Report from Stockholm by John Rogers, PhD

The following report was prepared by Dr John Rogers after attending the ANR meeting. He is a physicist at the University of Kent, near Canterbury in the UK. His daughter recently finished frontline NB therapy in the UK and the ch14.18 study at Children’s Hospital of Philadelphia. Many thanks go to John for permission to share his keen insights from this significant meeting.

Advances in Neuroblastoma Research Conference 21-24 June 2010 Stockholm

Report by John Rogers, September 2010. The views expressed in his report are the author’s personal views and opinions.

Held every two years, the Advances in Neuroblastoma Research (ANR) conference for 2010 took place in Stockholm, Sweden. The 600+ participants represent the bulk of the world’s effort into treating and curing neuroblastoma. All of the presentations were spread over four days and this report details some of what was presented. The conference is aimed at researchers and clinicians.

This report is intended to give an outline of some of the major topics and talking points raised at this year’s conference. It is aimed at parents of children with (or who have had) neuroblastoma and others with a general interest, and is written without a medical background. Although written from a U.K and to some degree European point of view, as the effort is international and most new treatments appear to be coming from the United States, it is relevant for all.

General Interest

Over the course of the conference presentations were given detailing general advances in related fields that could have an impact on neuroblastoma. From a talk that touched on a type of Omega-3 (that could be nature’s own anti-cancer wonder drug) to talks that described viruses commonly present in cattle that could stimulate cancer in humans, they were wide ranging and were primarily designed to get people thinking and discussing the topics.

A more immediate presentation was from Dr. Maris, Philadelphia where he described the impact of genetic testing on finding the roots of neuroblastoma. The clear point made was that neuroblastoma is a genetic disease, and it must be stressed that this is not the same as hereditary. It is widely known that a very small subset of neuroblastomas are hereditary.

The point made here was that evidence is building (from genetic analysis) that there is a genetic basis for being at-risk for neuroblastoma. In other words, environmental factors will not just ’cause’ neuroblastoma, despite what was suspected just a few years ago at academic meetings or what ‘conspiracy theorists’ will still tell you today.

Another interesting presentation was given Dr. Pat Reynolds of Texas who presented some reasons why drug companies would find it difficult to invest in a drug exclusively for neuroblastoma. The numbers involved and the regulatory hurdles in place mean they could never have a chance of recovering costs (minimally estimated to be up to $100 million or more).

A large section of the conference was devoted to Cancer Stem Cells (or tumour initiating cells, TICs). This work is currently an academic subject, and though potentially important for long-term success, is still in early development. Ideas expressed at the conference revealed current controversy, but as far as how this affects treatments now, it appears there remains much work to be done.

Frontline Treatment

From my view there were three main areas of interest regarding frontline therapy. These were the success of the ‘new’ ch14.18 antibody treatment, the use of genetic testing (specifically ALK) and new analysis of survival.

ch14.18

This year’s conference marked the first ANR gathering since the announcement in March 2009 that there was a significant improvement in survival in those patients randomized to receiving ch14.18 antibody with cis-retinoic acid as per the COG study (within 100 days of transplant and with the two cytokines IL-2 and GM-CSF) versus those receiving only cis-retinoic acid.

Alice Yu presented the results of the study again, and some history is appropriate for the treatment and future direction.

The COG study result was without a doubt the major news of the conference (even though this is at the time of writing 15 months old) and its implications for future survival was obvious. Never in history has a 20% improvement in survival resulted from a single treatment for high-risk neuroblastoma. It was pointed out publicly at the conference the puzzling situation that has now arisen: the COG institutions offer one type of ch14.18 treatment (the proven antibody with both cytokines) whereas SIOPEN randomizes between a slightly different antibody (ch14.18/CHO which is made from hamsters as opposed to mice) only, or that antibody with IL-2 (administered differently). In addition, there are other slightly different German trials.

The question was asked ‘Does it make sense to all be asking slightly different questions?‘ I would have put it more bluntly with the additional statement of ‘knowing the result of the COG study’ the only reason the European institutions are suddenly offering the ch14.18 treatment is the result of COG study. Yet none of the European institutions currently include it in their trials, let alone offer it as a ‘standard’ treatment. Some reasons floated are the practical difficulties in introducing such a complex treatment across multiple sites, but ultimately, after thoroughly pursuing the question I found it was due to regulatory and paperwork issues. After speaking with Dr. Ladenstein (Austria), who is leading the SIOPEN trial, I was left very disappointed with the situation, so long after the COG results. I feel it is not an acceptable reason if this is the case.

ALK

The discovery of the ALK mutation in 80% of familial neuroblastoma (the very rare hereditary form of neuroblastoma, around 1% of all neuroblastoma cases), representing a minority of cases, was an important step in research in this field. It also demonstrated the power of genetic analysis to introduce new treatments quickly. A drug to target ALK was already available and this is now under trial at some COG institutions (presented by Dr. Mosse).

Further to this, it was presented that resistance is expected to develop to this treatment (has been modelled) and therefore a combination of the Pfizer drug together with a monoclonal antibody is prepared to overcome this. Without knowing the outcome of these trials it is difficult to assess how important the current trial of ALK targeted treatment will be for neuroblastoma.

The speed at which it has been implemented in the U.S. is quite stunning and is a good indicator for the future there (that new candidate drugs could be implemented quickly). In this sense, the ALK discovery is more important to talk of in the way genetic testing can and will be used for prognosis and treatment on an individual frontline basis as well as for research for new treatments (something that is a difficult but crucial problem for the INRG and something that UK Prof. Pearson touched upon in his presentation). What it means for European centres and U.K. is not clear as the implementation of genetic testing of the tumours for this and other mutations, together with new trials of target drugs, may take years on a U.K. or European setting given the current situation.

Analysis of Survival

There were some important presentations regarding updated figures and studies.

More than one presentation dealt with analysis of treatment stratification. The use of a ‘wait and see’ approach for the low and intermediate risk presentation was discussed in one report. The COG presented the latest figures for survival of children with stage III disease. Although the figures did not separate out children who received the antibody and those who did not, figures of long term EFS around 90% for non-mycn amplified disease and approximately 70% for mycn-amplified disease were reported.

Analysis of time to relapse was reported on: while a relapse is never good news, it was reported that from analysis of the INRG database the ‘worst’ time to relapse is between 6 and 18 months from diagnosis. It should be made clear that there are still survivors from this period too. Late effects of neuroblastoma treatments were reported on. A presentation from the United States reported on the increased incidence of chronic health problems in survivors (from the harsh treatment). One of the surprising specifics of the report was the increasingly recognized side effect of Accutane treatment. It can be thought of as increasing bone age, so in effect survivors’ growth is affected (there is a risk of this effect).

The proven benefit still outweighs this possible side effect as the alternative is possible relapse, but it will be something that physicians will weigh into their judgements. Similar presentations came from the UK and Germany. Both reports showed a minority of survivors living free from any side effects, though for most the side effects, though serious, are manageable. It appeared from the multiple presentations that touched on these areas that most of the side effects could be attributed to the high doses of chemotherapy. Recognised treatment areas that also contribute to long term side effects are radiotherapy, surgery, Accutane and stem cell transplant.

For some types of tumours (usually low risk) there were reports of success in the use of surgery only. The target for would be to reduce the need for radiotherapy and stem cell transplant for as many children as possible (treatments with recognized long term implications).

Relapse and Refractory Treatments

One of things that make neuroblastoma a ‘difficult’ disease for doctors and researchers to approach and treat is the very varied nature with which it presents and responds to treatments. An interesting presentation regarding relapse treatment was from Germany, where it was reported that a group of relapse patients who received a stem cell transplant are appearing to achieve around 20% long term survival. This is a key survival option in Europe where there is not the slew of new types of treatment available for relapse and refractory patients that seem to be appearing in North America. It should be noted that the numbers were small and although it is early days, it is a “relapse treatment” that is widely available.

MIBG treatment figures were reported on at the conference, with one study showing around 50% overall survival at 4yrs after relapse (a NANT study that included high dose chemotherapy with MIBG presented by Dr. K. Matthay).

Dr. Kushner from the Memorial Sloan-Kettering Cancer Center (MSKCC) presented updated results of the treatment offered at their institution, specifically 3f8 with GM-CSF and Accutane for consolidation of 2nd complete or very good partial remission. It was an interesting report and stood out for me in one area. This was relapse treatment. Presented was a comprehensive analysis of relapse treatments. I am sure most other institutions do have strategies, but it appeared to me that at MSKCC it was more developed. At least in the area of CNS relapse they do offer a unique treatment in the form of the 8H9 antibody.

Future Direction

As someone that is in a position of recently being very interested in front line treatment options and now is becoming aware of relapse options, the ANR conference was informative.

During one session senior figures from the COG, SIOPEN and GPOH presented their vision for where treatment will progress.

John Maris from Philadelphia spoke of how induction treatment would likely change. It would hopefully include molecularly targeted agents and more extensive testing would enable further risk stratification. He noted the current ch14.18 trial (with IL-2 and GM-CSF), which is now purely being run to collect toxicity data for FDA approval. Other ways treatment could be improved mentioned were: in future there would be the hope of improving the efficacy of the antibody (via a trial of hu14.18 vs. ch14.18), adjustment of combinations of chemotherapy to reduce toxicity, introduction of fenretinide as a substitute for Accutane and the integration of basic science into relapse treatment.

Ruth Ladenstein from Austria spoke for SIOPEN, and detailed the current ch14.18/CHO antibody trial in their areas (including the UK). This started accruing last year and randomizes between antibody only and antibody and subcutaneous IL-2. They continue to accrue children on this trial and see the next step to provide antibody for relapsed and refractory patients. As well as the antibody the introduction of new chemotherapy agents and combinations is seen as one of the next steps.

Thorsten Simon spoke for GPOH and detailed the positive steps taken to use banked tumours for research and prognosis stratification. The current survival of around 35% long term survival for the German NB97 protocol was mentioned (retrospective comparison of the NB90 protocol with the NB97 protocol was used to dismiss the ch14.18 antibody treatment several years ago).

Currently there are several trials running in Germany that include ch14.18 after SCT and trials that have ch14.18 with IL-2 subcutaneously. Future work is seen as; reintroducing the ch14.18 widely in some form, improvement of the risk stratification, reduction of the late effects and the introduction of targeted therapies.

There were too many other talks to mention that showed early in-vitro results that point to a more sophisticated future in neuroblastoma treatment.

Discussion

The ANR 2010 conference in Stockholm was one of the best organized and run conferences I have been to (I have been to a lot). The doctors and researchers worked hard and are as a rule, I think, committed and dedicated. If anyone reading is involved in raising money for researchers to cure this disease, then from what I saw, their commitment shouldn’t be questioned. For a very few, the performance may be another matter, as well as the common sense, but I’ll come to that.

The immunotherapy treatments are destined to be part of frontline treatments. Currently the only treatment in this category proven to work is the COG ch14.18 treatment with IL2 and GMCSF. Despite this, SIOPEN institutions and those in Germany are proceeding with modified trials in the hope of either reducing treatment toxicity or improving the benefit from the COG protocol. I personally have no doubt that this is unethical, but all the European institutions look set to proceed until they have a strongly statistically significant result.

That the COG study have still not published their updated results in a major medical journal 18 months after the public announcement of improvement in survival is a mystery. Once published, it would be hoped that collaboration would take over from the current situation.

MSKCC continue to offer 3f8 and this will continue to be a key treatment option if a child does not qualify for 14.18 trials. It is worth noting (though I have not seen anyone point this out) that the success of the COG Ch14.18 trial in frontline treatment is to some degree a vindication of the reports of 3f8 from MSKCC. Their use of immunotherapy for  neuroblastoma since the mid-eighties was ground breaking and means we should pay attention to what new treatment options are developed there.

The key news at this year’s ANR conference was the impact of genetic analysis. Some will tell you that everything from pollution to food additives causes neuroblastoma. They might be right, but it isn’t proved (as it isn’t proved mobile phones are dangerous or that living close to power lines is harmful or that eating organic food will stop you getting cancer if you get my point – only weak research that suggests this, but that is not the same as proved). What is being proved is that you can be genetically predisposed to developing  neuroblastoma. I think that is important for some parents who do and always will question ‘what they did wrong’. Nothing.

The way this new genetic testing is going to be implemented is a major challenge for the neuroblastoma clinicians. This is especially true in Europe where regulation is a drag on getting the latest treatments to clinic quickly.

The continuing situation with the ch14.18 treatment in Europe is amazing, so I’ll go into some detail.

Currently within SIOPEN, as far as I am aware, children in frontline treatment are still being randomised to receive either antibody only or antibody with IL-2. I heard a figure of 70 so far at the ANR. Concerns about the antibody-only treatment go back to the fact that research in Germany published in 2004 concluded this treatment did not work. [1] Why? Now it has been suggested that the original German trial was faulty and anyway was not a randomised trial.

Verbally at the ANR 2008 the same researchers in Germany reportedly commented that they had seen less late relapses in the group who received the antibody, and in 2010 at the ANR showed the same data as used to conclude the antibody only did not work.

Now, several further years out, the comment was ‘coming along nicely’. Now, again, children are receiving this treatment. Over in Germany today they give antibody with IL-2 in some places and antibody only in others, but have widened access to relapse patients and others. All of this activity has only happened because of the dramatic success of the COG trial. The strong evidence for the beneficial use of ch14.18 is in the COG protocol with the two cytokines (GM-CSF and IL-2). Ignoring the fact that the antibody used in Europe is technically a little different to that used in the COG, you would expect that children in frontline treatment would be offered the best available treatment.

When SIOPEN met to discuss the new trial in light of the COG result, I have to assume some left common sense at the door on the way in. If the intention was to reduce the toxicity of the treatment, they could have designed the new trial to start with the proven COG protocol and ‘drop down’ to the other treatments if toxicity proved to be a problem. Quite simply, an academic question to move the research forward and improve treatment for tomorrow should not come at the expense of children today (several dozen children across SIOPEN have received antibody only this year). From what I can tell this is the only explanation of the situation.

If the research is taking a ‘leap of faith’ that the original German results do show significant benefit (and therefore that ch14.18 without cytokines is a potent treatment), that ‘leap of faith’ should extend to a comparison of the COG results and the different protocol. If it ever becomes possible to directly compare the current European treatment to the current COG protocol, I do hope the treatments are as good if not better as hoped. But if any one of them is not, I for one will be pointing it out.

International co-operation and conferences like the ANR mean that, at least in western nations, treatment protocols are similar. A notable difference is the number of truly unique types of trials available for children in relapse in North America (I am thinking of trials such as those involving ABT-751 and fenretinide). I make a difference between number of trials and ‘truly unique’ because it is much easier path to tread for a researcher to adjust a protocol with different amounts of (already approved by health watchdogs) chemotherapy than use new drugs or treatments never used before in children. It is in this area where doctors and researchers can be helped to find the cure, encouraging further international collaboration and lobbying for the relaxation of restrictions on treatments where children are out of treatment options.

As a final thought, doctors and researchers are aware and do consider the facts of life in the  third world. Almost all the treatments presented at the ANR conference showing increasing rates of survival are just impossible there.

Further Information

In addition to the site www.nbglobe.com an incredibly useful email posting service can be found at: http://listserv.acor.org/SCRIPTS/WA-ACOR.EXE?A0=N-BLASTOMA

I would advise anyone involved in neuroblastoma to sign up for this service. It is “an unmoderated discussion list for patients, family, friends, researchers and physicians, to discuss clinical and non-clinical issues and advances pertaining to neuroblastoma.”

Disclosure

The 2Simple Trust paid for John Rogers’s conference registration fee. He covered his own travel, subsistence costs and hotel costs. His daughter recently finished treatment for neuroblastoma (III myc-amp) at The Royal Marsden, U.K. and The Children’s Hospital of Philadelphia, U.S.A.

J. Rogers

rogersjohna@gmail.com

Abbreviations

References (ch14.18 and cytokines)

1. 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. PMID: 15337804

2. J Clin Oncol. 2009 Jan 1;27(1):85-91. Epub 2008 Dec 1. Phase I study of ch14.18 with granulocyte-macrophage colony-stimulating factor and interleukin-2 in children with neuroblastoma after autologous bone marrow transplantation or stem-cell rescue: a report from the Children’s Oncology Group. www.ncbi.nlm.nih.gov/pmc/articles/PMC2645092/

3. Biochem Soc Trans. 2002 Aug;30(4):518-20. Targeted cytokine delivery to neuroblastoma. PMID 12196127

4. Blood. 2002 Jun 1;99(11):4166-73. Antidisialoganglioside/granulocyte macrophage-colonystimulating factor fusion protein facilitates neutrophil antibody-dependent cellular cytotoxicity and depends on FcgammaRII (CD32) and Mac-1 (CD11b/CD18) for enhanced effector cell adhesion and azurophil granule exocytosis PMID: 12010822

5. J Clin Oncol. 2000 Dec 15;18(24):4077-85. Phase I study of chimeric human/murine antiganglioside G(D2) monoclonal antibody (ch14.18) with granulocyte-macrophage colonystimulating factor in children with neuroblastoma immediately after hematopoietic stem-cell transplantation: a Children’s Cancer Group Study. PMID: 11118469

6. Cancer. 2000 Jun 15;88(12):2838-44. A phase I dose escalation of combination chemotherapy with granulocyte-macrophage-colony stimulating factor in patients with neuroblastoma. PMID: 10870069

7. Blood. 1989 May 15;73(7):1936-41. GM-CSF enhances 3F8 monoclonal antibody-dependent cellular cytotoxicity against human melanoma and neuroblastoma. PMID: 2653466

Cologne, Germany has won the bid for the ANR 2014 meeting

Cologne is the home of the reknown NB expert Dr Frank Berthold:

As Head of the Paediatric Oncology Department at the University Hospital of Cologne and President of the ANRA Association from 2006 to 2008, Dr. Frank Berthold has seized the initiative to bring this extremely important scientific convention for the field of neuroblastoma to Cologne.

Dr Berthold has authored and co-authored more than 150 journal articles on neuroblastoma going back to 1981 (PubMed), and at the recent ANR 2010 meeting his name was listed on 19 abstracts. His colleagues include a long list of NB researchers: Drs Manfred Schwab, Barbara Hero, Frank Speleman, Thorsten Simon, and many others. Their recent work includes studying genomic profiles (400+ NB samples tested using microarray analysis) with the potential to identify more definitive prognostic information for risk assignment.

The next ANR (2012) will be held in Toronto, home of the University of Toronto and SickKids Hospital where researchers and clinicians interested in NB include Drs Sylvain Baruchel, Meredith Irwin, and David Kaplan. Their current neuroblastoma research includes identifying, isolating, and characterizing tumor initiating cells.

New trial for neuroblastoma opens at University of North Carolina – Chapel Hill

Temsirolimus and Valproic Acid in Treating Young Patients With Relapsed Neuroblastoma, Bone Sarcoma, or Soft Tissue Sarcoma

This phase I study will enroll 20 patients age 2 to 18 to determine the maximum tolerated dose of temsirolimus in combination with valproic acid, as well as safety, pharmacokinetics, and progression-free survival. Principal investigator is Dr Julie Blatt.

Valproic acid (VPA) has been used to treat epilepsy for decades. Recent research has show VPA to be a histone deacetylase inhibitor (HDACi), cell cycle modulator, and an antiangiogenetic agent. VPA also induces tumor cell death. Czech researchers published in March 2010 :

Preclinical data suggest that the anticancer effect of chemotherapy is augmented when VPA is used in combination with cytostatics. Besides the effects of pretreatment with HDAC inhibitors, which increases the efficiency of 5-aza-2′-deoxycytidine, VP-16, ellipticine, doxorubicin and cisplatin, pre-exposure to VPA increases the cytotoxicity of topoisomerase II inhibitors. There are two suggested cell death mechanisms caused by potentiation of anticancer drugs by HDAC inhibitors that are neither exclusive nor synergistic. The first involves apoptosis and can be both p53 dependent or independent; the second involves mechanisms other than apoptosis. In resistant chronic myeloid leukemia (CML), VPA restores sensitivity to imatinib. We have demonstrated the synergistic effects of VPA and cisplatin in neuroblastoma cells. VPA can be taken orally, crosses the blood brain barrier and can be used for extended periods.[1]

There are 229 valproic acid clinical trials listed in the NIH database; 68 are recruiting and 26 are for cancer conditions. There are 88 temsirolimus trials currently open to treat cancer.

In 2008 Italian researchers reported on the mechanism of cell death from valproic acid on 2 NB cell lines:

To our knowledge, this is the first demonstration of an HDAC inhibitor-dependent activation of the p53 pathway in neuroblastoma cells known for an abnormal p53 function that is responsible for their resistance to chemotherapy. As a consequence of this ability to restore p53 function, we consider HDAC inhibitors to be a promising class of drugs for the treatment of chemoresistant neuroblastoma tumours.[2]

Temsirolimus is a specific inhibitor of mTOR (mammalian target of rapamycin) and interferes with the synthesis of proteins that regulate proliferation, growth, and survival of tumor cells. FDA approval was granted in 2007 for the treatment of advanced renal cell carcinoma. It was used previously in a frontline NB study at St Jude’s. The NIH clinical trials site currently lists 15 open trials for children with solid tumors using temsirolimus in combination with a wide range of other agents.

There is apparently no published data (or submitted meeting abstracts) in the medical literature for the preclinical work using the combination of temsirolimus and valproic acid on cancer cell lines.

References

1. Curr Drug Targets. 2010 Mar;11(3):361-79. Valproic Acid in the complex therapy of malignant tumors. PMID: 20214599

2. Br J Pharmacol. 2008 Feb;153(4):657-68. Inhibitors of histone deacetylase (HDAC) restore the p53 pathway in neuroblastoma cells. PMID: 18059320 [free fulltext]

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

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

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

Current member institutions are:

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

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

Open trials are:

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

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

CEP-701

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

Oral fenretinide, IV fenretinide

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

BSO/Melphalan

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

Zometa + Cytoxan

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

Vorinostat (SAHA) and cis-retinoic acid

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

Aurora A kinase inhibitor

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

Emphasis on older patients

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

References

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

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

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

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

The trials currently open are:

.

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

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

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

.

DFMO time line: 690 days

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

April 17th 2008 ~

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

March 14th 2009 ~

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

March 8th 2010 ~

First patient enrolls on DFMO study in Vermont

Parent advocates ~

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

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

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

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

References

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

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

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

New donor transplant trial open for relapsed or refractory neuroblastoma

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

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

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

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

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

History of allogeneic transplants in neuroblastoma

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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