RTOG 3505: Randomized, Double Blinded Phase III Trial of Cisplatin and Etoposide plus Thoracic Radiation Therapy Followed By Nivolumab/Placebo for Locally Advanced Non-Small Cell Lung Cancer
- Clements University Hospital
David Gerber, M.D.
Patients will be enrolled and randomized 1:1 between two arms. The treatment allocation scheme described by Zelen (1974) will be used. Patients will be stratified by Zubrod Performance Status (0 vs. 1); histology (squamous vs. non-squamous), as there may be a trend toward greater benefit of nivolumab in squamous histology (Topalian 2012) tumor PD-L1 status.
The primary hypotheses of this study are (1) nivolumab increases oS with a hypothesized hazard ratio of 0.7; (2) nivolumab increases iRRC-determined PFS with a hypothesized hazard ratio of 0.667 (control arm is the reference level). in particular, assuming oS and PFS are exponentially distributed (at least approximately), the alternative hypothesis for oS is that patients receiving the experimental regimen will have a median survival time of at least 34.3 months, while those receiving the control regimen will have a median survival time of 24 month. Similarly, the alternative hypothesis for PFS assumes the median times for PFS will be 12 and 18 months for the control and experimental arms, respectively.
Step 1 Registration Prior to Chemoradiation:
1. Pathologically (histologically or cytologically) proven diagnosis of NSCLC with unresectable, medically inoperable disease, or patients who refuse resection stage IIIA or stage IIIB disease (AJCC 7th edition)
* Unresectable stage IIIA disease is defined by multiple and/or bulky N2 mediastinal lymph nodes on computed tomography (CT) scan such that, in the opinion of the treating investigator, the patient was not a candidate for surgical resection.
*N2 disease must have been documented by biopsy, or at a minimum by fluorodeoxyglucose positron emission tomography (PET) or CT if nodes were more than 2 cm.
* T4 disease is often considered resectable at the discretion of a thoracic surgeon.Patients with T4N0 or T4N1 disease can be enrolled if their case is reviewed by a thoracic surgeon and felt to be unresectable or if they are either medically inoperable or refuse surgery.
* Stage IIIB patients have N3 or T4N2 status. N3 status must have been documented by the presence of a contralateral (to the primary tumor) mediastinal lymph node or supraclavicular or scalene lymph node proven by biopsy, or at a minimum by fluorodeoxyglucose PET or more than 2 cm on CT scan. Patients with disease extending into the cervical region (defined as disease extending above cricoid cartilage) are not eligible.
* Patients with either N2 or N3 adenopathy and Tx disease will be eligible and categorized as Stage IIIA or IIIB based on their nodal status.
2. Appropriate stage for study entry based on the following diagnostic workup:
* History/physical examination, including documentation of height, weight, BSA, and vital signs,within 30 days prior to registration.
* CT scan with IV contrast (CT scan without contrast acceptable if IV contrast is medically contraindicated) of the lung and upper abdomen through the adrenal glands within 60 days prior to registration (recommended within 30 days prior to registration)
* MRI of the brain with contrast (or CT with contrast if MRI is medically contraindicated) within 60 days prior to registration; note: the use of intravenous contrast is required for the MRI or CT (unless medically contra-indicated)
* Whole-body FDG-PET/CT within 60 days prior to registration; note: patients do not need to have a separate CT of chest and upper abdomen with contrast if PET/CT imaging includes a high quality CT chest with contrast.
3. Age >= 18 years.
4.The trial is open to both genders.
5. Zubrod Performance Status of 0-1 within 30 days prior to registration.
6. Adequate hematologic function within 14 days prior to registration defined as follows:
* Absolute neutrophil count (ANC) >= 1,500 cells/mm3;
* Platelets >= 100,000 cells/mm3;
* Hemoglobin >= 9.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb >=9.0 g/dl is acceptable.);
7. Adequate renal function within 14 days prior to registration defined as follows:
* Serum creatinine within normal institutional limits or creatinine clearance >=60 ml/min
8. Adequate hepatic function within 14 days prior to registration defined as follows:
* Total bilirubin <= 1.5 x upper limit of normal (ULN) for the institution (except subjects with Gilbert Syndrome, who can have total bilirubin <3.0 mg/dL);
* ALT, AST <= 3.0 x ULN for the institution;
9. Adequate respiratory function within 180 days prior to registration defined as follows:
* FEV1 > 1.2 liters; DLCO >= 50% predicted.
10. Patients with post-obstructive pneumonia are eligible provided they no longer require intravenous antibiotics at registration.
11. Patients must be at least 3 weeks from prior thoracotomy (if performed); if prior thoracotomy then measurable disease on imaging must be present.
12. A pleural effusion, which is a transudate, cytologically negative and non-bloody, are eligible if the radiation oncologist feels the tumor can be encompassed within a reasonable field of radiotherapy; if pleural fluid is too small a volume to effectively sample by thoracentesis and does not show increased metabolic activity on CT/PET imaging, the patient will be remain eligible.
13. Negative serum pregnancy test within three days prior to registration for women of childbearing potential
14. The patient must provide study-specific informed consent prior to study entry. Patients who lack the psychological or intellectual capacity to consent for themselves are excluded.
15. Sites must verify that an archived tumor block (or that site will release punches instead of block) is available prior to Step 1 registration to the trial although the actual submission can be immediately after Registration Step 1 but at least 5 weeks prior to Registration Step 2. If an archived tumor block sample cannot be shipped for this study, then two 3mm punches from the core needle biopsy blocks may be provided for analysis. NOTE: core or excisional biopsy is required for this study. Fine needle aspirates (FNA) and cytology specimens are not adequate for PD-L1 analysis.
Step 2 Registration (after completion of chemoradiation, before randomization):
16. Zubrod performance Status of 0 or 1.
17. Must be randomized less than 12 weeks following completion of chemoradiotherapy to ensure nivolumab/placebo begins no later than 12 weeks following completion of chemoradiotherapy.
18. Laboratory values must meet the following criteria and must be obtained within 21 days prior to randomization
* WBC >= 2000/[MICRO-SYMBOL]L
* Neutrophils >= 1000/[MICRO-SYMBOL]L
* Platelets >= 50 x103/[MICRO-SYMBOL]L
* Hemoglobin > 9.0 g/dL (Note: The use of transfusion or other intervention to achieve Hgb >=9.0 g/dl is acceptable.)
* Serum creatinine <= 1.5 x ULN or creatinine clearance (CrCl) >= 40 mL/min (if using the Cockcroft-Gault formula below):
Female CrCl = (140 - age in years) x weight in kg x 0.85 / 72 x serum creatinine in mg/dL
Male CrCl = (140 - age in years) x weight in kg x 1.00 / 72 x serum creatinine in mg/dL
* AST/ALT <= 3 x ULN
* Total Bilirubin <= 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)
19. All toxicities attributed to prior chemoRT therapy other than alopecia, fatigue, or peripheral neuropathy must have resolved to <=Grade 2 (NCI CTCAE version 4) before administration of nivolumab or placebo.
20. Negative serum pregnancy test for women of childbearing potential within 7 days of randomization.
21. Agreement of women of childbearing potential to use highly effective contraception during receipt of study drug and up to 161 days (23 weeks) from the last dose of nivolumab/placebo and men receiving nivolumab/placebo who are sexually active with women of childbearing potential to use highly effective contraception during receipt of study drug for 31 weeks from the last dose of nivolumab/placebo.
22. Mandatory submission of H&E slide and block (or two 3mm punches from block) from core or excisional biopsy is required for PD-L1 and other biomarker analysis.