Ermittlung der Sicherheit und Durchführbarkeit einer primären Bestrahlung mit Kohlenstoffionen in Rasterscan-Technik bei Pancoast-Tumoren im Rahmen des trimodalen Behandlungskonzepts.
Die Standardtherapie beim lokal fortgeschrittenen und nicht fernmetastasierten Pancoast- Tumor mit nicht-kleinzelliger Histologie ist ein trimodales Vorgehen bestehend aus einer Radiochemotherapie und anschließender chirurgischer Resektion. Hoch-LET-Strahlung wie z. B. Kohlenstoffionen bieten theoretisch biologische Vorteile wie beispielsweise eine verbesserte biologische Effektivität. Die vorliegende Studie soll als monozentrische, einarmige, prospektive offene Pilotstudie am Heidelberger Ionentherapiezentrum (HIT) durchgeführt werden, bei der die Strahlentherapie des standardisierten trimodalen Konzepts mittels einer Bestrahlung mit Kohlenstoffionen durchgeführt wird. Nach nicht-invasiver Immobilisierung der Patienten und CT-basierter Bestrahlungsplanung, sollen 20 Patienten neoadjuvant mittels C12-Schwerionentherapie in 13 Fraktionen bis zu einer Gesamtdosis von 39 GyE kombiniert mit einer Standardchemotherapie behandelt werden. Primärer Endpunkt ist die Machbarkeit und Sicherheit dieses Therapiekonzepts an Hand der Inzidenz von Grad 3/4 NCI-CTC-AE Toxizität und/oder eines Abbruchs der geplanten Therapie aus jedwedem Grund. Sekundärer Endpunkt ist der Regressionsgrad im Präparat nach chirurgischer Resektion.
- Histologisch gesicherter Pancoast-Tumor (Nicht-kleinzellige Histologie)
- Maximal N1 im FDG-PET-CT (nicht älter als 6 Wochen) bei Lungentumor
- Karnofsky-Index von ≥ 70%
- Alter zwischen 18 und 75 Jahren
- Durchgeführte Patientenaufklärung und schriftliche Einwilligung
- Ablehnung der Studie durch den Patienten
- Medizinische Kontraindikation für eines der ELemente der trimodalen Therapie
- Patient ist nicht einwilligungsfähig
- N2 und N3 im FDG-PET-CT
- Stadium IV (Fernmetastasen)
- Dekompensierte Begleiterkrankung der Atmungsorgane, des Herz-Kreislauf-Systems, des Stoffwechsels, des hämatopoetischen Systems, der Gerinnung oder Nierenfunktion
- Vorangegangene Strahlentherapie im thorakalen Bereich
Gleichzeitige Teilnahme an einer anderen klinischen Studie, die die Ergebnisse dieser Studie beeinflussen könnte
- Aktive Medizin-Implantate, für die zum Zeitpunkt der Behandlung keine Genehmigung für eine Ionenbestrahlung existiert (z. B. Herzschrittmacher, Defibrillator, ...)
Fostering efficacy of anti – PD-1 – treatment: Nivolumab plus radiotherapy in advanced NSCLC.
- Age ≥ 18 years
- ECOG performance status 0-1
- Metastatic non-squamous NSCLC after failure of platinum-based doublet chemotherapy and
i.) the necessity of RT of a metastatic bone or soft tissue lesion (group A) or
ii.) no necessity of RT (group B)
- Presence of measurable disease by CT or MRI per RECIST 1.1 criteria
- FFPE material for PD-L1 evaluation must be available.
- Previous malignancies
- Known activating EGFR mutation or a known ALK translocation
- Prior immunotherapy
- Ongoing treatment with >10mg of prednisone (or steroid equivalent) daily
- Active or recent history of an autoimmune disease or syndrome that required systemic corticosteroids/ immunosuppressive medications
- Any serious or uncontrolled medical disorder or active infection that would impair the ability of the subject to receive protocol therapy
- Brain metastases mandating active treatment in terms of irradiation. Subjects with brain metastases are eligible, if metastases have been treated, treatment has been completed,and no progression is evident on MRI, or if metastases are stable/asymptomatic and do not require local therapy with irradiation.
Kombination der SBRT mit einer Immuntherapie (Pembrolizumab) bei medizinisch inoperablen Patienten
The purpose of this study is to assess the efficacy and safety of stereotactic body radiotherapy (SBRT) plus pembrolizumab (MK-3475) in the treatment of adult participants with medically inoperable Stage I or IIA non-small cell lung cancer (NSCLC).
The primary study hypotheses are:
- SBRT plus pembrolizumab prolongs Event-free Survival (EFS) compared to SBRT plus placebo (normal saline solution), and
- SBRT plus pembrolizumab prolongs Overall Survival (OS) compared to SBRT plus placebo.
- Has previously untreated NSCLC diagnosed by histology or cytology and confirmed as Stage I or IIA NSCLC (American Joint Committee on Cancer, AJCC) by chest computed tomography (CT) and positron emission tomography (PET) scan
- Cannot undergo thoracic surgery due to existing medical illness(es) as determined by the site's multi-disciplinary tumor board
- Has a Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2
- Is able to receive SBRT and does not have an ultra-centrally located tumor
- Has adequate organ function within 7 days prior to the start of study treatment
- A female is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: a) not a women of childbearing potential (WOCBP) OR b) A WOCBP who agrees to use study-acceptable contraception during treatment and for at least 120 days after last dose of study treatment
- Has received prior therapy with an anti-programmed cell death-1 (anti-PD-1), anti-programmed cell death-ligand 1 (anti-PD-L1), or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g. cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4], tumor necrosis factor receptor superfamily member 4 [OX-40], tumor necrosis factor receptor superfamily member 9 [CD137])
- Has received prior radiotherapy to the thorax, including radiotherapy to the esophagus, mediastinum, or breast
- Has received a live vaccine within 30 days prior to the first dose of study treatment
- Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment. Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study treatment
- Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
- Has a known hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
- Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
- Has a known history of Hepatitis B or known active Hepatitis C virus infection
- Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). However, replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency), while systemic, will be permitted for study eligibility.
- Has an active infection requiring systemic therapy
- Has a known history of human immunodeficiency virus (HIV) infection
- Has a known history of active tuberculosis (TB; Bacillus tuberculosis)
- Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment
- Has had an allogenic tissue/solid organ transplant
Kombination der SBRT mit einer Immuntherapie (Durvalumab) bei medizinisch inoperablen Patienten oder bei Ablehnung einer Operation
This is a Phase III, randomized, placebo-controlled, double-blind, multi-center study assessing the efficacy and safety of durvalumab versus placebo following SoC SBRT in patients with unresected clinical Stage I/II lymph node-negative (T1 to T3N0M0) NSCLC.
- Age ≥18 years
- Histologically or cytologically documented Stage I to II NSCLC, with clinical Stage I/II lymph node-negative (T1 to T3N0M0) disease and planned to receive definitive treatment with SBRT. Patients may be medically inoperable or are medically operable and refusing surgery or choosing to have SBRT (Stereotactic Body Radiation Therapy) as definitive therapy
- Completion of SoC SBRT as definitive treatment prior to randomization
- World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) PS of 0, 1, or 2
- Life expectancy of at least 12 weeks
- Body weight >30 kg
- Tumor sample required
- Adequate organ and marrow function required
- Patients with central or peripheral lesions are eligible
- Staging studies must be done within 8 weeks before randomization
- Mixed small cell and non-small cell cancer histology
- History of allogeneic organ transplantation
- History of another primary malignancy with exceptions
- History of active primary immunodeficiency
- Any unresolved toxicity National Cancer Institute (NCI) CTCAE Grade ≥2 from SBRT (Stereotactic Body Radiation Therapy)
Gleichzeitige Kombination der Immuntherapie (Pembrolizumab) mit der Strahlen-Chemotherapie
This is a trial in adult participants with unresectable, locally advanced, Stage III non-small cell lung cancer (NSCLC) treated with pembrolizumab in combination with platinum doublet chemotherapy and standard thoracic radiotherapy followed by pembrolizumab monotherapy. The primary hypothesis of the trial is that within each platinum doublet chemotherapy cohort, the percentage of participants who develop Grade 3 or higher pneumonitis is ≤10%.
- Male/female participants, who are at least 18 years of age on the day of signing informed consent with previously untreated, unresectable, pathologically confirmed NSCLC and Stage IIIA, IIIB or IIIC NSCLC by American Joint Committee on Cancer Version 8.
- No evidence of metastatic disease by whole body positron emission tomography/computed tomography (PET/ CT) scan, diagnostic quality CT scan, and brain imaging.
- Have measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology.
- Have provided tumor tissue sample (core, incisional, or excisional biopsy).
- Have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
- Have adequate pulmonary function test (PFT)
- Have adequate organ function
- A male participant must agree to use contraception through the end of treatment and refrain from donating sperm during this period.
- A female participant is eligible to participate if she is not pregnant, not breastfeeding, and if participant is a woman of childbearing potential (WOCBP), agrees to follow the contraceptive guidance as provided in the protocol through the end of treatment.
- A WOCBP who has a positive urine pregnancy test within 72 hours prior to treatment allocation
- Has small cell lung cancer.
- Has had documented weight loss >10% in the preceding 3 months.
- Participants whose radiation treatment plans are likely to encompass a volume of whole lung receiving >20 Gy in total (V20) of more than 31% of lung volume.
- Has received prior radiotherapy to the thorax, including radiotherapy to the esophagus or for breast cancer.
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent (programmed cell death protein 1 [PD-1] and its ligands, programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 [PD-L2]) or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
- Has received a live vaccine within 30 days prior to the first dose of study drug.
- Has had an allogenic tissue/solid organ transplant.
- Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg prednisone daily or equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug.
- Has a known additional malignancy that is progressing or has required active treatment within the past 5 years.
- Has severe hypersensitivity (Grade 3 or higher) to pembrolizumab and/or any of its excipients.
- Has a known severe hypersensitivity (Grade 3 or higher) to any of the study chemotherapy agents and/or to any of their excipients.
- Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
- Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease that requires steroids.
- Has an active infection requiring systemic therapy.
- Has a known history of human immunodeficiency virus (HIV) infection. HIV testing is not required unless mandated by local health authority.
- Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
- Has a known history of active tuberculosis (TB; Bacillus tuberculosis).
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
- Has a known psychiatric or substance abuse disorder that would interfere with cooperating with the requirements of the study.
- Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study through the end of treatment.
Konsolidierende Immuntherapie (Durvalumab +/- Tremelimumab) nach Strahlen-Chemotherapie des kleinzelligen Bronchialkarzinoms
This is a Phase III, Randomized, Double-blind, Placebo-controlled, Multi-center, International Study of Durvalumab or Durvalumab and Tremelimumab as Consolidation Treatment for Patients with LS-SCLC Who Have Not Progressed Following Concurrent Chemoradiation Therapy
- Histologically or cytologically documented limited-stage small cell lung cancer (stage I-III).
- Received 4 cycles of chemotherapy concurrent with radiotherapy, which must be completed within 1 to 42 days prior to randomization and the first dose of IP. Chemotherapy must contain platinum and IV etoposide. Radiotherapy must be either total 60-66 Gy over 6 weeks for the standard QD regimen or total 45 Gy over 3 weeks for hyperfractionated BD schedules.
- PCI may be delivered at the discretion of investigator and local standard of care, and must be conducted after the end of cCRT and completed between 1 to 42 days to first dose of IP.
- Have not progressed following definitive concurrent chemoradiation
- Life expectancy ≥ 12 weeks at Day 1.
- ECOG 0 or 1 at enrolment.
- Extensive-stage SCLC
- Active or prior documented autoimmune or inflammatory disorders
- Uncontrolled intercurrent illness, including but not limited to interstitial lung disease.
- Active infection including tuberculosis, HIV, hepatitis B and C
- Patients who received sequential chemotherapy and radiotherapy (no overlap of RT with chemotherapy)
Präoperative Immunmodulation durch lokale Strahlentherapie vor geplanter Operation im Frühstadium des Bronchialkarzinoms
Insufficient migration and activation of tumour specific effector T cells seems to be the one important reason for inadequate host anti-tumour immune response. Ionizing radiation can induce a variety of immune responses. The goal of this randomized trial is to assess if a preoperative single fraction low dose radiation is able to improve anti-tumour immune response in operable early stage lung cancer.
- Histologically proven clinical stage I to IIA pulmonary adenocarcinoma
- Lung tumor is felt to be curatively resectable by the treating physicians
- Sufficient pulmonary function for lobectomy according to current guidelines
- The patient is free of distant metastases as confirmed by contrast-enhanced chest and upper abdomen CT-scan and by contrast-enhanced CT or MRI of the brain
- Age over 50years at the time of consent due to federal radiation protection law
- In female patients of childbearing potential there must be a negative pregnancy test
- Eastern Cooperative Oncology Group performance status of 0,1, 2 or 3 at the time of randomization
- Patients who the investigator believes can and will comply with the requirements of this protocol
- Written informed consent according to good clinical practise and national/regional regulations
- The patient shows clinical signs of pneumonia
- The patient receives immunosuppressive drugs (alkylating agents, antimetabolites, methotrexate, azathioprine, mercaptopurine, cytotoxic antibodies, ciclosporin, tacrolimus, sirolimus, interferon, mycophenolate, small biological agents)
- The patient has been diagnosed with a potential immune mediated disease
- Elevated blood leukocyte count or erythrocyte sedimentation rate
- The patient has received any cancer specific treatment, including radiotherapy, immunotherapy, hormonal therapy or chemotherapy
- The patient is diagnosed with a concomitant malignancy and/or has a history of malignancy within the past five years or has had a malignancy that has been in complete remission for less than 5 years
- The patient needs chronic long term oxygen therapy
- The patient has undergone splenectomy
- The patient is known to be HIV positive
- The patient has an uncontrolled bleeding disorder
Gleichzeitige und konsolidierende Kombination der Immuntherapie (Nivolumab +/- Ipilimumab) mit der Strahlen-Chemotherapie
The primary purpose of the study is to compare the effectiveness of nivolumab + CCRT followed by nivolumab + ipilimumab (Arm A) vs CCRT followed by durvalumab (Arm C) in participants with untreated Locally Advanced Non-small Cell Lung Cancer
- Eastern Cooperative Oncology Group (ECOG) performance status ≤1
- Locally advanced stage IIIA, IIIB, or IIIC (T1-2 N2-3 M0, T3 N1-3 M0, or T4 N0-3 M0) histologically-confirmed NSCLC, according to 8th TNM classification.
- Newly diagnosed and treatment-naïve, with no prior local or systemic anticancer therapy given as primary therapy for locally advanced disease.
- Any condition including medical, emotional, psychiatric, or logistical that, in the opinion of the Investigator would preclude the patient from adhering to the protocol or would increase the risk associated with study participation.
- Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
- Active infection requiring systemic therapy within 14 days prior to randomization.
- Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured,
- Participants with an active, known or suspected autoimmune disease or a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of start of randomization.
- History of organ or tissue transplant that requires systemic use of immune suppressive agents.
- Clinical evidence of hearing loss and prior thoracic radiotherapy.