Clinical trial NCT02818920: Neoadjuvant Pembrolizumab
Official title: Pembrolizumab Prior to Surgery for Stage 1B, 2 or 3A Non-small Cell Lung Cancer (NSCLC): A Phase II Study
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Non-small Cell Lung Carcinoma
Keywords: Pembrolizumab
Neoadjuvant
Tumor Infiltrating Lymphocytes (TILs)
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2016-06-30
Enrollment: 35
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: Surgical Feasibility Rate as Measured by the Number of Subjects Who Undergo Surgery Following Neoadjuvant Pembrozulimab
timeFrame: 29-56 days after initiation of pembrolizumab
Secondary outcomes:
Other outcomes:
measure: Objective Response Rate
timeFrame: At the end of 2 cycles of neoadjuvant pembrolizumab (29-55 days after initiation)
measure: Disease-free Survival (DFS)
timeFrame: Until disease recurrence or death (up to 5 years)
measure: Change in Blood-based Biomarker Values
timeFrame: 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)
measure: Detectability of Tumor Infiltrating Lymphocytes (TILs)
timeFrame: End of protocol treatment (Estimated at 10.5 months from start depending on treatment components received by patient)
measure: Adverse Events
timeFrame: End of protocol treatment (estimated at 10.5 months from start depending on treatment components received by patient)
measure: Detectability of Circulating T Cells Specific Against TAA
timeFrame: End of protocol treatment (estimated at 10.5 months from start depending on treatment components received by patient)
measure: Pathologic Response Rate
timeFrame: At surgery (day 29-56)
measure: Change in Immunomodulatory Effects
timeFrame: 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)
measure: Detectability of Circulating T Cells Meeting New Definition of Detectability
timeFrame: End of protocol treatment ((Estimated at 10.5 months from start depending on treatment components received by patient)
measure: Gene Expression of the PD-1/PD-L1 Axis
timeFrame: End of protocol treatment ((Estimated at 10.5 months from start depending on treatment components received by patient)
measure: Correlation of Pathologic Response to the Presence of TILs
timeFrame: At surgery (day 29-56)
measure: Correlation of Pathologic Response to the Quality of TILs
timeFrame: At surgery (day 29-56)
measure: Correlation of Pathologic Response to the Quantity of TILs
timeFrame: At surgery (days 29-56)
measure: Patterns of Metastases as Measured by Frequency at Site.
timeFrame: Until disease recurrence or death (up to 5 years)]
Locations:
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center
state: New Hampshire
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
Study officials:
affiliation: Duke University
name: Neal Ready, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Tong BC, Gu L, Wang X, Wigle DA, Phillips JD, Harpole DH Jr, Klapper JA, Sporn T, Ready NE, D'Amico TA. Perioperative outcomes of pulmonary resection after neoadjuvant pembrolizumab in patients with non-small cell lung cancer. J Thorac Cardiovasc Surg. 2022 Feb;163(2):427-436. doi: 10.1016/j.jtcvs.2021.02.099. Epub 2021 Apr 9.