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J.P. Stevenson

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    MO09 - Mesothelioma I (ID 120)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track:
    • Presentations: 1
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      MO09.03 - A pilot and feasibility trial evaluating two different chemotherapy regimens in combination with intrapleural adenoviral-mediated interferon-alpha (SCH 721015, Ad.hIFN-alpha2b) gene transfer for malignant pleural mesothelioma (ID 3374)

      16:15 - 17:45  |  Author(s): J.P. Stevenson

      • Abstract
      • Presentation
      • Slides

      Malignant pleural mesothelioma is an incurable thoracic neoplasm for which combination chemotherapy offers limited improvement in survival. Novel agents that offer synergy with standard systemic cytotoxic therapy are under investigation. Among these agents are a variety of immunotherapeutics which can be administered either locally or in a systemic fashion.

      We conducted a Phase I/II “in situ vaccination” clinical trial commencing in March2011 involving repeated intrapleural administration of a replication-defective recombinant adenoviral vector containing the human interferon-alpha (hIFN-α2b) gene at a dose of 3x10[11 ]viral particles concomitant with a 14-day course of high-dose cyclo-oxygenase-2 (COX-2) inhibitor (Celecoxib). This was followed by standard first-line or second-line chemotherapy agents. Primary outcome measures were safety, overall best response rate, and survival.

      We completed accrual (n=25) in the first-line chemotherapy arm, in which all patients received pemetrexed-based chemotherapy regimens. This group included patients who previously received pemetrexed chemotherapy but did not subsequently receive this agent for >6 months. In the second-line chemotherapy arm, 13of a planned 15 subjects have enrolled (with 12 evaluable), all of whom received gemcitabine-based chemotherapy (Table 1). In both arms, the combination of intrapleural Ad.IFN-α2b vector, high-dose celecoxib, and systemic chemotherapy proved safe. Adverse events during the chemotherapy portion of the study were comparable to historical controls.Most patients experienced expected mild toxicities from vector (cytokine release syndrome, interferon production), including nausea, fatigue, anemia, lymphopenia (grade 3-4) and hypoalbuminemia. Serious adverse events included: pleural catheter infection (n=2); hypoxia (n=2); supraventricular tachycardia (n=1); and esophagitis (n=1), none directly attributable to the vector or vector administration. Serial chest CT and PET/CT scans demonstrated an overall response rate of 31% by Modified RECIST criteria and disease control rate (DCR) of 78% (partial and complete responses plus stable disease) at initial follow-up scan after the first two cycles of chemotherapy. Partial responses were seen in 9/25 evaluable patients with pemetrexed-based chemotherapy and 1/12 with gemcitabine. Patients who received first-line pemetrexed-based chemotherapy (n=14) had a median survival of 10.5 months, 95% ci=(5.5,inf), whereas second-line patients (n=21; 12 gemcitabine)had a median survival of 15.0 months, 95% ci=(9.0,inf).

      Pem/Platin (N=25) Gemcitabine (N=13)
      Male % 64% (16/25) 84.6% (11/13)
      Median Age 67 (51-86) 65 (43-81)
      Histologic Subtype % Epithelioid - 17 (68%) Biphasic - 4 (17%) Sarcomatoid - 4 (17%) Epithelioid - 11 (84.6%) Biphasic - 2 (15.4%) Sarcomatoid - 0
      Stage I - 2 (8%) II - 6 (24%) III - 13 (52%) IV - 4 (16%) III - 4 (30%) IV - 9 (70%)
      Prior Treatment Chemotherapy - 4 (16%) RP/PDT - 4 (16%) XRT - 5 (20%) Chemotherapy - 13 (100%) RP/PDT - 7 (53%) XRT - 2 (15%)
      Platin Agent Cisplatin - 12 Carboplatin - 10 Cis-Carbo - 1 None - 2 Cisplatin - 0 Carboplatin - 2 None - 8
      Median Cycles of Chemo 6 (1-6) 3 (0-6)
      TABLE 1

      The combination of intrapleural Ad.IFN-α2b vector, Celecoxib, and systemic chemotherapy proved safe. Disease control rates observed in this study compare favorably with historical data andthe especially encouraging OS in the second-line chemotherapy group argue strongly for proceeding with a multi-center randomized clinical trial of chemo-immunogene therapy versus chemotherapy alone.

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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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      P1.14-014 - Patients' Willingness to Participate in a Randomized Controlled Trial for Malignant Pleural Mesothelioma: A New Paradigm to Improve Accrual to Thoracic Oncology Trials (ID 3147)

      09:30 - 16:30  |  Author(s): J.P. Stevenson

      • Abstract

      Predicting if a trial will accrue is critical, especially for thoracic oncology trials that have notoriously low accruals. Our group demonstrated unusually good results treating malignant pleural mesothelioma (MPM) with radical pleurectomy (RP), intraoperative photodynamic therapy (PDT), and chemotherapy. To establish if PDT is contributing to our results, a randomized trial of RP+/-PDT is needed. To determine if such a trial is feasible, we conducted a willingness to participate (WTP) study. We quantified differences in WTP before and after physician training designed to increase WTP.

      All consecutive MPM patients who were candidates for RP+PDT were prospectively enrolled in this IRB-approved study. Patients participated in structured interviews, reviewed a written description of a hypothetical RCT comparing RP to RP+PDT, answered open-ended and focused questions regarding their motivations for and concerns about enrollment, and completed a written questionnaire. WTP was assessed using a 6-point Likert scale (1=definitely not, 6=definitely). Interview transcripts were analyzed using thematic data analysis and constant comparison techniques. Questionnaire and transcript data were used to educate physicians and modify their presentation of the RCT to subsequent patients.

      25 participants (median age 66yrs, 72% male, 88% epithelial histology) enrolled. Some had pre-existing knowledge of RP (44%) or PDT (40%). Following the first 8 patients enrolled, we identified 15 factors impacting WTP focusing on five themes: randomization, hope for cure, desire to compare treatments, altruism, and physician opinion (Table 1). Based on these findings, physicians were trained to more thoroughly explain the WTP and proposed RTC and addressed concerns raised by these initial 8 patients when meeting with subsequent patients. Physician time explaining the WTP increased following training (median 9min vs. 3min, p<0.0001). Overall, 56% “definitely” or “probably” would, 28% “may,” and 16% would “probably not” or “definitely not” participate. More patients would be “definitely” or “probably” willing to participate after physician training (71% vs. 25%, p=0.03). Furthermore, none of the initial 8 patients were “definitely” willing, compared with 8 of the subsequent 17 (p=0.02). Following consultation, 16 underwent surgical-based therapy, with no difference before or after training (50% vs. 71%, p=0.34).

      Table 1. Motivations (m) and concerns (c) reported by patients (N=25) when deciding if they would enroll in the proposed randomized clinical trial for malignant pleural mesothelioma
      Trial Design Factors N= Therapy-relate Factors N= Humanistic/Ethical Factors N=
      Randomization (c) 12 Hope for a cure (m) 10 Altruism towards other patients (m) 9
      Deference to physician opinion (m) 7 Desire to compare treatments (m) 8 Deference to family opinion (m) 4
      Concerns with experimentation (c) 2 PDT side effects (c) 6 Altruism towards science/physician/ hospital (m) 1
      Financial incentives (m) 1 Potential benefit of PDT (m) 3
      Reputation of the hospital (m) 1 Prior knowledge of PDT (m) 1
      Close follow-up (m) 1 Availability of alternative treatments (c) 1

      This study demonstrated analyzing and addressing patient motivations and concerns about enrollment, physician training, and increasing time spent with patients can increase WTP. In this study, most patients expressed a WTP in a RCT of RP+/-PDT for MPM. Performing WTP studies prior to planned prospective thoracic oncology trials should be considered to optimize trial design and accrual strategies.