Early clinical trials of new compounds reported at AACR

SAN DIEGO-At the 2008 AACR annual meeting, investigators reported preliminary results with a number of novel compounds entering clinical trials.

GDC-0449 in basal cell carcinoma

GDC-0449 (Genentech BioOncology) produced dramatic responses in a first-in-human, first-in-class phase I study of advanced multifocal or metastatic basal cell carcinoma patients (abstract LB-138). Durable clinical benefit (tumor shrinkage or disease stabilization) was observed in 8 of 9 patients, for a median of 176 days.

GDC-0449 is a small molecule that inhibits the Hedgehog pathway, which is important in cell growth and repair, and which is frequently mutated in basal cell carcinoma. The oral compound is dosed continually on a daily basis.

“The first patient had a dramatic response to the drug, and has shown clinical improvement for over 438 days, with only mild side effects,” reported Daniel D. Von Hoff, MD, physician in chief at the Translational Genomics Research Institute and chief medical officer for the Scottsdale Clinical Research Institute.

Cediranib in glioblastoma

Cediranib (AZD2171, AstraZeneca), an oral pan-VEGFR tyrosine kinase inhibitor, produced responses and prolonged survival in a phase II study of 31 patients with recurrent glioblastoma (abstract LB-247). Cediranib targets all three receptors for VEGF, one of which is expressed on

the endothelial cells in glioblastoma. Daily treatment reduced tumor volume by more than 50% in 17 of 30 patients (56%), and 25.8% were alive without progression at 6 months. Median progression-free survival was 117 days (compared with 63 days in historical controls), and median overall survival was 227 days (compared with 175 in historical controls).

Cediranib also alleviated cerebral edema and reduced or eliminated the need for steroids in virtually all patients, reported Tracy T. Batchelor, MD, executive director of the Stephen E. and Catherine Pappas Center for Neuro-Oncology at the Massachusetts General Hospital Cancer Center.

Two of the 31 patients were removed from the study because of fatigue, and dose reductions or interruptions were necessary for most patients, usually because of fatigue, hypertension, and diarrhea, Dr. Batchelor reported.

Certain biomarkers were found to predict treatment failure with cediranib: Fibroblast growth factor, which is related to new blood vessel growth, and Tie-2, a receptor that binds to angiopoietins, which are growth factors required for the formation of new blood vessels.

“We plan to move to phase III sometime this year in the United States, Canada, and Europe. We also have an NCI grant to combine cediranib with radiation and chemotherapy in newly diagnosed glioblastoma patients,” Dr. Batchelor said. The drug is also in phase II trials in colorectal cancer, NSCLC, ovarian cancer, and hepatocellular carcinoma.

MDV3100 in prostate cancer

MDV3100 (Medivation), a small molecule androgen receptor antagonist that blocks nuclear translocation of the androgen receptor and DNA binding, was evaluated in 38 patients with castration-resistant prostate cancer in a phase II trial (abstract LB-203). In the first 9 evaluable patients, 5 had PSA declines greater than 50%, and 7 are still on treatment up to 24 weeks with no evidence of progression. Patient accrual is continuing, said Howard I. Scher, MD, of Memorial Sloan-Kettering Cancer Center.

NPI-2358 in solid tumors and lymphoma

In a phase I trial, NPI-2358 (Nereus Pharmaceuticals, Inc), a vascular disrupting agent, was shown to decrease tumor flow on dynamic contrast-enhanced MRI scans of 25 patients with solid tumors and lymphomas, with 7 achieving stable disease (abstract LB-202).

The compound is proceeding into phase Ib/II trials in solid tumors, reported Monica Mita, MD, of the Institute for Drug Development, San Antonio.

AME-133v in follicular lymphoma

AME-133v (Eli Lilly), a second-generation anti-CD20 monoclonal antibody, has been engineered to achieve a much greater affinity for variant Fcγ receptors than rituximab (Rituxan), with less toxicity.

In a phase I study in 23 patients with low-affinity FcγRIIIa follicular lymphoma, AME-133v showed good tolerability, B-cell depletion, and clinical responses in patients who had received prior rituximab and chemotherapy (abstract LB-70). Four of 16 evaluable patients responded, reported Andres Forero, MD, of the University of Alabama, Birmingham, Comprehensive Cancer Center.

“Mutations in the receptor protein FcγRIIIa make tumors less responsive to standard therapy. These first results suggest that AME-133v provides a mechanism of action that may be more potent and ultimately more effective than current treatments for this subset,” Dr. Forero said. The drug was well tolerated at all doses. A phase II trial is accruing patients.

AV-951 in solid tumors

AV-951 (AVEO Pharmaceuticals; Kirin Pharma Company; Quintiles AB) is a potent and selective inhibitor of VEGFR-1, -2, and -3 tyrosine kinases. In a phase I trial of 40 patients with advanced solid tumors, clinical activity was observed across all dose levels (abstract LB-201).

Among 9 patients with renal cell carcinoma, there were 2 partial responses lasting 42 weeks and 128 weeks, respectively, and 7 patients with stable disease longer than 12 weeks, reported Ferry A.L.M. Eskens, MD, PhD, of Erasmus University Medical Center, Rotterdam.