Study Results
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View full resultsBasic Information
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TERMINATED
PHASE2
19 participants
INTERVENTIONAL
2016-05-31
2021-03-10
Brief Summary
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Detailed Description
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Several studies have shown that the passenger mutations may not be oncogenic drivers but may be of importance in adaptive immune resistance of a tumor. In particular the relevant mutations are likely to be the nonsynonymous exonic mutations in tumors; these may give rise to novel proteins that differ from their wild type counterparts and are immunogenically more relevant. The study will explore if there is a relationship between the genetic mutations and the success of pembrolizumab.
Conditions
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Study Design
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NON_RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Cohort 1
Subjects will receive single agent pembrolizumab 200 mg IV will be administered every 3 weeks for up to 2 years.
Pembrolizumab
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the immunoglobulin G4 (IgG4)/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2 (programmed cell death (PD) proteins).
Pembrolizumab 200 mg will be administered IV every 3 weeks.
Cohort 2
Subjects will receive pembrolizumab 200 mg IV every 3 weeks for up to 2 years with 2 cycles of nab-paclitaxel and carboplatin administered with cycles 1 and 2.
Pembrolizumab
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the immunoglobulin G4 (IgG4)/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2 (programmed cell death (PD) proteins).
Pembrolizumab 200 mg will be administered IV every 3 weeks.
Carboplatin
Carboplatin AUC (area under curve (AUC)) = 5 IV on day 1 every 3 weeks administered for 2 cycles concurrently with cycles 1 and 2 of pembrolizumab.
Nab-paclitaxel
Nab-paclitaxel 100 mg/m2 IV on days 1, 8 and 15 every 3 weeks administered for 2 cycles concurrently with cycles 1 and 2 of pembrolizumab.
Cohort 3
Subject will receive pembrolizumab 200 mg IV every 3 weeks for up to 2 years with 2 cycles of pemetrexed and carboplatin administered with cycles 1 and 2.
Pembrolizumab
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the immunoglobulin G4 (IgG4)/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2 (programmed cell death (PD) proteins).
Pembrolizumab 200 mg will be administered IV every 3 weeks.
Carboplatin
Carboplatin AUC (area under curve (AUC)) = 5 IV on day 1 every 3 weeks administered for 2 cycles concurrently with cycles 1 and 2 of pembrolizumab.
Pemetrexed
Pemetrexed 500 mg/m2 IV administered for 2 cycles concurrently with cycles 1 and 2 of pembrolizumab.
Interventions
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Pembrolizumab
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the immunoglobulin G4 (IgG4)/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2 (programmed cell death (PD) proteins).
Pembrolizumab 200 mg will be administered IV every 3 weeks.
Carboplatin
Carboplatin AUC (area under curve (AUC)) = 5 IV on day 1 every 3 weeks administered for 2 cycles concurrently with cycles 1 and 2 of pembrolizumab.
Nab-paclitaxel
Nab-paclitaxel 100 mg/m2 IV on days 1, 8 and 15 every 3 weeks administered for 2 cycles concurrently with cycles 1 and 2 of pembrolizumab.
Pemetrexed
Pemetrexed 500 mg/m2 IV administered for 2 cycles concurrently with cycles 1 and 2 of pembrolizumab.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Be willing and able to provide written informed consent/assent for the trial.
* Chemotherapy naïve NSCLC patients.For NSCLC patients with lung adenocarcinoma, tumors must be Epidermal Growth Factor Receptor (EGFR) and Anaplastic Lymphoma Kinase (ALK) wild-type; if a Kirsten Ras (KRAS) mutation is detected, EGFR and ALK testing is not required.
* Diagnosis must be documented by histology or cytology from brushings, washings, or needle aspiration of a defined lesion but not from sputum cytology.
* Be ≥ 18 years of age on day of signing informed consent.
* Have measurable disease based on RECIST 1.1.
* Sufficient archived tumor material available (equivalent to 2 core biopsies or greater); if insufficient archived tumor material available new tumor biopsy is mandatory.
* Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
* Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
* Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year.
* Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.
* Demonstrate adequate organ function as defined below, all screening labs should be performed within 10 days of treatment initiation.
\-- Hematological
* Absolute neutrophil count (ANC): ≥1,500 /mcL
* Platelets: ≥100,000 / microliter (mcL)
* Hemoglobin: ≥9 g/dL or ≥5.6 mmol/L
\-- Renal
* Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl): ≤1.5 X upper limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels \> 1.5 X institutional ULN
\-- Hepatic
* Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 ULN
* Aspartate aminotransferase (AST) (SGOT) and alanine aminotransferase (ALT) (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases
\-- Coagulation
* International Normalized Ratio (INR) or Prothrombin Time (PT): ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
* Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
Exclusion Criteria
* 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 had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
* Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
* Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
* Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment.
* 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 evidence of interstitial lung disease or active, non-infectious pneumonitis.Has an active infection requiring systemic therapy.
* Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, 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 trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
* Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
* Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
* Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., Hepatitis C (HCV) RNA \[qualitative\] is detected).
* Has a known history of active tuberculosis (TB)
* Has received a live vaccine within 30 days prior to the first dose of trial treatment.
* History of allergy or hypersensitivity to any component of the treatment.
18 Years
ALL
No
Sponsors
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Merck Sharp & Dohme LLC
INDUSTRY
Massachusetts General Hospital
OTHER
National Cancer Institute (NCI)
NIH
Columbia University
OTHER
Responsible Party
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Principal Investigators
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Naiyer Rizvi, MD
Role: PRINCIPAL_INVESTIGATOR
Columbia University
Locations
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Columbia University
New York, New York, United States
Fox Chase Cancer Center
Philadelphia, Pennsylvania, United States
Countries
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References
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Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, Stankevich E, Pons A, Salay TM, McMiller TL, Gilson MM, Wang C, Selby M, Taube JM, Anders R, Chen L, Korman AJ, Pardoll DM, Lowy I, Topalian SL. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010 Jul 1;28(19):3167-75. doi: 10.1200/JCO.2009.26.7609. Epub 2010 Jun 1.
Brahmer, J.R., et al., Clinical activity and safety of anti-PD1 (BMS-936558, MDX-1106) in patients with advanced non-small-cell lung cancer (NSCLC). J Clin Oncol, 2012(30): p. suppl; abstr 7509
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012 Jun 28;366(26):2443-54. doi: 10.1056/NEJMoa1200690. Epub 2012 Jun 2.
Brahmer JR. Harnessing the immune system for the treatment of non-small-cell lung cancer. J Clin Oncol. 2013 Mar 10;31(8):1021-8. doi: 10.1200/JCO.2012.45.8703. Epub 2013 Feb 11.
Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, Chen S, Klein AP, Pardoll DM, Topalian SL, Chen L. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012 Mar 28;4(127):127ra37. doi: 10.1126/scitranslmed.3003689.
Matsushita H, Vesely MD, Koboldt DC, Rickert CG, Uppaluri R, Magrini VJ, Arthur CD, White JM, Chen YS, Shea LK, Hundal J, Wendl MC, Demeter R, Wylie T, Allison JP, Smyth MJ, Old LJ, Mardis ER, Schreiber RD. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature. 2012 Feb 8;482(7385):400-4. doi: 10.1038/nature10755.
DuPage M, Cheung AF, Mazumdar C, Winslow MM, Bronson R, Schmidt LM, Crowley D, Chen J, Jacks T. Endogenous T cell responses to antigens expressed in lung adenocarcinomas delay malignant tumor progression. Cancer Cell. 2011 Jan 18;19(1):72-85. doi: 10.1016/j.ccr.2010.11.011.
DuPage M, Mazumdar C, Schmidt LM, Cheung AF, Jacks T. Expression of tumour-specific antigens underlies cancer immunoediting. Nature. 2012 Feb 8;482(7385):405-9. doi: 10.1038/nature10803.
Castle JC, Kreiter S, Diekmann J, Lower M, van de Roemer N, de Graaf J, Selmi A, Diken M, Boegel S, Paret C, Koslowski M, Kuhn AN, Britten CM, Huber C, Tureci O, Sahin U. Exploiting the mutanome for tumor vaccination. Cancer Res. 2012 Mar 1;72(5):1081-91. doi: 10.1158/0008-5472.CAN-11-3722. Epub 2012 Jan 11.
Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015 Apr 3;348(6230):69-74. doi: 10.1126/science.aaa4971.
Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, Ho TS, Miller ML, Rekhtman N, Moreira AL, Ibrahim F, Bruggeman C, Gasmi B, Zappasodi R, Maeda Y, Sander C, Garon EB, Merghoub T, Wolchok JD, Schumacher TN, Chan TA. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015 Apr 3;348(6230):124-8. doi: 10.1126/science.aaa1348. Epub 2015 Mar 12.
Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan
Other Identifiers
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