Non-Small Cell Lung Cancer
Conditions
Brief summary
This is a pilot study of neoadjuvant 'immunoradiation' (durvalumab or durvalumab plus tremelimumab) administered every 4 weeks for 2 doses, concurrently with standard thoracic radiation (RT) (45Gy in 25 fractions), with one dose of immunotherapy alone delivered in the pre-surgical window, prior to surgical resection, for patients with stage IIIA NSCLC that is deemed resectable with a lobectomy by a thoracic surgeon. If preliminary safety of the durvalumab/thoracic RT combination is established, a second cohort investigating the combination of durvalumab/tremelimumab/thoracic RT prior to surgical resection will be opened. After surgical resection, patients may receive standard adjuvant chemotherapy, as deemed appropriate by the treating investigator.
Interventions
DRUGDurvalumab
1500mg via IV infusion every 4 weeks for up to 3 doses/cycles
DRUGTremelimumab
75mg via IV infusion every 4 weeks
RADIATIONThoracic Radiation
5 days per week in once daily fractionation, 1.8-2.0 Gy per fraction
PROCEDURElobectomy
patients may proceed to surgery post drug and radiation intervention for lung lobectomy
DRUGStandard of care adjuvant chemotherapy
patients may or may not proceed to adjuvant chemotherapy post trial drug and radiation intervention and surgery
Sponsors
AstraZeneca
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent and any locally-required authorization obtained. * Histologically-confirmed diagnosis of stage III non-small cell lung cancer (NSCLC) * Age≥18 years * Life expectancy \>6 months * Body weight \>30kg * Subjects with non-small cell lung cancer deemed surgically resectable by an attending thoracic surgeon with lobectomy * ECOG Performance Status 0-1 * Normal bone marrow and organ function on routine laboratory tests, as defined in section 4.1 * Evidence of post-menopausal status or negative urinary/serum pregnancy test for female pre-menopausal subjects. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. * Ability to understand and willingness of sign consent form * Willingness to comply with the protocol for the duration of the study
Exclusion criteria
* Involvement in the planning and/or conduct of the study (includes AstraZeneca staff and staff at the study site) * Prior investigational therapy within 28 days/at least 5 half-lives before study drug administration * Prior chest radiation * Prior history of interstitial lung disease or pneumonitis requiring corticosteroids, or active non-infectious pneumonitis * Patients only suitable for surgical management with pneumonectomy, deemed by an attending thoracic surgeon * Prior therapy with PD-1, PD-L1, CTLA-4 or anti-cancer vaccines, including durvalumab and tremelimumab * Participation in another clinical study with an investigational product in the last 4 weeks or equivalent of 5 half-lives of the first dose of study treatment, whichever is shorter * History of another primary malignancy that requires active ongoing treatment or, in the opinion of the investigator, is likely to require treatment within 6 months of trial enrollment * Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. The following are exceptions to this criterion: * Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection) * Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent * Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) * Any unresolved toxicity (\>CTCAE grade 2) from previous anti-cancer therapy * Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, peripherally neuropathy) * Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable * Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug. * Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable * History of allogenic organ transplantation. * Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc\]). The following are exceptions to this criterion (vitiligo or alopecia; hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement; any chronic skin condition that does not require systemic therapy; active disease in the last 5 years may be included but only after consultation with the study physician; celiac disease controlled by diet alone.) * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent * Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Subjects with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of HBsAg) are eligible. Subjects positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. * Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab or tremelimumab * Female subjects who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control. * Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study result. * Known allergy or hypersensitivity to IP or any excipient * Uncontrolled psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written consent * Any condition that, in the opinion of the investigator would interfere with evaluation of study treatment or interpretation of patient safety or study results.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Toxicities as Measured by Number of Participants Experiencing Adverse Events | 3 months post surgery | Number of participants experiencing adverse events as defined by CTCAE v4.0. |
| Feasibility of Preoperative Immunoradiation | Up to 3 years | Number of participants with stage III resectable NSCLC who received durvalumab or durvalumab plus tremelimumab concurrently with thoracic radiation (RT) in the pre-surgical window prior to surgical resection, for whom planned surgical resection was not delayed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Surgical Morbidity and Mortality | Up to 3 months post-surgery | Number of participants who experience post-operative death. Calculated through log-rank test and Cox proportional hazards (PH) model. The values in the table represent the number of participants who experienced post-operative death. |
| Duration of Response as Measured by Recurrence-free Survival | Up to 3 years | Time from first evidence of response until recurrence when treated with preoperative immunoradiation followed by surgery. Calculated through log-rank test and Cox proportional hazards (PH) model. |
| Percentage of Participants With Radiologic Response | Up to 3 years | Percentage of participants with complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD) as defined by RECIST 1.1 and immune-related RECIST criteria when treated with preoperative immunoradiation followed by surgery. CR = disappearance of all target lesions, PR is =\>30% decrease in sum of diameters of target lesions, PD is \>20% increase in sum of diameters of target lesions, SD is \<30% decrease or \<20% increase in sum of diameters of target lesions. |
| Percentage of Participants With Pathologic Response | Up to 3 years | Percentage of participants with major pathologic response (MPR), partial response (PR) or no response (NR), where MPR is \>90% reduction in tumor cells, PR = 10-90% or NR = 0-10%. The percentage of patients whose tumor samples achieve MPR, PR and NR will be tabulated. |
| Overall Survival | Up to 3 years | Number of months alive after treatment with preoperative immunoradiation followed by surgery. Calculated through log-rank test and Cox proportional hazards (PH) model. |
Countries
Canada, United States
Participant flow
Pre-assignment details
The study was terminated due to low accrual on Arm A (Durvalumab with Radiation) so no participants were assigned to Arm B (Durvalumab and Trememlimumab with Radiation).
Participants by arm
| Arm | Count |
|---|---|
| Durvalumab With Radiation Drug: Durvalumab Other Names: MEDI4736
MEDI4736 1500mg via IV infusion every 4 weeks for up to 3 doses/cycles Intervention: Radiation: Thoracic Radiation 5 days per week in once daily fractionation, 1.8-2.0 Gy per fraction
Intervention: Procedure/Surgery: lobectomy patients may proceed to surgery post drug and radiation intervention for lung lobectomy
Intervention: Drug: Standard of care adjuvant chemotherapy patients may or may not proceed to adjuvant chemotherapy post trial drug and radiation intervention and surgery
Durvalumab: 1500mg via IV infusion every 4 weeks for up to 3 doses/cycles
Thoracic Radiation: 5 days per week in once daily fractionation, 1.8-2.0 Gy per fraction
lobectomy: patients may proceed to surgery post drug and radiation intervention for lung lobectomy
Standard of care adjuvant chemotherapy: patients may or may not proceed to adjuvant chemotherapy post trial drug and radiation intervention and surgery | 9 |
| Durvalumab and Trememlimumab With Radiation Drugs: Durvalumab + Tremelimumab Other Names: MEDI4736 and CP-675 MEDI4736 1500mg via IV infusion every 4 weeks for up to 3 doses/cycles + CP-675 206 75mg via IV infusion every 4 weeks up 3 doses/cycles Intervention: Radiation: Thoracic Radiation 5 days per week in once daily fractionation, 1.8-2.0 Gy per fraction Intervention: Procedure/Surgery: lobectomy patients may proceed to surgery post drug and radiation intervention for lung lobectomy
Intervention: Drug: Standard of care adjuvant chemotherapy patients may or may not proceed to adjuvant chemotherapy post trial drug and radiation intervention and surgery
Durvalumab: 1500mg via IV infusion every 4 weeks for up to 3 doses/cycles
Tremelimumab: 75mg via IV infusion every 4 weeks
Thoracic Radiation: 5 days per week in once daily fractionation, 1.8-2.0 Gy per fraction
lobectomy: patients may proceed to surgery post drug and radiation intervention for lung lobectomy
Standard of care adjuvant chemotherapy: patients may or may not proceed to adjuvant chemotherapy post trial drug and radiation intervention and surgery | 0 |
| Total | 9 |
Baseline characteristics
| Characteristic | Total | Durvalumab With Radiation |
|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 6 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 3 Participants |
| Age, Continuous | 66 years | 66 years |
| Race/Ethnicity, Customized Race/Ethnicity Asian Non-Hispanic | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Black/African-American Non-Hispanic | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Race/Ethnicity Unknown | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Race/Ethnicity White Ethnicity Unknown | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race/Ethnicity White Non-Hispanic | 4 Participants | 4 Participants |
| Region of Enrollment Canada | 3 Participants | 3 Participants |
| Region of Enrollment United States | 6 Participants | 6 Participants |
| Sex: Female, Male Female | 5 Participants | 5 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 0 |
| other Total, other adverse events | 9 / 9 | 0 / 0 |
| serious Total, serious adverse events | 3 / 9 | 0 / 0 |
Outcome results
Primary
Feasibility of Preoperative Immunoradiation
Number of participants with stage III resectable NSCLC who received durvalumab or durvalumab plus tremelimumab concurrently with thoracic radiation (RT) in the pre-surgical window prior to surgical resection, for whom planned surgical resection was not delayed.
Time frame: Up to 3 years
Population: The study closed early due to low accrual on Arm A Durvalumab with Radiation so no data was collected for Arm B Durvalumab and Trememlimumab with Radiation.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Durvalumab With Radiation | Feasibility of Preoperative Immunoradiation | 9 Participants |
| Durvalumab and Trememlimumab With Radiation | Feasibility of Preoperative Immunoradiation | 0 Participants |
Primary
Toxicities as Measured by Number of Participants Experiencing Adverse Events
Number of participants experiencing adverse events as defined by CTCAE v4.0.
Time frame: 3 months post surgery
Population: all participants who were assigned to the durvalumab with radiation arm
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Durvalumab With Radiation | Toxicities as Measured by Number of Participants Experiencing Adverse Events | 9 Participants |
| Durvalumab and Trememlimumab With Radiation | Toxicities as Measured by Number of Participants Experiencing Adverse Events | 0 Participants |
Secondary
Duration of Response as Measured by Recurrence-free Survival
Time from first evidence of response until recurrence when treated with preoperative immunoradiation followed by surgery. Calculated through log-rank test and Cox proportional hazards (PH) model.
Time frame: Up to 3 years
Secondary
Overall Survival
Number of months alive after treatment with preoperative immunoradiation followed by surgery. Calculated through log-rank test and Cox proportional hazards (PH) model.
Time frame: Up to 3 years
Secondary
Percentage of Participants With Pathologic Response
Percentage of participants with major pathologic response (MPR), partial response (PR) or no response (NR), where MPR is \>90% reduction in tumor cells, PR = 10-90% or NR = 0-10%. The percentage of patients whose tumor samples achieve MPR, PR and NR will be tabulated.
Time frame: Up to 3 years
Population: The study closed to enrollment before patients could be enrolled onto Arm B: durvalumab and trememlimumab with radiation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Durvalumab With Radiation | Percentage of Participants With Pathologic Response | 9 Participants |
| Durvalumab and Trememlimumab With Radiation | Percentage of Participants With Pathologic Response | 0 Participants |
Secondary
Percentage of Participants With Radiologic Response
Percentage of participants with complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD) as defined by RECIST 1.1 and immune-related RECIST criteria when treated with preoperative immunoradiation followed by surgery. CR = disappearance of all target lesions, PR is =\>30% decrease in sum of diameters of target lesions, PD is \>20% increase in sum of diameters of target lesions, SD is \<30% decrease or \<20% increase in sum of diameters of target lesions.
Time frame: Up to 3 years
Population: The study closed to enrollment before patients could be enrolled onto Arm B: durvalumab and trememlimumab with radiation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Durvalumab With Radiation | Percentage of Participants With Radiologic Response | 7 Participants |
| Durvalumab and Trememlimumab With Radiation | Percentage of Participants With Radiologic Response | 0 Participants |
Secondary
Surgical Morbidity and Mortality
Number of participants who experience post-operative death. Calculated through log-rank test and Cox proportional hazards (PH) model. The values in the table represent the number of participants who experienced post-operative death.
Time frame: Up to 3 months post-surgery
Population: The study closed to enrollment before patients could be enrolled onto Arm B: durvalumab and trememlimumab with radiation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Durvalumab With Radiation | Surgical Morbidity and Mortality | 0 Participants |
| Durvalumab and Trememlimumab With Radiation | Surgical Morbidity and Mortality | 0 Participants |