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

• ClinicalTrials.gov Identifier: NCT02775851
• Recruitment Status: Recruiting
• First Posted: May 18, 2016
• Last Update Posted: October 4, 2019
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Study Description

Brief Summary:

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 (unresectable). Monoclonal antibodies, like pembrolizumab, may block specific proteins which may strengthen the immune system and control tumor growth.

Condition or disease	Intervention/treatment	Phase
Desmoplastic Melanoma	Biological: Pembrolizumab; Procedure: Therapeutic Conventional Surgery	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 56 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II and Pilot Trial of PD-1 Blockade With MK-3475 (Pembrolizumab) in Patients With Resectable or Unresectable Desmoplastic Melanoma (DM)
• Actual Study Start Date: October 20, 2016
• Estimated Primary Completion Date: December 1, 2028

Arms and Interventions

Arm	Intervention/treatment
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.	Biological: Pembrolizumab; Given IV; Other Names: Keytruda; Lambrolizumab; MK-3475; SCH 900475; Procedure: Therapeutic Conventional Surgery; Undergo surgical resection
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.	Biological: Pembrolizumab; Given IV; Other Names: Keytruda; Lambrolizumab; MK-3475; SCH 900475

Outcome Measures

Primary Outcome Measures :

1. 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.
2. 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.

Secondary Outcome Measures :

1. Overall response rate (Cohort A) [ Time Frame: At 9 weeks ]
   Estimated with a 95% confidence interval.
2. Overall survival rate (Cohort A and B) [ Time Frame: At 9 weeks ]
   Estimated with a 95% confidence interval.
3. Progression free survival (Cohort A and B) [ Time Frame: At 9 weeks ]
   Estimated with a 95% confidence interval.
4. 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 ]
   Toxicity will be assessed across all patients receiving pembrolizumab.

Other Outcome Measures:

1. 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.
2. 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.
3. 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.

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:

• 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
• 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

Contacts and Locations

  Show 218 Study Locations

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Kari L Kendra; Southwest Oncology Group

More Information

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT02775851 History of Changes
• Other Study ID Numbers: 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 )
• First Posted: May 18, 2016
• Last Update Posted: October 4, 2019
• Last Verified: July 2019

Additional relevant MeSH terms:

Melanoma; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents