Neoadjuvant Pembrolizumab (TOP 1501)

• ClinicalTrials.gov Identifier: NCT02818920
• Recruitment Status: Active, not recruiting
• First Posted: June 30, 2016
• Results First Posted: February 18, 2020
• Last Update Posted: March 9, 2021
• Sponsor: Neal Ready
• Collaborator: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): Neal Ready, Duke University

Study Description

Brief Summary:

This multi-institutional, phase 2 clinical trial is studying two doses of pembrolizumab administered prior to surgery (neoadjuvant therapy) and 4 doses administered after surgery (adjuvant therapy) for stage IB, II or IIIA non-small cell lung cancer. Pembrolizumab is a type of immunotherapy that may enhance the ability of the immune system to fight off cancer. The study will investigate the effects of pembrolizumab on the immune system and how certain immune cells, called TILs (tumor infiltrating lymphocytes), respond to pembrolizumab. Previous studies suggest that pembrolizumab could alter the immune cells in a way that the the immune cells identify cancer cells. Pembrolizumab has been approved for the treatment of advanced lung cancer, but is investigational in this setting.

Condition or disease	Intervention/treatment	Phase
Non-small Cell Lung Carcinoma	Drug: Pembrolizumab	Phase 2

Detailed Description:

The presumed mechanism of action for pembrolizumab is the removal of T lymphocyte inhibition by masking the PD-1 receptor. Our hypothesis is that the masking of the PD-1 receptor by pembrolizumab results in the activation and proliferation of T lymphocytes with specificities against tumor associated antigens (TILs). In untreated lung cancer tumors, we would expect few tumors to have TIL cells with specificities against tumor associated antigens. Based on the response rate to pembrolizumab in advanced lung cancer, we hypothesize that at least 20% of lung cancers would have TIL cells with specificities against tumor associated antigens after pembrolizumab therapy.

Studying neoadjuvant pembrolizumab therapy is an attractive strategy for studying the immunologic changes caused by PD-1 (programmed death receptor 1) checkpoint masking. Most of the immunologic activity associated with pembrolizumab occurs in the tumor and surrounding microenvironment. Evaluation of post-pembrolizumab tumor will be important to understanding factors associated with pembrolizumab activity, immune tolerance, and discovery of other targets for immune therapy. Pembrolizumab has known benefit in non-small cell lung cancer. The addition of pembrolizumab for two doses prior to surgery and four doses after surgery has the potential to confer clinical benefit. Large randomized phase 3 trials are now testing whether PD-1 checkpoint antibodies improve survival as adjuvant therapy after resection of early stage lung cancer.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 35 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pembrolizumab Prior to Surgery for Stage 1B, 2 or 3A Non-small Cell Lung Cancer (NSCLC): A Phase II Study
• Actual Study Start Date: January 2017
• Actual Primary Completion Date: March 19, 2019
• Estimated Study Completion Date: March 2026

Arms and Interventions

Arm

Intervention/treatment

Experimental: Pembrolizumab prior to and after surgery

Drug: Pembrolizumab; Pembrolizumab (prior to surgery) 200 mg IV over 30 min, days 1 & 22, two cycles; followed by surgery; followed by standard adjuvant chemotherapy (per med. oncologist) +/- radiation therapy per institutional standard of care; followed by adjuvant pembrolizumab 200 mg IV over 30 min every 21 days for 4 cycles -Note: Standard radiation therapy in selected patients for standard clinical indications; Other Name: Keytruda

Outcome Measures

Primary Outcome Measures :

1. Surgical Feasibility Rate as Measured by the Number of Subjects Who Undergo Surgery Following Neoadjuvant Pembrozulimab [ Time Frame: 29-56 days after initiation of pembrolizumab ]
   A patient who meets the eligibility criteria, has received at least 1 dose of pembrolizumab, and undergone surgery in the window of 29-56 days after initiation of pembrolizumab is considered surgically feasible. All other situations are considered infeasible.

Other Outcome Measures:

1. Objective Response Rate [ Time Frame: At the end of 2 cycles of neoadjuvant pembrolizumab (29-55 days after initiation) ]
   The percentage of patients having a complete response or a partial response to protocol treatment. Objective response will be measured by RECIST 1.1.
2. Disease-free Survival (DFS) [ Time Frame: Until disease recurrence or death (up to 5 years) ]
   DFS is defined as the time from surgical resection to disease recurrence (first disease recurrence or death, whichever comes first) after surgery.The Kaplan-Meier estimator will be used to estimate median DFS and its confidence interval.
3. Change in Blood-based Biomarker Values [ Time Frame: Baseline (day 0), before surgery (days 29-56), 3-6 weeks after surgery, and after completion of adjuvant pembrolizumab (estimated at 10.5 months from start depending on treatment components received by patient) ]
   Changes in levels of blood-based biomarkers before and after protocol treatment and correlated with clinical outcomes, such as objective response, overall survival, and disease-free survival.
4. Detectability of Tumor Infiltrating Lymphocytes (TILs) [ Time Frame: End of protocol treatment (Estimated at 10.5 months from start depending on treatment components received by patient) ]
   Percentage of patients with detectable TILs, defined as greater than or equal to 0.05% (with each value also being at least twice that of the background unstimulated control value TIL)
5. Adverse Events [ Time Frame: End of protocol treatment (estimated at 10.5 months from start depending on treatment components received by patient) ]
   Safety will be evaluated for all treated patients using CTCAE V 4.0.
6. Detectability of Circulating T Cells Specific Against TAA [ Time Frame: End of protocol treatment (estimated at 10.5 months from start depending on treatment components received by patient) ]
   Proportion of patients with detectable circulating T cells specific against TAA after protocol treatment.
7. Pathologic Response Rate [ Time Frame: At surgery (day 29-56) ]
   Pathologic response rate for neoadjuvant pembrolizumab
8. Change in Immunomodulatory Effects [ Time Frame: Baseline (day 0), before surgery (days 29-56), 3-6 weeks after surgery, and after completion of adjuvant pembrolizumab (estimated at 10.5 months from start depending on treatment components received by patient) ]
   Determine if the immunomodulatory effects of neoadjuvant pembrolizumab have an impact on the suppressive mechanisms, restoring functional reactivity to important anti-tumor effects cell populations. Functional TAA-specific T cell reactivities will measured at 4 time points.
9. Detectability of Circulating T Cells Meeting New Definition of Detectability [ Time Frame: End of protocol treatment ((Estimated at 10.5 months from start depending on treatment components received by patient) ]
   Percentage of patients with circulating T cells meeting the new definition of detectable.
10. Gene Expression of the PD-1/PD-L1 Axis [ Time Frame: End of protocol treatment ((Estimated at 10.5 months from start depending on treatment components received by patient) ]
    Elucidate genes associated with function and modulation of the PD-1/PD-L1 axis.
11. Correlation of Pathologic Response to the Presence of TILs [ Time Frame: At surgery (day 29-56) ]
    A Fisher exact test will be used to evaluate the association of the presence of TILs with pathologic tumor response to neoadjuvant therapy.
12. Correlation of Pathologic Response to the Quality of TILs [ Time Frame: At surgery (day 29-56) ]
    A Fisher exact test will be used to evaluate the association of the quality of TILs with pathologic tumor response to neoadjuvant therapy.
13. Correlation of Pathologic Response to the Quantity of TILs [ Time Frame: At surgery (days 29-56) ]
    A Wilcoxon rank sum test will be used to test the association of the quantity of TILs and pathologic response to neoadjuvant therapy.
14. Patterns of Metastases as Measured by Frequency at Site. [ Time Frame: Until disease recurrence or death (up to 5 years)] ]
    The Kaplan-Meier estimator will be used to estimate median DFS and its confidence interval. The frequencies of metastases by site will be tabulated

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Histologically or cytologically confirmed NSCLC.
• Clinical stage IB (>/= 3 cm per CT), Stage IIA/IIB, or Stage IIIA (N0-2) amenable to surgical resection.
• Primary tumor >/= 3 cm (for all stages entered) to make it likely that excess tumor will be available after resection.
• Patient must be deemed a surgical candidate.
• ECOG performance status of 0 or 1 (Appendix C).
• No prior chemotherapy, radiation therapy or biologic/targeted therapy for current diagnosis of lung cancer.
• Adequate Organ Function
• Age ≥18 years.
• Non-pregnant. Females of child-bearing potential (not surgically sterilized or postmenopausal [a woman who is > 45 years of age and has not had menses for greater than 1 year]) must test negative for pregnancy within 48 hours prior to any initial study procedure based on a serum pregnancy test.
• No active invasive malignancy in the past 2 years other than non-melanoma skin cancer. Cancers that are in-situ are not considered invasive.
• Signed written informed consent including HIPAA according to institutional guidelines.
• Patients must agree to research blood sampling to participate in study.
• Have measurable disease based on RECIST 1.1.
• Post-op predicted FEV1 and DLCO > 40% predicted (or per institutional standard).

Exclusion Criteria:

• Treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry or used an investigational device within 4 weeks of the first dose of treatment.
• Has a known history of active TB (Bacillus Tuberculosis).
• Hypersensitivity to pembrolizumab or any of its excipients.
• Concurrent administration of any other anti-tumor therapy.
• Has received prior therapy with an anti-PD-1, anti-PD-L-1, or anti-PD-L2 agent.
• Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
• Inability to comply with protocol or study procedures.
• Active infection requiring antibiotics, antifungal or antiviral agents, that in the opinion of the investigator would compromise the patient's ability to tolerate therapy.
• Has known history of, or any evidence of active, non-infectious pneumonitis.
• Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
• 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 (e.g. thyroxine, insulin or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency etc) is not considered a form of systemic treatment. Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's Disease, are excluded from this study, as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [eg, Wegener's Granulomatosis]); motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome and Myasthenia Gravis).
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
• Has a known additional invasive malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
• Has had major surgery (other than definitive lung cancer surgery) within two weeks of study or other serious concomitant disorders that in the opinion of the investigator would compromise the safety of the patient or compromise the patient's ability to complete the study.
• Has received any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 30 days before or after any dose of pembrolizumab). Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines and are not allowed.
• Has history of myocardial infarction having occurred less than 6 months before inclusion, any known uncontrolled arrhythmia, symptomatic angina pectoris, active ischemia, or cardiac failure not controlled by medications. Patients with CAD recently treated with surgery and/or stent, if stable without symptomatic angina pectoris, active ischemia are eligible.
• Has a history of interstitial lung disease
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Prisoners or subjects who are compulsorily detained involuntarily incarcerated) for treatment of either psychiatric or physical (e.g., infectious) illness.

Contacts and Locations

Locations

United States, Minnesota

Mayo Clinic

Rochester, Minnesota, United States, 55905

United States, New Hampshire

Dartmouth-Hitchcock Medical Center

Lebanon, New Hampshire, United States, 03756

United States, North Carolina

Duke University Medical Center

Durham, North Carolina, United States, 27710

Sponsors and Collaborators

Neal Ready

Merck Sharp & Dohme Corp.

Investigators

• Principal Investigator: Neal Ready, MD; Duke University

  Study Documents (Full-Text)

Documents provided by Neal Ready, Duke University:

Study Protocol and Statistical Analysis Plan  [PDF] November 11, 2018

More Information

• Responsible Party: Neal Ready, Associate Professor of Medicine, Duke University
• ClinicalTrials.gov Identifier: NCT02818920
• Other Study ID Numbers: Pro00071629
• First Posted: June 30, 2016
• Results First Posted: February 18, 2020
• Last Update Posted: March 9, 2021
• Last Verified: March 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Neal Ready, Duke University:

Pembrolizumab; Neoadjuvant; Tumor Infiltrating Lymphocytes (TILs)

Additional relevant MeSH terms:

Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents