) infusion, twice a week, 3 out of 4 weeks. Doses were escalated sequentially in single-patient (6 and 12 mg/m 2 /day) and three-to-six-patient (≥25 mg/m 2 /day) cohorts according to a modified Fibonacci’s schema. Plasma pharmacokinetic (PK) profiles and biomarkers, including Hsp70 in PBMCs, HER-2 extracellular domain, and IGFBP2 in plasma, were performed. Results Thirty-five patients were treated at doses ranging from 6 to 225 mg/m 2 . A total of 10 DLTs in nine patients (2 events of fatigue, 83 and 175 mg/m 2 ; shock, abdominal pain, ALT increased, increased transaminases, and pain in extremity at 175 mg/m 2 ; extremity pain, atrial fibrillation, and metabolic encephalopathy at 225 mg/m 2 ) were noted. The PK profile of 17-AAG after the first dose appeared to be linear up to 175 mg/m 2 , with a dose-proportional increase in C max and AUC 0–inf . Hsp70 induction in PBMCs and inhibition of serum HER-2 neu extracellular domain indicated biological effects of CNF1010 at doses >83 mg/m 2 . Conclusion The maximum tolerated dose was not formally established. Hsp70 induction in PBMCs and inhibition of serum HER-2 neu extracellular domain indicated biological effects. The CNF1010 clinical program is no longer being pursued due to the toxicity profile of the drug and the development of second-generation Hsp90 molecules.