Clinical Trials /

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

NCT02965716

Description:

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.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Talimogene Laherparepvec and Pembrolizumab in Treating Patients With Stage III-IV Melanoma
  • Official Title: A Phase II Study of Combining T-VEC (NSC-785349) and Pembrolizumab (NSC-776864) in Patients With Advanced Melanoma Who Have Progressed on Anti-PD1/L1 Based Therapy

Clinical Trial IDs

  • ORG STUDY ID: NCI-2016-01698
  • SECONDARY ID: NCI-2016-01698
  • SECONDARY ID: S1607
  • SECONDARY ID: S1607
  • SECONDARY ID: S1607
  • SECONDARY ID: U10CA180888
  • NCT ID: NCT02965716

Conditions

  • Recurrent Melanoma
  • Stage III Skin Melanoma
  • Stage IIIA Skin Melanoma
  • Stage IIIB Skin Melanoma
  • Stage IIIC Skin Melanoma
  • Stage IV Skin Melanoma

Interventions

DrugSynonymsArms
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (talimogene laherparepvec, pembrolizumab)
Talimogene LaherparepvecICP34.5-, ICP47-deleted Herpes Simplex Virus 1 (HSV-1) Incorporating the Human GM-CSF Gene, Imlygic, JS1 34.5-hGMCSF 47- pA-, T-VECTreatment (talimogene laherparepvec, pembrolizumab)

Purpose

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. Monoclonal antibodies, such as pembrolizumab, 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

      PRIMARY OBJECTIVES:

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

      SECONDARY OBJECTIVES:

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

      II. To estimate the objective response rate (ORR) in the non-visceral, non-injected lesions.

      III. To estimate the objective response rate (ORR) in the visceral lesions (Cohort A).

      IV. To estimate the overall objective response rate (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.

      TERTIARY OBJECTIVES:

      I. To evaluate whether adding 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 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 T-VEC is associated with the tumor
      immune microenvironment.

      IV. To evaluate whether tumor mutational load and mutations in the IFN pathway is associated
      with response to T-VEC plus 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 18
      courses in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 6 months for up to 2
      years and then annually for a total of 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (talimogene laherparepvec, pembrolizumab)ExperimentalPatients receive talimogene laherparepvec IL and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity.

    Eligibility Criteria

            Inclusion Criteria:
    
              -  Patients must have pathologically confirmed Stage IV or unresectable Stage III
                 melanoma
    
              -  Patients must have measurable disease per Response Evaluation Criteria in Solid
                 Tumors (RECIST) 1.1; all measurable lesions must be assessed within 28 days prior to
                 registration; non-measurable disease must be assessed 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
                 must have at least 2 injectable 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
                 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; anti-PD1/L1
                 based therapy must be the immediate previous line of treatment prior to registration
    
              -  Patients must not have had surgery, chemotherapy, biologic therapy, hormonal therapy,
                 or radiation therapy within 14 days prior to registration; patients must not have had
                 an investigational agent or monoclonal antibodies, except anti-PD1/L1 antibodies,
                 within 28 days prior to registration; patients must have recovered from all side
                 effects from prior therapies prior to registration
    
              -  Patients must not have received prior treatment with T-VEC or other oncolytic virus
                 agents
    
              -  Patients must not have received any infectious disease vaccination within 7 days
                 prior to registration
    
              -  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
    
              -  Hemoglobin >= 8 g/dL
    
              -  Platelets >= 100,000/mcL
    
              -  Total bilirubin =< 2.0 x institutional upper limit of normal (IULN) except patients
                 with documented Gilbert's syndrome
    
              -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both < 3.0 x IULN
    
              -  Serum creatinine < 2.0 x IULN within 28 days prior to registration
    
              -  International normalized ratio (INR) or prothrombin time (PT) =< 2.0 x IULN if not
                 using anticoagulants within 28 days prior to registration; if using anticoagulants,
                 then the value must be within therapeutic range according to the condition for which
                 the patient is being treated within 28 days prior to registration
    
              -  Activated partial thromboplastin time (aPTT) =< 2.0 x IULN if not using
                 anticoagulants within 28 days prior to registration; if using anticoagulants, then
                 the value must be within therapeutic range according to the condition for which the
                 patient is being treated 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, human
                 immunodeficiency virus (HIV)
    
              -  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 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 including, but not
                 limited to, nonmalignant medical illnesses that are uncontrolled 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
    
              -  No other prior malignancy is allowed except for the following: adequately treated
                 basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated
                 stage I or II cancer from which the patient is currently in complete remission, or
                 any other cancer from which the patient has been disease free for two years
    
              -  Patients must not be pregnant or nursing; 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 willing to submit blood and tissue specimens for translational
                 medicine
    
              -  Patients must be offered the opportunity to participate in specimen banking for
                 future research
    
              -  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
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Durable response rate (DRR) defined as complete response (CR) or partial response (PR) with no evidence of disease progression from the initial documentation of CR/PR assessed by RECIST 1.1 (Cohort A and B)
    Time Frame:Up to 180 days
    Safety Issue:
    Description:

    Secondary Outcome Measures

    Measure:DRR (Cohort A and B)
    Time Frame:Up to 5 years
    Safety Issue:
    Description: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 n
    Measure:Median OS (Cohort A and B)
    Time Frame:Up to 6 months
    Safety Issue:
    Description:Will construct 95% Brookmeyer-Crowley confidence intervals.
    Measure:Median PFS (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
    Safety Issue:
    Description:Will construct 95% Brookmeyer-Crowley confidence intervals.
    Measure:ORR (Cohort B)
    Time Frame:Up to 5 years
    Safety Issue:
    Description:Will be estimated in injected lesions, non-injected lesions, across all lesions and construct 95% confidence intervals for the estimated rates.
    Measure:Response rate (complete and partial, confirmed and unconfirmed responses) assessed by RECIST1.1 (Cohort A)
    Time Frame:Up to 5 years
    Safety Issue:
    Description: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.

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:National Cancer Institute (NCI)

    Last Updated

    April 18, 2017