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Jose Antonio Lopez-Vilariño



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    MA 01 - SCLC: Research Perspectives (ID 650)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: SCLC/Neuroendocrine Tumors
    • Presentations: 1
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      MA 01.05 - Activity and Safety of the Combination of PM01183 and Doxorubicin in Relapsed SCLC. Final Results of a Phase Ib Trial (ID 9249)

      11:00 - 12:30  |  Author(s): Jose Antonio Lopez-Vilariño

      • Abstract
      • Presentation
      • Slides

      Background:
      Lurbinectedin (PM01183) is a new anticancer drug that binds to DNA, inhibits transactivated transcription and modulates tumor microenvironment. Preclinical evidence of synergism was observed for PM01183 in combination with doxorubicin (DOX).

      Method:
      Multicenter, phase I clinical trial to determine the recommended dose (RD) of the combination of PM01183 and DOX. An expansion cohort was recruited after finding striking activity in second-line small cell lung cancer (SCLC) patients. Due to hematological toxicity, the trial was amended to use a lower DOX dose and thus improve safety of the combination in selected indications. SCLC patients <75 years with ECOG performance status (PS) 0-1 and pretreated with no more than one chemotherapy line were included. Stable brain metastases were allowed. DOX was interrupted after 10 cycles and PM01183 could be continued as single-agent. Primary G-CSF prophylaxis was not mandatory.

      Result:
      48 patients were treated: 21 in Cohort A (PM01183 3-5 mg flat dose [FD] Day (D)1 + DOX 50 mg/m2 D1 every 21 days [q21d]), and 27 in Cohort B (PM01183 2 mg/m2 D1 + DOX 40 mg/m2 D1 q21d). Males: 74%; median age: 64 (48-77) years, ECOG 0-1: 37%-63%; known central nervous system (CNS) involvement: 10%; bulky disease (>50 mm): 67%. 85% responded to first line, including 4% with complete response (CR). Median chemotherapy free interval (CTFI): 3.4 months. Refractory (CTFI<30 days) 23%; resistant (CTFI 30-90 days) 34%; sensitive (CTFI>90 days) 43%. RD: PM01183 4 mg FD (or 2 mg/m2) + DOX 50 mg/m2 D1 q21d. Confirmed ORR: 50% (95CI: 35-65%) with 6% CR in both cohorts; ORR=69% (95CI: 49-85%) with 10% CR in sensitive patients. Cohort A: ORR=67% (95%CI: 43-85%) with 10% CR; ORR=92% (95%CI: 62-100%) in sensitive patients. Cohort B: ORR=37% (95%CI: 19-58%) with 4% CR; ORR=53% (95%CI: 28-77%) in sensitive patients. Median PFS (mPFS) 4.6 months (95%CI: 3.1-5.8), with mPFS 1.5 months (95%CI: 1.2-3.8) in resistant patients and 5.8 months (95%CI: 3.6-7.9) in sensitive patients. In both cohorts, grade 4 neutropenia/anemia/thrombocytopenia appeared in 73%/4%/15% of patients and febrile neutropenia in 21% (11% at RD). Non-hematological toxicity was mainly fatigue (G3=14%) and nausea (G3=5%).

      Conclusion:
      PM01183/DOX combination showed remarkable activity as second line in SCLC, especially in patients with CTFI>90 days, regardless of dose. Activity is higher than reported for CAV or topotecan in this setting. Reversible myelosuppression was the most frequent and expected side effect. A phase III trial with this combination in relapsed SCLC is ongoing.

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    P2.04 - Clinical Design, Statistics and Clinical Trials (ID 705)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Clinical Design, Statistics and Clinical Trials
    • Presentations: 1
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      P2.04-008 - ATLANTIS: Phase III Study of PM01183 with Doxorubicin vs. CAV or Topotecan in Small-Cell Lung Cancer After Platinum Therapy (ID 9326)

      09:30 - 16:00  |  Presenting Author(s): Jose Antonio Lopez-Vilariño

      • Abstract
      • Slides

      Background:
      Lurbinectedin (PM01183) is a new compound that blocks active transcription, produces DNA breaks and apoptosis, and affects the inflammatory microenvironment. First signs of synergism with doxorubicin (DOX) and responses, especially in relapsed small cell lung cancer (SCLC) (overall response rate [ORR] ~67%, including about 10% of complete responses [CR]), were reported in a phase I expansion cohort in 21 second-line SCLC patients (ASCO 2015, abstract 7509). Main toxicity was hematological. A lower dose was used to improve safety, and activity was confirmed in an expansion cohort of 27 patients with relapsed SCLC (~37%, with 4% of CR)

      Method:
      Multinational (20 countries), multicenter (154 sites), open-label, randomized phase III study of PM01183/DOX vs. a control arm with investigator choice of either standard cyclophosphamide, DOX and vincristine (CAV) or topotecan (T). A total of 600 patients will be randomized (1:1) and stratified according to ECOG performance status (PS), central nervous system (CNS) involvement, previous treatment with antiPD1/antiPD-L1, chemotherapy-free interval and investigator´s choice of control arm. Patients with clinical benefit after 10 cycles of the combination could continue with single-agent PM01183 or CAV, until progressive disease or unacceptable toxicity. An interim safety analysis by an independent data monitoring committee (IDMC) is planned when the first 150 patients have been randomized. Most relevant inclusion criteria includes: age ≥18 years and confirmed diagnosis of SCLC (if primary site is unknown, the patient will be eligible if Ki-67 expression >50%), mandatory previous platinum-containing line (additional immunotherapy is allowed), ECOG PS 0-2, and adequate major organ function (including LVEF >50%). Patients are excluded if chemotherapy-free interval is <30 days, pre-treated with PM01183, DOX or T, symptomatic or steroids-requiring CNS involvement, or any medical condition that might preclude safe compliance with study treatment. Primary objective is to determine a difference in progression-free survival (RECIST v.1.1) by independent review committee. Secondary endpoints include overall survival, survival rates at 12/18/24 months, antitumor response (RECIST v.1.1), duration of response, quality of life, safety, subgroup analyses and pharmacokinetics of PM01183/DOX.

      Result:
      The first patient was included in August 2016. An interim safety analysis, requested by the IDMC, was conducted on the first 50 patients randomized and treated with 2 cycles, and resulted in a recommendation to continue the trial unmodified.

      Conclusion:
      The ATLANTIS randomized phase III study is currently ongoing. Trial recruitment is expected to be completed at Q1 2018.

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