Carcinoma, Non-Small-Cell Lung
Conditions
Keywords
Lung neoplasms, Bronchial Neoplasms, Carcinoma, bronchogenic, Neoplasms, Neoplasms by site, Respiratory Tract Diseases, Respiratory Tract Neoplasms, Thoracic Neoplasms
Brief summary
The purpose of this study is to find out the effectiveness of the drug durvalumab (MEDI4736) with or without stereotactic body radiation therapy (SBRT) as treatment for stage I (tumors \> 2cm), II, and IIIA non-small cell lung cancer (NSCLC) prior to surgery and one year following surgery.
Detailed description
This is a randomized open label phase II trial of preoperative anti-PD-L1 antibody durvalumab with or without concurrent non-ablative radiation followed by surgical resection and postoperative monthly maintenance durvalumab for twelve months, following standard of care postoperative therapy.
Interventions
DRUGDurvalumab
Intravenously
OTHERDurvalumab plus SBRT
Intravenously plus radiotherapy
Sponsors
AstraZeneca
Weill Medical College of Cornell 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
1. Patient has histologically or cytologically proven clinical stages I (tumors \> 2 cm), II, and IIIA NSCLC and is considered eligible for surgical resection with curative intent. Patients with 2 primary non-small cell lung cancers are allowed. 2. Measureable disease, as defined by RECIST v1.1. 3. Written informed consent and HIPAA obtained from the subject prior to performing any protocol-related procedures. 4. Age \> 18 years at time of study entry 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 6. Adequate normal organ and marrow function as defined below: * Haemoglobin ≥ 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. * AST (SGOT)/ALT (SGPT), and alkaline phosphatase ≤ 2.5 x institutional upper limit of normal (ULN). * Serum creatinine CL\>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance: 7. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: Women \<50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy). Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic exogenous hormonal treatments, had radiation-induced menopause with last menses \>1 year ago, had chemotherapy-induced menopause with last menses \>1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). 8. 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. 9. No prior therapy for their lung cancer.
Exclusion criteria
Subjects should not enter the study if any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Major Pathological Response (MPR) | Durvalumab start date to surgical resection, up to 10 weeks | MPR is defined as ≤10% residual viable tumor in the resected specimen. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Kaplan-Meier Disease-Free Survival Proportion at 2 Years | From date of Durvalumab start date until the date of first documented progression or date of death from any cause, whichever came first, assessed every 6 months for 2 years. | Disease recurrence or death from any cause assessed using history, physical examination and CT scanning, histologically or cytologically confirmed whenever possible. |
| Objective Clinical Response Rate | Treatment day 1 up to weeks 6-7 | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by PET/CT scan: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of diameters of target lesions; Progressive Disease (PD), \>=20% increase in the sum of diameters of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v. 4.0 | Up to 72 weeks | Adverse events ≥G3 in both arms with and without possible or probable attribution to study drug and graded according to CTCAE v. 4.0 |
Countries
United States
Participant flow
Pre-assignment details
Of 64 enrolled participants, 60 met inclusion criteria and were randomized to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1 (Durvalumab Monotherapy) Durvalumab (MEDI4736) via IV infusion administered pre-operatively every 3 weeks for 2 cycles followed by surgical resection. Durvalumab monotherapy will be given for 12 months post-operatively.
Durvalumab: Intravenously | 30 |
| Arm 2 (Durvalumab Plus SBRT) Durvalumab (MEDI4736) via IV infusion administered pre-operatively every 3 weeks for 2 cycles plus radiotherapy delivered in 3 daily fractions starting concurrently with the first cycle of durvalumab (MEDI4736) followed by surgical resection. Durvalumab monotherapy will be given for 12 months post-operatively.
Durvalumab: Intravenously
Durvalumab plus SBRT: Intravenously | 30 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Adjuvant Durvalumab | Adverse Event | 2 | 6 |
| Adjuvant Durvalumab | Death | 0 | 1 |
| Adjuvant Durvalumab | Participant wishes | 12 | 7 |
| Adjuvant Durvalumab | Physician Decision | 2 | 1 |
| Adjuvant Durvalumab | Prostate cancer | 1 | 0 |
| Adjuvant Durvalumab | Recurrence | 2 | 0 |
| Adjuvant Durvalumab | Slow recovery after chemotherapy | 1 | 0 |
| Neoadjuvant (Preoperative) to Surgery | Death | 1 | 1 |
| Neoadjuvant (Preoperative) to Surgery | Disease progression | 2 | 3 |
| Neoadjuvant (Preoperative) to Surgery | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Arm 1 (Durvalumab Monotherapy) | Total | Arm 2 (Durvalumab Plus SBRT) |
|---|---|---|---|
| Age, Continuous | 70.5 years STANDARD_DEVIATION 7.5 | 70.2 years STANDARD_DEVIATION 8.5 | 69.6 years STANDARD_DEVIATION 9.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 6 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 30 Participants | 54 Participants | 24 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 | 2 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 7 Participants | 4 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 25 Participants | 48 Participants | 23 Participants |
| Region of Enrollment United States | 30 participants | 60 participants | 30 participants |
| Sex: Female, Male Female | 14 Participants | 29 Participants | 15 Participants |
| Sex: Female, Male Male | 16 Participants | 31 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 9 / 30 | 10 / 30 |
| other Total, other adverse events | 29 / 30 | 30 / 30 |
| serious Total, serious adverse events | 12 / 30 | 15 / 30 |
Outcome results
Primary
Number of Subjects With Major Pathological Response (MPR)
MPR is defined as ≤10% residual viable tumor in the resected specimen.
Time frame: Durvalumab start date to surgical resection, up to 10 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 (Durvalumab Monotherapy) | Number of Subjects With Major Pathological Response (MPR) | 2 Participants |
| Arm 2 (Durvalumab Plus SBRT) | Number of Subjects With Major Pathological Response (MPR) | 16 Participants |
Comparison: Fisher's exact test performed to compare the MPR proportion between the two treatment arms. Null hypothesis is that there is no difference in the MPR proportion between the two arms.p-value: 0.000195% CI: [26.7, 66.6]Fisher Exact
Secondary
Kaplan-Meier Disease-Free Survival Proportion at 2 Years
Disease recurrence or death from any cause assessed using history, physical examination and CT scanning, histologically or cytologically confirmed whenever possible.
Time frame: From date of Durvalumab start date until the date of first documented progression or date of death from any cause, whichever came first, assessed every 6 months for 2 years.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 (Durvalumab Monotherapy) | Kaplan-Meier Disease-Free Survival Proportion at 2 Years | 0.67 Proportion of subjects |
| Arm 2 (Durvalumab Plus SBRT) | Kaplan-Meier Disease-Free Survival Proportion at 2 Years | 0.80 Proportion of subjects |
Comparison: Kaplan-Meier survival analysis comparing the two arms.p-value: 0.89Log Rank
Secondary
Objective Clinical Response Rate
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by PET/CT scan: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of diameters of target lesions; Progressive Disease (PD), \>=20% increase in the sum of diameters of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
Time frame: Treatment day 1 up to weeks 6-7
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm 1 (Durvalumab Monotherapy) | Objective Clinical Response Rate | Pseudoprogression | 2 Participants |
| Arm 1 (Durvalumab Monotherapy) | Objective Clinical Response Rate | Complete Response | 0 Participants |
| Arm 1 (Durvalumab Monotherapy) | Objective Clinical Response Rate | Partial Response | 1 Participants |
| Arm 1 (Durvalumab Monotherapy) | Objective Clinical Response Rate | Stable Disease | 24 Participants |
| Arm 1 (Durvalumab Monotherapy) | Objective Clinical Response Rate | Progressive Disease | 3 Participants |
| Arm 2 (Durvalumab Plus SBRT) | Objective Clinical Response Rate | Progressive Disease | 1 Participants |
| Arm 2 (Durvalumab Plus SBRT) | Objective Clinical Response Rate | Partial Response | 14 Participants |
| Arm 2 (Durvalumab Plus SBRT) | Objective Clinical Response Rate | Complete Response | 0 Participants |
| Arm 2 (Durvalumab Plus SBRT) | Objective Clinical Response Rate | Stable Disease | 15 Participants |
| Arm 2 (Durvalumab Plus SBRT) | Objective Clinical Response Rate | Pseudoprogression | 0 Participants |
Comparison: Fisher's exact test performed to compare the objective clinical response proportion between the two treatment arms. Null hypothesis is that there is no difference in the objective clinical response proportion between the two arms. Objective clinical response proportion is defined as the proportion of patients in each arm who have complete response or partial response.p-value: 0.000195% CI: [24.4, 62.3]Fisher Exact
Other Pre-specified
Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v. 4.0
Adverse events ≥G3 in both arms with and without possible or probable attribution to study drug and graded according to CTCAE v. 4.0
Time frame: Up to 72 weeks
Population: All randomized patients
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 (Durvalumab Monotherapy) | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v. 4.0 | 12 Participants |
| Arm 2 (Durvalumab Plus SBRT) | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v. 4.0 | 15 Participants |