GDC-0449 in Treating Patients With Locally Advanced or Metastatic Solid Tumors (very generic for many cancers)

http://www.cancer.gov/clinicaltrials/JHOC-J06131

Purpose

RATIONALE: Drugs used in chemotherapy, such as GDC-0449, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing.

PURPOSE: This phase I trial is studying the side effects and best dose of GDC-0449 in treating patients with locally advanced or metastatic solid tumors


Drug: systemic Hedgehog antagonist GDC-0449


Criteria

DISEASE CHARACTERISTICS:

*

Histologically confirmed locally advanced or metastatic solid tumor that is refractory to standard therapy or for which no standard therapy exists
o

Progressed after first-line and second-line therapy (if there is a second-line therapy that has been shown to provide clinical benefit)
+ Must receive standard second-line therapy if second-line therapy has been shown to provide clinical benefit
*

Evaluable disease by physical examination, imaging, and/or one of the following:
o Two rising prostate-specific antigen (PSA) levels ≥ 2 weeks apart, with one obtained during screening (for patients with prostate cancer)
o Two rising CA-125 levels ≥ 2 weeks apart, with one obtained during screening (for patients with ovarian cancer)
* No CNS cancer, either primary lesions or metastatic disease, as the current malignancy
* No pleural effusions, ascites, or leptomeningeal disease as the only manifestation of the current malignancy

AST and ALT ≤ 1.5 times ULN (≤ 5 times the ULN for patients with liver metastases)

http://biz.yahoo.com/bw/080515/200805150...

A First-in-Human, First-in-Class, Phase I Study of Systemic Hedgehog Pathway Antagonist, GDC-0449, in Patients with Advanced Solid Tumors (Abstract #3516) Patricia LoRusso, D.O., Karmanos Cancer Center, Wayne State University, Detroit, Mich.; Oral Presentation; Sunday, June 1, 2008, 8:00 a.m. – 8:15 a.m. CDT; W375a

Interim results will be presented from a Phase I study evaluating the safety, tolerability and pharmacokinetic profile of GDC-0449, a small molecule antagonist of the Hedgehog signaling pathway, in 19 patients with refractory solid tumors that have not responded to prior treatment. GDC-0449 demonstrated a favorable pharmacokinetic profile, with high sustained micromolar plasma concentrations and a terminal half-life of greater than seven days. No dose-limiting adverse events were observed at the three dose levels of GDC-0449 studied.

Two cases of reversible drug-related Grade 3 hyponatremia (lowered serum sodium level) and one case of reversible Grade 3 drug-related fatigue were reported. Stable disease was achieved in two patients with adenocystic carcinoma (a rare cancer most commonly found in the salivary glands) and partial responses were observed during this study in two patients with advanced basal cell carcinoma (BCC).

Data were reported earlier this year (American Association for Cancer Research, April 2008) for nine patients with advanced BCC, including the two advanced BCC patients described here, from an expansion cohort of this study. Stable disease or partial responses were achieved in eight out of nine patients (six partial responses, two stable disease) without significant toxicity.

This is the first study to evaluate a systemic Hedgehog antagonist in human clinical trials. Abnormal activation of the Hedgehog pathway appears to be an important mechanism for tumors to survive and grow. Mutations of the Hedgehog pathway have been implicated in the development of several tumors, such as BCC. Additionally, the progression of several solid tumor cancers has been associated with over-expression of the Hedgehog ligand, including colorectal cancer.

Genentech is initiating three Phase II studies of GDC-0449 this year. A Phase II study in first-line metastatic colorectal cancer began enrolling patients in Q2 2008 and other studies are planned in advanced BCC and an advanced epithelial tumor. Genentech is developing GDC-0449 under a collaboration agreement with Curis, Inc.