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Phase 3 Study of Pembrolizumab with Concurrent Chemoradiation Therapy Followed by Pembrolizumab with or without Olaparib in Stage III NSCLC

TRIO MK7339-012/KEYLYNK-12: A Phase 3 Study of Pembrolizumab (MK-3475) in Combination with Concurrent Chemoradiation Therapy Followed by Pembrolizumab with or without Olaparib vs Concurrent Chemoradiation Therapy Followed by Durvalumab in Participants with Unresectable, Locally Advanced, Stage III Non-Small Cell Lung Cancer (NSCLC)

  • Clinical Trial Information

    Trial Contact: Thomas, Andrea L

    Trial Phone: 321.841.8284

  • IRB No: WIRB 20200319

    Protocol Abbrev: TRIO MK7339-012

    Principal Investigator: Jennifer E. Tseng, MD

    Phase: Drug: Phase III

    Age Group: Adult

    Secondary Protocol No: TRIO MK7339-012/KEYLYNK-12

    Treatment: After screening (an approximately 4-week period), approximately 870 eligible participants will be randomized (1:1:1) into 3 study groups: Group A – Participants will receive pembrolizumab 200 mg IV Q3W in combination with 3 cycles of platinum doublet chemotherapy and concurrent standard thoracic radiotherapy (60 Gy in 2 Gy fractions; during Cycles 2 and 3) followed by pembrolizumab plus matching olaparib placebo for 12 months or until specific discontinuation criteria are met Group B – Participants will receive pembrolizumab 200 mg IV Q3W in combination with 3 cycles of platinum doublet chemotherapy and concurrent standard thoracic radiotherapy (60 Gy in 2 Gy fractions; during Cycles 2 and 3) followed by pembrolizumab plus olaparib (300 mg BID) for 12 months or until specific discontinuation criteria are met Group C – Participants will receive 3 cycles of platinum doublet chemotherapy and concurrent standard thoracic radiotherapy (60 Gy in 2 Gy fractions; during Cycles 2 and 3) followed by durvalumab 10 mg/kg Q2W for 12 months or until specific discontinuation criteria are met

    Therapies Involved: Chemotherapy

    ClinicalTrials.gov ID: NCT04380636

  • Objective

    The primary objectives of the study include:
    - To compare PFS per RECIST 1.1 as assessed by BICR.
    - To compare OS
    - To evaluate the safety and tolerability of pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab compared to current chemotherapy radiation therapy followed by durvalumab
    - To compare pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab to concurrent chemoradiation therapy followed by durvalumab with respect to
    ORR and DOR per RECIST 1.1 as assessed by BICR
    - To evaluate the change from baseline (at Cycle 1) and the TTD in global health status/QoL, cough, chest pain, dyspnea and physical functioning following treatment with pembrolizumab
    with concurrent chemoradiation therapy followed by pembrolizumab plus olaparib compared to concurrent
    chemoradiation therapy followed by durvalumab.

  • Key Eligibility

    Inclusion Criteria
    1. Has pathologically (histologically or cytologically) confirmed NSCLC.
    2. Has Stage IIIA, IIIB, or IIIC NSCLC by American Joint Committee on Cancer Version 8.
    3. Is unable to undergo surgery with curative intent for Stage III NSCLC as documented by a multidisciplinary tumor board or by the treating physician in consultation with a thoracic surgeon.
    4. Has no evidence of metastatic disease, indicating Stage IV NSCLC, in whole-body fluorodeoxyglucose (FDG)-PET or FDG-PET/CT and CT or MRI scans of diagnostic quality of chest, abdomen, pelvis and brain.
    5. Has measurable disease as defined by RECIST 1.1, with at least one lesion being appropriate for selection as a target lesion, as determined by local site investigator/radiology review
    6. Has not received prior treatment (chemotherapy, targeted therapy or radiotherapy) for their Stage III NSCLC
    7. Has provided tumor tissue sample (tissue biopsy [core, incisional, or excisional]). FFPE blocks are preferred to slides. Newly obtained tumor sample is highly preferred over archival tissue and should be obtained prior to the thoracic imaging at screening
    8. Has a performance status of 0 or 1 on the ECOG Performance Status assessed within 7 days prior to the first administration of study intervention
    9. Has a life expectancy of at least 6 months
    10. Has adequate PFT defined as a FEV1 >50% of predicted normal volume and the carbon monoxide lung diffusing capacity (DLCO) >40% of predicted normal value. Participants for whom DLCO measurements are not available will be deemed to have adequate oxygen transfer if pulse oximetry (O2 saturation) is determined to be ≥90% on room air
    11. Has adequate organ function as defined in Table 1 of the protocol; all screening laboratory tests should be performed within 10 days prior to initiation of study intervention
    12. Is male or female of at least 18 years to 120 years of age inclusive, at the time of signing the informed consent
    13. A male participant must agree to use contraception as detailed in Appendix 4 of this protocol during the treatment period and for at least 180 days following the last dose of study intervention
    14. A female participant is eligible to participate if she is not pregnant (Appendix 4), not breastfeeding, and at least 1 of the following conditions applies: a. Not a WOCBP as defined in Appendix 4 of the protocol. OR b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 4 during
    the treatment period and for at least 180 days following the last dose of study intervention.
    15. Has (or legally acceptable representative if applicable) provided written informed consent/assent for the study. The participant may also provide consent/assent for future biomedical research. However, the participant may participate in the main trial without participating in future biomedical research.

    Exclusion Criteria
    Medical Conditions
    1. Has small cell lung cancer or a mixed tumor with presence of small cell elements. Note: Participants with squamous NSCLC are not eligible to receive pemetrexed-based chemotherapy.
    2. Has history, current diagnosis, or features suggestive of MDS/AML.
    3. Has had documented weight loss >10% (from baseline) in the preceding 3 months.
    Prior/Concomitant Therapy
    4. Has a radiation treatment plan that is likely to encompass a volume of whole lung (total lung V20-GTV) receiving > 20 Gy in total (V20) of more than 34% of lung volume. Note: The participant must be assessed by a radiation oncologist during screening who anticipates the tumor is treatable as defined in Section 8.1.8.2.4
    5. Has received prior radiotherapy to the thorax, including radiotherapy to the esophagus, mediastinum, or for breast cancer.
    6. Has received 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).
    7. Has received prior therapy with olaparib or with any other PARP inhibitor.
    8. Had major surgery <4 weeks prior to the first dose of study medication (except for placement of vascular access). Note: If participants received major surgery, or underwent placement of vascular access, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study intervention.
    9. Is expected to require any other form of antineoplastic therapy, while on study
    10. Has received a live vaccine within 30 days prior to the first dose of study medication. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, 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.
    11. Has received colony-stimulating factors (e.g., granulocyte colony-stimulating factor [GCSF], granulocyte-macrophage colony-stimulating factor [GM-CSF] or recombinant erythropoietin) within 28 days prior to the first dose of study intervention.
    12. Is currently receiving either strong (phenobarbital, enzalutamide, phenytoïn, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate (e.g. bosentan, efavirenz, modafinil) inducers of CYP3A4 that cannot be discontinued for the duration of the study. The required washout period prior to starting olaparib is 5 weeks
    for pentobarbital and 3 weeks for other agents.
    13. Is currently receiving either strong (eg, itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir,
    boceprevir, telaprevir) or moderate (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) inhibitors of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study. The required washout period prior to starting olaparib is 2 weeks.
    Pemetrexed-specific
    14. Is unable to interrupt aspirin or other NSAIDs, other than an aspirin dose ≤1.3 grams per day, for at least 2 days (5 days for long-acting agents [for example, piroxicam]) before, during, and for at least 2 days after administration of pemetrexed.
    15. Is unable/unwilling to take folic acid, vitamin B12, and dexamethasone
    Prior/Concurrent Clinical Study Experience
    16. 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 intervention.
    Diagnostic Assessments
    17. Has resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (eg, unstable ischemia, uncontrolled symptomatic arrhythmia,
    congestive heart failure, electrolyte disturbances, etc.), or participant has congenital long QT syndrome.
    18. 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 the first dose of study medication.
    19. Has a known additional malignancy that is progressing or has required active treatment within the past 5 years.
    20. Has severe hypersensitivity (≥ Grade 3) to study intervention and/or any of its excipients (refer to the IB and/or approved product label(s) for a list of excipients).
    21. 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).
    Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic
    treatment and is allowed.
    22. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease. Lymphangitic spread of the NSCLC is not exclusionary.
    23. Has an active infection requiring systemic therapy.
    24. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority.
    25. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
    26. Has active tuberculosis (TB; Mycobacterium tuberculosis) and is receiving treatment (no TB testing is required unless mandated by local health authority; participants who were
    previously treated are allowed).
    27. 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.
    28. In the opinion of the treating investigator, is considered a poor medical risk due to a serious, uncontrolled medical disorder or nonmalignant systemic disease. Examples
    include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord
    compression, or superior vena cava syndrome.
    29. Has a known psychiatric or substance abuse disorder that would interfere with the
    participant’s ability to cooperate with the requirements of the study.
    Other Exclusions
    30. Is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption (e.g. gastrectomy, partial bowel, obstruction, malabsorption).
    31. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 180 days after
    the last dose of study intervention.
    32. Has had an allogenic tissue/solid organ transplant.