Combretastatin Update 1: in Ohio Phase I Trial, Some Tumors Respond, Patients Experience Vascular Stress

November 8, 1999 /PSA Rising/ 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.
     Combretastatin may prove more effective then some standard chemotherapy drugs and in some respects easier to tolerate. But as one of the first anti-vascular cancer drugs to be tested on humans, it has been hyped. The idea of shrinking tumors by attacking their life support system has been championed by Judah Folkman, a physician and cancer researcher at Children's Hospital in Boston who has received worldwide attention for his work. Like endostatin and angiostatin, Dr. Folkman's discoveries, Combretastatin apparently causes no distress at all in mice.
     On the basis of this Ohio Phase I trial -- designed to test mainly for toxicity but watching, obviously, for efficacy -- combretastatin begins to look more ordinary.
     Combretastin comes from a substance found in the bark of an African willow. It is the first novel antitumor vascular-targeting agent to enter clinical testing. In preclinical, laboratory studies in animals, University of Florida researchers reported last November, it boosted the tumor-cell killing power of radiation therapy as much as 500 times. It was found to be synergistic also with Taxol.
     Phase I clinical trials of combretastatin alone, in what at the time were called "small doses," began last November at the Ireland Cancer Center at University Hospitals of Cleveland, Ohio. Other arms of the trial began at Pennsylvania Cancer Center and at Mount Vernon Hospital in Hammersmith, London, UK. The London trial still plans to try to escalate to twice the dose found to be tolerable for humans in Ohio.
    
Tumor Pain and Cardiac Symptoms
One of the patients in the Ohio trial was featured this fall in a US News & World Report article about the promise of innovative cancer therapies. Scott C. Remick. M.D. at Ireland Cancer Center is in charge of the Ohio trial. Last week Dr. Remick reported preliminary results at the XVII annual Chemotherapy Foundation Symposium in New York. I asked him more about this patient. Dr. Remick said the patient completed 10 3-week cycles and withdrew from the trial with a "complete response."
     As an anti-angiogenic agent, combretastatin has a major impact on tumor blood vessels. As well as messing up microtubule assembly (like taxol and other drugs) it also "attacks proliferating endothelial cells," Dr. Remick said. Animal studies showed "immediate shutdown" of blood vessels supplying the tumor but no apparent effect on other blood vessels. The drug acts quickly, peaking at 6 hours with effects sustained for 24 hours.
     Combretastatin sets off a process of apoptosis (death of damaged cells) in the tumor blood vessels, Dr. Remick said last week. And as it cuts off the tumor's blood supply, combretastatin also kills cancer cells (induces tumor necrosis) starting in the core of the tumor and radiating out.
     In Ohio, 19 men and woman have been treated so far. The patients took combretastatin intravenously once every 3 weeks (in Pennsylvania the dosing is once a day for 5 days on 3 week cycles). Most of them had had prior chemotherapy. They took thsi drug as a 10 minute IV infusion "in a light-protected environment." Doses ran from 18 mg/m2 to 90 mg/m2. Dr. Remick found combretastatin to be effective at 60 mg/m2 and toxic at 90/mg/ml2.
     Results look fairly promising except for side-effects. Out of the 19 patients, one patient with osteosarcoma and another with non-small cell lung cancer got 12-week partial responses. The osteosarcoma patient showed blood flow changes in tumor in bone in the hip area. A patient with renal cell cancer got 24 weeks of stable disease. A 55 year-old man with anaplastic thyroid cancer got the best result. He was able to take 10 cycles, over a period of about thirty weeks, and achieved a "complete" remission visible on scans.

Humans Respond Differently Than Mice
What are the side effects of the attack on tumor blood vessels? For several hours following infusion, across all dose levels, Dr. Remick reported last week, his patients experienced a "variable symptom complex." Faint flush, abdominal pain and other pain at the sites of known tumor occurred at all dose levels during the infusion. Nausea and vomiting occurred at higher doses and also fever, flush, lightheadedness, headache, diarrhea, bradycardia (slowed heart beat), tachychardia (rapid heart beat) transient blood pressure changes and "non-specific ST-T wave changes on electrocardiogram, which peak between 3 and 5 hours post-infusion."
   Although none of these side-effects were considered to be dose-limiting, tumor pain was "significant," Dr. Remick said. even more of a damper on some of the euphoric publicity surrounding blood-vessel targeting cancer therapies. Toxicity occurred at dose level 4 ( 90 mg/m2). One patient had an episode of "grade 3 pulmonary toxicity (shortness of breath)." Another, after only two doses, experienced a "reversible episode" of "acute coronary ischemia" thought to be secondary to "coronary vasospasm."
    Toxicities of this order are not unusual for potent chemotherapies -- although more typical of allergic reactions. But combretastatin was promoted so enthuisiastically before the trial, these results look rather disappointing.
    Dietmar Siemann, a professor of radiation oncology in UF's College of Medicine, said last year, before the trial began, that results from combining combretastatin with radiation "are very encouraging." (see our story Nov 1998)."We're able to achieve these effects by giving relatively low doses that produce no side effects in mice." he said. A lot depends, though, on what mice feel. Mice are mot, initially at least, apprehensive about taking a drug for cancer that may bring on sensations of heart attack.
    "The combretastatin approach is a little different from what Dr. Folkman has been doing," Siemann said last November. "The majority of research has focused on preventing the growth of new tumor blood vessels, the anti-angiogenesis strategy. What we are doing is attacking existing and newly formed tumor blood vessels directly by exploring a key difference between these vessels and those found in normal tissues."  "We and others have shown." Siemman said, "that these dividing cells can be selectively damaged by combretastatin. This approach leads to rapid and catastrophic shutdown in the vessels that serve the tumor, resulting in extensive tumor cell death."
    The theory was, this type of therapy would be both more effective and tolerable for human cancer patients than ordinary chemo. The Ohio investigators plan to try giving combretastatin as a one hour infusion instead of ten minutes (less of a shock to the body). They will continue to investigate the cardiac effects. © PSA Rising

See earlier article, Combretastatin, from African Bush Willow, in Early Trials November 23, '98.

The Ohio Phase I trial of combretastatin is supported by a clinical research grant from OXiGENE, Inc., Boston, MA. Results were reported November 5, 1999 at Chemotherapy Foundation Symposium XVII "Innovative Cancer Therapy for Tomorrow" in New York.

Dr. Scot C. Remick, M.D. is program leader for developmental therapeutics at the Ireland Cancer Center, Cleveland and associate professor of medicine at Case Western Reserve University School of Medicine.

Dietmar Siemann, of the Moffitt Cancer Center in Tampa, published a paper on their work on Combretastatin in the November 1998 issue of the International Journal of Radiation Oncology, Biology, Physics.