LONDON — November 7, 2011 — A new clinical trial testing ¹⁷⁷Lutetium-DOTATATE (LuDO) for relapsed neuroblastoma is due to start in the UK next year. The UK is the first country to plan a clinical trial for this new molecular radiotherapy treatment for treating relapsed high-risk neuroblastoma, although it is already used to treat rare adult neuro-endocrine cancers.

Neuroblastoma is the most common ‘solid’ cancer diagnosed in babies and children. It accounts for around 15 percent of cancer deaths in children and around 100 children are diagnosed every year in the UK. Of these 100, approximately half will have high risk disease and the long term survival rate for these patients is less than 40 percent.

A pilot study that was given funding by the Neuroblastoma Children’s Cancer Alliance, a charity that helps children and families affected by neuroblastoma, has investigated a new radiotherapy treatment that targets a particular receptor on neuroblastoma cells. Dr Jenny Gains presented the promising results of the of this pilot study at the Neuroblastoma Children’s Cancer Alliance parents’ meeting July 23, 2011 in London.

Following the success of the pilot study, a three-year Phase II clinical trial is expected to start in the UK in early 2012. During the trial, the new radiotherapy treatment will be offered to all UK patients who meet the eligibility criteria – primarily patients who have relapsed neuroblastoma. Although it is a UK-wide trial, the treatment itself will take place at the Royal Marsden and University College Hospital (UCH) in London.

The pilot was carried out by a team of researchers, including Dr Mark Gaze, Consultant Clinical Oncologist at UCH and Great Ormond Street and Dr Jenny Gains, Clinical Research Fellow at UCH . Six children were offered the new radiotherapy treatment, of which five were found to have stable or improved disease following treatment.

Currently the targeted radiotherapy treatment offered to neuroblastoma patients is a compound called ¹³¹I-mIBG. However, this treatment has various limitations as some neuroblastoma cells do not have the receptors which this compound attaches to, so will not be killed by this treatment. Also ¹³¹I-mIBG can have serious side effects for neuroblastoma patients as it is toxic to bone marrow, which is already depleted in neuroblastoma patients.

The new treatment uses a compound called ¹⁷⁷Lutetium-DOTATATE, or LuDO for short, which attaches to a different receptor that many neuroblastoma cells have on their surface. It is hoped that LuDO will be as effective in killing neuroblastoma cells as ¹³¹I-mIBG, but have fewer and less severe side effects. It is possible that it will be offered in combination with other radiotherapy drugs in the future.

“This pilot study, offers new hope for the families of children affected by the disease,” said Dr Gaze. “If the trial proves that the new drug is safe and effective, it may become part of the standard treatment for neuroblastoma patients receiving radiotherapy treatment. It is likely to be offered with other drugs in the future – combining drugs is likely to be more effective as more cells will be killed.”

Notes:

For more information, contact Alison Moy, Chief Executive of the Neuroblastoma Alliance UK, on 020 8203 0100, 07580 964 709 or alison@nballiance.org.uk; or Ingrid Marson on 01707 328 511 or ingrid@acornpr.org.uk

The clinical trial has been approved by National Cancer Research Institute, Clinical and Translational Radiotherapy Research Working Group (CTRad) and Clinical Trials Advisory Committee (CTAC), although it is still awaiting approval from the Ethics Committee, Medicines and Healthcare products Regulatory Agency and Administration of Radioactive Substances Advisory Committee (ARSAC).

The pilot was funded by the JACK appeal of the Neuroblastoma Alliance. The JACK appeal was set up by Yvonne and Richard Brown to raise money for their son Jack’s neuroblastoma treatment. Jack sadly died in May 2009.

More information on the pilot study are available in: J. E. Gains, J. B. Bomanji, N. L. Fersht, T. Sullivan, D. D’Souza, K. P. Sullivan, M. Aldridge, W. Waddington, M. N. Gaze. 177Lu-DOTATATE Molecular Radiotherapy for Childhood Neuroblastoma. Journal of Nuclear Medicine, 2011; DOI: 10.2967/jnumed.110.085100

The Neuroblastoma Alliance UK works to help children and families affected by neuroblastoma through providing financial assistance for treatment and to fund leading clinical research in recognised cancer centres.

The Neuroblastoma Children’s Cancer Alliance is a registered charity (no. 1135601), based at 3-4 Sentinel Square, Brent Street, London, NW4 2EL.

Editor’s note on this note-worthy conversation: Mooki Salzman is a mother of a child diagnosed with stage 4 neuroblastoma. Mooki’s brother, Dr Yoram Unguru, is a pediatric oncologist and happens to be a leader in the field in bioethics with regard to pediatric oncology research.

They were invited to present on opposite sides of the question:

Are randomized clinical trials ethical for children with cancer? 

Presented by Mooki Salzman, mom to Toby Pannone, at the annual meeting of the American Society of Bioethics and Humanities in Minneapolis, Minnesota on October 14, 2011. Mooki debated the ethics of phase III clinical trials in pediatric cancer research with her brother Dr Yoram Unguru, Attending Physician/Faculty Member, Division of Pediatric Hematology/Oncology at Herman and Walter Samuelson Children’s Hospital at Sinai, and Associate Faculty, Johns Hopkins Berman Institute of Bioethics.  Dr. Unguru argued to defend the ethical use of phase III clinical trials in pediatric oncology clinical research. He serves as an ethics committee and IRB member and is a member of the Children’s Oncology Group, Committee on Bioethics, and the American Academy of Pediatrics section on Bioethics.

Mooki extends special thanks to her brother Dr Yoram Unguru, Donna Ludwinski, Carie Carter, Pat Lacey and most of all to John London, who started it all with his heartwrenching words and compelling argument.

Who Shall Live and Who Shall Die?

It’s a provocative question, one with Old Testament roots and an attendant seriousness. It’s a question with wide application in ethical discourse.

And although it may be uncomfortable and perhaps sensationalistic, it is a question that we cannot ignore. Certainly in the world of pediatric cancer, “who shall live and who shall die” has very real meaning. For me, since my son Toby was diagnosed with stage IV neuroblastoma, the question “who shall live and who shall die” has become a constant backdrop to daily life.

Neuroblastoma is the most common solid tumor cancer in infants. The median age at diagnosis is 2 years old. At diagnosis, more than half of neuroblastoma patients have disease that has already metastasized to other parts of the body. Children with high-risk disease undergo aggressive high-dose chemotherapy, radiation, surgery, stem cell transplant, differentiation therapy, and antibody therapy. Even after this intense treatment, only 30% survive. If a patient relapses or stops responding to therapy, neuroblastoma is usually viewed as a terminal illness with less than a 10% chance of survival. For those that do survive, the late effects are significant: hearing loss, neurocognitive problems, sterility and secondary cancers.

Since my son was diagnosed in 2007 I have watched helplessly as child after child has died an often agonizing and prolonged death. Neuroblastoma parents describe the death of their children like this: “I’m literally seeing disease erupt all over his body, extraordinarily painful bone mets, fractured bones from disease, organ failure, breathing difficulty, seizures, paralysis, blindness.“ These families face the unthinkable.

In the blink of an eye, we have said goodbye to Liam and Evan, to Lucas, Penelope, Max, Erik, Sam, Erin and so many others that I could burn through my allotted time by reading their names. I think about these children every day. I try not to question their deaths, out of fear that I won’t be able to find my way back to sanity. So instead I remember their vibrancy, their beauty, their quintessential child-ness.

But in the dark hours, I ask why did Liam die? Why does Toby live? It is a terrible question. The randomness howls. And the world spins madly on.

*****

In March 2009, the Children’s Oncology Group released a statement halting the phase 3 trial of ANBL0032, a randomized study of chimeric antibody 14.18 in high risk neuroblastoma. Preliminary results of the phase 3 trial showed a significant increase in survival among those patients who received the antibody, as compared with those who didn’t. Not only was the trial stopped prematurely, but COG also stated that ch14.18 immunotherapy should become a standard part of upfront nb treatment.

The neuroblastoma world is not used to hearing good news. As a reminder, children diagnosed with high-risk disease have a 2 in 3 chance of DYING. So a trial that shows a 20% increase in survival is almost beyond belief.

This is what Dr. John Maris, Chief of the Oncology Division at Children’s Hospital of Philadelphia said about ANBL0032:

“The last clinical trial that showed a new treatment improving outcome in neuroblastoma was published in 1999, which means the study ended in about 1996. That was the one that showed that transplant helped and that Accutane helped, so it’s been a long time.”

But elation quickly turned to unease, as it became clear that ANBL0032 was a randomized trial that started accruing patients almost 8 years earlier, in October 2001. By the time of its halting, over 200 children had been accrued, ½ randomized to receive the antibody and the other ½ not.

Toby was not part of this trial. As a patient at Memorial Sloan-Kettering he, like every child treated there for the last 20 years, received a mouse-derived antibody as part of upfront treatment.

Before I go any further, I want to point out that I am a believer in research. Research has allowed my child to receive the best available treatment and it is important to understand that most neuroblastoma families gratefully sign their children up for trials, because the prognosis otherwise is so poor. In fact, virtually all children treated for neuroblastoma, both high and low-risk, are enrolled on a clinical trial. The cancer is ruthless and research offers a chance at new agents and therapies. I cannot relay how many times parents confess that they just need to keep their children alive until the next trial opens. String together enough trials and maybe you can buy another year or two for your child.

So back to ANBL0032: I, like many others, found myself asking if it was truly necessary to do a phase 3 randomized trial when the phase 1 and 2 data demonstrated that antibody was substantially better than anything we had seen before in the treatment of high-risk neuroblastoma.

More than 30 preclinical and early phase studies on this antibody were completed before ANBL0032 even started. If children were knowingly randomized to the non-antibody arm that was thought to be inferior, the trial was unethical. And more importantly, lives, children’s lives, were sacrificed.

Listen to John London, whose daughter Penelope was randomized to the non-antibody arm:

“I have to say how unethical it is to have designed a trial where 1) the average age of diagnosis is 2; 2) the survival rate for high risk is around 30%; and 3) the survival rate for relapse is below 10% AND then take a potentially promising agent and DISALLOW 50% of these children to receive it. All in the name of “perfect science”. My daughter was one of the children who was turned away. Would it have saved her? Who knows? But I sure would have liked the chance to see. Can you imagine if one of the scientists/researchers/clinicians/protocol designers for ANBL0032 had a child with high risk NB who was denied a potentially promising agent? Randomized studies in High Risk Stage 4 NB sacrifice too many children in the name of science and it needs to change.” 

Not all trials need to be randomized. Many in the medical community say that randomization is necessary to determine the best treatment and that improved survival in pediatric cancer is due to randomized trials. I would counter that increased survival is due to researchers using strong early phase evidence in choosing new treatment to test against old treatment. They are really good at this. Furthermore, if randomization provides better outcomes, why have changes to induction, radiation therapy and use of growth factors NOT been tested in RCTs? And if RCTs supposedly provide “proof” that one treatment is better than another, why is Memorial Sloan-Kettering not doing transplants when this was supposedly proven by 3 separate RCTs? And why is COG not doing rapid induction, as recommended by the International Society of Paediatric Oncology in Europe?

Earlier this year, the New York Times published an acclaimed series of articles on clinical trials in the treatment of melanoma. Many clinicians and researchers have said that the science behind the new drugs has eclipsed the old rules, and ethics, of testing them.

Dr. Charles Sawyers, chairman of human oncology at MSK on melanoma: “With these drugs (in development) that have minimal side effects and dramatic response rates, where we understand the biology, I wonder, why do we have to be so rigorous? This could be one of those defining cases that says, “Look, our system has to change.’”

To that point, if the odds of NB are already so abysmal, why not allow a promising agent to be used for all children? A different trial design could have built on previous knowledge. Perhaps results could have been compared historically to other studies. Perhaps children could have been allowed to cross-over. Either way it is clear that children did not need to be sacrificed to show that antibody is an effective treatment.

Dr. Richard Pazdur, director of the cancer drug office at the FDA has said, “new drugs in development, especially for intractable cancers, might require individual evaluation: This is an unprecendented situation that will, hopefully, be increasingly common, and it may require a regulatory flexibility and an open public discussion.”

The blunt truth is that we cannot control whether our child is diagnosed with cancer. WE do not determine when we live and when we die.

BUT we CAN control what treatment we provide. And where we have the opportunity to offer an increased chance at survival, we have the obligation to do so.

A society is defined by how it treats its most powerless and vulnerable members. We cannot turn a blind eye to injustice. As Abraham Joshua Heschel said, “To accept passively an unjust system is to cooperate with that system.” Yes, I say this to you as the parent of a child with cancer, but we are also fellow human beings. I urge you to search inside, locate our common humanity and give ALL our children a chance at life.

.
******

I am able to stand here today in large part thanks to the support and smarts of my brother, who is sitting right there. His care and advocacy during the past 4 years of treatment have been nothing short of incredible.

It’s not often that a brother and sister find themselves on the front lines of a cancer diagnosis, occupying opposite yet congruent sides of what some term the research/care divide. I believe that with Toby’s diagnosis, brother and sister have been able to transcend our respective boundaries. Certainly in the case of ANBL0032, I hope we are on the same side.

Toby has been the beneficiary of the dedication and care of a team of incredible doctors and nurses at multiple institutions. As a parent, I cope with one child who has cancer. Our doctors and NPs cope with the pain of hundreds of children every day. I want to thank them. They have chosen to face death, yet they engage with life. They care enough about our children to embrace hope, and through their work they affirm that people can change.

Thank you for giving me the opportunity to share my thoughts. I am grateful to be here in your company. I would also like to thank Donna Ludwinski, mother to Erik. She is the force behind my words. Her vast knowledge, pinpoint clarity and graceful support to the neuroblastoma community deserve unending recognition.

Thank you.

The Story of the Band of Parents and humanized 3F8

by Caryn Franca and Shirley Staples

It was summer of 2007.  A group of parents had asked Dr. Nai-Kong Cheung to meet and update them on new treatments for neuroblastoma at Memorial Sloan-Kettering Cancer Center.  Most had children with relapsed neuroblastoma; all knew the terrible odds.  Dr. Cheung, head of the neuroblastoma program at MSKCC, and a long-time proponent of antibody therapy, met with the group at Ronald McDonald House.  After the presentation, one dad posed a question.  “What,” he asked, “do you need, to give our children more treatment options?”   “Money” was the simple, yet daunting answer.

Dr. Cheung then described an important research goal—the development of a new, humanized form of the 3F8 antibody that had been used since 1986 to treat neuroblastoma at MSKCC.  Researchers believed the new version, “Hu3F8,” had the potential to be many times more effective in fighting neuroblastoma, but Dr. Cheung estimated that $2-3 million dollars would be needed to fund the development of the drug.  After the meeting, parents excitedly discussed this revelation. The consensus was that they could and would do whatever was necessary to make hu3F8 treatment a reality.  A crusade was born.

Within a matter of days, an online group had been created and parents had begun brainstorming.  The name of the new parent group came from a California dad:  the “Band of Parents.”  One group of parents began the discussions and eventually the legal steps to form a tax-exempt foundation. Seven dads began planning to bike across the United States to raise funds and awareness–a ride they called “The Loneliest Road” to reflect the daily challenges facing neuroblastoma families. Ultimately they raised over $200,000 for hu3F8. Soon there were 60 families in the “BOP,” and the energy was palpable, from garage and jewelry sales, to writing fundraising letters to friends, to telling individual stories to local newspaper reporters.

Donations began to pour in, some from as far away as the Middle East.  As December approached, a New York City mom conceived the idea of a massive bake sale of holiday cookies.  Over several weeks, parents, friends, and volunteers from the culinary world baked, packaged and shipped 96,000 cookies from a small rented kitchen, raising several hundred thousand dollars. A few months later, families in Virginia banded together to organize the “Rock’n for a Cure.”  Band of Parent funds were mounting.

The efforts that followed were too many and varied to detail, but the key phrase is “banded together” – parents of children with neuroblastoma, along with family, friends and perfect strangers, came together to raise the funds needed to create a new treatment option for children with neuroblastoma.  Great personal determination was required.  As the months passed, many Band of Parents members lost their child to neuroblastoma – including the parent who coined the name “Band of Parents,” the mother who conceived the cookie bake-off, three of the bikers on The Loneliest Road, and the first three presidents of the BOP.  However, parents pushed forward despite the grief and loss felt by all in the group.  Golf tournaments, yard sales, and concerts were organized, sometimes from hospital bedsides; holiday decorations, tee-shirts, and greeting cards were designed and sold.  Last but not least, the dedicated neuroblastoma team at MSKCC cleared the regulatory and many other hurdles to taking a new drug from the laboratory to the clinic.

In August 2011 the day finally arrived that so many had worked for and dreamed of.  A new phase 1 trial of hu3F8, a drug specifically designed for the treatment of neuroblastoma, opened at Memorial Sloan-Kettering, and the very first child received the promising new treatment. Ordinary people had accomplished an extraordinary labor of love. For all those involved, this will be remembered as a time when it was shown that, by banding together, a group of parents could give new hope in the battle against an aggressive childhood cancer.  Today, the members of the Band of Parents are still working to raise awareness and funding for research, so that someday no child will suffer from the terrible disease of neuroblastoma.

Editors note: the trial opened in August 2011 and is listed here: http://clinicaltrials.gov/ct2/show/NCT01419834

The trial allows for relapsed or refractory NB with evidence of disease, and is given without cytokines IL2 or GM-CSF.

New phase I trial opening soon at University of Alabama, Birmingham

This trial will enroll 6 patients at 2 dose levels for IL2 given with fixed dose of zoledronic acid. Zoledronic acid will be given IV once every 3 weeks, and daily subcutaneous IL2 given weekdays for 2 weeks.

Patients must have evidence of disease and have not received prior antibody therapy with IL2.

See NIH listing for rationale:

To further explore means of harnessing the immune system to attack NB, the investigators are studying the combination of zoledronic acid (ZOL) and interleukin-2 (IL-2). ZOL has been demonstrated to have direct anti-neuroblastoma effects in laboratory studies. ZOL also augments the production of tumor killing white blood cells called gamma-delta T cells. When used in combination with IL-2, ZOL is capable of eliciting potent anti-cancer effects in patients, in part, via the expansion of gamma-delta T cells. In this present trial the investigators aim to study the tolerability of the combination of ZOL and IL-2 in pediatric NB patients. Patients will also be monitored radiologically for tumor response to therapy. Correlative biological studies will study the ability of this drug combination to elicit the production of NB killing gamma-delta T cells in children.

Joseph Pressey, MD
Assistant Professor of Pediatrics at University of Alabama at Birmingham, and Director, Experimental Therapeutics Program

Dr. Pressey is a graduate of the University of Georgia and the Medical College of Georgia. After completing his pediatric residency at the Children’s Hospital Medical Center in Cincinnati, he trained in pediatric hematology-oncology at the Children’s Hospital of Philadelphia.  Dr. Pressey’s primary clinical interest is in the treatment of pediatric solid tumors, with a particular focus on pediatric sarcomas.  He serves as UAB’s principal investigator for the Children’s Oncology Group Phase I developmental therapeutics program and the Sarcoma Alliance for Research Through Collaboration (SARC) consortium.  Through these organizations, Dr. Pressey is interested in providing patients with access to cutting edge therapies for all types of relapsed and refractory cancers.  Dr. Pressey’s primary research interest is the biology and treatment of sarcomas. Working with others at UAB, he is studying pediatric tumors with the intent of finding more effective and tolerable therapies.  

Randomization to ch14.18 alone challenged, UK court rules in favor of child

The SIOPEN trial now accruing in 20 countries in Europe randomizes children to the antibody ch14.18 alone or ch14.18 with subcutaneous IL2. Part of this trial was amended after the March 2009 release of the Children’s Oncology Group early results showing 2-year event free survival of 66% with ch14.18, IL2, and GM-CSF versus 46% in children who received no antibody treatment. Both groups received cis-retinoic acid (isotretinoin). SIOPEN began accruing in the fall of 2009.

GM-CSF (Leukine or Sargramostim, a cytokine acquired by Genzyme) is not available in Europe. Ch14.18 was used without cytokines in a German trial and not reported to improve survival in a 2004 study (non-randomized) “Compared with oral maintenance chemotherapy and no consolidation treatment, ch14.18 had no clear impact on the outcome of patients.” In a 2011 publication, the German’s reported on long-term follow-up and  concluded that ch14.18 antibody therapy “may prevent late relapses.” In an April 2010 interview with Dr John Maris discussing the results of the COG trial, Dr Maris said: “for the cancer community in general, this is the first study to show that adding in the cytokines, the chemicals to rev up the immune system, are an important piece of the picture. Now, we didn’t study whether or not antibody alone, or if you need the GMCSF or the IL2 or both. We may never know that, but what we do know is that the whole package is effective, so now our obligation is to build on that, and our future clinical trials will take this result and try to improve upon that.”

The family of a child randomized to ch14.18 alone challenged the NHS trust and the court ruled that “it would be in her best interests to receive immunotherapy treatment that includes isotretinoin, anti-GD2 and IL2.”

The press release is below:

children’s cancer charity neuroblastoma alliance uk celebrates high court order against nhs trust

3 August 2011: The Neuroblastoma Children’s Cancer Alliance UK is today celebrating a High Court order that it is in the best interests of a child with neuroblastoma to receive a combination of immunotherapy drugs, if she withdraws from a clinical trial in which she had been randomly allocated to receive a single drug.

The Neuroblastoma Alliance UK, which was until recently known as the 2Simple Trust, helps families affected by neuroblastoma, an aggressive childhood cancer of the nervous system. The charity has supported the family during the legal case and has funded treatment for the child in the USA, as – despite the order – the NHS Trust, in the South of England, said it was unable to confirm it could provide the drugs in the UK to the mother.

“We are over the moon about this judgement. While we welcome further research, the interests of today’s children must come first. This mother was not prepared to accept the status quo and fought for her child to receive the drugs in the UK. We’re delighted she won this order and her hard work in taking this matter to court is likely to help many more parents in the future,” said Alison Moy, Chief Executive of the Neuroblastoma Alliance UK.

Anne-Marie Irwin, a solicitor at Irwin Mitchell, who helped the mother bring her case to the High Court said: “It was a hard fought battle to achieve this significant legal step for our client. Even though this order is too late for many, including the family of the claimant who have been forced to move to the USA so that their daughter has the best chance of survival, it is a step in the right direction for families who want their children to receive the best available treatment in the UK.”

The four-year-old child – known as CB* – suffers from high risk neuroblastoma, an advanced form of the cancer that has a very poor prognosis. The child is in the final stage of neuroblastoma treatment, known as immunotherapy. In the UK, immunotherapy treatment is only available to children that enrol onto a randomised trial, where they are randomly allocated either one or two drugs by a computer based in Austria*².

Last year, a study published in the New England Medical Journal in America, reported that giving children three drugs*³ – including two of the drugs being tested in the UK trial – during immunotherapy resulted in a 20 percent lower relapse rate and an 11 percent higher survival rate over a two year period.

When the mother heard in June that her child had been allocated to receive only one of the two drugs available in the UK, she decided to take her NHS Trust to court.

“When I heard that a computer had randomly selected my child to receive one of the three drugs that American scientists have shown can save a child’s life, I decided to take action,” said the mother. “Given that American scientists have already proven the effects of the three drugs in a clinical trial, why do UK doctors need to continue experimenting on children? I didn’t want my little girl to be part of this experiment.”

On 23 July, High Court judge Mr Justice Ryder ordered*⁴ that if the child withdrew from the clinical trial, it would be in her best interests to receive both drugs. This interim order opens the way for other neuroblastoma sufferers, who have only been allocated one drug in the trial, to challenge the decision.

The NHS Trust resisted CB’s application and has not yet confirmed that it would provide the drugs to the mother outside the trial. On the 22 July, the family travelled to the US, where CB started immunotherapy treatment on 25 July. The Neuroblastoma Alliance has funded the child’s treatment from the charity’s reserves. The treatment is expected to cost between $300,000-$400,000 (approximately £185,000-£245,000).

The mother plans to continue her legal battle against the NHS Trust, and hopes that all three immunotherapy drugs will be made available to UK neuroblastoma patients in the future.

“We were left with no choice but to take her to the USA, and I am just extremely grateful to the Neuroblastoma Alliance UK for helping us to fund the treatment,” she said. “I only hope that this court action paves the way for other families to receive the best possible cancer drug treatment for their children without having to travel abroad.”

The order was also welcomed by many of the other families that the Neuroblastoma Alliance UK supports, including John Rogers and Allison Hyde, whose three-year-old daughter Stella received treatment for neuroblastoma in the US last year.

“Until this legal action, parents were forced to accept the treatment they were offered in the randomised trial – even if the alternative treatment might offer better prospects for their child,” said John. “This court order is putting the interests of children before research – the lives of children shouldn’t come secondary to research.”

There are a number of other families in a similar situation and it may also be in their best interests to receive both drugs.

Notes 

* The child, the mother and the Trust are anonymous in this release on order of the court, which said the child should be known as “CB”, the mother as “SB” and the Trust as “S Trust”.

*² Neuroblastoma sufferers taking part in the SIOPEN trial (a neuroblastoma immunotherapy trial taking place in the UK and Europe) are offered either anti-GD2 (an antibody) or anti-GD2 and IL2 (a cytokine).

*³ The study carried out by the Child Oncology Group (COG) in US, Canada and Australia gave one set of patients standard neuroblastoma therapy of isotretinoin, and the other set of patients a combination of three drugs: anti-GD2, IL2 and GM-CSF (another type of cytokine).

The trial found that children receiving the immunotherapy treatment (anti-GD2, IL2 and GM-CSF) had an increased event-free survival rate (66% vs. 46% for standard therapy) and an increased overall survival rate (86% vs. 75% for standard therapy) over two years.

The study was published in the New England Medical Journal in September 2010. http://www.nejm.org/doi/full/10.1056/NEJMoa0911123

*⁴ The exact court order is as follows:

“IT IS DECLARED ON AN INTERIM BASIS THAT

1.         In the event that the Claimant withdraws from the current clinical trial at the <hospital name>, it would be in her best interests to receive immunotherapy treatment that includes isotretinoin, anti-GD2 and IL2″

The hospital name has been removed, in accordance with the judge’s order that the family and Trust are to remain anonymous.

http://www.childrenscancer.org.uk/latest-news/children-s-cancer-charity-neuroblastoma-alliance-uk-celebrates-high-court-order-against-nhs-trust.php

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SIOP’s BuMel results discussed, implications for COG

In this eleventh episode of “This Week in Pediatric Oncology” hosts Dr Tim Cripe and Dr Lars Wagner discuss with guest Dr Brian Weiss (Cincinnati Children’s Hospital) the implications of the recent results comparing two chemotherapy combinations for transplant regimens in children with high-risk neuroblastoma in Europe. The BuMel (busulfan, melphalan) regimen resulted in better survival and lower toxicity than CEM (carboplatin, etoposide, melphalan), a regimen used for transplant in the COG for a decade.

This SIOP trial was one of the plenary presentations at ASCO in June 2011.  In this lively and informative discussion, Dr Brian Weiss explains the COG response to these results due to the difference in induction regimens. The BuMel regimen will be used in the upcoming MIBG frontline pilot that Dr Weiss is leading as principal investigator.

Dr Weiss and TWiPO hosts also discussed the recent paper Safety and efficacy of tandem (131) I-metaiodobenzylguanidine infusions in relapsed/refractory neuroblastoma authored by Johnson et al in Pediatr Blood Cancer. 2011 Apr 14

Please send questions and comments to twipo@solvingkidscancer.org

Dr Ruth Ladenstein presents data in Plenary Session on randomized trial comparing BuMel vs CEM for transplant after Rapid COJEC induction

Considering that neuroblastoma accounts for 7% of pediatric cancers, and pediatric cancers comprises only 1% of adult cancers (that is .07% of all cancers, and high-risk NB makes up only half that number), it is really quite remarkable when highlighted presentations at ASCO focus on neuroblastoma.  This is on the heels of the ch14.18 results which was also big news at ASCO in 2009.

The European SIOPEN trial accrued 1,577 high-risk children since 2002.  Only 43% of these children were randomized for transplant regimen. The randomization was stopped after review showed superiority of BuMel (busulfan + melphalan) over CEM (carboplatin + etoposide + melphalan) in survival. Toxicity was greater in CEM arm, although more VOD (veno-occlusive disease) was observed in BuMel arm.

Dr Julie Park presented data as discussant comparing outcomes with the COG CEM transplant regimen. Clearly BuMel is better than CEM after Rapid COJEC induction, but a question remains if this would be true for the COG induction, which is very different (21 day schedule vs 10 day schedule which presents a different toxicity profile, higher cisplatin use in SIOPEN and no carboplatin is used in COG induction).

This treatment is now standard in SIOP, and COG is incorporating BuMel in a pilot trial.

For more information, see “Can New Standard of Care in Neuroblastoma Be Used in the US?” by Medscape.

http://abstract.asco.org/AbstView_102_79897.html

Abstract:

Background: The HR-NBL1 trial of the European SIOP Neuroblastoma Group randomised 2 MAT regimens with the primary aim to demonstrate superiority based on event free survival (EFS).

Methods: At randomisation closure, 1,577 high-risk neuroblastoma patients (944 males) had been included since 2002; with INSS stage 4 disease (1,369 pts) > 1 year, infants (65 pts) and stage II and III (143 pts) of any age with MYCN amplification. Response eligibility criteria prior to randomisation after Rapid COJEC Induction (J Clin Oncol, 2010) ± 2 courses of TVD (Cancer, 2003) included complete bone marrow remission and ≤ 3, but improved, mIBG positive spots. The MAT regimens were BuMel (oral busulfan till 2006, 4x150mg/m² in 4 equal doses, or after 2006 intravenous use according to body weight and melphalan 140mg/m²/day) and CEM (carboplatin ctn. infusion [4xAUC 4.1mg/ml.min/day], etoposide ctn. infusion [4x338mg/m²day or 4x200mg/m²/day*], melphalan [3x70mg/m²/day or 3x60mg/m²/day*. *reduced if GFR<100ml/min/1.73m²]). A minimum of 3x10E6 CD34/kgBW PBSC were requested. VOD prophylaxis included ursadiol, but not prophylactic defibrotide. Local control included surgery and radiotherapy of 21 Gy. A total of 598 patients were randomised (296 BuMel, 302 CEM). The median age at randomisation was 3 years (1-17.2) with a median follow up of 3 years.

Results: At the last analysis, the Peto rule of p<0.001 was met. A significant difference in EFS in favour of BuMel (3-years EFS 49% vs 33%) was observed as well as for overall survival (3-years OS 60% vs 48%, p=0.004). This difference was mainly related to the relapse and progression incidence, which was significantly (p<0.001) lower with BuMel (48% vs 60%). The severe toxicity rate up to day 100 (ICU and toxic deaths) was below 10%, but was significantly higher for CEM (p=0.014). The acute toxic death rate was 3% for BuMel and 5% for CEM (NS). The acute MAT toxicity profile favours the BuMel regimen in spite of a total VOD incidence of 18% (grade 3:5%). Based on these results and following advice from the DMC, the randomisation was closed early.

Conclusions: BuMel was demonstrated to be superior to CEM and hence is recommended as standard treatment.

Personalized medicine has arrived to pediatric cancers: neuroblastoma

This Neuroblastoma and Medulloblastoma Translational Research Consortium (NMTRC) feasibility trial will accrue 14 patients.

http://clinicaltrials.gov/ct2/show/NCT01355679

Inclusion Criteria:

Read more about this trial here:

http://www.nmtrc.org/personalized-medicine/

Four oncolytic virus trials open at Cincinnati Children’s for pediatric solid tumors

Dr Tim Cripe provided a very helpful comparison chart for the oncolytic virus trials currently open at Cincinnati Children’s, and permission to post it. To open a PDF of the chart, click on this link:

Viral study comparison (PDF document)

The chart lists the similarities and differences of the four oncolytic virus trials:  SVV-001 (NTX-010 or seneca Valley virus), HSV1716 (Herpes simplex), JX-594 (Jennerex vaccina), and Reolysin (reovirus).

Regarding age, the HSV1716 is open for ages 13 to 30, whereas the others are for 2 or 3 years up to 21. Both SVV-001 and Reolysin are given intravenously, whereas HSV1716 and JX-594 are given intratumoral (injected into the tumor).

HSV1716 and JX-594 require short inpatient stays, but Reolysin and SVV-001 are give outpatient. The SVV-001 is given in a single dose (one-hour infusion), whereas the JX-594 and HSV1716 can be administered to tumor sites every 28 days up to four times, and Reolysin is given in a one-hour infusion for five days, and this is repeated every 28 days for up to 12 months.

The chart also lists the current dose levels for each trial (all are phase I studies).

The SVV-001 and Reolysin are open in several COG Phase I centers, and the HSV1716 and JX-594 are only open at Cincinnati Children’s, and that is the only location that has all four trials open. Only the Reolysin trial restricts eligibility to those who have not had prior oncolytic viruses, so it is possible to enroll on these trials in sequence.

For more background on oncolytic virus trials for children, see the following links.

Review article: http://www.nbglobe.com/2010/11/19/status-on-oncolytic-virus-therapies-for-pediatric-solid-tumors/

Webinar: http://www.nbglobe.com/2011/01/26/webinar-on-oncolytic-viruses-for-children/

Neuroblastoma and Medulloblastoma Translational Research Consortium (NMTRC) moves to Grand Rapids, Michigan May 2, 2011

Dr Sholler completed medical school at New York Medical College, in Valhalla, NY. She was a resident in pediatrics and a fellow in pediatric hematology/oncology at Brown University before moving to the University of Vermont in 2005. Her research focuses on new therapies for neuroblastoma and medulloblastoma.

She describes her transition to new her position at Van Andel Research Institute (VARI) in an interview at AACR:

1.  Would you describe your new role at VARI, and continuing responsibilities at the University of Vermont and the NCI?

I will be Pediatric Oncologist, Spectrum Health Medical Group, Helen DeVos Children’s Hospital, Directing the Pediatric Oncology Therapeutic Discovery Clinic, focusing on NB and MB patients enrolling on our NMTRC trials and profiling all patients diagnosed with cancer and all relapses; Co-Director of the VARI/TGen Pediatric Oncology Research Program; and Associate Professor of the Neuroblastoma Translational Research Laboratory at Van Andel Research Institute. I will have a faculty appointment within Michigan State University’s College of Human Medicine.  I will continue as adjunct faculty at University of Vermont to continue key collaborations studying genomic profiles in neuroblastoma patients (with Jeff Bond) and work in Phage-display creating individualized antibodies (with David Krag).  I will continue as a Guest Researcher in the Pediatric Oncology Branch at the NCI where we will open the molecularly-guided protocol and I will be seeing NB patients in clinic monthly.

2.  How will this move enhance your goals for your research?
The Van Andel Research Institute is providing significant support and infrastructure to our research and consortium with a 5 year commitment.  The resources and collaboration at the Van Andel (with Craig Webb) and NCI (with Javed Khan and Melinda Merchant) has allowed this research to move forward, especially in the area of molecularly-guided therapy. I am thankful to have such a great team around us and this move will allow the research to flourish at an even faster rate.  Our goal are to bring understanding to each patients tumor and direct therapies to them as well as making promising new drugs available to kids with NB and MB.

3. During your time in Vermont, much has been accomplished. What is the most satisfying to you?
During my time in Vermont I have seen the creation of a new consortium  and the  bringing together of families and researchers for a common goal. It has been incredible to be a part of this evolving from nothing and out of many people caring about these children.  I am most satisfied to have been able to help many children in bringing them new therapies, I know that from this we will be able to improve the lives of kids with neuroblastoma.

4.  How will your move to VARI affect the operations of the NMTRC?
The Van Andel will now be the lead administrative site for the NMRTC, providing us with significant infrastructure which was minimal before and supported by family foundations. Now that money can go directly to supporting new research and trials. Dr. Jeff Trent, President and Research Director fo the Van Andel Research Instittue and TGen is devoted to making a difference in pediatric cancer and with his support and guidance I am excited about the possibilities of what we can do.

5.  Could you provide an update on the personalized medicine program you initiated?
We have completed our pilot study of molecularly-guided therapeutics showing it is possible in real-time to perform a biopsy, run a gene chip, analyze this using computer algorithms, hold a national tumor board to discuss the patient and create individual treatment plans in less than 2 weeks. We now have FDA approval for  a treatment study and IRB approval at 5 centers (DeVos Children’s Hospital, NCI, St. Louis Univeristy, Levine Children’s, and MDAnderson Orlando) and will be opening this trial in May 2011 when I arrive at the Van Andel.

Symposium for parents and researchers June 23 at VARI

Van Andel Research Institute and the NMTRC welcome all parents, foundations, scientists, and on physicians to attend the third symposium for progress and project updates on June 23rd, 2011 and more details will be forthcoming on the NMTRC site.

Poster presentation by Dr Sholler and colleagues at AACR 2011:

A pilot trial testing the feasibility of using molecular-guided therapy in patients with refractory or recurrent neuroblastoma