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L.M. Krug



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    MO09 - Mesothelioma I (ID 120)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track:
    • Presentations: 2
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      MO09.01 - Evaluation of tolerability and anti-tumor activity of GDC-0980, an oral PI3K/mTOR inhibitor, administered to patients with advanced malignant pleural mesothelioma (MPM) (ID 1712)

      16:15 - 16:20  |  Author(s): L.M. Krug

      • Abstract
      • Presentation
      • Slides

      Background
      The PI3K-AKT-mTOR signaling pathway is dysregulated in a wide variety of cancers. Pathway activation in mesothelioma may occur through diverse cellular mechanisms, including activation of receptor tyrosine kinases that signal through Ras and PI3K/Akt/mTOR, and loss of PTEN expression. GDC-0980 is a potent and selective oral dual inhibitor of class I PI3K and mTOR kinases that has demonstrated broad activity in various xenograft cancer models.

      Methods
      A phase I dose-escalation study was conducted in 2 Stages: Stage 1 evaluated oral, daily (QD) doses of 2-70 mg GDC-0980 given 21/28 or 28/28 days in a 3+3 dose escalation design. Stage 2 evaluated disease specific cohorts at the recommended phase 2 dose (RP2D), including a MPM cohort at 30 mg GDC-0980 QD 28/28 days. Safety and tolerability of GDC-0980 was assessed as well as pharmacokinetics (PK) and pharmacodynamics (PD) assessment of PI3K pathway inhibition by FDG-PET. Anti-tumor activity was assessed by modified RECIST; CT scans were centrally reviewed retrospectively by a radiologist with MPM expertise. Archival tumor tissue was evaluated for PIK3CA mutation by allele specific PCR or Sanger sequencing and PTEN expression was assessed by immunohistochemistry.

      Results
      33 MPM patients were enrolled: 6 in Stage 1 at 8-70 mg and 27 in Stage 2 at 30mg GDC-0980. Safety and tolerability of GDC-0980 in Stage 1 was similar in MPM compared to other solid tumor patients, with the exception of a Grade 5 pneumonitis that occurred in a MPM patient at 40 mg GDC-0980 QD. Based on Stage 1 tolerability data, a RP2D of 30 mg QD was evaluated in Stage 2 for MPM patients. The most frequent Grade ≥3 drug-related adverse events (AEs) at 30 mg GDC-0980 were rash (19%), with one patient (4%) having to discontinue GDC-0980. Other AEs were fatigue (15%), and hyperglycemia, diarrhea, and colitis (7% each). Reversible Grade 2 pneumonitis was reported for 2 patients (7%). Population PK analysis was used to assess the behavior of GDC‑0980 in MPM patients. Additionally, PK/PD relationships will be discussed for efficacy and safety, including exposure‑response, where appropriate. Archival tissue was analyzed for 29 MPM patients. Two samples had PIK3CA mutations (R88Q and E545G) and one sample showed loss of PTEN expression. PI3K pathway inhibition by FDG-PET responses was observed in 8 of 24 MPM patients with available scans. Anti-tumor activity was observed in both stages. Two patients achieved a partial response (PR) in Stage 1, one patient at 50 mg and one patient with the PIK3CA mutation R88Q at 8 mg GDC-0980. Two PRs were observed at the RP2D of 30 mg in Stage 2. Eleven (41%) MPM patients at the RP2D remained on study for >6 months, and 2 (7%) patients remained on study >12 months.

      Conclusion
      GDC-0980 was generally well tolerated in MPM patients at the RP2D. Anti-tumor activity, evidenced by tumor regression and prolonged disease control, has been observed. PIK3CA mutations and PTEN loss were uncommon.

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      MO09.04 - Defining BAP1 Syndrome: Preliminary results from an epidemiologic ascertainment study (ID 3437)

      16:30 - 16:35  |  Author(s): L.M. Krug

      • Abstract
      • Presentation
      • Slides

      Background
      Identifying tumorigenic mutations in malignant pleural mesothelioma (MPM) is essential to advance therapy. Somatic mutations in the BRCA-1 associated protein-1 (BAP1) gene occur in about 20% of MPM tumors (Bott et al., Nature Genetics, 2011). In a retrospective analysis evaluating demographics, exposures, and survival, a history of smoking was the only clinical feature associated with the presence of BAP1 mutations (Zauderer et al., in press, J Thorac Oncol, 2013). Germline BAP1 mutations have also been identified in families predisposed to MPM (Testa et al., Nature Genetics, 2011). BAP1 germline mutations have also been associated with other tumors including atypical Spitz nevi, uveal melanoma, and renal cell carcinoma. These discoveries suggest that BAP1 mutations in mesothelioma represent part of a new hereditary cancer syndrome but the exact clinical phenotype remains unclear. To establish the frequency of germline BAP1 mutations in MPM patients and to accurately assess exposure history and family histories in these patients, we have undertaken a clinical trial to prospectively collect this information from patients with MPM.

      Methods
      All consenting patients provide a saliva or blood specimen from which germline DNA is extracted. Existing tumor samples are collected and analyzed for BAP1 mutation. Everyone completes a questionnaire regarding asbestos exposure, personal cancer history, and family history of malignancy. First, we will perform a de-identified assessment of the prevalence of germline BAP1 mutation. Patients whose tumors harbor BAP1 mutation and/or meet prespecified high risk criteria will be approached for identified germline testing after appropriate pre-test counseling. Mutations identified through research testing with be confirmed with clinical testing and additional genetic counseling will be undertaken. Testing will be offered to family members of patients with identified BAP1 germline mutations. Please see Figure 1 for study flow. Figure 1

      Results
      During the first 3 months that this protocol was open, we accrued 26 patients with mesothelioma, 15 of whom qualify for identified research testing. We will present results from ongoing testing at the meeting.

      Conclusion
      Recruiting patients to perform both de-identified and identified germline testing is feasible. Given the paucity of information regarding penetrance and appropriate screening interventions, BAP1 germline testing should continue only in the context of research programs. Additional preclinical work is ongoing to exploit this potential therapeutic target. Supported, in part, by a grant from the Mesothelioma Applied Research Foundation.

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    MO13 - SCLC I (ID 118)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO13.10 - Prospective Molecular Evaluation of Small Cell Lung Cancer (SCLC) Utilizing the Comprehensive Mutation Analysis Program at Memorial Sloan-Kettering Cancer Center (MSKCC) (ID 3137)

      11:25 - 11:30  |  Author(s): L.M. Krug

      • Abstract
      • Presentation
      • Slides

      Background
      Oncogenic events in adenocarcinoma and squamous cell cancers of the lung are well described. In contrast, the repertoire of possible molecular targets in SCLC still is unclear. Recent studies using next generation sequencing on rare resected SCLC specimens have provided insights into the molecular heterogeneity of this disease. Comprehensive, prospective molecular profiling of patients with SCLC using the biopsy specimens available in clinical practice has not been performed.

      Methods
      Utilizing an IRB-approved protocol to prospectively test SCLC tumors (Small Cell Lung Cancer Mutation Analysis Program, “SCLC-MAP”), these biopsies are evaluated by: FISH for FGFR1 and MET amplification; immunohistochemistry (IHC) for MGMT and PTEN loss; point mutation genotyping with Sequenom for PIK3CA (and others); and next-generation sequencing with our MSK-IMPACT assay (Integrated Mutation Profiling of Actionable Cancer Targets). MSK-IMPACT uses exon capture followed by massively parallel sequencing to profile all protein-coding exons and select introns of 279 cancer-associated genes, enabling the identification of mutations, indels, and copy number alterations of these genes. First, we tested the feasibility of this approach in a series of SCLC patients that were identified retrospectively as they had banked matched tumor and normal pairs. We performed next generation sequencing with MSK-IMPACT, with findings confirmed by FISH on these samples. We are prospectively collecting and evaluating SCLC tumors of our patients in active treatment, as detailed above.

      Results
      For our feasibility cohort, we identified 21 patients with SCLC with FFPE samples available from both matched normal tissue and small tumor biopsies. After histologic review and DNA extraction, 10 patients had adequate tissue for MSK-IMPACT (3 core biopsies, 7 fine needle aspirates). The following were noted: recurrent mutations in Rb1 (N=7) and p53 (N=8), FGFR1 amplification (N=2), and MET amplification (N=1), using as little as 15 nanograms of DNA. FGFR1 and MET amplification were confirmed by FISH testing. We have initiated this prospective SCLC-MAP program for our SCLC patients undergoing active treatment. Since 2/2013, 25 patients have provided consent and tumor tissue for analysis (8 surgical resections, 12 core biopsies, 3 lymph node dissections, 2 fine needle aspirates). Preliminary data are available for 16 patients: AKT1 E17 mutation by Sequenom (N=1), MGMT loss by IHC (N=1); and PTEN loss by IHC (N=2).

      Conclusion
      As adequate biopsy specimens are necessary to match lung cancer patients and treatments, increased number of patients with SCLC are presenting with more tissue. Comprehensive molecular evaluation of SCLC is feasible on clinically available specimens, as seen in our feasibility cohort. Prospective collection of SCLC tumor samples and mutational analyses are ongoing. Such analyses will allow us to characterize the molecular diversity of this disease and identify patients who will be candidates for targeted therapies. Funded, in part, by the Lung Cancer Research Foundation.

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    MO14 - Mesothelioma II - Surgery and Multimodality (ID 121)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
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      MO14.11 - Safety of hemithoracic pleural intensity-modulated radiation therapy (IMRT) for malignant pleural mesothelioma (MPM) in the multimodality setting: interim analysis of a phase II study. (ID 2802)

      11:25 - 11:30  |  Author(s): L.M. Krug

      • Abstract
      • Presentation
      • Slides

      Background
      Pleurectomy/decortication (P/D) is increasingly used for the surgical management of MPM. The presence of the remaining ipsilateral lung poses a challenge when delivering adjuvant radiation therapy, as the risk for radiation pneumonitis (RP) is high. We developed an IMRT technique targeting the entire pleura of the involved hemithorax, with promising early results. Here, we present the interim results of a prospective phase II study to determine the safety and toxicity profile of pleural IMRT following induction chemotherapy and P/D.

      Methods
      Twenty-nine patients with locally advanced MPM have been enrolled to date. All patients received up to four cycles of pemetrexed/platinum chemotherapy. P/D was performed for all resectable patients. Sequential hemithoracic pleural IMRT was then administered with the intent of achieving a total planned dose of 50.4Gy in 28 fractions, as previously described (Rosenzweig et al., IJROBP 2012). All patients were simulated with a 4D-CT scan. A PET scan for image fusion and radiation planning was available for all patients. A Simon two-stage design was applied. A safety analysis after the first 9 patients led to the identification of only one case with ≥grade 3 RP in the first 3 months. The cohort was therefore expanded to 28 evaluable patients, defined as having initiated RT. The primary endpoint is the incidence of ≥grade 3 RP defined per Common Terminology Criteria for Adverse Events, v4.0. Steroids are typically initiated for ≥grade 2 RP.

      Results
      To date, 21 out of 29 patients total are evaluable. The median follow-up is 10 months. The median age at diagnosis is 66 years (range 38-79). Median KPS was 90% (range 70-90%). Three patients had sarcomatoid, 3 had biphasic and 23 had epithelioid MPM. All patients received chemotherapy. Eight patients (28%) had a partial response, nine patients (38%) progressed, and all others had stable disease. Twenty-four patients (83%) underwent surgical exploration. Five patients underwent an extended P/D or P/D, 11 had a partial P/D, and 8 were found to be unresectable. Eight patients were removed from the study prior to receiving IMRT (7 due to disease progression and 1 due to grade 4 pulmonary embolism after one cycle of chemotherapy). To date, nineteen patients have completed IMRT [median dose 4680cGy (range 4500 to 5040cGy)]; one patient had distant disease progression after 16 fractions; one patient is currently on treatment. Five patients experienced grade 2 RP that was successfully controlled with steroids. One patient experienced grade 3 RP requiring supplemental oxygen, but quickly improved after steroid initiation. Other commonly observed ≥grade 2 radiation-related toxicities included fatigue (37%), dyspnea (47%), nausea (42%), esophagitis (26%), and cough (11%). No grade 4 or 5 radiation-related toxicities were observed.

      Conclusion
      Hemithoracic pleural IMRT appears to have an acceptable toxicity profile in this ongoing phase II study. Early intervention with steroids is effective in controlling RP. This novel radiation technique has great promise as a component of lung-sparing multi-modality therapy in locally advanced MPM.

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    O22 - Mesothelioma III (ID 122)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
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      O22.02 - CD8 T-cell Infiltration and Tumor IL-7R Expression are Independent Prognostic Factors in Epithelioid Malignant Pleural Mesothelioma (ID 2935)

      16:25 - 16:35  |  Author(s): L.M. Krug

      • Abstract
      • Presentation
      • Slides

      Background
      Following our publication (Cancer Immunol Immunother 2011) demonstrating the prognostic importance of chronic inflammatory cell infiltration in epithelioid malignant pleural mesothelioma (MPM), we investigated the prognostic significance of the immune microenvironment in the tumor nest and the tumor-associated stroma in epithelioid MPM.

      Methods
      A tissue microarray (TMA) was constructed from 170 epithelioid MPM cases, with 6 representative tumor cores and 3 representative stromal areas. Immunohistochemical analyses for immune cell infiltration (CD3, CD4, CD8, CD20, FoxP3) and interleukin receptors (IL-7R and IL-12Rβ2) were performed. TMA slides were analyzed for immune cell infiltration of tumor and stroma (low vs high, divided by use of the median), as well as for immune marker expression (sum of intensity and distribution). Overall survival (OS) was estimated using Kaplan-Meier analysis, and log-rank tests and Cox proportional hazards models were used to analyze the association between each marker and OS.

      Results
      Analysis of single immune cell infiltration for all patients revealed that high tumor CD8+ T-cell infiltration, high CD20+ B-cell infiltration, and low tumor IL-7R expression correlated with higher OS (Figure). Combined tumor CD8+ and CD4+ cell infiltration significantly correlated with better OS (5-year OS, 36% [n=61] vs. 20% [n=96]; p=0.008). In a multivariate analysis including age, stage, lymph node metastases, lymphatic invasion, and vascular invasion, high CD8+ T-cell infiltration and low tumor IL-7R expression were independent predictors of OS (Table). Figure 1Figure 2

      Conclusion
      Tumor CD8+ T-cell infiltration and tumor IL-7R expression are independently associated with survival, which highlights the biologic and prognostic significance of the immune microenvironment for patients with epithelioid MPM.

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    P1.08 - Poster Session 1 - Radiotherapy (ID 195)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      P1.08-017 - Factors Influencing Utilization of Prophylactic Cranial Irradiation in Limited-Stage Small Cell Lung Cancer (ID 1915)

      09:30 - 09:30  |  Author(s): L.M. Krug

      • Abstract

      Background
      Prophylactic cranial irradiation (PCI) improves survival in limited-stage small cell lung cancer (LS-SCLC). However, PCI is not always delivered to these patients, possibly due to concerns about neurocognitive effects. Efforts to reduce neurotoxicity of PCI, such as hippocampal-sparing radiation, may mitigate these concerns. Little is known about the utilization rate of PCI and the reasons it is not delivered. Therefore, we reviewed the experience with LS-SCLC at a large academic institution to determine the rate of PCI use and factors associated with the lack of use.

      Methods
      We retrospectively reviewed all patients with LS-SCLC treated at our institution between 2000 and 2012. Receipt of PCI was recorded, as well as information about clinical presentation and initial treatment. In patients who did not receive PCI, we reviewed clinical notes from both medical and radiation oncologists to determine the reason. Overall survival (OS) and brain metastasis-free survival (BMFS) were estimated using the Kaplan-Meier technique. Pearson’s chi-squared test was used to evaluate factors associated with PCI use.

      Results
      We identified 229 patients treated with thoracic radiotherapy (TRT) for LS-SCLC at our institution. Median followup was 15.1 months. Of these, 119 (52.0%) did not receive PCI. Thirty-three patients (27.7%) had progressive disease or concern for progression after initial therapy and therefore did not receive PCI. The next most common causes for no PCI were patient refusal (n=25, 21%) or deemed medically unfit by an oncologist (n=25, 21%). In 20 patients (16.8%), the reason for lack of PCI could not be ascertained. Other infrequent causes were patient death or lack of followup (n=8), age (n=3), and prior radiotherapy to the head (n=2). Patients who did not get PCI were significantly older (p<0.001) and had worse performance status at initial presentation (p<0.001). Patients who received sequential rather than concurrent chemoradiation, or who received once-daily rather than twice-daily TRT, were also significantly less likely to receive PCI (p<0.001). Patients who did not receive PCI had significantly worse OS (median 17 vs. 30 months, p=0.01) and BMFS (71% vs. 91% at 1 year, p=0.02) than those who did.

      Conclusion
      Even at a major academic center, fewer than half of patients with LS-SCLC ultimately receive PCI. Patients receiving PCI had better intracranial control. They also had better OS, but this is likely also attributable to other clinical and treatment characteristics. Younger and fitter patients, as well as those receiving optimal TRT, are significantly more likely to undergo PCI. The most common reason for lack of PCI is progression of disease after initial therapy, which is clinically appropriate. However, a significant number of patients are appropriate for PCI yet refuse therapy, generally due to concerns about toxicity. PCI is withheld from an equivalent number of patients due to oncologist concerns about ability to tolerate therapy. This indicates that efforts to reduce neurotoxicity of PCI, such as hippocampal-sparing radiation, may impact a significant number of patients with LS-SCLC and expand the application of this survival-enhancing intervention.

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    P1.14 - Poster Session 1 - Mesothelioma (ID 194)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 1
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      P1.14-002 - Lack of response to chemotherapy for previously treated malignant pleural mesothelioma (MPM) (ID 656)

      09:30 - 09:30  |  Author(s): L.M. Krug

      • Abstract

      Background
      After initial therapy with pemetrexed/platinum, second-line therapy options are not well established. Gemcitabine and vinorelbine are often used based on small trials and first-line data. To augment the existing data, we examined our institutional experience using vinorelbine and gemcitabine in patients with previously treated MPM.

      Methods
      We reviewed the records of all patients treated with vinorelbine and/or gemcitabine as second- or third-line therapy for MPM between 2003 and 2010. Vinorelbine was administered at a dose of 25 mg/m[2] days 1 and 8 in a 3-week cycle and gemcitabine was given at 1000 mg/m[2] days 1, 8, and 15 in 28 day cycles. CT scans were generally performed after every two cycles. Imaging studies were reviewed with a radiologist according to the modified RECIST criteria.

      Results
      60 patients were identified: 33 treated with vinorelbine, 15 with gemcitabine, and 12 with both. Patient characteristics are as follows: 78% men: median age 67 (range 41-85); 63% epithelioid, 19% mixed histology, and 18% sarcomatoid; 83% received first-line pemetrexed-platinum therapy and 10% gemcitabine-platinum therapy. One partial radiographic response was identified among the 56 patients with follow up imaging available for review (Figure 1) giving a response rate of 2% (95% CI 0-5%). With gemcitabine, 10 patients (37%) had radiographic progression, 6 (22%) had clinical progression, 6 (22%) had radiographic stable disease, 4 (15%) had clinically stable disease, and 1 (4%) had radiographic partial response. With vinorelbine, 20 patients (43%) had radiographic progression, 2 (4%) had clinical progression, 19 (42%) had radiographic stable disease, 4 (8%) had clinically stable disease, and there were no responses. 53% experienced at least one episode of grade 3-4 toxicity, most commonly anemia, neutropenia, fatigue, and neutropenic fever. 24 patients received more than 2 cycles. Median progression free survival was 1.6 months and median overall survival was 5 months. Figure 1

      Conclusion
      Response to second-line therapy with gemcitabine or vinorelbine is rare. The rate of stable disease suggests some level of activity of these agents. Therefore, it remains a reasonable standard therapeutic option. However, survival was comparable to the placebo arm in the phase III vorinostat trial (Krug, ECCO/ESMO, 2011). This lack of efficacy supports the use of placebo control arms in randomized second-line MPM trials. Novel therapies are desperately needed for this patient population.

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    P2.14 - Poster Session 2 - Mesothelioma (ID 196)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 1
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      P2.14-014 - A Phase 2 Randomized, Double-blind, Placebo-Controlled, Multicenter Study of VS-6063 as Maintenance Therapy in Subjects with Malignant Pleural Mesothelioma which has Not Progressed on at least 4 Cycles of Pemetrexed/Platinum therapy (ID 3375)

      09:30 - 09:30  |  Author(s): L.M. Krug

      • Abstract

      Background
      Malignant pleural mesothelioma (MPM) is an aggressive tumor in the pleural lining of the lung usually caused by asbestos exposure. Median OS following frontline chemotherapy with pemetrexed/cisplatin is ~12 months. There is no established second line therapy. Approximately 50% of MPM patients exhibit homozygous disruption of the NF2 tumor suppressor gene by mutation and/or deletion resulting in lack of expression of functional merlin protein. Preclinical data have indicated that mesothelioma cell lines that lack NF2/Merlin are especially sensitive to focal adhesion kinase (FAK) inhibition in both cellular and animal models. Interestingly, pemetrexed and cisplatin increase cancer stem cells (CSCs), while FAK inhibitors have been found to decrease CSCs in mesothelioma models. Given the sensitivity of mesothelioma cells lacking NF2/Merlin and the effect on CSCs, the use of a FAK inhibitor in a maintenance setting after first line chemotherapy may be an attractive strategy to extend survival of MPM patients. VS-6063 is an orally bioavailable selective inhibitor of FAK. In a phase 1 trial VS-6063 was generally well tolerated, with grade 1/2 nausea, vomiting and fatigue as the most frequent adverse events (Jones SF J Clin Oncol 2011 29:1 suppl; abstr 3002).

      Methods
      A multinational, randomized, double-blind, placebo controlled, phase 2 clinical trial was designed to determine if VS-6063 provides superior clinical benefit compared with placebo as a maintenance treatment in patients with MPM following frontline therapy with pemetrexed/platinum therapy. The study aims to assess whether VS-6063 improves median OS and median PFS over placebo. Randomization will be stratified by Merlin status (high versus low) and patients will receive either VS-6063 400mg BID continuously or matched placebo (1:1). The study follows an adaptive enrichment design where, pending results from an interim analysis, sampling may be restricted to patients with low Merlin protein expression if promising results are observed among the subpopulation. Approximately 370 eligible patients with pathologically confirmed MPM, who have PR or SD following at least 4 cycles of pemetrexed with either cisplatin or carboplatin, Karnofsky PS ≥70%, will be enrolled. Patients will continue treatment until disease progression. Archival tumor tissue will be used for the analysis of Merlin status and is therefore required for participation. Secondary endpoints include patient-reported outcomes of health-related quality of life and disease- or treatment-related symptoms utilizing the LCSS-meso scale, objective response and safety and tolerability. Clinical trial information: NCT01870609.

      Results
      not applicable

      Conclusion
      not applicable

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    P3.13 - Poster Session 3 - SCLC (ID 202)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.13-007 - Pilot trial of an adjuvant pentavalent vaccine for patients with small cell lung cancer (SCLC) (ID 2830)

      09:30 - 09:30  |  Author(s): L.M. Krug

      • Abstract

      Background
      Despite initial responses to chemotherapy, SCLC typically progresses within a few months. Targeting residual disease has the potential to improve outcomes. A number of tumor specific glycolipid antigens have been identified and are potential targets for immune therapies. In a series of phase I clinical trials, vaccination with each of these antigens individually was safe and induced antibody responses in the majority of patients. Preclinical data indicate that combining these antigens will expand the immunogenicity across a broader array of SCLC tumor cells. We conducted this pilot trial to determine the safety and immunogenicity of a vaccine combining five of these antigens.

      Methods
      Patients with limited or extensive stage SCLC who have completed initial chemotherapy +/- thoracic or cranial irradiation with a maintained response are eligible. Vaccinations must start within 3-8 weeks of the last chemotherapy, and at least 1 week after radiation. Patients receive KLH-conjugates of GD2L, GD3L, Globo H, fucosyl GM1, and N-propionylated polysialic acid (30mcg each) plus OPT-821 adjuvant (150mcg) subcutaneously on weeks 1, 2, 3, 9, 20, and 32. One cycle of etoposide/platinum chemotherapy was administered in week 6. A significant immune response is defined as an antibody titer of ≥ 1:80 by ELISA against a given antigen or a ≥ 8 fold increase over baseline for patients with a detectable baseline titer. The vaccine would be deemed worthy of further study if >5 patients had an immune response to 3 or more antigens.

      Results
      Ten patients were treated, including 9 with extensive stage, 4 women, 7 with prior brain radiation. The number of vaccinations administered was: 1 (1pt), 3 (2), 4 (3), 5 (2), and 6 (2). Toxicity was limited to mild skin reactions. One patient was taken off study after he developed aphasia the day after the first vaccination; MRI brain was unremarkable and symptoms resolved spontaneously. No patients met the predefined criteria for immune response. Six patients had increases in IgM titers to 1-2 antigens. The median time to progression was 4 months. The two patients with the strongest IgM responses to Globo H and fucosyl GM1, and also the only IgG responses to fucosyl GM1, had progression of disease 7 and 9 months after starting the vaccines, and both progressed initially in the brain only.

      Conclusion
      The polyvalent vaccine is safe, but fewer patients than expected had a significant immune response, Two patients with immune responses experienced a longer than expected time to progression. A second cohort of patients is now receiving the vaccinations over a shorter period of time and without the added cycle of chemotherapy. Five out of 10 of those patients have been enrolled, and preliminary data will be available on those patients for the meeting. Following completion of this pilot trial, a multicenter randomized trial is planned. Supported by MabVax Therapeutics’s NIH grant R41 CA128363 and a grant from FAMRI.