Nanotechnology usually refers to an object that is 1-to–100 nanometers in size. A nanometer is a billionth of a meter. By comparison, the width of a strand of hair is approximately 100,000 times larger than a nanometer.
Prof. Peer and his team — Keren Cohen and Rafi Emmanuel from Peer’s Laboratory of Nanomedicine and Einat Kisin-Finfer and Doron Shabbat, from TAU’s Department of Chemistry — devised a cluster of nanoparticles called “gagomers,” which are made from fats and coated with a kind of polysugar. When filled with chemotherapy drugs (in this case doxorubicin), these clusters accumulate in tumors, producing dramatic therapeutic benefits.
The objective of Peer’s research is two-fold: to provide a specific target for anti-cancer drugs to increase their therapeutic benefits, and to reduce the toxic side effects of anti-cancer therapies.
Why Chemotherapy Fails
According to Prof. Peer, traditional courses of chemotherapy are not an effective line of attack. Chemotherapy’s failing lies in the inability of the medicine to be absorbed and maintained within the tumor cell long enough to destroy it. In most cases, the chemotherapy drug is almost immediately ejected by the cancer cell, severely damaging the healthy organs that surround it, leaving the tumor cell intact.
Gagomers (labeled in color) accumulating on ovarian cancer cells. (Credit: Image courtesy of American Friends of Tel Aviv University)
But with this new nanotechnology therapy, Peer and his colleagues saw a 25-fold increase in tumor-accumulated medication and a dramatic dip in toxic accumulation in healthy organs. Tested on laboratory mice, the gagomer affects a change in drug-resistant ovarian cancer tumor cells. Receptors on tumor cells recognize the sugar that encases the gagomer, allowing the binding gagomer to slowly release tiny particles of chemotherapy into the cancerous cell. As more and more of the drug accumulates within the tumor cell, the cancer cells begin to die off within 24-48 hours. In this preclinical setting, the doxorubicin encased gagomers even outperformed pegylated liposomal doxorubicin (Doxil) — a standard of care drug used to treat recurrent ovarian cancer.
“Tumors become resistant very quickly. Following the first, second, and third courses of chemotherapy, the tumors start pumping drugs out of the cells as a survival mechanism,” said Prof. Peer. “Most patients with tumor cells beyond the ovaries relapse and ultimately die due to the development of drug resistance. We wanted to create a safe drug-delivery system, which wouldn’t harm the body’s immune system or organs.”
A Personal Perspective
Prof. Peer chose to tackle ovarian cancer in his research because his mother-in-law passed away at the age of 54 from the disease. “She received all the courses of chemotherapy and survived only a year and a half,” Peer said. “She died from the drug-resistant aggressive tumors.”
“At the end of the day, you want to do something natural, simple, and smart. We are committed to try to combine both laboratory and therapeutic arms to create a less toxic, focused drug that combats aggressive drug-resistant cancerous cells,” said Prof. Peer. “We hope the concept will be harnessed in the next few years in clinical trials on aggressive tumors,” said Prof. Peer.
Iran expects to bring a cancer nanodrug called “Sinadoxosome” to market next month. Sinadoxosome is apparently similiar to pegylated liposomal doxorubicin which is marketed under the brand name “Doxil” in the U.S. and “Caelyx” in Europe. Doxil/Caelyx has been in extreme short supply in the U.S. and Europe, thereby causing potential detriment to many ovarian cancer patients.
Iran inaugurated the production line of an anti-cancer nanodrug under the name “Sinadoxosome” in the Northern city of Rasht, and the medicine will soon come to market.
In addition to producing the amount of nanodrug required by Iran, the new drug production line makes possible the exportation of the drug to other countries. The drug acquired the necessary certificates from Nanotechnology Committee of the Ministry of Health, Treatment, and Medical Education in November 2011.
Dr. Mahmoud Reza Ja’fari, the Managing Director of Exir Nano Sina Company, told the Iran Nanotechnology Initiative Council’s reporter that the anti-cancer drug Sinadoxosome would be presented to the market next month.
“This product has been produced by the knowledge-based company Exir Nano Sina in association with Iran Nanotechnology Initiative Council. It has acquired the production certificate from the Ministry of Health, Treatment, and Medical Education,” Dr. Ja’fari added.
Pointing to the fact that the production of this medicine had been “monopolized” by European countries (under the “Caelyx” brand name) and by the United States (under the “Doxil” brand name), the Head of Nanotechnology Research Centre of Mashhad University of Medical Sciences said: “The importation of this medicine cost [sic] $5 mln annually. However, this medicine will be presented to the patients at one-third of the price of the foreign drug after the establishment of Sinadoxosome production line.”
Sinadoxosome contains nano liposomes that contain doxorubicin anti-cancer medicine. It targets the tumor tissue and boosts the effect of the medicine but decreases its side effects. The medicine has applications in the treatment of ovarian cancer, breast cancer, leukemia, and Kaposi’s sarcoma (a type of soft tissue cancer).
The production line involving the Sinadoxosome anti-cancer drug was established on February 8, 2012, in the presence of Iran Nanotechnology Initiative Council’s authorities and the managing director and researchers of the Sobhan Oncology Pharmaceutical Company.
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In the YouTube video presented below, U.S. Senator Orrin Hatch (R-Utah), Ranking Member of the Senate Finance Committee, delivered the opening statement at a 2011 committee hearing examining the impact of drug shortages in America.
Exelixis, Inc. reported expanded Phase 2 study data with respect to cabozantinib (XL184) use in advanced ovarian cancer patients at the recent 2011 American Society of Clinical Oncology Annual Meeting. The overall solid tumor Phase 2 safety and tolerability data reference six deaths, including two ovarian cancer patients.
Ronald J. Buckanovich, M.D., Ph.D., Assistant Professor, Departments of Internal Medicine & Obstetrics and Gynecology, University of Michigan
On May 19, 2011, we reported promising cabozantinib phase 2 solid tumor (including ovarian) data, which was presented at an ASCO press briefing held in advance of the 2011 ASCO Annual Meeting. As noted in our May 19 article, cabozantinib demonstrated excellent activity against several solid tumors, including ovarian cancer. In addition, we reported that cabozantinib showed promising activity in ovarian cancer patients independent of prior response to platinum drug-based therapies.
Ronald J. Buckanovich, M.D., Ph.D., Assistant Professor, Departments of Internal Medicine & Obstetrics and Gynecology, University of Michigan, presented the expanded cabozantinib Phase 2 data relating to use of the drug in advanced ovarian cancer patients, on June 4 at the 2011 ASCO Annual Meeting.
Ovarian Cancer Patient Population & Overall Response Rate
(Image Source: Exelixis, Inc.)
The cabozantinib trial is an ongoing phase 2 adaptive randomized discontinuation trial. As of the February 11, 2011 cut-off date, accrual in the cabozantinib study cohort was complete at 70 patients.
The 70 patients enrolled in the ovarian cancer cohort received oral cabozantinib (100 mg) daily over a 12 week “Lead-in Stage.” These patients had a minimum follow-up of at least 12 weeks and were thus evaluable for safety and the primary efficacyendpoint of response per RECIST (Response Evaluation Criteria in Solid Tumors).
Patient tumor response was assessed every 6 weeks. Receipt of cabozantinib treatment beyond the 12 week open label Lead-in Stage was based upon patient response: (1) patients with a partial response (PR) or complete response (CR) continued taking cabozantinib, (2) patients with stable disease (SD) were randomized to the cabozantinib treatment arm or the placebo treatment arm (collectively referred to as the “Blinded Randomized Stage”), and (iii) patients with progressive disease (PD) discontinued study treatment. The study primary endpoint was overall response rate (ORR) per RECIST in the Lead-in Stage, and progression free survival (PFS) in the Blinded Randomized Stage. Accrual in any cohort could be halted for high ORR or PD.
Approximately half of the 70 patients enrolled in the cohort were considered platinum drug-refractory/-resistant (49%), defined as a platinum drug-free interval of 6 months or less, and the remainder of patients (51%) had platinum-sensitive disease based on a platinum-free interval greater than 6 months.
The baseline patient tumor histologiccharacteristics are as follows: serous ovarian cancer (79%), clear cell ovarian cancer (4%), endometrioid ovarian cancer (6%), and other forms of ovarian cancer (11%)
More than half the patients (57%) received 2 or more prior lines of platinum therapy prior to trial enrollment. Some patients also had additional prior lines of therapy with agents such as pegylated liposomal doxorubicin (brand name: Doxil®) or topotecan (brand name: Hycamtin®) (32%), gemcitabine (brand name: Gemzar®) (29%), and VEGF (vascular endothelial growth factor) pathway inhibitors (10%).
Evidence of objective tumor regression was observed in 73% of patients with at least 1 post-baseline medical imaging scan. The best overall response rate per RECIST criteria was 24% (16 PRs and 1 CR). The overall Week-12 disease control rate (DRC = CR + PR + SD) was 53%. The Week-12 DCRs in the platinum drug-refractory, -resistant, and -sensitive groups were 36%, 39%, and 67%, respectively.
Based on an observed high rate of clinical activity, randomization was halted, and randomized patients were unblinded. At this point, the unblinded randomized patients that were treated with placebo were allowed to “cross-over” to treatment with cabozantinib. Disease stabilization was experienced by some ovarian cancer patients who had progressive disease prior to treatment cross-over.
“These latest results in metastatic ovarian cancer demonstrate the potential broad utility of cabozantinib beyond bone-predominant types of cancers such as castration-resistant prostate cancer. The high rates of durable response with our dual inhibitor of MET and VEGFR2 compare favorably to those of other single-agent targeted therapies and cytotoxic agents in development,” said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. “These results underscore the potential of cabozantinib in metastatic ovarian cancer, and we are in discussions with leading cooperative groups to plan further evaluation of cabozantinib in randomized trials for this indication.”
Activity in Platinum Drug-Sensitive, -Refractory, and -Resistant Disease
Ignace Vergote, M.D., Ph.D., senior author of the cabozantinib (XL184) ASCO presentation & Chairman, Leuven Cancer Institute, University of Leuven, European Union
(Image Source: Exelixis, Inc.)
Two of 11 patients (18%) with platinum refractory disease, defined as a platinum-free interval of <1 month, achieved a confirmed response (1 CR and 1 PR).
In the subset of patients with platinum-resistant disease, defined as a platinum-free interval of 1-6 months, 5 of 23 (22%) achieved a PR.
Ten of 36 patients (28%) with platinum sensitive disease achieved a PR.
A total of 37 patients experienced reductions in the ovarian cancer tumor marker CA-125 (cancer antigen-125), including 8 with decreases greater than 50%. There is no consistent concordance between CA-125 changes and tumor regression. The median duration of response has not yet been reached with 36 weeks of median follow-up.
“The continued activity of cabozantinib in a larger population of ovarian cancer patients is very encouraging, especially with respect to the clinical benefit observed in both platinum-sensitive and platinum-resistant/refractory disease. This activity profile has not been observed with other single-agent TKIs [tyrosine kinase inhibitors], and cabozantinib has the potential to be an important new treatment for ovarian cancer,” said Ignace Vergote, M.D., Ph.D., senior author of the presentation and Chairman of the Leuven Cancer Institute at the University of Leuven, European Union. “The high rate of disease control in platinum-resistant and platinum-refractory disease suggests that cabozantinib may help to address the substantial unmet medical need faced by patients who have sub-optimal responses to platinum-based therapies. I believe that further evaluation will help to define the potential role of cabozantinib in the treatment of ovarian cancer.”
General Safety & Tolerability Data
Safety data are available for the 70 patients in the Lead-In phase of the cabozantinib study. The most common CTCAE (Common Terminology Criteria for Adverse Events) grade 3 or 4adverse events (AEs), regardless of causality, were diarrhea (10%), fatigue (9%), palmar-plantar erythrodysesthesia syndrome (also referred as “hand-foot syndrome”)(7%), vomiting (4%), abdominal pain (3%), hypomagnesemia (3%), and nausea, constipation, rash, increased transaminase, and hypertension (each 1%). At least one dose reduction was reported in 37% of patients. Less frequent important medical events, regardless of causality, were hemorrhage (11% all CTCAE grades, 0% CTCAE grade 3 or 4), venous thrombosis (6% all CTCAE grades, 4% CTCAE grade 3 or 4), and gastrointestinal perforation (6% all CTCAE grades, 0% CTCAE grade 3 or 4).
Six Deaths Reported (Including Two Ovarian Cancer Patients)
If you examine the Exelixis press release dated June 4 (entitled, Exelixis’ Cabozantinib Demonstrates Encouraging Clinical Activity in Patients with Metastatic Ovarian Cancer — Disease control rate of 53% at week 12, response rate of 24%), which addresses data for cabozantinib use in advanced ovarian cancer patients, pay particular attention to the wording under the heading entitled, “Safety and Tolerability.” Within the wording set forth under that heading, you will find the following statement: “Two cabozantinib-related grade 5 AEs [adverse events], one enterocutaneous fistula and one intestinal perforation, were reported after the Lead-In phase.” Pursuant to the CTCAE guidelines, a “grade 5 adverse event” is defined as “death related to AE [adverse event].”
We should also note that the two ovarian cancer deaths were summarized briefly in the ASCO presentation regarding cabozantinib use in advanced ovarian cancer.
The reporting of all six deaths is set forth in the Exelixis press release, dated June 5, 2011 (entitled, Exelixis’ Cabozantinib Demonstrates Broad Clinical Activity in Multiple Tumor Types), in similar fashion. Within this release, the sentence provided under the heading “Safety and Tolerability” states: “There were 6 (1%) cabozantinib-related grade 5 [adverse] events, all of which were reported after the Lead-In phase of the trial: respiratory compromise (breast cancer), hemorrhage (NSCLC [non-small cell lung cancer]), enterocutaneous perforation (ovarian cancer), intestinal perforation (ovarian cancer), gastrointestinal hemorrhage (pancreatic cancer), and death (CRPC [castrate resistant prostate cancer]).”
Exelixis Chief Executive Michael Morrissey said the safety statistics are consistent with targeted cancer therapies like cabozantinib that block a pathway used by tumor cells to secure blood vessels.
Cowen & Co analyst Eric Schmidt said the rate of cabozantinib treatment-related deaths — 1 percent — was “no different from what we have seen for every other Phase 1 and 2 trials here at ASCO.”
“While drug safety is of less concern in cancer indications than in others, the apparent morbidities associated with cabo[zantinib] use will confound interpretation of clinical benefit in a trial designed to show anything less than overall survival,” Canaccord analyst George Farmer said in a research note.
In a note to investors, Piper Jaffray analyst Edward Tenthoff said: “The company is exploring lower doses, but the concern is that cabo[zantinib] will not retain the impressive efficacy seen to date.”
Mr. Morrissey said Exelixis plans to move forward with the current daily 100 mg dose of the drug.
Dr. Nicholas J. Vogelzang (Director, Comprehensive Cancer Centers of Nevada) Discusses Mortalities in the Cabozantinib (XL184) Trial
Take Away Message
Cabozantinib demonstrates promising activity in both platinum drug-sensitive and platinum drug-resistant/-refractory ovarian cancer.
Week 12 overall disease control rate of 53%.
Response rates of 18% in platinum-refractory, 22% in platinum-resistant and 28% in platinum-sensitive patients.
Cabozantinib shows encouraging duration of response.
After 36 weeks of follow-up, median duration of response not reached.
Tolerability profile is consistent with that of other tyrosine kinase inhibitors (6 solid tumor patient deaths (1% of all solid tumor pts), including 2 ovarian cancer patients (3% of ovarian cancer pts)).
Discordant effects observed between CA-125 changes and clinical activity.
Simultaneous targeting of MET and VEGFR2 with cabozantinib results in robust effects in patients with advanced ovarian cancer.
Non-randomized expansion cohort is currently accruing in platinum-resistant/-refractory ovarian cancer.
About the MET & VEGFR2 Pathways
To learn more about (i) the role of MET in cancer, (ii) the relationship between the MET and VEGFR pathways, and (iii) the dual inhibition of MET and VEGFR2, visit http://www.metinhibition.com/.
About Cabozantinib (XL184)
Cabozantinib (XL184) is a potent, dual inhibitor of MET and VEGFR2. Cabozantinib is an investigational agent that provides coordinated inhibition of metastasis and angiogenesis to kill tumor cells while blocking their escape pathways. The therapeutic role of cabozantinib is currently being investigated across several tumor types. MET is upregulated in many tumor types, thus facilitating tumor cell escape by promoting the formation of more aggressive phenotypes, resulting in metastasis. MET-driven metastasis may be further stimulated by hypoxic conditions (i.e., deprivation of adequate oxygen supply) in the tumor environment, which are often exacerbated by selective VEGF-pathway inhibitors. In preclinical studies, cabozantinib has shown powerful tumoricidal, anti-metastatic and anti-angiogenic effects, including: (i) extensive apoptosis of malignant cells; (ii) decreased tumor invasiveness and metastasis; (iii) decreased tumor and endothelial cell proliferation; (iv) blockade of metastatic bone lesion progression; and (v) disruption of tumor vasculature.
About Exelixis
Exelixis, Inc. is a biotechnology company committed to developing small molecule therapeutics for the treatment of cancer. Exelixis is focusing its resources and development efforts exclusively on cabozantinib, its most advanced solely-owned product candidate, in order to maximize the therapeutic and commercial potential of this compound. Exelixis believes cabozantinib has the potential to be a high-quality, differentiated pharmaceutical product that can make a meaningful difference in the lives of patients. Exelixis has also established a portfolio of other novel compounds that it believes have the potential to address serious unmet medical needs. For more information, please visit the company’s web site at www.exelixis.com
EC145, in combination with pegylated liposomal doxorubicin (Doxil®/Caelyx®) in patients with platinum-resistant ovarian cancer, met its primary endpoint by showing an 85 percent (2.3 month) improvement in median progression-free survival in the intent-to-treat population, and a 260 percent (4.0 month) improvement in a subset of folate receptor positive patients. The final EC145 phase 2 clinical study data were presented today at the 2011 American Society of Clinical Oncology Annual Meeting.
EC145 delivers a very potent vinca chemotherapy directly to cancer cells by targeting the folate receptor expressed on cancer cells, but not on most normal cells. Approximately 80-90 percent of ovarian and lung cancers express the receptor, as do many other types of cancer. Click on the picture above to view a video regarding EC145's mechanism of action. (Photo: Endocyte, Inc.)
Endocyte, Inc., a biopharmaceutical company developing targeted small molecule drug conjugates (SMDCs) and companion imaging diagnostics for personalized therapy, today announced that the phase 2 PRECEDENT trial, which is investigating the company’s lead drug candidate, EC145, in combination with pegylated liposomal doxorubicin (PLD)(brand name: Doxil®/Caelyx®) in patients with platinum-resistant ovarian cancer, met its primary endpoint by showing: (i) an 85 percent (2.3 month) improvement in medianprogression-free survival (PFS) in the intent-to-treat population, and (ii) a 260 percent (4.0 month) improvement in a subset of folatereceptor positive patients. EC145 in combination with PLD showed limited additional toxicity compared to standard therapy with PLD alone. The most commonly occurring adverse events were neutropenia, small intestine obstruction, and palmar-plantar erythrodysesthesia (or hand-foot syndrome). EC145 is a therapeutic that targets the folate receptor and EC20 is a companion imaging diagnostic used to assess folate receptor presence.
These final PFS data from the PRECEDENT trial were presented today at the 2011 Annual Meeting of the American Society of Clinical Oncology (ASCO), in Chicago, Illinois and are available at http://investor.endocyte.com/events.cfm.
“I am encouraged by these data as EC145 is the first drug candidate to demonstrate a significant improvement in PFS in a randomized trial of patients with platinum-resistant ovarian cancer, a very challenging disease with a high unmet need. Historical data show that for these patients on standard therapy, PFS is approximately three months and overall survival is approximately twelve months. No new drug has been approved in the U.S. for this indication in over a decade,” said Wendel Naumann, M.D., Associate Director of Gynecologic Oncology at Blumenthal Cancer Center, Carolinas Medical Center. “In addition the companion imaging diagnostic, EC20, is designed to identify patients who over-express the targeted receptor and are most likely to respond to EC145. This represents a personalized therapeutic approach that I believe will help oncologists direct patients to the most promising treatment.”
EC145 Phase 2 PRECEDENT Clinical Study Data
The Phase 2 PRECEDENT trial was an international, multi-center, randomized study of 149 women with platinum-resistant ovarian cancer. Patients were randomized to receive EC145 plus PLD or PLD alone at a standard dose until disease progression or death. The primary endpoint of the study was progression-free survival. Secondary endpoints included response rate and overall survival.
The EC145 phase 2 PRECEDENT trial results are summarized below.
85 Percent (2.3 Month) Improvement in Median Progression-Free Survival for All Patients
Patients receiving EC145 in combination with PLD, regardless of folate receptor expression, had a median progression free survival of 5.0 months compared to 2.7 months for patients receiving single agent PLD. The hazard ratio for PFS was 0.626 (p=0.031). The overall response rate was 28 percent in the EC145 combination group versus 16 percent in the PLD-alone group. CA-125 (cancer antigen-125) responses were also more common in patients receiving EC145 in combination with PLD compared to those receiving PLD alone, with response rates (based on CA-125 blood serum measurement) of 38 percent and 19 percent, respectively.
260 Percent (4.0 Month) Improvement in Median Progression-Free Survival for Patients Most Positive for Folate Receptor
The study also utilized EC20, an investigational companion imaging diagnostic that is designed to identify patients with folate receptor positive tumors. As expected, in the folate receptor positive patients the improvement in PFS was even greater. In the subpopulation most positive for the folate receptor, PFS increased 4.0 months from 1.5 months to 5.5 months. The hazard ratio for PFS was 0.381 (p=0.018). This represents more than a 60 percent reduction in the risk of progression and provides evidence supporting the mechanism of action through targeting of the folate receptor. The overall response rate was 22 percent in the EC145 combination group versus 7 percent in the PLD alone group. CA-125 responses were also more common in patients receiving EC145 in combination with PLD compared to those receiving PLD alone, 43 percent and 13 percent, respectively.
“We see tremendous potential for continued development of EC145 based on these data that demonstrate, for the first time, a significant improvement in PFS in patients with platinum resistant ovarian cancer,” said Ron Ellis, President and Chief Executive Officer of Endocyte. “We have already advanced EC145 into Phase 3 evaluation with the PROCEED trial, which has a similar design to the PRECEDENT trial, and plan to file for regulatory approval in the European Union based on the PFS data from the PRECEDENT study.”
Plan to File PRECEDENT Data for Conditional Approval in Europe
As a result of Endocyte’s interaction with the European Medicines Agency (EMA), including a meeting with the Scientific Advice Working Party and written advice from the Committee for Medicinal Products for Human Use (CHMP), the Company will prepare marketing applications for both EC145 and EC20. Based on feedback from the CHMP, Endocyte plans to seek conditional marketing authorization for patients with platinum-resistant ovarian cancer who test positive for the folate receptor using the EC20 companion imaging diagnostic.
Phase 3 PROCEED Trial Initiated
Endocyte recently announced the initiation of patient enrollment in the Phase 3 PROCEED trial of EC145, which is structured to replicate the PRECEDENT trial design. The Phase 3 trial is a randomized, double-blinded trial of EC145 in combination with PLD compared to PLD plus placebo. The patient population — those with platinum-resistant ovarian cancer — will be the same as in the PRECEDENT trial, and the primary endpoint will be progression-free survival in patients selected by EC20 as folate-receptor positive. The trial will also be statistically powered for overall survival as a secondary endpoint with projected enrollment in excess of 500 patients. The trial will be conducted in approximately 150 sites in the U.S., Canada, and Europe. More information regarding the trial is available at www.clinicaltrials.gov.
About EC145
EC145 is a conjugate of the vitamin folate and a super-potent vinca alkaloid. Folate is required for cell division and rapidly dividing cancer cells often over-express folate receptors in order to capture enough folate to support cell division. By attaching a chemotherapy drug to folate through proprietary chemistry, EC145 targets cancer cells while avoiding most normal cells. This targeted approach is designed to provide treatment with super-potent drugs while lowering toxicity compared to standard chemotherapy.
About EC20
EC20 is a folate-targeted molecular imaging agent that is being developed as a non-invasive method to identify tumors that over-express folate receptors. These tumors are the molecular target of Endocyte’s folate-targeted therapeutic compounds such as EC145. To date, EC20 has been administered to over 500 patients and has been found to be well tolerated.
About Endocyte
Endocyte is a biopharmaceutical company developing targeted therapies for the treatment of cancer and inflammatory diseases. Endocyte uses its proprietary technology to create novel small molecule drug conjugates (SMDCs) and companion imaging diagnostics for personalized targeted therapies. The company’s SMDCs actively target receptors that are over-expressed on diseased cells, relative to healthy cells. This targeted approach is designed to enable the treatment of patients with highly active drugs at greater doses, delivered more frequently, and over longer periods of time than would be possible with the untargeted drug alone. The companion imaging diagnostics are designed to identify patients whose disease over-expresses the target of the therapy and who are therefore more likely to benefit from treatment.
EC145 PRECEDENT Trial Results — 2011 American Society of Clinical Oncology Annual Meeting Poster Presentation, June 5, 2011. [Adobe Reader PDF document]
The National Comprehensive Cancer Network (NCCN) recently updated the NCCN Guidelines for Ovarian Cancer to include two additional combination treatment regimens for women with select types of recurring ovarian cancer.
These modifications made to the NCCN Guidelines for ovarian cancer are based on results from recent studies in The Lancet and The Journal of Clinical Oncology demonstrating that both combination regimens improved medianprogression-free survival in women with specific types of recurring ovarian cancer as compared to conventional regimens. In addition, the carboplatin/weekly paclitaxel regimen improved overall survival.
Robert J. Morgan, Jr., M.D., F.A.C.P., Professor, Medical Oncology & Therapeutics Research, City of Hope Comprehensive Cancer Center
“Ovarian cancer is a challenge to treat because by the time the majority of the women are diagnosed with the disease, it has already progressed to stage III or IV,” says Robert J. Morgan, MD, of City of Hope Comprehensive Cancer Center and the chair of the NCCN Guidelines Panel for Ovarian Cancer. “Although finding effective screening tools remains a priority, new treatment options for women with ovarian cancer such as the ones outlined in the updated NCCN Guidelines, remains imperative to making steady progress against the disease.”
Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States and the country’s fifth most common cause of cancer mortality in women. In the year 2009, there were more than 21,000 new diagnoses and nearly 15,000 deaths from this neoplasm in the United States.
The National Comprehensive Cancer Network (NCCN), a not-for-profit alliance of 21 of the world’s leading cancer centers, is dedicated to improving the quality and effectiveness of care provided to patients with cancer. Through the leadership and expertise of clinical professionals at NCCN Member Institutions, NCCN develops resources that present valuable information to the numerous stakeholders in the health care delivery system. As the arbiter of high-quality cancer care, NCCN promotes the importance of continuous quality improvement and recognizes the significance of creating clinical practice guidelines appropriate for use by patients, clinicians, and other health care decision-makers. The primary goal of all NCCN initiatives is to improve the quality, effectiveness, and efficiency of oncology practice so patients can live better lives.
The 2009 American Society of Clinical Oncology (ASCO) Annual Meeting was held in Orlando, Florida from May 29 through June 2, 2009. We provide below select highlights from the 2009 ASCO Annual Meeting that relate to ovarian cancer and other general issues.
ASCO 2009: Fertility Preservation Guidelines Not Widely Followed, by Roxanne Nelson, Medscape Conference Coverage – American Society of Clinical Oncology (ASCO) 45th Annual Meeting, Medscape Today, June 1, 2009 (free registration required to view article).
Ginger (Zindol®) Quells Cancer Patients’ Chemotherapy-Related Nausea.
Extreme Drug Resistance (EDR) Assay Results Do Not Independently Predict Or Alter The Outcomes of Patients With Epithelial Ovarian Cancer Who Are Treated With Optimal Cytoreductive Surgery Followed By Platinum & Taxane Combination Chemotherapy in Either a Primary or Recurrent Setting.
Preliminary Results From Phase II Study of Oxaliplatin+Docetaxel+Bevacizumab As First Line Treatment of Advanced Ovarian Cancer Show 62% Overall Response Rate & 70% One-Year Progression Free Survival.
A Phase II Trial of Irinotecan & Oral Etoposide Chemotherapy in Recurrent Ovarian Cancer Patients Produces 47% Overall Response Rate & 81% Clinical Benefit Rate.
Single Agent Voreloxin Produces 11% Overall Response Rate & 52% Disease Control Rate in Phase II Study Involving Women with Platinum-Resistant Ovarian Cancer.
A Phase II Study of Patupilone In Patients With Platinum Refractory/Resistant Ovarian, Primary Fallopian, or Peritoneal Cancer Produces 48% Clinical Benefit Rate.
M.D. Anderson Cancer Center Finds That Increased Angiogenesis Is A Significant Predictor Of Poor Clinical Outcome In Patients With Sex-Cord Stromal Tumors; Suggests Anti-Angiogenesis Therapy is Warranted For This Subtype of Ovarian Cancer.
ZYBRESTAT™ (Combretastatin A-4 phosphate) Produces 32% Confirmed Partial Response Rate (RR) in Evaluable Patients With Platinum Resistant Ovarian Cancer (25% RR if total enrolled patients used as denominator).
ASSIST-5 Trial of TELCYTA® + Pegylated Liposomal Doxorubicin Produces 12% Response Rate (With One Complete Response) in Patients With Platinum Refractory and Resistant Ovarian Cancer.
Two Studies Provide Contradictory Data for Use of Carboplatin + Pegylated Liposomal Doxorubicin in Ovarian Cancer
Abstract #LBA5508. Carboplatin + Pegylated Liposomal Doxorubicin As First Line Treatment of Advanced Ovarian Cancer Produce Similar Results to Carboplatin + Paclitaxel But With Greater Toxicity.
Abstract #LBA5509. Carboplatin + Pegylated Liposomal Doxorubicin Better Than Carboplatin + Paclitaxel In Terms of Progression Free Survival & General Toxicity With Respect to Platinum Sensitive Ovarian Cancer Patients Enrolled In The CALYPSO Study of the Gynecologic Cancer Intergroup (GCIG).
OGX-427 Treatment Demonstrates Safety, Evidence of Declines in Circulating Tumor Cells and Reductions in Tumor Markers in a Phase I Cancer Trial, Including 60% Response Rate (Based Upon Declining CA125) For Ovarian Cancer Patients.
Carfilzomib(PX-171-007) Produces Stable Disease For 4+ Months In One Ovarian Cancer Patient Who Failed Under Four Previous Treatment Lines – Phase II Solid Tumor Trial.
The American Society of Clinical Oncology is a non-profit organization founded in 1964 with the overarching goals of improving cancer care and prevention. More than 27,000 oncology practitioners belong to ASCO, representing all oncology disciplines and subspecialties. Members include physicians and health-care professionals in all levels of the practice of oncology. To view 2009 ASCO Annual Meeting presentation abstracts, click here. To view 2009 ASCO Annual Meeting presentation abstracts regarding ovarian cancer, click here. To view ASCO ovarian cancer information, click here.
About Cancer.Net
Cancer.Net, formerly People Living With Cancer (PLWC), brings the expertise and resources of the American Society of Clinical Oncology (ASCO), the voice of the world’s cancer physicians, to people living with cancer and those who care for and care about them. ASCO is composed of more than 27,000 oncologists globally who are the leaders in advancing cancer care. All the information and content on Cancer.Net was developed and approved by the cancer doctors who are members of ASCO, making Cancer.Net the most up-to-date and trusted resource for cancer information on the Internet. Cancer.Net is made possible by The ASCO Cancer Foundation, which provides support for cutting-edge cancer research, professional education, and patient information.
Cancer.Net provides timely, oncologist-approved information to help patients and families make informed health-care decisions. All content is subject to a formal peer-review process by the Cancer.Net Editorial Board, composed of more than 150 medical, surgical, radiation, and pediatric oncologists, oncology nurses, social workers, and patient advocates. In addition, ASCO editorial staff reviews the content for easy readability. Cancer.Net content is reviewed on an annual basis or as needed.
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“Endocyte Inc. has announced the initiation of a randomized Phase II clinical study of the company’sinvestigational drug EC145 in women with platinum-resistant ovarian cancer. The phase II trial, also called the “PRECEDENT study,” will evaluate the efficacy and safety of EC145 when administered in combination with pegylated liposomal doxorubicin (PLD). …The PRECEDENT study will enroll 122 subjects and involve more than 50 clinical centers in the U.S., Canada, and Europe. … EC145 links a very potent anticancer drug to the vitamin folate, which is required forcell division. Rapidly dividing cancer cells over-express folate receptors to capture enough folate to support cell division. By combining a chemotherapy drug with folate, EC145 targets cancer cells while avoiding normal cells. This targeted approach is designed to provide treatment with more potent drugs with lower toxicity.”
″WEST LAFAYETTE, IN. – February 19, 2009 – Endocyte Inc. has announced the initiation of a randomized Phase II clinical study of the company’s investigational drugEC145 in women with platinum–resistant ovarian cancer. The phase II trial, also called the “PRECEDENT study,” will evaluate the efficacy and safety of EC145 when administered in combination with pegylated liposomal doxorubicin (PLD). PLD is widely used as a standard therapy for women with platinum-resistant ovarian cancer. The efficacy and safety of the combination of EC145/PLD will be compared to treatment with PLD without EC145. Ovarian cancer is the fifth most common cancer among women in the United States and the leading cause of death due to cancer of the female reproductive system. The PRECEDENT study will enroll 122 subjects and involve more than 50 clinical centers in the U.S., Canada, and Europe. Trial details can be found at www.endocyte.com and http://www.clinicaltrials.gov. EC145 links a very potent anticancer drug to the vitamin folate, which is required for cell division. Rapidly dividing cancer cells over-express folate receptors to capture enough folate to support cell division. By combining a chemotherapy drug with folate, EC145 targets cancer cells while avoiding normal cells. This targeted approach is designed to provide treatment with more potent drugs with lower toxicity.
Advanced Ovarian Cancer - Imaging folate-receptors cancer cells using EC20 (folate-Tc99m). Source: Endocyte
In addition to EC145, patients in the PRECEDENT trial will also be treated with a new molecular imaging agent called EC20 developed by Endocyte. By targeting folate receptors, EC20 imaging agent allows clinicians to identify tumors that overexpress the folate receptor. Using EC20, doctors may be able to identify, in advance, those patients who will benefit from EC145 therapy. According to Dr. Wendel Naumann of the Blumenthal Cancer Center, Carolinas Medical Center and principal investigator for the PRECEDENT study, ‘Patients with advanced, platinum resistant, ovarian cancer are in need of therapy that does not result in significant toxicity. The earlier clinical studies of EC145 were encouraging because they indicated that clinicians could use EC20 to identify women whose tumors expressed the molecular target of EC145. Therapy with EC145 might benefit these patients without causing significant additional toxicity.’ ‘The start of the PRECEDENT study is another important validation of Endocyte’s promising DGS [Drug Guidance System] technology platform,” said Dr. Richard Messmann, Endocyte’s vice president for medical affairs. ‘This also represents an important milestone in Endocyte’s efforts to develop a range of new drugs and predictive medicine tools to treat cancer and other serious diseases in the years ahead. ‘
About Endocyte
Endocyte is a privately-held biotechnology company with headquarters in the Purdue Research Park of West Lafayette, IN. Based on the applications of Endocyte’s advanced proprietary Drug Guidance System (DGS), the Company is working to develop new drugs and diagnostic agents to treat many types of cancer and other serious diseases. The DGS platform makes it possible to use highly-potent drugs on extended and frequent dosing schedules and in combination with other drugs to maximize efficacy. The technology improves drug targeting and reduces the risk of side effects by combining drugs with ligands that are able to identify and attach to receptors found on tumor and other disease cells. Endocyte is currently conducting three separate Phase 2 clinical trials for its lead compound, EC145, together with EC20, a companion molecular imaging agent, for the treatment of ovarian cancer and non-small cell lung cancer. Other clinical-stage products in the Endocyte pipeline include: EC0225, a combination of two potent anticancer drugs; BMS493, a potent drug being developed in partnership with Bristol-Myers Squibb; EC17, a targeted immunotherapy agent; and EC0489, a targeted cancer drug. The Company also has multiple product candidates in pre-clinical stage development. This press release contains “forward-looking statements” as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management’s current expectations and involve significant risks and uncertainties that may cause results to differ materially from those set forth in the statements. We undertake no obligation to publicly update any forwardlooking statement, whether as a result of new information, future events, or otherwise.
A list of the drugs/drug combinations is provided below. Any drug covered in depth through an earlier H*O*P*E*™ weblog post is noted. We also included 2008 ASCO Annual Meeting abstracts that provide “solid tumor” clinical trial results with respect to studies that enrolled patients with ovarian cancer tumors. When evaluating the potential enrollment in a clinical trial at various treatment points, an ovarian cancer survivor should evaluate trials dedicated to ovarian cancer patients in entirety, as well as general “solid tumor” trials that allow enrollment of ovarian cancer patients. Generally, a patient should give first priority to dedicated ovarian cancer trials and use the solid tumor trials as a “backup” to the ovarian cancer trials. All questions regarding the priority assigned to, or proper sequencing of, clinical trials should be discussed in detail with your doctor(s). Treatment priority and sequencing issues arise, for example, when enrollment in one clinical trial potentially disqualifies the patient for a subsequent second clinical trial based upon the protocol (i.e., inclusion/exclusion criteria) of the second trial. This example assumes that both clinical trials are currently enrolling patients when trial enrollment is being evaluated by you and your doctor.
NOV-002 plus carboplatin in platinum-resistant ovarian cancer(2008 ASCO Abstract #5593). Patients were heavily pretreated with 11/15 patients having received 3 prior [treatment] lines. Toxicity was mild-moderate with no G4 toxicity. There was no febrile neutropenia. The most common toxicities were nausea and fatigue, as well as abdominal pain and bowel obstruction thought to be related to underlying disease. To date, there is 1 patient with PR, 7 patients with SD and 5 patients with PD, with 1 patient off-trial for patient discretion. PFS is 14 weeks. Patients tolerated this regimen extremely well, with most toxicity attributable to carboplatin alone. Conclusion: The PFS was longer than expected, with a significant proportion of these platinum resistant patients achieving clinical benefit with prolonged stable disease. [61% disease control (CR+PR+SD) rate]
Final results of a phase I study of picoplatin and pegylated liposomal doxorubicin [e.g. Doxil™] in advanced solid tumor malignancies (2008 ASCO Annual Mtg. Abstr. #2568 ): Picoplatin is a novel, sterically hindered platinum(II) complex designed to circumvent mechanisms of platinum resistance. Given the single agent activity seen in multiple tumor types, we conducted a phase I study of picoplatin in combination with pegylated liposomal doxorubicin (PLD) in patients with advanced solid tumors. The Phase 1 trial enrolled 16 patients with advanced solid tumors who had received up to three prior regimens for metastatic disease. Patients were administered picoplatin followed by liposomal doxorubicin on day one of a 28-day cycle. Four dose levels of picoplatin and pegylated liposomal doxorubicin were tested: 100/20, 100/30, 100/40 and 120/40 (all mg/m2). A total of 62 courses of treatment were delivered to 16 patients with a median number of four cycles per patient. A total of 12 patients were evaluable for response. One patient experienced a CR (primary peritoneal cancer) and four experienced a PR (including three of five patients with ovarian cancer). Hematologic and non-hematologic toxicity were mild. Conclusion: This study suggests that picoplatin and liposomal doxorubicin is an active combination with promising results and can be given at standard dose levels with a minimal increase in toxicity. [41% disease control (CR+PR+SD) rate among evaluable patients]
Phase II study of weekly topotecan in recurrent ovarian cancer: duration of response based on a prolonged follow-up (ASCO Annual Mtg. Abstr. #16549). Nineteen patients (median age 52 yrs, range 45-72) with EOC who progressed after 3 (11/19 patients = 57.9%), 4 (7/19 patients= 36.8%) or 5 (1/19 patients= 5.3%) previous lines of chemotherapy were treated with Topotecan at the dose of 2.0 mg/m2 via a 30-minute intravenous infusion once every week until disease progression, unacceptable toxicity or when a stability of disease was reached. Results: All patients were evaluable for toxicity and clinical response. 16/19 patients enrolled (84.2%) had stage III-IV disease. Median number of chemotherapy cycles was 7 (range 3 – 12). A total of 107 cycles were administered. Dose reduction was necessary for 13% of the cycles. Main toxicities included anemia (G1-G2=57.9%), leucopenia (G1-G2=15.8%), thrombocytopenia (G1-G2=10.5%) and asthenia (20%). No one showed a CR, while 5/19 patients experienced a PR (26.4%), 6/19 patients experienced SD (31.5%), and 8/19 patients (42.1%) experienced DP. The median PFSwas 12 weeks in patients with PR; SD was maintained for a median time of 14 weeks. Conclusion: The rate of patients with ongoing stable disease (31.5%)suggests that the clinical benefit of weekly topotecan may be expected also in patients with no other viable therapeutic options. [57% disease control (CR+PR+SD) rate among evaluable patients]
A phase IB study evaluating BSI-201 in combination with chemotherapy in subjects with advanced solid tumors (2008 ASCO Annual Mtg. Abstr. #3579).Fifty-five subjects with advanced solid tumors have been treated with BSI-201 doses of 1.1 thru 8.0 mg/kg, in combination with cytotoxic chemotherapy. All dose combinations were well tolerated with a total of 21 serious adverse events reported for 10 trial participants, none of which were deemed related to study drug. A CR at 6 months was reported for 1 subject with ovarian cancer, and 5 subjects with renal, breast (2), uterine, and sarcoma experienced a PR. An additional 19 subjects had SD for 2 months or more. [45% disease control (CR+PR+SD) rate among evaluable patients]
A phase II study of sunitinib (SU11248 ) in patients (pts) with recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma – NCIC CTG IND 185 (2008 ASCO Annual Mtg. Abstr. #5522). Seventeen (16 eligible) pts have been accrued; Median age 55 years (range 41-82 ); tumor histology – 3 pts. with adeno, 1 pt. with endometrioid, 12 pts. with serous; 12 pts had 2 prior chemo regimens; total number of cycles 42, median 3 (range 1 – 5 ). PR has been seen in 2 pts, SD in 10 pts. (range 2.6-6.9 months), PD in 4. Notably, by size criterion alone 4 pts had tumor decrease > 30% but two developed effusions and were therefore catagorized as PD by RECIST; a further 9 pts. had decrease <30% measurable disease. Of 11 pts evaluable for CA125 response, 6 pts. were responders (3 pts. confirmed, 3 pts. unconfirmed), and 5 pts. were non-responders. [75% disease control (CR+PR+SD) rate among evaluable patients]
AZD2281, a PARP (poly ADP-ribose polymerase) inhibitor with single agent anticancer activity in patients with BRCA deficient ovarian cancer: Results from a phase I study (2008 ASCO Annual Mtg. Abstr. #5510)Thirty-two patients with BRCA-deficient ovarian cancer (i.e., patients with BRCA gene mutations) the majority of whom were platinum resistant/refractory are so far evaluable for response. All evaluable patients had either received treatment for at least 8 weeks (2 cycles) or progressed prior to completion of 2 cycles. Fourteen patients have achieved PR, 13 patients meeting GCIG- CA125 criteria and 10 patients meeting RECIST criteria. Of the responders, 1 patient has been on drug > 56 weeks whilst 7 patients have maintained responses for > 24 weeks. SD was seen in an additional 8 patients, 7 of whom continue on drug and 3 patients had SD > 16 weeks. Responses were seen at all dose levels from 100mg bd and above. Conclusion: AZD2281 is well tolerated and has demonstrated compelling activity in patients with BRCA deficient ovarian cancer. Responses were seen in all patient groups including platinum resistant disease. Updated efficacy data, together with a correlation of potential predictive factors including platinum free interval will be presented on a total planned cohort of 46 patients with BRCA-deficient ovarian cancer. A randomised study in BRCA-deficient ovarian cancer has been planned. [68% disease control (CR+PR+SD) rate among evaluable patients]
A phase II evaluation of pemetrexed (LY231514, IND #40061) in the treatment of recurrent or persistent platinum-resistant ovarian or primary peritoneal carcinoma: A study of the gynecologic oncology group (2008 ASCO Annual Mtg. Abstr. #5524). The purpose of the study was to estimate the anti-tumor activity of pemetrexed (LY231514) in patients with persistent or recurrent platinum-resistant epithelial ovarian or primary peritoneal cancer who have failed on higher priority treatment protocols and to determine the nature and degree of toxicity of pemetrexed in this cohort of patients. From July 6, 2004 to August 23, 2006, 51 patients were entered by 15 member institutions of the GOG. Overall, the treatment was well tolerated. More serious toxicities (G3 and G4) included neutropenia in 42%, leukopenia in 25%, anemia in 15%, and constitutional in 15%. No treatment-related deaths were reported. One patient (2%) had a CR and nine patients (19%) had PR with a median duration response of 6.8 months. Seventeen patients (35%) had SD for a median of 4.1 months. Eighteen patients (38%) had DP. Three patients (6%) were inevaluable. Median PFS was 3.0+ months and OS was 11.4+ months. Conclusion: Pemetrexed has demonstrated activity in the treatment of recurrent platinum resistant ovarian carcinoma at the dose and schedule tested [60% disease control (CR+PR+SD) rate among evaluable patients].
Phase II trial of sorafenib in persistent or recurrent epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC): A Gynecologic Oncology Group (GOG) study (2008 ASCO Annual Mtg. Abstr. #5537).Sorafenib is a tyrosine kinase inhibitor targeting raf and other receptor kinases (VEGF-R, PDGF-R, Flt3, c-KIT). Sorafenib may have anti-angiogenic activity through inhibition of VEGF-R. This phase II study was conducted to assess the activity and tolerability of sorafenib in patients with recurrent EOC. Methods: This was an open label multi-institutional phase II study …. Eligible patients had persistent or recurrent EOC/PPC after 1-2 prior cytotoxic regimens, measurable or detectable (e.g. by CA125) disease, and GOG performance status < 2. Patients were required to have progressed within 12 months of completing platinum based therapy. Treatment consisted of sorafenib 400 mg orally bid until disease progression or prohibitive toxicity. Primary endpoints were PFS at 6 months and toxicity by NCI criteria. Secondary endpoints were tumor response and duration of PFS/OS. Results: 73 patients were enrolled from 10/04 to 5/07 and as of 12/2007, 68 patients are evaluable (2 ineligible and 3 too early) for toxicity. Median age was 60 (range 33-80) years and prior treatment consisted of 1 regimen in 40 patients and 2 regimens in 28 patients. Significant G3 and G4 toxicities included: rash (12 patients), metabolic (10 patients), gastrointestinal (3 patients), cardiovascular (2 patients), and pulmonary (2 patients). No treatment related deaths were recorded. Only patients with measurable disease were used to assess efficacy. Among the 59 patients with measurable disease, 12 survived PFS at least 6 months. Three patients are yet to be determined. Two patients had PR; 20 had SD; 30 had DP, and 7 could not have their tumor assessed. Conclusions: Preliminary results suggest that sorafenib is tolerated in patients with recurrent EOC with dermatologic and metabolic abnormalities being the most common toxicities. Efficacy data is expected to reach maturity and be analyzed in the spring of 2007, and comprehensive results will be presented. [42% disease control (CR+PR+SD) rate among evaluable patients]
Phase II prospective study of weekly topotecan and bevacizumab in platinum refractory ovarian cancer or peritoneal cancer (OC) (2008 ASCO Annual Mtg. Abstr. #5551). Patients (pts) with platinum refractory OC have limited treatment options. Bevacizumab, an anti-angiogenesis agent has demonstrated efficacy in recurrent ovarian cancer. Bevacizumab combined with chemotherapy in other solid tumors has improved efficacy compared with bevacizumab or chemotherapy alone. Topotecan, an active drug in recurrent OC has been used in a weekly fashion with less toxicity and more acceptability than a standard 5 day regimen. Topotecan and bevacizumab have non-overlapping toxicities. We studied the efficacy and tolerability of weekly topotecan and bevacizumab in patients with platinum refractory OC. Methods: The primary objectives of this study were to evaluate PFS, OS, OR rate and toxicity of this combination regimen. Eligible pts included those with platinum refractory OC (recurrence < 6 months of platinum therapy) who had received a maximum of 2 prior chemotherapy regimens. Results: Twenty-two pts have been enrolled to date, with 11 pts remaining on study and 18 now evaluable. Best responses for the 18 evaluable pts were: 22.2% PR (n=4), 27.8% SD (n=5), and 50% DP (n=9). Eleven pts went off study due to DP (based on CT scan RECIST criteria [n=6] or general deterioration and/or bowel obstruction [n=5]). Median duration on study for the 18 evaluable pts was 15 wks (range 5-63 weeks). Four pts have had PFS >5 months. The 18 evaluable pts received a total of 91 treatment cycles. No pt went off study due to treatment related toxicity or suffered a bowel perforation. Conclusions: Combination bevacizumab and topotecan administered in a weekly fashion demonstrate good activity in platinum refractory OC with acceptable toxicity. G3-G4 Hematologic or Hypertensive Toxicities. [50% disease control (CR+PR+SD) rate among evaluable patients]
Phase I/II lapatinib plus carboplatin and paclitaxel in stage III or IV relapsed ovarian cancer patients (2008 ASCO Annual Mtg. Abstr. #5556). The purpose of this study was to establish the MTD and evaluate DLTs and response to therapy of combination therapy with carboplatin/paclitaxel and lapatinib, an oral dual tyrosine kinase inhibitor of both ErbB1 and ErbB2, in Stage III /IV relapsed ovarian cancer. Methods: This was an open-label, multicenter, phase I/II study of carboplatin/paclitaxel in combination with single agent lapatinib in Stage III/IV relapsed ovarian cancer patients. Measurable disease, adequate organ function and ECOG performance status of 0-2 were required. Results: 25 ovarian cancer patients are enrolled and four are too early to be evaluable. The median age is 57 (range 39-81). The median number of prior therapeutic regimens is 4 (range 1-10). GI toxicities were primarily < grade 2 and were successfully treated with aggressive bowel management. 10 patients (pts) experienced G3 toxicities. 4 pts- leukopenia, 2 pts-neutropenia, 2 pts-hyperglycemia, 2 pts-allergic reactions to carboplatin, 1 pt-thrombocytopenia, 1 pt-lymphopenia, 1 pt-hypokalemia, 1 pt-nausea, 1 pt-diarrhea, 1 pt-bowel obstruction. Response to therapy to date is: CR=21%, PR=29%, SD=29%, PD=21%. Two patients who were in complete remission both stopped IV chemotherapy and were maintained only with lapatinib. One is still in remission after six months and one relapsed. Conclusions: Lapatinib, an oral targeted molecular therapy which inhibits both EGFR 1 and 2 tyrosine kinase activity, can be safely administered with a weekly regimen of carboplatin and paclitaxel in heavily pretreated, ovarian cancer patients. The high response rates seen warrant further investigation. [79% disease control (CR+PR+SD) rate among evaluable patients]
Cisplatin-based combination chemotherapy consisting of ifomide, epirubicin, and cisplatin (IEP) is effective for patients with relapsed ovarian carcinoma (ROC) resistant or refractory to TC (paclitaxel/carboplatin) (2008 ASCO Annual Mtg. Abstr. #16507). The purpose of the study was to evaluate the efficacy and toxicity of IEP for patients (pts) with relapsed EOC. Methods: Eligible pts had histologically-confirmed serous, endometrioid, or transitional cell carcinoma of the ovary measuring more than 2 cm in diameter, age < 75 yrs, World Health Organization performance status < 3, adequate pulmonary, cardiac, hematopoietic, liver and renal functions, and written informed consent. Results: Forty eligible pts were enrolled in this study. The median age was 51 yrs (range, 41-64). All pts received more than 6 cycles of TC. Thirty- four of 40 pts (85%) had 1 or more previous chemotherapy other than TC. Histologic types were serous (33 pts), endometrioid (5 pts), and transitional (2 pts). After a median of 4 cycles (range, 2-10), we observed OR in 28 pts (70%), with 4 (10%) CRs and 24 (60%) PRs, and 12 (30%) SD. Median OS for all 40 pts was 24.3 months (mo) (range, 4 to 78). Median OS of pts achieving CR, PR, and SD were ‘not reached”, 23.6 months, 8.2 months, respectively (Log-rank, p < 0.001). The most frequent G3-G4 hematologic toxicities were; neutropenia 57.8%, anemia 43.3%, and thrombocytopenia 14.4%. Alopecia (G1-G2) occurred in 91.3%, but there was no G2 or G3 peripheral neuropathy, nephrotoxicity, or cardiotoxicity. Conclusion: IEP regimen has significant anti-tumor activity with acceptable toxicity and appreciable response duration. Several studies have demonstrated that cisplatin is more effective than carboplatin in almost all platinum-sensitive disease except OC (Lokich J: Cancer Invest 19: 756, 2001). In OC, carboplatin was demonstrated equal to cisplatin in anti-tumor response in optimal disease (GOG 158, AGO), but the equivalency was not demonstrated in suboptimal disease. We must reappraise cisplatin as an agent that should be included in the first line for platinum-sensitive OC. [100% disease control (CR+PR+SD) rate among evaluable patients for platinum-sensitive OC (ie., recurrence 12 months or more after completion of first-line platinum drug treatment)]
NKTR-102 (Pegylated irinotecan):
Phase I dose finding and pharmacokinetic study of NKTR-102 (PEGylated irinotecan): Early evidence of anti-tumor activity (2008 ASCO Annual Mtg. Abstr. #13518 ). NKTR-102 is a novel pegylated form of irinotecan with superior efficacy against a range of xenografts compared with irinotecan. Sustained tumor inhibition is associated with increased SN38 exposure. A phase I trial of NKTR-102 was conducted to establish the MTD and to characterize safety and PK in patients (pts) with refractory solid tumors. No CTC Grade 4 toxicity was observed. G3 diarrhea was dose limiting. Other toxicities included transient uncomplicated G3 neutropenia and transient infusion related visual disturbance. PK data are available for 12 pts. Two partial responses were observed in pts with advanced cervical cancer and small cell lung cancer. Anti-tumor activity was seen in 4 other pts; ovarian: CA-125 decreased from 2557 to 518, Hodgkin’s disease: 28% radiologic improvement with symptomatic benefit, adrenocortical: cortisol levels normalized, metabolic response by PET, esophageal: CEA decreased from 35.5 to 13.6, metabolic response by PET. Conclusions: NKTR-102 shows early evidence of activity in a wide spectrum of tumors. Cumulative SN38 exposure is 1.2 to 6.5 fold higher than that predicted for irinotecan. Toxicity is manageable; diarrhea (not neutropenia) is dose limiting.
Phase I study of ON 01910.Na, a novel polo-like kinase 1 pathway modulator, administered as a weekly 24-hour continuous infusion in patients with advanced cancer (2008 ASCO Annual Mtg. Abstr. #2515).ON 01910.Na induces G2/M cell cycle arrest, apoptosis, and cell death in a broad spectrum of cancer cells, but not in non-neoplastic cells. In vitro, cell killing is dependent on drug exposure time. Based on these preclinical findings, a weekly 24hr continuous infusion (CI) study to determine safety and MTD of ON 01910.Na was initiated. Methods: Patients with advanced cancers received ON 01910.Na as a weekly 24hr CI. Twenty-three pts (7:16 M:F, 45-80 yrs) have received ON 01910.Na. G2 toxicities (2-grade increase over baseline) included fatigue (3 pts) and anorexia (1 pt). Fatigue (11/23 pts) was the most common side effect, with no G3 or greater fatigue observed. Overall, three G3 events occurred, none of which were drug-related. The best response was a pt with advanced ovarian cancer who maintained stable disease for 36 wks of treatment. Conclusions: ON 01910.Na is well tolerated as a weekly 24h continuous infusion. In the dose range studied, the drug exhibited non-linear kinetics with rapid attainment of plasma concentrations that are cytotoxic to cancer cells in vitro, but have limited end-organ toxicity in vivo. Study data continues to accrue, and we expect to recommend a phase II dose shortly. Further analysis and combination phase I studies are planned.
BAY 73-4506:
Phase I study of BAY 73-4506, an inhibitor of oncogenic and angiogenic kinases, in patients with advanced solid tumors: Final results of a dose-escalation study (2008 ASCO Annual Mtg. Abstr. #2558 ). BAY 73-4506 is a potent tyrosine kinase inhibitor of receptor tyrosine kinases (VEGFR, PDGF, RET, KIT, FGFR) and serine/threonine kinases (raf and p38MAPK). In tumor xenograft models, BAY 73-4506 demonstrated a broad spectrum antitumor activity. Methods: This phase I study was a dose-escalation trial investigating the safety, PK, and pharmacodynamic (PD) profile of BAY 73-4506, given orally in 21 days on/7 days off cycles, until discontinuation due to toxicity or tumor progression. PK was assessed on days 1 and 21 of cycle 1. PD markers including DCE-MRI, soluble VEGFR-2 (sVEGFR-2) and VEGF plasma levels were assessed at each cycle. Tumor response was evaluated as per RECIST. Results: 52 patients (pts) with solid tumors and progressive disease were enrolled and treated with doses of 10 to 220 mg once daily. Frequent tumor types included colorectal cancer (CRC) (31%), malignant melanoma (10%), and ovarian cancer (10%). The median treatment duration was 49.5 days (min. 3, max. 609). Drug-related adverse events (AEs) of all grades reported in >20% of pts were hoarseness (54%), dermatological toxicities (50%; CTC G3-G4: 13%), mucositis (35%), diarrhea (25%; CTC 3: 2%), fatigue (23%; CTC 3: 2%), and hypertension (23%; CTC 3: 6%). Treatment-related AEs leading to dose reduction, interruption or discontinuation were hand foot skin reaction (15%), diarrhea (8%), and thrombopenia (6%). Of the 33 evaluable pts, 9% achieved a partial response (PR), 64% had stable disease (SD), at least 7 weeks after start of treatment, and 48% had SD or PR for more than 11 weeks. Conclusions: The recommended phase II dose for BAY 73-4506 is 160 mg daily, using the 21 days on/7 days off treatment schedule. Clinical activity (PR+SD) has been demonstrated in 73% of the evaluable pts. An extension cohort (dose level 160 mg) has been started.
HIPEC is used in conjunction with surgery and chemotherapy to treat patients with gastrointestinal tract and gynecological cancers and sarcomas that have spread to the lining of the abdomen. Even after surgical removal, cancer often recurs in the abdomen. So when the tumor spreads, it is difficult for doctors to treat with standard chemotherapy.
HIPEC involves using a using a heated sterile solution that is circulated throughout the abdominal cavity. With HIPEC treatment, patients are connected to a series of tubes and a pumping device that bathes the abdominal cavity for two hours with a heated sterile solution containing anticancer (chemotherapeutic) drugs. The high temperature of the chemotherapy increases the effect of the drug. The fluid goes through the abdomen to treat tumor cells that may remain after surgery. Both heat and direct contact with chemotherapy drugs kills the cancer cells.
Twenty-one patients were enrolled in this Phase I clinical trial. The maximum PLD dose evaluated in this trial was 100 mg/m² and was well tolerated. The most common grade 3/4 complications were superficial wound infection and prolonged ileus. One patient developed an anastomotic leak in the postoperative period, requiring re-exploration. The length of the median postoperative hospital stay was 7 days (range, 4-29 days), three patients required readmissions within 30 days, and there were no operative deaths.
The median follow-up time for was 13.7 months (range, 3-38 months). The median overall survival was 30.6 months with a median progression free survival (PFS) of 25 months. Based on these findings, the trial investigators concluded that HIPEC with PLD following maximal cytoreduction in patients with advanced abdominal-only, gastrointestinal or gynecologic malignancies is well tolerated. Moreover, the investigators stated that the encouraging survival period after cytoreduction and HIPEC with PLD suggests that a verification Phase II clinical trial is warranted.
For more information regarding the HIPEC procedure, go to HIPECTREATMENT.org. For a list of open clinical trials testing the HIPEC procedure using various chemotherapeutic agents, click here.
Libby's H*O*P*E* 