Phase III Prospective Randomized Trial of Primary Lung Tumor Stereotactic Body Radiation Therapy Followed by Concurrent Mediastinal Chemoradiation for Locally Advanced Non-Small Cell Lung Cancer
Description
Brief Summary
This phase III trial compares the effect of adding stereotactic body radiation therapy (SBRT)
to standard treatment (image guided radiation therapy [IGRT] and chemotherapy followed by
immunotherapy with durvalumab) versus standard treatment alone in treating patients with
non-small cell lung cancer that cannot be treated by surgery (inoperable). SBRT uses special
equipment to position a patient and deliver radiation to tumors with high precision. This
method may kill tumor cells with fewer doses over a shorter period and cause less damage to
normal tissue. IGRT is a type of radiation that uses a computer to create picture of the
tumor, to help guide the radiation beam during therapy, making it more accurate and causing
less damage to healthy tissue. Standard chemotherapy used in this trial consists of
combinations of the following drugs: cisplatin, carboplatin, paclitaxel, pemetrexed, and
etoposide. Cisplatin is in a class of medications known as platinum-containing compounds. It
works by killing, stopping or slowing the growth of tumor cells. Carboplatin is in a class of
medications known as platinum-containing compounds. It works in a way similar to the
anticancer drug cisplatin, but may be better tolerated than cisplatin. Carboplatin works by
killing, stopping or slowing the growth of tumor cells. Paclitaxel is in a class of
medications called antimicrotubule agents. It works by stopping the growth and spread of
tumor cells. Pemetrexed is in a class of medications called antifolate antineoplastic agents.
It works by blocking the action of a certain substance in the body that may help tumor cells
multiply. Etoposide is in a class of medications known as podophyllotoxin derivatives. It
blocks a certain enzyme needed for cell division and DNA repair and may kill tumor cells.
Immunotherapy with durvalumab, may induce changes in body's immune system and may interfere
with the ability of tumor cells to grow and spread. Adding SBRT to the standard treatment of
IGRT with chemotherapy and immunotherapy may be more effective at treating patients with
inoperable non-small cell lung cancer than giving the standard treatment alone.
Detailed Description
I. To compare the overall survival in patients with stage II-IIIC inoperable node-positive
non-small cell lung cancer (NSCLC) after image guided, motion-managed conventional
radiotherapy to the primary tumor and nodal metastases (arm 1) or after image guided,
motion-managed stereotactic body radiation therapy (SBRT) to the primary tumor followed by
conventionally fractionated radiotherapy to nodal metastases (arm 2) both given with
concurrent platinum-based chemotherapy.
II. To compare progression-free survival between the experimental arm (arm 2) and control arm
(arm 1).
SECONDARY OBJECTIVES:
I. To compare objective response rate (as defined by Response Evaluation Criteria in Solid
Tumors [RECIST] version [v] 1.1) between the experimental arm and control arm.
II. To compare the rate of local control between the experimental arm and control arm.
III. To compare patterns of failure (primary, locoregional, or distant) between the
experimental arm and control arm.
IV. To compare changes in pulmonary function (forced expiratory volume in 1 second [FEV1] and
diffusion capacity of the lung for carbon monoxide [DLCO] assessed at randomization and at 6
and 12 months following completion of radiation therapy) between the experimental arm and
control arm.
V. To compare changes in quality of life and patient-reported outcomes assessed from
pre-treatment to 3 months following radiation therapy of each treatment arm.
VI. To determine acute and late toxicity profiles of each treatment arm as measured by the
Common Terminology Criteria for Adverse Events (CTCAE) v5.
EXPLORATORY OBJECTIVES:
I. To characterize and compare longitudinal quality of life and patient-reported outcomes of
each treatment arm.
II. To collect biospecimens at baseline, after SBRT (for arm 2 patients), during last 2 weeks
of chemoradiation, and after first dose of consolidation therapy, to allow for future
analyses.
III. To collect 4-dimensional (4D) computed tomography (CT) planning scans and radiation dose
to calculate regional lung ventilation and explore pre-treatment 4D-CT based ventilation to
predict pulmonary toxicity.
IV. To characterize clinical outcomes, toxicities and changes in pulmonary function and
quality of life among patients receiving proton and photon radiotherapy.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients undergo conventional IGRT and receive standard of care chemotherapy
consisting of paclitaxel intravenously (IV) and carboplatin IV or pemetrexed IV and
carboplatin IV or etoposide IV and cisplatin IV or pemetrexed IV and cisplatin IV and then
receive durvalumab IV on study. Patients also undergo CT and/or positron emission tomography
(PET)/CT during follow up.
ARM II: Patients undergo SBRT and conventional IGRT and receive standard of care chemotherapy
consisting of paclitaxel IV and carboplatin IV or pemetrexed IV and carboplatin IV or
etoposide IV and cisplatin IV or pemetrexed IV and cisplatin IV and then receive durvalumab
IV on study. Patients also undergo CT and/or PET/CT during follow up.
Phase
N/AInclusion and Exclusion Criteria
- Pathologically (histologically or cytologically) proven diagnosis of stage II or III (American Joint Committee on Cancer [AJCC] eighth edition) non-small cell lung cancer (NSCLC) with known PD-L1 status prior to registration
- Patients must have an identified primary tumor and at least one nodal metastasis (peribronchial/hilar/intrapulmonary, mediastinal/subcarinal, supraclavicular/scalene)
- Up to 4 cycles of systemic therapy received prior to registration for the current study cancer is allowable; any prior chemotherapy for a different cancer is also permissible
- The patient must be deemed clinically appropriate for curative intent definitive combined modality therapy, based on the following staging assessments:
- History/physical examination prior to registration;
- Magnetic resonance imaging (MRI) scan of the brain (preferred) or CT scan of the brain (if available, contrast is preferred for all neuroimaging) prior to registration;
- CT chest with IV contrast (if contrast is available and unless contraindicated, such as for abnormal kidney function) prior to registration. PET/CT may be used if the CT portion is of identical diagnostic quality as achieved in a stand-alone CT
- No evidence of distant metastases based on FDG PET/CT scan obtain within 60 days of registration
- Primary tumor =< 7 cm
- Age >= 18
- Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- Hematologic function (e.g. platelets, leukocytes, hemoglobin) amenable, at the discretion of the treating physician, to allow for treatment with chemotherapy and concurrent radiation therapy
- Creatinine clearance >= 25 mL/min by the Cockcroft-Gault (C-G) equation
- Subjects with non-malignant pleural effusion are eligible provided the effusion is not known or demonstrated to be an exudative effusion
- If a pleural effusion is present, the following criteria must be met to exclude malignant involvement:
- When pleural fluid is visible on both the CT scan and on a chest x-ray, a pleuracentesis is required to confirm that the pleural fluid is cytologically negative;
- Effusions that are minimal (i.e., not visible on chest x-ray) that are too small to safely tap are eligible
- Medical history consistent with the patient being amenable, at the discretion of the treating physician, to allow for treating with consolidation immunotherapy. Patients with known EGFR/ALK mutation at the time of registration are eligible, and these patients can be treated with consolidation durvalumab or chemotherapy at the discretion of the treating physician
- Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen
- Negative pregnancy test =< 14 days prior to registration for participants of childbearing potential
- The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information
- Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields that is determined by the treating physician to impede the treatment of the study malignancy
- Patients without identifiable primary tumor and at least 1 pathologically enlarged lymph node are not eligible (T3-4N0 or T0N1-3 patients are not eligible). At least 1 radiographically-involved lymph node is required, but pathologic confirmation of involvement is not mandated
- Centrally located primary tumor < 2 cm from involved nodal disease which would result in significant overlap of the primary SBRT and nodal radiation fields. Centrally located is defined as within or touching the zone of the proximal bronchial tree, which is a volume 2 cm in all directions around the proximal bronchial tree (carina, right and left main bronchi, right and left upper lobe bronchi, intermedius bronchus, right middle lobe bronchus, lingular bronchus right and left lower lobe bronchi)
- Participants who are pregnant or unwilling to discontinue nursing
- Participants of childbearing potential (participants who may become pregnant or who may impregnate a partner) unwilling to use highly effective contraceptives during therapy and for the Food and Drug Administration (FDA)-labeled contraception timeframe required after the final dose of the selected chemotherapy regimen, because the treatment in this study may be significantly teratogenic
Sites
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