Carcinoma, Non-Small-Cell Lung
Conditions
Keywords
Lung, Unresectable NSCLC, Radiation
Brief summary
This study is to determine if Stage III NSCLC patients treated with ipilimumab with thoracic radiation therapy followed by nivolumab monotherapy every 4 weeks for up to 12 months show an improved 12-month Progression Free Survival (PFS) rate compared with a 12-month historical PFS rate of 49% among patients treated in a similar fashion with concurrent chemoradiotherapy.
Interventions
RADIATIONThoracic Radiotherapy
2 Gy in 30 fractions directed at all sites of suspected disease
Platinum based chemotherapy including cisplatin and etoposide, carboplatin and paclitaxel or cisplatin and pemetrexed (for patients with non-squamous histology).
DRUGipilimumab
ipilimumab 1mg/kg delivered concurrently with initiation of chemoradiotherapy and in week 4 of chemoradiotherapy
DRUGNivolumab
Nivolumab 480 mg (30 minute IV infusion) at least 7 days but no more than 21 days after completion of radiation and chemotherapy every 4 weeks for up to 12 cycles.
Sponsors
H. Lee Moffitt Cancer Center and Research Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Over 18 years of age * Participants must have signed and dated a written informed consent form. * Participants must be willing and able to comply with proposed visit and treatment schedule. * Patients with NSCLC documented by histology or cytology from brushing, washing, or needle aspiration of a defined lesion, but not from sputum cytology alone. * Patients must have presented at initial diagnosis with Stage III disease according to American Joint Committee on Cancer (AJCC) Staging Manual, 8th Edition; * Patients must be deemed by the treating investigator to be surgically unresectable. I * Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1 * Patients must initiate study treatment 60 days from the date of pathologic diagnosis. * Tumor biopsy specimen including at least formalin-fixed, paraffin-embedded (FFPE) tumor tissue block or 10 unstained slides of tumor sample (archival or recent) for biomarker evaluation must be available for submission to the central lab for correlative studies. * Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 14 days prior to the start of thoracic radiation therapy. * 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). * 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. Azoospermic males are exempt from contraceptive requirements. * 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. * WOCBP who are continuously not heterosexually active are exempt from contraception requirements. However, they must still undergo pregnancy testing as described in this section. * 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
Exclusion criteria
* 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). Exceptions may apply. * 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 * 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 some in situ cancers) 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. * Inadequate hepatic function. * Inadequate pancreatic function. * History of allergy or hypersensitivity to any of the study drugs or study drug components
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Unacceptable Toxicity Status at the End of 8-week Safety Observation Period | At 8 weeks of treatment | Unacceptable toxicity defined as: * Any grade 4 immune related adverse event (irAE) * Any grade 3 irAE, excluding pneumonitis, that does not downgrade to grade 2 within 7 days after onset of the event despite optimal medical management including systemic corticosteroids or does not downgrade to ≤ grade 1 or baseline within 14 days * Liver transaminase elevation \> 8 × ULN or total bilirubin \> 5 × ULN, * Any ≥ grade 3 non-irAE, with some exclusions. Result is provided as number of participants with unacceptable toxicity within 8 weeks of commencing study therapy. |
| Percentage of Participants Without Disease Progression at 12 Months | 12 months post treatment | Disease Progression defined as the duration from date of registration to date of first documentation of progression as defined using Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 and assessed by local investigator or symptomatic deterioration (as defined in Outcome 1) or death due to any cause. Patients last known to be alive without report of progression are censored at date of last disease assessment. For patients with a missing scan (or consecutive missing scans) whose subsequent scan determines progression, the expected date of the first missing scan (as defined by the disease assessment schedule) will be used as the date of progression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Experienced 12 Month Distant Metastasis Free Survival (DMFS) | 12 months post treatment | DMFS is defined as the duration from date of registration to date of first documentation of distant metastatic progression beyond the primary tumor site as well as regional lymph nodes assessed by local investigator or symptomatic deterioration (as defined in Outcome 1) or death due to any cause. Patients last known to be alive without report of distant metastatic progression are censored at date of last disease assessment. |
| Objective Response Rate (ORR) at 6 Months | 6 months | ORR is defined as the proportion of all treated subjects whose best overall response is either a complete response or partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Best Objective Response (BOR) will also be reported Complete Response (CR) or Partial Response (PR) determinations included in the assessment must be confirmed by a consecutive second (confirmatory) evaluation meeting the criteria for response that is performed at least 4 weeks after the criteria for response are first met. When Stable Disease (SD) is believed to be the best response, it must meet a minimum SD duration of 49 days. Measurements must have met the SD criteria at least once after study entry. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Radiation and Chemotherapy, Followed by Nivolumab Thoracic Radiotherapy with cytotoxic platinum based chemotherapy with cytotoxic platinum based chemotherapy including cisplatin and etoposide, carboplatin and paclitaxel or cisplatin and pemetrexed (for patients with non-squamous histology) and Ipilimumab.
Thoracic Radiotherapy: 2 Gy in 30 fractions directed at all sites of suspected disease
Platinum Based Chemotherapy: Platinum based chemotherapy including cisplatin and etoposide, carboplatin and paclitaxel or cisplatin and pemetrexed (for patients with non-squamous histology).
Ipilimumab: ipilimumab 1mg/kg delivered concurrently with initiation of chemoradiotherapy and in week 4 of chemoradiotherapy
Nivolumab 480 mg (30 minute IV infusion) after completion of radiation and chemotherapy for up to 12 cycles until progression.
Nivolumab: Nivolumab 480 mg (30 minute IV infusion) at least 7 days but no more than 21 days after completion of radiation and chemotherapy every 4 weeks for up to 12 cycles. | 19 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Radiation and Chemotherapy, Followed by Nivolumab |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 10 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 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 | 17 Participants |
| Region of Enrollment United States | 19 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 9 / 19 |
| other Total, other adverse events | 19 / 19 |
| serious Total, serious adverse events | 13 / 19 |
Outcome results
Primary
Percentage of Participants Without Disease Progression at 12 Months
Disease Progression defined as the duration from date of registration to date of first documentation of progression as defined using Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 and assessed by local investigator or symptomatic deterioration (as defined in Outcome 1) or death due to any cause. Patients last known to be alive without report of progression are censored at date of last disease assessment. For patients with a missing scan (or consecutive missing scans) whose subsequent scan determines progression, the expected date of the first missing scan (as defined by the disease assessment schedule) will be used as the date of progression.
Time frame: 12 months post treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Radiation and Chemotherapy, Followed by Nivolumab | Percentage of Participants Without Disease Progression at 12 Months | 58 percentage of participants |
Primary
Unacceptable Toxicity Status at the End of 8-week Safety Observation Period
Unacceptable toxicity defined as: * Any grade 4 immune related adverse event (irAE) * Any grade 3 irAE, excluding pneumonitis, that does not downgrade to grade 2 within 7 days after onset of the event despite optimal medical management including systemic corticosteroids or does not downgrade to ≤ grade 1 or baseline within 14 days * Liver transaminase elevation \> 8 × ULN or total bilirubin \> 5 × ULN, * Any ≥ grade 3 non-irAE, with some exclusions. Result is provided as number of participants with unacceptable toxicity within 8 weeks of commencing study therapy.
Time frame: At 8 weeks of treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Radiation and Chemotherapy, Followed by Nivolumab | Unacceptable Toxicity Status at the End of 8-week Safety Observation Period | 6 Participants |
Secondary
Objective Response Rate (ORR) at 6 Months
ORR is defined as the proportion of all treated subjects whose best overall response is either a complete response or partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Best Objective Response (BOR) will also be reported Complete Response (CR) or Partial Response (PR) determinations included in the assessment must be confirmed by a consecutive second (confirmatory) evaluation meeting the criteria for response that is performed at least 4 weeks after the criteria for response are first met. When Stable Disease (SD) is believed to be the best response, it must meet a minimum SD duration of 49 days. Measurements must have met the SD criteria at least once after study entry.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Radiation and Chemotherapy, Followed by Nivolumab | Objective Response Rate (ORR) at 6 Months | 66 percentage of participants |
Secondary
Percentage of Participants Who Experienced 12 Month Distant Metastasis Free Survival (DMFS)
DMFS is defined as the duration from date of registration to date of first documentation of distant metastatic progression beyond the primary tumor site as well as regional lymph nodes assessed by local investigator or symptomatic deterioration (as defined in Outcome 1) or death due to any cause. Patients last known to be alive without report of distant metastatic progression are censored at date of last disease assessment.
Time frame: 12 months post treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Radiation and Chemotherapy, Followed by Nivolumab | Percentage of Participants Who Experienced 12 Month Distant Metastasis Free Survival (DMFS) | 63.2 percentage of participants |