Talimogene Laherparepvec and Pembrolizumab in Treating Patients With Stage III-IV Melanoma

Study Overview
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Brief Summary
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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.

Detailed Description
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PRIMARY OBJECTIVE: I. To evaluate the objective response rate (confirmed complete and partial responses) of treatment with talimogene laherparepvec (T-VEC) in combination with pembrolizumab (MK-3475) 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 durable response rate. II. To estimate the objective response rate (ORR) defined as confirmed and unconfirmed, complete and partial responses in the injected lesions. III. To estimate the ORR in the non-visceral, non-injected lesions. IV. To estimate the ORR in the visceral lesions (Cohort A). 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, mutations in the IFN pathway, and circulating tumor deoxyribonucleic acid (DNA) profile are is associated with response to talimogene laherparepvec (T-VEC) plus pembrolizumab (MK-3475) 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.

Official Title
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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

Conditions
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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

Intervention / Treatment
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* Biological: Pembrolizumab
* Biological: Talimogene Laherparepvec


Participation Criteria
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Eligibility Criteria
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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 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 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 be >= 18 years of age 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 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 Exclusion Criteria: Cohort B: Patients must not have any visceral lesions 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 for cancer treatment, 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 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) in the past 2 years; 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (talimogene laherparepvec, pembrolizumab)<br>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<br>* Given IV<br>* Other names: SCH 900475;Biological: Talimogene Laherparepvec<br>* Given IL<br>* Other names: T-VEC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | The proportion of participants whose best response to treatment was a confirmed complete or partial response as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. All participants who received at least one dose of treatment are included in the denominator. Disease assessments were performed by CT, MRI, or skin measurement at 9 weeks following the initiation of treatment, followed by a confirmatory assessment 4 weeks later, and then every 12 weeks until discontinuation of protocol treatment. The same measurement modality used at baseline was required to be used for all follow-up assessments. | At 9 weeks following the initiation of treatment, followed by a confirmatory assessment 4 weeks later, and then every 12 weeks for up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Durable response rate | The proportion of patients who maintain either a complete response (CR) or partial response (PR) for at least 180 days from the initial documentation of CR/PR with no evidence of disease progression during the interval; assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.The denominator is the number of patients who achieved either a confirmed or unconfirmed complete or partial response. Disease assessments were performed by CT, MRI, or skin measurement at 9 weeks following the initiation of treatment, followed by a confirmatory assessment 4 weeks later, and then every 12 weeks until discontinuation of protocol treatment. The same measurement modality used at baseline was required to be used for all follow-up assessments. | Every 12 weeks (84 days) from the date of the initial documentation of CR/PR up to 180 days from the date of the initial documentation of CR/PR | 
| Objective Response rate in the injected lesions | The proportion of confirmed or unconfirmed complete and partial responses, using a modified RECIST which treats only the measurable (per RECIST 1.1) injected lesions as target lesions, with all other lesions treated as non-target lesions. All other disease must be stable or better with no new visceral or otherwise uninjectable lesions. The denominator is all participants with at least one target lesion deemed injectable, whether actually injected or not, at any time prior to disease progression. Disease assessments were performed by CT, MRI, or skin measurement at 9 weeks following the initiation of treatment, followed by a confirmatory assessment 4 weeks later, and then every 12 weeks until discontinuation of protocol treatment. The same measurement modality used at baseline was required to be used for all follow-up assessments. Proportions will be estimated along with exact 95% confidence intervals for the estimated rates. | At 9 weeks following the initiation of treatment, followed by a confirmatory assessment 4 weeks later, and then every 12 weeks for up to 5 years | 
| Objective response rate in the non-visceral, non-injected lesions | The proportion of confirmed and unconfirmed, complete and partial responses, using a modified RECIST which treats only measurable (per RECIST 1.1) lesions that were not injected and non-visceral as target lesions, with all other lesions treated as non-target lesions. The denominator is all participants with at least one target lesion present at baseline that was not injected. Disease assessments were performed by CT, MRI, or skin measurement at 9 weeks following the initiation of treatment, followed by a confirmatory assessment 4 weeks later, and then every 12 weeks until discontinuation of protocol treatment. The same measurement modality used at baseline was required to be used for all follow-up assessments. Proportions will be estimated and along with exact 95% confidence intervals. | At 9 weeks following the initiation of treatment, followed by a confirmatory assessment 4 weeks later, and then every 12 weeks for up to 5 years | 
| Objective response rate in the visceral lesions (Cohort A only) | The proportion of confirmed and unconfirmed, complete and partial responses, using a modified RECIST which treats only measurable (per RECIST 1.1) visceral lesions as target lesions, with all other lesions treated as non-target lesions. The denominator is all participants with at least one target visceral lesion present at baseline. Disease assessments were performed by CT, MRI, or skin measurement at 9 weeks following the initiation of treatment, followed by a confirmatory assessment 4 weeks later, and then every 12 weeks until discontinuation of protocol treatment. The same measurement modality used at baseline was required to be used for all follow-up assessments. Proportions will be estimated along with exact 95% confidence intervals for the estimated rates. | At 9 weeks following the initiation of treatment, followed by a confirmatory assessment 4 weeks later, and then every 12 weeks for up to 5 years | 
| Progression-free survival (PFS) | 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. PFS estimates will be calculated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to construct 95% confidence intervals for the median PFS. | Up to 5 years | 
| Overall survival (OS) | 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. OS estimates will be calculated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to construct 95% confidence intervals for the median PFS. | Up to 5 years | 
| DRR (Cohort A and B) | 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. | At baseline and day 28 | 
| Circulating tumor deoxyribonucleic acid (DNA) profile (ctDNA) fraction | Will assess whether ctDNA fraction at baseline and day 28 is associated with ORR using a two-sample t-test at the two-sided 0.05 level. | At baseline and day 28 |