Dr Michael Burke from the University of Minnesota is the Principal Investigator of the Seneca Valley Virus trial COG-ADVL0911:

“Seneca Valley Virus-001 in Treating Young Patients With Relapsed or Refractory Neuroblastoma, Rhabdomyosarcoma, or Rare Tumors With Neuroendocrine Features”

Dr Burke gave a presentation on this trial at the CNCF parent conference July 10, 2010.

By early July, this Phase I trial had enrolled three children (two with NB) since March 2010, with a planned accrual of 34 children, and is currently open at:

• Alabama ~ UAB Comprehensive Cancer Center
• California ~ Children’s Hospital of Orange County
• Illinois ~ Children’s Memorial Hospital – Chicago
• Indiana ~ Indiana University Melvin and Bren Simon Cancer Center
• Michigan ~ C.S. Mott Children’s Hospital at University of Michigan Medical Center
• Minnesota ~ Masonic Cancer Center at University of Minnesota
• Missouri ~ Siteman Cancer Center at Barnes-Jewish Hospital – Saint Louis
• Ohio ~ Cincinnati Children’s Hospital Medical Center
• Pennsylvania ~ Children’s Hospital of Pittsburgh
• Texas ~ Baylor University Medical Center – Houston
• Washington ~ Children’s Hospital and Regional Medical Center – Seattle

Seneca Valley Virus, or NTX-010, is the first picornavirus (small RNA virus) to be evaluated as an anticancer agent. This virus is very small–about one-fourth the size of adenovirus so can penetrate tumor cells and replicate rapidly. It is highly selective for cancer cells with neuroendocrine features and does not harm normal cells, humans lack pre-existing neutralizing antibodies (ie prior exposure in humans is very rare), does not cause disease in humans or animals, and not transmitted among people or animals. It was accidentally discovered in a laboratory growth medium, and thought to be naturally occurring in pigs. [1]

NTX-010 was tested first in adults, with a trial that opened in 10 locations in 2006 and enrolled 42 adults with tumors with neuroendocrine features. This trial was sponsored by Neotropix and the results of this phase I study were presented at the 2009 ASCO meeting:

NTX-010 is the first picornavirus to be evaluated as an anticancer therapeutic. A single IV dose of 10¹¹ vp/kg of NTX-010 is safe, has predictable viral kinetics, and shows promising activity against neuroendocrine tumors. [2]

A Phase II randomized study for small cell lung cancer has recently opened and will enroll 99 adults.[3]

Neotropix scientists published a summary of the preclinical work with Seneca Valley Virus on cell lines and mice in 2007, and the image below shows the response of SCLC small-cell lung cancer tumors in mice to a single infusion of the virus.

The authors concluded on p. 1632:

The life cycle of SVV-001 is very rapid and is completed within 12 hours, thus allowing for rapid spread to neighboring tumor cells and several rounds of virus replication before the development of an immune response. SVV-001 is a simple single-stranded RNA virus and therefore does not require an intermediate DNA step during replication, so there is no possibility for insertion mutagenesis of viral RNA into the host genome. Moreover, the genomes of picornaviruses carry no oncogenes that may induce tumors in animals. Finally, SVV-001 replicates in the mouse, which is a widely accepted relevant model in which to study toxicity and efficacy.

Nonpathogenicity in humans and animal species and stability of the viral genome in vitro and in vivo are two other desirable properties of oncolytic viruses. SVV-001 is not linked to any disease condition in pigs, the natural host of the virus (Hales LM, Jones BJ, Knowles NJ, Landgraf JG, Swenson SL, Skele KL, et al.: unpublished data). We found that systemic administration of the virus into immune-competent and immune-deficient mice was well tolerated and caused no toxicity. Moreover, to evaluate the ability of SVV-001 to adapt to replicate in nonpermissive cells, the virus was passaged intentionally three times in nonpermissive cell lines A549, H460, and Hep3B, and no virus was produced, suggesting that the virus did not change its tropism (data not shown). In addition, no antibody escape mutants of SVV-001 were produced in PER.C6 cells when SVV-001 was grown with media containing anti-SVV mouse hyper immune serum (data not shown). These data suggest that the genome of SVV-001 is stable.

Our study has several potential limitations. Although the in vivo efficacy data reported here were generated using immune-deficient athymic mice, it is unknown whether immune responses in cancer patients would limit the effectiveness of SVV-001 in patients and prevent repeat administration, if it was necessary. In addition, studies were done using subcutaneous tumor models using well-defined cell lines and, as such, may not simulate patients with metastases. Immune-competent and metastasis models are currently being explored to address these limitations.[4]

The virus is toxic to embryonic cell lines, so the first adult study required surgical sterilization of females who were of childbearing age.[5]

The preclinical pediatric testing was just published (Aug 2010) “Initial testing of the replication competent Seneca Valley virus (NTX-010) by the pediatric preclinical testing program” (p. 299):

NTX-010 shows high-level activity against selected cell lines and xenografts from the PPTP’s in vitro and in vivo panels. A single dose of NTX-010 induced complete responses in 8 of 10 of the rhabdomyosarcoma and neuroblastoma xenografts evaluated, including all 4 alveolar rhabdomyosarcoma xenografts studied. Of note is the similar sensitivity to NTX-010 in Rh30 xenografts (established at diagnosis) and Rh30R xenografts (established at patient relapse), suggesting NTX-010 has therapeutic utility in both chemosensitive and chemorefractory disease.[6]

Considering this trial for a child with relapsed or refractory neuroblastoma

Phase I studies are safety studies, so evidence of efficacy has not been established. Since phase I agents are usually tried in adults first, it is encouraging if responses are seen, but of course adults have different tumors (in the phase I adults with carcinoid tumors showed responses[2]). All of this information indicate some agents hold more promise than others. The attractive thing about this study is the lack of toxicity, and the short time commitment to the study (infusion of virus, then test blood and stool for 28 days or until virus clears).  A child with a small tumor burden, or a child with stable disease may be a good candidate for this trial since the risk of progression while on study may be minimal. As always, discussing treatment options with a trusted pediatric oncologist is essential.

References

1.  NTX-010 A Novel Mechanism Anti-Cancer Agent in Phase I/II Clinical Development (2007 Neotropix summary)

2. Rudin CM, Senzer N, Stephenson J, et al. Phase I study of intravenous Seneca Valley virus (NTX-010), a replication competent oncolytic virus, in patients with neuroendocrine (NE) cancers. J Clin Oncol 2009;27: abstract 4629.

3. Seneca Valley Virus-001 After Chemotherapy in Treating Patients With Extensive-Stage Small Cell Lung Cancer; NCT01017601

4. J Natl Cancer Inst. 2007 Nov 7;99(21):1623-33. Epub 2007 Oct 30. [fulltext]

5. Safety Study of Seneca Valley Virus in Patients With Solid Tumors With Neuroendocrine Features;  NCT00314925

6. Pediatr Blood Cancer. 2010 Aug;55(2):295-303. PMID 20582972

http://online.wsj.com/article/BT-CO-20100714-708425.html

DOW JONES NEWSWIRES

Keryx Biopharmaceuticals Inc. (KERX) said the U.S. Food and Drug Administration has given orphan-drug designation to perifosine, a treatment for cancer including neuroblastoma, or cancer of the nervous system in infants.

Shares of the biopharmaceutical company jumped 13% to $4.04 in recent trading, while U.S.-traded shares of Keryx’s Canadian partner Aeterna Zentaris Inc. (AEZ.T, AEZS) were recently up 10% to $1.20.

The designation was announced three months after the drug received fast-track status, which authorizes an expedited review for drugs that treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs.

“The Orphan Drug designation is an important component of our development plan for perifosine in neuroblastoma, an indication where no FDA-approved therapies currently exist,” said Chief Executive Ron Bentsur.

The Orphan Drug Act provides incentives to create therapies for so-called orphan diseases–those that affect fewer than 200,000 Americans. There are about 7,000 such maladies, most of them serious, that have few or no drugs to treat them. Getting an orphan-drug designation opens the door to incentives once the FDA approves a medicine for sale in the U.S., including seven years’ marketing exclusivity and tax breaks.

Bentsur said the company is exploring the next steps for the development, which “we hope, ultimately, could provide a new treatment option for children and infants” suffering with the illnesses.

Perifosine also is in Phase 3 clinical trial for treating refractory advanced colon cancer and multiple myeloma, as well as in Phase 1 and Phase 2 trials for several other tumor types.

-By Jodi Xu, Dow Jones Newswires; 212-416-3037; jodi.xu@dowjones.com

Perifosine is currently offered to neuroblastoma patients (relapsed/refractory pediatric solid tumors) in two trials at Memorial-Sloan Kettering:

http://clinicaltrials.gov/ct2/show/NCT01049841

http://clinicaltrials.gov/ct2/show/NCT00776867

From AP:

Perifosine also has orphan drug status as a colorectal cancer treatment, and the FDA has said it will conduct a faster-than-normal review of the drug in both colorectal cancer and multiple myeloma.

Keryx has the rights to market perifosine in North America. Canadian drugmaker Aeterna Zentaris holds the rights in all other countries except South Korea.

Recap of presentations

I have so much more to report on ASCO and ANR (coming soon), but should share information about this conference first. This year’s conference was exceptional.  The presentations covered a wide range of important topics, and I am convinced the 130 parents in attendance walked away with essential information for their families. This conference is extraordinary in that no rare disease organization provides such a quality forum for education by top experts in the field—for free, including hotel, meals, children’s program, bereavement session, and even transportation costs for those with the greatest need.  I have met attendees from Australia, Turkey, and other nations. This concept is unprecedented, and CNCF president Pat Tallungan works incredibly hard at the challenge to raise funds for this conference every year. CNCF accepts and appreciates donations for this conference (see www.nbhope.org ).

Dr Yanik in particular expressed his amazement at the difficult and insightful questions posed by the parents. I was struck by the contrast I had just seen at the ASCO and ANR meetings. Attendees come in and out during presentations, and often no questions are asked so no discussion ensues. I was amazed at how many researchers travel great distances to give five minute presentations, or just show a poster. The presenters at this conference spoke for at least 30 minutes and appreciated a very attentive audience. The impact is significant in that parents learn first hand from experts about this disease, and are exposed to information about new treatments which can facilitate quick enrollment on trials.

Speakers and topics were:

Susan Cohn ~ Overview of Neuroblastoma and Intermediate Risk Study

Yael Mosse ~  ALK inhibitor, Aurora A Kinase inhibitor, and ABT-751 Update

Giselle Sholler ~  Update on NMTRC Trials

Patrick Reynolds ~ Adult Oncology Connection/Update on Fenretinide trial

Shakeel Modak ~   3F8, NK Cell Therapy, and 8H9 Update

Sandeep Soni ~  Reduced Intensity Allogeneic Transplant

Kate Matthay ~   Overview of NANT trials

Peter Zage ~  3F8/Accutane Randomized Trial (national)

Greg Yanik ~  MIBG Scoring/Ultratrace Trials

Michael Burke ~  Oncolytic Virus Trial

Melissa Alderfer ~   Post Traumatic Stress Syndrome

David Salsberg ~  Neuropsych/learning issues facing NB Children

A few presentations will be covered in each post.

Overview of neuroblastoma and intermediate risk study update

Dr Sue Cohn gave a great overview on neuroblastoma and an update on the current intermediate risk study ANBL0531 (see http://clinicaltrials.gov/ct2/show/NCT00499616 ). This study opened in 2007, is enrolling at 180 locations, and will accrue 395 children. Intermediate risk is a challenging group to design studies for. The numbers are small, with approximately 10-20% of all neuroblastomas diagnosed as intermediate risk. This means there are roughly 100 intermediate risk children diagnosed each year in the US. The past and current studies are complex, with multiple treatment arms depending on tumor characteristics and response to therapy. This study includes 2, 4, or 8 cycles of outpatient (medium dose) chemotherapy, and cis-retinoic acid (Accutane) for some children. The goal is to accurately assign children to the right treatment arm and see if reducing therapy for some children will result in the same overall high survival seen in previous studies.

ALK inhibitor, Aurora A Kinase inhibitor, and ABT-751 updates

Dr Yael Mosse spoke about the research at CHOP (Children’s Hospital of Philadelphia) on ALK mutation and the remarkable speed in which a trial (ADVL0912) was opened to treat children with a drug already available for the mutation in lung cancer. The drug PF-02341066 now has a name, crizotinib. So far 5 children with NB with ALK aberration have been enrolled, and 5 with other diseases.  Dr Mosse shared some of the same information presented at both ASCO and ANR (see previous post on ALK).

The aurora A kinase inhibitor MLN8237 trial COG-ADVL0812 is closed now that the phase I is complete. The data is under review to determine if the drug is active against neuroblastoma for those who enrolled (11 NB children) on the phase I portion of the trial.  If so, the phase II trial will open for neuroblastoma only. In mice, striking synergy is seen with this inhibitor when combined with irinotecan and temozolomide. This combination is planned for an upcoming new NANT (New Approaches to Neuroblastoma Therapy) trial N09-03 directed by Steven DuBois.

A phase II trial of ABT-751 ran from 2007 to 2009 and accrued 91 children. The response data will be released at the fall COG (Children’s Oncology Group) meeting. Right now compassionate access is open at CHOP for second remission.

INRG Task Force

In 1988 an international task force was formed to standardize the risk group classification for neuroblastoma. The reason this is so important is because international studies could not be compared to each other with different patient cohorts. One “high risk” study might actually include children considered to be intermediate risk by another group, and the outcomes reported may consequently look “better.”

Today there are 64 investigators in the INRG task force which includes North America, Australia, Europe, and Japan. A consensus for a pre-treatment risk assignment has been accomplished, which includes image-defined risk factors (IDRFs) for staging. This believed to be more reproducible with radiologists.

A database of 8800 children diagnosed between 1990 and 2002 was used to characterize the new risk assignment scheme. In all of these children, the EFS was 63% ± 1% for all risk groups. The percentage of children in each risk group for the entire database breaks down to:

• 28% were very low risk
• 26% were low risk
• 9% were intermediate risk
• 36% were high risk

So far there have been many studies and reports using this data set.  Any investigator is invited to submit a bid for the use of the database analysis.

The most significant changes in risk assignment from this work is using IDRFs and including 11q status.

The challenge now is to incorporate and analyze approximately 4000 more children diagnosed since 2004 and added to the database.  This brings the total to over 16,000. New data items included are gender, ethnicity, therapy, and other causes of death.

A web-based interactive INRG database network has been proposed, and the goal is to collect biological data, phenotype, clinical outcome, and have tumor samples available for further analysis. A question for the future: will clinical features be abandoned and only genetic features used to classify risk assignment? This could allow for tweaking frontline therapy for children who have genetic aberrations predicting poor response to a particular therapy.

Clearly, this ambitious project will continue to offer a rich source of data to better predict outcomes and required therapy for children with neuroblastoma.

References:

Criteria for evaluation of disease extent by (123)I-metaiodobenzylguanidine scans in neuroblastoma: a report for the International Neuroblastoma Risk Group (INRG) Task Force. Matthay KK, Shulkin B, Ladenstein R, Michon J, Giammarile F, Lewington V, Pearson AD, Cohn SL. Br J Cancer. 2010 Apr 27;102(9):1319-26. Review.PMID: 20424613

International consensus for neuroblastoma molecular diagnostics: report from the International Neuroblastoma Risk Group (INRG) Biology Committee. Ambros PF, Ambros IM, Brodeur GM, Haber M, Khan J, Nakagawara A, Schleiermacher G, Speleman F, Spitz R, London WB, Cohn SL, Pearson AD, Maris JM. Br J Cancer. 2009 May 5;100(9):1471-82.PMID: 19401703

Consensus criteria for sensitive detection of minimal neuroblastoma cells in bone marrow, blood and stem cell preparations by immunocytology and QRT-PCR: recommendations by the International Neuroblastoma Risk Group Task Force. Beiske K, Burchill SA, Cheung IY, Hiyama E, Seeger RC, Cohn SL, Pearson AD, Matthay KK; International neuroblastoma Risk Group Task Force. Br J Cancer. 2009 May 19;100(10):1627-37. Epub 2009 Apr 28.PMID: 19401690

The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report. Monclair T, Brodeur GM, Ambros PF, Brisse HJ, Cecchetto G, Holmes K, Kaneko M, London WB, Matthay KK, Nuchtern JG, von Schweinitz D, Simon T, Cohn SL, Pearson AD; INRG Task Force. J Clin Oncol. 2009 Jan 10;27(2):298-303. Epub 2008 Dec 1.PMID: 19047290

History of ANR: Advances in Neuroblastoma Research

See photos posted on the ANR site!  http://www.anr2010.com/photos/5166/Page.aspx

Dr Audrey Evans initiated this meeting in 1974, and interestingly, this was the same year she helped found the first Ronald McDonald House in Philadelphia. Approximately 50 researchers and clinicians participated in that first ANR meeting. There was one abstract submitted on genetics/genomics that year.

This meeting has 600+ registrants from 37 countries who submitted 500+ abstracts. Over 200 abstracts are on genetics or genomics. This is also the largest pediatric oncology meeting that Sweden has ever hosted. There are 4 Nobel prize winners participating here in the “home” of the prize.

This year is also the 200th anniversary of the prestigious Karolinska Institute, founded as a training course for military surgeons in 1810 and now one of the premiere medical research institutions in the world.

Update on ALK mutations and implications for treatment

The first day offered an update course on neuroblastoma as well as the welcome ceremonies. A significant focus was on genome wide association studies which describe the association of mutations with incidence of neuroblastoma, as well as potential prognostic information, cell origin,  and new targets. The technology is rapidly expanding to produce more data, and the cost is falling. Eventually the most expensive part will be the data handling. This technology is extremely important for the future of NB diagnosis and treatment. The landmark discoveries of the ALK mutation (and previously known PHOX2b mutation) from Dr Maris’ lab has provided strong evidence that neuroblastoma is not associated with environmental factors, but rather a “perfect storm” of genetic mutations. Since some of these mutations have functional implications, they can serve as targets for treatment, as in the case of the ALK inhibitor. As the mutations are further described, it may be possible to more accurately identify those intermediate risk cases that require more treatment, and the ultra-high risk cases that are likely to fail front- line therapy, allowing for new treatment strategies for that group.

Dr Yael Mosse presented the clinical relevance of ALK mutations, and elucidated the significance of hereditary features, target potential, and future possibilities. At this point they have found in familial NB cases ~80% have ALK mutations and ~10% have PHOX2B mutations. A variety of other genes will likely describe the remaining 10%.

Out of 1148 NB cases including all risk categories, 7.3% were found to have ALK mutation. But in older children (10 years old or older at diagnosis) the proportion is higher at 17%. To date over 20 ALK mutations have been discovered, but there are three “hot spots” and of those, R1275Q (~42%) and F1174L (~17%) are the most common.

In today’s plenary session Yael Mosse discussed “Exploitation of ALK as a therapeutic target in neuroblastoma” and explained that they found 11.5% of MYCN amplified tumors have ALK mutations, as well as 8.8% of all high risk.

The most significant and surprising issue is that after this mutation was discovered in NB, a drug happened to be already available to target this mutation (previously found in lung cancer). To date several NB children with ALK mutation have been enrolled on the trial and while it is too early to guess at the potential for responses, it is encouraging to know there is already an antibody suggested for use in overcoming any possible acquired resistance.

A humble offering

A news source for parents about the advances in neuroblastoma research is envisioned here. My goal is to highlight interesting published research, bring attention to clinical trial openings, and report on presentations from oncology meetings. Like all “reporters” I do have a bias though, described in the About page.

There is so much I don’t know that I admit even suggesting such a source of information is very intimidating. But I would like to try. I am hoping astute readers will keep me accurate and on top of things.

Check back here for reports on the Chicago ASCO 2010 meeting June 4 – 8 (see interesting abstracts below) and the ANR 2010 meeting June 21 – 24 in Stockholm, Sweden. I was granted an ASCO Patient Advocate scholarship to travel to Chicago for the ASCO meeting in part due to volunteer efforts working on the Parent Handbook for CNCF, and my generous mother is paying for the trip to Stockholm to attend the ANR meeting.

I heartily welcome your corrections, criticisms, and comments.

High-risk neuroblastoma is a difficult disease and controversies continue, important questions remain unanswered, and too many children still die in spite of so many dedicated researchers who have spent their careers working toward improving survival rates. Even though I have lost my own son to neuroblastoma, I am encouraged to see the survival rate significantly improve in my own lifetime—in the 18+ years since my son was diagnosed. So I am a believer in research, and have seen with my own eyes that progress—though excruciatingly slow—is being accomplished.

If you are interested in being notified of posts here on neuroblastoma news, consider subscribing to the RSS feed to be notified of all the updates.

A sampling of some interesting abstracts from ASCO 2010:

• 9532 Phase I trial of lestaurtinib for children with refractory neuroblastoma (NB): A New Approach to Neuroblastoma Therapy (NANT) Consortium Study. Jane E. Minturn
• 9562 Reduced intensity conditioning regimen and allogeneic stem cell transplantation from related or unrelated HLA identical donor in high risk neuroblastoma. Arcangelo Prete
• 9563 Tandem stem cell transplantation as consolidation therapy for high risk neuroblastoma: The Childrens Healthcare of Atlanta experience. Muna Qayed
• 9529 A pediatric phase I trial and pharmacokinetic study of MLN8237, an oral selective small molecule inhibitor of aurora a kinase: A Children’s Oncology Group Phase I Consortium study. Yael P. Mosse
• 9516 MIBG scoring as a prognostic indicator in patients with stage IV neuroblastoma: A COG study. Gregory A Yanik
• 9517 Racial and ethnic disparities in disease presentation and survival among children with neuroblastoma (NBL): A Children’s Oncology Group (COG) study. Susan Lerner Cohn, MD
• 9518 Clinical and biological features predictive of survival after relapse of neuroblastoma: A study from the International Neuroblastoma (NB) Risk Group (INRG) Database. Wendy B. London, PhD
• Discussion: Prognostic Variables in Neuroblastoma Andrew Pearson, MD, FRCP

If you go to ASCO abstracts you can search or browse the list of abstracts. If you have questions for the presenters, please post your questions in “comments” below.

More coming soon,

Donna Ludwinski

This work is licensed under a Creative Commons Attribution 3.0 Unported License.