We invite you to participate in this month’s Quick Poll (see left-hand margin) which addresses the use of PET or PET/CT scans in malignant lymphoma management.

Another reminder about CME accredited educational activities scheduled for 2007:

A series of six Oncology Highlights^SM meetings are scheduled for 2007. These CME-accredited events provide expert key opinion leader discussions of the most important clinically relevant abstracts presented at the 43rd Annual Meeting of the American Society of Clinical Oncology in Chicago on June 1-5, 2007. The schedule for the highlights meetings is as follows: July 14 in New York, July 21 in Miami, July 28 in Chicago, August 4 in Las Vegas, August 11 in New York, and August 18 in San Francisco. We invite you to visit our Web site for additional information and online registration.

On March 29, 2007 the FDA’s Cellular, Tissue and Gene Therapies Advisory Committee will review Dendreon’s biologics license application (BLA) for sipuleucel-T (Provenge^®), an experimental active cellular immunotherapy for the treatment of patients with asymptomatic, metastatic, androgen-independent (hormone-refractory) prostate cancer. The company completed the submission of its BLA in November 2006, and the FDA granted priority review status to the application in January 2007 (see January 2007 issue of OncoFacts™). The company anticipates a decision by the FDA by May 15, 2007. The BLA submission is based primarily on the results of a phase III trial (D9901) that demonstrated a statistically significant 4.5 month improvement in overall survival (OS) in patients receiving Provenge vs those given a placebo (median 25.9 vs 21.4 months; p = 0.01).

Pharmion and GPC Biotech have presented the final progression-free survival (PFS) results from the double-blind, randomized phase III registrational trial, the SPARC trial, evaluating satraplatin plus prednisone vs placebo plus prednisone in 950 patients with hormone-refractory prostate cancer whose disease had failed prior chemotherapy. Last month GPC Biotech announced that it had completed the rolling submission of a new drug application (NDA) for satraplatin use in this indication when it submitted the final portion, the clinical section, to the FDA. The SPARC trial data demonstrate that satraplatin, an orally bioavailable compound given as capsules, achieves a highly statistically significant prolongation of PFS compared to placebo. Satraplatin significantly reduces the risk of disease progression in these patients using the protocol-specified log-rank test (hazard ratio [HR] of 0.6 = a 40% reduction in relative risk). The improvement in PFS in the satraplatin arm was not affected by the type of prior chemotherapy, and improvement was similar for patients who had received prior docetaxel, as well as for those who received other types of chemotherapy.

In accordance with the recommendation of the independent data monitoring board, patients who have not progressed continue to be treated and all patients will be followed for overall survival (OS). OS data are expected to be available later this year. Pharmion expects to file a marketing authorization application in Europe in the second quarter of 2007.(Back)

Oral estrogen taken as hormone replacement therapy (HRT) to counteract the effects of menopause increases the risk of venous thromboembolism (VTE) in postmenopausal (postMP) women. Would transdermal estrogen be safer? Results of a six-year French study from the Estrogen and Thromboembolism Risk (ESTHER) Study Group published in the February 20 issue of Circulation shed some light on this question. A case-control study of VTE among postMP women aged 45 to 70 years recruited 271 consecutive cases with a first-documented episode of idiopathic VTE (208 hospital cases, 63 outpatient cases) and 610 matched controls (426 hospital, 184 community). After adjustment for potential confounding factors, odds ratios (OR) for VTE in current users of oral and transdermal estrogen compared with nonusers were 4.2 and 0.9, respectively. The authors conclude that oral estrogen but not transdermal estrogen is associated with an increased VTE risk.
Ref: Circulation 115: 840-845, 2007.

The March 1, 2007 issue of the New England Journal of Medicine presents a very interesting article titled “Vancomycin-Induced Immune Thrombocytopenia”. Neutropenia is a well-recognized complication of therapy with vancomycin, but the glycopeptide antibiotic has only rarely been implicated as a cause of thrombocytopenia (only 12 cases reported). Patients receiving vancomycin may have life-threatening bacterial sepsis and are often given heparin; vancomycin may not be considered as the cause of thrombocytopenia (Tpenia) in these patients because both sepsis and heparin are frequently associated with Tpenia. The authors describe the clinical and laboratory findings in 29 patients in whom Tpenia developed while they were receiving vancomycin and they present evidence that this complication was caused by vancomycin-dependent, platelet-reactive antibodies. Their observations indicate that this condition can cause life-threatening bleeding in an acutely ill patient being treated with this antibiotic and that vancomycin as a cause of Tpenia can be overlooked.

Drug-dependent, platelet-reactive antibodies of IgG class, IgM class, or both were identified in 34 patients, and clinical follow-up information was obtained from 29 of them (16 had only IgG, 3 had only IgM, and 10 had both IgG and IgM antibodies). All 29 patients in whom vancomycin-dependent antibodies (Abs) were detected had been exposed to the drug—most for at least 6 days, a time sufficient to mount an immune response to the drug—before Tpenia developed. On average, the nadir platelet count was reached about 8 days after vancomycin was started, and the mean nadir platelet count was 13,600. The platelet levels returned to pretreatment values in all 26 survivors (3 died from sepsis) after the drug was discontinued. The median time required for the platelet count to return to at least 150,000 after the drug was stopped was 7.5 days. Ten patients (34%) had severe bleeding characterized by florid petechial hemorrhages, ecchymoses, and oozing from the buccal mucosa (“wet purpura”). Of these 10 patients, 1 had gross hematuria, 2 lower GI hemorrhages requiring transfusion, 2 pulmonary hemorrhages, and 2 had excessive bleeding from venipuncture sites. The mean platelet count in the 10 patients with severe bleeding was 8,400. Bleeding of this severity is unusual in patients with Tpenia induced by other drugs, even when the platelet count is very low. Platelet transfusions failed to elevate platelet levels in 11 of 14 patients who received them. Five patients received corticosteroids, 3 were given IV IgG, 2 were treated with plasma exchanges, and 1 was given anti-Rh, but no clinically significant rise in platelet count occurred until vancomycin was discontinued.

The authors conclude that the detection of vancomycin-dependent antiplatelet Abs in patients receiving the antibiotic in whom Tpenia develops, and the absence of antibodies in the 25 patients given the drug in whom Tpenia did not develop, indicate that these Abs are the cause of the Tpenia.
Ref: NEJM 356 (9): 904-910, 2007.

A recent issue of the JCO published findings from the AIPC Study of Calcitriol ENhancing Taxotere (ASCENT) trial, a randomized phase II study designed to compare the safety and activity of DN-101 (Asentar™, Novacea), a new high-dose oral formulation of calcitriol designed for cancer therapy, plus docetaxel (Taxotere^®, sanofi-aventis) with placebo and docetaxel in androgen-independent prostate cancer (AIPC). Calcitriol is the natural ligand for the vitamin D receptor (VDR) and has been shown, in many studies using models of adenocarcinoma of the prostate, to possess significant antitumor activity. The antineoplastic activity of VDR ligands is synergistic or addictive with the activity of several classes of agents including cytotoxic chemotherapy drugs such as docetaxel.

In the ASCENT study, 250 patients with metastatic AIPC were randomized to receive weekly docetaxel 36 mg/m² IV for 3 weeks out of a 4-week cycle combined with either 45 mcg DN-101 or placebo taken orally one day before docetaxel. The primary endpoint was PSA response within 6 months of enrollment, defined as a 50% reduction confirmed at least 4 weeks later. Results: Within 6 months, PSA responses were seen in 58% of DN-101 patients and in 49% of placebo patients (p = 0.16). Overall, PSA responses were 63% (DN-101) and 52% (placebo), p = 0.07. The secondary endpoint of overall survival after adjustment for baseline characteristics of hemoglobin and ECOG performance status showed a statistically significant improvement in the DN-101 group which had a HR for death of 0.67 (p = 0.04). While the median survival in the placebo group was 16.4 months, it has not been reached in the DN-101 group, but is estimated to be 24.5 months using the adjusted HR. This represents a 49% increase in survival for the DN-101 plus docetaxel group compared to the placebo plus docetaxel patients. Grade 3/4 adverse events occurred in 58% of DN-101 patients and in 70% of placebo patients (p = 0.07). The authors conclude that this study suggests that DN-101 treatment was associated with improved survival, but this will require confirmation because survival was not a primary endpoint. The addition of weekly DN-101 did not increase the toxicity of weekly docetaxel.
Ref: JCO 25(6): 669-674, 2007.(Back)

AstraZeneca has begun a new phase III study of its investigational once-daily oral drug vandetanib (Zactima™), a potent and selective inhibitor of multiple tyrosine kinases (VEGFR, EGFR, RET), to be combined with pemetrexed (Alimta^®) as a second-line treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of first-line cancer treatment. The trial, called Study 36, is expected to enroll at least 508 patients. The primary objective of the study will evaluate PFS with vandetanib 100 mg plus pemetrexed 500 mg/m² vs the same dose of pemetrexed plus placebo in this patient population.

GlaxoSmithKline (GSK) has announced the start of an international phase III trial of lapatinib (Tykerb^®), in squamous cell carcinoma of the head and neck (SCCHN). This large adjuvant trial will compare the efficacy of oral lapatinib versus placebo given in high-risk patients following surgery. The study will enroll 680 high-risk patients with locally advanced head and neck cancer (stages II, III, and IVa) who have undergone surgery. Patients will receive, within 4 to 7 weeks after surgery, either lapatinib or placebo tablets once daily with radiation and cisplatin for 7 weeks. After this time, patients will continue with either lapatinib or placebo for one year. The principal objective will be to investigate the length of time without disease symptoms, as well as OS.(Back)