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Study 15

  • Research type

    Research Study

  • Full title

    A multicentre, randomised trial comparing combination gemcitabine/carboplatin and hydroxychloroquine versus carboplatin/etoposide therapy alone in small cell lung cancer (SCLC)

  • IRAS ID

    198726

  • Contact name

    Siow M Lee

  • Contact email

    siow-ming.lee@uclh.nhs.uk

  • Sponsor organisation

    University College London

  • Eudract number

    2015-004170-15

  • Clinicaltrials.gov Identifier

    NCT02722369

  • Duration of Study in the UK

    4 years, 5 months, 1 days

  • Research summary

    Research Summary

    The Study 15 trial is a phase II trial to examine whether the addition of hydroxychloroquine (HCQ) to chemotherapy can improve progression free survival in patients with small cell lung cancer (SCLC).

    Lung cancer, the leading cause of cancer-related death, accounting for nearly 1.4 million deaths worldwide every year, and has an annual incidence of over 41,000 in the UK. 10-15% are SCLC, representing about 4500 new cases per annum in the UK. Compared with non-small cell lung cancer (NSCLC), patients with SCLC are more responsive to chemotherapy (with an objective response rate of about 70-80%) and radiation treatment but relapse quickly with treatment-resistant disease. The survival rates are poor, with less than 10% of patients alive by 5 years. In a previous CR UK & UCL Cancer Trials Centre trial involving 724 patients, the median survival was 10.3 months. The standard first line chemotherapy treatment remains a platinum-based chemotherapy and this has been unchanged for 20 years. Novel active treatment approaches are urgently needed to improve survival in SCLC.

    There is increasing interest in targeting autophagy as a means of selectively killing cancer cells. Numerous pre-clinical studies have demonstrated that small molecule inhibitors of autophagy including chloroquine (CQ) and its analogue, hydroxychloroquine (HCQ), enhances the activity of a broad array of anticancer agents. These results have recently led to multiple clinical trials to evaluate autophagy inhibition in combination with conventional chemotherapy. More recently, CQ was found to have tumour vasculature normalising properties, thereby increasing platinum delivery to tumour tissue and improved chemosensitivity. The advantage of using HCQ instead of CQ is less cumulative retinal toxicity issue. Previous preclinical studies demonstrate that HCQ and etoposide are mutually antagonistic. Study 15 will combine HCQ with gemcitabine/carboplatin chemotherapy in the investigational arm to avoid the antagonistic interaction with etoposide. The control arm remains carboplatin/etoposide due to the fact that this remains the Standard of Care for patients at sites throughout the UK. We previously demonstrated carboplatin-gemcitabine is as effective as standard carbo/etoposide and associated with a better toxicity profile and cognitive function. The Study 15 trial will therefore investigate whether the combination of HCQ with carboplatin-gemcitabine compared with standard chemotherapy (carboplatin/etoposide) confers additional survival benefit.

    Each patient will be randomised between the control arm (carboplatin/etoposide) and the investigational arm (carboplatin/gemcitabine + HCQ). All eligible patient that consent to take part in the trial will be randomised onto the trial and will receive 4-6 cycles of chemotherapy, those randomised to the investigational arm will also receive HCQ alongside chemotherapy for up to 30 months. All patients will be followed up for up 36 months after the last trial treatment is administered to the last patient or until death.

    The trial will be undertaken throughout the UK in approximately 30 NHS sites. The target accrual is 112 patients. The trial is funded by the London Lung Cancer Group (LLCG), endorsed by Cancer Research UK and sponsored by University College London.

    The trial will be coordinated by the CR UK & UCL Cancer Trials Centre.

    Summary of Results

    Study15 was a phase II trial which looked at whether the addition of the drug hydroxychloroquine (HCQ) increased the effectiveness of combination chemotherapy in patients diagnosed with small cell lung cancer (SCLC). Patients were randomly allocated (randomised) to receive either etoposide and carboplatin chemotherapy, or gemcitabine and carboplatin chemotherapy with HCQ.

    Who carried out the research?:
    The trial was sponsored by University College London, was run on their behalf by Cancer Research UK & UCL Cancer Trials Centre (UCL CTC), and was funded by London Lung Cancer Group.

    What public involvement there was in the study?:
    Patients and the public were involved in the trial design, recruitment and close out phases of the trial, with the Trial Steering Committee (TSC) meeting 1-2 times per year which included a lay member of the public. The trial was also presented to the UCL CTC Lung Patient and Public involvement and Engagement (PPIE) group in February 2020 which includes 8 members with a previous history of lung cancer.

    Where and when the study took place:
    The trial was conducted in 14 hospital trusts in the UK and ran between March 2017 to March 2021.

    Why was the research needed?:
    The trial was needed as patients with SCLC, despite being responsive to chemotherapy, their cancer quickly returns and grows again (relapses) with treatment-resistant disease. The survival rates for patients with SCLC are also poor, with less than 10% of patients alive by 5 years. The standard chemotherapy treatment when the trial was designed was platinum-based chemotherapy, and this had been unchanged for 20 years. New treatment approaches were needed to improve survival in patients with SCLC.

    What were the main questions studied?:
    Study 15 aimed to investigate how effective gemcitabine and carboplatin chemotherapy with HCQ was at treating patients with SCLC before they relapsed (called Progression Free Survival) versus the standard of care treatment of carboplatin and etoposide. It was also important to look at whether the addition of hydroxychloroquine to chemotherapy could prolong survival among patients (called Overall Survival), was safe with acceptable side effects, and did not significantly impact patient’s quality of life whilst receiving or following treatment.

    Who participated in the study?:
    Patients with SCLC were invited to participate in this study if they met the following criteria: Stage IV disease (advanced); over the age of 18; negative pregnancy test (where applicable); deemed able to tolerate chemotherapy.
    This study aimed to recruit 112 patients, but it did not meet this target. Seventy-two patients had participated in this study by the time the trial closed, of these 56% (40/72) were male and 44% (32/72) were female. The average patient age was 67 years old, and 92% (66/72) of patients had either previously smoked or were current smokers.

    What treatments or interventions did the participants take/receive?:
    The patients in this trial were randomly assigned to receive:
    Interventional treatment (a combination of the investigational drug and chemotherapy – Hydroxychloroquine (400mg BD) + Gemcitabine* (1000mg/m2 on days 1 and 8 of cycle) and Carboplatin (AUC5 on Day 1 of each cycle) for a maximum of 6 cycles) and Standard of care Chemotherapy alone (carboplatin (AUC5 on day 1 of each cycle) and Etoposide (on day 1, followed by oral etoposide 100mg BD on Day 2 and Day 3 OR IV etoposide 100mg/m2 on Days 1-3 ) for a maximum of 6 cycles)
    *note: Gemcitabine done was reduced from 1250 mg/m2 to 1000mg/m2 in an amendment in January 2019.

    What medical problems (adverse events) did the participants have?:
    There were a greater number of adverse events among patients that had received HCQ and chemotherapy compared to those receiving the standard of care.

    What happened during the study?:
    The trial was stopped early due to a lack of benefit and more side effects among patients receiving the combination of HCQ and chemotherapy.

    What were the results of the study?:
    A similar number of patients had relapsed in both arms and there was no apparent survival benefit in patients receiving HCQ and chemotherapy when compared to those receiving the standard of care.
    Moreover, among those receiving HCQ and chemotherapy, 83% of patients had high grade (grade 3+) events compared to 25% in patients receiving standard of care. The higher the grade the more serious the side effect.
    The results show that receiving the interventional treatment did not reduce the number of patients that had relapsed or improve survival among patients with small cell lung cancer, and showed an increased toxicity compared to the standard of care.

    How has this study helped patients and researchers?:
    This trial has provided important information on the use of autophagy inhibitors such as HCQ in combination with chemotherapy in patients with SCLC. It also highlights the potential safety implications of this treatment combination.
    This could help inform researchers for future work.

    Details of any further research planned:
    There are currently no plans for any further research.

    Where can I learn more about this study?:
    More information about the trial can be found on the:
    Cancer Research UK website (https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agbZ0oYz60WoglvPkqIfU1HPHTUfauCq2ZPvNtWjz0kGXSOCiSOfyPyipJY7AGHLby8z6XWzkzExpdTAhWwnPTLh4-3D0AzL_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YJw0fi8xT8H-2BLTnYhBvQo464gHgwGTCOwa5OQ-2Bxp2f3fq2h4ZtbKAROxLdvqr4GZMpx-2FDiNORbw0ZD4troFW9iXIT5oik9XXXAI4bTIRUm5-2FquDqqzaEZ1RlxoXgl-2FRNLOFFJrf29ekYtpaIiQ9BMq6mNDP3geOtnJraMLqtLTc8g-3D-3D&data=05%7C01%7Capprovals%40hra.nhs.uk%7C8a759a30efd54539fca008da4d46622f%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C637907261931324421%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=JI4vApgf9tDlQHCC%2BdSRRLbQrsBTPuUkdfpuJOWMEW4%3D&reserved=0 UCL CTC website (https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3DouFFm-2FZqrUn2jjUD5TieZAZy6yD6vnjIb1Z7JkRr-2B9lFlo7VbTzRVJygPt1cbCaXr6GUk2k1b37C3-2FO-2BF8RObIAkf4SXpUUTv7BAUOV3zv4-3DE8FD_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YJw0fi8xT8H-2BLTnYhBvQo46S1KmYG5eVMwfCCNkno8RbjTKkeG1XvoJDFEpwzO2KejN6N7LV0aJo9KOxh1WVE14zGbwobt8sp1WYsbbEVUL9vyDF7fDqWHVI0nNR16x4YWcjvmLoIBFmTxMQyj0P0CY1zeKbZ2xZzSmQWCZd7g30g-3D-3D&data=05%7C01%7Capprovals%40hra.nhs.uk%7C8a759a30efd54539fca008da4d46622f%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C637907261931324421%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=21asH%2F4v5EVotO63xkUbl%2FwGRb8jaO7QbiViA7dXD1g%3D&reserved=0
    Clinicaltrials.gov website (https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agbRehJ-2Fi4xyo44sEgJVCl5BcbW9wgc64X2JjNxW-2BqMpAMS4H6RhrUgMd43s1PoCP01X5jqjeq1RgdEbTcdjPCaamtGX1KfHKek4c8bowLvENdEgRW_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YJw0fi8xT8H-2BLTnYhBvQo46qazenPkxGoCHzIZR5BTVZ9tjLWEWDGi9ok1gqBiR1Scb0LsXI673vdE0YW6-2FyNEP-2F7GgzG9NmDJjDOuNMyYw4pF2GNdwNJCl8XgIrjkHo8cTPuVT-2B-2BpuG5orNSWLXjoeweMcRUxj1BAAZ3GwtZNYSw-3D-3D&data=05%7C01%7Capprovals%40hra.nhs.uk%7C8a759a30efd54539fca008da4d46622f%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C637907261931324421%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=nvapVzO%2Bp3OwOEku4VQMPUAmL7f42NZ%2F92oxuV%2B053U%3D&reserved=0

  • REC name

    East Midlands - Derby Research Ethics Committee

  • REC reference

    16/EM/0380

  • Date of REC Opinion

    17 Nov 2016

  • REC opinion

    Further Information Favourable Opinion

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