A Trial of Pembrolizumab in Combination With Chemotherapy and Radiotherapy in Stage III NSCLC (KEYNOTE-799, MK-3475-799). (KEYNOTE-799)

• Sponsor: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): Merck Sharp & Dohme Corp.

Study Description

Brief Summary:

This is a trial in adult participants with unresectable, locally advanced, Stage III non-small cell lung cancer (NSCLC) treated with pembrolizumab in combination with platinum doublet chemotherapy and standard thoracic radiotherapy followed by pembrolizumab monotherapy. The primary hypothesis of the trial is that within each platinum doublet chemotherapy cohort, the percentage of participants who develop Grade 3 or higher pneumonitis is ≤10%.

Condition or disease	Intervention/treatment	Phase
Non-small Cell Lung Cancer	Drug: Pembrolizumab 200 mg; Drug: Paclitaxel 45 mg/m^2; Drug: Carboplatin AUC6; Drug: Cisplatin 75 mg/m^2; Drug: Pemetrexed 500 mg/m^2; Radiation: Thoracic Radiation Therapy (TRT); Drug: Paclitaxel 200 mg/m^2; Drug: Carboplatin AUC2	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 216 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Trial of Pembrolizumab (MK-3475) in Combination With Platinum Doublet Chemotherapy and Radiotherapy for Participants With Unresectable, Locally Advanced Stage III Non-Small Cell Lung Cancer (NSCLC) (KEYNOTE-799).
• Actual Study Start Date: October 19, 2018
• Estimated Primary Completion Date: December 15, 2020
• Estimated Study Completion Date: March 14, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort A; Participants will receive 1 cycle of pembrolizumab 200 mg on Day 1 with paclitaxel 200 mg/m^2, and carboplatin area under the curve (AUC) AUC6. Approximately 3 weeks later, participants will receive 2 cycles of pembrolizumab 200 mg administered every 3 weeks (Q3W) and carboplatin AUC2 with paclitaxel 45 mg/m^2 administered weekly for 6 weeks in conjunction with standard thoracic radiotherapy (60 Gray [Gy]). To conclude the study treatments, participants will receive 14 additional cycles of pembrolizumab 200 mg administered Q3W.	Drug: Pembrolizumab 200 mg; Pembrolizumab 200 mg intravenous (IV) infusion on Days 1 of each 3-week cycle for up to 17 cycles; Other Name: MK-3475; Drug: Paclitaxel 45 mg/m^2; Paclitaxel 45 mg/m^2 IV infusion on Days 1, 8, 15 of each 3-week cycle for Cycles 2, and 3 during radiation therapy.; Drug: Carboplatin AUC6; Carboplatin AUC6 IV infusion on Day 1 of the 21-day cycle for Cycle 1.; Radiation: Thoracic Radiation Therapy (TRT); The target total dose of TRT will be 60 Gy in 30 daily fractions of 2 Gy, prescribed to the planning target volume.; Drug: Paclitaxel 200 mg/m^2; Paclitaxel 200 mg/m^2 IV infusion on Day 1 of the 21-day cycle of Cycle 1.; Drug: Carboplatin AUC2; Carboplatin AUC2 IV infusion on Day 1, 8, 15 for Cycles 2 and 3 during radiation therapy.
Experimental: Cohort B; Participants will receive 3 cycles of pembrolizumab 200 mg on Day 1 of each 3-week cycle and 3 cycles of pemetrexed 500 mg/m^2 and cisplatin 75 mg/m^2. Treatment will be given in conjunction with standard thoracic radiotherapy (60 Gy) in Cycles 2 and 3. To conclude the study treatments, participants will receive 14 additional cycles of pembrolizumab 200 mg administered Q3W.	Drug: Pembrolizumab 200 mg; Pembrolizumab 200 mg intravenous (IV) infusion on Days 1 of each 3-week cycle for up to 17 cycles; Other Name: MK-3475; Drug: Cisplatin 75 mg/m^2; Cisplatin 75 mg/m^2 IV infusion on Day 1 of each 21-day cycle for Cycles 1, 2, 3.; Drug: Pemetrexed 500 mg/m^2; Pemetrexed 500 mg/m^2 IV infusion on Day 1 of each 21-day cycle for Cycles 1, 2, and 3.; Radiation: Thoracic Radiation Therapy (TRT); The target total dose of TRT will be 60 Gy in 30 daily fractions of 2 Gy, prescribed to the planning target volume.

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants Who Develop Grade 3 or Higher Pneumonitis [ Time Frame: Up to approximately 1 year ]
   Pneumonitis is an immune-mediated adverse event which is of interest in light of the mechanism of action of pembrolizumab.
2. Percentage of Participants with a Complete or Partial Response [ Time Frame: Up to approximately 1 year ]

   Complete Response (CR):

   Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.

   Partial Response (PR):

   At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Secondary Outcome Measures :

1. Progression Free Survival (PFS) [ Time Frame: Up to approximately 1 year ]
   PFS defined as the time from enrollment to the first documented disease progression of local recurrence or distant metastasis or death due to any cause, whichever occurs first, as assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
2. Overall Survival (OS) [ Time Frame: Up to approximately 1 year ]
   OS is defined as the time from enrollment to death due to any cause.
3. Adverse Events (AEs) [ Time Frame: Up to approximately 1 1/4 years ]
   Percentage of participants who experienced one or more AEs.
4. Discontinuations due to AEs [ Time Frame: Up to approximately 1 year ]
   Percentage of participants discontinuing study treatment(s) due to an AE.

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:

• Male/female participants, who are at least 18 years of age on the day of signing informed consent with previously untreated, unresectable, pathologically confirmed NSCLC and Stage IIIA, IIIB or IIIC NSCLC by American Joint Committee on Cancer Version 8.
• No evidence of metastatic disease by whole body positron emission tomography/computed tomography (PET/ CT) scan, diagnostic quality CT scan, and brain imaging.
• Have measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology.
• Have provided tumor tissue sample (core, incisional, or excisional biopsy).
• Have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
• Have adequate pulmonary function test (PFT)
• Have adequate organ function
• A male participant must agree to use contraception through the end of treatment and refrain from donating sperm during this period.
• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and if participant is a woman of childbearing potential (WOCBP), agrees to follow the contraceptive guidance as provided in the protocol through the end of treatment.

Exclusion Criteria:

• A WOCBP who has a positive urine pregnancy test within 72 hours prior to treatment allocation
• Has small cell lung cancer.
• Has had documented weight loss >10% in the preceding 3 months.
• Participants whose radiation treatment plans are likely to encompass a volume of whole lung receiving >20 Gy in total (V20) of more than 31% of lung volume.
• Has received prior radiotherapy to the thorax, including radiotherapy to the esophagus or for breast cancer.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent (programmed cell death protein 1 [PD-1] and its ligands, programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 [PD-L2]) 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.
• Has had an allogenic tissue/solid organ transplant.
• 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.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg prednisone daily or equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug.
• Has a known additional malignancy that is progressing or has required active treatment within the past 5 years.
• Has severe hypersensitivity (Grade 3 or higher) to pembrolizumab and/or any of its excipients.
• Has a known severe hypersensitivity (Grade 3 or higher) to any of the study chemotherapy agents and/or to any of their excipients.
• Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease that requires steroids.
• Has an active infection requiring systemic therapy.
• Has a known history of human immunodeficiency virus (HIV) infection. 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.
• Has a known history of active tuberculosis (TB; Bacillus tuberculosis).
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
• Has a known psychiatric or substance abuse disorder that would interfere with cooperating with the requirements of the study.
• Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study through the end of treatment.

Contacts and Locations

Contacts

Contact: Toll Free Number; 1-888-577-8839; Trialsites@merck.com

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Sponsors and Collaborators

Merck Sharp & Dohme Corp.

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme Corp.

More Information

• Responsible Party: Merck Sharp & Dohme Corp.
• ClinicalTrials.gov Identifier: NCT03631784 History of Changes
• Other Study ID Numbers: 3475-799; MK-3475-799 ( Other Identifier: Merck Protocol Number )
• First Posted: August 15, 2018
• Last Update Posted: August 9, 2019
• Last Verified: August 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

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

Keywords provided by Merck Sharp & Dohme Corp.:

PD1; PD-1; PDL1; PD-L1

Additional relevant MeSH terms:

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Paclitaxel; Albumin-Bound Paclitaxel; Cisplatin; Carboplatin; Pembrolizumab; Pemetrexed; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Immunological; Enzyme Inhibitors; Folic Acid Antagonists; Nucleic Acid Synthesis Inhibitors