Looked at the futures this morning and decided to wait. I remember when Rick saw large blocks of LSBC go by. A couple of weeks passed . . . and then the rise began as he charted in post #2. I figure I've got a couple of days for the GenomeWeb hype to die down. <g> Nothing new there. No elephants this morning in either AGNT or MCLS. The two candidates in the WatchList that look vulnerable right now are RIGL, which I like under 5, and INGN, ditto. RIGL has a thread, INGN does not. The latter got a pop from preclinical news announced before ASCO and from ASCO itself.
INGN hyped two of them. One I posted yesterday (NSCLC). Here's the other (ovarian), and I've appended a third that looked interesting. There's a fourth on bladder cancer. Comments on these invited.
>>1025
Phase I Intraperitoneal Adenoviral p53 Gene Transfer in Ovarian Cancer.
Carolyn Y. Muller, Robert L. Coleman, Paula Rogers, James A. Merritt, Karen Parker, David Scott Miller, UT Southwestern Medical Center, Dallas, TX; Introgen Therapeutics, Houston, TX.
Objective: To determine the safety, pharmacokinetics, maximal tolerated dose (MTD), biologic and clinical endpoints of intraperitoneal (IP) Ad5p53 gene transfer. Methods: From 9/98-2/00, ten women with refractory ovarian cancer were treated with Ad5p53 (RPR/INGN 201, Introgen Therapeutics, Houston Tx) gene vector weekly (day 1,8 and 15) of a 28 day cycle at entry dose levels (3x10 10 [n=3], 1x10 11 [n=3], 3x10 11 [n=4], 1x10 12 , 3x10 12 vps. Dose escalations were given at subsequent cycles if no treatment related toxicity until the maximal dose was reached. "Pharmacokinetics" were collected at 0 and 24 hours after dosing on treatment day 1,8,15 and at the first escalated doses. CPE assays (sputum, rectal, urine), serum and ascites complement levels, flow cytometric analyses of ascitic tumor cells for count and p53 expression and serum anti-adenoviral titres were performed. Serum CA-125, disease response and toxicities were recorded. Results: The median number of doses received was 6 (2-34); 7 patients received dose escalations with 3 reaching the maximal dose level. No replication competent virus was isolated. Complement levels were not significantly changed in either serum or ascites. Pretreatment p53 expression was seen in 15% or less of CD45- cells in 4 of 5 patients. Post-treatment expression increased at 24 hours (1.4-2.6 fold) with 2,8-17 fold maximal increase within the initial 28 day cycle. Median pre-treatment titres of anti-ad5 antibodies was 1:128 (range 32-512) with all but 2 demonstrating a minimal 16 fold increase by weeks 2-4 (maximal 256 fold). Of evaluable patients, the maximal response was stable disease (n=5). Autopsy confirmed severe intraabdominal adhesions in 3 of 4 patients. Treatment related toxicities were minimal, not defining an MTD. Conclusion: Weekly intraperitoneal adenoviral p53 gene therapy with dose escalation is safe. The MTD has not yet been reached. Anti-ad5 antibodies are elicited in most which may promote adhesions but did not interfere with expression.
1045
A Phase I and Pharmacokinetic Study of Intravenous (IV) p53 Gene Therapy with RPR/INGN-201 in Patients (pts) with Advanced Cancer.
Desiree Hao, Eric K Rowinsky, Leslie A Smetzer, Leonel Ochoa, Lisa A Hammond, Alison Garner, Lon Smith, Karen Parker, J A Merritt, Anthony W Tolcher, Institute for Drug Development, San Antonio, TX; Insitute for Drug Development, San Antonio, TX; Introgen Therapeutics, Houston, TX.
BACKGROUND: Mutation of the tumor suppressor gene, p53 occurs in approximately 50% of all cancers, confers resistance to apoptosis and is associated with a poor prognosis in many malignancies. RPR/INGN-201 is a replication defective, adenoviral vector encoding a wild-type (wt) p53 gene driven by the cytomegalovirus promotor (Ad5CMV-p53). In vitro, various cell lines have been successfully transduced with Ad5CMV-p53. In vivo, expression and function of the transgenic product correlated with tumor regression and improved survival. In early clinical trials, intra-tumoral administration of RPR/INGN-201 has been shown to be safe, with preliminary evidence of activity in lung and head and neck cancers. This study was conducted to evaluate the safety, tolerability and pharmacokinetic profile of RPR/INGN-201 administered IV daily for three days, every 28 days. RESULTS: To date, 10 pts (median age=56, median ECOG performance status=1, male:female=2:3) have received 25 monthly courses of RPR/INGN-201 at escalating doses of 3 x 1010 , 1 x 1011, 3 x 1011 and 1 x 1012 viral particles (vp) per infusion. One pt had grade 2 neutropenia. One of 5 pts treated at 1 x 1012 vp experienced dose limiting, grade 3 diarrhea. Non-hematologic toxicity across all courses has been mild ([less than or equal to] Grade 2) including fever (7 episodes), fatigue (4), arthralgias/myalgias (4), nausea/vomiting (4/3), and diarrhea (3). Four pts have had transient, asymptomatic transaminase elevations ([less than or equal to] grade 2) typically occurring between day 1-2 and resolving by day 4. One pt with metastatic colon cancer was safely treated with 10 cycles of RPR/INGN-201. CONCLUSIONS: IV administration of RPR/INGN-201 represents a novel delivery method for gene therapy with the potential for more widespread delivery of p53 in pts with disseminated cancers. Evaluation of p53 expression in pre- and post-treatment tumor biopsies is pending. IV administration of doses up to 1 x 1012 vp appears well tolerated and accrual at this dose level is ongoing to further define the maximum tolerated dose.<<
Tolcher again. I know: he did some of IMGN's studies, too.
Cheers, Tuck |
