The Story of the Band of Parents and humanized 3F8

by Caryn Franca and Shirley Staples

It was summer of 2007.  A group of parents had asked Dr. Nai-Kong Cheung to meet and update them on new treatments for neuroblastoma at Memorial Sloan-Kettering Cancer Center.  Most had children with relapsed neuroblastoma; all knew the terrible odds.  Dr. Cheung, head of the neuroblastoma program at MSKCC, and a long-time proponent of antibody therapy, met with the group at Ronald McDonald House.  After the presentation, one dad posed a question.  “What,” he asked, “do you need, to give our children more treatment options?”   “Money” was the simple, yet daunting answer.

Dr. Cheung then described an important research goal—the development of a new, humanized form of the 3F8 antibody that had been used since 1986 to treat neuroblastoma at MSKCC.  Researchers believed the new version, “Hu3F8,” had the potential to be many times more effective in fighting neuroblastoma, but Dr. Cheung estimated that $2-3 million dollars would be needed to fund the development of the drug.  After the meeting, parents excitedly discussed this revelation. The consensus was that they could and would do whatever was necessary to make hu3F8 treatment a reality.  A crusade was born.

Within a matter of days, an online group had been created and parents had begun brainstorming.  The name of the new parent group came from a California dad:  the “Band of Parents.”  One group of parents began the discussions and eventually the legal steps to form a tax-exempt foundation. Seven dads began planning to bike across the United States to raise funds and awareness–a ride they called “The Loneliest Road” to reflect the daily challenges facing neuroblastoma families. Ultimately they raised over $200,000 for hu3F8. Soon there were 60 families in the “BOP,” and the energy was palpable, from garage and jewelry sales, to writing fundraising letters to friends, to telling individual stories to local newspaper reporters.

Donations began to pour in, some from as far away as the Middle East.  As December approached, a New York City mom conceived the idea of a massive bake sale of holiday cookies.  Over several weeks, parents, friends, and volunteers from the culinary world baked, packaged and shipped 96,000 cookies from a small rented kitchen, raising several hundred thousand dollars. A few months later, families in Virginia banded together to organize the “Rock’n for a Cure.”  Band of Parent funds were mounting.

The efforts that followed were too many and varied to detail, but the key phrase is “banded together” – parents of children with neuroblastoma, along with family, friends and perfect strangers, came together to raise the funds needed to create a new treatment option for children with neuroblastoma.  Great personal determination was required.  As the months passed, many Band of Parents members lost their child to neuroblastoma – including the parent who coined the name “Band of Parents,” the mother who conceived the cookie bake-off, three of the bikers on The Loneliest Road, and the first three presidents of the BOP.  However, parents pushed forward despite the grief and loss felt by all in the group.  Golf tournaments, yard sales, and concerts were organized, sometimes from hospital bedsides; holiday decorations, tee-shirts, and greeting cards were designed and sold.  Last but not least, the dedicated neuroblastoma team at MSKCC cleared the regulatory and many other hurdles to taking a new drug from the laboratory to the clinic.

In August 2011 the day finally arrived that so many had worked for and dreamed of.  A new phase 1 trial of hu3F8, a drug specifically designed for the treatment of neuroblastoma, opened at Memorial Sloan-Kettering, and the very first child received the promising new treatment. Ordinary people had accomplished an extraordinary labor of love. For all those involved, this will be remembered as a time when it was shown that, by banding together, a group of parents could give new hope in the battle against an aggressive childhood cancer.  Today, the members of the Band of Parents are still working to raise awareness and funding for research, so that someday no child will suffer from the terrible disease of neuroblastoma.

Editors note: the trial opened in August 2011 and is listed here: http://clinicaltrials.gov/ct2/show/NCT01419834

The trial allows for relapsed or refractory NB with evidence of disease, and is given without cytokines IL2 or GM-CSF.

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.

Neuroblastoma bits from November 2010

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NCI featured article on ALK inhibitor Crizotinib

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

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

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FDA discusses Crizotinib pediatric trial design

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

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

Committee discussion questions

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Insight Genetics Awarded Qualifying Therapeutic Discovery Program Grant

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

www.eurojournals.com

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

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

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

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Search goes on for toxins to kill neuroblastoma

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

Why Scientists Are Searching for Cures Underwater – Newsweek

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Childhood cancer survival in Australia

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

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

www.nature.com

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

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

Severe Acne Linked to Suicide Risk Even Before Treatment Is Started

cme.medscape.com

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

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

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

(will accrue 63 patients)

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

(will accrue 53 patients)

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

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

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

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

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

Other 3F8 trials

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

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

From the abstract:

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

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

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

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

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

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

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

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

References

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

High-dose 3F8 trials for high-risk neuroblastoma in first remission

High-Dose 3F8/GM-CSF Immunotherapy Plus 13-Cis-Retinoic Acid for Consolidation of First Remission After Non-Myeloablative Therapy in Patients With High-Risk Neuroblastoma

High-Dose 3F8/GM-CSF Immunotherapy Plus 13-Cis-Retinoic Acid for Consolidation of First Remission After Myeloablative Therapy and Autologous Stem-Cell Transplantation

The purpose of these studies is to see if high-dose 3F8 and GM-CSF is better than standard dose 3F8 in treating neuroblastoma in first remission.

The study with children who have not undergone transplant will accrue 58 patients, and the study that includes children who have undergone transplant as part of frontline therapy will accrue 43 patients.

Both studies include Accutane (13-cis-retinoic acid) and use high-dose (80 mg/m2/day) 3F8 for the first 4 cycles, and standard 3F8 dosage (20 mg/m2/day) in subsequent cycles.

13-cis-retinoic acid is started after cycle 2 in both studies.

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]