Anti Angiogenesis

Antiangiogenesis drugs are supposed to work by not allowing the tumor to create new blood vessels, thereby cutting off its supply of blood and killing it. This section contains the references I found, but is not as well developed as the "biologic agents" section because I have been more interested in the antibodies and vaccines lately. I plan to revise this section in the future if I have time.

Contents

Overview

4/23/01 Angiogenesis Foundation
4/20/01 Angiogenesis inhibitors clinical trial listing from NCI - Expanded Listing
4/20/01 Angiogenesis Inhibitors in Clinical Research NCI-Good Overview. Especially see table of all anti angiogenesis drugs
4/20/01 Listing of all antiangiogenesis drugs and phase trials
4/20/01 ANTI-ANGIOGENESIS OVERVIEW from the National Ovarian Cancer Assn.
4/20/01 Angiogenesis Inhibitors in Cancer Research. NCI Press Release. Description of Different Mechanisms of Action. Listing of Angiogenesis Inhibitors in Clinical Trials: SU5416 (Sugen, Inc.), RhuMabVEGF (Genentech), Thalidomide (EntreMed), AG3340 (Agouron), ZD0101 (Zeneca Pharmaceuticals), TNP-40 (TAP Pharmaceuticals), IM862 (Cytran)
4/20/01 CancerProtocol.com. (Angiogenesis Low Dose Chemotherapy. See especially angiogenesis inhibitors/anti-angiogenesis)
7/12/01 Angiogenesis (ASCO 2001 Meeting) Robert S. Mocharnuk, MD In an integrated symposium session devoted to the subject of angiogenesis, several speakers paid tribute to the pioneering work of Dr. Judah Folkman and colleagues at Harvard Medical School, Boston, Massachusetts, which was originally published 30 years ago.
5/02/01 Cancer-drug treatment: Less might prove more By John Crewdson and Judy Peres Tribune Staff Writers April 2, 2000 Folkman, low dose chemotherapy, anti angiogenesis. . TNP-470 that was discovered several years ago in his lab to be a moderate angiogenesis inhibitor, is being combined with Taxol in clinical trials at M.D. Anderson Cancer Center in Houston. The anti-angiogenic agent used in Kerbel's lab is DC101, a small molecule that blocks a key protein on the surface of blood-vessel cells and is about to enter human trials in the U.S. According to its maker, ImClone Systems of New York City, the drug first will be tested alone and then combined with an approved cancer "If you're a clinician and you want to do something," Kerbel said, "you've got three choices: interferon, thalidomide and the COX-2 inhibitors,"

Ribozome Pharmaceuticals, Inc. (RZYM) Homepage News BNews YMsg RBMsg Trials Angiozyme, Heptazyme

See also Analysis of How to Choose Between 2 Trial Drugs
9/7/01 #0741 Preclinical efficacy, clinical safety and pharmacokinetics of ANGIOZYME, an antiangiogenic ribozyme targeting the flt-1 VEGF receptor Proceedings of the 1999 AACR · NCI · EORTC International Conference We have demonstrated significant inhibition of both primary tumor growth and metastases in two rodent models. Preclinical toxicology studies indicate that the drug is well tolerated at single doses up to 6000 mg/m2 and multiple doses up to 300 mg/m2. Pharmacokinetic results from rodent and primate studies have shown good subcutaneous bioavailability. Based on positive preclinical efficacy results and an excellent safety profile, ANGIOZYME has advanced into clinical trials
9/7/01 Ribozyme and Chiron Commence Phase II ANGIOZYME(TM) Colorectal Cancer Trial June 20 /PRNewswire/ -- Ribozyme Pharmaceuticals Inc. (RPI) (Nasdaq: RZYM - news) and Chiron Corporation (Nasdaq: CHIR - news) today announced treatment of the first patient in a Phase II clinical trial evaluating the safety and efficacy of the ribozyme anti- angiogenic drug ANGIOZYME in patients with metastatic colorectal cancer The principal investigator for this trial is Alan Venook, M.D., of the University of California, San Francisco Comprehensive Cancer Center. Additional sites include The Cleveland Clinic Foundation, Duke University Medical Center, The Sarah Cannon Cancer Center, and several sites of US Oncology, headquartered in Houston, Texas.
9/19/01 Phase I and Pharmacokinetic Studies of Angiozyme, a Synthetic Ribozyme Targeting the VEGF Receptor Flt-1 ASCO 2000 Two Phase I studies have been completed to date
9/19/01 Angiozyme Pharmacokinetic and Safety Results: a Phase I/II Study in Patients with Refractory Solid Tumors. The primary endpoint of the study was safety. Secondary endpoints included determination of pharmacokinetic parameters and antitumor activity A total of 28 patients were treated for at least 29 days
9/19/01 Angiozyme: a novel angiogenesis inhibitor Weng DE, Usman N. Curr Oncol Rep 2001 Mar;3(2):141-146 Preliminary results demonstrate Angiozyme to be well tolerated, without significant side effects. Several phase II trials are underway for patients with advanced malignancy to test therapeutic efficacy

Oxigene (OXGN) Homepage News BNews YMsg RBMsg Combretastatin
11/06/01 Thursday, Nov 1 2001 In the most recent phase I trial, conducted at Case Western Reserve University School of Medicine in Cleveland, Ohio, one 55-year-old male patient experienced a "pathological complete remission," according to OxiGene. The patient has remained disease free for more than 2 years after undergoing CA4P treatment. Two other patients experienced "prolonged periods of freedom from progression of their disease," according to researchers. "It is certainly rare to see a 'complete responder' in a phase I clinical trial," lead investigator Dr. Scot Remick said in a statement. "Given the absence of cytotoxic side effects normally seen with traditional chemotherapy drugs, the research team is enthusiastic about the potential of combining CA4P therapy with other anti-cancer treatments."
6/19/01 OXiGENE's Combretastatin - In Combination Therapy - Shows Powerful Anti-Cancer Potential - Pre-clinical Independent Studies Demonstrate Efficacy of Adding Vascular Targeting Agent to Conventional Therapy
4/16/01 Phase I/II Combretastatin and Declopramide, second line therapy Oxigene.com
8/30/01 Combretastatin Clinical Trial
8/30/01 Firms in cancer-starving drug race Boston Business Journal August 3, 2001 While Endostatin is a conventional angiogenesis inhibitor, there are others that use different mechanisms to starve tumors. One such promising drug is Combretastatin A4 Prodrug, a vascular targeting agent (VTA) that is being developed locally by Watertown-based Oxigene Inc. "It's a totally different approach to angiogenesis," said Oxigene's chairman and chief executive officer, Dr. Bjorn Nordenvall. Angiogenesis inhibitors, like Endostatin, stop new blood vessels from forming inside a tumor, preventing it from growing further. However, Combretastatin attacks existing blood vessels within the tumor, starving tumor cells until they eventually die. With Combretastatin, Nordenvall said, the blood vessels inside the tumor collapse within 15 minutes of injection, and within an hour, he said, one can see the tumor dying due to the lack of blood supply. With angiogenesis inhibitors, according to Nordenvall, patients would have to take the drug every day for the rest of their lives, because new vessels would grow without it.
8/30/01 Combretastatin Update 1: in Ohio Phase I Trial, Some Tumors Respond, Patients Experience Vascular Stress November 8, 1999 Early results from a Phase I clinical trial of combretastatin A4 (CA4P) show that the drug can starve tumors of their blood supply and does shrink some solid tumors. One patient so far who took the drug for about six months obtained a complete remission. Combretastatin does not, apparently, cause two of the commoner side-effects of chemo -- low blood counts and hair loss. But even at the lowest doses given in this Ohio trial, Combretastatin has caused tumor pain. At higher doses in some patients it caused lung and heart stress.
8/30/01 Progress report on Phase I trials of Combretastatin A4 Phosphate (CA4-P) Last update: 8th November 2000 Combretastatin has been shown in the laboratory to shut down the blood supply to tumours. It is one of the first vascular targeting drugs to be tested in patients. This drug was originally isolated from the African Bush Willow. The first studies in patients with this drug were aimed at finding out whether it can be safely given to patients, what side effects it produces and whether it can actually shut down the blood supply to human tumours. Fewer than 100 patients have so far received CA4-P.
8/30/01 Bristol-Myers Squibb Announces Clinical Development Program for Combretastatin A4 Prodrug November 29, 2000 Bristol-Myers Squibb Company (NYSE: BMY), a world leader in oncology, and OXiGENE, Inc. (Nasdaq: OXGN, SSE: OXGN), a world leader in the field of vascular targeting, today reported on an Investigational New Drug (IND) submission for the systemic use of Combretastatin A4 Prodrug (CA4P). Bristol-Myers Squibb has announced its intention to initiate a clinical program for the compound, an anti-tumor vascular targeting agent which is currently being evaluated in three Phase I clinical trials conducted by OXiGENE
8/30/01 Squibb announces clinical program for combretastatin A4 prodrug 1 Dec 2000 Bristol-Myers Squibb has announced its intention to initiate a clinical program for the compound, an anti-tumour vascular targeting agent which is currently being evaluated in three Phase I clinical trials conducted by OXiGENE. It is currently anticipated that the first patient will be dosed as early as 30 days after an acceptance of this submission. Bristol-Myers Squibb licensed the technology for the systemic use of CA4P from OXiGENE in December 1999.
8/30/01 OXiGENE's Combretastatin Retards Growth of Liver Metastases as a Single Agent Presentation at Bio 2001, San Diego, CA The company will discuss its global technology platforms, financial status and highlight a recent publication of data supporting OXiGENE's vascular targeting agent Combretastatin (CA4P), showing a profound effect on tumor growth and microvasculature in a murine liver metastatic model. Dr. O'Brien showed that when used alone, CA4P significantly decreased the percentage of colorectal tumor metastasis to the liver. This work showed dramatic effects after only one hour of treatment with no damage to normal tissue.
9/19/01 Combretastatin A4 Phosphate (CA4P) Reduces Tumor Blood Flow in Animals and Man, Demonstrated by MRI. ASCO 2001
9/19/01 Phase 1 Study of Weekly Intravenous Combretastatin A4 Phophate (CA4P): Pharmacokinetics and Toxicity ASCO 2001 CA4P was well tolerated in 11/13 patients at 52 or 68 mg/m2, and tumour blood flow reduction is reproducibly seen at these doses

Sugen (owned by Pharmacia, PHA) Homepage News BNews YMsg RBMsg Trials SU5416
8/30/01 Study of the Anti-Angiogenesis Drug SU5416 and Camptosar Chemotherapy in the Treatment of Advanced Colon and Rectal Cancer Prior 5-FU ok, but not Camptosar
8/30/01 A Phase I-II Study of Escalating Doses of SU5416 (NSC 696819) in Combination with CPT-11 in Patients with Advanced Colorectal Carcinoma Cannot have received prior Camptosar but 5-FU ok (Same trial as Above - Location MD Anderson
5/1/01 Pharmacia Presents New Data on Cancer Drugs Showing Promise in Controlling and Shrinking Tumors - HAMBURG, Germany, Oct. 13 2000 /PRNewswire/
5/1/01 A Phase I/II Study of SU5416 in Combination with 5-FU/Leucovorin in Patients with Metastatic Colorectal Cancer. May, 2000 ASCO Abstract. Mayo Clinic, Roswell Park. To date, responses include 1 CR, 5 PR, 9 SD, and 4 PD. 21 patients remain active on protocol
9/4/01 Efficacy Results of a Phase I/II Study of SU5416 (S)/5-Fluorouracil (F)/Leucovorin (L) Relative to Results in Random Subsets of Similar Patients (Pts) from a Phase III Study of Irinotecan (C)/F/L or F/L Alone in the Therapy of Previously Untreated Metastatic Colorectal Cancer (MCRC). ASCO Abstract
4/20/01 Clinical trial using SU5416, VEGF receptors

Entremed (ENMD) Homepage News BNews YMsg RBMsg Trials Endostatin, Angiostatin
4/29/01 The Endostatin Clinical Trial Phase I dose escalation trial Enrollment from September 28, 1999 through October 4, 1999.
4/29/01 NCI Names Two Sites for Early Endostatin Trials University of Wisconson, MD Anderson NCI March 24, 1999
4/20/01 Cancer Studies Favor New EntreMed Drug Tests Point to Treatment's Impact on Tumors Washington Post Nov 9 2000 Positive results for Endostatin. EntreMed, angiogenesis Dana-Farber,MD Anderson, U Wisconsin Cancer Center
4/30/01 EntreMed's Endostatin Appears Safe, Well-Tolerated in Phase I Trials WASHINGTON (Reuters Health) Nov 10 2000 Phase II Trials starting 1st quarter 2001
4/30/01 University of Wisconsin ENDOSTATIN UPDATE January 2001 Also has links to other Endostatin info
4/30/01 Cancer patients desperate to be in UW endostatin test From the Journal Sentinel Last Updated: Dec. 12, 1999 Thousands have called the University of Wisconsin-Madison, trying to secure one of the 30 or fewer slots in the preliminary endostatin safety test
5/1/01 MJF talk at 11:45 today Post 32242 Monday, 26 Feb 2001 at 3:07 PM EST Entremed, Folkman Interview
5/03/01 Tumors themselves may hold a cure By John Crewdson Tribune Staff Writer May 9, 1999 American Association for Cancer Research in Philadelphia, Northwestern University's Gerald Soff The production of angiostatin and its companion protein, endostatin, thus appears to be the body's way of protecting itself against the fatal spread of cancer Dr. Judah Folkman
4/18/01 Lycos Raging Bull Message Board April 17, 2001 Post 33974. C225, Iressa (ZD1839), MEDX, ENMD Entremed Inc Alternatives to C225, anaphylaxis (safety issue)

Celgene (CELG) Homepage News BNews YMsg RBMsg Thalomid (Thalidomide)
8/30/01 Use of the Anti-Angiogenesis Drug Thalidomide After Surgical Removal of all Metastases in Patients with Metastatic or Relapsed Colon or Rectal Cancer Phase II Randomized Study of Adjuvant Oral Thalidomide Following Metastasectomy in Patients with Recurrent Colorectal Cancer
4/20/01 The Use of Thalidomide in Treating Cancer with Peter Boasberg, MD anti angiogenesis
5/18/01 THALIDOMIDE IN ONCOLOGY: THE PERIL AND THE PROMISE Rod Quilitz, PharmD From the Pharmacy Service at the H. Lee Moffitt Cancer Center & Research Institute, Tampa, Fla. Info on Thalidomide costs
5/20/01 Irinotecan and Thalidomide in Metastatic Colorectal Cancer: Preliminary Results of a Phase II Study Thalidomide moderates AE
9/7/01 Thalidomide regimen for multiple myeloma linked to increased DVT risk Wednesday, Aug 29 2001 Thalidomide in combination with multiagent chemotherapy and dexamethasone increases the risk of deep-vein thrombosis (DVT) in patients treated for multiple myeloma, according to a report published in the September 1st issue of Blood.

AstraZeneca (AZN) Homepage News BNews YMsg RBMsg Irissa
4/18/01 Iressa, AstraZenica pipeline
4/18/01 Experimental Drug Shows Promise Against Solid Tumors POSTED 12.06.1999 By Joel B. Finkelstein (Iressa) oncology.com news
4/21/01 ASTRAZENECA REPORTS CONTINUED STRONG PROGRESS ACROSS R&D PORTFOLIO- Iressa in Phase III AstraZeneca News Release Dec 12, 2000
9/19/01 Final Results of a Phase I Intermittent Dose-Escalation Trial of ZD1839 ('Iressa') In Japanese Patients With Various Solid Tumours 2001 ASCO Abstract Pts were not selected on the basis of individual EGFR status. . Thirty-one pts (median age 63 yrs; PS 0/1) with NSCL (23), colorectal (5), H&N (2), and breast (1) tumors were recruited All 23 pts with NSCLC had been heavily treated with chemotherapy The antitumor results from the 23 pts are: 5 pts (from 225 to 700 mg) with partial responses (lasting from 1 to 11+ months, all are adenocarcinoma, 3 are follow-up); 1 pt had stable disease for 3+ months. In conclusion, once-daily oral ZD1839 is well tolerated and shows evidence of clinical activity in Japanese pts not selected on the basis of individual EGFR status.
9/19/01 [Tyrosine kinase inhibitors--solid cancers]. Gan To Kagaku Ryoho 2001 May;28(5):608-613 However, with non-small cell lung cancer, the most difficult tumor among solid cancers for an anticancer agent to be effective, not only was ZD1839 effective, but showed clear effectiveness in combination chemotherapy in the pretreatment stage. Moreover, the time for the expression of its tumor reduction effect was virtually the same as with conventional anticancer drugs, and its effectiveness proved to last longer after its initial expression. ZD1839 has succeeded in remaking the very image of molecular target agents for cancer treatment. In what follows, we focus mainly on the EGFR tyrosine kinase inhibitor, ZD1839
9/19/01 Intermittent Oral ZD1839 (Iressa), a Novel Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI), Shows Evidence of Good Tolerability and Activity: Final Results from a Phase I Study ASCO 2000 64 pts (25M:39F), median age of 54 (range 28-75) years and median WHO performance status 1, were enrolled in this trial. Pts had >1 prior treatment and tumor types included NSCLC (16 pts), ovarian (8), breast (8), colorectal (7), prostate (2) and head and neck (2). DLT was observed at the 700mg dose level, with grade 3 diarrhea in 2 pts. 15 pts with a range of tumor types had stable disease or response for ?4 months. Antitumor response was most evident among the 16 NSCLC pts: 2 pts had a partial response (300 mg, 9+ mo; 525 mg, 6+ mo); an additional 2 pts had confirmed significant regression of disease (400 mg, 2 mo; 700 mg, 6+ mo); 2 pts had stable disease (225 mg, 5 mo; 525 mg, 5+ mo)
9/19/01 Continuous Administration of ZD1839 (Iressa), a Novel Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI), in Patients with Five Selected Tumor Types: Evidence of Activity and Good Tolerability ASCO 2000 Combined data from two dose-escalation studies (150-1000 mg; 14 patients [pts] per cohort/study) are being assessed to establish the safety, pharmacokinetics and antitumor activity of ZD1839. In total, 127 pts (68M:59F). Tumor types are NSCLC (50 pts), ovarian (21) colorectal (20), prostate (12) and head and neck (24). The maximum tolerated dose has not been reached; the 800 mg dose is under evaluation. 29 pts had stable or improved disease for ?3 months. Confirmed partial responses to date include: 1 pt with NSCLC (150 mg, 9+ months) and 1 pt with hormone-refractory prostate cancer (225 mg, 6+ months). 3 pts had a reduction in measurable disease (1 pt head and neck; 2 pts NSCLC).
9/19/01 ASCO Daily News May 14, 2001 The Iressa study, "Small Molecule EGF Receptor Tyrosine Kinase Inhibitor ZD 1839 (Iressa) Inhibits HER2/neu (erb-2) Overexpressing Tumor Cells," was presented by Stacy Moulder, MD, of Vanderbilt University Medical Center. Dr. Moulder reported results from in vitro experiments involving exposure of multiple HER2-overexpressing human breast tumor cell lines to EGFR-specific tyrosine kinase inhibitors. Dr. Moulder and colleagues found that by inhibiting EGFR tyrosine kinase, ZD1839 blocks the transactivation of HER2 and that Herceptin plus ZD1839 may be effective for the treatment of breast tumors that overexpress HER2 and express EGFR. According to Dr. Baselga, the study demonstrates that EGFR is a key regulator of the ErbB family-mediated signaling processes and cellular proliferation in breast cancer. He believes the study presents a strong rationale to test the hypothesis in the clinic.
9/19/01 A Pilot Trial Demonstrates the Safety of ZD1839 ('Iressa'), an Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI), in Combination with Carboplatin (C) and Paclitaxel (P) in Previously Untreated Advanced Non-Small Cell Lung Cancer (NSCLC). ASCO 2001 25 pts have been enrolled The combination is being tested in a placebo-controlled Phase III trial in patients with advanced NSCLC
9/19/01 Inhibition by ZD1839 (Iressa) of Epidermal Growth Factor (EGF) and Heregulin Induced Signaling Pathways in Human Breast Cancer Cells ASCO 2001 We analyzed the effects of ZD1839 (Iressa), a novel EGF receptor tyrosine kinase inhibitor under clinical development, on cell proliferation and ligand-activated signaling transduction pathways in the human breast cancer cell line BT-474, that overexpress HER2 and express the EGF receptor. ZD1839 was a potent and dose-dependent inhibitor of cell proliferation (48% inhibition at 0.1[mu]M and 83% inhibition at 1[mu]M, relative to untreated cells
9/19/01 Small Molecule EGF Receptor Tyrosine Kinase Inhibitor ZD1839 (IRESSA) Inhibits HER2/Neu (erb-2) Overexpressing Breast Tumor Cells ASCO 2000 These data imply that low concentrations of EGFR TKIs will be effective against HER2-overexpressing breast tumor cells that also express EGFR. These results support the use of EGFR TKIs in combination with HER2 antibodies in patients with HER2-overexpressing mammary cancers
9/19/01 EGF Receptor Blockers Take Center Stage in Cancer Research May 2001

Genaera (GENR) Homepage News BNews YMsg RBMsg Squalimine
8/30/01 The Antiangiogenesis Drug Squalamine in the Treatment of Relapsed Solid Tumors Phase I Study of Continuous Infusion Squalamine Lactate for Refractory or Recurrent Solid Tumors

Miscellaneous
4/18/01 New Ways to Attack Cancer Researchers Develop Specialized Weapons ABC News.com. Nov. 17 2000 Anti Angiogenesis, EGF, Iressa, AstraZeneca, EGF, Sloan Kettering, Dr. Mark Kris
4/18/01 Complete Remission: Pill's Dramatic Early Success Gives Hope to Leukemia Patients Part II, Chicago Tribune Feb 28, 2000 (Iressa, Article about new approaches)
4/18/01 Abgenix (ABGX) And Immunex Corporation (IMNX) To Initiate Phase 2 Clinical Trial Of ABX-EGF In Kidney Cancer 4/18/2001 ABX-EGF targets EGFr , Abgenix (ABGX), Immunex (IMNX). Phase II kidney cancer trial, Phase I
4/19/01 Good news for colorectal cancer victims Jan. 27, 2000 USA Today New Therapies: Oxaliplatin, SU5416, IM682, P53, Proteasome inhibitors
4/23/01 Genaera (GENR) Presents Data for Squalamine in Cancer at AACR March 27, 2001 Richard Pietras, PhD, MD of the UCLA School of Medicine, Jonsson Cancer Center, Los Angeles, California Kimmel Cancer Center of Thomas Jefferson University in Philadelphia, Pennsylvania, Genaera Corporation, formerly Magainin Pharmaceuticals Inc VEGF, antiangiogenesis Blocks VEGF signaling
5/2/01 Subject: THE AMAZING SCIENCE OF Anti-ANGIOGENESIS Links to other info and posts. Posting on Yahoo Board. Date: Tue Apr 3, 2001 10:54 pm Folkman, anti angiogenesis
4/21/01 OSI's Plunge May Disguise Its Promise BusinessWeek Online THE BIOTECH BEAT -- , OSI-774 (oral agent),small molecule, Irissa (competitor), OSI Pharmaceutical
5/03/01 Cancer victim makes remarkable comeback By John Crewdson Tribune Staff Writer May 9, 1999 1997 paper published by a group of Northwestern University scientists led by Dr. Gerald Soff. Soff's group reported that it had succeeded in making angiostatin with a less complicated method than the recombinant method pioneered by Folkman. But there was no ethical or legal bar to giving the girl captopril and urokinase, in the hope that they might encourage the formation of extra tumor-fighting angiostatin in her body.
5/01/01 Drugs will be tested mostly on patients beyond any hope By John Crewdson Tribune Staff Writer April 11, 1999 Phase I trials ineffective because test on worst patients

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