Randomized Phase II, Open-label Efficacy and Safety Study of Second-line Durvalumab Plus Tremelimumab Versus Platinum-based Chemotherapy Alone in Patients With NSCLC and First-line Checkpoint-inhibitor Therapy Followed by 2 Cycles of Platinum-based Chemotherapy (Re-Check)
Overview
- Phase
- Phase 2
- Intervention
- combination regimen tremelimumab /durvalumab
- Conditions
- NSCLC Stage IV
- Sponsor
- AIO-Studien-gGmbH
- Locations
- 1
- Primary Endpoint
- PFS1
- Status
- Withdrawn
- Last Updated
- 3 years ago
Overview
Brief Summary
This is an open label, randomized, Phase II multicenter study designed to evaluate the safety and efficacy of two different second-line strategies: After failure of first line mono-immunotherapy with checkpoint inhibitors (anti-PD-1/PD-L1), and subsequent 2 cycles of standard of care platinum-based chemotherapy, 2 treatment arms will be compared: Arm A (Experimental Arm): After randomization, patients will receive a combination regimen featuring a single, priming dose of tremelimumab together with conventional durvalumab dosing. Durvalumab maintenance therapy will subsequently be continued as study treatment for up to 12 cycles.
Arm B: After randomization, patients will continue to receive another 2-4 cycles of platinum-based chemotherapy. Afterwards, patients will end treatment or receive maintenance pemetrexed therapy as per marketing authorization (depending on histology, maximum of 13 cycles) at the discretion of the investigator
Detailed Description
Patients without progression after two cycles of chemotherapy (induction treatment phase) will be randomized at a 1:1 ratio into one of 2 treatment arms (combination treatment phase). PD-L1 expression status will be evaluated based on available data. To better focus on patients with expected good clinical benefit from immunomodulating agents, only patients with checkpoint-inhibitor treatment as first-line monotherapy and a progression-free survival of at least 12 weeks will enter the study (at least two re-assessments after initiation of first-line treatment). Consequently, patients with disease progression as best response of first-line therapy cannot enter this study. Directly re-challenging patients with anti-PD-L1 and anti-CTLA agents after disease progression on checkpoint-inhibitor monotherapy will be avoided by the previous application of two cycles of platinum-based chemotherapy as induction treatment, which may also enhance the antigen release from tumor cells and may further support the subsequent immunotherapy.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Signed Informed Consent Form
- •Age \>18 years at time of study entry
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •Histologically or cytologically confirmed, stage IV NSCLC (per the Union Internationale contre le Cancer/American Joint Committee on Cancer staging system).
- •Indication for standard-of-care second line platinum-based chemotherapy, using cisplatin or carboplatin in combination with pemetrexed, paclitaxel, nab-paclitaxel, vinorelbine or gemcitabine
- •Life expectancy of \> 12 weeks
- •Body weight \> 30 kg
- •First-line mono-immunotherapy with checkpoint inhibitors (anti-PD1/PD-L1) with a best response of stable disease (SD) or better
- •Documented tumor PD-L1 expression status of ≥50%. Any existing data can be used.
- •First-line progression-free survival of at least 12 weeks after at least two re-assessments after initiation of first-line treatment.
Exclusion Criteria
- •Use of immunosuppressive medication (including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antitumor necrosis factor \[anti-TNF\] agents) within 14 days prior to randomization. The following are exceptions to this criterion:
- •Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be eligible after discussion with the study chair.
- •The use of inhaled corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed.
- •Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
- •Systemic corticosteroids at physiologic doses not exceeding 10 mg/day of prednisone or its equivalent
- •Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
- •Prior treatment with other immune-modulating agents (other than anti-PD-1/PD-L1)
- •Treatment with systemic immunostimulatory agents (including but not limited to IFNs, IL-2) within 4 weeks or five half-lives of the drug, whichever is longer, prior to randomization. Prior treatment with cancer vaccines is allowed.
- •Involvement in the planning and/or conduct of the study (applies to both sponsor staff and/or staff at the study site)
- •Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
Arms & Interventions
Arm A: tremelimumab /durvalumab (1 cycle), subsequently Durvalumab maintenance therapy
Intervention: combination regimen tremelimumab /durvalumab
Arm B: platinum-based chemotherapy (SoC)
Intervention: platinum-based chemotherapy (SoC)
Outcomes
Primary Outcomes
PFS1
Time Frame: 49 months
Progression-free survival 1 using Investigator assessments according to RECIST 1.1, defined as the time from randomization in the study until objective tumor progression and do not include deaths
Secondary Outcomes
- PFS2(49 months)
- OS(49 months)
- ORR(49 months)
- Subgroup analysis(49 months)
- DoR(49 months)
- TFST(49 months)
- Tolerability and adverse events(49 months)
- QoL(49 months)