Small Cell Lung Cancer, Extensive-stage Small Cell Lung Cancer
Conditions
Keywords
Thoracic, Radiotherapy, Platinum Based Chemotherapy, Immunotherapy, Ipilimumab, Nivolumab, Extensive-Stage Disease Small Cell Lung Cancer (ED-SCLC)
Brief summary
The purpose of the safety run in Phase I portion of this study is to confirm the recommended Phase II dose of ipilimumab and nivolumab among participants 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. The purpose of the Phase II portion of this study is to estimate the 6-month Progression Free Survival (PFS) rate among participants 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.
Detailed description
This study is a nonrandomized, phase II, single arm, multicenter trial evaluating safety and efficacy of thoracic radiation therapy followed by nivolumab and ipilimumab in participants with Extensive-Stage Disease Small Cell Lung Cancer (ED-SCLC) who have completed a first-line platinum-based chemotherapy regimen and achieved ongoing complete response (CR), partial response (PR), or stable disease (SD). This study will determine whether nivolumab and ipilimumab delivered 2 weeks following consolidative thoracic radiation therapy demonstrates acceptable toxicity and whether the treatment regimen will improve 6-month progression-free survival (PFS) compared with a similar historical control cohort in this participant population. Additional objectives include further characterization of overall survival, adverse event profile, patterns of failure analysis, and potential predictive biomarkers of response to nivolumab in combination with ipilimumab and thoracic radiation therapy in patients with ED-SCLC.
Interventions
RADIATIONThoracic Radiation Therapy
All participants will receive radiation therapy (3Gy x 10 fractions) to the chest for 10 days (Monday through Friday for 2 weeks).
DRUGIpilimumab
Ipilimumab 3 mg/kg (90 minute IV infusion) will be administered every 3 weeks for 4 doses.
DRUGNivolumab
Nivolumab 1 mg/kg (30 minute IV infusion) will be administered every 3 weeks for 4 doses, followed by nivolumab 480 mg every 4 weeks.
Sponsors
Bristol-Myers Squibb
H. Lee Moffitt Cancer Center and Research Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed Written Informed Consent * 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 * Have presented at initial diagnosis with extensive-stage disease * Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1 * Have received 4-6 cycles of platinum-based first-line chemotherapy and have an ongoing response of complete response (CR), partial response (PR), or stable disease (SD) after completion of chemotherapy. Acceptable combinations, as recommended per National Comprehensive Cancer Network (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 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 less than or equal to 8 weeks (56 days) from the last dose of platinum-based first line chemotherapy. * 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. * Participant 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. * Men and women at least 18 years of age * Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test 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. * Additional criteria may apply
Exclusion criteria
* 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 MRI or CT brain with contrast is required after treatment of brain metastases before initiation of thoracic radiation therapy. In addition, participants 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 which at the discretion of the treating radiation oncologist precludes delivery of protocol radiation therapy * 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 (NCI 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 randomization. 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) * Inadequate hematologic function according to study guidelines * Inadequate hepatic function according to study guidelines * History of allergy or hypersensitivity to any of the study drugs or study drug components * Additional criteria may apply
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I: Confirmation of Recommended Phase II Dose | 13 weeks | Recommended Phase II dose of ipilimumab and nivolumab among participants 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. Investigators will initially enroll 6 patients and wait until completion of the 13-week safety observation period following initiation of ipilimumab + nivolumab combination treatment. |
| Phase II: Progression Free Survival (PFS) | 6 months | PFS is defined as the duration from date of registration to date of first documentation of progression assessed by local investigator or symptomatic deterioration (as defined above) or death due to any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | 1 year | OS is defined as the duration from date of registration to date of death due to any cause. Participants last known to be alive are censored at date of last contact. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Combination Therapy Consolidative Ipilimumab and Nivolumab with Thoracic Radiotherapy after Platinum Based Chemotherapy. Radiotherapy, followed by a 14 to 21 day break between radiotherapy and the beginning of study drug treatment.
Thoracic Radiation Therapy: All participants will receive radiation therapy (3Gy x 10 fractions) to the chest for 10 days (Monday through Friday for 2 weeks).
Ipilimumab: Ipilimumab 3 mg/kg (90 minute IV infusion) will be administered every 3 weeks for 4 doses.
Nivolumab: Nivolumab 1 mg/kg (30 minute IV infusion) will be administered every 3 weeks for 4 doses, followed by nivolumab 480 mg every 4 weeks. | 21 |
| Total | 21 |
Baseline characteristics
| Characteristic | Combination Therapy |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 11 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants |
| Age, Continuous | 66 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 19 Participants |
| Region of Enrollment United States | 21 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 6 / 21 |
| other Total, other adverse events | 21 / 21 |
| serious Total, serious adverse events | 13 / 21 |
Outcome results
Primary
Phase I: Confirmation of Recommended Phase II Dose
Recommended Phase II dose of ipilimumab and nivolumab among participants 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. Investigators will initially enroll 6 patients and wait until completion of the 13-week safety observation period following initiation of ipilimumab + nivolumab combination treatment.
Time frame: 13 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Combination Therapy | Phase I: Confirmation of Recommended Phase II Dose | Ipilimumab | 3 mg/kg dose |
| Combination Therapy | Phase I: Confirmation of Recommended Phase II Dose | Nivoumab | 1 mg/kg dose |
Primary
Phase II: Progression Free Survival (PFS)
PFS is defined as the duration from date of registration to date of first documentation of progression assessed by local investigator or symptomatic deterioration (as defined above) or death due to any cause.
Time frame: 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Therapy | Phase II: Progression Free Survival (PFS) | 4.5 months |
Secondary
Overall Survival (OS)
OS is defined as the duration from date of registration to date of death due to any cause. Participants last known to be alive are censored at date of last contact.
Time frame: 1 year
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Therapy | Overall Survival (OS) | 11.7 months |