News Summaries-March 2010
Additional news items are summarized in the News Module and News Archives (Requires Login).
After repeated offers to negotiate a deal, Astellas Pharma launched an unsolicited bid to acquire OSI Pharmaceuticals for $52 a share for a total of $3.5 billion. Upon OSI's rejection of the offer, Astellas sued OSI. OrbiMed, a major shareholder of OSI, suggested that a more equitable offer would value the company at $60 per share. OSI's revenues are derived from its anticancer drug erlotinib (Tarceva) marketed by Roche. OSI's oncology pipeline includes 3 drugs in clinical development.
Aveo Pharmaceuticals is planning an IPO of 7 million common shares at between $13 and $15 per share.
According to results from a phase III clinical trial (protocol ID: EFC6193; NCT00417079), dubbed TROPIC, presented at the Genitourinary Cancers Symposium sponsored by the American Society for Clinical Oncology (ASCO), the American Society for Radiation Oncology (ASTRO) and the Society of Urologic Oncology (SUO), the median overall survival of patients treated with sanofi-aventis' novel anticancer drug cabazitaxel (Jevtana) in combination with prednisone/prednisolone was 15.1 months compared to 12.7 months in the mitoxantrone with prednisone/prednisolone combination arm; median PFS was 2.8 months and 1.4 months, respectively. The company has initiated a rolling New Drug Application (NDA) submission to the FDA.
The primary endpoint of improvement in overall survival (OS) was not met in the pivotal phase III clinical trial with Novelos' NOV-002, in combination with first line chemotherapy, in advanced non-small cell lung cancer (nsclc). Detailed trial results are to be presented in an appropriate scientific venue later in 2010.
Genentech reports that according to results from a phase III clinical trial, the addition of Avastin (bevacizumab) to a standard carboplatin and paclitaxel regimen followed by maintenance use with Avastin alone, increased progression-free survival (PFS) in women with previously untreated advanced ovarian cancer compared to chemotherapy alone. No details were provided. Data from the trial will be submitted for presentation at the American Society of Clinical Oncology (ASCO) annual meeting, June 4 to 8, 2010.
In the AVAGAST phase III clinical trial (protocol ID: AVF4200g; BO20904; NCT00548548) the addition of bevacizumab (Avastin) in a chemotherapy regimen consisting of capecitabine (Xeloda) or 5-FU, and cisplatin, did not extend survival of chemotherapy-naïve patients with inoperable, advanced or metastatic gastric cancer or esophageal junction cancer, compared to chemotherapy alone. Data from the trial will be submitted for presentation at the 2010 American Society of Clinical Oncology (ASCO) annual meeting.
A research study (Manuyakorn A, etal, JCO, 8 Feb 2010; epub ahead of print) of cellular levels of histone modifications, conducted by PrognosDx Health collaborators at the University of California Los Angeles (UCLA), identified subsets of patients with pancreatic cancer with distinct epigenetic phenotypes and clinical outcomes. Data was culled from a multicenter, randomized, 195-patient phase III clinical trial (RTOG-9704; E-R9704; SWOG-R9704; NCT00003216) conducted by the Radiation Therapy Oncology Group (RTOG), comparing adjuvant chemoradiation with gemcitabine versus 5-FU, and a 140-patient cohort with Stage I or II cancer from the UCLA Medical Center. Histone modifications may thus serve as novel, independent prognostic and predictive biomarkers in several tumor types, including prostate, kidney, lung, breast and ovarian cancer, with lower levels predicting significantly poorer survival. This is particularly true in pancreatic cancer and may predict response to chemotherapy.
ERYtech Pharma entered into a collaboration with investigators at M. D. Anderson Cancer Center to evaluate a biomarker useful in selecting patients with solid tumors likely to benefit from the company's anticancer drug Graspa.
The first patient was treated in a new phase II clinical trial of Genta's anticancer drug tesetaxel, a small molecule oral taxane, in advanced, inoperable or metastatic melanoma in the second line setting.
The pivotal, multicenter, international, randomized, double-blind phase III clinical trial (protocol ID: 20050103; NCT00321620) that compared Amgen's denosumab with zoledronic acid (Zometa; Novartis) in the treatment of bone metastases in 1,901 patients (mean age=71) with advanced, hormone-refractory prostate cancer (HRPC) met its primary and secondary endpoints.
In vitro Assessments/Novel Targets
CD200, a negative regulator of the immune system
Normally expected innate immune responses against malignant cells are prevented by negative regulation of the immune system by the tumor itself. CD200 has been identified among effectors used by tumors to suppress T-cell-mediated immune responses in both hematologic malignancies and solid tumors. Therefore, inhibition of CD200 appears to be a potential therapeutic strategy for a variety of malignancies and is currently being evaluated in clinical trials.
In vitro tests (IVT) in ovarian cancer
Over 30 companies are developing in vitro tests in ovarian cancer for early diagnosis and further assessment of disease status, to select patients and/or assess tumor sensitivity for certain treatments, for treatment/disease monitoring, etc. In addition, many trials evaluating novel targeted agents in clinical development in ovarian cancer are using some type of biomarker to select patients, assess drug effectiveness, and interpret results.
Myriad Pharmaceuticals is developing MPI-0485520 and other inhibitors of IKKE, a recently identified oncogene playing a role in controlling proliferation of certain cancer cells through regulation of constitutive NFkappaB activity.
Midkine is a heparin-binding growth factor with mitogenic activity for fibroblasts and neuroectoderm cells. This multifunctional cytokine is expressed during midgestation but is highly restricted in normal adult tissues. Midkine's role in early cancer formation has been validated in clinical studies. Midkine levels in the circulation are greatly elevated in the early stages of cancer formation and high midkine levels have been linked to poor prognosis in numerous malignancies.
Chromosomal rearrangements enhance the activity of receptor tyrosine kinase (RTK) anaplastic lymphoma kinase (ALK) and are implicated in various malignancies, including non-Hodgkin's lymphoma (NHL), neuroblastoma and non-small cell lung cancer (nsclc).
Additional items are summarized in the In Vitro Assessments/Novel Targets page.
Special Report
Braf, BrafV600E and related pathway inhibitors
The complexities of targeted anticancer treatment were once again brought to the forefront as researchers report that in patients with malignant melanoma harboring wild type Braf, treatment with Braf inhibitors may spur tumor growth (news link). Although Braf inhibitors have resulted in dramatic responses in some patients in early stage clinical trials, two research groups found that in laboratory tests the drugs spurred the growth of some tumors. Current inhibitors primarily target the V600E Braf mutation that activates the mitogen-activated protein kinase (MAPK) signaling pathway. This mutation is present in about 50% of cases of malignant melanoma and at lower rates in many other malignancies. In preclinical trials, the BrafV600E inhibitors appeared to activate signaling in melanoma tumors with wild type (wt) Braf and mutations in the Ras gene, which is part of the Braf pathway. Also there may be another player, Craf (RAF1) that activates the ERK1/2 pathway in wt Braf cells that are resistant to Braf(V600E) inhibitors (Halaban R, etal, Pigment Cell Melanoma Res, 10 Feb 2010; epub ahead of print). These findings imply that direct inhibition of one or more targets may be insufficient or even harmful depending on the complete molecular profile of the cancer cell harboring the intended target. For instance, the behavior of the inhibitor of a specific target may vary depending on other mutations/activated pathways in a given cancer cell. Such a scenario renders highly targeted approaches impractical favoring more generalized anticancer treatments that target processes shared by most cancer cells as in the case with cytotoxics, angiogenesis, etc. For instance, the HSP90 inhibitor geldanamycin effectively promotes the degradation of Craf to overcome resistance to RAF inhibition in a subset of BRAF-mutant tumors. Currently, the Braf findings could have implications for the multi-targeted anticancer agent sorafenib (Nexavar; Bayer), the only approved documented Braf inhibitor, and for the various novel Braf inhibitors in clinical and preclinical development, as well as drugs inhibiting the Ras/Raf/MEK/ERK pathway that is activated in approximately 30% of all human tumors.
PARP Inhibitors and Synthetic Lethality
Poly(ADP-ribose) polymerase-1 (PARP1) is an abundant nuclear enzyme which promotes the repair of DNA breaks. Inhibition of PARP1, and hence of DNA repair, enhances the efficacy of certain anticancer agents. It is an attractive anticancer target as it participates in mechanisms involved in most solid tumors that may be the key culprits of resistance to most anticancer agents.
PARP1 is one of the most effective participants in DNA repair; it is a component of the DNA base excision repair (BER) protein complex that includes DNA ligase III, XRCC1 and DNA polymerase U. There are about 1 to 2 million PARP-1 molecules per cell, or one molecule per kilobase of DNA), which are activated 100 to 500-fold by DNA-strand breaks.
In early clinical trials, PARP-1 inhibitors have produced promising results when used in situations involving synthetic lethality, a mechanism well known for a long time but only recently demonstrated in the clinic. To date, at least 6 PARP1 inhibitors have entered the clinic and results are very promising in patients with hereditary breast or ovarian cancer who are carriers of mutations in the BRCA1/2 genes.
BRCA1 and BRCA2 are tumor suppressors that are mutated in cases of hereditary breast, ovarian, and prostate cancer. In their normal state, they are a critical part of the homologous recombination pathway, which fixes double strand DNA breaks impaired in cells carrying mutated versions of these genes. Because of synthetic lethality, tumor cells may survive an impaired BER state or mutated BRCA1/2, but not the combination of both.
Using PARP1 inhibition in this context represents the ultimate approach to targeted anticancer strategy, i.e. targeting only tumor cells carrying the intended homozygous mutation. PARP1 inhibitors should not affect normal cells with redundant DNA repair mechanisms, including heterozygous BRCA1/2 cells carrying one normal and one mutant BRCA allele.
Now that it has been demonstrated that this strategy works in patients with homozygous mutations in BRCA1/2 resulting in an impaired homologous recombination pathway, assays are needed to detect such impairments in other tumor types to expand the utility of PARP1 inhibitors.
Cancer Clinical Pipeline Updates
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The OSI Pharmaceuticals Pipeline
OSI Pharmaceuticals is evaluating 3 agents in clinical trials, all oral targeted drugs with one in phase III clinical trials.
The AVEO Pharmaceuticals Pipeline
Aveo Pharmaceuticals is evaluating 2 anticancer agents in clinical trials, including a phase III clinical trial with tivozamib, its lead antiangiogenesis inhibitor, in patients with refractory advanced or metastatic renal cell carcinoma (RCC).
The CytRx Pipeline in Oncology
As of January 2010, CytRx had 2 new and 1 marketed anticancer drug in clinical development and was planning multiple phase II clinical trials in both solid tumors and hematologic malignancies.
The Clavis Pharma Pipeline
Clavis Pharma is developing three distinct anticancer agents, two in clincial trials and one in preclinical evaluation. A recent partnering agreement with Clovis Oncology is accelerating development of its CP-4126, a lipid formulation of gemitabine for the treatment of pancreatic cancer. The mechanism of action of CP-4126 may overcome cancer cell resistance that commonly develops with gemcitabine. A test is in development to classify patients according to the expression of the hENT1 (human equilibrative nucleoside transporter 1) pancreatic tumor protein, a cell membrane transporter believed to be critical for gemcitabine entry into tumor cells; CP-4126 enters and kills tumor cells in a hENT1-independent manner.
The AstraZeneca Oncology Pipeline
AstraZeneca has a well balanced clinical pipeline in oncology with 15 novel agents in clinical development, mostly targeted small molecule and biologic inhibitors. Targets include aurora B (STK12/Aurora-1); CD22; checkpoint 1 (Chk1); endothelin receptor type A (EDNRA), ETAr; ephrin type A receptor 2 (EphA2); epidermal growth factor receptor (EGFr ); HEr2/neu; HEr3; insulin-like growth factor 1 (IGF1); insulin-like growth factor 2 (IGF2); mammalian target of rapamycin (mTOR); mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinases (MEK); platelet-derived growth factor receptor alpha (PDGFrA); poly (ADP-ribose) polymerase (PARP); Src (c-src, ASV); Abl; vascular endothelial growth factor receptor (VEGFr) and VEGFr2; RET; glial cell-line derived neurotrophic factor receptor (GDNFr); and c-Kit. The pipeline consists of agents in all stages of development with one, Zactima (vandetanib), having been filed with the FDA and the EMEA, but sinsce withdrawn, for use in combination with chemotherapy for the treatment of advanced non-small cell lung cancer (nsclc) in patients previously treated with one anticancer therapy (second line); AstraZeneca will await results from ongoing trials to decide refiling for approval. The pipeline includes 3 agents having advanced to phase III development; 8 of the 15 agents are in early phase I development.
The NeoPharm Pipeline
Additional items are summarized in the Cancer Pipeline Updates (Requires Login).
Novel Anticancer Agents
The new year has not been kind so far to developers of novel cytotoxics. Three new drugs, 2 about to be reviewed by ODAC, and one with recent results from late stage clinical trials seem to have to overcome significant hurdles in their quest for regulatory approval. Cell Therapeutics' pixantrone (Pixvuri) and ChemGenex Pharmaceutical's omacetaxine (Omapro) are to be reviewed by ODAC in the near future and Poniard Pharmaceuticals is planning FDA meetings to establish a regulatory path for its platinum drug picoplatin as a neuropathy-sparing platinum agent in metastatic colorectal cancer. More (Log in to continue)
In a report published in the journal Natural Products, investigators at Uppsala University, in Sweden, report that cardiac glycosides, among them oleandrin, proscillaridin A, digitoxin and digoxin, exhibit cytotoxic activity against colon cancer in combination with any of four clinically relevant cytotoxic drugs, 5-fluorouracil, oxaliplatin, cisplatin, or irinotecan.
Aflibercept (VEGF Trap), under development by Regeneron Pharmaceuticals and sanofi-aventis, is an inhibitor of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) in late stage development in various malignancies. As of November 2009, three phase III clinical trials, in lung, colorectal and prostate cancer were >80% enrolled with results anticipated by mid-2010 and early 2011. Regeneron and sanofi-aventis also expanded and extended their existing global collaboration to discover, develop, and commercialize fully human therapeutic monoclonal antibodies (MAb) with the annual funding commitment by sanofi-aventis to increase from $100 million to $160 million beginning in 2010, and the research funding to extend through 2017.
In October 2009, Arzerra (ofatumumab) received accelerated approval from the FDA for use in patients with chronic lymphocytic leukemia (CLL) that is refractory to treatment with fludarabine and alemtuzumab. The drug is being commercialized by GlaxoSmithKline under a global license from Genmab. Arzerra is a monoclonal antibody (MAb) that attaches to the small and large loop epitopes on CD20 found on the surface of B-cells, and recruits the body's natural defenses to attack and kill these selected cells that are implicated in cancer, and autoimmune and inflammatory diseases. Arzerra is one of several approaches currently in development for the treatment of CLL, an incurable hematologic malignancy (see http://www.ncbi.nlm.nih.gov/pubmed/19619273?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=9). Arzerra is in development for other indications, mostly in combination with other approved agents.
Supportive Care
Denosumab (Prolia), under development by Amgen, is the first fully human monoclonal antibody (MAb) in late stage clinical development that specifically targets RANK Ligand (RANKL), an essential regulator of osteoclasts, the cells that break down bone. Among other indications, Prolia is being investigated for the treatment and prevention of bone loss resulting from hormone ablation in patients with breast and prostate cancer, as well as for its potential to delay bone metastases and inhibit and treat bone destruction in patients with multiple myeloma and across many stages of cancer. In direct evaluation against zoledronic acid (Zometa; Novartis), the current standard of treatment of bone loss associated with cancer metastasized to the bone, denosumab was superior to Zometa in preventing skeletal related events (SRE) and delayed worsening of bone pain in a phase III clinical trial of 2,046 patients with advanced breast cancer. In addition, denosumab also presented some potential tolerability advantages for many patients, including a lower incidence of renal toxicity and acute phase reactions, combined with the convenience of a monthly SC injection. Similarly, in another phase III clinical trial, denosumab was non-inferior to Zometa in the treatment of bone metastases in 1,776 patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma and superior to Zometa in delaying the time to the first on-trial skeletal related event (SRE) for a hazard ratio (HR) of 0.82, and reducing the rate of multiple SRE (HR=0.82) in patients with hormone-refractory prostate cancer (HRPC).
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