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Francisco Robert



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    OA 14 - New Paradigms in Clinical Trials (ID 681)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Clinical Design, Statistics and Clinical Trials
    • Presentations: 1
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      OA 14.07 - Progress in Lung Squamous Cell Carcinoma from the Lung-MAP Master Protocol (S1400) Sub-Studies S1400A, S1400B, S1400C and S1400D (ID 9593)

      12:05 - 12:15  |  Author(s): Francisco Robert

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung-MAP (S1400) is a master umbrella protocol designed to establish genomic screening for previously treated squamous cell lung cancer patients (SqCCA), and independently evaluate targeted therapies with matching biomarkers and alternative therapies (designated non-match therapy) in patients without putative markers. The protocol opened June 16, 2014 with four biomarker-driven sub-studies and one non-match sub-study.

      Method:
      Eligibility stipulated advanced SqCCA, progressing after at least one prior platinum-based chemotherapy, PS 0–2, and EGFR/ALK wild-type. Tumor samples were required and analyzed for gene alterations by FoundationOne NGS assay (Foundation Medicine). The original biomarker and non-match studies were: S1400B evaluating taselisib for PI3K mutations, S1400C evaluating palbociclib for cell cycle gene alterations (CCGA), S1400D evaluating AZD4547 for FGFR mutations, S1400E evaluating rilotumumab and erlotinib for c-MET positive tumors, and S1400A evaluating durvalumab in patients with no matching biomarkers. The original design included randomization to a control arm, but was amended to a single-arm phase 2 design. The primary endpoint for each modified sub-study was response.

      Result:
      As of June 16, 2017 all original sub-studies have been closed to accrual; 1298 patients registered to the screening component of the trial and 486 patients have registered to a sub-study. Two new sub-studies have been launched and are currently accruing. Details of the completed sub-studies are included in the table.

      Sub-study Final Accrual Biomarker prevalence/% of sub-study registrations Closure Date Response to investigational therapy N (%) Status
      S1400A (non-match) Total: 116 Durvalumab: 78 Docetaxel: 38 NA/59% 12/18/15 Docetaxel arm closed: 4/22/15 11 (16%) Administratively closed to enable activation of new non-match study.
      S1400B PI3K Total: 39 taselisib: 31 Docetaxel: 8 8%/9% 12/12/16 Docetaxel arm closed: 12/18/15 1 (4%) Closed at interim futility analysis.
      S1400C (CCGA+) Total: 54 Palbociclib: 37 Docetaxel: 17 19%/15% 09/01/16 Docetaxel arm closed: 12/18/15 2 (6%) Closed at interim futility analysis.
      S1400D (FGFR+) Total: 45 AZD4547: 35 Docetaxel: 10 16%/12% 10/31/16 Docetaxel arm closed: 12/18/15 2 (7%) Closed at interim futility analysis.
      S1400E (MET+) Total: 9 R+E: 4 E: 5 N/A (closed too early) 11/26/2014 N/A Closed d/t discontinuation of development of rilotumumab


      Conclusion:
      Lung-MAP as a master genomic screening protocol has demonstrated feasibility with respect to accrual and evaluation of targeted therapies in lower prevalence patient populations. This dynamic, centralized, single-IRB platform is well positioned to efficiently assess multiple novel therapeutics for advanced SqCCA patients.

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    P1.03 - Chemotherapy/Targeted Therapy (ID 689)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Chemotherapy/Targeted Therapy
    • Presentations: 1
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      P1.03-022 - A Phase 1B Study of TRC105 in Combination with Paclitaxel/Carboplatin and Bevacizumab in Patients with Stage 4 Non-Squamous Cell Lung Cancer (ID 8262)

      09:30 - 09:30  |  Author(s): Francisco Robert

      • Abstract
      • Slides

      Background:
      Given the modest/transitory benefit of bevacizumab(B)/chemotherapy(CT) in advanced non-small cell lung cancer (NSCLC) and the tendency of tumors to develop escape pathways of angiogenesis,investigation of dual anti-angiogenic therapy may result in more effective angiogenesis inhibition. TRC105 is an antibody to endoglin,an essential angiogenic target expressed on proliferating endothelial cells,and overexpresed in response to VEFG inhibition.This phase 1b study of TRC105 in combination with standard (STD) dose of B with paclitaxel/carboplatin(P/Crb) in advanced non-squamous (NSQ) NSCLC had the primary objectives of safety/tolerability and to determine a recommended phase 2 dose.Secondary objectives included preliminary evidence of antitumor activity and pharmacokinetic(Pks) profile of TRC105.

      Method:
      A dose finding study (3+3 design) of TRC105 with B(15mg/kg), P(200mg/m2),and Crb(AUC6), given iv on day 1 of each 21 day cycle.Two dose levels of TRC105 were evaluated: 8mg/kg (cohort 1) and 10mg/kg (cohort 2), administered iv weekly. An expanded cohort at dose level 2 is being evaluated. A maintenance phase with TRC105 + B was considered after of induction therapy in those pts without evidence of progressive disease. Safety and efficacy assessments were determined by the NCI-CTCAE (v 4),and RECIST 1.1,respectively. Eligible pts had PS 0-1, chemotherapy naive stage 4 NSQ-NSCLC,measurable disease, and no significant cardiovascular comorbidities. Pts with asymptomatic treated CNS metastases were allowed.Other parameters assessed included Pks,immunogenicity,and angiogenic biomarkers in plasma.Descriptive statistics were used to summarize pt characteristics, safety, efficacy, Pks and biomarkers.

      Result:
      Overall safety population comprised 9 pts receiving ≥ 1 cycle of treatment . Median age was 65 years, 55% were women, and one pt had brain metastases. A total of 67 cycles of treatment were delivered (median of 8 cycles). The most frequent grade (G) 3 adverse events:anemia (55%),fatigue (55%),,and neuropathy (44%).There was a G3 epistaxis and a G5 neutropenic event. Responses shown below: Figure 1



      Conclusion:
      TRC105 with STD CT was associated with an acceptable safety profile.

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    P1.04 - Clinical Design, Statistics and Clinical Trials (ID 690)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Clinical Design, Statistics and Clinical Trials
    • Presentations: 1
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      P1.04-012 - A Phase 1b Dose-Escalation Study of TRC105 in Combination with Nivolumab  in Patients with Metastatic Non-Small Cell Lung Cancer (ID 8386)

      09:30 - 09:30  |  Author(s): Francisco Robert

      • Abstract
      • Slides

      Background:
      Nivolumab (N) has demonstrated clinical benefit in advanced non-small cell lung cancer (NSCLC) patients (PTS) who have progressed to platinum-based chemotherapy: improved overall survival (OS) versus (Vs) docetaxel in squamous NSCLC (median OS of 9.2 months [mo} Vs 6 mo) and in non-squamous NSCLC (median OS of 12.2 mo Vs 9.4 mo). TRC105 is an antibody to endoglin, a receptor expressed on proliferating endothelial cells and myeloid derived suppressor cell (MDSCs). MDSCs also inhibit anti-cancer immunity, but by a mechanism of action that is distinct from that inhibited by N. TRC105 inhibits tumor growth in preclinical models and complements the activity of antibodies that target the programmed death receptor (PD-1). Its toxicity profile is distinct from that of N. By targeting MDSCs, TRC105 has the potential to complement N and improve clinical efficacy over that seen with single agent N.

      Method:
      This is a phase 1b,dose-finding (3+3 design) study of TRC105 in combination with standard dose (240mg) of N in pts with advanced NSCLC with disease progression to platinum-containig doublet chemotherapy.The primary objective is to evaluate safety and tolerability and determine a recommended phase 2 dose of TRC105 in combination with standard dose of N. Secondary objectives include: preliminary evidence of antitumor activity by assessing response rate and progression-free survival; characterize the pharmacokinetic profile of TRC105 when given in combination with N; and to explore biologic effects of TRC105 and N on circulating immune cells. Two dose levels of TRC105 are initially considered: Dose Level I: 8mg/kg intravenously (IV) weekly for 4 weeks → 15mg/kg every 2 weeks; Level II: 10mg/kg (iv) for 4 weeks → 15mg/kg every 2 weeks. N will be administered IV every 2 weeks in both cohorts of pts.Toxicity and efficacy assessments will be determine using NCI-CTCAE(V 4) and RECIST (V 1.1),respectively. The dose-limiting toxicity (DLT) evaluation period will be the first 4 weeks of the first cycle of treatment. It is anticipated that up to 18 pts will be enrolled in the study,and up to 12 pts at the maximum tolerated dose(MTD).. Main criteria for inclusion are: confirmed stage 4 NSCLC,prior platinum-based doublets,measurable disease,ECOG PS 0-1,PD-L1 expression >/ 1%,adequate organ function,and no prior therapy with an immuno check point inhibitor. Descriptive statistics will be used to summarize pt characteristics,safety/efficacy/pharmacokinetic parameters ,and immunologic biomarkers.

      Result:
      Section not applicable

      Conclusion:
      Section not applicable

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