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]

MIBG non-avid at diagnosis = better outcome?

POC39 (p. 211) Neuroblastomas with non-avid I-123 MIBG scan and negative urinary catecholamine secretion: A single institute’s experience

PL30 (p. 102) Analysis of MIBG scoring as a prognostic indicator in patients with stage 4 neuroblastoma. A Children’s Oncology Group (A3973) report

Dui Yen Soh, Sylvain Baruchel, and Meredith Irwin at Sick Kids in Toronto reviewed 148 children diagnosed between 1999 and 2009 (all stages and risk groups). They confirmed the interesting observation that non-avid MIBG and negative urine catecholamines at diagnosis are associated with low stage and favorable outcome. Of the MIBG non-avid children, 5 were low risk, 3 were intermediate risk, and 3 were high risk. These numbers are too small to confirm better outcome for MIBG non-avid (at diagnosis) high-risk, but Greg Yanik (University of Michigan) mentioned an interesting observation of better survival for those high-risk children who are MIBG non-avid at diagnosis (of n= 280 enrolled in COG-A3973, 29 were MIBG negative at diagnosis) in his presentation on a new scoring method to stratify patients at the end of induction. He presented at ASCO 2010 Chicago, ANR 2010 Stockholm, and will present again next week at the CNCF Parent Conference in Chicago. More on Dr Yanik’s presentation to come.[1]

Any ideas why MIBG non-avid survival might be better? No answers proposed yet.

Tandem transplant in Korea

POC40 (p. 211) Efficacy of tandem high-dose chemotherapy and autologous stem cell rescue in patients with high-risk Neuroblastoma: a preliminary report of NB 2004 study at Samsung Medical Center (Republic of Korea)

Ki Woong Sung and group reported at ANR results of 47 children diagnosed 2004 to 2008 and enrolled on NB 2004.  Of the 44 patients that went through tandem transplant, 36 (82%) remain event-free after median follow-up of 3 years (14-72 months) with probability of 5 year overall and event-free survival determined to be 68% ± 20%  and 67% ±  16%, with no treatment-related deaths.  Another report from the same center in 2007 gave results of 52 children diagnosed from 1997 to 2005 (44 had second SCT with TBI).  That study had 15% treatment-related deaths, 33 (75%) were event-free with median follow-up of 53 months (19-117 mo) from diagnosis.[2]  A retrospective study of 141 patients enrolled 2000 to 2005 from the Korean Society of Pediatric Hematology-Oncology (KSPHO) published May 2010 also showed improved 5-year event-free survival in the tandem group over the single transplant group (51 ±12% vs. 31 ±12%, P=0.030).[3]

Korean single and tandem retrospective study 1997 to 2005

These studies show strikingly comparable results to a larger COG pilot (97 children diagnosed 1994 to 2002) reported in 2006, which was the rationale for the current frontline single-versus-tandem trial in the COG.[4]

Germans report no difference in outcome using cis-retinoic acid (Accutane) or ch14.18/CHO antibody

POC37 (p. 210) Comparison of anti-GD2-antibody ch14.18 and 13-cis-retinoic acid as consolidation therapy for high-risk neuroblastoma. Results of the German NB97 trial

Thorsten Simon and group from GPOH (German pediatric oncology study group) reported retrospectively on two similar—but not randomized groups—showing that the outcome was not statistically different with almost 8 years of median follow-up for 74 children who received only ch14.18 antibody (1997-2002) and 75 children who received only cis-retinoic acid (2002-2004). The 3-year event-free survival from diagnosis was 53% ± 6% and 51% ± 6% (p=.209) respectively. While this result is interesting with regard to single-agent efficacy, it is very important to note that none of the children received both antibodies and cis-retinoic acid, nor were the children given cytokines (IL2 or GM-CSF) with the antibody as in the current COG trial. The GPOH previously reported no advantage to ch14.18 (no cytokines) over oral maintenance chemotherapy.[5]  But at ANR 2008 (Japan) the GPOH group reported no late relapses in the ch14.18 group. At this 2010 ANR they also said they have now seen a difference in the retrospective study after 10 years with statistically significant improved survival for the ch14.18 group. During the Special Clinical Session at ANR on Tuesday Dr Thorsten Simon said the GPOH will be revisiting the question of ch14.18/CHO given the remarkable survival advantage shown in the COG study report from Mar 2009.[6]  They are now considering using subcutaneous administration of IL2 to reduce toxicity (as is SIOP in the UK and the rest of Europe), and exploring the use of other agents such as IL15 or lenalidomide with the antibody.

References

1. J Clin Oncol 28:15s, 2010 (suppl; abstr 9516)
2. Bone Marrow Transplant. 2007 Jul;40(1):37-45. Epub 2007 Apr 30. PMID 17468771
3. J Korean Med Sci. 2010 May;25(5):691-7. Epub 2010 Apr 21. PMID 20436703 [full text]
4. J Clin Oncol. 2006 Jun 20;24(18):2891-6. PMID: 16782928 [full text]
5. J Clin Oncol. 2004 Sep 1;22(17):3549-57. PMID: 15337804
6. J Clin Oncol 27:15s, 2009 (suppl; abstr 10067z)

The 2010 ASCO meeting is in full swing.  Attending a meeting with more than 30,000 cancer specialists from around the world is an incredible experience and provides an unparalleled opportunity to learn about cancer. The organization, logistics, and technology displayed are absolutely mind boggling. The vast exhibitor hall has spectacular booths set up by every pharmaceutical company ever heard of. There are 350 patient advocates here–and the vast majority are focused on adult cancers. On my first shuttle ride to the conference I visited with a charming adult oncologist from Slovakia, on the return trip I chatted with a lovely young French-speaking oncologist from Montreal. The whole city of Chicago appears to be populated by oncologists!

To say the meeting is overwhelming is an understatement. I decided to purchase the Virtual Meeting as well so I can review the sessions I have heard, as well as see other presentations happening simultaneously. This means that there will be ample opportunity to carefully review the material and update this site with much more meaningful information over the next few weeks.

Day 1 and Day 2 consisted of the following presentations (termed Education Sessions).

Childhood Cancer Survivorship: Lessons Learned and Future Steps
Kevin C. Oeffinger, MD
~ Current guidelines for follow up of the survivors of pediatric cancers.
Current new areas of research including issues related to genetic
susceptibility to toxicities
Smita Bhatia, MD, MPH
~ Long-term psycho-social effects following the treatment of pediatric
cancers.
Christopher Recklitis, MPH, PhD
~ Discussion of the Childhood Cancer Survivor Study (CCSS)
Gregory T. Armstrong, MD, MSCE

Current Challenges for Cellular Therapies
~ When should immunablative therapies be considered in the treatment of
pediatric cancer?
John M. Cunningham, MBBS
~ Adoptive cellular therapies utilizing gene modified lymphocytes
Laurence Cooper, MD, PhD
~ The role of NK cells in transplant and the non-transplant scenario
Wing H. Leung, MD, PhD

The Expanding Role of Antibody-based Therapy in Children,
Adolescents, and Young Adults with Cancer
~ Progress in treatment of high-risk neuroblastoma with immunotherapy
Alice L. Yu, MD, PhD
~ Update on Immunotherapy Strategies in the Treatment of Lymphomas in
children, adolescents and young adults
Mitchell S. Cairo, MD
~ The efficacy of epitope-specific IGFR1 antibodies in therapy of pediatric,
adolescent and young adult solid tumors
Douglas Yee, MD

New Treatments for Sarcoma in Children, Adolescents, and Young Adults
~ Optimal approaches for achieving local control in children, adolescents, and
young adults with sarcoma
R. Lor Randall, MD, FACS
~ Optimal strategies for controlling metastatic disease in children,
adolescents, and young adults with sarcoma
Douglas S. Hawkins, MD
~ Treatment of childhood, adolescent, and young adult sarcoma. Where do
we go from here?
Stephen X. Skapek, MD

Last session today was a terrific presentation on how pediatric oncology clinical trials serve as a model for “comparative effectiveness research.” More on this later.

Brief comments on sessions so far:

Genetic predisposition for heart damage in some children

The most important finding shared about late effects was the genetic mutations discovered that predispose a child for cardiotoxicity from low-dose anthracyclines, and this is significant for NB parents because almost all NB kids get doxorubicin as part of induction. There is consideration now of testing children in future trials for the mutations, and if one is found, reducing or eliminating anthracyclines from frontline therapy, or using a cardioprotectant. Further information will be presented on this topic on Monday morning session.[1]

Reduced-intensity allogeneic transplants and NK and T cell therapies

The discussion on reduced intensity transplant was really interesting and I look forward to looking at the data more closely. Many studies in adults have been completed for different diseases, and most show lower toxicity and better survival. Tomorrow there is a poster presentation on a study from Italy in NB kids. I will follow up with data and referenced studies. There has been so much work on NK cell therapies it is very exciting to see the possibilities emerging for NB. If you do a search for NK cell therapies on the National Institutes of Health site (www.clinicaltrials.gov) there are more that 200 open trials for various cancers. Memorial Sloan-Kettering is currently accruing for their NK cell therapy trial, but this trial was not discussed in any detail. MD Anderson also has an open Phase II study using donor NK cells for those who relapse or are refractory after stem cell transplant. Several papers have been recently published and after reviewing them I can report more fully on this topic. It was encouraging to hear the discussant Dr Leung say that he sees NK cells as an ideal treatment after frontline induction and consolidation, before antibody treatment. He believes this could be the next big jump in survival for frontline therapy.[2]

Antibody update

Dr Yu gave an excellent presentation updating on all things anti-GD2. She reviewed the history of all antibodies for NB, and said that two humanized antibodies (hu14.18-IL2 and hu14.18K332A) and a new anti-iodiotype antibody 1A7 are all considered for future trials. The 1A7 is interesting because it works like a vaccine. Instead of injecting antibodies into a child, this antibody induces the production of antibodies against GD2 continuously. After the session I asked her about the supply of ch14.18. The supply is good for two years since NCI made two more “batches” and a manufacturer has committed to produce the ch14.18. Then we discussed the trouble in the UK with access to GM-CSF for use with the ch14.18 antibody, and she said that she was going to speak to the Genzyme representative since they recently “inherited” the drug. Later I went to talk to Genzyme too. Genzyme said that there are regulatory issues with the UK (not the US) that prohibit the importing of the drug. He said to tell families interested in working with their doctor to contact Idis (www.idispharma.com) because Idis is an expert in getting access to drugs. They developed a program called Named Patient Program (see http://idispharma.com/patients.php ) to help gain access to drugs blocked by regulatory hurdles. Another question I have though, and could not be answered yet, is will SIOP rewrite the protocol to include GM-CSF? Dr Yu mentioned they are currently using IL2 (subcutaneously). Perhaps this can be further clarified for us by the families in the UK who are on the SIOP trial. Another question I have is whether the access to GM-CSF affects the other countries in Europe.

1.  J Clin Oncol 28:7s, 2010 (suppl; abstr 9512)

2.  Leung, Wing. The Role of Natural Killer Cells in Transplant and the Nontransplant Scenario. ASCO 2010 Educational Book, p 377-381