ASCO 2010 ~ Abstract impact and drugs for neuroblastoma

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.