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Phased avelumab combined with chemotherapy as first-line treatment for patients with advanced small cell lung cancer (SCLC): The PAVE study, a Hellenic Cooperative Oncology Group Study
abstracts
Annals of Oncology
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CLEPSIDRA trial: A pilot, biomarker-guided study to assess safety, tolerability, dose finding and efficacy of iadademstat in combination with platinum-etoposide in patients with relapsed, extensive-stage small cell lung cancer 1
2
2
2
2
2
A.F. Navarro Mendivil , S. Gutierrez , T. Maes , R. Bullock , M. Ropacki , C. Buesa Medical Oncology Department, Vall d’Hebron University Hospital, Barcelona, Spain, Clinical Research, Oryzon Genomics SA, Cornell a De Llobregat, Spain
1
2
Monitoring Committee: Oryzon Genomics SA; Advisory / Consultancy: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy: BMS; Advisory / Consultancy: AstraZeneca. S. Gutierrez: Full / Part-time employment: Oryzon Genomics SA. T. Maes: Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Oryzon Genomics SA; Officer / Board of Directors: Mendelion Lifesciences. R. Bullock: Full / Parttime employment, Officer / Board of Directors: Oryzon Genomics SA. M. Ropacki: Full / Part-time employment: Oryzon Genomics SA. C. Buesa: Shareholder / Stockholder / Stock options, Full / Parttime employment, Officer / Board of Directors: Oryzon Genomics SA.
Volume 30 | Supplement 5 | October 2019
Phased avelumab combined with chemotherapy as first-line treatment for patients with advanced small cell lung cancer (SCLC): The PAVE study, a Hellenic Cooperative Oncology Group Study
H. Linardou1, G. Mountzios2, A. Psyrri3, A. Christopoulou4, K. Sakellariou1, H. Vaja5, A. Grivas6, T. Makatsoris7, G. Aravantinos8, E. Samantas9 1 Oncology Unit, Metropolitan Hospital, Athens, Greece, 22nd Department of Medical Oncology, Henry Dunant Hospital Center, Athens, Neo Psychiko, Greece, 3Internal Medicine/Medical Oncology, Attikon University Hospital, Athens, Greece, 4Medical Oncology, Agios Andreas General Hospital of Patras, Athens, Greece, 5Oncology, Attikon University Hospital, Athens, Greece, 6Oncology, Hellenic Cooperative Oncology Group, Athens, Greece, 7Oncology, University Hospital Patras, Patras, Greece, 82nd Department of Medical Oncology, General Oncological Hospital of Kifisia "Agioi Anargyroi", Kifisia, Greece, 9Oncology, General Oncological Hospital of Kifisia "Agioi Anargyroi", Kifisia, Greece Background: Advanced small cell lung cancer (SCLC) remains a disease with dismal prognosis and new therapeutics are urgently needed. SCLC is notably chemosensitive and first-line chemotherapy with platinum analogs and etoposide is associated with high rates of initial objective responses that unfortunately do not last long. This initial tumor shrinkage provokes neoantigen release in the circulation, sometimes clinically expressed as “tumor lysis syndrome”, rendering thus the disease potently immunogenic. We hypothesized that initial chemotherapy with two cycles of cisplatin-etoposide may trigger tumor lysis and subsequent release of neo-antigens that may in turn enhance immune responses against tumor cells with the addition of an anti-PD-L1 monoclonal antibody, such as avelumab. Trial design: PAVE (Phased Avelumab combined with chemotherapy as first-line treatment for patients with advanced small-cell lung cancer) is a Greek, investigatorinitiated, single arm open- label phase II study of Avelumab in combination with cisplatin or carboplatin/ etoposide. The study will include an initial safety run-in, openlabel, single arm part (Part 1), and the actual phase II study (Part 2). The total number of patients will not change (the safety run-in patients will be included in the final total number of participants). The safety run-in period will not alter the total study timelines, as phase II accrual will follow immediately after the safety run-in. Eligible patients will receive: The standard 1st-line therapy for advanced small cell lung cancer, consisting of: Cisplatin 80 mg/m2 or Carboplatin 5 AUC D1 q three weeks for 4-6 cycles Etoposide 100 mg/m2 D1-D3 every three weeks for 4-6 cycles and Avelumab 10 mg/kg q 2 weeks will be given as a 1 hour intravenous infusion (IV) every two weeks starting from the third chemotherapy cycle until chemotherapy completion and as maintenance treatment every two weeks (q 2 weeks) thereafter until disease progression. Clinical trial identification: PAVE study (HE1/17) Identifier: NCT03568097. Legal entity responsible for the study: Hellenic Cooperative Oncology Group (HeCOG). Funding: Merck KGaA. Disclosure: All authors have declared no conflicts of interest.
doi:10.1093/annonc/mdz264 | v717
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz264.016/5577123 by guest on 24 October 2019
Background: Small cell lung cancer (SCLC), a fast growing and aggressive neuroendocrine malignancy, shows a dismal prognosis with the current pharmacopeia. Notch is a tumor suppressor repressed in SCLC. Iadademstat (ORY-1001) is the leading selective LSD1 inhibitor and has been shown to re-activate the NOTCH pathway in SCLC, resulting in the repression of ASCL1, a well-known non-druggable SCLC tumor driver, and to produce robust, and in some cases complete and durable, tumor regression in some chemoresistant PDX models. In a previous phase I study in acute leukemia, iadademstat was safe and well tolerated, supporting it is a meaningful candidate for combination therapy with other agents. This is the first combo clinical trial in SCLC with a LSD1 inhibitor and the current chemotherapeutic treatments. Trial design: CLEPSIDRA (EudraCT n 2018-000469-35) is an ongoing phase II study of iadademstat in combination with platinum plus etoposide in patients with relapsed extensive stage SCLC who are candidate to re-challenge chemotherapy. To increase likelihood of response to iadademstat treatment, inclusion of patients requires confirmation of positive expression to iadademstat candidate predictive biomarkers in archival primary tumor tissue or in metastatic tissue samples. This clinical trial is an open label single-arm multicenter study to assess for the first time the safety, tolerability, dose finding and efficacy of iadademstat in combination with chemotherapy in SCLC patients. The study is composed of a dose/regime finding phase aimed to establish the recommended dose and regime of the combination, and a second phase to assess clinical activity of the combination including tumor response according RECIST criteria version 1.1, duration of response, time to progression, time to response, objective response, progression-free survival and overall survival. It is planned to enroll up to 36 patients. The first patient was included November 2018 and the last-patient-in is expected by Q1 2020. Clinical trial identification: EudraCT n 2018-000469-35. Approval date: 10/10/2018. Legal entity responsible for the study: Oryzon Genomics SA. Funding: Oryzon Genomics SA. Disclosure: A.F. Navarro Mendivil: Honoraria (self), Advisory / Consultancy, member Safety
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Annals of Oncology
1751TiP
CLEPSIDRA trial: A pilot, biomarker-guided study to assess safety, tolerability, dose finding and efficacy of iadademstat in combination with platinum-etoposide in patients with relapsed, extensive-stage small cell lung cancer 1
2
2
2
2
2
A.F. Navarro Mendivil , S. Gutierrez , T. Maes , R. Bullock , M. Ropacki , C. Buesa Medical Oncology Department, Vall d’Hebron University Hospital, Barcelona, Spain, Clinical Research, Oryzon Genomics SA, Cornell a De Llobregat, Spain
1
2
Monitoring Committee: Oryzon Genomics SA; Advisory / Consultancy: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy: BMS; Advisory / Consultancy: AstraZeneca. S. Gutierrez: Full / Part-time employment: Oryzon Genomics SA. T. Maes: Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Oryzon Genomics SA; Officer / Board of Directors: Mendelion Lifesciences. R. Bullock: Full / Parttime employment, Officer / Board of Directors: Oryzon Genomics SA. M. Ropacki: Full / Part-time employment: Oryzon Genomics SA. C. Buesa: Shareholder / Stockholder / Stock options, Full / Parttime employment, Officer / Board of Directors: Oryzon Genomics SA.
Volume 30 | Supplement 5 | October 2019
Phased avelumab combined with chemotherapy as first-line treatment for patients with advanced small cell lung cancer (SCLC): The PAVE study, a Hellenic Cooperative Oncology Group Study
H. Linardou1, G. Mountzios2, A. Psyrri3, A. Christopoulou4, K. Sakellariou1, H. Vaja5, A. Grivas6, T. Makatsoris7, G. Aravantinos8, E. Samantas9 1 Oncology Unit, Metropolitan Hospital, Athens, Greece, 22nd Department of Medical Oncology, Henry Dunant Hospital Center, Athens, Neo Psychiko, Greece, 3Internal Medicine/Medical Oncology, Attikon University Hospital, Athens, Greece, 4Medical Oncology, Agios Andreas General Hospital of Patras, Athens, Greece, 5Oncology, Attikon University Hospital, Athens, Greece, 6Oncology, Hellenic Cooperative Oncology Group, Athens, Greece, 7Oncology, University Hospital Patras, Patras, Greece, 82nd Department of Medical Oncology, General Oncological Hospital of Kifisia "Agioi Anargyroi", Kifisia, Greece, 9Oncology, General Oncological Hospital of Kifisia "Agioi Anargyroi", Kifisia, Greece Background: Advanced small cell lung cancer (SCLC) remains a disease with dismal prognosis and new therapeutics are urgently needed. SCLC is notably chemosensitive and first-line chemotherapy with platinum analogs and etoposide is associated with high rates of initial objective responses that unfortunately do not last long. This initial tumor shrinkage provokes neoantigen release in the circulation, sometimes clinically expressed as “tumor lysis syndrome”, rendering thus the disease potently immunogenic. We hypothesized that initial chemotherapy with two cycles of cisplatin-etoposide may trigger tumor lysis and subsequent release of neo-antigens that may in turn enhance immune responses against tumor cells with the addition of an anti-PD-L1 monoclonal antibody, such as avelumab. Trial design: PAVE (Phased Avelumab combined with chemotherapy as first-line treatment for patients with advanced small-cell lung cancer) is a Greek, investigatorinitiated, single arm open- label phase II study of Avelumab in combination with cisplatin or carboplatin/ etoposide. The study will include an initial safety run-in, openlabel, single arm part (Part 1), and the actual phase II study (Part 2). The total number of patients will not change (the safety run-in patients will be included in the final total number of participants). The safety run-in period will not alter the total study timelines, as phase II accrual will follow immediately after the safety run-in. Eligible patients will receive: The standard 1st-line therapy for advanced small cell lung cancer, consisting of: Cisplatin 80 mg/m2 or Carboplatin 5 AUC D1 q three weeks for 4-6 cycles Etoposide 100 mg/m2 D1-D3 every three weeks for 4-6 cycles and Avelumab 10 mg/kg q 2 weeks will be given as a 1 hour intravenous infusion (IV) every two weeks starting from the third chemotherapy cycle until chemotherapy completion and as maintenance treatment every two weeks (q 2 weeks) thereafter until disease progression. Clinical trial identification: PAVE study (HE1/17) Identifier: NCT03568097. Legal entity responsible for the study: Hellenic Cooperative Oncology Group (HeCOG). Funding: Merck KGaA. Disclosure: All authors have declared no conflicts of interest.
doi:10.1093/annonc/mdz264 | v717
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz264.016/5577123 by guest on 24 October 2019
Background: Small cell lung cancer (SCLC), a fast growing and aggressive neuroendocrine malignancy, shows a dismal prognosis with the current pharmacopeia. Notch is a tumor suppressor repressed in SCLC. Iadademstat (ORY-1001) is the leading selective LSD1 inhibitor and has been shown to re-activate the NOTCH pathway in SCLC, resulting in the repression of ASCL1, a well-known non-druggable SCLC tumor driver, and to produce robust, and in some cases complete and durable, tumor regression in some chemoresistant PDX models. In a previous phase I study in acute leukemia, iadademstat was safe and well tolerated, supporting it is a meaningful candidate for combination therapy with other agents. This is the first combo clinical trial in SCLC with a LSD1 inhibitor and the current chemotherapeutic treatments. Trial design: CLEPSIDRA (EudraCT n 2018-000469-35) is an ongoing phase II study of iadademstat in combination with platinum plus etoposide in patients with relapsed extensive stage SCLC who are candidate to re-challenge chemotherapy. To increase likelihood of response to iadademstat treatment, inclusion of patients requires confirmation of positive expression to iadademstat candidate predictive biomarkers in archival primary tumor tissue or in metastatic tissue samples. This clinical trial is an open label single-arm multicenter study to assess for the first time the safety, tolerability, dose finding and efficacy of iadademstat in combination with chemotherapy in SCLC patients. The study is composed of a dose/regime finding phase aimed to establish the recommended dose and regime of the combination, and a second phase to assess clinical activity of the combination including tumor response according RECIST criteria version 1.1, duration of response, time to progression, time to response, objective response, progression-free survival and overall survival. It is planned to enroll up to 36 patients. The first patient was included November 2018 and the last-patient-in is expected by Q1 2020. Clinical trial identification: EudraCT n 2018-000469-35. Approval date: 10/10/2018. Legal entity responsible for the study: Oryzon Genomics SA. Funding: Oryzon Genomics SA. Disclosure: A.F. Navarro Mendivil: Honoraria (self), Advisory / Consultancy, member Safety
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