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

Dr Peter Zage from MD Anderson in Houston TX gave a presentation at the Children’s Neuroblastoma Cancer Foundation (CNCF) conference Saturday July 10, 2010 on the 3F8 randomized trial:

A Study of MAb-3F8 Plus Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Versus 13-cis-Retinoic Acid (RA) Plus GM-CSF in Primary Refractory Neuroblastoma Patients (NCT00969722)

This trial is funded by United Therapeutics, who recently retained rights to 3F8. This trial is currently open in 15 locations and began accruing in 2009, with a planned accrual of 40 children 18 months to 13 years old. United Therapeutics has also entered into an agreement with Memorial Sloan-Kettering Cancer Center (MSKCC) to exclusively license certain rights to the  antibody 8H9, used for brain relapse of certain tumors, including neuroblastoma.

This phase II randomized trial is a “registration trial” with the goal of gaining FDA approval for 3F8. The objective is to compare response rates in children with primary refractory disease to either 3F8 + GM-CSF or cis-retinoic acid (Accutane) + GM-CSF. Children who do not respond after two cycles may cross over to the other arm for the next two cycles. The children who have primary refractory disease–defined in this case as bone marrow or bone disease after induction or transplant, but no soft tissue disease– represent roughly 10% of all NB high-risk cases, or about 30 per year in the US, according to Dr Zage.  Children are not eligible if they have soft tissue disease, brain metastases, and they cannot have radiation during this trial.

A phase III (non-randomized) registration trial COG-ANBL0931 also opened in January 2010 and will accrue 105 patients: “Monoclonal Antibody Ch14.18, Sargramostim, Aldesleukin, and Isotretinoin After Autologous Stem Cell Transplant in Treating Patients With Neuroblastoma.”  The purpose of this trial is to gain FDA approval for the ch14.18 antibody.  According to the NIH clinical trials listing it is currently open in 29 locations. This trial also allows residual disease (primary refractory after stem cell transplant) by MIBG scan, CT scan, MRI, bone marrow aspiration, or biopsy.

The landmark phase III study COG-ANBL0032 that revealed efficacy for ch14.18 with IL2 and GM-CSF upon early analysis is also still open in 155 locations, with randomization ceased so all enrolled will receive ch14.18 (with GM-CSF and IL-2). [1]  The trial will accrue a total of 423. This trial also allows primary refractory disease described by the protocol.

Dr Zage gave a brief history of the development, production, and use of monoclonal antibodies in neuroblastoma. [2]

This is the first time 3F8 antibody has been available at an institution other than Memorial-Sloan Kettering in New York or Queen Mary Hospital in Hong Kong.

References

1. J Clin Oncol 27:15s, 2009 (suppl; abstr 10067z)

2. Cancer Biol Ther. 2009 May;8(10):874-82. Epub 2009 May 9. Review. [fulltext]

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….

SEL 10 (p. 136) “Persistence of disease in long-term survivors of high-risk neuroblastoma. Analysis of ENSG5 cooperative trial”

Presented by Lucas Moreno of UK

A report on long-term survivors of high-risk neuroblastoma with persistent (refractory) disease was presented at ANR by Lucas Moreno on Tuesday as one of the selected posters in the clinical session.

This is the first time persistence of disease in long-term survivors has ever been studied.

The European trial ENSG5 randomized 262 children from 1990 to 1999 (and an additional 177 children were not randomized) to two different induction regimens: same chemotherapy and dose, but different time schedule consisting of 21-day chemotherapy schedule (OPEC/OJEC) versus 10-day schedule (rapid COJEC), then all went on to autologous transplant. This study reports on children who did NOT reach remission at the end of induction and were alive 5 years after diagnosis.

In this study, 62 children with refractory neuroblastoma at the end of induction were alive at five years after diagnosis. Two groups were defined, those with persistent metastatic disease (group 1) and those with persistent primary disease (group 2).

Of those with persistent metastatic disease after 5 years, 2 had bone marrow disease up to 9 years after diagnosis, and 6 had persistent MIBG positive skeletal (bone) disease up to 16 years after diagnosis.

Of those with persistent primary site disease, 7 still had disease up to 16 years after diagnosis.

The group reports that “some patients can be long-term survivors despite persistent disease.”

I think this is encouraging news for refractory neuroblastoma.

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.

MIBG non-avid at diagnosis = better outcome?

POC39 (p. 211) Neuroblastomas with non-avid I-123 MIBG scan and negative urinary catecholamine secretion: A single institute’s experience

PL30 (p. 102) Analysis of MIBG scoring as a prognostic indicator in patients with stage 4 neuroblastoma. A Children’s Oncology Group (A3973) report

Dui Yen Soh, Sylvain Baruchel, and Meredith Irwin at Sick Kids in Toronto reviewed 148 children diagnosed between 1999 and 2009 (all stages and risk groups). They confirmed the interesting observation that non-avid MIBG and negative urine catecholamines at diagnosis are associated with low stage and favorable outcome. Of the MIBG non-avid children, 5 were low risk, 3 were intermediate risk, and 3 were high risk. These numbers are too small to confirm better outcome for MIBG non-avid (at diagnosis) high-risk, but Greg Yanik (University of Michigan) mentioned an interesting observation of better survival for those high-risk children who are MIBG non-avid at diagnosis (of n= 280 enrolled in COG-A3973, 29 were MIBG negative at diagnosis) in his presentation on a new scoring method to stratify patients at the end of induction. He presented at ASCO 2010 Chicago, ANR 2010 Stockholm, and will present again next week at the CNCF Parent Conference in Chicago. More on Dr Yanik’s presentation to come.[1]

Any ideas why MIBG non-avid survival might be better? No answers proposed yet.

Tandem transplant in Korea

POC40 (p. 211) Efficacy of tandem high-dose chemotherapy and autologous stem cell rescue in patients with high-risk Neuroblastoma: a preliminary report of NB 2004 study at Samsung Medical Center (Republic of Korea)

Ki Woong Sung and group reported at ANR results of 47 children diagnosed 2004 to 2008 and enrolled on NB 2004.  Of the 44 patients that went through tandem transplant, 36 (82%) remain event-free after median follow-up of 3 years (14-72 months) with probability of 5 year overall and event-free survival determined to be 68% ± 20%  and 67% ±  16%, with no treatment-related deaths.  Another report from the same center in 2007 gave results of 52 children diagnosed from 1997 to 2005 (44 had second SCT with TBI).  That study had 15% treatment-related deaths, 33 (75%) were event-free with median follow-up of 53 months (19-117 mo) from diagnosis.[2]  A retrospective study of 141 patients enrolled 2000 to 2005 from the Korean Society of Pediatric Hematology-Oncology (KSPHO) published May 2010 also showed improved 5-year event-free survival in the tandem group over the single transplant group (51 ±12% vs. 31 ±12%, P=0.030).[3]

Korean single and tandem retrospective study 1997 to 2005

These studies show strikingly comparable results to a larger COG pilot (97 children diagnosed 1994 to 2002) reported in 2006, which was the rationale for the current frontline single-versus-tandem trial in the COG.[4]

Germans report no difference in outcome using cis-retinoic acid (Accutane) or ch14.18/CHO antibody

POC37 (p. 210) Comparison of anti-GD2-antibody ch14.18 and 13-cis-retinoic acid as consolidation therapy for high-risk neuroblastoma. Results of the German NB97 trial

Thorsten Simon and group from GPOH (German pediatric oncology study group) reported retrospectively on two similar—but not randomized groups—showing that the outcome was not statistically different with almost 8 years of median follow-up for 74 children who received only ch14.18 antibody (1997-2002) and 75 children who received only cis-retinoic acid (2002-2004). The 3-year event-free survival from diagnosis was 53% ± 6% and 51% ± 6% (p=.209) respectively. While this result is interesting with regard to single-agent efficacy, it is very important to note that none of the children received both antibodies and cis-retinoic acid, nor were the children given cytokines (IL2 or GM-CSF) with the antibody as in the current COG trial. The GPOH previously reported no advantage to ch14.18 (no cytokines) over oral maintenance chemotherapy.[5]  But at ANR 2008 (Japan) the GPOH group reported no late relapses in the ch14.18 group. At this 2010 ANR they also said they have now seen a difference in the retrospective study after 10 years with statistically significant improved survival for the ch14.18 group. During the Special Clinical Session at ANR on Tuesday Dr Thorsten Simon said the GPOH will be revisiting the question of ch14.18/CHO given the remarkable survival advantage shown in the COG study report from Mar 2009.[6]  They are now considering using subcutaneous administration of IL2 to reduce toxicity (as is SIOP in the UK and the rest of Europe), and exploring the use of other agents such as IL15 or lenalidomide with the antibody.

References

1. J Clin Oncol 28:15s, 2010 (suppl; abstr 9516)
2. Bone Marrow Transplant. 2007 Jul;40(1):37-45. Epub 2007 Apr 30. PMID 17468771
3. J Korean Med Sci. 2010 May;25(5):691-7. Epub 2010 Apr 21. PMID 20436703 [full text]
4. J Clin Oncol. 2006 Jun 20;24(18):2891-6. PMID: 16782928 [full text]
5. J Clin Oncol. 2004 Sep 1;22(17):3549-57. PMID: 15337804
6. J Clin Oncol 27:15s, 2009 (suppl; abstr 10067z)