PARP Inhibitor Olaparib Benefits Women With Inherited Ovarian Cancer Based Upon Platinum Drug Sensitivity

Olaparib (AZD2281), a new type of cancer drug known as a “PARP inhibitor,” produced promising results in patients with platinum-refractory, platinum-resistant, and platinum-sensitive ovarian cancer linked to an inherited BRCA1 or BRCA2 gene mutation.

A new type of cancer drug — known as a “PARP inhibitor” — produced promising results in patients with ovarian cancer linked to an inherited BRCA1 or BRCA2 gene mutation. The trial results were published online in the Journal of Clinical Oncology on April 19th.

Scientists at The Institute of Cancer Research (ICR) and The Royal Marsden Hospital, working with pharmaceutical company KuDOS Pharmaceuticals, now a subsidiary of AstraZeneca, found the experimental drug olaparib shrank or stabilized tumors in approximately half of ovarian cancer patients possessing BRCA1 or BRCA2 mutations.

The five-year survival rate for ovarian cancer is just 40 per cent as the majority of patients are diagnosed with an advanced form of the disease. Most patients initially respond well to radical surgery and platinum and taxane-based chemotherapy, but relapse after an average of 18 months. Subsequent treatments generally become less effective as patients build up resistance.

Professor Stan Kaye, Head of Section of Medicine, Institute of Cancer Research; Head of Drug Development Unit, The Royal Marsden Hospital; and Cancer Research UK-funded scientist

“There is an urgent need to find new drugs for women diagnosed with ovarian cancer,” says Professor Stan Kaye, Head of the Section of Medicine at the ICR and Head of the Drug Development Unit at The Royal Marsden Hospital and a Cancer Research UK-funded scientist. “Olaparib is still in early-stage testing but the results so far are very encouraging. These findings raise the possibility that carefully selected patients in future may well be offered olaparib as an alternative to chemotherapy during the course of their treatment.”

Between 2005 and 2008, about 50 women with confirmed or suspected BRCA1 or BRCA2 mutations began treatment with olaparib in a dose escalation and single-stage expansion of a Phase I trial. Twenty patients responded with their tumors shrinking or with significant falls in their ovarian cancer marker CA125, or both. The disease also stabilized in three patients. The drug was effective for an average of seven months. Notably, several patients are still taking olaparib (for nearly two years). Drug side-effects were generally mild, especially when compared to current chemotherapy treatments.

Olaparib is a new type of drug known as a PARP inhibitor that works by turning a tumor’s specific genetic defect against itself. In susceptible cells, olaparib prevents the repair of naturally occurring breaks in DNA, which healthy cells are able to repair. Susceptible cancer cells – those with an existing defect in a DNA repair pathway caused by a mutation in the BRCA1 or BRCA2 genes – are unable to repair themselves, and therefore, die.

Platinum-based chemotherapy, particularly carboplatin, is one of the main treatments used for ovarian cancer. When this treatment ceases to be effective, theoretically, olaparib might be less effective too, so the ICR scientists examined whether olaparib would still benefit patients whose response to previous platinum-based drugs was limited. Finding new drugs to treat these “platinum-resistant” ovarian cancer patients (those who relapsed within six months of previous platinum therapy) is a particularly high priority as they have a lower chance of benefiting from re-treatment with chemotherapy and a poorer prognosis.

The research team found that the clinical benefit rate with olaparib was indeed higher — 70% — among patients with “platinum-sensitive disease” (disease recurrence more than six months after previous platinum therapy). Crucially, however, the clinical benefit rate was still 46% in platinum resistant patients.

ICR Study Findings:

• 50 patients participated in the study (13 had platinum-sensitive disease, 24 had platinum-resistant disease, and 13 had platinum-refractory disease (according to platinum-free interval).

• 20 patients (40%) achieved complete or partial responses under RECIST (Response Evaluation Criteria in Solid Tumors) criteria and/or tumor marker (CA125) responses.

• 3 patients (6.0%) maintained RECIST disease stabilization for more than 4 months.

• Overall clinical benefit rate (complete response + partial response + stable disease) = 46%.

• Median response duration was 28 weeks.

• There was a significant association between the clinical benefit rate and platinum-free interval across the platinum-sensitive, resistant, and refractory patient subgroups (69%, 45%, and 23%, respectively).

• Analyses indicated associations between platinum sensitivity and extent of olaparib response.

• CONCLUSION: Olaparib has antitumor activity in BRCA1/2 mutation ovarian cancer, which is associated with platinum sensitivity.

Up to 15 per cent of breast and ovarian cancers have known BRCA1 or BRCA2 mutations on blood testing and, importantly, laboratory data strongly suggests that olaparib may also be effective in cancers linked to DNA repair defects not caused by BRCA1 and BRCA2 mutations. This could apply in about half the cases of the most common histological type of ovarian cancer.

“We have good reason for thinking that the benefit seen with olaparib in BRCA mutation-linked ovarian cancer may well extend to a broader population of patients with this disease,” says Professor Kaye.

Randomised trials of olaparib – in which some patients receive the drug and others a placebo – are underway and results will be available later this year.

KuDOS Pharmaceuticals (a wholly owned subsidiary of AstraZeneca) was the major funder of the trial, along with Cancer Research UK and the National Institute for Health Research. Olaparib was identified and developed at KuDOS Pharmaceuticals and subsequently at AstraZeneca.

PARP Inhibitor Clinical Trials:

To view a list of open ovarian cancer clinical trials that are testing olaparib (AZD2281), click here.

To view a list of open solid tumor clinical trials that are testing olaparib (AZD2281), click here.

To view a list of open ovarian cancer clinical trials that are testing various PARP inhibitors, click here.

To view a list of open solid tumor clinical trials that are testing various PARP inhibitors, click here.

About The Institute of Cancer Research (ICR)

* The ICR is Europe’s leading cancer research centre.

* The ICR has been ranked the UK’s top academic research centre, based on the results of the Higher Education Funding Council’s Research Assessment Exercise.

* The ICR works closely with partner The Royal Marsden NHS Foundation Trust to ensure patients immediately benefit from new research. Together the two organisations form the largest comprehensive cancer centre in Europe.

* The ICR has charitable status and relies on voluntary income, spending 95 pence in every pound of total income directly on research.

* As a college of the University of London, the ICR also provides postgraduate higher education of international distinction.

* Over its 100-year history, the ICR’s achievements include identifying the potential link between smoking and lung cancer which was subsequently confirmed, discovering that DNA damage is the basic cause of cancer and isolating more cancer-related genes than any other organization in the world.

* The ICR is home to the world’s leading academic drug development team. Several important anti-cancer drugs used worldwide were synthesised at the ICR and it has discovered an average of two preclinical candidates each year over the past five years.

For more information visit www.icr.ac.uk.

About The Royal Marsden Hospital

The Royal Marsden opened its doors in 1851 as the world’s first hospital dedicated to cancer treatment, research and education. Today, together with its academic partner, The Institute of Cancer Research, it is the largest and most comprehensive cancer centre in Europe treating over 40,000 patients every year. It is a centre of excellence, and the only NHS Trust to achieve the highest possible ranking in the Healthcare Commission’s Annual Health Check for the third year in a row. Since 2004, the hospital’s charity, The Royal Marsden Cancer Campaign, has helped raise over £43 million to build theatres, diagnostic centres, and drug development units. Prince William became President of The Royal Marsden in 2007, following a long royal connection with the hospital.

For more information, visit www.royalmarsden.nhs.uk

About Cancer Research UK

* Cancer Research UK is the world’s leading charity dedicated to beating cancer through research.

* The charity’s groundbreaking work into the prevention, diagnosis and treatment of cancer has helped save millions of lives. This work is funded entirely by the public.

* Cancer Research UK has been at the heart of the progress that has already seen survival rates double in the last thirty years.

* Cancer Research UK supports research into all aspects of cancer through the work of more than 4,800 scientists, doctors and nurses.

* Together with its partners and supporters, Cancer Research UK’s vision is to beat cancer.

For further information about Cancer Research UK’s work or to find out how to support the charity, please call 020 7121 6699 or visit www.cancerresearchuk.org

About Experimental Cancer Medicine Centre (ECMC)

Experimental Cancer Medicine Centre (ECMC) status has been awarded to 19 centres in the UK that are specialist centres conducting research into new cancer treatments. The aim is to bring together cancer doctors, research nurses and lab scientists to make clinical trials of new treatments quicker and easier. The ECMC initiative is funded by Cancer Research UK and the Departments of Health of England, Scotland, Wales and Northern Ireland. Together they are giving a total of £35 million pounds over five years to the 19 centres. The centres will use this money to run trials of new and experimental treatments. They will also analyse thousands of blood and tissue samples (biopsies) to help find out more about how treatments work and what happens to cancer cells.

Sources:

• Drug Benefits Patients with Inherited Ovarian Cancer, News Release, The Institute of Cancer Research, April 20, 2010.

• Fong PC, Yap TA, Boss DS, et. al. Poly(ADP)-Ribose Polymerase Inhibition: Frequent Durable Responses in BRCA Carrier Ovarian Cancer Correlating With Platinum-Free Interval. J Clin Oncol. 2010 Apr 20. [Epub ahead of print] PubMed PMID: 20406929.

Endocyte’s EC145 Produces Significant Anti-Tumor Activity In Advanced Stage Chemoresistant Ovarian Cancer Patients

Endocyte, Inc., … presented data from a Phase 2a clinical trial for EC145, … In 49 women with advanced-stage ovarian cancer, EC145 was shown to have anti-tumor activity in a significant percentage of participants in the trial. …[T]he overall disease control rate, defined as stable disease, partial or complete response to therapy, was 40.8 percent (20 of 49). … In the subgroup of patients who were EC20 “positive” and who had failed four or fewer prior therapies, the disease control rate was 75 percent (9 of 12) and two patients exhibited a RECIST partial response. …

Companion diagnostic images of ovarian cancer patients using folate-receptor targeted imaging agent (EC20-Tc99m). Patient on the top shows no targeting to tumor (negative profile). Patient on the bottom shows targeting to tumor (positive profile)(Photo: Endocyte, Inc.)

Endocyte, Inc., a cancer drug discovery and development company, presented data from a Phase 2a clinical trial for EC145, currently in development as a potential treatment for advanced ovarian cancer. Results were presented at the European Society of Gynaecologic Oncology (ESGO) meeting in Belgrade, Serbia last week. In 49 women with advanced-stage ovarian cancer, EC145 was shown to have anti-tumor activity in a significant percentage of participants in the trial.

The study participants had disease that was highly resistant to standard chemotherapy. Subjects had a median of four prior exposures to chemotherapy (with a range of 1 to 14), and 88 percent were diagnosed with “bulky disease,” defined as having a tumor volume of greater than five centimeters in diameter. However, in spite of this, the overall disease control rate, defined as stable disease, partial or complete response to therapy, was 40.8 percent (20 of 49).

Prior to the start of treatment with EC145, the women were scanned with 99mTc-EC20 [EC20], a molecular imaging agent that binds to folate receptors (FR) and is being developed by Endocyte as a companion diagnostic tool to identify patients whose tumors express FR, the molecular target for the EC145 therapy. When scanned with EC20, 76 percent of patients were found to be folate-receptor “positive.” In the subgroup of patients who were EC20 “positive” and who had failed four or fewer prior therapies, the disease control rate was 75 percent (9 of 12) and two patients exhibited a RECIST partial response. Across all patients, the drug was well tolerated with no grade 4 toxicities. The most common grade 3 toxicity was fatigue (8.2 percent).

According to Dr. Richard Messmann, Endocyte’s VP for medical affairs, “These preliminary results provide significant additional support for Endocyte’s technology platform and for the important role that Endocyte’s co-development of targeted therapeutics and companion diagnostics can play in cancer drug discovery. Based upon these promising results, EC145 is now being evaluated in our Phase 2b PRECEDENT study, an international randomized study of EC145 in combination with Doxil®/Caelyx® versus Doxil®/Caelyx® alone in women with platinum–resistant ovarian cancer.”

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’s clinical development of EC20 and EC145 is progressing with the recent completion of accrual for the Phase 2a trials in advanced ovarian and lung cancer. EC20 and EC145 are now being studied in an international Phase 2b trial of EC145 in combination with Doxil® for the treatment of women with platinum resistant ovarian cancer. Other clinical-stage products in the Endocyte pipeline include EC0225, a targeted combination of two potent anticancer drugs; BMS753493, a potent drug being developed in partnership with Bristol-Myers Squibb; EC0489, a targeted cancer drug; and EC17, a targeted immunotherapy agent. The company also has multiple product candidates in pre-clinical stage of development.

Information about the PRECEDENT study can be found at http://clinicaltrials.gov/ct2/show/NCT00722592.

Sources:

• Endocyte presents data on EC145 in treatment of ovarian cancer at the 16th annual meeting of the European Society of Gynaecologic Oncology (Adobe Reader PDF Document), News Release, Endocyte, Inc., October 21, 2009.

• A Randomized Phase II Trial Comparing EC145 and Pegylated Liposomal Doxorubicin (PLD/Doxil/Caelyx) in Combination, Versus PLD Alone, in Subjects With Platinum-Resistant Ovarian Cancer, NCT 00722592 Clinical Trial Summary, Clinicaltrials.gov.

A Weekly Combination of Topotecan & Docetaxel Produces Clinical Benefit In Heavily Pretreated Ovarian Cancer Patients

Recurrent and metastatic endometrial and ovarian cancers can be notoriously difficult to treat. … Physicians at the Albert Einstein College of Medicine of Yeshiva University showed that a combination of two chemotherapy drugs not only produced clinical benefit for such patients but were also well tolerated.  The results of this phase II study were published online in Gynecologic Oncology on March 21st. …[T]he researchers concluded that the combination of weekly topotecan and docetaxel has clinical benefit and is well tolerated in this heavily treated epithelial ovarian and uterine cancer patient population.  The researchers also noted that patients with platinum-resistant tumors had clinical benefit and should be considered for further study with this regimen. …

Recurrent and metastatic endometrial and ovarian cancers can be notoriously difficult to treat.  Both diseases are capable of  spreading to other organs and developing resistance to chemotherapy.  Typically, under this scenario, the patients have been heavily treated with chemotherapy and may not be able to endure additional treatment. Physicians at the Albert Einstein College of Medicine of Yeshiva University showed that a combination of two chemotherapy drugs not only produced clinical benefit for such patients but were also well tolerated.  The results of this phase II clinical study were published online in Gynecologic Oncology on March 21st.

Mark H. Einstein, M.D., M.S., Associate Professor of Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine of Yeshiva University

“Women with recurrent gynecologic cancers have often had multiple rounds of chemotherapy, which can cause tumor cells to develop resistance to these drugs,” says Mark H. Einstein, M.D., M.S., Associate Professor of Obstetrics & Gynecology and Women’s Health at Einstein, who headed the study. “This resistance can make it difficult for doctors to devise a treatment protocol that will impact the cancers while avoiding the often-severe side effects that certain chemotherapy drugs can cause, particularly when patients have already been heavily pretreated with other anti-cancer drugs.”Under the trial protocol, eligible patients with recurrent epithelial ovarian or uterine cancers were treated with weekly topotecan 3.5 mg/m(2) and docetaxel 30 mg/m(2) for 3 consecutive weeks. Cycles were repeated every 4 weeks for 6 cycles or until evidence of disease progression or unacceptable toxicity. Patient response was assessed under Response Evaluation Criteria In Solid Tumors (RECIST) or, when appropriate, Rustin’s Criteria.  The majority of patients had received 2 prior chemotherapy regimens (9 pts had received 1 previous regimen, 16 pts. had received 2, 1 pt. had received 3, and 1 pt. had received 4).  Of the twenty-seven patients registered, 24 were evaluable for response.  The results of the trial are set forth below.

• 86 cycles of chemotherapy were administered.
• There were three grade 4 (all neutropenia) and ten grade 3 toxicities.Six of the grade 3 toxicities were unrelated to treatment.
• There were 8 dose delays and 4 dose reductions.
• The overall response rate was 25%  (8% CR, 17% PR).
• The clinical benefit rate was 38% (8% CR+17% PR+13% SD).
• The median duration of response was 8.5 months (range 3-19 months).
• The median overall survival was 18.5 months (range 1.8-50.7 months.

Based upon the foregoing results, the researchers concluded that the combination of weekly topotecan and docetaxel has clinical benefit and is well tolerated in this heavily treated epithelial ovarian and uterine cancer patient population.  The researchers also noted that patients with platinum–resistant tumors had clinical benefit and should be considered for further study with this regimen.Compared with previous clinical trials, an unusually high proportion of these women had been heavily pretreated with chemotherapy─yet nearly 40 percent of them experienced clinical benefit. In addition, the overall survival with the drug combination (median survival of 18.5 months) was higher than in previous phase II studies that evaluated the drugs on an individual basis.  Finally, there were few and relatively mild side effects from the drug combination compared with toxicities observed in similar studies.

The effectiveness and safety outcomes of the trial are “promising enough to justify a larger clinical study of this drug combination for women with recurrent gynecologic cancers,” Dr. Einstein said.

Other researchers at Einstein involved in the trial were Divya Gupta, M.D., Ricky L. Owers, M.D., Mimi Kim, Sc.D., Dennis Yi-Shin Kuo, M.D., Gloria S. Huang, M.D., Shohreh Shahabi, M.D., and Gary L. Goldberg, M.D. Dr. Einstein’s research was funded, in part, by investigator-initiated grants from Sanofi-Aventis and GlaxoSmithKline Oncology for research-related trial costs.

Sources:

• Gupta D, Owers RL, Kim M, et. al. A phase II study of weekly topotecan and docetaxel in heavily treated patients with recurrent uterine and ovarian cancers. Gynecol Oncol. 2009 Mar 21. [Epub ahead of print].  PMID: 19307014.

• New Treatment Shows Promise Against Recurrent Gynecologic Cancers, Einstein News, Albert Einstein College of Medicine of Yeshiva University, April 21, 2009.

ProLindac Produces 66% Disease Stabilization In Heavily-Pretreated Patients Within Phase II Study High Dose Groups

“… ACCESS PHARMACEUTICALS, INC. … , announced today positive safety and efficacy results from its Phase 2 monotherapy clinical study of ProLindac(TM) in late-stage, heavily pretreated ovarian cancer patients. In this monotherapy study 66% of patients who received the highest dose achieved clinically meaningful disease stabilization according to RECIST [Response Evaluation Criteria in Solid Tumors] criteria. No patient in any dose group exhibited any signs of acute neurotoxicity, which is a major adverse side-effect of the approved DACH platinum, Eloxatin, and ProLindac was well tolerated overall. The maximum tolerated dose of ProLindac was established as well as the recommended dose levels for future combination studies. …”

“66% of evaluable heavily-pretreated patients in the high dose groups achieved disease stabilization. ProLindac was well tolerated overall.

DALLAS, March 5 /PRNewswire-FirstCall/ — ACCESS PHARMACEUTICALS, INC. (OTCBB: ACCP), announced today positive safety and efficacy results from its Phase 2 monotherapy clinical study of ProLindac(TM) in late-stage, heavily pretreated ovarian cancer patients. In this monotherapy study 66% of patients who received the highest dose achieved clinically meaningful disease stabilization according to RECIST [Response Evaluation Criteria in Solid Tumors] criteria. No patient in any dose group exhibited any signs of acute neurotoxicity, which is a major adverse side-effect of the approved DACH platinum, Eloxatin, and ProLindac was well tolerated overall. The maximum tolerated dose of ProLindac was established as well as the recommended dose levels for future combination studies.

‘We are very pleased with these results. ProLindac was well tolerated in an absolute sense and relative to commercially-available platinum therapies. We saw significant DACH platinum activity and efficacy in patients at the highest dose levels which is very encouraging given that this study involved monotherapy in a heavily pretreated patient population that typically only respond to an aggressive drug combination,’ commented Dr. David Nowotnik, Access’ Senior Vice President R&D. ‘The DACH platinum activity level seen benchmarked favorably with published studies of monotherapy oxaliplatin in similar but less heavily pre-treated patient populations. Having achieved the recommended dose for future combination studies, we look forward to moving ahead in the clinic ourselves and with our regional partners.’

This 26 patient Phase 2 study explored 3 different dose levels and 2 dosing regimens of ProLindac as a monotherapy treatment for advanced ovarian cancer, to provide data on the monotherapy anticancer activity and safety of ProLindac. Of patients eligible for evaluation according to standard RECIST criteria, clinically-meaningful disease stabilization was achieved in 42% of all patients, and 66% of all patients in the higher dose groups. Sustained and significant reductions in Ca-125, the established specific serum marker for ovarian cancer, were also observed in several patients.

‘We are delighted that the results from this study support our belief that ProLindac is an active platinum agent with a favorable side effect profile,’ stated Jeffrey B. Davis, Access’ President & CEO. ‘These data provide us with a strong incentive to continue the clinical development of ProLindac. As previously announced, we are currently planning a number of combination trials, looking at combining ProLindac with other cancer agents, such as taxol and gemcitabine, in multiple solid tumor indications including colorectal and ovarian.’

Access has previously announced that it has licensed ProLindac to Jiangsu Aosaikang Pharmaceutical Co., Ltd. (“ASK”) for the Greater China Region and to JCOM, Ltd for South Korea. Under these agreements both of these partners will be conducting Phase 2 combination studies with ProLindac in specific tumor types at their expense based on these results. Access is currently in discussion with potential partners for development and commercialization of ProLindac in additional territories.

About ProLindac(TM):

ProLindac is a novel DACH platinum prodrug which has been shown to be active in a wide variety of solid tumors in both preclinical models and in human trials. Access believes that ProLindac’s unique molecular design potentially could eliminate some of the toxic side effects seen in the currently marketed DACH platinum, Eloxatin, which has sales in excess of $2 billion.

About Access:

Access Pharmaceuticals, Inc. is an emerging biopharmaceutical company that develops and commercializes propriety products for the treatment and supportive care of cancer patients. Access’ products include ProLindac(TM), currently in Phase 2 clinical testing of patients with ovarian cancer, and MuGard(TM) for the management of patients with mucositis. The company also has other advanced drug delivery technologies including Cobalamin(TM)-mediated targeted delivery and oral drug delivery, its proprietary nanopolymer delivery technology based on the natural vitamin B12 uptake mechanism; Angiolix(R), a humanized monoclonal antibody which acts as an anti-angiogenesis factor and is targeted to breast cancer; Prodrax(R), a non-toxic prodrug which is activated in the hypoxic zones of solid tumors to kill cancer cells; Alchemix, a chemotherapeutic agent that combines multiple modes of action to overcome drug resistance. Access is also developing Phenylbutyrate (“PB”), an HDAC inhibitor and differentiating agent currently a Phase 2 clinical candidate. Access recently announced the acquisition of MacroChem Corporation. This acquisition provides Access with three additional late-stage product candidates. Pexiganan, a novel topical anti-infective for the treatment of diabetic foot infection, has already completed two Phase 3 trials. EcoNail is a topically applied econazole lacquer based on Access’ proprietary SEPA polymer technology, for the treatment of onychomycosis, a condition commonly known as nail fungus. Thiarabine is a new generation nucleoside analog which has demonstrated both pre-clinical and clinical activity in certain cancers. For additional information on Access Pharmaceuticals, please visit our website at www.accesspharma.com.

This press release contains certain statements that are forward-looking within the meaning of Section 27a of the Securities Act of 1933, as amended, and that involve risks and uncertainties. These statements include those relating to: clinical trial plans and timelines and clinical results for ProLindac and product candidates acquired in the MacroChem transaction, our ability to execute licensing agreements in the future, Access’ plans to continue and initiate clinical trials, the value of its products in the market, its ability to achieve clinical and commercial success and its ability to successfully develop marketed products. These statements are subject to numerous risks, including but not limited Access’ need to obtain additional financing in order to continue the clinical trial and operations and to the risks detailed in Access’ Annual Reports on Form 10-K and other reports filed by Access with the Securities and Exchange Commission.”

Quoted Source:  66% of evaluable heavily-pretreated patients in the high dose groups achieved disease stabilization. ProLindac was well tolerated, Press Release, lAccess Pharmaceuticals, Inc., March 5, 2009.