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Trial record 1 of 1 for:    S1607
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Talimogene Laherparepvec and Pembrolizumab in Treating Patients With Stage III-IV Melanoma

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ClinicalTrials.gov Identifier: NCT02965716
Recruitment Status : Recruiting
First Posted : November 17, 2016
Last Update Posted : June 11, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase II trial studies how well talimogene laherparepvec and pembrolizumab work in treating patients with stage III-IV melanoma. Biological therapies, such as talimogene laherparepvec, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop tumor cells from growing. 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. Giving talimogene laherparepvec and pembrolizumab may work better in treating patients with melanoma by shrinking the tumor.

Condition or disease Intervention/treatment Phase
Advanced Melanoma Recurrent Melanoma Stage III Cutaneous Melanoma AJCC v7 Stage IIIA Cutaneous Melanoma AJCC v7 Stage IIIB Cutaneous Melanoma AJCC v7 Stage IIIC Cutaneous Melanoma AJCC v7 Stage IV Cutaneous Melanoma AJCC v6 and v7 Unresectable Melanoma Biological: Pembrolizumab Biological: Talimogene Laherparepvec Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the durable response rate of treatment with talimogene laherparepvec (T-VEC) in combination with MK-3475 (pembrolizumab) following progression on prior anti-PD-1 or anti-PD-L1 therapy alone or in combination with other agents different from talimogene laherparepvec (T-VEC).

SECONDARY OBJECTIVES:

I. To estimate the objective response rate (ORR) defined as confirmed and unconfirmed, complete and partial responses in the injected lesions.

II. To estimate the ORR in the non-visceral, non-injected lesions. III. To estimate the ORR in the visceral lesions (Cohort A). IV. To estimate the ORR. V. To estimate the median progression-free survival (PFS). VI. To estimate the median overall survival (OS). VII. To evaluate the toxicity of the regimen.

TRANSLATIONAL OBJECTIVES:

I. To evaluate whether adding talimogene laherparepvec (T-VEC) to PD1 blockade can increase T-cell infiltration into tumors and whether change in T-cell infiltration is associated with response.

II. To evaluate whether adding talimogene laherparepvec (T-VEC) to PD1 blockade can increase T-cell receptor (TCR) clonality in tumors and in peripheral blood and whether increased TCR clonality is associated with response.

III. To evaluate whether intra-tumoral injection of talimogene laherparepvec (T-VEC) can improve the tumor immune microenvironment.

IV. To evaluate whether tumor mutational load and mutations in the IFN pathway is associated with response to talimogene laherparepvec (T-VEC) plus MK-3475 (pembrolizumab) therapy in the anti-PD1/L1 therapy refractory melanoma patients.

OUTLINE:

Patients receive talimogene laherparepvec intralesionally (IL) and pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 36 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for up to 1 year and then annually for a total of 5 years.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 64 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Combining Talimogene Laherparepvec T-VEC (NSC-785349) and MK-3475 (Pembrolizumab) (NSC-776864) in Patients With Advanced Melanoma Who Have Progressed on Anti-PD1/L1 Based Therapy
Actual Study Start Date : October 2, 2017
Estimated Primary Completion Date : July 15, 2019
Estimated Study Completion Date : July 15, 2019


Arm Intervention/treatment
Experimental: Treatment (talimogene laherparepvec, pembrolizumab)
Patients receive talimogene laherparepvec IL and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 36 cycles in the absence of disease progression or unacceptable toxicity.
Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Biological: Talimogene Laherparepvec
Given IL
Other Names:
  • ICP34.5-, ICP47-deleted Herpes Simplex Virus 1 (HSV-1) Incorporating the Human GM-CSF Gene
  • Imlygic
  • JS1 34.5-hGMCSF 47- pA-
  • T-VEC




Primary Outcome Measures :
  1. Durable response rate (DRR) (Cohort A and B) [ Time Frame: Up to 180 days ]
    Will be defined as complete response (CR) or partial response (PR) with no evidence of disease progression from the initial documentation of CR/PR and assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.


Secondary Outcome Measures :
  1. Response rate (Cohort A) [ Time Frame: Up to 5 years ]
    Will be defined by complete and partial, confirmed and unconfirmed responses. Will be estimated by three different methods. RECIST 1.1 will be applied, but with the following restrictions: 1) considering only the injected lesions as target lesions, 2) considering only the non-injected lesions as target lesions, 3) considering only the visceral lesions as target lesions and 4) across all lesions. 95% confidence intervals will be constructed for the estimated rates.

  2. Objective response rate (Cohort B) [ Time Frame: Up to 5 years ]
    Will be estimated in injected lesions, non-injected lesions, across all lesions and construct 95% confidence intervals for the estimated rates.

  3. Median progression-free survival (Cohort A and B) [ Time Frame: From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause, assessed up to 6 months ]
    Will construct 95% Brookmeyer-Crowley confidence intervals.

  4. Median overall survival (Cohort A and B) [ Time Frame: Up to 6 months ]
    Will construct 95% Brookmeyer-Crowley confidence intervals.

  5. DRR (Cohort A and B) [ Time Frame: Up to 5 years ]
    Will assess the association between durable response rate and CD8 T-cell infiltration in the injected tumors using a two-sample t-test to test for difference in mean quantitative CD8 expression between patients who have a durable response and patients who do not have a durable response. If the distributions are far from normal or subject to influential points, then instead of t-tests, robust, rank based or non-parametric alternatives such as the Wilcoxon test will be used. The analysis will be repeated to assess the association between durable response rate and CD8 T-cell infiltration in the non-injected tumors.


Other Outcome Measures:
  1. Change in T-cell infiltration (Cohort A and B) [ Time Frame: Baseline to day 28 ]
    CD8 expression levels will be compared using a paired t-test. Among patients that progress, the analysis will be repeated to compare CD8 expression at progression to baseline with the understanding that there is potentially informative missingness in that patients who do not progress may have higher infiltration.

  2. Change in increased T-cell infiltration (Cohort A and B) [ Time Frame: Baseline to day 28 ]
    Associated with higher DRR. The change in CD8 expression between day 28 and baseline will be computed and compared to the change in CD8 expression between durable responders and non-durable responders using a two-sample t-test at the two-sided 0.05 level.

  3. Change in T cell receptor (TCR) clonality levels assessed in peripheral blood (Cohort A) [ Time Frame: Baseline to day 28 ]
    Will compute the clonality metric as the normalized Shannon entropy for all patients at baseline and day 28. The change in clonality metric will be computed and compared between durable responders and non-durable responders using a two-sample t-test with significance determined at the two-sided alpha=0.05 level.

  4. Change in TCR clonality within tumor assessed in peripheral blood (Cohort B) [ Time Frame: Baseline to day 28 ]
    To assess the hypothesis that TCR clonality is higher in patients who respond to the combination therapy, suggesting that the T-cells are targeting the tumor, the clonality metric will be computed as the normalized Shannon entropy for all patients at baseline and day 28. The change in clonality will be compared between durable responders and non-durable responders using a two-sample t-test with significance determined at the two-sided alpha=0.05 level. The analyses examining TCR clonality in peripheral blood will be repeated.

  5. Change in tumor microenvironment following talimogene laherparepvec (Cohort A and B) [ Time Frame: Baseline to day 28 ]
    Will examine the expression of approximately 10 candidate immune markers: PD-L1, PD-1, dendritic cell markers (CD80, CD86), immune suppressive cell markers (anti-FoxP3 for regulatory T cell, anti-CD68 antibody for macrophage, clone PG-M1, DAKO, anti-CD14 for monocyte, and CD15 for granulocytes). For each marker, a difference in expression will be tested between baseline and day 28 using paired t-tests at the alpha = 0.005 level to accommodate multiple comparisons. The association between change in expression level of each marker (from baseline to 28 days) with response using a two-sample t-test at the alpha = 0.005 level will be tested.

  6. Mutational load (Cohort A and B) [ Time Frame: Baseline to day 28 ]
    Will assess the association between overall mutational load at each time point, separately, and durable response rate. Logistic regression to regress response status on the mutation rates (at baseline or at day 28) and use a 1-df test to obtain a p-value for the association between durable response and mutation rate will be used.



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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 pathologically confirmed stage IV or unresectable stage III melanoma; patients must not have disease that is suitable for local therapy, administered with curative intent
  • Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (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, or the limbs is required only if the patient has a lesion(s) in these areas; 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's 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)
  • Cohort A: Patients must have at least one measurable visceral lesion (per RECIST 1.1); a visceral lesion is any solid organ except for skin, lymph node, and musculoskeletal tissue; at least one of these visceral lesions must be measurable per RECIST 1.1
  • Cohort B: Patients must not have any visceral lesions
  • Patients must, in the opinion of the treating physician, be candidates for intralesional administration into cutaneous, subcutaneous, or nodal lesions
  • Patients may have brain metastases if all lesions have been treated with stereotactic radiation therapy, craniotomy, or gamma knife therapy with no evidence of progression (demonstrated by imaging at least 4 weeks post treatment) and have not required steroids for at least 14 days prior to registration
  • Patient must have had prior treatment with anti-PD-1 or anti-PD-L1 agents and have documented disease progression on these agents prior to registration; patients who have progressed after adjuvant anti-PD1/L1 agents are eligible
  • Patients must not have had surgery, biologic therapy, or hormonal therapy within 14 days prior to registration; patients must not have had chemotherapy, targeted small molecule therapy, or radiation therapy within 14 days prior to registration; patients must not have had a monoclonal antibody, except anti-PD1/L1 antibodies, within 28 days prior to registration

    • Patients must have recovered from all adverse events due to prior anti-cancer therapy (residual toxicity =< grade 1) prior to registration, with the exception of patients with =< grade 2 neuropathy, =< grade 2 hypothyroidism, or =< grade 2 alopecia
    • If patients received major surgery, they must have recovered adequately from toxicity and/or complications from the intervention prior to registration
  • Patients must not have received prior treatment with talimogene laherparepvec (T-VEC); prior treatment with T-VEC is defined as receiving at least one injection with 1 x 10^8 plaque forming units (pfu)
  • Patients must not have received any live vaccine within 30 days prior to registration; seasonal flu vaccines that do not contain live virus are permitted
  • Patients must not be planning to receive other biologic therapy, radiation therapy, hormonal therapy, chemotherapy, surgery, or other therapy while on this protocol; palliative radiation therapy or surgery can be considered for symptomatic non-target lesions after discussions with the study team
  • Patients must have Zubrod performance status =< 2
  • Absolute neutrophil count (ANC) >= 1,500/mcL (within 28 days prior to registration)
  • Hemoglobin >= 8 g/dL (within 28 days prior to registration)
  • Platelets >= 100,000/mcL (within 28 days prior to registration)
  • Albumin >= 2.5 g/dL (within 28 days prior to registration)
  • Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) except patients with documented Gilbert's syndrome (=< 3 x IULN is eligible) (within 28 days prior to registration)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both =< 3 x IULN (within 28 days prior to registration)
  • Patients must have lactate dehydrogenase (LDH) obtained prior to registration
  • Patients must have complete physical examination and medical history obtained within 28 days prior to registration
  • Patients must not require use of systemic corticosteroid within 14 days prior to registration or during protocol treatment; patients with preexisting severe autoimmune disease requiring systemic corticosteroids or ongoing immunosuppression are not eligible
  • Patients must not have known history of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) due to contraindication of talimogene laherparepvec (T-VEC) in immune-compromised patients and that administration of talimogene laherparepvec (T-VEC) has not been tested in HIV-positive patients; the use of physiologic doses of corticosteroids may be approved after consultation with the study chair
  • 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 nor a viral infection requiring intermittent treatment with an antiherpetic drug, other than intermittent topical use
  • Patients must not have active herpetic skin lesions or prior complications of herpetic infection (e.g., herpetic keratitis or encephalitis) which requires intermittent or chronic treatment with an anti-herpetic drug other than intermittent topical use
  • Patients must not have organ allografts
  • Patients must not have an uncontrolled intercurrent illness or whose control may be jeopardized by the treatment with the study therapy, or psychiatric illness/social situations which would limit compliance with study requirements
  • Patients must not have active autoimmune disease (e.g., pneumonitis, glomerulonephritis, vasculitis, or other) that requires systemic treatment (i.e., use of corticosteroids, immunosuppressive drugs or biological agents used for treatment of autoimmune diseases) that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (e.g., thyroxine for hypothyroidism, insulin for diabetes or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment for autoimmune disease
  • Patient must not have evidence of any clinically significant immunosuppression such as the following:

    • Primary immunodeficiency state such as severe combined immunodeficiency disease;
    • Concurrent opportunistic infection;
    • Receiving systemic immunosuppressive therapy (> 2 weeks) including oral steroid doses > 10 mg/day of prednisone or equivalent within 2 months prior to enrollment
  • Patients must not have any other malignancy that requires active treatment
  • Patients must not be pregnant or nursing due to risk of fetal or nursing infant harm; women of reproductive potential must have a negative serum pregnancy test within 7 days prior to registration; women/men of reproductive potential must have agreed to use an effective contraceptive method while on study and for 120 days after last study treatment; 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 be offered the opportunity to submit archival tissue for translational medicine; patients must also be willing to undergo biopsies and submit tissue and blood for translational medicine; with patients consent, any remaining specimens will be banked for future use
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02965716


Locations
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United States, California
Los Angeles County-USC Medical Center Recruiting
Los Angeles, California, United States, 90033
Contact: Site Public Contact    323-865-0451      
Principal Investigator: Gino K. In         
USC / Norris Comprehensive Cancer Center Recruiting
Los Angeles, California, United States, 90033
Contact: Site Public Contact    323-865-0451      
Principal Investigator: Gino K. In         
UCLA / Jonsson Comprehensive Cancer Center Recruiting
Los Angeles, California, United States, 90095
Contact: Site Public Contact    888-798-0719      
Principal Investigator: Antoni Ribas         
United States, Indiana
Indiana University/Melvin and Bren Simon Cancer Center Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Site Public Contact    317-278-5632    iutrials@iu.edu   
Principal Investigator: Amikar Sehdev         
United States, Kansas
University of Kansas Hospital-Westwood Cancer Center Recruiting
Westwood, Kansas, United States, 66205
Contact: Site Public Contact    913-945-7552    ctnursenav@kumc.edu   
Principal Investigator: Gary C. Doolittle         
United States, Michigan
Henry Ford Cancer Institute-Downriver Recruiting
Brownstown, Michigan, United States, 48183
Contact: Site Public Contact    313-916-3721    CTOResearch@hfhs.org   
Principal Investigator: Ding Wang         
Henry Ford Macomb Hospital-Clinton Township Recruiting
Clinton Township, Michigan, United States, 48038
Contact: Site Public Contact    313-916-3721    CTOResearch@hfhs.org   
Principal Investigator: Ding Wang         
Henry Ford Hospital Recruiting
Detroit, Michigan, United States, 48202
Contact: Site Public Contact    313-916-3721    CTOResearch@hfhs.org   
Principal Investigator: Ding Wang         
Allegiance Health Recruiting
Jackson, Michigan, United States, 49201
Contact: Site Public Contact    313-916-3721    CTOResearch@hfhs.org   
Principal Investigator: Ding Wang         
Henry Ford West Bloomfield Hospital Recruiting
West Bloomfield, Michigan, United States, 48322
Contact: Site Public Contact    313-916-3721    CTOResearch@hfhs.org   
Principal Investigator: Ding Wang         
United States, Missouri
Kansas City Veterans Affairs Medical Center Recruiting
Kansas City, Missouri, United States, 64128
Contact: Site Public Contact    800-525-1483      
Principal Investigator: Nisreen A. Haideri         
United States, Ohio
Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Site Public Contact    800-293-5066    Jamesline@osumc.edu   
Principal Investigator: Kari L. Kendra         
United States, Utah
Huntsman Cancer Institute/University of Utah Recruiting
Salt Lake City, Utah, United States, 84112
Contact: Site Public Contact    888-424-2100    cancerinfo@hci.utah.edu   
Principal Investigator: Siwen Hu-Lieskovan         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Siwen Hu-Lieskovan Southwest Oncology Group

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02965716     History of Changes
Other Study ID Numbers: NCI-2016-01698
NCI-2016-01698 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
S1607
S1607 ( Other Identifier: SWOG )
S1607 ( Other Identifier: CTEP )
U10CA180888 ( U.S. NIH Grant/Contract )
First Posted: November 17, 2016    Key Record Dates
Last Update Posted: June 11, 2019
Last Verified: June 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Melanoma
Skin Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Neoplasms by Site
Skin Diseases
Pembrolizumab
Talimogene laherparepvec
Antineoplastic Agents, Immunological
Antineoplastic Agents