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.

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

Anti-ALK antibody explored at Children’s Hospital of Philadelphia

An increasingly important research topic in neuroblastoma focuses on anaplastic lymphoma kinase (ALK) mutation or expression. At AACR there were 8 presentations on ALK and NB. While efforts are ongoing to better target the ~7% of NB cases that have an ALK mutation, now there is also compelling research on the ALK protein expression which is found in 90% of NB cases. ALK expression is found in some cancers (primary lymphoma) and is detected using monoclonal antibodies. In normal tissues, ALK protein is expressed in only a few cells within the developing and mature nervous system (glial cells, neurons, endothelial cells and pericytes).[1]

Dr Max van Noesel from Erasmus MC-Sophia Children’s Hospital, Rotterdam, Netherlands presented interesting data showing that the percent of NB cells in a tumor sample that are positive for ALK protein expression correlate with outcome and risk stratification. His team examined 71 NB cases (all risk categories) for ALK expression, and found that tumor samples that showed 75-100% positive cells for ALK expression had the worst outcome,  and that response to the ALK inhibitor TAE684 was dependent on higher ALK expression. Tumors with ALK mutation had higher ALK protein expression and responded better to in vitro testing of the ALK inhibitor.[2]

Meanwhile, Dr Erica Carpenter, a researcher in Dr Yael Mosse’s lab at CHOP, examined targeting NB cells with anti-ALK antibody. Given that the worst NBs express the ALK protein, this is a compelling idea for several reasons. Although this work is still in early preclinical stage, researchers will be seeking to answer many questions including– could this antibody strategy be more effective than anti-GD2 antibodies? Could this therapy present less toxicity?

Dr Carpenter also explored the combination of anti-ALK antibody with the ALK inhibitor PF-02341066 in NB cell lines, and found that the combination is more effective than either agent alone because the ALK inhibitor drives up ALK protein expression on the NB cell surface:

Therefore, we hypothesized that antibody targeting of ALK in neuroblastoma was a therapeutically appropriate strategy. To first confirm the potential of anti-ALK antibody-mediated immunotherapy, we used in vitro assays to demonstrate enhanced immune-cell induced cytotoxicity of antibody-treated human neuroblastoma-derived cell lines. We next showed that in vitro antibody treatment of neuroblastoma cell lines expressing activated ALK led to growth inhibition and cell death. These effects were enhanced by treatment with PF-02341066, an orally available small-molecule inhibitor of the ALK tyrosine kinase. To identify the mechanism behind this enhanced combined effect, we used flow cytometry to show that PF-02341066 sensitizes cells to antibody treatment by inducing accumulation of cell-surface ALK, thus increasing the accessibility of antigen for antibody binding. Finally, to further predict in vivo cytotoxic mechanisms of dual ALK targeting, we used flow cytometry to demonstrate enhanced apoptosis and proliferation inhibition resulting from combined antibody and inhibitor treatment as compared to either drug alone.[3]

The next step in this exciting project is developing a clinical grade antibody, which is underway, and after further preclinical testing, the agent will be ready for clinical trials.

References

1. http://www.nordiqc.org/Epitopes/ALK1/ALK1.htm
2. Anaplastic lymphoma kinase (ALK) expression is an independent prognostic factor in neuroblastoma patients and correlates well with ALK inhibitor response in vitro
3. Antibody targeting of anaplastic lymphoma kinase induces cytotoxicity of human neuroblastoma

Antibodies for relapsed neuroblastoma

Given that recent studies such as COG-3973 [1] and others reveal that half or more of all children with high-risk neuroblastoma are refractory to induction or relapse, and that the majority worldwide never received antibodies as part of frontline treatment, there is currently a significant demand for access to antibody treatment after relapse.

Currently, the only offerings of antibodies for relapse are:

• 3F8 (murine) at Memorial-Sloan Kettering Cancer Center,
• ch14.18/CHO (chimeric) at Griefswald in Germany, and
• hu14.18K322A (humanized) at St Jude’s, Memphis TN

Memorial-Sloan Kettering Cancer Center (MSKCC) in New York has been using 3F8 antibodies in the relapse setting for 20 years or more [2]. Ideally the relapsed disease must first be reduced to minimal or undetectable levels. Dr Kushner presented at ASCO in 2007 showing that 20% of children with bone marrow refractory disease became long term survivors [3]. Bone disease and soft tissue relapses are less responsive to 3F8. Since MSKCC uses a 100% mouse antibody, the child can make antibodies against the 3F8, called HAMA, for human anti-mouse antibodies. These antibodies prevent further treatment with 3F8, unless HAMA can be reduced using Rituxan (rituximab) and waiting for HAMA to subside. Rituxan, also an antibody, targets CD20 that is highly expressed on B-cells which are responsible for making antibodies. Prior to beginning treatment with 3F8, high doses of cyclophosphamide are given (4200 mg/m2) in order to reduce the immune system’s capacity to produce HAMA.

MSKCC has opened various 3F8 trials in the past decade, including heat-modified [4], with beta-glucan, high-dose, and use after donor (parent) NK cells, with the latter two open currently for relapse. The Band of Parents funds neuroblastoma projects at MSKCC and anticipates a humanized version of 3F8 and a “turbo” version of 3F8 to be available in 2011 for children with relapsed or refractory disease. In short, antibodies have been available for relapse at MSKCC for the past 20 years.

Meanwhile, the chimeric (25% mouse/75% humanized) antibody ch14.18 given with IL2 and GM-CSF that improved the two-year event-free survival by 20% over the no-antibody arm is now available to all children as part of frontline treatment in the COG (North America and Australia). Randomization was stopped after early review in March 2009, and the study continues to accrue for more safety and efficacy data (COG-ANBL0032), as well as an additional study open for the registration data to gain FDA approval (COG-ANBL0931). This antibody is not currently available to relapsed children in the COG. A NANT trial for relapsed children will open in late 2011 with ch14.18 in combination with lenalidomide (stimulates production of natural cytokines in the tumor environment), and NED (remission) after relapse will be eligible.

In Europe, the availability of ch14.18/CHO (produced from hamster rather than mouse cells) for frontline treatment is limited to those treated on the current SIOP high-risk protocol. The study has been modified several times since it opened in 2002. These randomization arms have closed:

• G-CSF or no G-CSF –all get G-CSF after showing less neutropenia, fever, hospitalization days, chemo delays [5]
• busulfan + melphalan (BuMel) or carboplatin + etoposide + melphalan --all now receive BuMel for survival advantage [not published as of 3/2011]
• ch14.18 or no ch14.18 –all get ch14.18 with or without subcutaneous IL2 [trial listing not updated as of 3/2011]

Dr Holger Lode has a trial open to treat relapsed and refractory neuroblastoma with ch14.18 and IL2 at Griefswald in Germany. In the past year families have traveled from the UK, Australia, and other countries to access this treatment.

A COG trial using hu14.18-IL2 with GM-CSF and cis-retinoic acid is opening very soon, and will be open to relapsed and refractory neuroblastoma with measurable or detectable disease (second response will not be eligible). This is a humanized antibody with IL2 fused directly to the antibody. It has completed phase I and phase II studies in neuroblastoma and melanoma, and a pilot is ongoing for melanoma at University of Wisconsin-Madison.

Now that hu14.18-IL2 and ch14.18 are licensed to Apeiron and United Therapeutics respectively, availability for trials will be governed by these companies.

Extrapolating the annual incidence of high-risk neuroblastoma and relapse, a minimum of 800 children in SIOP and COG countries will require ch14.18 for frontline treatment every year, and potentially another 400 for relapse treatment. Hopefully, this demand will be satisfied soon. Since melanoma expresses GD2 also, these anti-GD2 antibodies may be in demand to treat melanoma also.

References

1. Response and toxicity to a dose-intensive multi-agent chemotherapy induction regimen for high risk neuroblastoma (HR-NB): A Children’s Oncology Group (COG A3973) study. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 9505

2. GM-CSF enhances 3F8 monoclonal antibody-dependent cellular cytotoxicity against human melanoma and neuroblastoma. Blood. 1989 May 15;73(7):1936-41.

3. Anti-GD2 monoclonal antibody 3F8 plus granulocyte-macrophage colony-stimulating factor (GM-CSF) for primary refractory neuroblastoma (NB) in bone marrow (BM). Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 9502

4. Successful Multifold Dose Escalation of Anti-G_D2 Monoclonal Antibody 3F8 in Patients With Neuroblastoma: A Phase I Study; J Clin Oncol. 2011 Feb 22.

5. Randomized Trial of prophylactic granulocyte colony-stimulating factor during rapid COJEC induction in pediatric patients with high-risk neuroblastoma: the European HR-NBL1/SIOPEN study. J Clin Oncol. 2010 Jul 20;28(21):3516-24. Epub 2010 Jun 21.

Big antibody news

The “third generation” humanized anti-GD2 antibody with protein fusion of IL2 to the antibody has completed Phase I and II clinical trials for melanoma and neuroblastoma, and is now ready for use in Phase III clinical trials. The license for hu14.18-IL2 was just acquired by a small biotech in Vienna called Apeiron. The license was acquired from Merck.

Apeiron’s press release:

Apeiron Licenses Phase II/III Anticancer Ab-IL2 Fusion Protein from Merck KGaA

Long-term follow up of children with and without ch14.18/CHO in German trials NB90 and NB97

It has been a very long wait to finally see this graph. The Germans reported on this at ANR 2008 in Japan, and again at ANR 2010 in Stockholm.  See Graph A in Figure 2. “Follow-up analysis of the patient cohort indicated that immunotherapy with ch14.18 [no cytokines] may prevent late relapses.” Remember this group reported in 2004 “analysis failed to demonstrate an advantage of antibody treatment” –

http://jco.ascopubs.org/content/22/17/3549.long

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The statement about late relapses is a little puzzling to me. Graph A shows that “events” (which are usually relapses) occurred up until 10 years in both the ch14.18 and maintenance groups. Only the “no consolidation” group had later events.

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The authors concluded:”Today, the most effective way of antibody based maintenance therapy seems to be a combination immunotherapy with MAB ch14.18, cytokines, and retinoic acid. But these results need confirmation by at least another randomized trial. Further, metronomic low dose oral chemotherapy consolidation was found as effective as MAB ch14.18 consolidation in this retrospective analysis and, therefore, also warrants further evaluation. Prospective clinical trials must demonstrate if the concept of low dose metronomic chemotherapy is feasible and effective after ASCT and in combination with immunotherapy.”

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Since the early results did not show a benefit of ch14.18 without cytokines, and yet the COG trial showed 20% advantage in early results, it could be argued that there might be a big difference in survival between oral metronomic chemotherapy and ch14.18 with cytokines.

http://www.biomedcentral.com/content/pdf/1471-2407-11-21.pdf

Germans report on outcomes of relapsed NB patients who received three different regimens

Treatment and outcomes of patients with relapsed, high-risk neuroblastoma: Results of German trials.

Simon, T., Berthold, F., Borkhardt, A., Kremens, B., De Carolis, B. and Hero, B. (2011), Treatment and outcomes of patients with relapsed, high-risk neuroblastoma: Results of German trials. Pediatric Blood & Cancer, 56: 578–583. doi: 10.1002/pbc.22693

This is an important publication and was presented at ANR 2010. Few groups have tackled relapsed NB in any systematic way. Wendy London’s abstract presented at ASCO 2010 and ANR 2010 on survival after relapse suggests that some relapsed NB children are salvageable, and the Germans and Swedes are advancing understanding in treating relapse. This same approach looking at more aggressive measures for relapsed leukemia kids is how relapse protocols were developed to treat relapsed leukemias.

Drs John Maris and Yael Mosse awarded patent for ALK mutation link to diagnosis, prognosis, and treatment of neuroblastoma

Summary of patent:

CHK1 suspected to be a promising target in NB — inhibitors are being tested in adults

‎”CHK1 mRNA expression was higher in MYC–Neuroblastoma-related (MYCN)–amplified (P < 0.0001) and high-risk (P = 0.03) tumors.”

RNAi screen of the protein kinome identifies checkpoint kinase 1 (CHK1) as a therapeutic target in n

www.pnas.org

Edited by Stephen J. Elledge, Harvard Medical School, Boston, MA, and approved December 17, 2010 (received for review August 23, 2010)

Protein May Be Key to New Treatment in a Childhood Cancer — PHILADELPHIA, Feb. 7, 2011 /PRNewswire-

Neuroblastoma bits from November 2010

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NCI featured article on ALK inhibitor Crizotinib

While encouraging responses are being seen in lung cancer patients with ALK mutation, drug resistance is expected to be a problem.

Crizotinib Continues to Show Promise for Some Lung Tumors, Faces Challenge of Drug Resistance

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FDA discusses Crizotinib pediatric trial design

Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee (ODAC) Nov 30, 2010

“If the current COG Phase I/II studies evaluating crizotinib in refractory pediatric solid tumors or ALCL shows promising activity in neuroblastoma, should crizotinib be evaluated in the post-transplant relapsed/refractory setting or should a randomized trial in a less heavily treated population be considered? If the former population (i.e., post-transplant relapsed or refractory) is a more appropriate setting, please discuss whether Progression Free Survival (PFS) is an adequate endpoint.”

Committee discussion questions

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Insight Genetics Awarded Qualifying Therapeutic Discovery Program Grant

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http://www.eurojournals.com/ejsr_40_1_15.pdf

www.eurojournals.com

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Scientific American describes the recent advances in viruses that kill cancer — now available to children this year for the first time –

Cancer Therapy Goes Viral: Progress Is Made Tackling Tumors with Viruses: Scientific American

“A new generation of oncolytic viruses are entering late-stage clinical trials, repurposing smallpox and herpesvirus to take on tough tumors.”

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Search goes on for toxins to kill neuroblastoma

“Luesch is experimenting with toxins—drawn from several species of cyanobacteria—on several types of cancer, including neuroblastoma, a childhood disease that attacks nerve cells. In July 2009, he launched a four-year, $1.2 million NCI-funded study, part of which entails… largazole testing on mice.”

Why Scientists Are Searching for Cures Underwater – Newsweek

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Childhood cancer survival in Australia

“Survival outcomes using the period method for 11903 children diagnosed with cancer between 1983 and 2006 and prevalent at any time between 1997 and 2006. The overall relative survival was 90.4% after 1 year,  79.5% after 5 years and 74.7% after 20 years.”

Population-based survival estimates for childhood cancer in Australia during the period 1997–2006

www.nature.com

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Accutane (cis-retinoic acid or isotretinoin) and depression?

A child with neuroblastoma is far more more often a preschooler than a teen. So the risk of suicide and depression is unlikely with such small children. It is a concern with the few teens and young adults with neuroblastoma on this drug, especially since the dosing is 2 to 10 times higher than what is prescribed for acne, and the lower dose is the basis for all the previous studies looking at incidence of depression and suicide. This small study gives important evidence that the drug may not contribute entirely to increased risk:

Severe Acne Linked to Suicide Risk Even Before Treatment Is Started

cme.medscape.com

In a retrospective Swedish cohort, suicide attempts were associated with severe acne even before treatment with isotretinoin was started.

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Rare news

A disease that afflicts only 350 children per year in the US (in the high-risk form) does not make headlines very often. But after the September 30, 2010 publication of the New England Journal of Medicine article revealing the results of the phase III chimeric antibody trial (ch14.18 given with two cytokines GM-CSF and IL2), neuroblastoma was all over the news including prime time national news. Over 200 news stories appeared within the next 2 days and over 3000 blogs reported on the story. Click on image below for a nice example of one of the medical blogs:

From Science Life blog at University of Chicago

The news was actually first released March 19, 2009 after an early review of the study. The study was amended so that the randomization was stopped and all eligible children could  receive the antibody.

This is quite a dramatic story on many levels.

An absolute must read is an excellent article giving more background on the story in the NCI Cancer Bulletin. The article details the incredible perseverance required of Dr Alice Yu, Dr Paul Sondel, Dr Malcolm Smith, and the entire COG team to bring this antibody to children with neuroblastoma. The research on this antibody began in 1985, and yet it took 25 years to get solid proof that the antibody improves survival. Why did it take so long?

Antibody and drug development are not the same

Antibodies are first isolated from mice that are “challenged” with a tumor and produce antibodies against that tumor. The production is shown in the illustration below from a wikipedia article which describes the process:

This particular antibody targets GD2 which is a glycolipid (sugar-fat) antigen on the surface of NB cells. This antigen is also present on other cancers, including melanoma. GD2 is also expressed on some normal nerve cells, which is why the treatment causes pain. “First generation” antibodies are entirely mouse products (termed “murine”) and is why a normal immune system reacts quickly to produce anti-mouse human antibodies (HAMA) which effectively neutralize the action of the mouse antibody. Examples of first generation anti-GD2 antibodies are Memorial Sloan-Kettering’s 3F8 antibody (research also began in 1985[1]) and 14G1,14G2b, and 14G2a antibodies.[2]  The ch14.18 chimeric antibody is a “second generation” anti-GD2 antibody, since it has been engineered to be 75% human and 25% mouse in makeup, and why it is labeled chimeric (a “mix” of human and mouse). This greatly reduced the incidence of forming antibodies against the ch14.18. Two “third generation” antibodies that are fully humanized have been developed to date  and have been tested in clinical trials:

• St Jude’s hu14.18K322A, in a phase 1 study now for neuroblastoma and melanoma, and given without cytokines
• hu14.18-IL2, a fusion protein where the cytokine IL2 is attached to the antibody (in phase 2 study now for melanoma)

The hu14.18-IL2 antibody has already shown significant efficacy in a phase II study for relapsed and refractory neuroblastoma with results just published in October 4, 2010 issue of the Journal of Clinical Oncology.[3]

Plans are underway now for both ch14.18 and hu14.18-IL2 to be used in further clinical trials in combination with other promising agents for relapsed/refractory neuroblastoma and these trials will begin accruing at COG institutions in 2011.

More to the story

Ironically, this pivotal phase III ch14.18 trial that showed such a dramatic improvement to survival had some difficulty accruing. It is interesting to note that the other recent phase III studies all accrued patients at a relatively even pace (~90-100 patients per year) with the exception of this ch14.18 antibody study:

• CCG-3891 (1991 – 1996) double randomization of transplant and cis-retinoic acid accrued 539 over 6 years or ~ 90 per year [4]
• COG-A3973 (2001 – 2006) randomization for purge vs no purge of stem cells for stem cell transplant accrued 489 over 5 years or ~ 98 per year [5]
• COG-ANBL0032 (2001 – 2009) randomization of ch14.18 vs no ch14.18 accrued 226 over 7.5 years or ~ 30 per year [6]
• COG-ANBL0532 (2007 – 2012) randomization of single vs tandem transplant is accruing on schedule (should be complete by fall 2012) at 495 over 5 years or ~ 99 per year [7]

The striking fact is that if the early analysis had not revealed a significant difference in outcome, accruing at this rate this trial might have been ongoing until 2014.

Medical ethics, trial design, and real children

With success also comes inevitable heart ache. Hindsight can be a bitter pill to swallow. It is impossible to forget the children who did not receive the antibody and had increased chance of relapse as a result. By the time 2 years elapsed from randomization, 38/113 children had relapsed after receiving the antibody,  but 61 children had relapsed after receiving no antibody, an excess incidence of relapse in 23 children. Was it really necessary to randomize the antibody? If it was a promising treatment why was it not just given to everyone?

There are no easy answers to this fair and difficult question. While there were high hopes the ch14.18 antibody given with two cytokines would help, no one really knew if it would make a difference in survival. After all, in 2004 the German study group (GPOH) had published their retrospective findings that the ch14.18/CHO antibody (made with hamsters instead of mice, and given without cytokines) made no difference in survival when groups were compared from GPOH NB90 and NB97 protocols.[8]

A perfect example of this very quandary was played out with neuroblastoma not long ago. A method was devised in the early 1990s to purge stem cells of neuroblastoma with monoclonal antibodies (of all things) and magnetic beads. The purged stem cells could then be frozen and returned to children after high-dose (myeloablative) chemotherapy. This idea made so much sense: why not clean up the stem cells first and remove the risk of re-infusing the child with NB cells?

Fast forward to the negative results of a very costly and lengthy phase III study — purging had made no difference at all in the survival of high-risk NB children. These results were presented at the 2007 ASCO meeting, but are still not published to date. [9]

So what are the implications? The purging costs upwards of $30,000 per child. It also wastes 50% or more of the stem cells in the process. Knowing that this expensive, wasteful  process is not needed is a very important finding. A similar finding could have been in store for ch14.18 with cytokines. Randomizing is not necessary when a dramatic and consistent response results from a treatment. Not every child responded to ch14.18 treatment in earlier studies, so efficacy had to be proven before it could become a standard treatment. After all, 5 months of ch14.18 treatment with cytokines is a very expensive and complex ordeal, and children are required to spend up to 7 additional weeks in the hospital for this intensive treatment.

In the midst of the celebration over this genuine breakthrough, it is nevertheless heartbreaking to realize that a total of 99 children out of the 226 (both groups) had relapsed by two years — or 44%. It is poignant to note that each of the researchers interviewed about this remarkable study also made the comment “We must do better.” There is an impressive array of researchers and clinicians who have dedicated their entire careers to pushing that sad high-risk neuroblastoma survival curve upward. They see the faces of the children who have been lost along the way in those curves too.

Costly development and production

Developing an antibody (a biopharmaceutical) is far more complex that developing a drug. Cost of production and additional regulatory requirements make this an expensive endeavor. For example, $8 million of 2009 stimulus funds were awarded December 2009 to SAIC-Frederick (NCI research partner) to produce a two year supply of ch14.18:

NCI, through the BDP [Biopharmaceutical Development Program], is to deliver sufficient number of vials of finished product to treat all neuroblastoma patients for whom antibody Ch14.18 has become the clinical standard of care. This 2-year interval for NCI production can be used as a transition to licensing and commercial production. In addition, for the Cancer Immunotherapy Network, the NCI, through the BDP, will develop and supply vials of agents of great interest of the extramural community for further clinical investigation.

Transitioning is currently underway for United Therapeutics to begin producing ch14.18, and complete the FDA registration process. Keeping an eye on further use in melanoma is of interest since that will potentially make ch14.18 a more profitable product for United Therapeutics.[10]

Implications for Europe

At ANR (Advances in Neuroblastoma Research) in 2008 and 2010 and at SIOP 2009 the German group (GPOH) reported that after longer follow-up, the ch14.18/CHO treatment might prevent late relapses. The GPOH is planning to reintroduce ch14.18/CHO treatment. The large SIOP trial SIOP-EUROPE-HR-NBL-1 opened in 2002 and had planned to randomize ch14.18 but since the results of the COG study, the SIOP study was amended to give all eligible children ch14.18 with or without subcutaneous IL2. There is such a great body of evidence showing that GM-CSF is an essential part of this treatment, hopefully the regulatory hurdles will be quickly resolved and children in Europe will soon have the opportunity to get this better treatment regimen. See John Roger’s ANR report for more on this very important subject.

References

1. Biochem Biophys Res Commun. 1985 Feb 28;127(1):1-7. Ganglioside GD2 specificity of monoclonal antibodies to human neuroblastoma cell.

2. Cancer Research 49, 2857-2861, June 1, 1989. Functional Properties and Effect on Growth Suppression of Human Neuroblastoma Tumors by Isotype Switch Variants of Monoclonal Antiganglioside GD2 Antibody 14.18

3. J Clin Oncol. 2010 Oct 4. Antitumor Activity of Hu14.18-IL2 in Patients With Relapsed/Refractory Neuroblastoma: A Children’s Oncology Group (COG) Phase II Study

4. J Clin Oncol. 2009 Mar 1;27(7):1007-13. Long-Term Results for Children With High-Risk Neuroblastoma Treated on a Randomized Trial of Myeloablative Therapy Followed by 13-cis-Retinoic Acid: A Children’s Oncology Group Study

5.  Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 9505 Response and toxicity to a dose-intensive multi-agent chemotherapy induction regimen for high risk neuroblastoma (HR-NB): A Children’s Oncology Group (COG A3973) study

6. N Engl J Med. 2010 Sep 30;363(14):1324-34. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma.

7. Correspondence with investigators

8. J Clin Oncol. 2004 Sep 1;22(17):3549-57. Consolidation treatment with chimeric anti-GD2-antibody ch14.18 in children older than 1 year with metastatic neuroblastoma.

9.  Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 9505 Response and toxicity to a dose-intensive multi-agent chemotherapy induction regimen for high risk neuroblastoma (HR-NB): A Children’s Oncology Group (COG A3973) study

10.  Clinical Cancer Research August 1997 3; 1277 Phase IB trial of chimeric antidisialoganglioside antibody plus interleukin 2 for melanoma patients.

Pilot study: 131I-MIBG radiotherapy with chemotherapy after induction for newly diagnosed

Dr Greg Yanik (University of Michigan) presented preliminary results of the NANT (New Approaches to Neuroblastoma Therapy) NANT-2001-02 phase 2 MIBG + CEM (131I-MIBG radiotherapy with carboplatin, etoposide, and melphalan) stem cell transplant trial on June 23rd 2010 at the Advances in Neuroblastoma Research meeting in Stockholm, Sweden in the “Novel clinical strategies” session. The data are still under review and will be presented at the COG meeting next month. The trial has been completed but the NIH clinical trials listing has not yet been updated to reflect this.[1]

The results of 12 relapsed and refractory children treated in the phase I MIBG+CEM trial was published in 2002.[2]

The encouraging results in the phase II study with 50 refractory children who did not completely respond to induction provide promising expectations for a new pilot trial COG-ANBL09P1 using this concept for frontline therapy for newly diagnosed. The principal investigator is Dr Brian Weiss (Cincinnati Children’s) and the trial will soon begin, accruing 49 patients up to 30 years old in select locations.

Upon completing this protocol, children will also be eligible for the new phase III antibody study using ch14.18 + GM-CSF + IL2 COG-ANBL0931. This trial opened in January 2010 and will accrue 105 (currently open in 29 locations) to further establish safety and efficacy of the antibody ch14.18 given with cytokines GM-CSF and IL2 to obtain FDA approval. This trial is open to all ages.

Is this the first time MIBG will be used in frontline therapy for newly diagnosed (as opposed to just for those refractory at the end of induction)? In 2008 researchers in the Netherlands reported the use of MIBG as initial therapy before chemotherapy and surgery for 44 newly diagnosed high-risk children.

From the abstract:

The protocol dictated at least two cycles of (131)I-MIBG with a fixed dose of 7.4 and 3.7 GBq, respectively, followed by surgery, if feasible, or followed by neoadjuvant chemotherapy and surgery. This was followed by consolidation with four courses of chemotherapy myeloablative chemotherapy and autologous stem-cell transplantation (ASCT). Consolidation therapy with 13-cis-retinoic acid was given for 6 months.

Of 44 consecutive patients, 41 were evaluable after two courses of (131)I-MIBG. The objective response rate at this point was 66%. In 24 patients, (131)I-MIBG was continued as pre-operative induction treatment. Seventeen patients required additional chemotherapy before surgery. After pre-operative therapy and surgery, the overall response rate was 73%.[3]

References

1. OR58 Phase II trial of MIBG with intensive chemotherapy and Autologous Stem Cell Transplant (ASCT) for high risk neuroblastoma. A New Approaches to Neuroblastoma Therapy (NANT) Study (p. 123 ANR Programme Abstract Book, June 2010)

2. J Clin Oncol. 2002 Apr 15;20(8):2142-9. Pilot study of iodine-131-metaiodobenzylguanidine in combination with myeloablative chemotherapy and autologous stem-cell support for the treatment of neuroblastoma. PMID: 11956276

3. Eur J Cancer. 2008 Mar;44(4):551-6. Epub 2008 Feb 11. Iodine-131-metaiodobenzylguanidine as initial induction therapy in stage 4 neuroblastoma patients over 1 year of age. PMID: 18267358

C10 (p. 80) “Late effects in neuroblastoma”

Dr Lisa Diller (Boston Children’s/Dana-Farber Cancer Institute) reviewed recent published data on late effects and presented new data in the Neuroblastoma Update Course on June 21st, 2010 at the Advances in Neuroblastoma Research meeting in Stockholm, Sweden. The session was organized by Sue Cohn and Andrew Pearson and chaired by Sue Cohn and Rani George.

The Childhood Cancer Survivor Study provided long-term survivorship data for those treated for neuroblastoma between 1970 and 1986, and results on 954 5-year survivors were published in Journal of the National Cancer Institute August 2009.[1]

Of the 954 children, 832 records were abstracted, and only about 10% were stage 4 survivors, so the vast majority (~90%) of the survivor data most likely represented low and intermediate risk survivors.  Only 38% of the survivors had surgery + chemotherapy + radiation.  Of all the survivors, at least 90% had 15 years of follow-up. Of 1358 there were 84 deaths (41 recurrences)  and higher risk of death if diagnosed over the age of 5 and had multimodal therapy. The children treated for neuroblastoma were compared to a cohort of 3899 siblings to determine if there was a higher incidence of health problems. There was a higher incidence of chronic health conditions involving the neurological, sensory, endocrine, and musculoskeletal systems in children treated for neuroblastoma.

Dr Diller also mentioned evidence from soon-to-be published institutional data that advanced bone age or epiphyseal closure is more common in children treated with cis-retinoic acid than children who did not have cis-retinoic acid. There is a theoretical toxicity proposed related to cis-retinoic acid given with anti-GD2 antibody (ch14.18) because of clearance issues, but this has yet to be verified.[2]

References

1. J Natl Cancer Inst. 2009 Aug 19;101(16):1131-40. Epub 2009 Jul 31. [fulltext]

2. ANR 2010 “Neuroblastoma Update Course” ANR 2010 Abstract Programme, p 80.

Memorial-Sloan Kettering (MSKCC) has opened two more high-dose 3F8 trials for neuroblastoma

High-Dose 3F8/GM-CSF Immunotherapy Plus 13-Cis-Retinoic Acid for Consolidation of Second or Greater Remission of High-Risk Neuroblastoma

(will accrue 63 patients)

High-Dose 3F8/GM-CSF Immunotherapy Plus 13-Cis-Retinoic Acid for Primary Refractory Neuroblastoma in Bone Marrow

(will accrue 53 patients)

MSKCC is now offering four phase 2 high-dose 3F8 trials, two for frontline therapy with and without stem cell transplant, and two for relapse and refractory neuroblastoma.

These all use high dose 3F8 (80 mg/m2/day) for 4 cycles and lower dose 3F8 (20 mg/m2/d) for remaining cycles, and all trials include Accutane (13-cis-retinoic acid) and GM-CSF.

3F8 versus 13-cis-retinoic acid randomized trial just closed due to lack of enrollment

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

Lack of enrollment is cited for the reason this trial closed, which opened August 2009. This trial randomized primary refractory neuroblastoma patients to either 3F8 or 13-cis-retinoic acid, as opposed to giving the two agents together. This trial was sponsored by United Therapeutics and the goal was to obtain FDA approval for 3F8. More information is available in article posted here July 25, 2010.

Other 3F8 trials

Beta-Glucan and Monoclonal Antibody in Treating Patients With Metastatic Neuroblastoma

This phase 1 study using barley-derived beta-glucan for relapsed or refractory opened in 2001 with a planned accrual of 24 patients within 2 years. An abstract with results was presented at ASCO in 2007.[1]

From the abstract:

Fourteen children completed 1 cycle, 4 had 2 cycles, 2 had 3, and 6 had 4 cycles. Wleven patients had stable disease and 13 had progressive disease. Six children had elevated HAMA that caused withdrawal from the study.

14/23 patients with positive MIBG scans prior to therapy demonstrated improvement after one cycle. Responses did not correlate with BG dose received. 7 patients, all with residual disease survive at a median of 40 (range 24–45) months post-treatment. Conclusions: 3F8/BG is well tolerated and shows activity against resistant NB. Further clinical investigation of this novel combination is warranted.

Phase I Study of Oral Yeast β-Glucan and Intravenous Anti-GD2 Monoclonal Antibody 3F8 Among Patients With Metastatic Neuroblastoma

This study using a yeast beta-glucan opened in 2005 with a planned accrual of 42. It is currently listed as not recruiting participants.

Phase II Study of Anti-GD2 3F8 Antibody and Biologic Response Modifiers for High-Risk Neuroblastoma

This phase 2 study using beta-glucan opened in 2004 and was to accrue 74 patients. It was listed as completed in 2007, and no abstracts or publications yet.

Monoclonal Antibody 3F8 and Sargramostim (GM-CSF) in Treating Patients With Neuroblastoma

This study opened in 2003 with a projected accrual of 325. It is listed as still open and accruing, but with the high-dose trials just opening for patients with the same eligibility criterial I suspect it will be terminated soon if not already.

References

1.  Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 25, No 18S (June 20 Supplement), 2007: 9566