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.

A review of a new therapy for neuroblastoma

Significant and accelerating progress is underway in the oncolytic virus arena. In the past decade numerous clinical trials using several different oncolytic viruses against adult cancers have been completed and more are underway. Many trials have shown anti-tumor activity in various adult tumors. A major milestone was reached this year with three oncolytic virus trials open to children for the first time in the US using vaccinia, Seneca Valley virus, and herpes simplex virus, and two more to open next year using reovirus and modified measles. In addition, a Newcastle disease virus trial will enroll children in Jerusalem.[1] Researchers from Spain published a recent report describing a few cases of oncolytic adenovirus given to children with neuroblastoma, with encouraging responses observed in two children.[2] One more oncolytic virus is in early development, Maraba, so at least eight oncolytic viruses are currently of interest for treating children with cancer.

This exciting field holds great promise for many reasons. After decades of exploring combination therapies that primarily utilize highly toxic treatments, 80% of all children diagnosed with a malignancy (in the most developed countries) can expect to still be alive after five years. While this denotes a significant degree of success, there are still 20% who do not survive five years. Added to this, the serious issue of late effects, late relapses, secondary malignancies, and increased morbidity continue to darken the future for childhood cancer survivors. Clearly more work is needed to find non-toxic and more effective therapies for all of these children. There is great potential for oncolytic viruses to dramatically solve these challenges – the increasing possibility of tumor-specific viruses that replicate in tumor tissue and kill tumor cells only while completely sparing normal tissue presents an extremely attractive scenario.

This report outlines the “state-of-the-art” of oncolytic virus therapy for children.

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A spotted history

An excellent review, “Oncolytic Virotherapy Reaches Adolescence” published August 2010 in Pediatric Blood & Cancer by Drs Adrienne Hammill and Timothy Cripe (Cincinnati Children’s), reads more like an intriguing historical account than a dry scientific treatise.[3] Beginning with anecdotal observations of infections followed by spontaneous remissions of various cancers documented since the mid-1800s, the authors trace the efforts of researchers to advance the understanding and use of oncolytic viruses. Numerous studies in the 1960s and 1970s were performed and remissions documented. However, some investigators planned and carried out unethical experiments, such as extracting viruses from infected patients and directly infecting other patients with body fluids, and even injecting human tumor cells into prisoners and patients without consent.[4] The resulting public outrage led to the modern era of robust regulatory oversight for all phases of clinical research. Meanwhile, interest in oncolytic virotherapy research diminished during the next few decades.

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A virus revival

Why then has there been a sudden resurgence of research in this field now? Renewed interest has soared the past decade because of dramatic progress in understanding cell processes, tumor biology and microenvironment, immunology, and the advent of recombinant DNA technology among many other advances. In the past, wild-type viruses carried the risk of uncontrolled infectious complications. Newly created attenuated viruses are harmless to normal tissue and engineered to be far more tumor-specific. Techniques have been developed and regulations defined to safely produce, purify, and administer the oncolytic viruses to patients. Many new viruses have been identified, modified, and tested on cancer cell lines and in animal models. Publications have exponentially increased, and hundreds of researchers in both academic and industry-sponsored laboratories are actively involved in cancer virotherapy research. The 2009 NCI funded research portfolio returns 532 results totaling over $200 million in a search with the keyword “oncolytic virus.”[5]

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Oncolytic virus trials for childhood tumors

These are indeed exciting times for advances in treating pediatric cancer, and rapid progress in opening these trials for children is the direct result of significant funding and support from pediatric cancer research non-profit charities such as Solving Kids’ Cancer in addition to public funding. In the Hamill review, four oncolytic virus trials for pediatric tumors are described including the background of preclinical studies and adult trials. Currently five oncolytic virus trials are open (or soon to open) for children in the US:

• Herpes simplex virus-1 (HSV1716) – intratumoral injection: CURRENTLY OPEN for enrollment for patients aged 13-30 years with solid tumors (non-CNS)
• Vaccinia (JX-594) – intratumoral injection: CURRENTLY OPEN for enrollment for patients for patients aged 2-21 years with solid tumors (non-CNS)
• Seneca Valley virus (SVV-001/NTX-010) – intravenous route: CURRENTLY OPEN for enrollment for patients for patients aged 3-21 years with solid tumors (non-CNS)
• Modified Measles virus (MV-CEA) – local injection into resected recurrent tumor bed: NOT OPEN/estimated to open first quarter 2011 for patients aged 2-21 years with recurrent medulloblastoma
• Reovirus (Reolysin) – intravenous route: NOT OPEN/estimated to open fourth quarter 2011, for patients aged 3-21 with solid tumors.

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Prior experience in adult tumors

HSV1716

The safety of intratumoral injection of HSV1716 virus has been studied in five phase I clinical trials in glioma, melanoma, and squamous cell carcinoma. No toxicities were observed, and evidence of tumor necrosis and viral replication in tumor were seen. Tumor response was seen in a glioma and melanoma patient.[3]

JX-594

The vaccinia virus is a poxvirus, and has been tested in five clinical trials using intratumoral injection from 1964 to 2001. In metastatic melanoma, 25/44 showed an objective response, with complete response in injected tumor site in 11/25  patients. In bladder cancer, 3 of 4 patients were in complete response four years later. Modifications to increase tumor specificity in vaccinia resulted in the JX-594 virus. Four trials have been launched in adults using both intratumoral and intravenous administration in several adult cancers with responses and stable disease observed. The recently completed phase II in hepatocellular carcinoma will have results released in 2011. Mild flu-like symptoms only were observed.[3]

SVV-001/NTX-010

A phase I of intravenous Seneca Valley virus (SVV-001) in 30 adults with advanced solid tumors (with neuroendocrine features) showed objective response in a carcinoid tumor and stable disease longer than 16 months in a lung cancer patient. A phase II is currently ongoing for lung cancer to determine if efficacy is improved in combination with chemotherapy.[3]

MV-CEA

The modified measles (MV-CEA) was tested in a phase I trial for ovarian carcinoma in 21 women with recurrent ovarian carcinoma by intraperitoneal injection. No dose limiting toxicity observed with fever, fatigue, and abdominal pain. A phase I Intra-tumoral MV-CEA for recurrent glioblastoma is ongoing at Mayo Clinic.[8]

Reovirus/Reolysin

Numerous studies have been completed in adults with the reovirus in various tumors with both intravenous and intratumoral injection. Indications of efficacy have been observed, with no toxicities beyond flu-like symptoms. More studies using combination therapies have been completed and are underway, including plans for a phase III with chemotherapy for head and neck cancers.[3]

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Delivering the virus to the tumor

Oncolytic viruses can be safely administered via intratumoral injection or intravenous route. The virus self-replicates in the tumor and can then spread throughout the body. Tumor kill in distant metastases has been observed, as well as vaccine-like effects with anti-tumor immune responses. The intravenous route delivers the virus systemically, but some viruses stimulate an immune response and the antibodies produced can interfere with the desired effect.  Ongoing research seeks to solve this challenge.

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Current status of pediatric trials

Investigators have provided updates on the oncolytic virus trials November 2010 for various pediatric solid tumors. The first child to receive an oncolytic virus in the US was treated with Seneca Valley (SVV-001/NTX-010) virus at the University of Minnesota in March 2010. As of November 2010 eight children (four with neuroblastoma, four with other solid tumors including carcinoid tumors) have been treated with SVV-001/NTX-010 at six different COG (Children’s Oncology Group) phase I consortium sites (MN, AL, PA, IN, TN, TX) with six children receiving the first dose level and two receiving the second dose level. Three young patients have been treated with HSV1716 (at lung, pelvic, and neck sites) at Cincinnati Children’s and the second dose level cohort will be open to enrollment December 2010 after routine safety review. The first child enrolled November 2010 in the JX-594 trial at Cincinnati Children’s with hepatocellular carcinoma. The reovirus trial has just been approved CTEP (Cancer Therapy Evaluation Program), and will be open at COG phase I consortium sites in 2011. This trial includes low-dose oral cyclophosphamide and children will be eligible to receive up to 12 cycles of the reovirus (given days 1-5 of each 28 day cycle). Plans to open the measles virus trial for recurrent medulloblastoma are also underway.

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Toxicities

Some children have had mild flu-like symptoms and some have had pain at tumor sites from tumor swell. No other serious toxicities have been observed, and virus clearance has occurred as expected. Many adult trials have established the safety of virus administration, as well as demonstrating responses and disease stabilization. A significant point to consider is the low “opportunity cost” for a child enrolling in an oncolytic virus trial—the risk of eliminating the child from further therapy options is very unlikely. Most of these trials require a month or less of observation for virus clearance, and no other toxicities are expected to affect eligibility for other trials, such as bone marrow suppression or organ toxicities. This provides a promising option for children with resistant disease because many current therapies contribute to cumulative organ toxicities.

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Future directions

New viruses have been recently identified and modified that demonstrate potent tumor specificity such as double-mutated Maraba virus in neuroblastoma.[6] These promising viruses deserve the attention of funding mechanisms and accelerated introduction to clinical trials. With encouraging results from adult trials being reported,[7] growing enthusiasm is appropriate for the use of oncolytic virus therapy in children.

More information on oncolytic virus trials in adults can be found in recent Molecular Therapy editorial [9], European Journal of Scientific Research [10], NCI Journal [11], and  companies involved in developing oncolytic viruses in a market analysis on BioMedReports.[12]. A 2009 review discusses preclinical work testing herpes simplex viruses in pediatric cell lines, including neuroblastoma.[13]

The chart below shows adult phase II and III oncolytic virus trials (click on the image below to go to the April 2010 JNCI article) [11]:

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References

1. Clinical Application of Intravenous New Castle Disease Virus – HUJ Oncolytic Virus in the Treatment of Advanced Glioblastoma Multiforme, Soft and Bone Sarcomas and Neuroblastoma Patients, Resistant to Conventional Anti- Cancer Modalities. NCT01174537
2. Discovery Medicine. Oct 2010; 53.  Oncolytic Virotherapy for Neuroblastoma.
3. Pediatric Blood Cancer. 2010 Dec 15;55(7):1253-63. Oncolytic Virotherapy Reaches Adolescence.
4. New England Journal of Medicine 2004; 351:628-630. Sins of Omission — Cancer Research without Informed Consent.
5. NCI Funded Research Portfolio 2009 (keyword: oncolytic virus)
6. Molecular Therapy. 2010 Aug;18(8):1440-9. Epub 2010 Jun 15. Identification of genetically modified Maraba virus as an oncolytic rhabdovirus.
7. Pediatr Blood Cancer. 2010 Dec 15;55(7):1253-63. Oncolytic Virotherapy Reaches Adolescence.
8. Personal communication, Dr Corey Raffel, Nationwide Children’s Hospital, Columbus, OH
9. Molecular Therapy 2010 18 (2), 233–234. doi:10.1038/mt.2009.314  Oncolytic Viruses: An Approved Product on the Horizon?
10. European Journal of Scientific Research, ISSN 1450-216X Vol.40 No.1 (2010), pp.156 -171. Oncolytic Viruses in Cancer Therapy
11. J Natl Cancer Inst. 2010 May 5;102(9):590-5. Epub 2010 Apr 26. Oncolytic viruses move forward in clinical trials.
12. BioMedReports, Nov 22, 2010. Oncolytic Viruses: Are They The Future of Cancer Therapy?
13. Molecular Therapy 2009  July; 17(7): 1125–1135. Herpes Simplex Virus Oncolytic Therapy for Pediatric Malignancies [full text]

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Trial open at Penn State Hershey Medical Center

A Phase I Trial Combining Decitabine, IFN-gamma, and Vaccine Therapy for Patients With Neuroblastoma

The phase I trial will enroll 15 children ages 2 months to 17 years who have relapsed neuroblastoma.

The stated purpose:

This treatment study for relapsed high-risk neuroblastoma involves an autologous cancer testis (CT) antigen specific dendritic cell (DC) vaccine preceded by decitabine as a demethylating chemotherapy and IFN-gamma to stimulate an immune response.

The vaccine is given in the following schedule:

“Meet the Experts” session

Drs Huib Caron (The Netherlands) and Suzanne Shusterman (Boston Childrens/DFCI) presented on MIBG therapy in “Meet the Experts” session Friday Oct 22 and Saturday Oct 23, 2010 at the SIOP meeting in Boston.

Completed and ongoing studies

Dr Caron covered the therapeutic considerations, and Dr Shusterman spoke about the practical and logistic issues surrounding the design of MIBG therapy rooms and handling the radioactive material.

MIBG (meta-iodobenzylguanidine) is a synthetic analogue to norepinephrine, developed in the 1970s at University of Michigan as a potential agent for use in hypertension. It is taken up by 90% of neuroblastomas. The compound (also called iobenguane) is useful for both imaging with I-123 isotope which has a shorter half-life of 13 hours and produces better resolution images, and radiation therapy with I-131 which has a longer half-life of 8 days.

The compound with a radioactive isotope of iodine attached (I-131) is taken up in the NB cell but is not lethal to that cell. The beta particles from I-131 decay kills cells up to 2 mm away, and gamma radiation from decay (as in imaging) reaches 2 m or greater distance, but is not lethal to cells in that path. The resulting beta particle decay “cross-fire” is why MIBG radiation therapy appears to be more effective in clumps of disease rather than in diffuse or trace disease. Dr Caron commented in his presentation that this is why he believes using MIBG radiation therapy at the end of induction with minimal or undetectable disease will have questionable efficacy, and why studies in the Netherlands have used double MIBG treatments at the beginning of induction (1989-1999 in 41 children).[1]   Dr Maris countered in a later conversation that there is evidence of efficacy from a double MIBG therapy study where children who respond completely to the first MIBG therapy receive a second MIBG treatment and do well. He also mentioned that it is very common to see much more disease in a post-MIBG therapy scan, revealing that often the imaging dose of MIBG does not show as much disease, and therefore using MIBG therapy at the end of induction even in children with negative MIBG scans may successfully treat undetectable or trace disease. This question (as well as feasibility) will be addressed by the new frontline pilot study now open in several centers using MIBG at the end of induction with CEM transplant for 49 newly diagnosed high-risk NB (see previous article). The German group GPOH is using MIBG therapy in frontline therapy in the ongoing NB2004 study a the end of induction for children who have remaining MIBG positive primary uptake. This study plan is to accrue 360 children.[2]

Other completed and ongoing studies were reviewed, including an ongoing study using MIBG upfront with topotecan in 15 children, a GPOH study using MIBG + gemcitabine phase I/II for refractory and relapsed NB and should finish within the year. The NANT 2007-03 phase I MIBG + vorinostat trial is based on the fact vorinostat (an HDAC inhibitor) increases the norepinephrine transporter expression, and in mice the combination results showed improved response. In 2006 Matthay et al published in JCO the results of the phase I MIBG + CEM transplant in 24 children where the 3-year event-free survival (EFS) was 30% and the 3-year overall survival (OS) was 60% for primary refractory disease. The dose levels from this study were used in the phase II which was recently completed and preliminary results were presented at ANR in June 2010 in Stockholm by Dr Greg Yanik (OR58). MIBG has been tested at 8 to 18 mCi in various trials. In 2007 a Phase II was published in JCO showing promising effectiveness in 164 relapsed or refractory patients with a median of 3 prior regimens (range 1 – 13).[3]  A study in the UK planned to use topotecan with MIBG for relapsed or refractory NB closed before it accrued. Another NANT phase I study N2004-06 used MIBG with irinotecan and vincristine, and results are pending. In Sweden a study using haploidentical donor transplant with MIBG was completed in 5 children.[4] In France a study is ongoing using topotecan with MIBG in relapsed and refractory children.

Approval status for 131-I MIBG

131-I MIBG is made by Draximage (a division of Draxis Health) in Canada, and another company Molecular Insights makes Azedra (Ultratrace MIBG with no cold contaminants). 131-I MIBG is approved for treatment of neuroblastoma in Europe, but still an investigational new drug (IND) in the US.

Future focus

Conclusions drawn from this session include the fact that MIBG therapy is obviously an important agent in the treatment of neuroblastoma, with a long history of studies completed since the 1980s. An important challenge for all researchers involved is figuring out the optimum way to use this agent. An excellent review published in 2008 by Drs Matthay and Dubois provides more information.[5]

References

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

2.  Randomized Study of Standard Induction Chemotherapy Versus Topotecan Hydrochloride-Containing Induction Chemotherapy Followed by Myeloablative Autologous Stem Cell Transplantation and Consolidation Therapy With Isotretinoin in Pediatric Patients With High-Risk Neuroblastoma GPOH-NB2004-HR

3. J Clin Oncol. 2007 Mar 20;25(9):1054-60. Phase II study on the effect of disease sites, age, and prior therapy on response to iodine-131-metaiodobenzylguanidine therapy in refractory neuroblastoma. PMID: 17369569

4. Biol Blood Marrow Transplant. 2009 Sep;15(9):1077-85. Epub 2009 Jul 8. High-dose iodine-131-metaiodobenzylguanidine with haploidentical stem cell transplantation and posttransplant immunotherapy in children with relapsed/refractory neuroblastoma. PMID: 19660720

5. Q J Nucl Med Mol Imaging. 2008 Dec;52(4):403-18. Radiolabeled metaiodobenzylguanidine for imaging and therapy of neuroblastoma. PMID: 19088694

Travel to this meeting was supported by:

• Lighthouse Laboratories
• Max’s Ring of Fire
• Magic Water
• Friends of Will
• Solving Kids’ Cancer
• Children’s Neuroblastoma Cancer Foundation

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Rare news

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

From Science Life blog at University of Chicago

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

This is quite a dramatic story on many levels.

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

Antibody and drug development are not the same

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

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

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

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

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

More to the story

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

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

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

Medical ethics, trial design, and real children

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

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

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

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

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

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

Costly development and production

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

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

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

Implications for Europe

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

References

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

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

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

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

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

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

7. Correspondence with investigators

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

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

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

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.