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

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

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

See NIH listing for rationale:

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

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

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

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

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

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

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

The press release is below:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Notes 

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

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

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

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

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

*⁴ The exact court order is as follows:

“IT IS DECLARED ON AN INTERIM BASIS THAT

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

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

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

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

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

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

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

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

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

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

Abstract:

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

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

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

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

Personalized medicine has arrived to pediatric cancers: neuroblastoma

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

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

Inclusion Criteria:

Read more about this trial here:

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

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

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

Viral study comparison (PDF document)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Symposium for parents and researchers June 23 at VARI

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

Poster presentation by Dr Sholler and colleagues at AACR 2011:

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

A new trial opens: prolonged use of isotretinoin

Aflac ST1001 Prolonged Isotretinoin

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.

New clinical trials using oncolytic viruses for pediatric solid tumors

Solving Kids’ Cancer hosted a fantastic webinar on oncolytic viruses for children with solid tumors January 25, 2011.

All four principal investigators of five trials for children presented–starting with an overview given by Dr Tim Cripe:

• Dr Michael Burke on Seneca Valley virus (NTX-101/SVV-001)
• Dr Timothy Cripe on herpes simplex (HSV1716) and vaccinia (JX-594)
• Dr Corey Raffel on modified measles (MV-CEA)
• Dr E. Anders Kolb on reovirus (Reolysin)

The meeting was recorded and the video is 1 hour and 40 minutes long.

Nearly 100 parents and researchers participated in this live event.

These novel, low-toxicity therapies are advancing quickly and present great promise– perhaps one day children with cancer will be cured without chemotherapy!

Oncolytic Virotherapy for Pediatric Solid Tumors from D Ludwinski on Vimeo.

Many therapies, robust rationale needed

For years I have (obsessively) tracked clinical trials and therapies available to children with relapsed and refractory neuroblastoma, driven by hope that curing relapsed NB is possible. Since there are many therapies for “unspecified solid tumors” as well as specifically for neuroblastoma, the resulting variety of trials is quite astounding.

I started tracking these trials for possibilities for my son, discussing with other astute parents, and watching and praying for responses in their children to new treatments. I searched for meeting abstracts for unpublished results, and scrutinized the published results of trials. Between the heterogeneity of the disease and the varied treatment paths of each child the comprehensive study of effective relapse therapies is nearly impossible.

A parent naturally wants to know what options are available when their child is fighting for survival–but far more critical is knowing which option to choose at a given point in time. Finding all the options is conceivable, but determining the best possible option is a completely different problem. The question “What is available?” is easy to answer. The question “What should we do?” is not easy to answer.

In part, this activity led to a bigger project. Several volunteers (about 30 in all) worked on a “NB Parent Handbook” during the period 2006 – 2008 for Children’s Neuroblastoma Cancer Foundation. The entire book (220 pages) can be found on the CNCF site at cncfhope.org. The project is ongoing–new chapters are being added and material is being updated. I am currently updating the relapse chapter.

My purpose in posting this update on relapse treatment is two-fold:

1 – draw attention to the Handbook project and attract more help

2 – generate some dialogue concerning the question of relapse therapy — is a “rational” approach even possible?

Approach to relapse therapy differs widely from one study group to another, and one institution to another. There are no firm rules or universal recommendations, although one study group has recently recommended a very general plan for NB relapse treatment using salvage chemotherapy and MIBG only.  Much depends on the experience of the treating oncologist, careful consideration of the child’s history and status, and trials that may be open and accruing at the local institution.

What makes this landscape so incredibly complex is that there are many options, but the options are spread far and wide. Once a parent begins to consider options at a distant facility, the close oversight of the oncologist most familiar with the child is often jeopardized, and the parents have to make choices based on limited information.

It is impossible to describe just how terrifying and overwhelming it is for a parent to walk away from a child’s trusted primary oncologist and the loyalty developed for the home hospital, into the unknown. An unintended but serious consequence is the risk of the parent assuming full responsibility for the outcome–especially when things do not go well.

“Of all the treatments available, what is best for my child at this point in time?”

Think about how difficult this is to answer. The primary oncologist has a limited set of treatments to offer, and limited experience with treatments that are not offered at the home hospital. This creates a difficulty for the parents when they look beyond the confines of the home hospital, and strive to understand the potential for treatments available elsewhere. What we need is an oncologist who is familiar with every treatment and intimately knows the patient, and can recommend the best course of action in a thoroughly objective manner. But the reality is — that is asking too much — no oncologist has the time to scrutinize 50 or 100 open trials in addition to many off-the-shelf therapies to determine the best fit for a particular child. There is no incentive to send patients away, either.

So what is the solution? Is there a solution? I don’t know. That is why I am asking for feedback.

The medical community recognizes that there is a role in this arena for patient advocates. However, the patient advocate role presents a grave quandary — the advocate may be trusted for lack of any agenda other than concern for a child’s life, but the patient advocate is not a doctor and not qualified to recommend any treatment decisions.

Your feedback, thoughts, ideas, concerns, and brainstorms are greatly appreciated. What if you had a comprehensive list of every treatment possible, right now. How would you chose the best treatment for a given situation? What would help you the most? What do you think?

An outline of the of the draft follows — see the CNCF website for the full chapter (pages 113- 123).

Dealing with Relapse — draft outline

(treatments discussed are being updated now)

Beginning Relapse Treatment.

Relapse Treatment Rationale

Your doctor will take into consideration many factors when recommending treatment for relapse:

• Age of child
• How long the child was in remission after treatment
• Where disease is located
• How much disease (tumor burden)
• Rate of tumor growth
• Prior treatment history
• Organ function
• Available stem cells
• Changing characteristics of the child’s NB, or new information
• Goals of treatment

Treatments for relapse vary in approach and intensity.

Can we know what will actually work against my child’s NB?

• High-dose chemo/radiation.
• Medium-dose chemo.
• Low-dose chemo.
• Targeted drugs (“small molecules”) and biologics.
• Immunological treatments – antibodies.
• Immunological treatments – vaccines and viruses.

Second remission treatment issues.

Special issues with late relapse.

Maximizing your child’s treatment options is an important part of the relapse decision process.

Weighing quality of life and other considerations.

Investigating doctors and clinical trials.

It is common for children to see one or more of the following treatment categories during the battle against relapse:

• Enrollment on phase I or II clinical trials. These may be specific to NB or for unspecified solid tumors. Phase III studies are rare for relapsed pediatric tumors including NB.
• Treatment “per” a clinical trial protocol although not enrolled, if not eligible and drugs are already FDA approved.
• Treatment with “off the shelf” agents that are FDA approved.
• Treatment on a “compassionate use” basis with drugs not yet FDA approved.

Phase I and Phase II distinctions.

Timing of entry.

Interpreting “response” from study reports.

Risks and benefits of treatment.

SUMMARY

The rigors of relapse treatment cannot be minimized. You may be consulting with new and different doctors, traveling far from home for your child’s treatment on various clinical trials, weighing difficult quality of life issues for your family, and at times making treatment decisions based on a leap of faith. An oncologist with experience in treating relapsed NB, and equally importantly, someone you feel comfortable with and can communicate with effectively, is the key resource in making your treatment decisions. However, the more informed you are, the more comfortable you will feel that you have made the best possible choices for your child.

There are successes in relapse situations.  Unfortunately, because the relapse population involves such variation in relapse sites, in amount of disease, types of treatments tried, multiple treatment centers, and many other variables, it is virtually impossible to report long-term survival statistics. Even so, the reports of long-term survivors in some studies, the increasing numbers and approaches of available treatments, and the anecdotal evidence — all suggest that the prospect for long survivorship after relapse is improving.  There is increasing hope for relapsed children, and having an NB team who expresses and shares your hope is also essential to this stage of the battle.