Allogeneic Tumor Cell Vaccination With Oral Metronomic Cytoxan in Patients With High-Risk Neuroblastoma (ATOMIC)

Researchers at Texas Children’s Hospital/Center for Cell and Gene Therapy, Baylor College of Medicine will begin accruing patients soon on a new phase I/II trial using an allogeneic neuroblastoma vaccine with low-dose chemotherapy. Drs Chrystal Louis and Malcom Brenner are the principal investigators. The trial will accrue 30 children up to age 21.

Eight injections of the vaccine will be given over 20 weeks, along with low-dose cyclophosphamide (Cytoxan). The vaccine is created from neuroblastoma cell lines modified to enhance immune response.

The rationale for adding low-dose cyclophosphamide is two-fold:

• a well-documented anti-angiogenesis effect in many tumors
• it decreases regulatory T-cells (or suppressor T-cells) which can suppress the immune system and aid tumor cells in “hiding.”

For more background on vaccine trials for neuroblastoma see prior article posted here.

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

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]

Dr Michael Burke from the University of Minnesota is the Principal Investigator of the Seneca Valley Virus trial COG-ADVL0911:

“Seneca Valley Virus-001 in Treating Young Patients With Relapsed or Refractory Neuroblastoma, Rhabdomyosarcoma, or Rare Tumors With Neuroendocrine Features”

Dr Burke gave a presentation on this trial at the CNCF parent conference July 10, 2010.

By early July, this Phase I trial had enrolled three children (two with NB) since March 2010, with a planned accrual of 34 children, and is currently open at:

• Alabama ~ UAB Comprehensive Cancer Center
• California ~ Children’s Hospital of Orange County
• Illinois ~ Children’s Memorial Hospital – Chicago
• Indiana ~ Indiana University Melvin and Bren Simon Cancer Center
• Michigan ~ C.S. Mott Children’s Hospital at University of Michigan Medical Center
• Minnesota ~ Masonic Cancer Center at University of Minnesota
• Missouri ~ Siteman Cancer Center at Barnes-Jewish Hospital – Saint Louis
• Ohio ~ Cincinnati Children’s Hospital Medical Center
• Pennsylvania ~ Children’s Hospital of Pittsburgh
• Texas ~ Baylor University Medical Center – Houston
• Washington ~ Children’s Hospital and Regional Medical Center – Seattle

Seneca Valley Virus, or NTX-010, is the first picornavirus (small RNA virus) to be evaluated as an anticancer agent. This virus is very small–about one-fourth the size of adenovirus so can penetrate tumor cells and replicate rapidly. It is highly selective for cancer cells with neuroendocrine features and does not harm normal cells, humans lack pre-existing neutralizing antibodies (ie prior exposure in humans is very rare), does not cause disease in humans or animals, and not transmitted among people or animals. It was accidentally discovered in a laboratory growth medium, and thought to be naturally occurring in pigs. [1]

NTX-010 was tested first in adults, with a trial that opened in 10 locations in 2006 and enrolled 42 adults with tumors with neuroendocrine features. This trial was sponsored by Neotropix and the results of this phase I study were presented at the 2009 ASCO meeting:

NTX-010 is the first picornavirus to be evaluated as an anticancer therapeutic. A single IV dose of 10¹¹ vp/kg of NTX-010 is safe, has predictable viral kinetics, and shows promising activity against neuroendocrine tumors. [2]

A Phase II randomized study for small cell lung cancer has recently opened and will enroll 99 adults.[3]

Neotropix scientists published a summary of the preclinical work with Seneca Valley Virus on cell lines and mice in 2007, and the image below shows the response of SCLC small-cell lung cancer tumors in mice to a single infusion of the virus.

The authors concluded on p. 1632:

The life cycle of SVV-001 is very rapid and is completed within 12 hours, thus allowing for rapid spread to neighboring tumor cells and several rounds of virus replication before the development of an immune response. SVV-001 is a simple single-stranded RNA virus and therefore does not require an intermediate DNA step during replication, so there is no possibility for insertion mutagenesis of viral RNA into the host genome. Moreover, the genomes of picornaviruses carry no oncogenes that may induce tumors in animals. Finally, SVV-001 replicates in the mouse, which is a widely accepted relevant model in which to study toxicity and efficacy.

Nonpathogenicity in humans and animal species and stability of the viral genome in vitro and in vivo are two other desirable properties of oncolytic viruses. SVV-001 is not linked to any disease condition in pigs, the natural host of the virus (Hales LM, Jones BJ, Knowles NJ, Landgraf JG, Swenson SL, Skele KL, et al.: unpublished data). We found that systemic administration of the virus into immune-competent and immune-deficient mice was well tolerated and caused no toxicity. Moreover, to evaluate the ability of SVV-001 to adapt to replicate in nonpermissive cells, the virus was passaged intentionally three times in nonpermissive cell lines A549, H460, and Hep3B, and no virus was produced, suggesting that the virus did not change its tropism (data not shown). In addition, no antibody escape mutants of SVV-001 were produced in PER.C6 cells when SVV-001 was grown with media containing anti-SVV mouse hyper immune serum (data not shown). These data suggest that the genome of SVV-001 is stable.

Our study has several potential limitations. Although the in vivo efficacy data reported here were generated using immune-deficient athymic mice, it is unknown whether immune responses in cancer patients would limit the effectiveness of SVV-001 in patients and prevent repeat administration, if it was necessary. In addition, studies were done using subcutaneous tumor models using well-defined cell lines and, as such, may not simulate patients with metastases. Immune-competent and metastasis models are currently being explored to address these limitations.[4]

The virus is toxic to embryonic cell lines, so the first adult study required surgical sterilization of females who were of childbearing age.[5]

The preclinical pediatric testing was just published (Aug 2010) “Initial testing of the replication competent Seneca Valley virus (NTX-010) by the pediatric preclinical testing program” (p. 299):

NTX-010 shows high-level activity against selected cell lines and xenografts from the PPTP’s in vitro and in vivo panels. A single dose of NTX-010 induced complete responses in 8 of 10 of the rhabdomyosarcoma and neuroblastoma xenografts evaluated, including all 4 alveolar rhabdomyosarcoma xenografts studied. Of note is the similar sensitivity to NTX-010 in Rh30 xenografts (established at diagnosis) and Rh30R xenografts (established at patient relapse), suggesting NTX-010 has therapeutic utility in both chemosensitive and chemorefractory disease.[6]

Considering this trial for a child with relapsed or refractory neuroblastoma

Phase I studies are safety studies, so evidence of efficacy has not been established. Since phase I agents are usually tried in adults first, it is encouraging if responses are seen, but of course adults have different tumors (in the phase I adults with carcinoid tumors showed responses[2]). All of this information indicate some agents hold more promise than others. The attractive thing about this study is the lack of toxicity, and the short time commitment to the study (infusion of virus, then test blood and stool for 28 days or until virus clears).  A child with a small tumor burden, or a child with stable disease may be a good candidate for this trial since the risk of progression while on study may be minimal. As always, discussing treatment options with a trusted pediatric oncologist is essential.

References

1.  NTX-010 A Novel Mechanism Anti-Cancer Agent in Phase I/II Clinical Development (2007 Neotropix summary)

2. Rudin CM, Senzer N, Stephenson J, et al. Phase I study of intravenous Seneca Valley virus (NTX-010), a replication competent oncolytic virus, in patients with neuroendocrine (NE) cancers. J Clin Oncol 2009;27: abstract 4629.

3. Seneca Valley Virus-001 After Chemotherapy in Treating Patients With Extensive-Stage Small Cell Lung Cancer; NCT01017601

4. J Natl Cancer Inst. 2007 Nov 7;99(21):1623-33. Epub 2007 Oct 30. [fulltext]

5. Safety Study of Seneca Valley Virus in Patients With Solid Tumors With Neuroendocrine Features;  NCT00314925

6. Pediatr Blood Cancer. 2010 Aug;55(2):295-303. PMID 20582972

http://online.wsj.com/article/BT-CO-20100714-708425.html

DOW JONES NEWSWIRES

Keryx Biopharmaceuticals Inc. (KERX) said the U.S. Food and Drug Administration has given orphan-drug designation to perifosine, a treatment for cancer including neuroblastoma, or cancer of the nervous system in infants.

Shares of the biopharmaceutical company jumped 13% to $4.04 in recent trading, while U.S.-traded shares of Keryx’s Canadian partner Aeterna Zentaris Inc. (AEZ.T, AEZS) were recently up 10% to $1.20.

The designation was announced three months after the drug received fast-track status, which authorizes an expedited review for drugs that treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs.

“The Orphan Drug designation is an important component of our development plan for perifosine in neuroblastoma, an indication where no FDA-approved therapies currently exist,” said Chief Executive Ron Bentsur.

The Orphan Drug Act provides incentives to create therapies for so-called orphan diseases–those that affect fewer than 200,000 Americans. There are about 7,000 such maladies, most of them serious, that have few or no drugs to treat them. Getting an orphan-drug designation opens the door to incentives once the FDA approves a medicine for sale in the U.S., including seven years’ marketing exclusivity and tax breaks.

Bentsur said the company is exploring the next steps for the development, which “we hope, ultimately, could provide a new treatment option for children and infants” suffering with the illnesses.

Perifosine also is in Phase 3 clinical trial for treating refractory advanced colon cancer and multiple myeloma, as well as in Phase 1 and Phase 2 trials for several other tumor types.

-By Jodi Xu, Dow Jones Newswires; 212-416-3037; jodi.xu@dowjones.com

Perifosine is currently offered to neuroblastoma patients (relapsed/refractory pediatric solid tumors) in two trials at Memorial-Sloan Kettering:

http://clinicaltrials.gov/ct2/show/NCT01049841

http://clinicaltrials.gov/ct2/show/NCT00776867

From AP:

Perifosine also has orphan drug status as a colorectal cancer treatment, and the FDA has said it will conduct a faster-than-normal review of the drug in both colorectal cancer and multiple myeloma.

Keryx has the rights to market perifosine in North America. Canadian drugmaker Aeterna Zentaris holds the rights in all other countries except South Korea.

Significance of abstracts submitted to ASCO

The meeting at ASCO (America Society of Clinical Oncology) provides a prime opportunity for oncologists and other researchers to present results of clinical trials and studies before publication in peer-reviewed journals.

This year ASCO had over 5000 abstracts submitted. Abstracts are reviewed for scientific and practice-changing merit and some are selected for either:

• Poster Discussion (a discussant comments for 15 minutes on up to 10 posters/abstracts)
• Oral Abstract Session (author speaks for 15 minutes on one study), with an expert in the field serving as discussant commenting 15 minutes on up to four Oral Abstracts.

The rest of the abstracts are shown in a the General Poster Session in a great hall where approximately 500 posters are displayed for a 4-hour period. The authors stand by their posters available for one-on-one discussion. This year a new session was added: Trials in Progress Poster Session.

At a higher impact level there are Education Sessions, Special Sessions, Award Lectures, Plenary Sessions, Scientific Sessions, Clinical Science Symposia, and so on for reviewing the state-of-the-art and continuing education.

Why explain this? It helps to understand the level of impact a particular study has by the assigned presentation format. The highest impact studies are the subjects of press releases by ASCO before, during, and after the meeting. Industry sponsors also produce their own press releases. For example, this year a high-impact study revealed the first-ever improvement in survival of melanoma in a phase III study. Last year the early results of the ch14.18 study was a pinnacle abstract of the 2009 meeting. These highlighted studies represent the top 0.2% of all abstracts submitted.

This year, therapy studies specifically focused on neuroblastoma did not rank quite that high, but there were results of some studies that included children with neuroblastoma. Five of the abstracts below were included in the poster discussion session (aurora a kinase inhibitor, lestaurtinib/CEP-701, pemetrexed, perifosine, and temsirolimus). There were 22 posters on the list for a one-hour presentation, so the discussants spoke somewhat generally about trial design and related issues concerning phase I and II trials, rather than specifics of the studies. Brief bits from the abstracts are included in the description, and my comments are in italics.

Results of therapies for neuroblastoma

Phase I trial MLN8237, an oral selective small molecule inhibitor of aurora a kinase. (Mosse et al) J Clin Oncol 28:7s, 2010 (suppl; abstr 9529)

37 patients were enrolled, 32 were evaluable for toxicity, recommended pediatric phase 2 dose and schedule of MLN8237 is 80 mg/m2/d administered once daily for 7 days. No response data reported.

Phase I trial of lestaurtinib for children with refractory neuroblastoma (NB): A New Approach to Neuroblastoma Therapy (NANT) Consortium study. (Minturn et al) J Clin Oncol 28:7s, 2010 (suppl; abstr 9532)

Lestaurtinib, a multi-kinase inhibitor with potent activity against Trk kinases, has demonstrated anti-tumor activity in preclinical models of human NB. 47 patients with recurrent or refractory high-risk neuroblastoma were enrolled, and 10 dose levels explored, two objective responses and 10 patients had prolonged stable disease at dose levels ≥5, (median: 12 cycles) before disease progression (pending review), recommended phase II dose of 120 mg/m²/dose BID, well tolerated in this heavily pre-treated patient group. The author said the manufacturer has no further interest in making this drug.

Phase I trial of oxaliplatin and doxorubicin in children and adolescents with recurrent solid tumors. (Mascarenhas et al) J Clin Oncol 28:7s, 2010 (suppl; abstr 9543)

Responding patients were treated for a maximum of 8 courses, 17 patients were enrolled, objective (≥partial) responses were noted in 3 neuroblastomas and 1 each of osteosarcoma, mixed germ cell tumor, neurofibrosarcoma, thymic neuroendocrine carcinoma and nasopharyngeal carcinoma, 4 patients completed all 8 courses of protocol therapy. Oxaliplatin 105 mg/m² on day 1 combined with doxorubicin 20 mg/m² days 1-3 was the MTD. Significant anti-tumor activity was noted.

Pilot study of the novel chemotherapy regimen of topotecan, ifosfamide, and carboplatin (TIC) in children with refractory/recurrent solid tumors. (Lee at al) J Clin Oncol 28:7s, 2010 (suppl; abstr 9545)

The combination of ifosfamide, carboplatin, and etoposide (ICE) has previously been demonstrated to be an effective regimen in children with recurrent or refractory solid tumors (Cairo et al JPHO, 2001). Substituting topotecan (a Topoisomerase I inhibitor) for etoposide (a Topoisomerase II inhibitor) may be a more efficacious regimen due to the cytotoxic activity of topotecan in pediatric solid tumor xenografts, as well as its in vitro synergistic activity with platinum and alkylating agents. 14 patients (3-18 yrs) with relapsed/refractory disease (Wilms 2; osteosarcoma 2; germ cell tumor 2; high grade glioma 1; rhabdomyosarcoma 1; sarcoma 1; non-Hodgkin’s lymphoma 1; neuroblastoma 1; medulloblastoma 1; hepatoblastoma 1; neurocytoma 1). Disease response showed 4/14 with CR, 2/14 with PR, and 1/14 with SD for an overall response rate (ORR) of 43%. These preliminary results demonstrate that the combination of topotecan, ifosfamide, and carboplatin (TIC) is feasible, induces a >40% ORR in relapsed/refractory patients, and warrants further study in children with CNS and solid tumors.

Phase II trial of pemetrexed in children with refractory solid tumors: A Children’s Oncology Group study. (Warwick et al) J Clin Oncol 28:7s, 2010 (suppl; abstr 9535)

Pemetrexed is a multi-targeted antifol that inhibits key enzymes involved in nucleotide biosynthesis. Refractory or recurrent solid tumors to estimate the response rate and further define its toxicity profile. A two-stage design (10 + 10) was employed for each of the following disease strata: osteosarcoma, Ewing sarcoma/ peripheral PNET, rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/ supratentorial PNET and non-brainstem high-grade glioma. Of 72 eligible subjects, 68 were evaluable for response. No complete or partial responses were observed. Stable disease, for a median (range) of 5 (4- 8+) cycles, was observed in 5 patients: ependymoma, Ewing sarcoma, medulloblastoma, neuroblastoma, osteosarcoma (n=1 each); one patient with Ewing sarcoma is still on study after 8 cycles. Although reasonably well tolerated, pemetrexed as administered in this study has no significant activity in a broad spectrum of refractory pediatric solid tumors.

Phase II study of temsirolimus in children with high-grade glioma, neuroblastoma, and rhabdomyosarcoma. (Geoerger et al) J Clin Oncol 28:7s, 2010 (suppl; abstr 9541)

Temsirolimus (TEMSR), an mTOR inhibitor, prolongs survival in adults with advanced renal cell carcinoma. Part 2 of the study explored the safety and efficacy in children with neuroblastoma, high grade glioma or rhabdoymyosarcoma. Primary efficacy endpoint was objective response (OR; complete response + partial response [PR]) within first 12 weeks. If fewer than 2 ORs occurred after 12 evaluable pts were enrolled in one of each tumor types, then enrollment in that tumor type would be stopped for lack of efficacy. 52 pts were enrolled (17 glioma, 19 neuroblastoma, 16 rhabdomyosarcoma), at 12 weeks, 2 pts had PR (1 neuroblastoma, 1 rhabdomyosarcoma). 11 pts achieved stable disease ≥12 weeks (5 neuroblastoma and 6 glioma). Two pts with neuroblastoma remain on treatment >2 years. Temsirolimus 75 mg/m2 was well tolerated, the OR rate failed to meet the threshold level set for study continuation and efficacy. Nevertheless, observed OR and prolonged stable disease in merits further evaluation.

“Trials in progress” posters

Phase I study of single-agent perifosine for recurrent pediatric solid tumors. (Becher et al)  J Clin Oncol 28:7s, 2010 (suppl; abstr 9540)

Perifosine is a synthetic alkylphospholipid which inhibits Akt activity. Single agent trials of perifosine in adults have demonstrated responses in patients with renal cell carcinoma, advanced brain tumors, soft-tissue sarcomas, hepatocellular carcinoma, as well as in hematologic malignancies including multiple myeloma. Pediatric patients with recurrent solid tumors were enrolled and 9 pts with high-grade glioma (n=5), medulloblastoma (n=2) or neuroblastoma (n=2) have been treated to date.  Perifosine is well tolerated in children with advanced solid tumors. The poster showed 2 patients with NB had stable disease 48 weeks and 55+ weeks, and dose level 4 is open. This study opened in 2008, with planned accrual 36. Another study with perifosine and temsirolimus just opened as well. The discussant mentioned the difficulty of completing accrual for this single-agent trial when a combination trial using this drug is open at the same institution.

A phase I trial of TPI-287 as a single agent and its combination with temozolomide in relapsed neuroblastoma or medulloblastoma. (Sholler et al) J Clin Oncol 28:7s, 2010 (suppl; abstr TPS329)

A novel anti- microtubule agent, TPI 287, is synthetically manufactured from naturally occurring taxanes extracted from yew starting material. The synthesis involves modifications of the side chain to make the drug more lipophilic, and modification of the baccatin ring structure which circumvents multidrug resistance (MDR)-based resistance and allows for binding to mutant tubulin. The primary objective is to determine the safety, tolerability and maximum tolerated dose (MTD) of TPI 287. The secondary objectives are to examine the activity of TPI 287 as a single agent and in combination with temozolomide (TMZ) in these tumor types based on overall response rate (ORR), progression free survival (PFS), and median overall survival (OS) and to evaluate the pharmacokinetics (PK) of TPI 287. There are 4 dose level escalations with the MTD of single agent therapy defined as the dose level below which DLTs are seen in ≥ two of six patients dosed.