Ipilimumab, Nivolumab, and Thoracic Radiation Therapy in Treating Patients with Extensive-Stage Small Cell Lung Cancer after Chemotherapy
- Participants must have signed and dated an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved written informed consent form in accordance with regulatory and institutional guidelines; this must be obtained before the performance of any protocol-related procedures that are not part of normal patient care
- Participants must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests and other requirements of the study
- Patients with small cell lung cancer (SCLC) documented by histology or cytology from brushing, washing, or needle aspiration of a defined lesion, but not from sputum cytology alone
- Participants must have presented at initial diagnosis with extensive-stage disease (defined as stage IV [T any, N any, M1a/b] per National Comprehensive Cancer Network [NCCN] guidelines version 1.2015, American Joint committee on Cancer [AJCC] staging manual, seventh [7th] edition, 2010)
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
- Participants must have received 4-6 cycles of platinum-based first-line chemotherapy and must have an ongoing response of complete response (CR), partial response (PR), or stable disease (SD) after completion of chemotherapy; acceptable combinations, as recommended per NCCN guidelines, include cisplatin or carboplatin combined with either etoposide or irinotecan * As an exception to the above criterion, participants receiving only 3 cycles of chemotherapy due to toxicity are eligible, if they have an ongoing PR or CR after the third (3rd) cycle * Participants who have received > 6 cycles of platinum-based first-line chemotherapy are not eligible
- Participants must initiate study treatment with thoracic radiation therapy =< 8 weeks (56 days) from the last dose of platinum-based first line chemotherapy; * Thoracic radiation therapy must not be administered < 3 weeks (21 days) from the last dose of platinum-based first line chemotherapy * Ipilimumab/nivolumab study therapy must not be administered < 13 days and not more than 21 days from the last dose of thoracic radiotherapy
- Whenever possible, a formalin-fixed, paraffin-embedded (FFPE) tumor tissue block or 10 unstained slides of tumor sample (archival or recent) for biomarker evaluation should be made available and submitted to the central lab for correlative studies
- Patient re-enrollment: this study permits the re-enrollment of a participant who has discontinued the study due to pre-treatment failure (i.e., participant has not been treated); if re-enrolled, the participant must be re-consented
- Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hours prior to the start of thoracic radiation therapy
- Women must not be breastfeeding
- WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus 5 half-lives of study drug (half-life up to 25 days) plus 30 days (duration of ovulatory cycle) for a total of 5 months post-treatment completion
- Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug (s) plus 5 half-lives of the study drug (half-life up to 25 days) plus 90 days (duration of sperm turnover) for a total of 7 months post-treatment completion
- Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements; however they must still undergo pregnancy testing * Investigators shall counsel WOCBP and male participants who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy; investigators shall advise on the use of highly effective methods of contraception, which have a failure rate of < 1% when used consistently and correctly
- Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) study therapy plus 5 half-lives of the study drug study therapy up to 25 days plus 90 days (duration of sperm turnover) for a total of 31 weeks post-treatment completion
- Azoospermic males are exempt from contraceptive requirements
- Male participants must be willing to refrain from sperm donation during the entire study and for 5 half-lives of study drug plus 90 days (duration of sperm turnover)
- At a minimum, participants must agree to the use of one highly effective method of contraception as listed below: * Highly effective methods of contraception have a failure rate of < 1% when used consistently and correctly; WOCBP participants and female partners of male participants who are WOCBP are expected to use one of the highly effective methods of contraception listed below; male participants must inform their female partners who are WOCBP of the contraceptive requirements of the protocol and are expected to adhere to using contraception with their partner; contraception methods are as follows: ** Progestogen-only hormonal contraception associated with inhibition of ovulation ** Hormonal methods of contraception, including oral contraceptive pills containing combined estrogen + progesterone, vaginal ring, injectables, implants, and intrauterine devices (IUDs) such as Mirena ** Nonhormonal IUDs, such as ParaGard ** Bilateral tubal occlusion ** Vasectomized partner with documented azoospermia 90 days after procedure *** Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of the WOCBP trial participant and that the vasectomized partner has received medical assessment of the surgical success ** Intrauterine hormone-releasing system (IUS) ** Complete abstinence *** Complete abstinence is defined as the complete avoidance of heterosexual intercourse *** Complete abstinence is an acceptable form of contraception for all study drugs and must be used throughout the duration of the study treatment (plus 5 half-lives of the investigational drug plus 30 days) *** It is not necessary to use any other method of contraception when complete abstinence is elected *** Participants who choose complete abstinence must continue to have pregnancy tests *** Acceptable alternate methods of highly effective contraception must be discussed in the event that the participant chooses to forego complete abstinence *** The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the participant * UNACCEPTABLE METHODS OF CONTRACEPTION ** Periodic abstinence (calendar, symptothermal, post-ovulation methods) ** Withdrawal (coitus interruptus) ** Spermicide only ** Lactation amenorrhea method (LAM)
- Participants with previous brain metastases are eligible provided that they are treated and asymptomatic not requiring steroids or anticonvulsants, and have stable disease at the screening tumor assessment; a 4 week disease stable interval as confirmed by magnetic resonance imaging (MRI) or computed tomography (CT) brain w/ contrast is required after treatment of brain metastases before initiation of thoracic radiation therapy; in addition, subjects must have been either off corticosteroids, or on a stable or decreasing dose of 10 mg daily prednisone (or equivalent)
- Participants who have received prior chest radiation are excluded
- Carcinomatous meningitis
- Pleural effusion that cannot be controlled with appropriate interventions
- All toxicities attributed to prior anti-cancer therapy must have been resolved to grade 1 (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 4) or baseline before administration of study drug(s) other than: * Patients with toxicities attributed to prior anti-cancer therapy that either are not expected to resolve and/or result in long-lasting sequelae, such as neuropathy after platinum-based therapy, or are not expected to interfere with treatment on study, such as fatigue, alopecia, or grade 2 hematologic toxicity are eligible
- Women who are pregnant or breastfeeding
- Active, known, or suspected autoimmune disease; patients with an autoimmune paraneoplastic syndrome requiring concurrent immunosuppressive treatment are excluded; patients with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
- A condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of study initiation; corticosteroids with minimal systemic absorption (inhaled or topical steroids) and adrenal replacement steroid doses > 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease
- Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T cell co-stimulation or checkpoint pathways)
- Interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity
- Any patient requiring supplemental oxygen therapy
- Previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, or breast) unless a complete remission was achieved at least 2 years prior to study entry AND no additional therapy is required during the study period
- Known medical condition that, in the investigator’s opinion, would increase the risk associated with study participation or study drug(s) administration or interfere with the interpretation of safety results
- Major surgery or significant traumatic injury that is not recovered at least 14 days before the initiation of thoracic radiation therapy
- Positive test for hepatitis B virus (HBV) using HBV surface antigen (HBVsAg) test or positive test for hepatitis C virus (HCV) using HCV ribonucleic acid (RNA) or HCV antibody test indicating acute or chronic infection * Individuals with a positive test for HCV antibody but no detection of HCV RNA indicating no current infection are eligible
- Known medical history of testing positive for human immunodeficiency virus (HIV) or known medical history of acquired immunodeficiency syndrome (AIDS)
- Absolute neutrophil count (ANC) < 1,000/mm^3
- Platelet count < 100,000/mm^3, or
- Hemoglobin level < 8.0 g/dL
- Total bilirubin level >= 1.5 times the upper limit of normal (ULN) (except patients with Gilbert syndrome, who are excluded if total bilirubin >= 3 times ULN), or
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels >= 2.5 times the ULN or >= 5 times the ULN if liver metastases are present
- Lipase > 1.5 ULN; participants with lipase > 1.5 ULN may enroll if there are neither clinical nor radiographic signs of a pancreatitis
- Amylase > 1.5 ULN; participants with amylase > 1.5 ULN may enroll if there are neither clinical nor radiographic signs of a pancreatitis
- History of allergy or hypersensitivity to any of the study drugs or study drug components
- Prisoners or individuals who are involuntarily incarcerated
- Individuals who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness
I. To confirm the recommended phase II dose of ipilimumab and nivolumab among patients treated with combined thoracic radiation therapy (30 Gy in 10 fractions) and nivolumab/ipilimumab following standard treatment with 4-6 cycles of platinum-based chemotherapy. (Phase I)
II. To estimate the 6-month progression free survival (PFS) rate among patients treated with ipilimumab and nivolumab with thoracic radiation therapy (30 Gy in 10 fractions) after standard treatment with 4 to 6 cycles of platinum based chemotherapy. (Phase II)
I. To estimate the median PFS among patients treated with ipilimumab and nivolumab with thoracic radiotherapy (30 Gy in 10 fractions) after standard treatment with 4-6 cycles of platinum-based chemotherapy.
II. To estimate 1-year overall survival (OS) rate among patients treated with ipilimumab and nivolumab with thoracic radiotherapy after standard treatment with 4-6 cycles of platinum-based chemotherapy.
III. To estimate median OS among patients treated with ipilimumab and nivolumab with thoracic radiotherapy after standard treatment with 4-6 cycles of platinum-based chemotherapy.
I. To document and explore patterns of radiographic response and progression both inside and outside the treated radiotherapy field.
II. To bank and store formalin-fixed, paraffin-embedded diagnostic tumor biopsy specimens for future potential predictive and/or prognostic biomarkers.
III. To bank and store peripheral blood specimens for future rigorous evaluation of future potential predictive and/or prognostic biomarkers.
Patients undergo thoracic radiation therapy daily in 10 daily fractions for 2 weeks, 3-8 weeks after completing systemic chemotherapy. Beginning 14-21 days after thoracic radiation therapy, patients receive nivolumab intravenously (IV) over 30 minutes and ipilimumab IV over 90 minutes on days 1 and 22. Treatment repeats every 42 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 30 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 5 weeks, 12 weeks after first follow up, and then every 3 months thereafter.
Trial Phase Phase I/II
Trial Type Treatment
Moffitt Cancer Center
Bradford Alan Perez
- Primary ID MCC-18914
- Secondary IDs NCI-2017-00285
- Clinicaltrials.gov ID NCT03043599