New Approaches to Neuroblastoma Therapy (NANT) consortium offers trials for relapsed and refractory neuroblastoma

Dr Kate Matthay spoke at the Children’s Neuroblastoma Cancer Foundation CNCF parent conference in Chicago July 10, 2010, detailing the status of several NANT trials. She mentioned that these trials open and close periodically, so contacting the principal investigator is the best way for an interested parent to get the most current information about the trial.

NANT is a consortium of researchers and investigators that now includes 15 institutions in North America, lead by Dr Kate Matthay (UCSF) and Dr Judith Villablanca (CHLA). NANT was formed in 2000 as a result of National Cancer Institute (NCI) award for a proposal submitted by Dr Robert Seeger.

Current member institutions are:

• C.S. Mott Children’s Hospital, University of Michigan – Ann Arbor, MI
• Children’s Healthcare of Atlanta (CHOA) – Atlanta, Georgia
• Childrens Hospital and Regional Medical Center – Seattle, WA
• Children’s Hospital Boston, Dana-Farber Cancer Institute – Boston, MA
• Childrens Hospital Los Angeles – Los Angeles, CA
• Children’s Hospital Medical Center – Cincinnati, OH
• Childrens Hospital of Philadelphia – Philadelphia, PA
• Cook Children’s Health Care System – Fort Worth, TX
• Hospital for Sick Children – Toronto, Ontario Canada
• Lucile Packard Children’s Hospital – Palo Alto, CA
• Morgan Stanley Children’s Hospital of New York-Presbyterian (Columbia) – New York, NY
• Texas Childrens Cancer Center, Baylor College of Medicine – Houston, TX
• University of California, San Francisco – San Francisco, CA
• University of Chicago Comer Children’s Hospital – Chicago, IL
• University of Wisconsin Comprehensive Cancer Center – Madison, WI

It is significant to note that the core NANT investigators are the ones who conducted the research in the 1990s that established the current global standard of care for neuroblastoma, including the use of stem cell transplant and cis-retinoic acid. The NANT trials that are planned and conducted now for relapsed and refractory neuroblastoma provide the rationale for better future frontline therapies.

Open trials are:

• N99-02: Modulation of Intensive Melphalan (L-PAM) by Buthionine Sulfoximine (BSO) (NSC-326321) and Autologous Stem Cell Support For Recurrent High-Risk Neuroblastoma (NCI 68).
• N2004-03: A Phase I study of intravenous fenretinide in pediatric neuroblastoma.
• N2004-04: A Phase I Study of Fenretinide Lym-X-Sorb^TM (LXS) Oral Powder in Patients with Recurrent or Resistant Neuroblastoma (IND # 68,254)
• N2004-06: Irinotecan and Vincristine with ¹³¹I-MIBG Therapy for Resistant/Relapsed High-Risk Neuroblastoma
• N2007-01: A Phase 2a Study of Ultratrace^TM Iobenguane I 131 in Patients with Relapsed/Refractory High-Risk Neuroblastoma
• N2007-02: A Phase I Study Of Bevacizumab With Bolus And Metronomic Cyclophosphamide And Zoledronic Acid In Children With Recurrent Or Refractory Neuroblastoma
• N2007-03: Vorinostat and MIBG in Recurrent or Resistant Neuroblastoma Patients

Dr Matthay presented an update on NANT drug trials, and Dr Greg Yanik spoke about trials using MIBG radiotherapy.

CEP-701

In her presentation Dr Matthay noted that new NANT trials will focus on the use of approved agents to avoid the unfortunate circumstance when a company decides to drop a new drug because of lack of efficacy in other cancers. This is what happened to CEP-701, a Trk inhibitor, even though it was granted orphan drug status in 2006. In 10 dose levels given to 47 patients no MTD (maximum tolerated dose) was reached. There were 2 partial responses and 9 stable disease in the neuroblastoma relapse/refractory children.

Oral fenretinide, IV fenretinide

A new phase I trial using the oral powder formulation of fenretinide is open for relapsed or refractory children, and those in a second remission are also be eligible. An arm will include the use of the antifungal drug ketoconazole to help raise the plasma levels of fenretinide. A phase I trial using IV fenretinide has also opened, and a video consent explains the trial. The results of the first phase I oral powder was presented at ASCO in 2009, showing 4 complete responses and 6 stable disease in 30 patients.[1]

BSO/Melphalan

As of July this phase I trial accrued 18 patients with dose levels 20-64 mg/m2. The next dose level is 80 mg/m2. Total to be accrued is 30. A video consent explains this study in more detail.

Zometa + Cytoxan

The phase I has been completed and responses are being evaluated. A new phase I has opened that uses intravenous and oral Cytoxan in combination with zometa and Avastin (a humanized antibody that targets VEGF-A or vascular endothelial growth factor A). Since December 2009 6 patients have enrolled.

Vorinostat (SAHA) and cis-retinoic acid

SAHA, approved for lymphoma, is a histone deacetylase inhibitor (HDACi) and slows neuroblastoma growth. It has shown preclinical synergy with cis-retinoic acid.

Aurora A kinase inhibitor

Aurora A kinase inhibitor has shown increased effectiveness against MYCN-amplified cell lines, and NANT is planning to combine this inhibitor with irinotecan and temozolomide in a new trial.

Emphasis on older patients

Neuroblastoma normally affects very young children, but the needs of the small population of adolescents and young adults also require special attention. This is becoming a new focus for NANT, first demonstrated by the raised age limits for NANT trials to 30. Some NANT investigators see a large number of teens and young adults with neuroblastoma.

References

1. J Clin Oncol 27:15s, 2009 (suppl; abstr 10009)

New drug combinations, personalized medicine proof-of-concept demonstrated, parents involved

Dr Giselle Sholler is the chair for the The Neuroblastoma and Medulloblastoma Translational Research Consortium (NMTRC) based at Vermont Children’s Hospital at Fletcher Allen Heath Care,  University of Vermont College of Medicine. Dr Sholler presented an update on trials offered by the NMTRC to parents at the CNCF conference in Chicago July 9, 2010.

The consortium includes 11 hospitals with locations in Burlington VT, Hartford CT, Bethesda MD (NCI), Charlotte NC, Charleston SC, Orlando FL, Grand Rapids MI, St Louis MO, Houston TX, San Diego CA, and Portland OR.

The trials currently open are:

.

Dr Sholler described the personalized medicine research she has initiated. A feasibility trial was recently completed, proving that the technology and logistics are in place to generate a treatment plan based on FDA approved drugs found to be effective against a particular tumor within 14 days after a biopsy is taken from the child’s tumor. A follow-on trial is in the planning. A phase I trial of nifurtimox has also been completed, and the resulting abstract was submitted to ASCO in 2008.[1]

Trials for relapsed or refractory neuroblastoma have been conceived, opened, completed, and manuscripts submitted for publication with remarkable speed due to parent involvement and support of the research. All trials were funded by parent-founded charities including the NB Alliance, Solving Kids Cancer, and others.

John London of Solving Kids Cancer tells the remarkable story of how parent involvement can speed the launch of a trial:

.

DFMO time line: 690 days

Another dramatic story reveals the parent involvement in the launch of the DFMO trial.

April 17th 2008 ~

Dr. Bachmann’s research at AACR meeting (American Association for Cancer Research) attracts the attention of two parent advocates (Neil of MagicWater and Scott of Solving Kids Cancer).  They introduce Andre to Giselle

March 14th 2009 ~

Parent advocates raise money and send a grant to Andre  for preclinical work for the DFMO study

March 8th 2010 ~

First patient enrolls on DFMO study in Vermont

Parent advocates ~

• Introduced both doctors to get this project started
• Raised the the money to fund the pre-clinical work
• Raised the money to fund the phase I study.

From the day the poster was seen at AACR until the day the first patient enrolled in the study took just 1 year 10 months and 19 days — 690 days in total.  The story was recently highlighted in a news article.[2]

The accomplishments of the joint efforts of the parents, researchers, and ultimately the formation of the NMTRC is remarkable when comparisons are made to how currently clinical trials are conceived, funded, and filled. The Institute of Medicine published a report in April 2010 that details some of the chronic challenges and need for rapid improvement to the current system: A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program

The insufficient funding for clinical trials, slow launch, and high proportion of trials that never finish accruing is reported.[3]

References

1.  J Clin Oncol 26: 2008. A phase I study of nifurtimox in patients with relapsed/refractory neuroblastoma. (May 20 suppl; abstr 2561)

2. http://www.staradvertiser.com/news/hawaiinews/20100626_old_drug_has_new_promise_to_fight_cancer.html

3. IOM (Institute of Medicine). 2010. A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program. Washington, DC: The National Academies Press.

New donor transplant trial open for relapsed or refractory neuroblastoma

Dr Sandeep Soni spoke at CNCF (Children’s Neuroblastoma Cancer Foundation) Parent Conference in Chicago July 10, 2010. Dr Soni is a member of the Pediatric Blood and Marrow Transplant program at Nationwide Children’s Hospital and an Assistant Professor of Clinical Pediatrics at Ohio State University College of Medicine in Columbus.

Dr Soni presented the novel allogeneic transplant trial now open for relapsed and refractory neuroblastoma in Columbus:

Fludarabine, Busulfan, and Antithymocyte Globulin Followed By Donor Stem Cell Transplant in Treating Young Patients With High-Risk Neuroblastoma That Has Relapsed or Not Responded to Treatment

This is a phase II study with a planned accrual of 25 children 1 to 18 years old. The goals of this study are to determine the feasibility of this protocol using a reduced-intensity conditioning regimen, engraftment, transplant-related mortality, and development of acute and chronic graft-vs-host disease. Secondary goals are to learn about the role of natural killer (NK) cells as effectors of graft-vs-tumor effect in these patients, and the role of killer immunoglobulin-like receptor (KIR) mismatches in the donor-recipient pairs on the outcomes of these patients.

Dr Soni explained that the role of NK cells are much better understood today, and recently the potential importance of mismatch in KIR is being explored. He also noted that depleting T-cells reduces the risk of graft-versus-host disease (GVHD) whereas in leukemia T-cells are required for graft-versus-tumor effect. In neuroblastoma, there is evidence that NK cells are more important for graft-versus-tumor. Modified T-cells have also been explored by investigators at CHOP (Children’s Hospital of Philadelphia).

History of allogeneic transplants in neuroblastoma

While allogeniec transplants have been used much less frequently in solid tumors, research continues to explore the potential for graft-versus-tumor effect seen in liquid tumors, primarily leukemia.

In February 2010 Dr Stephen Grupp and colleagues from CHOP published a review of “Autologous and allogeneic cellular therapies for high-risk pediatric solid tumors” including the work on modified T-cells:

Chimeric immunoreceptor (CIR). The CIR is an engineered T-cell receptor (TCR) comprised of an antibody-like extracellular domain fused to an intracellular, functional TCR domain. The CIR was first described by Eshhar in 1993, and has been developed and extended over the last 15 years. The first report of CIR-modified T cells specific for neuroblastoma was published in 2001, and research since that time has led to an early-phase clinical trial published in 2007. To redirect T cells safely against a tumor, the CIR must target a tumor-specific antigen that is minimally expressed on normal tissues.

These trials, and others examining the use of CIR-modified T cells in other malignancies, have shown the feasibility of using genetic modification to redirect autologous T cells against malignancies. As technologies improve, and the experience with CIRs increases, harnessing a patient’s own immune system in the treatment for high-risk pediatric cancers will likely become a promising new therapeutic frontier.[1]

Dr Grupp also published a review of transplants for neuroblastoma in January 2008 (fulltext is available):

Finally, as an alternative to autologous SCT, some groups have studied allogeneic SCT in an attempt to harness an immunotherapeutic effect. A graft-versus-malignancy effect has been well described in allogeneic transplant for liquid tumors, but has not yet been convincingly demonstrated in the setting of solid tumors. Although initial studies of conventional allogeneic SCT for high-risk neuroblastoma failed to show clear benefit, the advent of nonmyeloablative conditioning regimens has provided hope that reduced intensity conditioning will reduce TRM and allow for the detection of a therapeutic benefit. As a result, institutions are beginning to explore the possibility of an allogeneic effect in neuroblastoma. At this point, this is still an investigational and unusual application of allogeneic transplant, with 38 such cases reported to the EBMT from 1991 to 2002. Some recent case reports have provided preliminary evidence for a graft-versus-tumor effect in neuroblastoma. A 2003 case report described a patient who underwent allogeneic SCT after a relapse. Although the patient received further chemotherapy after the allogeneic transplant and response could not be correlated to GVHD, the patient did enter a CR sustained for at least 4 years. In a more recent report, development of GVHD correlated temporally with disease response in a patient who had undergone a reduced-intensity allogeneic bone marrow transplant. In a similar regard, the group at Columbia has been testing reduced intensity allogeneic cord blood transplants in patients with a wide range of diagnoses, including neuroblastoma.[2]

The use of allogeneic transplants may hold promise in neuroblastoma, with progress being made in reducing the risk of acute graft-versus-host disease and reduced treatment-related mortality with reduced intensity regimens. Families who are interested in pursuing this treatment choice for a child with relapsed or refractory neuroblastoma should be aware that some therapies available in current clinical trials prohibit prior donor transplants as part of the eligibility, but many current clinical trials do allow prior allogeneic transplant.

1. Pediatr Clin North Am. 2010 Feb;57(1):47-66. Autologous and allogeneic cellular therapies for high-risk pediatric solid tumors. PMID: 20307711

2. Bone Marrow Transplant. 2008 January; 41(2): 159–165. Stem cell transplantation for neuroblastoma. PMCID: PMC2892221 [fulltext]

Allogeneic Tumor Cell Vaccination With Oral Metronomic Cytoxan in Patients With High-Risk Neuroblastoma (ATOMIC)

Researchers at Texas Children’s Hospital/Center for Cell and Gene Therapy, Baylor College of Medicine will begin accruing patients soon on a new phase I/II trial using an allogeneic neuroblastoma vaccine with low-dose chemotherapy. Drs Chrystal Louis and Malcom Brenner are the principal investigators. The trial will accrue 30 children up to age 21.

Eight injections of the vaccine will be given over 20 weeks, along with low-dose cyclophosphamide (Cytoxan). The vaccine is created from neuroblastoma cell lines modified to enhance immune response.

The rationale for adding low-dose cyclophosphamide is two-fold:

• a well-documented anti-angiogenesis effect in many tumors
• it decreases regulatory T-cells (or suppressor T-cells) which can suppress the immune system and aid tumor cells in “hiding.”

For more background on vaccine trials for neuroblastoma see prior article posted here.

Three new oncolytic virus trials to treat neuroblastoma: vaccinia (JX-594), herpes simplex (HSV1716), and Newcastle Disease virus

Vaccinia JX-594

A Phase I, Open-Label, Dose Escalation Study of JX-594 (Vaccinia GM-CSF/Thymidine Kinase-Deactivated Virus) Administered by Intratumoral Injection in Pediatric Patients With Unresectable Refractory Solid Tumors

A phase I study using intratumoral injection of modified vaccinia virus derived from the smallpox virus is scheduled to begin accruing children 2 to 21 years old with refractory solid tumors, including neuroblastoma. The principal investigator is Dr Timothy Cripe and the trial is sponsored by Jennerex Biotherapeutics and Solving Kids Cancer. Locations are Cincinnati Children’s Hospital Medical Center in Ohio and Texas Children’s Hospital in Houston, and a  total of 15 will be enrolled. The Jennerex site shows a diagram of their oncolytic viruses in the pipeline (click on image):

Recent use of this virus is detailed in a 2009 review from Leeds in the UK:

JX-594 is a replication-competent Wyeth strain vaccinia virus that was genetically modified to inactive the endogenous thymidine kinase gene and to express human GM-CSF and LacZ genes. In development by Jennerex Inc and licensee Green Cross Corp, the modified virus is a novel therapy for treatment-refractive metastatic malignancies from various sites of origin. Targeted oncolytic virotherapy has demonstrated promise in preclinical studies, and more than ten viral species have subsequently entered clinical trials. JX-594 has been modified to augment the intrinsic targeting and oncolytic potential of the vaccinia virus and to enhance antitumor immunity by the expression of the GM-CSF transgene in situ. In vitro and in vivo animal studies have demonstrated the replication specificity of JX-594 for cancer cell lines and tumors, and the restriction of serum human GM-CSF expression to tumor-bearing animals, resulting in significantly reduced tumor burden and an increase in median survival. In phase I trials, JX-594 was well tolerated, with mild systemic toxicity reported. In a phase I trial in seven patients with melanoma, one partial response and one complete response after surgery were observed. In another phase I trial in patients with hepatic carcinoma, three out of ten evaluable patients had a partial response and six had stable disease; the MTD was also established. A phase II trial in patients (expected n = 30) with unresectable primary hepatocellular carcinoma was recruiting at the time of publication, with completion expected in March 2010, and a phase III trial in patients with hepatocellular carcinoma was planned for the second half of 2010. Further clinical investigations are needed to explore the potential of this agent as a single therapy and as part of multimodal treatment regimens.[1]

This oncolytic virus has been used to treat liver and other cancers, as reported in Lancet in this 2008 study from Korea. Details from the abstract:

JX-594 is a targeted oncolytic poxvirus designed to selectively replicate in and destroy cancer cells with cell-cycle abnormalities and epidermal growth factor receptor (EGFR)-ras pathway activation. Direct oncolysis plus granulocyte-macrophage colony-stimulating factor (GM-CSF) expression also stimulates shutdown of tumour vasculature and antitumoral immunity. We aimed to assess intratumoral injection of JX-594 in patients with refractory primary or metastatic liver cancer.

Between Jan 4, 2006, and July 4, 2007, 14 patients with histologically confirmed refractory primary or metastatic liver tumours (up to 10.9 cm total diameter) that were amenable to image-guided intratumoral injections were enrolled into this non-comparative, open-label, phase I dose-escalation trial. Patients received one of four doses of intratumoral JX-594 every 3 weeks at Dong-A University Hospital (Busan, South Korea). The primary aims were to ascertain the maximum-tolerated dose (MTD) and safety of JX-594 treatment.

Of 22 patients with liver tumours who were assessed for eligibility, eight patients did not meet inclusion criteria. Therefore, 14 patients, including those with hepatocellular, colorectal, melanoma, and lung cancer, were enrolled. Patients were heavily pretreated and had large tumours. Patients received a mean of 3.4 cycles of JX-594. All patients experienced grade I-III flu-like symptoms, and four had transient grade I-III dose-related thrombocytopenia. Grade III hyperbilirubinaemia was dose-limiting in both patients at the highest dose. JX-594 replication-dependent dissemination in blood was shown, with resultant infection of non-injected tumour sites. GM-CSF expression resulted in grade I-III increases in neutrophil counts in four of six patients at the MTD. Tumour responses were shown in injected and non-injected tumours. Ten patients were radiographically evaluable for objective responses. Three patients had partial response, six had stable disease, and one had progressive disease.

Intratumoral injection of JX-594 into primary or metastatic liver tumours was generally well-tolerated. Direct hyperbilirubinaemia was the dose-limiting toxicity. Safety was acceptable in the context of JX-594 replication, GM-CSF expression, systemic dissemination, and JX-594 had anti-tumoral effects against several refractory carcinomas. Phase II trials are now underway. [2]

This photo from Jennerex shows the needle developed for intratumoral injection.

Herpes Simplex Virus-1 Mutant HSV1716

A Phase I Dose Escalation Study of Intratumoral Herpes Simplex Virus-1 Mutant HSV1716 in Patients With Refractory Non-Central Nervous System (Non-CNS) Solid Tumors

This study opened in March 2010 and will accrue 18 young patients aged 13 to 30. This trial is also supported by Solving Kids Cancer lead by Dr Tim Cripe and open at Cincinnati Children’s. This particular oncolytic virus has been tried in squamous cell carcinomas, melanoma, and brain tumors.  A mouse study published by researchers from Mass General in 2008 revealed neuroblastoma tumor reduction with a related oncolytic virus. [4]

Newcastle Disease Virus (NDV)

Clinical Application of Intravenous New Castle Disease Virus – HUJ Oncolytic Virus in the Treatment of Advanced Glioblastoma Multiforme, Soft and Bone Sarcomas and Neuroblastoma Patients, Resistant to Conventional Anti- Cancer Modalities

This phase I/II study for recurrent or refractory solid tumors will begin accruing September 2010 at Hadassah Medical Organization in Jerusalem, Israel.  This trial uses the Newcastle Disease Virus systemically rather than intratumorally, and a total of 30 patients will receive daily doses of the oncolytic virus at least 5 days a week for a minimum of a year or until disease progression. For more information on Newcastle Disease Virus the University of Minnesota provides a helpful brief review of the use of NDV as an oncolytic virus.

References

1.  Curr Opin Investig Drugs. 2009 Dec;10(12):1372-82. JX-594, a targeted oncolytic poxvirus for the treatment of cancer. PMID: 19943208

2.  Lancet Oncol. 2008 Jun;9(6):533-42. Epub 2008 May 19. Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial. PMID 18495536

3. Recent Pat CNS Drug Discov. 2009 Jan;4(1):1-13.  Advances in oncolytic virus therapy for glioma. [full text]

4.  Clin Cancer Res. 2008 Dec 1;14(23):7711-6. Combination Immunotherapy for Tumors via Sequential Intratumoral Injections of Oncolytic Herpes Simplex Virus 1 and Immature Dendritic Cells. [full text]

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

SEL11 (p 136) “High dose MIBG and haploidentical stem cell transplantation with cell therapy in therapy resistant neuroblastoma”

Janek Toporski presented (5 minutes) for the Swedish group in the “Clinical” session for selected posters at ANR Tuesday June 22 .

This was a very small study with only 10 patients. The purpose was to evaluate the feasibility of high dose MIBG radiation therapy followed by reduced-intensity conditioning and T-cell depleted haploidentical peripheral blood stem cells, donated from a parent.

Six relapsed children (4 had prior autologous stem cell transplant) and 4 refractory children were enrolled in the study. The children received high-dose MIBG on day -20, then fludarabine, thiotepa, and melphalan from day -8 to -1.  On day 0 haploidentical cells from a parent were infused, along with donor (n=7) or third party (n=3) mesenchymal stem cells. A single dose of rituximab was given on day +1. Seven children received donor lymphocyte infusion.

The abstract states:

Analysis of immunologic recovery showed fast reappearance of potentially immunocompetent natural killer (NK) and T cells, which might have acted as effector cells responsible for the graft-versus-tumor effect.

Treatment was well tolerated, with no treatment-related deaths. Two children had acute graft-versus-host disease (aGVHD), and five were treated successfully for aGVHD that developed after donor lymphocyte infusion.

Eight children are alive and 4 remain free of disease 53, 52, 8 and 5 months after transplant, and 4 are alive with stable/slowly progressive disease 52, 17, 5, and 4 months post transplant. Two children died of progressive disease 5 and 12 months after transplant.

Clinical and biological features predictive of survival after relapse of neuroblastoma: A study from the International Neuroblastoma Risk Group (INRG) Database.

Citation: J Clin Oncol 28:15s, 2010 (suppl; abstr 9518)

Wendy London is the Lead Statistician for neuroblastoma research for the Children’s Oncology Group (COG), and Data Center Statistics Committee Chair for the International Neuroblastoma Risk Group (INRG) project and has recently joined the team at Boston Children’s/Dana-Farber.

Dr London spoke on this topic at both ASCO 2010 (15 minute presentation on Monday for the Pediatric Oncology II session) and at ANR 2010 (25 minute presentation during the Monday Neuroblastoma Update Course)  and another 15 minute presentation on this same topic was given by by Victoria Castel on Thursday during the clinical plenary session. Three presentations–two at ANR!  This alone gives you an idea of the importance of this study–the largest ever done on this topic.

As I was preparing to report on this study, I saw that OncologySTAT.com (an excellent source of trustworthy oncology information by Elsevier, a world-leading publisher of medical information)  just released a report of their own. I highly encourage you to read their article.

Of 8800 INRG patients, 2266 experienced a “non-death first event.”

The INRG database includes all risk groups diagnosed from 1990 to 2002 in North America, Europe, Japan, and Australia.

Events are defined as relapse, progression, or second malignancy. Death as a first event was not included in this study.

Although prognostic factors are used to stratify treatment at diagnosis, no one has previously analyzed what factors are predictive of outcome post-relapse.  This study posed the question: is time-to-relapse a factor affecting outcome? Are there any other factors affecting outcome?

Of all the children who had events, median follow-up was 3.6 years (1 day to 13.7 years) and the characteristics of these children were:

• 73% ≥ 18 months old
• 72% were stage 4
• 33% were MYCN amplified

The median time to relapse for the 2266 children who had events was 13.2 months with a range of 1 day to 11.4 years. An anecdotal aside, I happen to know a fellow who relapsed 13.5 years after high-risk diagnosis, obviously not included in this data although he was diagnosed at Boston Children’s in 1991. He survived almost 5 years post-relapse.

The overall survival at 5 years after first event (all risk groups) is 20% ± 1%.

Those who had a first event in less than 1 year from diagnosis (n=1012) had approximately 25% overall survival and those who had first event after 1 year (n=1254) had about 10% overall survival.

When looking at those who relapsed before (n=2081) and after (n=184) 3 years, the gap closes at close to 20% survival.

The risk of death differs over time.

Time-to-first-event, age >18 mo, stage 4, MYCN amplified, diploidy, high MKI, undifferentiated grade, and 1p aberration were significantly predictive of death after relapse (p<0.0001), but not 11q aberration. Compared to children who had a first event more than 6 mo from diagnosis, those who relapsed 6-<18 mo from diagnosis had increased risk of death, while relapses ≥18 mo from diagnosis had decreased risk of death. Shorter time- to-first-event was not independently predictive of death after adjustment for undifferentiated grade, high MKI, MYCN amplification, or diploidy.

In a survival tree regression analysis that adjusted for time-to-relapse, disease stage was identified as the most highly significant variable for survival post relapse. Stage 4 patients (n=1578)  had a 5-year survival of 8% ± 1%, compared with 52% ± 3%  for those who were stage 1, 2, 3, or 4S (n=622).

Three groups were defined as salvageable for relapse treatment:

• stage 4, with nonamplified MYCN, and less than 18 months of age.
• stage 1, 2, 3, or 4S with MYCN amplification.
• stage 1, 2, 3, or 4S with nonamplified MYCN and undifferentiated grade histology.

Patients who had stage 4 disease and MYCN amplification had a 5-year survival of 4% ± 1% , compared with 12% ± 2% for stage 4 patients with nonamplified MYCN.

This information can help stratify children for relapse therapies.

NOTE: None of this data included how the children were treated for relapse. I am hoping this work will eventually lead to a rational plan for relapse therapy.

My take on this report? There WERE survivors in every group of relapse children….

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.