Recurrent Small Cell Lung Carcinoma
Conditions
Brief summary
This randomized clinical trial studies how well tremelimumab and durvalumab with or without radiation therapy works in treating patients with small cell lung cancer that has returned after a period of improvement. Monoclonal antibodies, such as tremelimumab and durvalumab, may limit the ability of tumor cells to grow and spread by enhancing immune function. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving tremelimumab and durvalumab together with radiation therapy may lead to improved clinical benefit.
Detailed description
PRIMARY OBJECTIVE: I. To assess the efficacy (progression free survival \[PFS\] and objective response rate \[ORR\]) of combined immune checkpoint inhibitor therapy as treatment for relapsed small-cell lung cancer (SCLC). SECONDARY OBJECTIVES: I. To assess the impact of antigen priming using radiation therapy (XRT) on the efficacy of immune checkpoint inhibitors. II. To determine immune related objective response rate. III. To estimate overall survival measured as time from randomization to death from any cause. TERTIARY OBJECTIVES: I. To characterize tumor infiltrating lymphocytes (TILs) and programmed cell death 1 ligand 1 (PD-L1)/programmed cell death 1 (PD1) expression in paired tumor biopsies at baseline, end of cycle 2 and at the time of progression. II. To determine dynamic changes in cell free deoxyribonucleic acid (DNA) (cfDNA) and the immunophenotype of peripheral blood repertoire of circulating lymphocytes using multiparameter flow cytometry. III. To determine changes in circulating cytokine mediators of inflammation and immunity using Luminex assay. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive tremelimumab intravenously (IV) over 1 hour on day 1. Treatment repeats every 4 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients also receive durvalumab IV over 1 hour on day 1. Treatment repeats every 4 weeks for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients achieving disease control may restart treatment upon evidence of progressive disease, with or without confirmation. ARM II: Patients undergo radiation therapy daily for 5 days over 1 week or for 3 fractions every other day for 1 week and then receive the same treatment as in Arm I. After completion of study treatment, patients are followed up periodically.
Interventions
BIOLOGICALDurvalumab
Given IV
RADIATIONHypofractionated Radiation Therapy
Undergo hypofractionated radiation therapy
RADIATIONStereotactic Body Radiation Therapy
Undergo SBRT
BIOLOGICALTremelimumab
Given IV
Sponsors
AstraZeneca
Emory University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent and any locally-required authorization (e.g.,) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 * Hemoglobin ≥ 9.0 g/dL * Absolute neutrophil count (ANC) ≥ 1.5 x 10⁹/L (≥ 1500 per mm³) * Platelet count ≥ 100 x 10⁹/L (≥ 100,000 per mm³) * Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN); this will not apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤ 5 x ULN * Serum creatinine clearance (CL) \> 40 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance * Female subjects must either be of non-reproductive potential (i.e., post-menopausal by history: ≥ 60 years old and no menses for ≥ 1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy upon study entry * Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up * Patients must have baseline evaluations performed prior to the first dose of study drug and must meet all inclusion and
Exclusion criteria
* Patients must have histologically or cytologically confirmed small cell lung cancer * Patients must have measurable disease, defined as at least one lesion (excluding the lesion for XRT) that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as \> 20 mm with conventional techniques or as \> 10 mm with spiral computed tomography (CT) scan * Patient must have failed or found to be intolerant of standard frontline platinum-based regimens and must not have received \> 2 prior lines of therapy (nota bene \[NB\]: retreatment with a platinum-based doublet for sensitive relapse counts as another line therapy; however substitution of cisplatin with carboplatin or vice versa due to toxicity does not count as a separate regimen) * Negative serum pregnancy test within 48 hours before starting study treatment in women with childbearing potential * Ability to understand and the willingness to sign a written informed consent document
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | From initiation of systemic therapy to first documented disease progression, assessed through study completion, up to 2 years | Time from initiation of therapy to objective disease progress or death |
| Objective Response Rate | After every 2 cycles of treatment (1 cycle = 4 weeks), assessed through study completion, up to 2 years | Disease response to therapy measured according to RECIST 1.1 criteria |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Immune-related Objective Response Rate | Assessed after every 2 cycles (1 cycle = 4 weeks) on treatment; assessed through study completion, up to 2 years | Disease response to treatment using immune-related response rate (irRR) criteria |
| Overall Survival | From randomization until death from any cause, assessed through study completion, up to 2 years | Time interval from entering the study until death |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Proportion of Lymphocyte Subset (CD8+ICOS+) Between Baseline and On-Treament (End of Cycle 1) | Result presented for assessment at baseline and the end of cycle 1. | Change in circulating and tumor-infiltrating lymphocytes between baseline and on-treatment samples at the end of Cycle 1. The proportion was calculated as the number of specific lymphocytes subset out of the total number of lymphocytes at baseline compared to the same proportion at the end of cycle 1. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Tremelimumab, Durvalumab) Patients receive tremelimumab IV over 1 hour on day 1. Treatment repeats every 4 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients also receive durvalumab IV over 1 hour on day 1. Treatment repeats every 4 weeks for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients achieving disease control may restart treatment upon evidence of progressive disease, with or without confirmation.
Durvalumab: Given IV
Tremelimumab: Given IV | 9 |
| Arm II (RT, Tremelimumab, Durvalumab) Patients undergo stereotactic body radiation therapy (SBRT) or hypofractionated radiation therapy daily for 5 days over 1 week or for 3 fractions every other day for 1 week and then receive the same treatment as in Arm I.
Durvalumab: Given IV
Hypofractionated Radiation Therapy: Undergo hypofractionated radiation therapy
Stereotactic Body Radiation Therapy: Undergo SBRT
Tremelimumab: Given IV | 9 |
| Total | 18 |
Baseline characteristics
| Characteristic | Arm I (Tremelimumab, Durvalumab) | Arm II (RT, Tremelimumab, Durvalumab) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 5 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 4 Participants | 8 Participants |
| Age, Continuous | 70.5 years | 66.86 years | 67.76 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 9 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 8 Participants | 5 Participants | 13 Participants |
| Region of Enrollment United States | 9 participants | 9 participants | 18 participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 7 Participants |
| Sex: Female, Male Male | 6 Participants | 5 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 9 / 9 | 8 / 9 |
| other Total, other adverse events | 0 / 9 | 0 / 9 |
| serious Total, serious adverse events | 0 / 9 | 0 / 9 |
Outcome results
Primary
Objective Response Rate
Disease response to therapy measured according to RECIST 1.1 criteria
Time frame: After every 2 cycles of treatment (1 cycle = 4 weeks), assessed through study completion, up to 2 years
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Arm I (Tremelimumab, Durvalumab) | Objective Response Rate | 2.76 months | Standard Deviation 3.9 |
| Arm II (RT, Tremelimumab, Durvalumab) | Objective Response Rate | 2.76 months | Standard Deviation 3.9 |
Primary
Progression Free Survival (PFS)
Time from initiation of therapy to objective disease progress or death
Time frame: From initiation of systemic therapy to first documented disease progression, assessed through study completion, up to 2 years
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Arm I (Tremelimumab, Durvalumab) | Progression Free Survival (PFS) | 2.1 months | Standard Deviation 0 |
| Arm II (RT, Tremelimumab, Durvalumab) | Progression Free Survival (PFS) | 3.3 months | Standard Deviation 28.6 |
Secondary
Immune-related Objective Response Rate
Disease response to treatment using immune-related response rate (irRR) criteria
Time frame: Assessed after every 2 cycles (1 cycle = 4 weeks) on treatment; assessed through study completion, up to 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Tremelimumab, Durvalumab) | Immune-related Objective Response Rate | 9 Participants |
| Arm II (RT, Tremelimumab, Durvalumab) | Immune-related Objective Response Rate | 9 Participants |
Secondary
Overall Survival
Time interval from entering the study until death
Time frame: From randomization until death from any cause, assessed through study completion, up to 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Tremelimumab, Durvalumab) | Overall Survival | 2.8 months |
| Arm II (RT, Tremelimumab, Durvalumab) | Overall Survival | 5.7 months |
Other Pre-specified
Change From Baseline in the Proportion of Lymphocyte Subset (CD8+ICOS+) Between Baseline and On-Treament (End of Cycle 1)
Change in circulating and tumor-infiltrating lymphocytes between baseline and on-treatment samples at the end of Cycle 1. The proportion was calculated as the number of specific lymphocytes subset out of the total number of lymphocytes at baseline compared to the same proportion at the end of cycle 1.
Time frame: Result presented for assessment at baseline and the end of cycle 1.
Population: All patients with at least 2 paired samples collected at baseline and on-treatment at end of cycle 1
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm I (Tremelimumab, Durvalumab) | Change From Baseline in the Proportion of Lymphocyte Subset (CD8+ICOS+) Between Baseline and On-Treament (End of Cycle 1) | 1.399 proportion of CD8+ICOS+ Tcells |