Trial document




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  DRKS00010244

Trial Description

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Title

Dose-intensified neoadjuvant radiochemotherapy for operable locally advanced NSCLC Stage III A & B

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Trial Acronym

NEOAHA-I

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URL of the Trial

[---]*

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Brief Summary in Lay Language

Patients are planned for induction chemotherapy (3 cycles cisplatin/paclitaxel) followed by intensified neoadjuvant radiotherapy with concurrent chemotherapy (cisplatin/ vinorelbine) followed by curative resection. After neoadjuvant chemoradiotherapy, patients will be reevaluated within an interdisciplinary tumorboard and, in the case of operability, shall be resected.
In the case, patients are rated inoperable, or patients refuse surgery, respectively, treatment will be completed with definitive radiochemotherapy.
Under continuous toxicity monitoring, this phase-I study will evaluate an intensified neoadjuvant radiotherapy regimen based on an ‚involved-field’ target volume concept with integrated boost in the macroscopic tumor. Patients without distant progression who are rated inoperable after the neoadjuvant treatment phase will receive a conventionally fractionated radiation boost.
Furthermore, this trial shall pilot further dose escalation of the definitive radiotherapy. Inoperable patients or those who deny resection will be offered sequentially escalated boost radiation (Def0, Def1, Def2, Def3).
While Def0 is aimed at a total dose of 72 Gy, further study arms will stepwise increase the dose using an integrated boost concept based on an adaptive target volume reduction based on sequential PET/CT imaging (pre- and post-induction chemotherapy).
For the dose levels Def1, Def2, and Def3, total doses of 75.6 Gy, 80.5 Gy, and 85.2 Gy, respectively, are foreseen in the primary tumour.

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Brief Summary in Scientific Language

Patients are planned for induction chemotherapy (3 cycles cisplatin/paclitaxel) followed by intensified neoadjuvant radiotherapy with concurrent chemotherapy (cisplatin/ vinorelbine) followed by curative resection. After neoadjuvant chemoradiotherapy, patients will be reevaluated within an interdisciplinary tumorboard and, in the case of operability, shall be resected.
In the case, patients are rated inoperable, or patients refuse surgery, respectively, treatment will be completed with definitive radiochemotherapy.
Under continuous toxicity monitoring, this phase-I study will evaluate an intensified neoadjuvant radiotherapy regimen based on an ‚involved-field’ target volume concept with integrated boost in the macroscopic tumor (GTV: 54 Gy/1.8 Gy bid, 5 times per week) and a base dose of 45 Gy (1.5 Gy bid, 5 fx/ w) in the adjacent PTV (study arm: Neo1). Patients without distant progression who are rated inoperable after the neoadjuvant treatment phase will receive a conventionally fractionated radiation boost with 18 Gy (2 Gy/fx, total dose 72 Gy: study arm Def0).
Furthermore, this trial shall pilot further dose escalation of the definitive radiotherapy. After neoadjuvant chemoradiotherapy, about 20% of patients will not undergo surgery (either due to patients’ refusal or medical reasons, respectively). These patients will be offered sequentially escalated boost radiation (Def0, Def1, Def2, Def3).
While Def0 is aimed at a total dose of 72 Gy, further study arms will stepwise increase the dose using an integrated boost concept based on an adaptive target volume reduction based on sequential PET/CT imaging (pre- and post-induction chemotherapy). Dose-escalation will be pursued after 7 patients per dose-level if at maximum two dose-limiting toxic events or one treatment-related death is observed.
For the study arms Def1, Def2, and Def3, total doses of 75.6 Gy, 80.5 Gy, and 85.2 Gy, respectively, are foreseen in the primary tumour.
Primary endpoint of the study is dose-limiting toxicity due to radiotherapy and resection.

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Organizational Data

  •   DRKS00010244
  •   2016/04/04
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  •   yes
  •   Approved
  •   13-5574-BO, Ethik-Kommission der Medizinischen Fakultät der Universität Duisburg-Essen
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Secondary IDs

  •   U1111-1181-2922 
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Health Condition or Problem studied

  •   nonsmall-cell lung cancer (NSCLC)
  •   C34 -  Malignant neoplasm of bronchus and lung
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Interventions/Observational Groups

  •   NEO1: Induction chemotherapy (3 cycles cisplatin/ paclitaxel) followed by accelerated-hyperfractionated radiotherapy (1.5 Gy (PTV1)/1.8 Gy (PTV1Boost=integrated Boost) per fraction bid, 5 days per week, 30 fractions, up to a cumulative total dose of 45 Gy/ 54 Gy [PTV1/PTV1boost]) with concurrent chemotherapy (cisplatin/ vinorelbine) followed by curative resection.
    According to the institutional standard at the University Hospital Essen, three cycles chemotherapy will be applied during induction before the start of study treatment:
    •Paclitaxel 175 mg/m2 iv over 3 h, d 1 of a 21-d-course
    •Cisplatin 50 mg/m2 iv over 1 h (following paclitaxel-application on d1 and 8 of a 21-d-course
    Courses are to be repeated every 21 days.
    Concurrent chemotherapy:
    •Cisplatin 50 mg/m2 iv over 1 h, d 2 and 9 after the start of neoadjuvant radiotherapy
    •Navelbine 20 mg/m2 iv, d 2 and 9 after the start of neoadjuvant radiotherapy

    In the case of inoperability after the neoadjuvant treatment phase, patients will receive definitive radiochemotherapy (2nd treatment phase) analogous to Def0.
  •   In the case of inoperability or patients refusal to resection, patients will receive definitive chemoradiotherapy (with concurrent cisplatin/vinorelbine). Definitive chemoradiotherapy will be escalated in 4 dose-levels:
    1. Def0: PTV2, 18 Gy/2 Gy/fraction, 5x/ week, 9 fractions, cumulative total dose (PTV2) 72 Gy.
    2. Def1: PTV2/ PTV2Boost (integrated boost), 18 Gy/ 21.6 Gy, 2 Gy/ 2.4 Gy/ fraction, 5x/ week, 9 fractions, cumulative total dose (PTV2/ PTV2Boost) 72 Gy/ 75.6 Gy
    3. Def2: PTV2/ PTV2Boost (integrated boost), 22 Gy/ 26.4 Gy, 2 Gy/ 2.4 Gy/fraction, 5x/ week, 11 fractions, cumulative total dose (PTV2/ PTV2Boost) 76 Gy/ 80.4 Gy
    4. Def3: PTV2/ PTV2Boost (integrated boost), 26 Gy/ 31.2 Gy, 2 Gy/ 2.4 Gy/fraction, 5x/ week, 13 fractions, cumulative total dose (PTV2/ PTV2Boost) 80 Gy/ 85.2 Gy.
    In the case of inoperability after the neoadjuvant treatment phase, a second concurrent chemotherapy cycle parallel to the 2nd radiotherapy phase (boost irradiation) is planned:
    •Cisplatin 40 mg/m2 iv over 1 h on d 2 of the boost radiotherapy (d 23 after the start of radiotherapy)
    •Navelbin 15 mg/m2 iv on d 2 and 9 of the boost radiotherapy (d 23 / 30)
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Characteristics

  •   Interventional
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  •   Non-randomized controlled trial
  •   Open (masking not used)
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  •   Active control (effective treament of control group)
  •   Treatment
  •   Other
  •   I
  •   No
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Primary Outcome

Dose-limiting toxicity within 120 days after the start of radiotherapy and 30 days after surgery.

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Secondary Outcome

Incidence of grade 3 or higher toxicity within 360 days after the start of radiotherapy.
Incidence of grade 2 or higher pneumonitis within 360 days after the start of radiotherapy.

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
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Recruitment

  •   Planned
  •   2016/04/04
  •   35
  •   Monocenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional Inclusion Criteria

• Histopathologically proven non-small cell lung cancer. Biopsy must be taken from either primary tumour or regional lymph node.
• At the time of initial diagnosis before any treatment, patients must be clinical stage IIIA [T1-3 N2, T4 N0-1, all M0] or IIIB [T4 N2, T1-3 N3, all M0, UICC, 7. ed.] with one or more of the following criteria:
• T1-T4 tumour, proven by endoscopy or mediastinoscopy or CT or MRI.
• N2 or N3 mediastinal lymph node involvement, histopathologically or cytopathologically verified by either transbronchial fine-needle aspiration (EBUS-TBNA) or mediastinoscopy. T4 N3 stages are to be excluded (see below).
• For enrollment in Neo1, patients must have been deemed potentially resectable by an interdisciplinary tumour board (comprising medical oncologist, radiation oncologist, thoracic surgeon) within four months before study inclusion.
For enrollment in Def0-3, patients should have been either primarily selected for definitive chemoradiotherapy by the interdisciplinary tumour board or have personally voted against neoadjuvant treatment followed by resection, respectively. Reasons for preference of definitive chemoradiation are: tumour is not resectable with acceptable risk, or the cost-benefit comparison between resection and definitive chemoradiation is worse for surgery.
• 18F-FDG-PET/CT is mandatory before mediastinoscopy and treatment start.
• Brain imaging (MRI or CT) before treatment start is mandatory.
• Patients must at least undergo 2 cycles of the specified induction chemotherapy. Following these, a restaging PET/CT within three weeks of radiotherapy treatment planning is mandatory to exclude distant metastases.
• Patients with chronic obstructive pulmonary disease are eligible.
• Patients must have FEV1 ≥ 1.2 l and no dyspnea or hypoxia ≥ grade 2 (CTC).
• Patients with Acquired Immune Deficiency Syndrome (AIDS) or equivalent immune-compromising diseases are eligible when their condition is stable and they are able to undergo a combined chemoradiotherapy regimen.
• Karnofsky Performance Status 80 - 100% at the time of study inclusion.
• Age ≥ 18 y
• Written informed consent

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Exclusion Criteria

• Patients who are not treatable within normal tissue dose-volume constraints of the protocol.
• Any component of small-cell histology.
• Stage T4 N3
• Pleural effusion, larger than minimal or exsudative, or cytologically proven malignant.
• Malignant pericardial effusion
• Distant metastases at initial diagnosis or detected on restaging PET/CT
• acute infection requiring specific treatment > 10 days
• Pregnancy or breast feeding. In women of childbearing potential, pregnancy must be excluded before treatment.
Patients must be willing to use medically acceptable forms of contraception, otherwise will be excluded.
• Other invasive malignancies, except for non-melanomatous skin cancer (controlled for at least 5 years).
• Prior radiotherapy to the region of the study cancer, precluding high-dose irradiation.
• Insufficient patients’ compliance, e.g. due to active psychiatric disorders or language barriers.

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Addresses

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    • Universitätsklinikum Essen
    • Hufelandstraße 55
    • 45147  Essen
    • Germany
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    • Universitätsklinikum Essen, Klinik für Strahlentherapie,
    • Mr.  Prof. Dr.  Martin  Stuschke 
    • Hufelandstraße 55
    • 45147  Essen
    • Germany
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    • Universitätsklinikum Essen, Klinik für Strahlentherapie,
    • Mr.  PD Dr.  Christoph  Pöttgen 
    • Hufelandstraße 55
    • 45147  Essen
    • Germany
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Sources of Monetary or Material Support

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    • Universitätsklinikum Essen
    • Hufelandstraße 55
    • 45147  Essen
    • Germany
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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

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