2011 ASCO: Additional Phase III Study Data Support the Potential Role of Avastin in Newly-Diagnosed & Recurrent Ovarian Cancer

Positive results from two bevacizumab (Avastin®) phase III clinical studies were presented at the 2011 American Society of Clinical Oncology Annual Meeting on June 4. The data reported add to the growing body of evidence in support of bevacizumab use to treat recurrent and newly-diagnosed ovarian cancer.

Positive results from two bevacizumab (Avastin®) phase III clinical studies were presented at the 2011 American Society of Clinical Oncology Annual Meeting on June 4. The data reported add to the growing body of evidence in support of bevacizumab use to treat recurrent and newly-diagnosed ovarian cancer.

About Bevacizumab (Avastin®)

A diagram illustrating the role of the VEGF protein in the formation of new blood vessels that support tumor growth. Click on the picture above to view a video regarding the mechanism of action with respect to bevacizumab (Avastin®). (Photo: Genentech)

Angiogenesis” refers to the process of new blood vessel formation. When tissues need more oxygen, they release molecules that encourage blood vessel growth. Angiogenesis is a normal and vital process in human growth and development, as well as in wound healing. Unfortunately, cancer tumors also utilize this same process to enhance their own blood supply in order to nourish their aberrant growth.

Ovarian cancer is associated with high concentrations of vascular endothelial growth factor (VEGF), a protein associated with tumor growth and spread. Studies have shown a correlation between a high concentration of VEGF and ascites  (excess fluid in the body cavity) development, disease worsening, and a poorer prognosis in women with ovarian cancer.[1-2]

Bevacizumab is a humanized monoclonal antibody designed to specifically bind to the VEGF protein, which plays an important role throughout the lifecycle of the tumor to develop and maintain blood vessels through angiogenesis. The drug interferes with the tumor blood supply by directly binding to the VEGF protein to prevent interactions with receptors on blood vessel cells. The tumor blood supply is thought to be critical to a tumor’s ability to grow and spread in the body (metastasize).

Bevacizumab is the first U.S. Food and Drug Administration (FDA) approved therapy designed to inhibit angiogenesis. Although FDA-approved for several forms of cancer, bevacizumab is not yet approved for the treatment of ovarian cancer. Patients treated with bevacizumab may experience side effects. In past clinical trials, some people treated with bevacizumab experienced serious and sometimes fatal side effects, related to gastrointestinal (GI) perforation, surgery and wound healing, and severe bleeding. For more information, review the Avastin BOXED WARNINGS and Additional Important Safety Information.

OCEANS Phase III Clinical Study: Women with Recurrent Platinum Sensitive Ovarian Cancer Experience 78% Response Rate & 52% Reduction In Disease Progression Risk

  • About the OCEANS Study

“OCEANS” is a multicenter, randomized, double-blind, placebo-controlled Phase III study in 484 women with platinum drug-sensitive recurrent ovarian, primary peritoneal or fallopian tube cancer.[3] Women in the OCEANS study received no more than one treatment regimen prior to study enrollment.  The OCEANS study randomized enrolled women to one of two clinical study arms:

Arm A: Intravenous carboplatin (area under the curve (AUC) 4; Day 1) + gemcitabine  (1,000 mg/m2; Day 1 & 8; brand name: Gemzar®) + placebo (Day 1) every 21 days x 6 cycles, followed by placebo maintenance every 21 days, until disease progression or unacceptable toxicity occurred.

Arm B: Carboplatin + gemcitabine + bevacizumab (15 mg/kg; Day 1) every 21 days x 6 cycles, followed by single agent bevacizumab maintenance every 21 days, until disease progression or unacceptable toxicity occurred.

The primary endpoint of the OCEANS study was progression free survival. The secondary endpoints of the study included overall survival, objective response, duration of response and safety profile.

  • OCEANS Study Data

Carol Aghajanian, M.D. speaks during the Oral Abstract Session: Gynecologic Cancer at the American Society of Clinical Oncology Annual Meeting on Saturday June 4, 2011. (Photo: ASCO/GMG/Silas Crews 2011)

Carol Aghajanian, M.D., chief of the gynecologic medical oncology service at Memorial Sloan-Kettering Cancer Center, presented the data from the OCEANS study comparing efficacy and safety of chemotherapy and antiangiogenic therapy in platinum drug-sensitive recurrent ovarian cancer.

Two hundred forty-two women were allocated to each study arm and the median follow-up period was 24 months. Patient characteristics were well-matched in the two treatment groups with regard to age (median age ~60), race (~91% white), performance status (~75%, PS = 0), histologic subtype (~80% serous), cytoreductive surgery (~11%), and platinum-free interval (defined as the time between finishing front-line platinum-based therapy and starting second-line chemotherapy) of more than 12 months (~60%). The study stratification variables were platinum-free interval (6 to 12 months vs. more than 12) and cytoreductive surgery for recurrent disease (yes vs. no).

The median number of chemotherapy cycles was six for each group, and a median of 11 cycles of bevacizumab or placebo was given. At least one-third of the patients received more than six cycles of carboplatin and gemcitabine, although slightly more of the placebo-treated group continued chemotherapy beyond six cycles.

Progression-free survival was significantly longer for women given bevacizumab (12.4 months vs. 8.4 months in the placebo-treated group (hazard ratio [HR]: 0.484; 95% confidence interval (CI) [0.388, 0.605]; p < 0.0001). These results were corroborated by the analyses of an independent review committee. Analyses according to platinum-free interval, cytoreductive surgery, age, and baseline performance status indicate a consistent benefit in all subgroups.

Objective response rate increased by 21.1% (p < 0.0001), from 57.4% in the placebo group to 78.5% in the bevacizumab treated group; duration of response increased from a median of 7.4 months to 10.4 months, respectively (HR: 0.534; 95% CI [0.408, 0.698]; p < 0.0001). Overall survival data are still premature, with median survival of 29.9 months in the placebo group and 35.5 months in the bevacizumab treatment group.

Sixty-five percent of the patients in the placebo group were withdrawn from the protocol due to disease progression, compared with only 41% of the treatment group, but 23% of the discontinuations in the bevacizumab group were due to adverse events, compared with only 5% in the placebo group. Much of this increase was due to grade 3 (or worse) adverse events; specifically hypertension and proteinuria associated with bevacizumab therapy. Overall, the safety profile of bevacizumab was consistent with past trials.

  • OCEANS Study Commentary

Dr. Aghajanian concluded that the OCEANS study results demonstrate a statistically significant and clinically relevant benefit when bevacizumab is added to carboplatin and gemcitabine. Aghajanian stated that this regimen should be considered a new option for the treatment of recurrent, platinum drug-sensitive ovarian cancer. As expected, the rate of adverse events was higher among patients who received bevacizumab, explained Dr. Aghajanian. “Hypertension and proteinuria were increased, but febrile neutropenia was the same in both arms.” “The safety data are reassuring and consistent with the known bevacizumab side-effect profile, and there were no new safety signals,” said Dr. Aghajanian.

“In advanced ovarian cancer, just as in advanced breast cancer, there is often an opportunity to intervene with different lines of chemotherapy,” said Andrew Seidman, M.D., attending physician for the breast cancer medicine service at Memorial Sloan-Kettering Cancer Center and professor of medicine at Weill Medical College of Cornell University. “There are many chapters in the story, so to speak,” said Dr. Seidman, who moderated a press briefing held in advance of the presentation. “We want to prolong each and every chapter in the disease, and make the story longer and ultimately improve survival. These trials results are certainly an important step in that direction.”

“Women with recurrent ovarian cancer need new treatment options, and it is therefore an important advance to halve the risk of disease progression in this incurable cancer,” said Hal Barron, M.D., chief medical officer and head of Roche Holdings Global Product Development. “These data add to the growing body of evidence supporting Avastin’s potential role in this disease, which includes two previously presented Phase III clinical trials [Gynecologic Oncology Group (GOG)-218 [4] & ICON7] in women with newly diagnosed ovarian cancer.”

In his discussion of the study, Anil K. Sood, M.D., professor and director of the Blanton-Davis Ovarian Cancer Research Program in the Departments of Gynecologic Oncology and Cancer Biology at the University of Texas M.D. Anderson Cancer Center, suggested that further understanding of the timing and dosing of bevacizumab should be pursued in light of (i) its great financial cost, and (ii) reports that inhibition of angiogenesis in animal models reduces primary cancer tumor growth, but accelerates invasion and metastasis — unintended consequences that might be linked to the failure of bevacizumab to extend overall survival in most clinical trials.

ICON7 Phase III Clinical Study:  Newly-Diagnosed Women with High-Risk Ovarian Cancer Experience 36% Reduction in Risk of Death

Gunnar Kristensen M.D., Ph.D. speaks during the Women's Cancers Press Briefing at the American Society of Clinical Oncology Annual Meeting on June 4, 2011. (Photo: ASCO/GMG/Scott Morgan 2011)

ICON7 was designed to investigate safety and efficacy of adding bevacizumab to standard chemotherapy in women with newly diagnosed ovarian cancer. [5] Gunnar Kristensen, M.D, Ph.D., senior consultant in the Department for Gynecologic Oncology of the Norwegian Radium Hospital located in Oslo, reported the Phase III clinical study results.

  • About the ICON7 Study

From December 2006 to February 2009, 1,528 women were randomized from 263 centers in 7 Gynecologic Cancer InterGroups. Eligible women with high-risk early FIGO (Federation of International Gynecology and Obstetrics) stage I or IIa (grade 3 or clear cell histology), capped ≤10%) or advanced (stage IIb-IV) epithelial ovarian, primary peritoneal or fallopian tube cancer were randomizsed (1:1) to one of two study arms:

Arm A: 6 cycles of 3 weekly chemotherapy (carboplatin AUC 5 or 6 and paclitaxel 175mg/m2) alone;  or

Arm B: Same chemotherapy as in Arm A, given concurrently with bevacizumab (7.5mg/kg) for 5 or 6 cycles, followed by continued 3-weekly single-agent bevacizumab maintenance therapy for 12 additional cycles (up to 12 months) or until disease progression (whichever event occurs first).

The baseline patient characteristics were balanced between both study arms: median age (57 years); ECOG Performance Status 0-1 (47%); high-risk early-stage disease (9%); poor prognosis patients (30%); histology (69% serous, 8% endometrioid, 8% clear cell).

  • Updated ICON7 Progression Free Survival Data

Data from the ICON7 study were presented for the first time at the 2010 European Society of Medical Oncology (ESMO) Congress. As reported at ESMO, chemotherapy-naïve ovarian cancer patients who received bevacizumab in combination with standard chemotherapy, and then continued with single agent bevacizumab maintenance therapy, experienced approximately 27% improvement (18.3 months versus 16 months) in the likelihood of living longer without the disease worsening (i.e., progression-free survival) compared to those women who received only chemotherapy (hazard ratio = 0.79, p=<0.0010), which corresponds to a 21% reduction in risk of cancer progression or death. The ICON7 data presented at ESMO was based upon mature progression-free survival results.

The updated ICON7 progression-free survival data presented at the ASCO annual meeting were consistent with the data reported last year at ESMO. In the updated analysis, women assigned to the bevacizumab arm experienced longer progression-free survival than those in the control group (19.8 months vs 17.4 months; HR, 0.87; p =.039). “There is a substantial prolongation of time to progression,” said Dr. Kristensen, adding that the gain was 2.4 months.

  • ICON7 Overall Survival Data Immature; But Clear Benefit To Women With “Poor Prognosis.” 

At a median follow-up of 28 months, there were fewer deaths among women who received bevacizumab than among those who received standard chemotherapy (178 vs 200). Although this represents a 15% overall reduction in mortality risk, the difference did not reach statistical significance (hazard ratio [HR], 0.85; P = .11). The final analyses for overall survival will be performed when 715 patient deaths have occurred. The current analysis was conducted because an interim analysis with at least 365 deaths was requested by the FDA and the European Medicines Agency for licensing consideration.

Although the overall survival data is not mature, a subgroup analysis of women with a “poor prognosis” (defined as FIGO stage III patients debulked to >1.0cm of visible diease or FIGO stage IV with debulking) was performed. Within this subgroup, there were 79 deaths within the bevacizumab arm and 109 deaths in the control arm. Based on this data, there was a 36% reduction in the risk of death (HR=0.64, 95% CI=0.48 to 0.85, p=0.0022 with p=0.015 for test for interaction (treatment/risk group)) among the poor prognosis subgroup.  This result was statistically significant. “We have previously shown that [the high-risk] group has a greater benefit from bevacizumab than the other patients,” said Dr. Kristensen. “For this group, there is a very clear gain for overall survival.”

  • ICON7 Study Commentary

“We conclude that the addition of concurrent and continued bevacizumab for 12 months does improve progression-free survival,” said Dr. Kristensen.  Kristensen also noted that, on the basis of an interim analysis involving approximately 53% of the number of deaths needed for the final analysis, there is an overall trend for improvement in overall survival.

“In this study, we see the ability of antiangiogenic therapy to delay the progression of ovarian cancer, this time in the first-line setting,” said Andrew Seidman, M.D. He added that previous studies have demonstrated the efficacy of bevacizumab in ovarian cancer. “These lend support to a potential role for bevacizumab as the first biologic agent to be used in this disease,” said Seidman, who moderated a press briefing during which study highlights were presented.

There are many strengths in a study like this, in that it addresses questions about the role of anti-VEGF therapies in this setting, said Anil Sood, M.D., who served as a discussant for this paper. “The randomized design is obviously a major strength.”

However, there are potential issues to examine, explained Dr. Sood. “One is the role of bevacizumab in the combination setting, compared with the maintenance setting.”

“How useful is bevacizumab in the combination setting up front? Is the real role for bevacizumab in the maintenance setting following initial chemotherapy,” he asked.

The issue of bevacizumab dosing was also raised by Dr. Sood. “One of the questions is whether higher doses are needed,” he said. “There are data emerging from other studies showing that lower doses are as efficacious, if not more so.”

References:

1/Rudlowski C, Pickart AK, Fuhljahn C, et. al. Prognostic significance of vascular endothelial growth factor expression in ovarian cancer patients: a long-term follow-up. Int J Gynecol Cancer. 2006 Jan-Feb;16 Suppl 1:183-9. PubMed PMID: 16515588.

2/Cooper BC, Ritchie JM, Broghammer CL, et. al. Preoperative serum vascular endothelial growth factor levels: significance in ovarian cancer. Clin Cancer Res. 2002 Oct;8(10):3193-7.  PMID: 12374688

3/Aghajanian C, Finkler NJ, Rutherford T, et. alOCEANS: A randomized, double-blinded, placebo-controlled phase III trial of chemotherapy with or without bevacizumab (BEV) in patients with platinum-sensitive recurrent epithelial ovarian (EOC), primary peritoneal (PPC), or fallopian tube cancer (FTC)J Clin Oncol 29: 2011 (suppl; abstr LBA5007)[2011 American Society of Clinical Oncology Annual Meeting].

4/ Burger RA, Brady MF, Bookman MA, et. alPhase III trial of bevacizumab in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC): a Gynecologic Oncology Group study [GOG 218 Abstract]J Clin Oncol 28:18s, 2010 (suppl; abstr LBA1).

5/Kristensen G, Perren T, Qian W., et. alResult of interim analysis of overall survival in the GCIG ICON7 phase III randomized trial of bevacizumab in women with newly diagnosed ovarian cancerJ Clin Oncol 29: 2011 (suppl; abstr LBA5006) [2011 American Society of Clinical Oncology Annual Meeting].

Additional Sources & Helpful Information:

Bevacizumab (Avastin®) Clinical Trial Information

Related WORD of HOPE Ovarian Cancer Podcast™

Related Libby’s H*O*P*E*™ Postings

Related Libby’s H*O*P*E*™ Videos

  • To view videos regarding bevacizumab (Avastin®), click here.


Trojan Horse* For Ovarian Cancer–Nanoparticles Turn Immune System Soldiers Against Tumor Cells

In a feat of trickery, Dartmouth Medical School immunologists have devised a Trojan horse to help overcome ovarian cancer, unleashing a surprise killer in the surroundings of a hard-to-treat tumor. Using nanoparticles–ultra small bits– the team has reprogrammed a protective cell that ovarian cancers have corrupted to feed their growth, turning the cells back from tumor friend to foe. Their research, published online July 13 for the August Journal of Clinical Investigation, offers a promising approach to orchestrate an attack against a cancer whose survival rates have barely budged over the last three decades …

Hanover, N.H.—In a feat of trickery, Dartmouth Medical School immunologists have devised a Trojan horse to help overcome ovarian cancer, unleashing a surprise killer in the surroundings of a hard-to-treat tumor.

Using nanoparticles–ultra small bits– the team has reprogrammed a protective cell that ovarian cancers have corrupted to feed their growth, turning the cells back from tumor friend to foe. Their research, published online July 13 for the August Journal of Clinical Investigation, offers a promising approach to orchestrate an attack against a cancer whose survival rates have barely budged over the last three decades.

Dr. Jose Conejo-Garcia (right) with graduate student Juan Cubillos-Ruiz  (Photo Source:  Dartmouth Medical School News Release,

Dr. Jose Conejo-Garcia (right) with graduate student Juan Cubillos-Ruiz (Photo Source: Dartmouth Medical School News Release, 13 Jul. 09)

“We have modulated elements of the tumor microenvironment that are not cancer cells, reversing their role as accomplices in tumor growth to attackers that boost responses against the tumor,” said Dr. Jose Conejo-Garcia, assistant professor of microbiology and immunology and of medicine, who led the research. “The cooperating cells hit by the particles return to fighters that immediately kill tumor cells.”

The study, in mice with established ovarian tumors, involves a polymer now in clinical trials for other tumors. The polymer interacts with a receptor that senses danger to activate cells that trigger an inflammatory immune response.

The Dartmouth work focuses on dendritic cells–an immune cell particularly abundant in the ovarian cancer environment. It does take direct aim at tumor cells, so it could be an amenable adjunct to other current therapies.

“The cooperating cells hit by the particles return to fighters that immediately kill tumor cells.” —Dr. Jose Conejo-Garcia

“That’s the beautiful part of story–people usually inject these nanoparticles to target tumor cells. But we found that these dendritic cells that are commonly present in ovarian cancer were preferentially and avidly engulfing the nanoparticles. We couldn’t find any tumor cells taking up the nanoparticles, only the dendritic cells residing in the tumor,” explained Juan R. Cubillos-Ruiz, graduate student and first author.

Dendritic cells are phagocytes–the soldiers of the immune system that gobble up bacteria and other pathogens, but ovarian cancer has co-opted them for its own use, he continued. “So we were trying to restore the attributes of these dendritic cells–the good guys; they become Trojan horses.”

Cancer is more than tumor cells; many other circulating cells including the dendritic phagocytes converge to occupy nearby space. The dendritic cells around ovarian cancer scoop up the nanocomplexes, composed of a polymer and small interfering RNA (siRNA) molecules to silence their immunosuppressive activity.

Nanoparticle incorporation transforms them from an immunosuppressive to an immunostimulatory cell type at tumor locations, provoking anti-tumor responses and also directly killing tumor cells. The effect is particularly striking with an siRNA designed to silence the gene responsible for making an immune protein called PD-L.

The new findings also raise a warning flag about the use of gene silencing complexes in cancer treatment. Inflammation is a helpful immune response, but the researchers urge caution when using compounds that can enhance inflammation in a patient already weakened by cancer.

Ovarian cancer, which claims an estimated 15,000 US lives a year, is an accessible disease for nanoparticle delivery, according to the investigators. Instead of systemic administration, complexes can be put directly into the peritoneal cavity where the phagocytes take them up.

Samples of human ovarian cancer cells show similar responses to nanoparticle stimulation, the researchers observed, suggesting feasibility in the clinical setting. It could be part of a “multimodal approach,” against ovarian cancer, said Conejo-Garcia also a member of the Dartmouth’s Norris Cotton Cancer Center. “The prevailing treatment is surgical debulking, followed by chemotherapy. Our findings could complement those because they target not the tumor cells themselves, but different cells present around the tumor.”

Co-authors are Xavier Engle, Uciane K. Scarlett, Diana Martinez, Amorette Barber, Raul Elgueta, Li Wang, Yolanda Nesbeth and Charles Sentman of Dartmouth; Yvon Durant of University of New Hampshire, Andrew T Gewirtz of Emory, and Ross Kedl of University of Colorado.

The work was supported by grants from the National Institutes of Health, including the National Cancer Institute and National Center for Research Resources, a Liz Tilberis Award from the Ovarian Cancer Research Fund, and the Norris Cotton Cancer Center Nanotechnology Group Award.

Read an interview of Jose Conejo – Garcia with the Ovarian Cancer Research Fund.

Source: Trojan Horse for Ovarian Cancer–Nanoparticles Turn Immune System Soldiers against Tumor Cells, News Release, Dartmouth Medical School, July 13, 2009 (summarizing Cubillos-Ruiz JR, Engle X, Scarlett UK, et. al. Polyethylenimine-based siRNA nanocomplexes reprogram tumor-associated dendritic cells via TLR5 to elicit therapeutic antitumor immunity. J Clin Invest. 2009 Aug 3;119(8):2231-2244. doi: 10.1172/JCI37716. Epub 2009 Jul 13).

__________________

* The Trojan Horse was a tale from the Trojan War, as told in Virgil’s Latin epic poem The Aeneid. The events in this story from the Bronze Age took place after Homer’s Iliad, and before Homer’s Odyssey. It was the strategy that allowed the Greeks finally to enter the city of Troy and end the conflict. In the best-known version, after a fruitless 10-year siege of Troy, the Greeks built a huge horse figure and hid a select force of men within it. The Greeks left the Horse at the city gates of Troy and pretended to sail away.  Thereafter, the Trojans pulled the Horse into their city as a victory trophy. That night the Greek force crept out of the Horse and opened the gates for the returning Greek army, which had sailed back to Troy under cover of night. The Greek army entered and destroyed the city, decisively ending the war. A “Trojan Horse” has come to mean any trick that causes a target to invite a foe into a securely protected bastion or place.

Mesothelin – A Potential New Target For Ovarian Cancer ImmunoTherapy

Researchers have generated altered immune cells that are able to shrink, and in some cases eradicate, large tumors in mice. The immune cells target mesothelin, a protein that is highly expressed, or translated in large amounts from the mesothelin gene, on the surface of several types of cancer cells. The approach, developed by researchers at the National Cancer Institute (NCI), part of the National Institutes of Health, and at the University of Pennsylvania School of Medicine, shows promise in the development of immunotherapies for certain tumors. The study appeared online the week of Feb. 9, 2009, in the Proceedings of the National Academy of Sciences. In a more recent study, appearing online May 5, 2009, in Molecular Cancer Therapeutics, NCI researchers developed a human antibody against mesothelin that shows potential, in laboratory experiments, for cancer treatment and diagnosis.

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Preclinical Results Validate Lpathomab As A Potential Future Treatment for Ovarian Cancer

“Lpath, Inc. … , the category leader in bioactive-lipid-targeted therapeutics, reported compelling new in vivo and in vitro results relating to its preclinical drug candidate, Lpathomab, in various ovarian cancer studies …”

“Lpath Presents Compelling New Preclinical Results of Its Anti-Cancer Drug Candidate, Lpathomab(TM), at the AACR 100th Annual Meeting –

New In Vivo and In Vitro Results Provide Further Validation of Lpathomab as Potential Treatment for Cancer

SAN DIEGO, CA, Apr 20, 2009 (MARKET WIRE via COMTEX)Lpath, Inc. (OTCBB: LPTN), the category leader in bioactivelipid-targeted therapeutics, reported compelling new in vivo and in vitro results relating to its preclinical drug candidate, Lpathomab, in various ovarian cancer studies. The results were presented today by Lpath scientists at the 100th Annual Meeting of the American Association for Cancer Research (AACR) in Denver, Colorado.

Lpathomab is a monoclonal antibody that binds to the bioactive lipid lysophosphatidic acid (LPA) and acts as a molecular sponge to absorb LPA, thereby neutralizing LPA-mediated biological effects on tumor growth, angiogenesis, and metastasis. LPA has been associated with a variety of cancer types, but the correlation with ovarian cancer and breast cancer has been particularly strong.

Using the human ovarian cell line called SKOV3, Lpath’s preclinical studies demonstrated Lpathomab significantly reduced IL-8 and IL-6 cytokine release in SKOV3-conditioned media and blocked tumor-cell migration triggered by LPA (both IL-8 and IL-6 promote tumor angiogenesis and metastasis). More important, Lpathomab inhibited the progression of SKOV3 tumor cells when injected into the peritoneal cavity of mice and reduced levels of pro-metastatic factors in these animals.

Lpathomab also reduced neovascularization (new blood-vessel growth) in two classical angiogenic models and showed preliminary anti-metastatic activity when tested in a classical experimental metastasis model.

According to Roger Sabbadini, Ph.D., Lpath’s founder and chief scientific officer, ‘In view of these promising preclinical results, we believe Lpathomab has the potential to augment the efficacy of current ovarian cancer therapy by blocking the growth-promoting, angiogenic, and metastatic effects of LPA.’

About Lpath

San-Diego-based Lpath, Inc. is the category leader in bioactive-lipid-targeted therapeutics, an emerging field of medical science whereby bioactive signaling lipids are targeted for treating important human diseases. ASONEP(TM), an antibody against Sphingosine-1-Phosphate (S1P), is currently in a Phase 1 clinical trial in cancer patients and also holds promise against multiple sclerosis and various other disorders. ASONEP is being developed with the support of partner Merck-Serono as part of a worldwide exclusive license. A second product candidate, iSONEP(TM) (the ocular formulation of the S1P antibody), has demonstrated superior results in various preclinical models of age-related macular degeneration (AMD) and retinopathy and is in a Phase 1 clinical trial in wet-AMD patients. Lpath’s third product candidate, Lpathomab(TM), is an antibody against lysophosphatidic acid (LPA), a key bioactive lipid that has been long recognized as a valid disease target (cancer, neuropathic pain, fibrosis). The company’s unique ability to generate novel antibodies against bioactive lipids is based on its ImmuneY2(TM) drug-discovery engine, which the company is leveraging as a means to expand its pipeline. For more information, visit www.Lpath.com …”

Sources:

CNTO 328 Shows Promise For Ovarian Cancer In Small Clinical Trial, Say U.K. Scientists.

British scientists have developed and clinically tested a drug that could prolong the lives of ovarian cancer patients. A clinical trial of the drug, codenamed CNTO328, has been carried out at the Centre for Experimental Cancer Medicine, which is part of Barts and the London School of Medicine and Dentistry. … The drug is an antibody which works by targeting a molecule called Interleukin 6, which is made by cancer cells and is vital to help them multiply, spread and develop their own blood supply. … “At the end of the trial, eight of the women were either stable or getting better. Their cancer had stopped growing. That doesn’t sound great, but in ovarian cancer that’s pretty good because [without the drug] the disease would have progressed in all of them,” said McNeish.

British scientists have developed and clinically tested a drug that could prolong the lives of ovarian cancer patients.  A clinical trial of the drug, codenamed CNTO328, has been carried out at the Centre for Experimental Cancer Medicine, which is part of Barts and the London School of Medicine and Dentistry.

Eight of the 18 women enrolled in the trial experienced tumor stabilization or shrinkage.  The investigators noted that the percentage of women who received clinical benefit from CNTO328 is an unusually high proportion for an experimental cancer drug study. Typically only between 5%  and 20% of participants secure any benefit from taking untried treatments, according to the investigators.

Iain McNeish, MA, Ph.D., MRCP, Professor of Gynecological Oncology, Honorary Consultant in Medical Oncology,  Deputy Director Centre for Experimental Cancer Medicine Centre for Molecular Oncology & Imaging, Barts and the London School of Medicine & Denistry

Iain McNeish, MA, Ph.D., MRCP, Professor of Gynecological Oncology, Honorary Consultant in Medical Oncology, Deputy Director Centre for Experimental Cancer Medicine Centre for Molecular Oncology & Imaging, Barts and the London School of Medicine & Denistry, London, United Kingdom

Professor Iain McNeish, a professor of gynaecological oncology at Barts hospital in London and chief investigator of the trial, said: “We have taken the drug from the laboratory into patients and the results are promising.  The hope with this group of patients was to slow down the progress of their ovarian cancer, improve the quality of their life and possibly make them live longer. We have been quite successful in doing that. If this becomes a treatment, this is a whole new approach to treating ovarian cancer.”

The drug is an antibody which works by targeting a molecule called Interleukin 6, which is made by cancer cells and is vital to help them multiply, spread and develop their own blood supply.  Interleukin 6 is found in many cancers but plays a key role in ovarian cancer’s movement into the abdomen. The antibody binds to the Interleukin 6, blocks its progress by ensuring that it cannot bind itself to the cancer cells to assist their growth and thus renders it harmless.

McNeish hopes that, if further trials confirm the drug’s potential, it could prove as effective in tackling ovarian cancer as Herceptin has been in breast cancer. CNTO328 works in a similar way to Herceptin, which has revolutionized breast cancer treatment in recent years. “The dream scenario is that a combination of the existing chemotherapy drugs and this type of antibody will be a big breakthrough and open up a new avenue for the treatment of ovarian cancer”, said McNeish.

The new drug is the result of a collaboration between Professor Fran Balkwill, an expert in cancer and inflammation at the Institute of Cancer, Barts and the London School of Medicine and Denistry, and a Dutch biotech company called Centocor, which is now owned by Johnson & Johnson.

Eighteen women with the disease from north-east London and Essex joined the trial which began in late 2007.  All 18 were expected to live for less than a year when they began receiving the drug because their cancer had returned after undergoing several courses of chemotherapy.  Ten women died but the health of eight women improved. Seven of those eight women are still alive.  “At the end of the trial, eight of the women were either stable or getting better. Their cancer had stopped growing. That doesn’t sound great, but in ovarian cancer that’s pretty good because [without the drug] the disease would have progressed in all of them,” said McNeish.

Annwen Jones, chief executive of the UK charity Target Ovarian Cancer, said there were too few drugs available to treat ovarian cancer because of a lack of research. “This early stage trial certainly shows promise, because it appears that the growth of tumors has been slowed down in a good proportion of the patients who took part in the study,” said Jones. “Women being treated for ovarian cancer could be forgiven for despair, particularly when they grow resistant to chemotherapy and there are no drugs that can get them over this hurdle. Research projects like this are vital if we are to develop desperately needed new treatments,” she said.

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New Monoclonal Antibody Offers Hope In the Fight Against Ovarian Cancer

“Kellogg, an associate professor of pathology and laboratory medicine at the Brody School of Medicine at [East Carolina University] ECU, created the antibody, called DS-6, that attaches to cancer cells in her laboratory at ECU. DS-6 will serve as a delivery vehicle for a highly potent cell-killing agent developed by ImmunoGen specifically for delivery to cancer cells by antibodies. The antibody latches on to tumor cells and enables the whole compound – the antibody and the attached cell-killing agent – to enter the cancer cell. Once inside, the cell-killing agent becomes activated and kills the tumor cell as it divides.”

“A discovery by an East Carolina University pathologist might be a breakthrough in an evolving class of drugs used to fight cancer.

Dr. Anne Kellogg has developed a monoclonal antibody that could play a vital role in treating the most common form of ovarian cancer, breast cancer and other cancers. She is working with two major drug firms, ImmunoGen Inc. and sanofi-aventis, that have expertise in formulating antibodies into cancer therapies and taking them to clinical trials in humans.

Kellogg, an associate professor of pathology and laboratory medicine at the Brody School of Medicine at ECU, created the antibody, called DS-6, that attaches to cancer cells in her laboratory at ECU. DS-6 will serve as a delivery vehicle for a highly potent cell-killing agent developed by ImmunoGen specifically for delivery to cancer cells by antibodies. The antibody latches on to tumor cells and enables the whole compound – the antibody and the attached cell-killing agent – to enter the cancer cell. Once inside, the cell-killing agent becomes activated and kills the tumor cell as it divides.

‘We can’t give such a potent chemotherapy agent on its own because it would be too toxic, but if we can link it to an antibody, it goes inside the tumor cell and is released inside the tumor cell, which is really an amazing feat,’ Kellogg said.

The antibody with the cell-killing agent linked to it circulates in the body in an inactive state. The cell-killing agent becomes active only when it reaches the tumor cell, so ImmunoGen refers to its technology as Tumor-Activated Prodrug, or TAP, technology. Sanofi-aventis has rights to develop specific anticancer agents using ImmunoGen’s TAP technology and is in charge of advancing the TAP compound containing the DS-6 antibody licensed from ECU into human clinical testing.

Monoclonal antibodies are manufactured proteins, produced from a single parent cell, that bind to a specific substance. They can be used to detect or purify that substance and are widely used in hospital and pathology laboratories as components of diagnostic tests. Monoclonal antibodies gained attention as a possible way to treat cancer in the 1980s. In the 1990s, scientists refined techniques to expand their usefulness as therapeutics by making subtle changes to the antibodies so the human body would not reject them as foreign tissue. One of the best-known monoclonal antibodies is trastuzumab, sold under the brand name Herceptin and used to treat breast cancer.

Kellogg began working with monoclonal antibodies in the early 1990s looking for ones pathologists could use to diagnose cancer. A few years later, working with Dr. Diane Semer, a gynecologic oncologist formerly with ECU, Kellogg turned her attention to identifying an antibody that could not only recognize tumors but also be useful in treating them. She isolated DS-6 in the late 1990s and then began characterizing the antibody for its ability to recognize various types of cancer with the help of Dr. Nancy Smith, a former ECU pathologist.

‘Drugs that are developed from monoclonal antibodies are potentially more specific for tumors and risk less in the way of toxicity to the patient,’ said Dr. Adam Asch, associate director of the Leo W. Jenkins Cancer Center at ECU. Kellogg added that the treatment could have benefits even if it falls short of curing cancer. ‘You may be able to convert cancer to a very chronic disease you can treat if we can provide oncologists with a wider array of treatment options,’ she said.

‘This has been an amazing education for me and personally very rewarding to get a ringside seat in seeing the complex process of drug discovery and development take place. It has also demonstrated how well academia, biotechnology and pharmaceutical companies can work together in this process,’ Kellogg said.

Kellogg’s research has been funded in part by ECU and the Department of Pathology and Laboratory Medicine. ‘We feel we made a wise investment that will help advance the treatment of cancer by providing funds for Dr. Kellogg’s research,’ said Dr. Peter Kragel, chair of the department. Future grants from ImmunoGen and sanofi-aventis are under discussion.”

[Quoted Source: New Antibody Offers Hope for Treating Ovarian, Breast Cancer, NewsWise Medical News Release dated May 22, 2008.]

2008 American Society of Clinical Oncology (ASCO) Annual Meeting Abstracts Available On-Line

The 44th Annual Meeting of the American Society of Clinical Oncology (ASCO) will be held on May 30th through June 3rd, 2008 in Chicago, Illinois. Under a new policy, ASCO publicly released clinical trial brief abstracts two weeks before the start of its 2008 Annual Meeting on May 30th, where full results will be presented before thousands of cancer doctors. The new ASCO policy was intended to avoid stock trading on non-public information that was believed to have occurred under a prior policy in which ASCO mailed out abstracts under embargo weeks before its annual meeting.

I have provided hyperlinks below to a variety of cancer topics that may be of interest to ovarian cancer survivors. Please note that with the exception of the first “ovarian cancer” category listed below, the remaining categories will contain abstracts that address various types of cancer. H*O*P*E*™ will provide one or more posts that address ovarian cancer abstract highlights after the completion of the 2008 ASCO Annual Meeting on June 3rd.

Gynecologic Cancer:

Ovarian Cancer

Developmental Therapeutics: Cytotoxic Chemotherapy:

Cytotoxic Chemotherapy
Drug Resistance
Pharmacology / Pharmacokinetics
Phase I Studies

Developmental Therapeutics: Immunotherapy:

Antibodies
Cell-Based Therapy
Cytokines
Other: developmental therapeutics: immunotherapy
Vaccines

Developmental Therapeutics: Molecular Therapeutics:

Antiangiogenic or Antimetastatic Agents
Cell Cycle Inhibitors
Chemoprevention
Epigenetic Strategies
Functional Imaging
Gene Therapy/Antisense Strategies
Other Novel Agents
Pharmacodynamics
Pharmacogenomics
Pro-Apoptotic Agents
Receptor-Targeted Antibodies/Ligands
Tyrosine Kinase Inhibitors
Vascular Targeting

Tumor Biology and Human Genetics:

Cancer Genetics
Epidemiology / Molecular Epidemiology
Immunobiology
Molecular Diagnostics and Staging
Molecular Targets
Other: Tumor Biology and Human Genetics
Prognostic Factors
Radiation Biology
Tumor and Cell Biology

Cancer Prevention:

Cancer Prevention

Patient Care:

Cancer in Older Patients
Cancer-Related Complications
End-of-Life Care
Other: patient care
Palliative Care
Quality-of-Life Management
Supportive Care

Health Services Research:

Health Services Research
Outcomes Research
Practice Management/Professional Issues