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Completed

NCT Number: NCT04068181

Talimogene Laherparepvec With Pembrolizumab in Melanoma Following Progression on Prior Anti-PD-1 Based Therapy (MASTERKEY-115) (Mk-3475-A07/KEYNOTE-A07).

This is a phase 2, open-label, single-arm, multicenter clinical trial designed to evaluate the efficacy and safety of talimogene laherparepvec in combination with pembrolizumab following disease progression on prior anti-programmed cell death protein (anti-PD-1) therapy in unresectable/metastatic melanoma (stage IIIB-IVM1d) or prior anti-PD-1 therapy in the adjuvant setting. Subjects will be treated with talimogene laherparepvec and pembrolizumab until confirmed complete response, disappearance of all injectable lesions, documented confirmed disease progression per modified immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST), intolerance of study treatment, or 102 weeks from the first dose of talimogene laherparepvec and/or pembrolizumab, whichever occurs first.

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Key information

Conditions

Melanoma Neoplasms Neoplasms by Histologic Type Neoplasms by Site Neoplasms, Germ Cell and Embryonal Neoplasms, Nerve Tissue Neuroectodermal Tumors Neuroendocrine Tumors Nevi and Melanomas Skin Diseases Skin Neoplasms Skin and Connective Tissue Diseases

Age range

18 year–99 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Melanoma Institute Australia, North Sydney, New South Wales, Australia

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Key Inclusion Criteria:

  • Age ≥ 18 years with histologically confirmed diagnosis of stage IIIB to IVM1d melanoma and for whom surgery is not recommended. Subjects with stage IVM1d disease may be enrolled with up to 3 cerebral metastases, provided that all lesions have been adequately treated with stereotactic radiation therapy, craniotomy, or gamma knife therapy, with no evidence of progression and not requiring steroids for at least 2 months prior to enrollment.
  • Subjects must have measurable disease and be a candidate for intralesional therapy administration into cutaneous, subcutaneous, or nodal lesions.
  • Subjects must have had prior treatment (for at least 2 to 3 consecutive cycles within an 8 week period) with a PD-1 inhibitor and have confirmed disease progression (as defined by RECIST v1.1 criteria). The anti-PD-1 therapy must be the immediate prior line of therapy before enrollment and subjects with disease progression on more than 1 line of anti-PD-1 therapy are not eligible.
  • ECOG performance status of 0 or 1.
  • Adequate hematologic, renal, hepatic, and coagulation function.

Key Exclusion Criteria:

  • Subjects considered by the investigator to have rapid clinical progression due to melanoma
  • Subjects with prior treatment and disease progression on more than 1 line of anti-PD-1 therapy
  • Stage IVM1d subjects must not have greater than 3 cerebral melanoma metastases, or clinically active cerebral melanoma metastases requiring therapy, and/or carcinomatous meningitis regardless of clinical stability.
  • Primary uveal or mucosal melanoma, history or evidence of melanoma associated with immunodeficiency states or history of other malignancy within the past 3 years.
  • Subjects must not have history or evidence of symptomatic autoimmune glomerulonephritis, vasculitis, or other symptomatic autoimmune disease, or active autoimmune disease or syndrome requiring systemic treatment in the past 2 years (ie, with use of disease modifying agents, steroids or immunosuppressive agents) except vitiligo or resolved childhood asthma/atopy, or evidence of clinically significant immunosuppression.
  • Subjects may not have been previously treated with talimogene laherparepvec or any other oncolytic virus.
  • Subjects must not have active herpetic skin lesions or prior complications of herpetic infection and must not require intermittent or chronic treatment with an antiherpetic drug (eg, acyclovir), other than intermittent topical use.

Treatment and study plan

Talimogene Laherparepvec

Drug

Intralesional injection into injectable cutaneous, subcutaneous and nodal legions.

Pembrolizumab

Drug

Intravenous (IV) infusion.

Primary outcomes

  1. Objective Response Rate (ORR) Per Modified RECIST v1.1

    Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months

    ORR was defined as the incidence of a best overall response (BOR) of complete response (CR) or partial response (PR) per modified RECIST v1.1:

    • CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to < 10 mm. All lymph nodes must have been non-pathological in size (< 10mm short axis).
    • PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
    • Non-CR/Non-progressive disease (PD): Persistence of 1 or more non-target lesion(s).

Secondary outcomes

  1. Complete Response Rate (CRR) Per Modified RECIST v1.1

    Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months

    CRR was defined as the incidence of a BOR of CR per modified RECIST v1.1:

    • CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to < 10 mm. All lymph nodes must have been non-pathological in size (< 10mm short axis).

    Confirmation of CR was not required per modified RECIST v1.1.

  2. Complete Response Rate (iCRR) Per Modified Immune-related Response Criteria (irRC) RECIST v1.1

    Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months

    iCRR was defined as the incidence of a best overall response (iBOR) of a complete response (iCR) per modified irRC-RECIST:

    • iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new). Any pathological lymph nodes (whether target or nontarget) must have had a reduction in short axis to < 10 mm.

    Confirmation of iCR was required per modified irRC-RECIST.

  3. BOR Per Modified RECIST v1.1

    Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months

    BOR was the best overall visit response up to & including the first overall visit response of PD:

    • CR: Disappearance of all target & non-target lesions. Any pathological lymph nodes must have had a reduction in short axis to <10 mm. All lymph nodes must have been non-pathological in size.
    • PR: ≥30% decrease in the sum of diameters of target lesions.
    • Stable disease (SD): Neither sufficient shrinkage to qualify for PR/CR nor sufficient increase to qualify for PD.
    • PD: ≥20% increase in the sum of diameters of target lesions and an increase of ≥5mm. Progression of existing non-target lesions.
    • Unable to evaluate (UE): Any lesion present at baseline which was not assessed or unable to be evaluated leading to an inability to determine the status of that particular tumor.
    • Non-CR/Non-PD: Persistence of 1+ non-target lesion(s). Non-CR/non-PD was relevant to participants who did not have measurable disease at baseline.

    Confirmation of CR, PR & PD were not required per modified RECIST 1.1.

  4. Best Overall Response (iBOR) Per Modified irRC-RECIST

    Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months

    iBOR was defined as the best overall visit response up to and including the first overall visit response of progressive disease (iPD) per modified irRC-RECIST:

    • iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new). Any pathological lymph nodes (whether target or nontarget) must have a reduction in short axis to < 10 mm.
    • Partial response (iPR): Decrease in tumor burden ≥ 30% relative to baseline.
    • Stable disease (iSD): Neither sufficient shrinkage to qualify for iPR or iCR nor sufficient increase to qualify for iPD.
    • iPD: Increase in tumor burden ≥ 20% and at least 5 mm absolute increase.
    • Unable to evaluate (iUE): Any lesion present at baseline or a new measurable lesion which was not assessed or was unable to be evaluated leading to an inability to determine the status of that particular tumor for that time point.

    Confirmation of iCR, iPR and iPD was required per modified irRC-RECIST.

  5. Durable Response Rate (DRR) Per Modified RECIST v1.1

    Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months

    DRR was defined as the percentage of participants with a CR or PR per modified RECIST v1.1 with a duration of response (DOR) ≥ 6 months. One month was calculated based on 365.25 days per year.

    • CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to < 10 mm. All lymph nodes must have been non-pathological in size (< 10mm short axis).
    • PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

    Confirmation of CR and PR were not required per modified RECIST v1.1.

  6. Durable Response Rate (iDRR) Per Modified irRC-RECIST

    Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months

    iDRR was defined as the percentage of participants with an iCR or iPR per modified irRC-RECIST with a duration of response (iDOR) ≥ 6 months. One month was calculated based on 365.25 days per year.

    • iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new). Any pathological lymph nodes (whether target or nontarget) must have a reduction in short axis to < 10 mm.
    • iPR: Decrease in tumor burden ≥ 30% relative to baseline.

    Confirmation of iCR and iPR were required per modified irRC-RECIST.

  7. DOR Per Modified RECIST v1.1

    Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months

    DOR was defined as the time from the date of an initial response of CR or PR to the earlier of PD/death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment date before start of first subsequent anticancer therapy. One month was calculated based on 365.25 days per year.

    • CR:Disappearance of all target & non-target lesions. All lymph nodes must have a reduction in short axis to <10 mm. Any pathological lymph nodes must have had a reduction in short axis to <10 mm. All lymph nodes must have been non-pathological in size (<10mm short axis).
    • PR:At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
    • PD:At least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an increase of at least 5mm. Unequivocal progression of existing non-target lesions.

    Confirmation of CR, PR and PD were not required per modified RECIST v1.1.

  8. iDOR Per Modified irRC-RECIST

    Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months

    iDOR was defined as the time from the date of an initial response that is subsequently confirmed to the earlier of iPD per modified irRC-RECIST.

    Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment date before start of first subsequent anticancer therapy. One month was calculated based on 365.25 days per year.

    • iCR: Disappearance of all target and non-target lesions. All lymph nodes must have a reduction in short axis to < 10 mm.
    • iPR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
    • iPD: At least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. Unequivocal progression of existing non-target lesions.

  9. Disease Control Rate (DCR) Per Modified RECIST v1.1

    Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months

    DCR per modified RECIST v1.1 was defined as the incidence of a BOR of CR, PR or SD.

    • CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to < 10 mm. All lymph nodes must have been non-pathological in size (< 10mm short axis
    • PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
    • SD: Neither sufficient shrinkage to qualify for PR or CR nor sufficient increase to qualify for PD.

    Confirmation of CR and PR were not required per modified RECIST v1.1.

  10. Disease Control Rate (iDCR) Per Modified irRC-RECIST

    Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months

    iDCR per modified irRC-RECIST was defined as the incidence of an iBOR of iCR, iPR or iSD.

    • iCR: Disappearance of all target and non-target lesions. All lymph nodes must have a reduction in short axis to < 10 mm.
    • iPR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
    • iSD: Neither sufficient shrinkage to qualify for iPR or iCR nor sufficient increase to qualify for iPD.

    Confirmation of iCR and iPR were required per modified irRC-RECIST.

  11. Objective Response Rate (iORR) Per Modified irRC-RECIST

    Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months

    iORR was defined as the incidence of an iBOR of iCR or iPR per modified irRC-RECIST

    • iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new). Any pathological lymph nodes (whether target or nontarget) must have a reduction in short axis to < 10 mm.
    • iPR: Decrease in tumor burden ≥ 30% relative to baseline.

    Confirmation of iCR and iPR were required per modified irRC-RECIST.

  12. Progression Free Survival (PFS) Per Modified RECIST v1.1

    Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months

    PFS per modified RECIST 1.1 was defined as the interval from first dose to the earlier event of PD or death from any cause. Participants without an event were censored at their last evaluable post-baseline tumor assessment if available, otherwise were censored on study Day 1. One month was calculated based on 365.25 days per year.

    • PD: At least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. Unequivocal progression of existing non-target lesions.

  13. Progression Free Survival (iPFS) Per Modified irRC-RECIST

    Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months

    iPFS per modified irRC-RECIST was defined as the interval from first dose to the earlier event of iPD or death from any cause. Participants without an event were censored at their last evaluable post-baseline tumor assessment if available, otherwise were censored on study Day 1. One month was calculated based on 365.25 days per year.

    • iPD: Increase in tumor burden ≥ 20% and at least 5 mm absolute increase.

  14. Overall Survival (OS)

    Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months

    OS was defined as the interval from first dose to death from any cause. Participants without an event were censored at the last date known to be alive. One month was calculated based on 365.25 days per year.

  15. Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)

    Time frame: Serious TEAEs were collected up to 90 days post-last dose of treatment. Non-serious TEAEs were collected up to 30 days post-last dose of treatment. The maximum duration of treatment exposure was 105.9 weeks.

    Evaluation of TEAEs included the number of participants with at least 1:

    • TEAE
    • Treatment-related TEAE
    • Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 TEAE
    • Treatment-related CTCAE grade ≥ 3 TEAE
    • Serious TEAE
    • Serious treatment-related TEAE
    • Fatal TEAE
    • Fatal treatment-related TEAE
    • TEAE of interest

    Serious TEAEs were collected up to 90 days post-last dose of treatment. Non-serious TEAEs were collected up to 30 days post-last dose of treatment.

    A CTCAE grade ≥ 3 was determined using the CTCAE grading systems based on CTCAE version 5.0 per the below definitions:

    • Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living.
    • Grade 4: Life-threatening consequences; urgent intervention indicated.
    • Grade 5: Death related to TEAE.

    Abnormal laboratory tests were also recorded as TEAEs.

  16. Time to First Subsequent Anti-cancer Therapy

    Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months

    Time to first subsequent anti-cancer therapy was defined as the time from enrollment to the start of subsequent anticancer therapy. Participants who did not start subsequent anticancer therapy were censored as the last known to be alive date. One month was calculated based on 365.25 days per year.

Sponsors and collaborators

Lead sponsor

Amgen

Industry

Collaborators

  • Merck Sharp & Dohme LLC

Registry information

Official study title

Phase 2 Study of Talimogene Laherparepvec in Combination With Pembrolizumab in Subjects With Unresectable/Metastatic Stage IIIB-IVM1d Melanoma Who Have Progressed on Prior Anti PD-1 Based Therapy

Important dates

Study start
2020
Primary completion
2021
Study completion
2024
First posted
Aug 28, 2019
Registry last updated
Jan 7, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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