Clinical Trials

The James Cancer Center Columbus, OH

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

Protocol: SWOG-S1512

Full Title

A Phase II and Pilot Trial of PD-1 Blockade with MK-3475 (Pembrolizumab) in Patients with Resectable or Unsectable Desmoplastic Melanoma (DM)

Purpose

This pilot phase II trial studies how well pembrolizumab works in treating patients with desmoplastic melanoma (DM) that can or cannot be removed by surgery. Monoclonal antibodies, like pembrolizumab, may block specific proteins which may strengthen the immune system and control tumor growth.

Study Objective

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). (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)

TERTIARY OBJECTIVES:

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

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:

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

COHORT B: Patients with unresectable disease receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days 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.

Are you eligible?

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 measurable disease that, in the judgment of the surgeon is deemed completely resectable resulting in free surgical margins

COHORT B: Patients must have histologically or cytologically confirmed primary desmoplastic melanoma that is unresectable

Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1); contrast-enhanced computed tomography (CT) scans of the neck, 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 patients 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 7 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 chemotherapy for this cancer within 21 days prior to registration; patients must not have received radiation therapy, non-cytotoxic agents or investigational agents or systemic corticosteroids within 14 days prior to registration

Patients must have healed from any prior surgery

Absolute neutrophil count (ANC) >= 1500/mcl

Platelets >= 100,000/mcl

Hemoglobin >= 9 g/dL

Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (or =< 3.0 x ULN with Gilbert's syndrome)

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (or 5 x IULN for patients with known liver metastases)

Patients must have Zubrod Performance Status =< 2

Patients must not have known active, non-infectious 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–Guérin (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 cluster of differentiation 4 (CD4) counts (>= 350 mm^3), and serum HIV viral load of < 25,000 IU/ml; patients may be on or off anti-viral therapy so long as they meet the CD4 count criteria

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

Patients must have specimens available and institutions must be planning to submit for centralized pathology review and for integrated translational medicine objectives

Patients or their legally authorized representative 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