Non-Small Cell Lung Cancer, Non-Squamous Cell Lung Cancer, Squamous Cell Lung Cancer
Conditions
Brief summary
This is a Phase II, multicentre, open-label, randomized, and controlled study, evaluating the efficacy and safety of combined modularized treatment of treosulfan, pioglitazone and clarithromycin in patients with with squamous and non- squamous cell lung cancer, respectively after platin failure.
Detailed description
Patients will be randomized 1:1, and will be stratified according to histology (squamous cell carcinoma vs adenocarcinoma). 86 patients with platin refractory Non-Small Cell Lung Cancer (NSCLC) will be treated either with metronomic low-dose treosulfan, pioglitazone and clarithromycin (experimental arm) or with nivolumab (squamous cell lung cancer and nonsquamous cell lung cancer). Patients will undergo tumor assessments at baseline and every 6 weeks (approximately every two cycles) thereafter, until progression. Patients without progression after 36 weeks will undergo tumor assessments every 12 weeks.
Interventions
DRUGPioglitazone
Pioglitazone 25 mg once daily, p.o.
DRUGnivolumab
3 mg per kilogram of body weight every 2 weeks, p.o. (standard treatment)
DRUGTreosulfan
Treosulfan 250 mg twice daily, p.o.
DRUGClarithromycin
Clarithromycin 250 mg twice daily p.o.
Sponsors
The Anticancer Fund
University Hospital Regensburg
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed Informed Consent Form * Ability to comply with protocol * Age ≥ 18 years * Measurable disease, as defined by RECIST v1.1 * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Life expectancy ≥ 12 weeks * Histologically or cytologically confirmed locally advanced or metastatic (i.e., Stage IIIB not eligible for definitive chemoradiotherapy, Stage IV, or recurrent) NSCLC (per the Union Internationale Contre le Cancer/American Joint Committee on Cancer \[UICC/AJCC\] staging system); * Disease progression during or following treatment with a prior platinum containing regimen for locally advanced, unresectable/inoperable or metastatic NSCLC or disease recurrence within 6 months of treatment with a platinum based adjuvant/neoadjuvant regimen * No more than 2 cytotoxic chemotherapy regimens * Patients that have progressed during or after treatment with EGFR Tyrosine Kinase Inhibitor (TKI) in first line, or are intolerant to treatment with erlotinib, gefitinib, or another EGFR TKI may be included. * Patients that have progressed during or after , or intolerant to treatment with crizotinib or another ALK inhibitor * The last dose of prior systemic anti-cancer therapy must have been administered ≥ 21 days prior to randomization (≥ 14 days for vinorelbine or other vinca alkaloids or gemcitabine.) * The last dose of treatment with any investigational agent must have ended ≥ 28 days prior to randomization. * Prior radiation therapy is allowed provided recovery from any toxic effects thereof and ≥ 7 days between the last fraction and randomization. * Adequate hematologic and end organ function, defined by the following (max 14 days prior study treatment): Absolute Neutrophil Count (ANC) ≥ 1500 cells/μL (without granulocyte colonystimulating factor support within 2 weeks of sampling), White Blood Cell (WBC) counts \> 2,500/μL and \< 15,000/μL, lymphocyte count ≥ 500/μL, Platelet count ≥ 100,000/μL (without transfusion within 2 weeks of sampling), Hemoglobin ≥ 9.0 g/dL. Transfusion or erythropoietic treatment is allowed. * Liver function tests meeting one of the following criteria: Aspartate Transaminase (AST) or Alanine Transaminase (ALT) ≤ 2.5 × ULN, with normal alkaline phosphatase or AST and ALT ≤ 1.5 × ULN in conjunction with alkaline phosphatase \> 2.5 × ULN; Serum bilirubin ≤ 1.0 × ULN. Patients with known Gilbert's disease must have serum bilirubin level ≤ 3 × ULN. * Prothrombin Time - International Normalized Ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN, without anticoagulants. Patients receiving therapeutic anticoagulation must be on a stable dose for at least 1 week prior to randomization. * For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use a highly effective form of contraception (e.g., surgical sterilization, a reliable barrier method, birth control pills, or contraceptive hormone implants) and to continue its use for 6 months after the last dose of the combined modularized treatment. * Patients must have recovered from all acute toxicities from previous therapy, excluding alopecia.
Exclusion criteria
Cancer-Specific
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Progression Free Survival | up to 6 months after study completion |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response | up to 6 months after study completion | — |
| Number of participants experiencing adverse events related to the study drugs | up to 6 months after study completion | Safety and Tolerability assessments will include the incidence, nature, and severity of adverse events and laboratory abnormalities graded per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v4.0). Laboratory safety assessments will include, but are not limited to, the regular monitoring of hematology and blood chemistry |
| Number of participants experiencing a change in cellular secretome analytics in serum | at screening, at the beginning of each new treatment cycle (each cycle consists of 28 days) and at the end of treatment visit, which will take place within 3 weeks of the last intake of study drug | To measure the effect on inflammation, angiogenesis and immune response (proteomics, lipidomics) on serum samples |
| Overall Survival | up to 6 months after study completion | — |
| Comparison of participants tumour response according to (Response Evaluation Criteria in Solid Tumors) RECIST criteria version 1.1 and Peroxisome proliferator-activated receptor gamma (PPAR-γ) expression | Baseline | tissue microarray for analysis of PPAR-γ expression for each tumour sample will be performed. |
| description of change in predictive and prognostic exploratory biomarkers for each participant | at screening,at the beginning of each treatment cycle (each treatment cycle consists of 28 days), and at the end of treatment visit, which will take place within 3 weeks of the last intake of study drug | For patients participating in University Clinic Regensburg only: Secretome analytics (proteomics, lipidomics) will be performed to monitor functions of tumor-associated cellular compartments on serum samples. Serum samples are taken at the beginning of each new treatment cycle. epidermal growth factor receptor (EGFR), K-ras, Anaplastic lymphoma kinase (ALK), and Programmed cell death protein 1 (PD-1) will be analyzed. |
| proportion of patients who report a considerable degree of impairment in a respective dimension, i.e. a score value <50 | up to 6 months after study completion | evaluate and compare patient reported outcomes (PROs) of lung cancer symptoms and patient functioning between treatment arms |
Countries
Germany
Contacts
Primary ContactAlbrecht Reichle, MD
Outcome results
None listed