Clinical trial NCT02628067: Study of Pembrolizumab (MK-3475) in Participants With Advanced Solid Tumors (MK-3475-158/KEYNOTE-158)
Official title: A Clinical Trial of Pembrolizumab (MK-3475) Evaluating Predictive Biomarkers in Subjects With Advanced Solid Tumors (KEYNOTE 158)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Advanced Cancer
Anal Carcinoma
Anal Cancer
Biliary Cancer
Cholangiocarcinoma
Bile Duct Cancer
Neuroendocrine Tumor
Carcinoid Tumor
Endometrial Carcinoma
Endometrial Cancer
Cervical Carcinoma
Cervical Cancer
Vulvar Carcinoma
Vulvar Cancer
Small Cell Lung Carcinoma
Small Cell Lung Cancer (SCLC)
Mesothelioma
Thyroid Carcinoma
Thyroid Cancer
Salivary Gland Carcinoma
Salivary Gland Cancer
Salivary Cancer
Parotid Gland Cancer
Advanced Solid Tumors
Colorectal Carcinoma
Keywords: Programmed Cell Death-1 (PD1, PD-1)
Programmed Death-Ligand 1 (PDL1, PD-L1)
microsatellite instability (MSI)
mismatch repair (MMR)
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2015-12-11
Enrollment: 1609
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: In this study, participants with multiple types of advanced (unresectable and/or metastatic) solid tumors who have progressed on standard of care therapy will be treated with pembrolizumab (MK-3475).


Eligibility criteria: Inclusion Criteria:

- Histologically or cytologically-documented, advanced solid tumor of one of the following types:

* Anal Squamous Cell Carcinoma
* Biliary Adenocarcinoma (gallbladder or biliary tree (intrahepatic or extrahepatic cholangiocarcinoma) except Ampulla of Vater cancers)
* Neuroendocrine Tumors (well- and moderately-differentiated) of the lung, appendix, small intestine, colon, rectum, or pancreas
* Endometrial Carcinoma (sarcomas and mesenchymal tumors are excluded)
* Cervical Squamous Cell Carcinoma
* Vulvar Squamous Cell Carcinoma
* Small Cell Lung Carcinoma
* Mesothelioma
* Thyroid Carcinoma
* Salivary Gland Carcinoma (sarcomas and mesenchymal tumors are excluded)
* Any advanced solid tumor, with the exception of colorectal carcinoma (CRC), which is Microsatellite Instability (MSI)-High (MSI-H) OR
* Any advanced solid tumor (including Colorectal Carcinoma \[CRC\]) which is Mismatch Repair Deficient (dMMR)/MSI-H in participants from mainland China who are of Chinese descent. (CRC participants will have a histologically proven locally advanced unresectable or metastatic CRC which is dMMR/MSI-H that has received 2 prior lines of therapy) OR
* Any advanced solid tumor that has failed at least one line of therapy and is TMB-H (≥10 mut/Mb, F1CDx assay), excluding dMMR/MSI-H tumors.

Note: For participants to be eligible for enrollment they must have failed at least one line of standard of care systemic therapy (ie, not treatment naïve), with the exception of CRC participants who must have failed at least 2 lines of standard of care systemic therapy, as per CRC specific eligibility criteria. Participants must not have melanoma or NSCLC.

* Progression of tumor or intolerance to therapies known to provide clinical benefit. There is no limit to the number of prior treatment regimens
* Can supply tumor tissue for study analyses (dependent on tumor type)
* Radiologically-measurable disease
* Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale within 3 days prior to first dose of pembrolizumab
* Life expectancy of at least 3 months
* Adequate organ function
* Female participants of childbearing potential must be willing to use adequate contraception during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. The length of time required to continue contraception for each study intervention is as follows: MK-3475 (120 days)

Exclusion Criteria:

* Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of study treatment
* Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment
* Active autoimmune disease that has required systemic treatment in the past 2 years
* Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or not recovered from an adverse event caused by mAbs administered more than 4 weeks earlier
* Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks of study Day 1 or not recovered from adverse events caused by a previously administered agent
* Known additional malignancy within 2 years prior to enrollment with the exception of curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin and/or curatively resected in situ cancers
* Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
* Has known glioblastoma multiforme of the brain stem
* Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
* Active infection requiring systemic therapy
* Known psychiatric or substance abuse disorders that would interfere with the participant's ability to cooperate with the requirements of the study
* Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment
* Previously participated in any other pembrolizumab (MK-3475) study, or received prior therapy with an anti-programmed cell death (PD)-1, anti-PD-Ligand 1 (anti-PD-L1), anti-PD-Ligand 2 (anti-PD-L2), or any other immunomodulating mAb or drug specifically targeting T-cell co-stimulation or checkpoint pathways
* Known history of Human Immunodeficiency Virus (HIV)
* Known active Hepatitis B or C
* Received live vaccine within 30 days of planned start of study treatment
* Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
* Known history of active tuberculosis (TB, Bacillus tuberculosis)
* Has had an allogenic tissue/solid organ transplant.

Primary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: Up to approximately 10.5 years
Secondary outcomes:
measure: Duration of Response (DOR)
timeFrame: Up to approximately 10.5 years
measure: Progression Free Survival (PFS)
timeFrame: Up to approximately 10.5 years
measure: Overall Survival (OS)
timeFrame: Up to approximately 10.5 years
measure: Percentage of Participants with Adverse Events (AEs)
timeFrame: Up to approximately 27 months
measure: Percentage of Participants who Discontinue Study Intervention due to AEs
timeFrame: Up to approximately 2 years
Other outcomes:
Locations:
city: New Brunswick
country: United States
facility: Call for Information (Investigational Site 0008)
state: New Jersey
city: Sao Paulo
country: Brazil
facility: MSD Brasil
city: Santiago
country: Chile
facility: Merck Sharp & Dohme (I.A.) Corp.
city: Bogota
country: Colombia
facility: MDS Colombia SAS
city: Glostrup
country: Denmark
facility: MSD Denmark
city: Paris
country: France
facility: MSD France
city: Hod Hasharon
country: Israel
facility: Merck Sharp & Dohme Co. Ltd.
city: Rome
country: Italy
facility: MSD Italia S.r.l.
city: Seoul
country: Korea, Republic of
facility: MSD Korea LTD
city: Mexico City
country: Mexico
facility: MSD Comercializadora, S. de R.L. de C.V.
city: Haarlem
country: Netherlands
facility: Merck Sharp & Dohme BV
city: Lima
country: Peru
facility: Merck Sharp & Dohme, Peru S.R.L.
city: Warsaw
country: Poland
facility: MSD Polska Sp. Z o.o.
city: Paco D'arcos
country: Portugal
facility: Merck Sharp & Dohme Lda.
city: Moscow
country: Russian Federation
facility: Merck Sharp & Dohme IDEA, Inc.
city: Midrand
country: South Africa
facility: MSD (Pty) LTD South Africa
city: Madrid
country: Spain
facility: Merck Sharp and Dohme de Espana S.A.
city: Taipei
country: Taiwan
facility: Merck Sharp & Dohme (I.A.) Corp.
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord JP, Geva R, Gottfried M, Penel N, Hansen AR, Piha-Paul SA, Doi T, Gao B, Chung HC, Lopez-Martin J, Bang YJ, Frommer RS, Shah M, Ghori R, Joe AK, Pruitt SK, Diaz LA Jr. Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol. 2020 Jan 1;38(1):1-10. doi: 10.1200/JCO.19.02105. Epub 2019 Nov 4.
citation: O'Malley DM, Bariani GM, Cassier PA, Marabelle A, Hansen AR, De Jesus Acosta A, Miller WH Jr, Safra T, Italiano A, Mileshkin L, Amonkar M, Yao L, Jin F, Norwood K, Maio M. Health-related quality of life with pembrolizumab monotherapy in patients with previously treated advanced microsatellite instability high/mismatch repair deficient endometrial cancer in the KEYNOTE-158 study. Gynecol Oncol. 2022 Aug;166(2):245-253. doi: 10.1016/j.ygyno.2022.06.005. Epub 2022 Jul 11.
citation: Even C, Delord JP, Price KA, Nakagawa K, Oh DY, Burge M, Chung HC, Doi T, Fakih M, Takahashi S, Yao L, Jin F, Norwood K, Hansen AR. Evaluation of pembrolizumab monotherapy in patients with previously treated advanced salivary gland carcinoma in the phase 2 KEYNOTE-158 study. Eur J Cancer. 2022 Aug;171:259-268. doi: 10.1016/j.ejca.2022.05.007. Epub 2022 Jun 28.
citation: Maio M, Ascierto PA, Manzyuk L, Motola-Kuba D, Penel N, Cassier PA, Bariani GM, De Jesus Acosta A, Doi T, Longo F, Miller WH, Oh DY, Gottfried M, Xu L, Jin F, Norwood K, Marabelle A. Pembrolizumab in microsatellite instability high or mismatch repair deficient cancers: updated analysis from the phase II KEYNOTE-158 study. Ann Oncol. 2022 Sep;33(9):929-938. doi: 10.1016/j.annonc.2022.05.519. Epub 2022 Jun 6.
citation: Maio M, Amonkar MM, Norquist JM, Ascierto PA, Manzyuk L, Motola-Kuba D, Penel N, Cassier PA, Bariani GM, De Jesus Acosta A, Doi T, Longo F, Miller WH Jr, Oh DY, Gottfried M, Wang R, Norwood K, Marabelle A. Health-related quality of life in patients treated with pembrolizumab for microsatellite instability-high/mismatch repair-deficient advanced solid tumours: Results from the KEYNOTE-158 study. Eur J Cancer. 2022 Jul;169:188-197. doi: 10.1016/j.ejca.2022.03.040. Epub 2022 May 16.
citation: Shapira-Frommer R, Mileshkin L, Manzyuk L, Penel N, Burge M, Piha-Paul SA, Girda E, Lopez Martin JA, van Dongen MGJ, Italiano A, Xu L, Jin F, Norwood K, Ott PA. Efficacy and safety of pembrolizumab for patients with previously treated advanced vulvar squamous cell carcinoma: Results from the phase 2 KEYNOTE-158 study. Gynecol Oncol. 2022 Aug;166(2):211-218. doi: 10.1016/j.ygyno.2022.01.029. Epub 2022 Mar 28.
citation: Marabelle A, Cassier PA, Fakih M, Kao S, Nielsen D, Italiano A, Guren TK, van Dongen MGJ, Spencer K, Bariani GM, Ascierto PA, Santoro A, Shah M, Asselah J, Iqbal S, Takahashi S, Piha-Paul SA, Ott PA, Chatterjee A, Jin F, Norwood K, Delord JP. Pembrolizumab for previously treated advanced anal squamous cell carcinoma: results from the non-randomised, multicohort, multicentre, phase 2 KEYNOTE-158 study. Lancet Gastroenterol Hepatol. 2022 May;7(5):446-454. doi: 10.1016/S2468-1253(21)00382-4. Epub 2022 Feb 1.
citation: O'Malley DM, Bariani GM, Cassier PA, Marabelle A, Hansen AR, De Jesus Acosta A, Miller WH Jr, Safra T, Italiano A, Mileshkin L, Xu L, Jin F, Norwood K, Maio M. Pembrolizumab in Patients With Microsatellite Instability-High Advanced Endometrial Cancer: Results From the KEYNOTE-158 Study. J Clin Oncol. 2022 Mar 1;40(7):752-761. doi: 10.1200/JCO.21.01874. Epub 2022 Jan 6.
citation: Yap TA, Nakagawa K, Fujimoto N, Kuribayashi K, Guren TK, Calabro L, Shapira-Frommer R, Gao B, Kao S, Matos I, Planchard D, Chatterjee A, Jin F, Norwood K, Kindler HL. Efficacy and safety of pembrolizumab in patients with advanced mesothelioma in the open-label, single-arm, phase 2 KEYNOTE-158 study. Lancet Respir Med. 2021 Jun;9(6):613-621. doi: 10.1016/S2213-2600(20)30515-4. Epub 2021 Apr 6.
citation: Marabelle A, Fakih M, Lopez J, Shah M, Shapira-Frommer R, Nakagawa K, Chung HC, Kindler HL, Lopez-Martin JA, Miller WH Jr, Italiano A, Kao S, Piha-Paul SA, Delord JP, McWilliams RR, Fabrizio DA, Aurora-Garg D, Xu L, Jin F, Norwood K, Bang YJ. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 2020 Oct;21(10):1353-1365. doi: 10.1016/S1470-2045(20)30445-9. Epub 2020 Sep 10.
citation: Piha-Paul SA, Oh DY, Ueno M, Malka D, Chung HC, Nagrial A, Kelley RK, Ros W, Italiano A, Nakagawa K, Rugo HS, de Braud F, Varga AI, Hansen A, Wang H, Krishnan S, Norwood KG, Doi T. Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: Results from the KEYNOTE-158 and KEYNOTE-028 studies. Int J Cancer. 2020 Oct 15;147(8):2190-2198. doi: 10.1002/ijc.33013. Epub 2020 May 2.
citation: Strosberg J, Mizuno N, Doi T, Grande E, Delord JP, Shapira-Frommer R, Bergsland E, Shah M, Fakih M, Takahashi S, Piha-Paul SA, O'Neil B, Thomas S, Lolkema MP, Chen M, Ibrahim N, Norwood K, Hadoux J. Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Neuroendocrine Tumors: Results From the Phase II KEYNOTE-158 Study. Clin Cancer Res. 2020 May 1;26(9):2124-2130. doi: 10.1158/1078-0432.CCR-19-3014. Epub 2020 Jan 24.
citation: Chung HC, Ros W, Delord JP, Perets R, Italiano A, Shapira-Frommer R, Manzuk L, Piha-Paul SA, Xu L, Zeigenfuss S, Pruitt SK, Leary A. Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol. 2019 Jun 10;37(17):1470-1478. doi: 10.1200/JCO.18.01265. Epub 2019 Apr 3.