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

Phase 2

Active, not recruiting

Conditions: Desmoplastic Melanoma

Interventions: Procedure: Biopsy Procedure
Procedure: Biospecimen Collection
Procedure: Computed Tomography
Procedure: Magnetic Resonance Elastography
Biological: Pembrolizumab
Procedure: Positron Emission Tomography
Procedure: Therapeutic Conventional Surgery

Registration Number: NCT02775851

Lead Sponsor: National Cancer Institute (NCI)

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 pembrolizumab (MK-3475). (Cohort A) II. To evaluate the complete response rate (confirmed and unconfirmed) in patients with unresectable desmoplastic melanoma treated with pembrolizumab (MK-3475). (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 pembrolizumab (MK-3475) 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 pembrolizumab (MK-3475) 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 and circulating tumor deoxyribonucleic acid (DNA) profile from blood samples 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 enrolled 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.

Patients undergo computed tomography (CT) scan and may undergo position emission tomography (PET) and magnetic resonance imaging (MRI) throughout the study. Patients also undergo blood sample collection at screening and tumor biopsy throughout the study.

After completion of study treatment, patients are followed up at 6 weeks after the last dose, then every 12 weeks to the end of the first year, then every 6 months to the end of the fifth year after registration. After progression, patients are followed every 6 months for up to 2 years from the date of registration, then annually thereafter until 5 years from registration.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 57

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, 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
Patients must be >= 18 years of age
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 generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
Patients known to be human immunodeficiency virus (HIV) positive prior to registration 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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort A (pembrolizumab, surgery)	Biopsy Procedure	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. Patients undergo CT scan and may undergo PET and MRI throughout the study. Patients also undergo blood sample collection at screening and tumor biopsy throughout the study.
Cohort A (pembrolizumab, surgery)	Biospecimen Collection	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. Patients undergo CT scan and may undergo PET and MRI throughout the study. Patients also undergo blood sample collection at screening and tumor biopsy throughout the study.
Cohort A (pembrolizumab, surgery)	Computed Tomography	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. Patients undergo CT scan and may undergo PET and MRI throughout the study. Patients also undergo blood sample collection at screening and tumor biopsy throughout the study.
Cohort A (pembrolizumab, surgery)	Magnetic Resonance Elastography	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. Patients undergo CT scan and may undergo PET and MRI throughout the study. Patients also undergo blood sample collection at screening and tumor biopsy throughout the study.
Cohort A (pembrolizumab, surgery)	Pembrolizumab	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. Patients undergo CT scan and may undergo PET and MRI throughout the study. Patients also undergo blood sample collection at screening and tumor biopsy throughout the study.
Cohort A (pembrolizumab, surgery)	Positron Emission Tomography	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. Patients undergo CT scan and may undergo PET and MRI throughout the study. Patients also undergo blood sample collection at screening and tumor biopsy throughout the study.
Cohort A (pembrolizumab, surgery)	Therapeutic Conventional 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. Patients undergo CT scan and may undergo PET and MRI throughout the study. Patients also undergo blood sample collection at screening and tumor biopsy throughout the study.
Cohort B (pembrolizumab)	Biopsy Procedure	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. Patients undergo CT scan and may undergo PET and MRI throughout the study. Patients also undergo blood sample collection at screening and tumor biopsy throughout the study.
Cohort B (pembrolizumab)	Biospecimen Collection	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. Patients undergo CT scan and may undergo PET and MRI throughout the study. Patients also undergo blood sample collection at screening and tumor biopsy throughout the study.
Cohort B (pembrolizumab)	Computed Tomography	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. Patients undergo CT scan and may undergo PET and MRI throughout the study. Patients also undergo blood sample collection at screening and tumor biopsy throughout the study.
Cohort B (pembrolizumab)	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. Patients undergo CT scan and may undergo PET and MRI throughout the study. Patients also undergo blood sample collection at screening and tumor biopsy throughout the study.
Cohort B (pembrolizumab)	Positron Emission Tomography	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. Patients undergo CT scan and may undergo PET and MRI throughout the study. Patients also undergo blood sample collection at screening and tumor biopsy throughout the study.
Cohort B (pembrolizumab)	Therapeutic Conventional Surgery	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. Patients undergo CT scan and may undergo PET and MRI throughout the study. Patients also undergo blood sample collection at screening and tumor biopsy throughout the study.

Primary Outcome Measures

Name	Time	Method
Pathologic Complete Response (pCR) Rate (Cohort A)	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.
Complete Response (CR) Rate (Cohort B)	Up to 5 years	Complete response (per RECIST 1.1) defined as: disappearance of all target and non-target lesions no new lesions, no disease related symptoms, and any lymph nodes must have reduction in short axis to \< 1.0 cm.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs	Duration of treatment and follow-up until death or 5 years post registration.	Only adverse events that are possibly, probably or definitely related to study drug are reported. CTCAE Version 4.0 was used for all AE reporting.
9 Week Response Rate (Cohort A)	Up to 3 months	Unconfirmed complete (CR) and partial responses (PR) at end of neoadjuvant treatment assessment among patients with measurable disease. CR and PR per response evaluation criteria in solid tumors (RECIST v1.1): CR is complete disappearance of all target and non-target lesions, no new lesions, no disease related symptoms, and lymph nodes must have reduction in short axis to \<1.0cm. PR is greater than or equal to 30% decrease under baseline of the sum of appropriate diameters of all target measurable lesions, no unequivocal progression of non-measurable disease, and no new lesions. Overall response = CR + PR.
Overall Survival (Cohort A and B)	Up to 5 years	From date of registration to date of death due to any cause. Patients last known to be alive are censored at date of last contact.
Progression Free Survival (Cohort B)	Up to 5 years	From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause. Patients last known to be alive without report of progression are censored at date of last contact. Progression is defined using Response Evaluation Criteria in Solid Tumors (RECIST v1.1), as 20% increase in the sum of appropriate diameters of target measurable lesions over smallest sum observed (over baseline if no decrease during therapy) using the same techniques as baseline, as well as an absolute increase of at least 0.5 cm, unequivocal progression of non-measurable disease in the opinion of the treating physician (an explanation must be provided), appearance of any new lesion/site, or death due to disease without prior documentation of progression and without symptomatic deterioration

Trial Locations

Locations (281): Fairbanks Memorial Hospital
🇺🇸
Fairbanks, Alaska, United States
Cancer Center at Saint Joseph's
🇺🇸
Phoenix, Arizona, United States
Mercy Hospital Fort Smith
🇺🇸
Fort Smith, Arkansas, United States
CHI Saint Vincent Cancer Center Hot Springs
🇺🇸
Hot Springs, Arkansas, United States
Mission Hope Medical Oncology - Arroyo Grande
🇺🇸
Arroyo Grande, California, United States
City of Hope Comprehensive Cancer Center
🇺🇸
Duarte, California, United States
Epic Care-Dublin
🇺🇸
Dublin, California, United States
Bay Area Breast Surgeons Inc
🇺🇸
Emeryville, California, United States
Epic Care Partners in Cancer Care
🇺🇸
Emeryville, California, United States
Los Angeles General Medical Center
🇺🇸
Los Angeles, California, United States
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Fairbanks Memorial Hospital
🇺🇸Fairbanks, Alaska, United States