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Pembrolizumab in Treating Patients With Desmoplastic Melanoma That Can or Cannot Be Removed by Surgery

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ClinicalTrials.gov Identifier: NCT02775851
Recruitment Status : Recruiting
First Posted : May 18, 2016
Last Update Posted : May 20, 2020
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE May 16, 2016
First Posted Date  ICMJE May 18, 2016
Last Update Posted Date May 20, 2020
Actual Study Start Date  ICMJE October 20, 2016
Estimated Primary Completion Date December 1, 2028   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 2, 2018)
  • Pathologic complete response (pCR) rate (Cohort A) [ Time Frame: Up to 5 years ]
    Pathologic complete response is defined as no evidence of viable tumor cells on complete pathological evaluation of the surgical specimen per institutional standard of care. Will assess the association between overall mutational load and pCR rate.
  • Complete response (CR) rate (Cohort B) [ Time Frame: Up to 5 years ]
    Complete response defined as disappearance of all target and non-target lesions. Will assess the association between overall mutational load and CR rate.
Original Primary Outcome Measures  ICMJE
 (submitted: May 16, 2016)
  • Complete response rate (Cohort B) [ Time Frame: Up to 5 years ]
    Complete response defined as disappearance of all target and non-target lesions.
  • Pathologic complete response rate (Cohort A) [ Time Frame: Up to 5 years ]
    Pathologic complete response is defined as no evidence of viable tumor cells on complete pathological evaluation of the surgical specimen per institutional standard of care.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 31, 2019)
  • Overall response rate (Cohort A) [ Time Frame: At 9 weeks ]
    Estimated with a 95% confidence interval.
  • Overall survival rate (Cohort A and B) [ Time Frame: At 9 weeks ]
    Estimated with a 95% confidence interval.
  • Progression free survival (Cohort A and B) [ Time Frame: At 9 weeks ]
    Estimated with a 95% confidence interval.
  • Incidence of toxicity (Cohort A) [ Time Frame: Up to 9 weeks ]
    Will be measured by the National Cancer Institute Common Terminology for Adverse Events version 4.0. Toxicity will be assessed across all patients receiving pembrolizumab.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 16, 2016)
  • Incidence of toxicity as measured by the National Cancer Institute Common Terminology for Adverse Events version 4.0 (Cohort A) [ Time Frame: Up to 9 weeks ]
  • OS rate [ Time Frame: At 9 weeks ]
    Estimated with a 95% confidence interval
  • Overall response rate (Cohort A) [ Time Frame: At 9 weeks ]
    Estimated with a 95% confidence interval
  • PFS [ Time Frame: At 9 weeks ]
    Estimated with a 95% confidence interval
Current Other Pre-specified Outcome Measures
 (submitted: March 2, 2018)
  • Change in CD8 expression (Cohort A and B) [ Time Frame: Baseline up to week 9 ]
    Will examine whether change in T-cell infiltration following treatment is higher in the DM patients who respond. The change in CD8 expression will be computed and compared to the change between responders and non-responders using a two-sample t-test.
  • Change in T-cell receptor clonality (Cohort A and B) [ Time Frame: Baseline up to week 9 ]
    Will be compared between responders and non-responders using a two-sample t-test with significance determined at the two-sided alpha=0.05 level.
  • Change in PD-L1 expression (Cohort A and B) [ Time Frame: Baseline up to week 9 ]
    Will examine adaptive immune resistance by first evaluating whether PD-L1 expression is increased at week 4 and week 9 as compared to baseline using paired t-tests and controlling the type I error at the two-sided alpha=0.05 level. The change in expression will be computed and then compared to the change between responders and non-responders using a two-sample t-test.
Original Other Pre-specified Outcome Measures
 (submitted: May 16, 2016)
  • Change in CD8 expression (Cohort A) [ Time Frame: Baseline up to week 9 ]
    Will examine whether change in T-cell infiltration following treatment is higher in the DM patients who respond. The change in CD8 expression will be computed and compared to the change between responders and non-responders using a two-sample t-test.
  • Change in PD-L1 expression (Cohort A) [ Time Frame: Baseline up to week 9 ]
    Will examine adaptive immune resistance by first evaluating whether PD-L1 expression is increased at week 4 and week 9 as compared to baseline using paired t-tests and controlling the type I error at the two-sided alpha=0.05 level. The change in expression will be computed and then compared to the change between responders and non-responders using a two-sample t-test.
  • Change in TCR clonality (Cohort A) [ Time Frame: Baseline up to week 9 ]
    Will be compared between responders and non-responders using a two-sample t-test with significance determined at the two-sided alpha=0.05 level.
 
Descriptive Information
Brief Title  ICMJE Pembrolizumab in Treating Patients With Desmoplastic Melanoma That Can or Cannot Be Removed by Surgery
Official Title  ICMJE A Phase II and Pilot Trial of PD-1 Blockade With MK-3475 (Pembrolizumab) in Patients With Resectable or Unresectable Desmoplastic Melanoma (DM)
Brief Summary This pilot phase II trial studies how well pembrolizumab works in treating patients with desmoplastic melanoma (DM) that can be removed by surgery (resectable) or cannot be removed by surgery (unresectable). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.
Detailed Description

PRIMARY OBJECTIVES:

I. To evaluate the pathologic complete response rate (pCR) in patients with resectable desmoplastic melanoma treated with neoadjuvant MK-3475 (pembrolizumab). (Cohort A) II. To evaluate the complete response rate (confirmed and unconfirmed) in patients with unresectable desmoplastic melanoma treated with MK-3475 (pembrolizumab). (Cohort B)

SECONDARY OBJECTIVES:

I. To estimate the 9 week response rate (RR) (unconfirmed complete and partial responses) among patients with measurable disease. (Cohort A) II. To estimate the median overall survival (OS). (Cohort A) III. To evaluate safety and tolerability of MK-3475 (pembrolizumab) in the neoadjuvant setting. (Cohort A) IV. To estimate the median progression-free survival (PFS). (Cohort B) V. To estimate the median overall survival (OS). (Cohort B) VI. To evaluate safety and tolerability of MK-3475 (pembrolizumab) in this setting. (Cohort B)

OTHER OBJECTIVES:

I. To evaluate the hypothesis that higher mutational load in the patient derived baseline tumor biopsy samples is associated with higher pathologic complete response (pCR).

II. To evaluate T cell infiltration into the tumors in DM patients and correlate with response to programmed cell death protein 1 (PD-1) blockade.

III. To evaluate the clonality of tumor infiltrating T cells in DM patients and correlate with response to PD-1 blockade.

IV. To evaluate adaptive immune resistant mechanism in DM tumors.

OUTLINE: Patients are assigned to 1 of 2 cohorts.

COHORT A: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 3 cycles. Patients with potentially resectable disease undergo surgery. Patients with tumor progression and unresectable disease may receive one additional cycle of pembrolizumab.

COHORT B: Patients with unresectable disease receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 34 cycles in the absence of disease progression or toxicity.

After completion of study treatment, patients are followed up at 6 and 12 weeks, then every 3 months for 1 year, and every 6 months for 4 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Desmoplastic Melanoma
Intervention  ICMJE
  • Biological: Pembrolizumab
    Given IV
    Other Names:
    • Keytruda
    • Lambrolizumab
    • MK-3475
    • SCH 900475
  • Procedure: Therapeutic Conventional Surgery
    Undergo surgical resection
Study Arms  ICMJE
  • Experimental: Cohort A (pembrolizumab, surgery)
    Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 3 cycles. Patients with potentially resectable disease undergo surgery. Patients with tumor progression and unresectable disease may receive one additional cycle of pembrolizumab.
    Interventions:
    • Biological: Pembrolizumab
    • Procedure: Therapeutic Conventional Surgery
  • Active Comparator: Cohort B (pembrolizumab)
    Patients with unresectable disease receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 34 cycles in the absence of disease progression or toxicity.
    Intervention: Biological: Pembrolizumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 4, 2019)
56
Original Estimated Enrollment  ICMJE
 (submitted: May 16, 2016)
67
Study Completion Date  ICMJE Not Provided
Estimated Primary Completion Date December 1, 2028   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • COHORT A: Patients must have histologically or cytologically confirmed primary desmoplastic melanoma that is deemed resectable; the decision to perform surgery on patients must be based on good clinical judgment; eligible patients for surgical resection must have disease that, in the judgment of the surgeon, is deemed completely resectable resulting in free surgical margins; patients must have residual disease after initial biopsy which can be measurable or non-measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; residual disease can either be confirmed with fine-needle aspiration (FNA) or if measurable disease is present, no FNA needs to be obtained OR
  • COHORT B: Patients must have histologically or cytologically confirmed primary desmoplastic melanoma that is unresectable; patients in Cohort B must have measurable disease per RECIST 1.1
  • Contrast-enhanced computed tomography (CT) scans of the chest, abdomen and pelvis are required; a whole body positron emission tomography (PET)/CT scan with diagnostic quality images and intravenous iodinated contrast may be used in lieu of a contrast enhanced CT of the chest, abdomen and pelvis; imaging of the head and neck is required only if the patient has a head/neck primary; contrast may be omitted if the treating investigator believes that exposure to contrast poses an excessive risk to the patient; if skin lesions are being followed as measurable disease, photograph with a ruler included and physician measurements, must be kept in the patient's chart as source documentation; all measurable lesions must be assessed within 28 days prior to registration; tests to assess non-measurable disease must be performed within 42 days prior to registration; all disease must be assessed and documented on the baseline tumor assessment form (RECIST 1.1)
  • Patients must not have known brain metastases unless brain metastases have been treated and patient is asymptomatic with no residual neurological dysfunction and has not received enzyme-reducing anti-epileptic drugs or corticosteroids for at least 14 days prior to registration
  • Patients must not have received prior systemic treatment for this melanoma
  • Patients must not be planning to receive concomitant other biologic therapy, radiation therapy, hormonal therapy, other chemotherapy, anti-cancer surgery or other anti-cancer therapy while on this protocol
  • Patients must not have received radiation therapy, non-cytotoxic agents or investigational agents or systemic corticosteroids within 14 days prior to registration
  • Patients may have received prior surgery; all adverse events associated with prior surgery must have resolved to =< grade 1 (per Common Terminology Criteria for Adverse Events [CTCAE] 4.0) prior to registration
  • Absolute neutrophil count (ANC) >= 1,500/mcl (obtained within 28 days prior to registration)
  • Platelets >= 50,000/mcl (obtained within 28 days prior to registration)
  • Hemoglobin >= 8 g/dL (obtained within 28 days prior to registration)
  • Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (or =< 3.0 x IULN with Gilbert's syndrome) (obtained within 28 days prior to registration)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (or < 5 x IULN for patients with known liver metastases) (obtained within 28 days prior to registration)
  • Patients must have lactate dehydrogenase (LDH) performed within 28 days prior to registration
  • Patients must have Zubrod performance status =< 2
  • Patients must not have history of (non-infectious) pneumonitis that required steroids or current pneumonitis
  • Patients must not have an active infection requiring systemic therapy
  • Patients must not have active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
  • Patients must not have received live vaccines within 42 days prior to registration; examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, shingles, yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid (oral) vaccine; seasonal influenza vaccines for injection are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist) are not allowed
  • Patients known to be human immunodeficiency virus (HIV) positive are eligible if they meet the following criteria within 30 days prior to registration: stable and adequate CD4 counts (>= 350 mm^3), and serum HIV viral load of < 25,000 IU/ml; patients must be on a stable anti-viral therapy
  • No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, adequately treated in situ cancer, adequately treated stage I or II cancer (including multiple primary melanomas) from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years
  • Women of childbearing potential must have a negative urine or serum pregnancy test within 28 days prior to registration; women/men of reproductive potential must have agreed to use an effective contraceptive method for the course of the study through 120 days after the last dose of study medication; 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; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy, or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures; patients must not be pregnant or nursing due to unknown teratogenic side effects
  • Patients must have specimens available and institutions must be planning to submit for centralized pathology review and for integrated translational medicine objectives
  • Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines
  • As a part of the Oncology Patient Enrollment Network (OPEN) registration process, the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02775851
Other Study ID Numbers  ICMJE NCI-2016-00666
NCI-2016-00666 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
S1512
S1512 ( Other Identifier: SWOG )
S1512 ( Other Identifier: CTEP )
U10CA180888 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Kari L Kendra Southwest Oncology Group
PRS Account National Cancer Institute (NCI)
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP