Adjuvant Pembrolizumab vs Observation Following Curative Resection for Stage I Non-small Cell Lung Cancer (NSCLC) With Primary Tumors Between 1-4 cm

• ClinicalTrials.gov Identifier: NCT04317534
• Recruitment Status: Recruiting
• First Posted: March 23, 2020
• Last Update Posted: March 10, 2022
• Sponsor: Greg Durm, MD
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Greg Durm, MD, Big Ten Cancer Research Consortium

Tracking Information

• First Submitted Date: March 19, 2020
• First Posted Date: March 23, 2020
• Last Update Posted Date: March 10, 2022
• Actual Study Start Date: May 5, 2020
• Estimated Primary Completion Date: April 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 19, 2020)

Disease Free Survival (DFS) [ Time Frame: Up to 3 years from time of randomization ]

To evaluate whether the addition of adjuvant Pembrolizumab following surgical resection improves disease free survival compared with observation following surgical resection in patients with stage I non-small cell lung cancer (NSCLC) that is between 1-4 cm in size, regardless of PD-L1 TPS score. Median Disease Free Survival (DFS) will be reported.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: March 19, 2020)

• Overall Survival (OS) [ Time Frame: Up to 3 years from time of randomization ]
  To evaluate whether the addition of adjuvant Pembrolizumab following surgical resection improves overall survival compared with observation in patients with stage I non-small cell lung cancer (NSCLC) with primary tumors between 1-4 cm in size, regardless of PD-L1 TPS. Median Overall Survival will be reported
• 1 Year Disease Free Survival Rate [ Time Frame: Up to 1 year from time of randomization ]
  To evaluate the disease-free survival rate at 1 year on each arm.
• 1 Year Overall Survival Rate [ Time Frame: Up to 1 year from time of randomization ]
  To evaluate the overall survival rate at 1 year on each arm.
• 2 Year Disease Free Survival Rate [ Time Frame: Up to 2 years from time of randomization ]
  To evaluate the disease-free survival rate at 2 years on each arm.
• 2 Year Overall Survival Rate [ Time Frame: Up to 2 years from time of randomization ]
  To evaluate the overall survival rate at 2 years on each arm.
• 3 Year Disease Free Survival [ Time Frame: Up to 3 years from time of randomization ]
  To evaluate the disease-free survival rate at 3 years on each arm.
• 3 Year Overall Survival Rate [ Time Frame: Up to 3 years from time of randomization ]
  To evaluate the overall survival rate at 3 years on each arm.
• Summarize Grade 3 & 4 Adverse Events [ Time Frame: Up to 3 years from time of randomization ]
  To characterize the toxicity profile of adjuvant Pembrolizumab following surgical resection in patients with stage I non-small cell lung cancer (NSCLC) with primary tumors between 1-4 cm in size.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Adjuvant Pembrolizumab vs Observation Following Curative Resection for Stage I Non-small Cell Lung Cancer (NSCLC) With Primary Tumors Between 1-4 cm
• Official Title: A Randomized Phase II Trial of Adjuvant Pembrolizumab Versus Observation Following Curative Resection for Stage I Non-small Cell Lung Cancer (NSCLC) With Primary Tumors Between 1-4 cm: Big Ten Cancer Research Consortium BTCRC-LUN18-153

Brief Summary

A randomized trial of adjuvant Pembrolizumab following surgical resection versus observation following surgical resection in patients with stage I non-small cell lung cancer (NSCLC) with primary tumors between 1-4 cm.

Patients will be randomized (1:1) 4-12 weeks following surgery to either:

• Arm A: Pembrolizumab 400 mg every 6 weeks × 9 cycles
• Arm B: Observation

Stratification factors will include: PD-L1 TPS (<50% vs. ≥50%), and tumor size (1-2 cm vs. >2-4 cm)

Detailed Description

A randomized trial of adjuvant Pembrolizumab following surgical resection versus observation following surgical resection in patients with stage I non-small cell lung cancer (NSCLC) with primary tumors between 1-4 cm.

Patients will be randomized (1:1) 4-12 weeks following surgery to either:

• Arm A: Pembrolizumab 400 mg every 6 weeks × 9 cycles
• Arm B: Observation

Stratification factors will include: PD-L1 TPS (<50% vs. ≥50%), and tumor size (1-2 cm vs. >2-4 cm)

Primary Objective:

• To evaluate whether the addition of adjuvant Pembrolizumab following surgical resection improves disease free survival compared with observation following surgical resection in patients with stage I non-small cell lung cancer (NSCLC) with primary tumors between 1-4 cm in size, regardless of PD-L1 TPS score.

Secondary Objectives:

• To evaluate whether the addition of adjuvant Pembrolizumab following surgical resection improves overall survival compared with observation in patients with stage I non-small cell lung cancer (NSCLC) with primary tumors between 1-4 cm in size, regardless of PD-L1 TPS.
• To evaluate the disease-free survival and overall survival rates at 1 year, 2 years, and 3 years on each arm.
• To characterize the toxicity profile of adjuvant Pembrolizumab following surgical resection in patients with stage I non-small cell lung cancer (NSCLC) with primary tumors between 1-4 cm in size.

Exploratory Objectives:

• To evaluate whether the addition of adjuvant Pembrolizumab following surgical resection improves disease free survival compared with observation following surgical resection in patients with stage I non-small cell lung cancer (NSCLC) with primary tumors between 1-4 cm in size and a PD-L1 tumor proportion score (TPS) of ≥ 50%.
• To evaluate whether the addition of adjuvant Pembrolizumab following surgical resection improves disease free survival compared with observation following surgical resection in patients with stage I non-small cell lung cancer (NSCLC) with primary tumors between 1-4 cm in size and a high tumor mutation burden (TMB) defined as ≥ 10 mutations/MB.
• To evaluate whether the addition of adjuvant Pembrolizumab following surgical resection improves disease free survival compared with observation following surgical resection in patients with stage I non-small cell lung cancer (NSCLC) with primary tumors between 1-4 cm in size and a high tumor mutation burden (TMB) defined as ≥ 16 mutations/MB.
• To evaluate the disease free survival and overall survival for patients stratified by PD-L1 status (TPS ≥ 50% vs. < 50%), and tumor size (1-2 cm vs. >2-4 cm).
• To evaluate the association between various known prognostic variables, including, but not limited to, tumor differentiation (well-differentiated, moderately well differentiated, poorly differentiated), lymphovascular invasion, sex (male, female), PET max SUV and disease free survival and overall survival in patients treated with adjuvant Pembrolizumab for stage I non-small cell lung cancer (NSCLC) with primary tumors between 1-4 cm in size.
• To evaluate whether the presence of circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs) following surgical resection predicts relapse in patients with stage I non-small cell lung cancer (NSCLC) with primary tumors between 1-4 cm in size.
• To evaluate whether the presence of ctDNA or CTCs following surgical resection in patients with stage I non-small cell lung cancer (NSCLC) with primary tumors between 1-4 cm in size can predict which patients benefit from adjuvant Pembrolizumab compared to observation.
• To evaluate potential biomarkers (which may include genomics, RNA, tumor infiltrating lymphocytes, CD4 and CD8 expression, JAK2, STK11/LB1 loss of function, macrophage profile, neutrophil/lymphocyte ratio, and microbiome) as prognostic or predictive for improved disease free survival and overall survival.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: NSCLC, Stage I

Intervention

Drug: Pembrolizumab

Pembrolizumab 400mg IV

Study Arms

• Experimental: Arm A- Pembrolizumab
  Pembrolizumab 400mg IV every 6 weeks x 9 cycles
  Intervention: Drug: Pembrolizumab
• No Intervention: Arm B - Observation
  Observation only

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 19, 2020): 368
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: April 2026
• Estimated Primary Completion Date: April 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• The participant (or legally acceptable representative if applicable) must provide written informed consent for the study. The participant may also provide consent for future unspecified research samples. However, the participant may participate in the study without participating in the future unspecified research sample collection.
• Males and females age ≥ 18 years at the time of consent.
• ECOG Performance Status of 0-1 within 28 days prior to registration.

• Patients must have undergone complete surgical resection of their stage I NSCLC between 4-12 weeks prior to registration and have negative surgical margins (R0).

  • NOTE: Both squamous and non-squamous histologies are allowed into the study. Cancers with a histology of "adenosquamous" are considered a type of adenocarcinoma and thus "non-squamous histology".
  • NOTE: Staging will be according to the AJCC 8th edition.
• Pathological tumor size must be 1.0 - 4.0 cm in greatest dimension.
• Surgery for this lung cancer must be completed at least 28 days prior to registration.
• Must have either previous NGS and PD-L1 results available using the Dako 22C3 antibody or have archival tissue of surgical specimen from current diagnosis available to perform analyses. If prior PD-L1 results with Dako 22C3 antibody are not available from a CLIA-accredited laboratory, subjects must be able to provide 5µm x 4unstained slides for prospective analysis to be used for stratification. If NGS results are not available, subjects must be able to provide at least 10 x 10µm unstained and 1 x 4µm H&E slides from current diagnosis for future NGS and/or other genetic analyses.
• Demonstrate adequate organ function as defined in the protocol; all screening labs to be obtained within 28 days prior to registration.

• Females of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to registration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. For subjects randomized to the pembrolizumab arm: If there is > 72 hours between the screening test and C1D1, another pregnancy test (urine or serum) must be performed and must be negative before the subject may start C1D1.

  • NOTE: Females are considered of childbearing potential unless: they are postmenopausal; are surgically sterile; or they have a congenital or acquired condition that prevents childbearing. See Section 5.1.4 for definitions.
  • NOTE: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:

  • Not a woman of childbearing potential (WOCBP) OR
  • A WOCBP who is using a highly effective contraceptive method (failure rate of <1% per year), or is abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) during the intervention period and for at least 120 days after the last dose of study drug. The investigator should evaluate the potential for contraceptive method failure (i.e., noncompliance, recently initiated) in relationship to the first dose of study drug. See contraceptive guidance in Section 5.1.4 of the protocol.
• As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study

Exclusion Criteria:

• Current lung cancer is <1 cm or > 4 cm in size or is stage II, III, or IV.
• Patients with tumors that are known to harbor actionable EGFR mutations.
• Prior chemotherapy, radiation therapy, or immunotherapy for the treatment of this lung cancer.
• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. NOTE: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma in situ, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
• Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
• Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.

• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.

  • Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to randomization.
• Has had an allogenic tissue/solid organ transplant.
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• Has an active infection requiring systemic therapy.
• Has a known history of Human Immunodeficiency Virus (HIV). Note: HIV testing is not required unless mandated by local health authority.
• Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: Hepatitis B and Hepatitis C testing is not required unless mandated by local health authority.
• Has active TB (Bacillus Tuberculosis) infection.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Greg Durm, MD; 317-944-3940 ext 40; gdurm@iu.edu

Contact: Milena Petkov; 317-634-5842; mpetkov@hoosiercancer.org

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04317534
• Other Study ID Numbers: BTCRC-LUN18-153
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Greg Durm, MD, Big Ten Cancer Research Consortium
• Study Sponsor: Greg Durm, MD
• Collaborators: Merck Sharp & Dohme LLC

Investigators

• Principal Investigator: Greg Durm, MD; Indiana University Melvin and Bren Simon Cancer Center

• PRS Account: Big Ten Cancer Research Consortium
• Verification Date: March 2022