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]

Dr Michael Burke from the University of Minnesota is the Principal Investigator of the Seneca Valley Virus trial COG-ADVL0911:

“Seneca Valley Virus-001 in Treating Young Patients With Relapsed or Refractory Neuroblastoma, Rhabdomyosarcoma, or Rare Tumors With Neuroendocrine Features”

Dr Burke gave a presentation on this trial at the CNCF parent conference July 10, 2010.

By early July, this Phase I trial had enrolled three children (two with NB) since March 2010, with a planned accrual of 34 children, and is currently open at:

• Alabama ~ UAB Comprehensive Cancer Center
• California ~ Children’s Hospital of Orange County
• Illinois ~ Children’s Memorial Hospital – Chicago
• Indiana ~ Indiana University Melvin and Bren Simon Cancer Center
• Michigan ~ C.S. Mott Children’s Hospital at University of Michigan Medical Center
• Minnesota ~ Masonic Cancer Center at University of Minnesota
• Missouri ~ Siteman Cancer Center at Barnes-Jewish Hospital – Saint Louis
• Ohio ~ Cincinnati Children’s Hospital Medical Center
• Pennsylvania ~ Children’s Hospital of Pittsburgh
• Texas ~ Baylor University Medical Center – Houston
• Washington ~ Children’s Hospital and Regional Medical Center – Seattle

Seneca Valley Virus, or NTX-010, is the first picornavirus (small RNA virus) to be evaluated as an anticancer agent. This virus is very small–about one-fourth the size of adenovirus so can penetrate tumor cells and replicate rapidly. It is highly selective for cancer cells with neuroendocrine features and does not harm normal cells, humans lack pre-existing neutralizing antibodies (ie prior exposure in humans is very rare), does not cause disease in humans or animals, and not transmitted among people or animals. It was accidentally discovered in a laboratory growth medium, and thought to be naturally occurring in pigs. [1]

NTX-010 was tested first in adults, with a trial that opened in 10 locations in 2006 and enrolled 42 adults with tumors with neuroendocrine features. This trial was sponsored by Neotropix and the results of this phase I study were presented at the 2009 ASCO meeting:

NTX-010 is the first picornavirus to be evaluated as an anticancer therapeutic. A single IV dose of 10¹¹ vp/kg of NTX-010 is safe, has predictable viral kinetics, and shows promising activity against neuroendocrine tumors. [2]

A Phase II randomized study for small cell lung cancer has recently opened and will enroll 99 adults.[3]

Neotropix scientists published a summary of the preclinical work with Seneca Valley Virus on cell lines and mice in 2007, and the image below shows the response of SCLC small-cell lung cancer tumors in mice to a single infusion of the virus.

The authors concluded on p. 1632:

The life cycle of SVV-001 is very rapid and is completed within 12 hours, thus allowing for rapid spread to neighboring tumor cells and several rounds of virus replication before the development of an immune response. SVV-001 is a simple single-stranded RNA virus and therefore does not require an intermediate DNA step during replication, so there is no possibility for insertion mutagenesis of viral RNA into the host genome. Moreover, the genomes of picornaviruses carry no oncogenes that may induce tumors in animals. Finally, SVV-001 replicates in the mouse, which is a widely accepted relevant model in which to study toxicity and efficacy.

Nonpathogenicity in humans and animal species and stability of the viral genome in vitro and in vivo are two other desirable properties of oncolytic viruses. SVV-001 is not linked to any disease condition in pigs, the natural host of the virus (Hales LM, Jones BJ, Knowles NJ, Landgraf JG, Swenson SL, Skele KL, et al.: unpublished data). We found that systemic administration of the virus into immune-competent and immune-deficient mice was well tolerated and caused no toxicity. Moreover, to evaluate the ability of SVV-001 to adapt to replicate in nonpermissive cells, the virus was passaged intentionally three times in nonpermissive cell lines A549, H460, and Hep3B, and no virus was produced, suggesting that the virus did not change its tropism (data not shown). In addition, no antibody escape mutants of SVV-001 were produced in PER.C6 cells when SVV-001 was grown with media containing anti-SVV mouse hyper immune serum (data not shown). These data suggest that the genome of SVV-001 is stable.

Our study has several potential limitations. Although the in vivo efficacy data reported here were generated using immune-deficient athymic mice, it is unknown whether immune responses in cancer patients would limit the effectiveness of SVV-001 in patients and prevent repeat administration, if it was necessary. In addition, studies were done using subcutaneous tumor models using well-defined cell lines and, as such, may not simulate patients with metastases. Immune-competent and metastasis models are currently being explored to address these limitations.[4]

The virus is toxic to embryonic cell lines, so the first adult study required surgical sterilization of females who were of childbearing age.[5]

The preclinical pediatric testing was just published (Aug 2010) “Initial testing of the replication competent Seneca Valley virus (NTX-010) by the pediatric preclinical testing program” (p. 299):

NTX-010 shows high-level activity against selected cell lines and xenografts from the PPTP’s in vitro and in vivo panels. A single dose of NTX-010 induced complete responses in 8 of 10 of the rhabdomyosarcoma and neuroblastoma xenografts evaluated, including all 4 alveolar rhabdomyosarcoma xenografts studied. Of note is the similar sensitivity to NTX-010 in Rh30 xenografts (established at diagnosis) and Rh30R xenografts (established at patient relapse), suggesting NTX-010 has therapeutic utility in both chemosensitive and chemorefractory disease.[6]

Considering this trial for a child with relapsed or refractory neuroblastoma

Phase I studies are safety studies, so evidence of efficacy has not been established. Since phase I agents are usually tried in adults first, it is encouraging if responses are seen, but of course adults have different tumors (in the phase I adults with carcinoid tumors showed responses[2]). All of this information indicate some agents hold more promise than others. The attractive thing about this study is the lack of toxicity, and the short time commitment to the study (infusion of virus, then test blood and stool for 28 days or until virus clears).  A child with a small tumor burden, or a child with stable disease may be a good candidate for this trial since the risk of progression while on study may be minimal. As always, discussing treatment options with a trusted pediatric oncologist is essential.

References

1.  NTX-010 A Novel Mechanism Anti-Cancer Agent in Phase I/II Clinical Development (2007 Neotropix summary)

2. Rudin CM, Senzer N, Stephenson J, et al. Phase I study of intravenous Seneca Valley virus (NTX-010), a replication competent oncolytic virus, in patients with neuroendocrine (NE) cancers. J Clin Oncol 2009;27: abstract 4629.

3. Seneca Valley Virus-001 After Chemotherapy in Treating Patients With Extensive-Stage Small Cell Lung Cancer; NCT01017601

4. J Natl Cancer Inst. 2007 Nov 7;99(21):1623-33. Epub 2007 Oct 30. [fulltext]

5. Safety Study of Seneca Valley Virus in Patients With Solid Tumors With Neuroendocrine Features;  NCT00314925

6. Pediatr Blood Cancer. 2010 Aug;55(2):295-303. PMID 20582972

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

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

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

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

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

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

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

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

References

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

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

Recap of presentations

I have so much more to report on ASCO and ANR (coming soon), but should share information about this conference first. This year’s conference was exceptional.  The presentations covered a wide range of important topics, and I am convinced the 130 parents in attendance walked away with essential information for their families. This conference is extraordinary in that no rare disease organization provides such a quality forum for education by top experts in the field—for free, including hotel, meals, children’s program, bereavement session, and even transportation costs for those with the greatest need.  I have met attendees from Australia, Turkey, and other nations. This concept is unprecedented, and CNCF president Pat Tallungan works incredibly hard at the challenge to raise funds for this conference every year. CNCF accepts and appreciates donations for this conference (see www.nbhope.org ).

Dr Yanik in particular expressed his amazement at the difficult and insightful questions posed by the parents. I was struck by the contrast I had just seen at the ASCO and ANR meetings. Attendees come in and out during presentations, and often no questions are asked so no discussion ensues. I was amazed at how many researchers travel great distances to give five minute presentations, or just show a poster. The presenters at this conference spoke for at least 30 minutes and appreciated a very attentive audience. The impact is significant in that parents learn first hand from experts about this disease, and are exposed to information about new treatments which can facilitate quick enrollment on trials.

Speakers and topics were:

Susan Cohn ~ Overview of Neuroblastoma and Intermediate Risk Study

Yael Mosse ~  ALK inhibitor, Aurora A Kinase inhibitor, and ABT-751 Update

Giselle Sholler ~  Update on NMTRC Trials

Patrick Reynolds ~ Adult Oncology Connection/Update on Fenretinide trial

Shakeel Modak ~   3F8, NK Cell Therapy, and 8H9 Update

Sandeep Soni ~  Reduced Intensity Allogeneic Transplant

Kate Matthay ~   Overview of NANT trials

Peter Zage ~  3F8/Accutane Randomized Trial (national)

Greg Yanik ~  MIBG Scoring/Ultratrace Trials

Michael Burke ~  Oncolytic Virus Trial

Melissa Alderfer ~   Post Traumatic Stress Syndrome

David Salsberg ~  Neuropsych/learning issues facing NB Children

A few presentations will be covered in each post.

Overview of neuroblastoma and intermediate risk study update

Dr Sue Cohn gave a great overview on neuroblastoma and an update on the current intermediate risk study ANBL0531 (see http://clinicaltrials.gov/ct2/show/NCT00499616 ). This study opened in 2007, is enrolling at 180 locations, and will accrue 395 children. Intermediate risk is a challenging group to design studies for. The numbers are small, with approximately 10-20% of all neuroblastomas diagnosed as intermediate risk. This means there are roughly 100 intermediate risk children diagnosed each year in the US. The past and current studies are complex, with multiple treatment arms depending on tumor characteristics and response to therapy. This study includes 2, 4, or 8 cycles of outpatient (medium dose) chemotherapy, and cis-retinoic acid (Accutane) for some children. The goal is to accurately assign children to the right treatment arm and see if reducing therapy for some children will result in the same overall high survival seen in previous studies.

ALK inhibitor, Aurora A Kinase inhibitor, and ABT-751 updates

Dr Yael Mosse spoke about the research at CHOP (Children’s Hospital of Philadelphia) on ALK mutation and the remarkable speed in which a trial (ADVL0912) was opened to treat children with a drug already available for the mutation in lung cancer. The drug PF-02341066 now has a name, crizotinib. So far 5 children with NB with ALK aberration have been enrolled, and 5 with other diseases.  Dr Mosse shared some of the same information presented at both ASCO and ANR (see previous post on ALK).

The aurora A kinase inhibitor MLN8237 trial COG-ADVL0812 is closed now that the phase I is complete. The data is under review to determine if the drug is active against neuroblastoma for those who enrolled (11 NB children) on the phase I portion of the trial.  If so, the phase II trial will open for neuroblastoma only. In mice, striking synergy is seen with this inhibitor when combined with irinotecan and temozolomide. This combination is planned for an upcoming new NANT (New Approaches to Neuroblastoma Therapy) trial N09-03 directed by Steven DuBois.

A phase II trial of ABT-751 ran from 2007 to 2009 and accrued 91 children. The response data will be released at the fall COG (Children’s Oncology Group) meeting. Right now compassionate access is open at CHOP for second remission.