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Neoadjuvant Immunoradiation for Resectable Non-Small Cell Lung Cancer

Primary Purpose

Non-Small Cell Lung Cancer

Status
Active
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Durvalumab
Tremelimumab
Thoracic Radiation
lobectomy
Standard of care adjuvant chemotherapy
Sponsored by
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Non-Small Cell Lung Cancer

Eligibility Criteria

18 Years - 100 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Johns Hopkins Bayview Medical Center
  • Princess Margaret Cancer Centre

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Durvalumab with Radiation

Durvalumab and Trememlimumab with Radiation

Arm Description

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

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

Outcomes

Primary Outcome Measures

Toxicities as Measured by Number of Participants Experiencing Adverse Events
Number of participants experiencing adverse events as defined by CTCAE v4.0.
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.

Secondary Outcome Measures

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.
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.
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.
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.
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.

Full Information

First Posted
July 19, 2017
Last Updated
October 12, 2023
Sponsor
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators
AstraZeneca
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1. Study Identification

Unique Protocol Identification Number
NCT03237377
Brief Title
Neoadjuvant Immunoradiation for Resectable Non-Small Cell Lung Cancer
Official Title
Neoadjuvant Immunoradiation for Stage III Resectable Non-Small Cell Lung Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
December 12, 2017 (Actual)
Primary Completion Date
November 4, 2021 (Actual)
Study Completion Date
May 28, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators
AstraZeneca

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Non-Small Cell Lung Cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
9 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Durvalumab with Radiation
Arm Type
Experimental
Arm Description
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
Arm Title
Durvalumab and Trememlimumab with Radiation
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Durvalumab
Other Intervention Name(s)
[MEDI4736]
Intervention Description
1500mg via IV infusion every 4 weeks for up to 3 doses/cycles
Intervention Type
Drug
Intervention Name(s)
Tremelimumab
Other Intervention Name(s)
[CP-675 206]
Intervention Description
75mg via IV infusion every 4 weeks
Intervention Type
Radiation
Intervention Name(s)
Thoracic Radiation
Intervention Description
5 days per week in once daily fractionation, 1.8-2.0 Gy per fraction
Intervention Type
Procedure
Intervention Name(s)
lobectomy
Intervention Description
patients may proceed to surgery post drug and radiation intervention for lung lobectomy
Intervention Type
Drug
Intervention Name(s)
Standard of care adjuvant chemotherapy
Intervention Description
patients may or may not proceed to adjuvant chemotherapy post trial drug and radiation intervention and surgery
Primary Outcome Measure Information:
Title
Toxicities as Measured by Number of Participants Experiencing Adverse Events
Description
Number of participants experiencing adverse events as defined by CTCAE v4.0.
Time Frame
3 months post surgery
Title
Feasibility of Preoperative Immunoradiation
Description
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
Secondary Outcome Measure Information:
Title
Surgical Morbidity and Mortality
Description
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
Title
Percentage of Participants With Pathologic Response
Description
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
Title
Percentage of Participants With Radiologic Response
Description
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
Title
Duration of Response as Measured by Recurrence-free Survival
Description
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
Title
Overall Survival
Description
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
100 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Patrick Forde, MD
Organizational Affiliation
Johns Hopkins University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Johns Hopkins Bayview Medical Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21224
Country
United States
Facility Name
Princess Margaret Cancer Centre
City
Toronto
State/Province
Ontario
Country
Canada

12. IPD Sharing Statement

Learn more about this trial

Neoadjuvant Immunoradiation for Resectable Non-Small Cell Lung Cancer

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