2011 Summary:
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Neuroblastoma is a rare disease and accounts for approximately 8% of childhood cancers in the United States. Currently, less than 40% of children over 1 year of age at diagnosis survive.  Despite an aggressive combination of intensive chemotherapy, surgery, radiation and autologous bone marrow transplant, fewer than 10% of patients can be salvaged after initial relapse. For these children the 5-year survival rate is <10%.  Furthermore, the short- and long- term morbidity of these treatments is significant and often renders patients unable to tolerate salvage therapy following relapse. More effective and better tolerated new treatments are urgently needed.

MetronomX is supporting the development of a promising new drug for treatment of neuroblastoma. MNX-100 is an orally administered version of nifurtimox that has been used in tens of thousands of patients worldwide for an alternative and unrelated medical indication.  Preclinical data have shown that single-agent nifurtimox has both in vitro and in vivo cytotoxicity against neuroblastoma cell lines and xenograft models, including tumors established from TIC’s (‘tumor initiating cells’) directly from neuroblastoma patients.  A recent Phase I trial of MNX-100 in children with relapsed/refractory neuroblastoma established a maximum tolerated dose of 30 mg/kg/day. The trial also evaluated tumor response with MNX-100 alone and then combined with topotecan and cyclophosphamide, with promising results achieved.

The mechanism of action of MNX-100 is multifactorial, which probably explains its potent activity in cancer.  It decreases the activity of important signaling molecules (pAKT) involved in chemoresistance.  It induces the NF-E2 related factor 2 (NRF2) stress response pathway by inducing the the generation of free radicals, increasing the cellular concentration of superoxide, hydroxyl free radicals and/or hydrogen peroxide. Cell death occurs as a consequence of the resulting oxidative damage to DNA, membrane lipids and/or proteins and induction of the apoptotic cellular death pathway.  The drug not only generates anion radicals, but also interacts with catecholamines by generating semiquinone free radicals that exacerbate damage to functionally important biomolecules found in neuroendocrine tumors, leading to apoptosis of neuroblastoma cell lines.  Neuroendocrine tumors, in particular, neuroblastomas are known to contain high levels of catecholamines, thereby potentially leading to the relative specific targeting of these cells.  A number of other tumor cell lines are sensitive to the drug, including medulloblastoma, lung cancer, glioblastoma and others. In vivo tumor xenograft models have shown inhibition of tumor growth with a histologic evidence of decreased proliferation and increased apoptosis. MNX-100 is also synergistic with a variety of widely used cancer chemotherapeutic drugs.  Nifurtimox is well understood from a pharmacokinetic and pharmacodynamic perspective and is well tolerated in children and adults.

Currently MNX-100 is being tested for anti-tumor activity in a multicenter (over ten  centers in the US) Phase II clinical trial for refractory and relapsed neuroblastoma and medulloblastoma patients. It is designed to assess the antineoplastic effect when given in combination with cyclophosphamide and topotecan to children with neuroblastoma with first relapse, or who have multiply relapsed (received up to 2 previous chemotherapy regimens) or are refractory to standard initial therapy.  So far, given the ongoing encouraging clinical results in neuroblastoma patients, we are confident that it will lead us to conduct a Phase III trial within the near future.

Clinical Development

The current Phase II trial is designed to evaluate the anti-tumor efficacy of nifurtimox in children with neuroblastoma and medulloblastoma. Nifurtimox is a synthetic  compound that has been used safely since the 1970’s in both adults and children.  The drug has never been approved for use in the US.  In 2002, a patient with progressive refractory neuroblastoma who was being treated with cyclophosphamide and topotecan contracted Chagas disease from a blood transfusion and was treated with nifurtimox.   Her tumor subsequently regressed.  This observation was made by her pediatric oncologist, Dr. Giselle Sholler, currently Director of Pediatric Oncology at the Van Andel Institute in Michigan.  Subsequently six multiply relapsed neuroblastoma patients were treated by Dr. Sholler and team with nifurtimox (20 mg/kg/day) combined with cyclophosphamide and topotecan through compassionate release.  Five of the six patients showed a response to treatment and two of these patients attained a complete remission on this therapy and remained without evidence of disease for more than one year after beginning treatment. 

A Phase I trial of MNX-100 in children with multiply relapsed/refractory neuroblastoma has been completed (see publication Saulnier Sholler, GL, Bergendahl, G, Brard, L, Singh, AP, Heath, B, Bingham, P, Ashikaga, T, Kamen, B, Homans, A, Slavik, MA, Lenox, S, Higgins, T, Ferguson, W. J. Pediatric Oncology 33: 2011; 25-30).  The primary objective was to determine the maximum tolerated dose of this medication, which was found to be 30 mg/kg/day divided in 3 doses.  The Phase I trial also evaluated tumor response.  Fourteen patients were evaluable for efficacy following MNX-100 treatment alone. According to RECIST criteria (NCI guidelines for solid tumor responses), six patients displayed stable disease, and eight had progressive disease.  In addition to RECIST criteria, patients were also evaluated for a clinical response as defined by radiological stable disease with either a 50% decrease in VMA or clearance of bone marrow or resolution of MIBG activity.  A clinical response was seen in two (33%) of the six patients with stable disease.  Of these patients, one had resolution of bone marrow disease, which was confirmed on subsequent bone marrow biopsies, and one had greater than 50% decrease in urinary VMA. Fourteen patients with relapsed/refractory neuroblastoma were enrolled in this study. Based on previous data of nifurtimox for Chagas treatment in thousands of patients over 40 years, many of the gastrointestinal and neurological toxicities observed in this study were expected.  Only grade 1 and 2 toxicities were seen at the doses of 20 and 30 mg/kg/day.


The combination of cyclophosphamide and topotecan was chosen for combination therapy because it has shown efficacy in the treatment of relapsed neuroblastoma; in an earlier phase II study evaluating this combination conducted by the Pediatric Oncology Group, there was a 32% response rate among patients with first relapsed neuroblastoma (see publication London, WE, Frantz, CN, Campbell, LA, Seeger, RC, Brumback, BA, Cohn, SL, Matthay, KK, Castleberry, RP, Diller, L. J. Clinical Oncology 2010 20:3808-3815).  The patients that have been treated in the Phase I and II trials with nifurtimox are multiply relapsed patients, with much lower responses expected to topotecan and cyclophosphamide, since most have previously been treated with the combination chemotherapy and already relapsed (in contrast to the patient population noted above, which was first relapse patients who were never previously exposed to topotecan and cyclophosphamide). We hypothesize that there will be greater response and more durable response in the multiply relapsed patient population when they are re-treated with topotecan and cyclophosphamide in combination with nifurtimox. 

Tumor response was measured by Response Evaluation Criteria in Solid Tumors (RECIST). There was a secondary assessment of clinical response, defined as patients who have radiological stable disease with either a 50% decrease in urinary catecholamines if elevated at study entry, clearance of bone marrow disease on greater than 2 biopsies, or resolution of MIBG activity. 14 patients were evaluable for tumor response following nifurtimox treatment alone. According to RECIST criteria, 6 patients displayed stable disease, and 8 had progressive disease. Five out of the six patients with stable disease were evaluable for clinical response and 2 showed a clinical response: one had resolution of bone marrow disease, which was confirmed on subsequent bone marrow biopsies, and the other had greater than 50% decrease in urinary catecholamines. These data indicate that nifurtimox alone has clinical activity in this patient population. Of the 10 patients that were evaluable for tumor response after three cycles of nifurtimox, cytoxan and topotecan treatment, 3 showed a partial response, 5 had stable disease, and 2 had progressive disease according to RECIST criteria. Of the 5 patients with stable disease, 3 had clinical response. These 3 patients continued to have either clearance of bone marrow disease or a greater than 50% decrease in urinary catecholamines. The mean progression-free survival for all 14 patients who began nifurtimox treatment was 9.1 months. It is important to note that as stated above, the mean historical PFS for this group of patients, at least as measured by failure to therapy in five previous negative clinical trials, is about 1.4 month.

The trial also revealed some unique qualities of nifurtimox that makes it an attractive drug for pediatric patients. Toxicities were generally mild and reversible at the MTD. Administration of the drug is straightforward since it is in tablets which if needed can be easily crushed and combined with food. Compliance data showed that, on average, patients took 96.7% of their prescribed pills, showing that the treatment regimen could be easily followed.  In conclusion, nifurtimox alone and in combination with cytoxan and topotecan had acceptable toxicity in heavily pretreated relapsed/refractory neuroblastoma patients. Stabilization of disease and clinical response was seen as a single agent; in combination therapy, radiographic and clinical responses were seen in patients who had previously progressed through multiple chemotherapy regimens. Given these encouraging results, 30 mg/kg/day nifurtimox alone and in combination with cytoxan and topotecan was selected to test its anti-tumor efficacy in a Phase II study for patients with relapsed/refractory neuroblastoma and medulloblastoma.

A total of 29 patients are currently evaluable with the combination therapy in the Phase II trial to date (36 enrolled). Most toxicities are Grade I and II, with anorexia as being the most prevalent, but with a few reversible neurotoxicities. According to RECIST criteria, 7 (24%) have showed a partial response (PR) and 13 (45%) showed a stable disease (69% combined PR and SD). The progression free survival (PFS) data of 1.4 months in progressive disease PFS data is consistent with historical data of about 1.4 months in a series of trials in this population with failed therapies. In contrast, the median PFS data in the Phase II nifurtimox responders is quadruple that of the non responding patients (197 days vs. 49 days) and the patients with stable disease had nearly a double median PFS compared to non responding patients (112 days vs. 49 days). The response and PFS results are consistent with the nifurtimox preclinical and Phase I data, which suggest that nifurtimox may have single agent activity as well as act as a potent sensitizer to topotecan and cytoxan treatment, and have significant benefit in terms of PFS in this advanced patient population. Of the three medulloblastoma patients treated with the triple treatment, one had a stable disease, one had a CR and one had a PR. This PR has no evidence of active disease as measured by PET scan and may in the future be objectively scored as a CR.

Current sites and Principal Investigators for Clinical Trials

Giselle Sholler, MD

Pediatric Hematology-Oncology
Vermont Cancer Center at UVM College of Medicine Vermont Children’s Hospital
Smith 559a
111 Colchester Ave Burlington, VT 05401
Phone: (802) 847-2850
Fax: (802) 847-5557
Email: gsholler@UVM.edu

William Ferguson, MD
Pediatric Hematology-Oncology
Cardinal Glennon Children’s Medical
Center/Saint Louis University School of Medicine
1465 S. Grand Blvd.
Saint Louis, MO 63104
Phone: (314)-577-5638
Fax: (314)268-4081
Email: fergusws@slu.edu

William Roberts, MD
Pediatric Hematology/Oncology
Rady Children's Hospital San Diego
3020 Childrens Way MC5035
San Diego, CA 92123-4282
Phone: 858-966-5811
Fax: 858-966-8035
Email: wroberts@chsd.org

Deanna Mitchell, MD
Michigan State University
Helen DeVos Children’s Hospital
Tel: 616-391-2086
Email: Deanna.Mitchell@devoschildrens.org

Don Eslin, MD
Pediatric Hematology/Oncology
92 West Miller Street, MP 318
Orlando, FL 32806
Tel: 321-841-8588
Email: Don.Eslin@orlandohealth.com

Jacqueline Kraveka, DO
Assistant Professor of Pediatrics
Medical University of South Carolina
Division of Pediatric Hematology-Oncology
135 Rutledge Avenue, Room 480
MSC 558
Charleston, SC 29425
Tel: 843-792-2957
Fax: 843-792-8912
Email: kravekjm@musc.edu

Joel Kaplan, DO, MPH
Levine Children’s Hospital
1000 Blythe Blvd
Charlotte, NC 28203
Tel: 704-381-9900
Fax: 704-381-9901
Email: Joel.Kaplan@carolinashealthcare.org

Nehal Parikh, MD
Assistant Professor of Pediatrics
Connecticut Children's Medical Center
Division of Hematology / Oncology 2J
282 Washington Street Hartford, CT 06106
Phone: 860-545-9630
Fax: 860-545-9622
Email: Nparikh@ccmckids.org

See also www.clinicaltrials.gov

How to enroll in the MNX-100 clinical trial

Please contact:

Shannon R. Lenox, BS, CCRP
Clinical Research Coordinator
Vermont Children's Hospital-UVM College of Medicine
HSRF 326, 149 Beaumont Avenue
Burlington, VT 05405
f: 802.656.2140
email: Shannon.Lenox@med.uvm.edu


Genevieve Bergendahl, RN
Senior Research Nurse Coordinator
Vermont Cancer Center
UVM College of Medicine
149 Beaumont Avenue HSRF 326
Burlington, VT 05405
Phone: 802-656-4511
Fax: 802-656-2140
E-Mail: Genevieve.bergendahl@uvm.edu


See also www.nmtrc.org