Pilot study: 131I-MIBG radiotherapy with chemotherapy after induction for newly diagnosed

Dr Greg Yanik (University of Michigan) presented preliminary results of the NANT (New Approaches to Neuroblastoma Therapy) NANT-2001-02 phase 2 MIBG + CEM (131I-MIBG radiotherapy with carboplatin, etoposide, and melphalan) stem cell transplant trial on June 23rd 2010 at the Advances in Neuroblastoma Research meeting in Stockholm, Sweden in the “Novel clinical strategies” session. The data are still under review and will be presented at the COG meeting next month. The trial has been completed but the NIH clinical trials listing has not yet been updated to reflect this.[1]

The results of 12 relapsed and refractory children treated in the phase I MIBG+CEM trial was published in 2002.[2]

The encouraging results in the phase II study with 50 refractory children who did not completely respond to induction provide promising expectations for a new pilot trial COG-ANBL09P1 using this concept for frontline therapy for newly diagnosed. The principal investigator is Dr Brian Weiss (Cincinnati Children’s) and the trial will soon begin, accruing 49 patients up to 30 years old in select locations.

Upon completing this protocol, children will also be eligible for the new phase III antibody study using ch14.18 + GM-CSF + IL2 COG-ANBL0931. This trial opened in January 2010 and will accrue 105 (currently open in 29 locations) to further establish safety and efficacy of the antibody ch14.18 given with cytokines GM-CSF and IL2 to obtain FDA approval. This trial is open to all ages.

Is this the first time MIBG will be used in frontline therapy for newly diagnosed (as opposed to just for those refractory at the end of induction)? In 2008 researchers in the Netherlands reported the use of MIBG as initial therapy before chemotherapy and surgery for 44 newly diagnosed high-risk children.

From the abstract:

The protocol dictated at least two cycles of (131)I-MIBG with a fixed dose of 7.4 and 3.7 GBq, respectively, followed by surgery, if feasible, or followed by neoadjuvant chemotherapy and surgery. This was followed by consolidation with four courses of chemotherapy myeloablative chemotherapy and autologous stem-cell transplantation (ASCT). Consolidation therapy with 13-cis-retinoic acid was given for 6 months.

Of 44 consecutive patients, 41 were evaluable after two courses of (131)I-MIBG. The objective response rate at this point was 66%. In 24 patients, (131)I-MIBG was continued as pre-operative induction treatment. Seventeen patients required additional chemotherapy before surgery. After pre-operative therapy and surgery, the overall response rate was 73%.[3]

References

1. OR58 Phase II trial of MIBG with intensive chemotherapy and Autologous Stem Cell Transplant (ASCT) for high risk neuroblastoma. A New Approaches to Neuroblastoma Therapy (NANT) Study (p. 123 ANR Programme Abstract Book, June 2010)

2. J Clin Oncol. 2002 Apr 15;20(8):2142-9. Pilot study of iodine-131-metaiodobenzylguanidine in combination with myeloablative chemotherapy and autologous stem-cell support for the treatment of neuroblastoma. PMID: 11956276

3. 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

C10 (p. 80) “Late effects in neuroblastoma”

Dr Lisa Diller (Boston Children’s/Dana-Farber Cancer Institute) reviewed recent published data on late effects and presented new data in the Neuroblastoma Update Course on June 21st, 2010 at the Advances in Neuroblastoma Research meeting in Stockholm, Sweden. The session was organized by Sue Cohn and Andrew Pearson and chaired by Sue Cohn and Rani George.

The Childhood Cancer Survivor Study provided long-term survivorship data for those treated for neuroblastoma between 1970 and 1986, and results on 954 5-year survivors were published in Journal of the National Cancer Institute August 2009.[1]

Of the 954 children, 832 records were abstracted, and only about 10% were stage 4 survivors, so the vast majority (~90%) of the survivor data most likely represented low and intermediate risk survivors.  Only 38% of the survivors had surgery + chemotherapy + radiation.  Of all the survivors, at least 90% had 15 years of follow-up. Of 1358 there were 84 deaths (41 recurrences)  and higher risk of death if diagnosed over the age of 5 and had multimodal therapy. The children treated for neuroblastoma were compared to a cohort of 3899 siblings to determine if there was a higher incidence of health problems. There was a higher incidence of chronic health conditions involving the neurological, sensory, endocrine, and musculoskeletal systems in children treated for neuroblastoma.

Dr Diller also mentioned evidence from soon-to-be published institutional data that advanced bone age or epiphyseal closure is more common in children treated with cis-retinoic acid than children who did not have cis-retinoic acid. There is a theoretical toxicity proposed related to cis-retinoic acid given with anti-GD2 antibody (ch14.18) because of clearance issues, but this has yet to be verified.[2]

References

1. J Natl Cancer Inst. 2009 Aug 19;101(16):1131-40. Epub 2009 Jul 31. [fulltext]

2. ANR 2010 “Neuroblastoma Update Course” ANR 2010 Abstract Programme, p 80.

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.

Three new oncolytic virus trials to treat neuroblastoma: vaccinia (JX-594), herpes simplex (HSV1716), and Newcastle Disease virus

Vaccinia JX-594

A Phase I, Open-Label, Dose Escalation Study of JX-594 (Vaccinia GM-CSF/Thymidine Kinase-Deactivated Virus) Administered by Intratumoral Injection in Pediatric Patients With Unresectable Refractory Solid Tumors

A phase I study using intratumoral injection of modified vaccinia virus derived from the smallpox virus is scheduled to begin accruing children 2 to 21 years old with refractory solid tumors, including neuroblastoma. The principal investigator is Dr Timothy Cripe and the trial is sponsored by Jennerex Biotherapeutics and Solving Kids Cancer. Locations are Cincinnati Children’s Hospital Medical Center in Ohio and Texas Children’s Hospital in Houston, and a  total of 15 will be enrolled. The Jennerex site shows a diagram of their oncolytic viruses in the pipeline (click on image):

Recent use of this virus is detailed in a 2009 review from Leeds in the UK:

JX-594 is a replication-competent Wyeth strain vaccinia virus that was genetically modified to inactive the endogenous thymidine kinase gene and to express human GM-CSF and LacZ genes. In development by Jennerex Inc and licensee Green Cross Corp, the modified virus is a novel therapy for treatment-refractive metastatic malignancies from various sites of origin. Targeted oncolytic virotherapy has demonstrated promise in preclinical studies, and more than ten viral species have subsequently entered clinical trials. JX-594 has been modified to augment the intrinsic targeting and oncolytic potential of the vaccinia virus and to enhance antitumor immunity by the expression of the GM-CSF transgene in situ. In vitro and in vivo animal studies have demonstrated the replication specificity of JX-594 for cancer cell lines and tumors, and the restriction of serum human GM-CSF expression to tumor-bearing animals, resulting in significantly reduced tumor burden and an increase in median survival. In phase I trials, JX-594 was well tolerated, with mild systemic toxicity reported. In a phase I trial in seven patients with melanoma, one partial response and one complete response after surgery were observed. In another phase I trial in patients with hepatic carcinoma, three out of ten evaluable patients had a partial response and six had stable disease; the MTD was also established. A phase II trial in patients (expected n = 30) with unresectable primary hepatocellular carcinoma was recruiting at the time of publication, with completion expected in March 2010, and a phase III trial in patients with hepatocellular carcinoma was planned for the second half of 2010. Further clinical investigations are needed to explore the potential of this agent as a single therapy and as part of multimodal treatment regimens.[1]

This oncolytic virus has been used to treat liver and other cancers, as reported in Lancet in this 2008 study from Korea. Details from the abstract:

JX-594 is a targeted oncolytic poxvirus designed to selectively replicate in and destroy cancer cells with cell-cycle abnormalities and epidermal growth factor receptor (EGFR)-ras pathway activation. Direct oncolysis plus granulocyte-macrophage colony-stimulating factor (GM-CSF) expression also stimulates shutdown of tumour vasculature and antitumoral immunity. We aimed to assess intratumoral injection of JX-594 in patients with refractory primary or metastatic liver cancer.

Between Jan 4, 2006, and July 4, 2007, 14 patients with histologically confirmed refractory primary or metastatic liver tumours (up to 10.9 cm total diameter) that were amenable to image-guided intratumoral injections were enrolled into this non-comparative, open-label, phase I dose-escalation trial. Patients received one of four doses of intratumoral JX-594 every 3 weeks at Dong-A University Hospital (Busan, South Korea). The primary aims were to ascertain the maximum-tolerated dose (MTD) and safety of JX-594 treatment.

Of 22 patients with liver tumours who were assessed for eligibility, eight patients did not meet inclusion criteria. Therefore, 14 patients, including those with hepatocellular, colorectal, melanoma, and lung cancer, were enrolled. Patients were heavily pretreated and had large tumours. Patients received a mean of 3.4 cycles of JX-594. All patients experienced grade I-III flu-like symptoms, and four had transient grade I-III dose-related thrombocytopenia. Grade III hyperbilirubinaemia was dose-limiting in both patients at the highest dose. JX-594 replication-dependent dissemination in blood was shown, with resultant infection of non-injected tumour sites. GM-CSF expression resulted in grade I-III increases in neutrophil counts in four of six patients at the MTD. Tumour responses were shown in injected and non-injected tumours. Ten patients were radiographically evaluable for objective responses. Three patients had partial response, six had stable disease, and one had progressive disease.

Intratumoral injection of JX-594 into primary or metastatic liver tumours was generally well-tolerated. Direct hyperbilirubinaemia was the dose-limiting toxicity. Safety was acceptable in the context of JX-594 replication, GM-CSF expression, systemic dissemination, and JX-594 had anti-tumoral effects against several refractory carcinomas. Phase II trials are now underway. [2]

This photo from Jennerex shows the needle developed for intratumoral injection.

Herpes Simplex Virus-1 Mutant HSV1716

A Phase I Dose Escalation Study of Intratumoral Herpes Simplex Virus-1 Mutant HSV1716 in Patients With Refractory Non-Central Nervous System (Non-CNS) Solid Tumors

This study opened in March 2010 and will accrue 18 young patients aged 13 to 30. This trial is also supported by Solving Kids Cancer lead by Dr Tim Cripe and open at Cincinnati Children’s. This particular oncolytic virus has been tried in squamous cell carcinomas, melanoma, and brain tumors.  A mouse study published by researchers from Mass General in 2008 revealed neuroblastoma tumor reduction with a related oncolytic virus. [4]

Newcastle Disease Virus (NDV)

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

This phase I/II study for recurrent or refractory solid tumors will begin accruing September 2010 at Hadassah Medical Organization in Jerusalem, Israel.  This trial uses the Newcastle Disease Virus systemically rather than intratumorally, and a total of 30 patients will receive daily doses of the oncolytic virus at least 5 days a week for a minimum of a year or until disease progression. For more information on Newcastle Disease Virus the University of Minnesota provides a helpful brief review of the use of NDV as an oncolytic virus.

References

1.  Curr Opin Investig Drugs. 2009 Dec;10(12):1372-82. JX-594, a targeted oncolytic poxvirus for the treatment of cancer. PMID: 19943208

2.  Lancet Oncol. 2008 Jun;9(6):533-42. Epub 2008 May 19. Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial. PMID 18495536

3. Recent Pat CNS Drug Discov. 2009 Jan;4(1):1-13.  Advances in oncolytic virus therapy for glioma. [full text]

4.  Clin Cancer Res. 2008 Dec 1;14(23):7711-6. Combination Immunotherapy for Tumors via Sequential Intratumoral Injections of Oncolytic Herpes Simplex Virus 1 and Immature Dendritic Cells. [full text]