Pembrolizumab in Treating Patients With Advanced Merkel Cell Cancer

• ClinicalTrials.gov Identifier: NCT02267603
• Recruitment Status: Completed
• First Posted: October 17, 2014
• Results First Posted: March 1, 2019
• Last Update Posted: July 5, 2023
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Study Description

Brief Summary:

This phase II trial studies how well pembrolizumab works in treating patients with Merkel cell cancer that cannot be removed by surgery or controlled with treatment, or has spread to other parts of the body. Pembrolizumab may stimulate the immune system to identify and destroy cancer cells.

Condition or disease	Intervention/treatment	Phase
Recurrent Merkel Cell Carcinoma; Stage III Merkel Cell Carcinoma AJCC v7; Stage IIIA Merkel Cell Carcinoma AJCC v7; Stage IIIB Merkel Cell Carcinoma AJCC v7; Stage IV Merkel Cell Carcinoma AJCC v7	Other: Laboratory Biomarker Analysis; Biological: Pembrolizumab	Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the clinical efficacy of MK-3475 (pembrolizumab) as the first systemic intervention for patients with advanced Merkel cell carcinoma (MCC).

SECONDARY OBJECTIVES:

I. To determine the clinical activity of MK-3475 as the first systemic intervention for patients with advanced MCC.

TERTIARY OBJECTIVES:

I. To determine the immune correlates of the clinical activity of MK-3475.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 24 months in the absence of disease progression* or unacceptable toxicity.

* NOTE: Patients with confirmed disease progression may continue to receive treatment if they are otherwise clinically stable until there is an increase in tumor burden of 25% or more following initial confirmation of progression. Under exceptional circumstances, and with protocol principal investigator (P.I.) and Cancer Immunotherapy Trials Network (CITN) P.I. approval, patients may receive treatment beyond 2 years.

After completion of study treatment, patients are followed up at 30 days and then every 3 months for 1 year, every 6 months for 2 years, annually until the patient has completed 3 years of follow up for disease assessment, and then every 12 weeks.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 50 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of MK-3475 in Patients With Advanced Merkel Cell Carcinoma (MCC)
• Actual Study Start Date: November 25, 2014
• Actual Primary Completion Date: February 6, 2018
• Actual Study Completion Date: December 15, 2021

Arms and Interventions

Arm

Intervention/treatment

Experimental: Treatment (pembrolizumab); Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 24 months in the absence of disease progression* or unacceptable toxicity. * NOTE: Patients with confirmed disease progression may continue to receive treatment if they are otherwise clinically stable until there is an increase in tumor burden of 25% or more following initial confirmation of progression. Under exceptional circumstances, and with protocol P.I. and CITN P.I. approval, patients may receive treatment beyond 2 years.

Other: Laboratory Biomarker Analysis; Ancillary studies; Biological: Pembrolizumab; Given IV; Other Names: Keytruda; Lambrolizumab; MK-3475; SCH 900475

Outcome Measures

Primary Outcome Measures :

1. Objective Response Rate (ORR) Defined as the Proportion of Patients Who Have Achieved Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [ Time Frame: Up to 3 years ]
   ORR will be estimated as the number of responders as a percent of the number of eligible participants who received at least one dose of treatment. If a substantial amount of data is missing, analyses will be performed using parametric generalized linear models fit by maximum likelihood. A generalized linear model for the ORR will use a binomial error distribution. The model will include as covariates all available baseline predictors of the missing outcomes. Responses to continued pembrolizumab will be chronicled and reported.

Secondary Outcome Measures :

1. Progression-free Survival (PFS) Using RECIST 1.1 [ Time Frame: Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 16 months ]
   Survival curves for PFS will be estimated using the Kaplan-Meier method. Assessed percentage of participants with progression free survival up to 16 months.
2. Duration of Response (DOR) [ Time Frame: Time interval between the date of first response (CR/PR) and the date of progression, assessed up to 3 years ]
   Survival curves for DOR will be estimated using the Kaplan-Meier method.
3. Overall Survival (OS) [ Time Frame: Time interval between the start of treatment to death due to any cause, assessed up to 60 months. ]
   Survival curves for OS will be estimated using the Kaplan-Meier method.
4. Incidence of Adverse Events (AEs) Graded Using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 [ Time Frame: Up to 90 days post-treatment ]
   Safety will be assessed by quantifying the toxicities and grades experienced by subjects including serious AEs (SAEs) and events of clinical interest. Safety and tolerability will be assessed by clinical review of all relevant parameters including AEs, laboratory tests, vital signs, and electrocardiogram measurements. Assessed number of participants who experienced grade 3 to 5 adverse events.

Other Outcome Measures:

1. Immune Correlates of the Clinical Activity of Pembrolizumab [ Time Frame: Baseline ]
   This will include immunohistochemical and gene expression analysis focusing on delineating the immune components and immunologic milieu within the tumor before therapy.
2. Merkel Polyomavirus (MCPyV)-Specific Immune Response, Assessed With Enzyme-linked Immunosorbent Spot and Serology Assays [ Time Frame: After 2 years of treatment ]
   Responses will be assessed at baseline, after initiating therapy, and correlated with clinical responses over time. Among patients with corresponding MHC-peptide tetramers, pre- and post-treatment samples of circulating MCPyV-specific CD8 T cells will be isolated and subjected to deep immunophenotyping by messenger ribonucleic acid (mRNA) expression analysis.

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:

• Patients must have biopsy-proven metastatic MCC or locoregional MCC that has recurred following standard locoregional therapy with surgery and/or radiation therapy

• Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessed by computed tomography (CT) scan, or for skin lesions not measurable by CT scan, measurements may be performed with caliper or flexible ruler

  • Note: stage IV no evidence of disease (NED) is excluded by this criterion
• Have a performance status of =< 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
• Life expectancy of greater than 6 months
• Leukocytes >= 2,000/mcL (labs should be performed within 14 days of treatment initiation)
• Absolute neutrophil count >= 1,500/mcL (labs should be performed within 14 days of treatment initiation)
• Platelets >= 100,000/mcL (labs should be performed within 14 days of treatment initiation)
• Hemoglobin >= 9 g/dL OR >= 5.6 mmol/L (labs should be performed within 14 days of treatment initiation)
• Serum total bilirubin =< 1.5 x upper limit of normal (ULN) OR direct bilirubin =< ULN for patients with total bilirubin levels > 1.5 x ULN (labs should be performed within 14 days of treatment initiation)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN OR =< 5 x ULN for patients with liver metastases (labs should be performed within 14 days of treatment initiation)

• Serum creatinine =< 2.5 x ULN OR measured or calculated* creatinine clearance (CrCl) (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 30 mL/min for subject with creatinine levels > 2.5 x institutional ULN

  • Creatinine clearance should be calculated per institutional standard (labs should be performed within 14 days of treatment initiation)
• Thyroid stimulating hormone (TSH) within institutional limits (i.e.: normal); if TSH is greater or less than institutional limits patients may participate if their T4 is within normal limits (WNL); patients may be on a stable dose of replacement thyroid medication; dose adjustments are allowed if needed (labs should be performed within 14 days of treatment initiation)

• Patients must provide tissue from an archival tumor sample or newly obtained core, punch or excisional biopsy of a tumor lesion if deemed relatively safe and technically feasible

  • Note: newly obtained biopsy is preferable

• Female patients of childbearing potential must have a negative urine or serum pregnancy within 72 hours before 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

  • Note: women of child-bearing potential must agree to use 2 methods of birth control, or be surgically sterile, or abstain from heterosexual activity beginning with the screening visit and for the duration of study participation, through 120 days beyond last dose of MK-3475 administration; patients of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
• Men treated or enrolled on this protocol must agree to use 2 adequate methods of contraception starting with the screening visit, for the duration of study participation, and through 120 days after the last dose of MK-3475 administration
• Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria:

• Patient has had prior systemic therapy for MCC

  • Note: prior systemic cytotoxic chemotherapy will be allowed if it was administered in the adjuvant setting (no clinically detectable MCC at the time) and treatment concluded more than 6 months prior to beginning study treatment

• Patient is currently participating in or has participated in a study of an investigational systemic agent to treat MCC; or is using an investigational device within 4 weeks of the first dose of treatment

  • NOTE: if patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
  • Toxicity from surgery or associated interventions that has not recovered to =< grade 1 is allowed if it meets the inclusion requirements for laboratory parameters
• Patients with locoregional disease that have not received appropriate standard locoregional therapy with surgery and/or radiation therapy
• Patient has had radiation therapy within 2 weeks of beginning study treatment
• Toxicity from prior radiation therapy has NOT resolved to grade 1 or less
• Patient has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of trial treatment
• Patient has had a prior monoclonal antibody for treatment of MCC
• Patient has had a prior monoclonal antibody for a non-cancer therapy indication within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events (AEs) due to agents administered more than 4 weeks earlier
• Patient 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

• Patient has known active central nervous system (CNS) metastases and/or carcinomatous meningitis

  • Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 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
• Patient has a history of allergic reactions attributed to compounds of similar chemical or biologic composition to MK-3475
• Patient has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents; patients with vitiligo or resolved childhood asthma/atopy would be an exception to this rule; patients that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study; the use of physiologic doses of corticosteroids may be approved after consultation with the protocol principal investigator (PI) and Cancer Immunotherapy Trials Network (CITN); patients with hypothyroidism stable on hormone replacement or Sjogren's syndrome will not be excluded from the study
• Patient has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator
• Patient has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Patient has uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, interstitial lung disease, non-infectious pneumonitis, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

• Patient 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

  • NOTE: pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with MK-3475
  • Men and nonpregnant, non-breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or are considered highly unlikely to conceive; highly unlikely to conceive is defined as (1) surgically sterilized, or (2) postmenopausal (a woman who is >= 45 years of age and has not had menses for greater than 1 year will be considered postmenopausal), or (3) not heterosexually active for the duration of the study; the 2 birth control methods can be barrier method or a barrier method plus a hormonal method to prevent pregnancy; subjects should start using birth control from the screening visit throughout the study period up to 120 days after the last dose of study therapy
  • The following are considered adequate barrier methods of contraception: diaphragm, condom (by the partner), copper intrauterine device, sponge, or spermicide; appropriate hormonal contraceptives will include any registered and marketed contraceptive agent that contains an estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents)
  • Patients should be informed that taking the study medication may involve unknown risks to the fetus (unborn baby) if pregnancy were to occur during the study; in order to participate in the study, they must adhere to the contraception requirement (described above) for the duration of the study and during the follow-up period described above; if there is any question that a subject will not reliably comply with the requirements for contraception, that subject should not be entered into the study
  • Pregnancy: if a patient inadvertently becomes pregnant while on treatment with MK-3475, the patient will immediately be removed from the study; the site will contact the patient at least monthly and document the patient's status until the pregnancy has been completed or terminated; the outcome of the pregnancy will be reported without delay and within 24 hours if the outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other disabling or life-threatening complication to the mother or newborn); the study investigator will make every effort to obtain permission to follow the outcome of the pregnancy and report the condition of the fetus or newborn; if a male patient impregnates his female partner the study personnel at the site must be informed immediately and the pregnancy reported and followed
  • Subjects who are breast-feeding are not eligible for enrollment
• Patient is human immunodeficiency virus (HIV) positive

Note: patients who are human immunodeficiency virus (HIV) positive may participate IF they meet the following eligibility requirements:

• They must be stable on their anti-retroviral regimen, and they must be healthy from an HIV perspective
• They must have a cluster of differentiation (CD)4 count of greater than 250 cells/mcL

• They must not be receiving prophylactic therapy for an opportunistic infection

  • Patient has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)

• Note: a positive hepatitis B serology indicative of previous immunization (i.e., hepatitis B surface antibody [HBsAb]-positive and hepatitis B core antibody [HBcAb]-negative) or a fully resolved acute hepatitis B infection is not an exclusion criterion

  • Has active non-infectious pneumonitis >= grade 2; or history of grade 3 non-infectious pneumonitis within the past 12 months; or any history of grade 4 non-infectious pneumonitis
  • History of other pulmonary disease such as emphysema or chronic obstructive pulmonary disease (COPD), (forced expiratory volume in 1 second [FEV1] < 60% of predicted for height and age); pulmonary function tests (PFTs) are required in patients with prolonged smoking history or symptoms of respiratory dysfunction
  • Cardiovascular disease that meets one of the following: congestive heart failure (New York Heart Association class III or IV), active angina pectoris, or recent myocardial infarction (within the last 6 months)
  • Prior organ allograft or allogeneic transplantation, if the transplanted tissue is still in place
  • Patient has had live vaccines within 30 days before the first dose of trial treatment and while participating in the trial; examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, seasonal flu, H1N1 flu, rabies, bacille de Calmette et Guérin (BCG), and typhoid vaccine

Contacts and Locations

Locations

United States, California

Stanford Cancer Institute Palo Alto

Palo Alto, California, United States, 94304

UCSF Medical Center-Mount Zion

San Francisco, California, United States, 94115

United States, Connecticut

Yale University

New Haven, Connecticut, United States, 06520

United States, Florida

Moffitt Cancer Center

Tampa, Florida, United States, 33612

United States, Georgia

Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia, United States, 30322

United States, Louisiana

Louisiana State University Health Science Center

New Orleans, Louisiana, United States, 70112

University Medical Center New Orleans

New Orleans, Louisiana, United States, 70112

United States, Maryland

Johns Hopkins University/Sidney Kimmel Cancer Center

Baltimore, Maryland, United States, 21287

United States, New York

Mount Sinai Hospital

New York, New York, United States, 10029

United States, North Carolina

Duke University Medical Center

Durham, North Carolina, United States, 27710

United States, Ohio

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, United States, 43210

United States, Pennsylvania

University of Pittsburgh Cancer Institute (UPCI)

Pittsburgh, Pennsylvania, United States, 15232

United States, Washington

Seattle Cancer Care Alliance

Seattle, Washington, United States, 98109

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Paul Nghiem; Cancer Immunotherapy Trials Network

  Study Documents (Full-Text)

Documents provided by National Cancer Institute (NCI):

Study Protocol and Statistical Analysis Plan  [PDF] May 22, 2018

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Nghiem P, Bhatia S, Lipson EJ, Sharfman WH, Kudchadkar RR, Brohl AS, Friedlander PA, Daud A, Kluger HM, Reddy SA, Boulmay BC, Riker A, Burgess MA, Hanks BA, Olencki T, Kendra K, Church C, Akaike T, Ramchurren N, Shinohara MM, Salim B, Taube JM, Jensen E, Kalabis M, Fling SP, Homet Moreno B, Sharon E, Cheever MA, Topalian SL. Three-year survival, correlates and salvage therapies in patients receiving first-line pembrolizumab for advanced Merkel cell carcinoma. J Immunother Cancer. 2021 Apr;9(4):e002478. doi: 10.1136/jitc-2021-002478.

Nghiem P, Bhatia S, Lipson EJ, Sharfman WH, Kudchadkar RR, Brohl AS, Friedlander PA, Daud A, Kluger HM, Reddy SA, Boulmay BC, Riker AI, Burgess MA, Hanks BA, Olencki T, Margolin K, Lundgren LM, Soni A, Ramchurren N, Church C, Park SY, Shinohara MM, Salim B, Taube JM, Bird SR, Ibrahim N, Fling SP, Homet Moreno B, Sharon E, Cheever MA, Topalian SL. Durable Tumor Regression and Overall Survival in Patients With Advanced Merkel Cell Carcinoma Receiving Pembrolizumab as First-Line Therapy. J Clin Oncol. 2019 Mar 20;37(9):693-702. doi: 10.1200/JCO.18.01896. Epub 2019 Feb 6.

Nghiem PT, Bhatia S, Lipson EJ, Kudchadkar RR, Miller NJ, Annamalai L, Berry S, Chartash EK, Daud A, Fling SP, Friedlander PA, Kluger HM, Kohrt HE, Lundgren L, Margolin K, Mitchell A, Olencki T, Pardoll DM, Reddy SA, Shantha EM, Sharfman WH, Sharon E, Shemanski LR, Shinohara MM, Sunshine JC, Taube JM, Thompson JA, Townson SM, Yearley JH, Topalian SL, Cheever MA. PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma. N Engl J Med. 2016 Jun 30;374(26):2542-52. doi: 10.1056/NEJMoa1603702. Epub 2016 Apr 19.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT02267603
• Other Study ID Numbers: NCI-2014-00848; NCI-2014-00848 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); MK-3475; CITN-09; CITN-09 ( Other Identifier: Cancer Immunotherapy Trials Network ); CITN-09 ( Other Identifier: CTEP ); K24CA139052 ( U.S. NIH Grant/Contract ); P30CA015704 ( U.S. NIH Grant/Contract ); U01CA154967 ( U.S. NIH Grant/Contract )
• First Posted: October 17, 2014
• Results First Posted: March 1, 2019
• Last Update Posted: July 5, 2023
• Last Verified: June 2023

Additional relevant MeSH terms:

Carcinoma, Merkel Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Polyomavirus Infections; DNA Virus Infections; Virus Diseases; Infections; Tumor Virus Infections; Carcinoma, Neuroendocrine; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Adenocarcinoma; Neoplasms, Nerve Tissue; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action