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

Melanoma Clinical Trial

Official 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04068181
• Other study ID #: 20180115
• Secondary ID: 2019-001906-61
• Status: Completed
• Phase: Phase 2
• Start date: January 22, 2020
• Est. completion date: February 26, 2024

Study information

• Verified date: March 2024
• Source: Amgen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 72
• Est. completion date: February 26, 2024
• Est. primary completion date: August 19, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

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.

Related Conditions & MeSH terms

• Melanoma

Intervention

Drug:
• Talimogene laherparepvec
Intralesional injection into injectable cutaneous, subcutaneous and nodal legions.
• Pembrolizumab
Intravenous (IV) infusion.

Locations

Country	Name	City	State
Australia	Peter MacCallum Cancer Centre	Melbourne	Victoria
Australia	The Alfred Hospital	Melbourne	Victoria
Australia	Melanoma Institute Australia	North Sydney	New South Wales
Australia	Tasman Oncology Research	Southport	Queensland
Australia	The Queen Elizabeth Hospital	Woodville South	South Australia
Canada	Jewish General Hospital	Montreal	Quebec
Canada	CHU de Quebec-Universite Laval	Quebec
Canada	Princess Margaret Cancer Centre	Toronto	Ontario
France	Centre Hospitalier Universitaire de Bordeaux - Hôpital Saint André	Bordeaux
France	Centre Hospitalier Universitaire de Grenoble - Hopital Nord Michallon	Grenoble Cedex 9
France	Centre Hospitalier Universitaire de Nantes, Hôpital Hôtel Dieu	Nantes Cedex 1
France	Hopital Saint Louis	Paris
France	Centre Hospitalier Lyon Sud	Pierre Benite Cedex
France	Gustave Roussy	Villejuif
Germany	Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden	Dresden
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Universitätsklinikum Regensburg	Regensburg
Germany	Universitätsklinikum Tübingen	Tübingen
Greece	General Hospital of Athens Laiko	Athens
Greece	University Hospital of Ioannina	Ioannina
Greece	Bioclinic of Thessaloniki	Thessaloniki
Italy	Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII	Bergamo
Italy	IRCCS - Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori"	Meldola FC
Italy	IRCCS Istituto Europeo di Oncologia	Milano
Netherlands	Nederlands Kanker Instituut, Antoni van Leeuwenhoekziekenhuis	Amsterdam
Netherlands	Erasmus Medisch Centrum	Rotterdam
Poland	Uniwersyteckie Centrum Kliniczne Centrum Medycyny Nieinwazyjnej	Gdansk
Poland	Szpital Kliniczny im Heliodora Swiecickiego Uniwersytetu Medycznego im Karola Marcinkowskiego w Pozn	Poznan
Poland	Narodowy Instytut Onkologii im Marii Sklodowskiej-Curie â€" Panstwowy Instytut Badawczy	Warszawa
Spain	Hospital Universitari Vall d Hebron	Barcelona
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Madrid Sanchinarro	Madrid
Spain	Hospital Clinico Universitario Virgen de la Victoria	Malaga	AndalucÃ-a
Spain	Onkologikoa	San Sebastian	PaÃ-s Vasco
United Kingdom	Guys Hospital	London
United Kingdom	Royal Marsden Hospital	London
United States	New York Oncology Hematology, PC	Albany	New York
United States	Texas Oncology Austin Central	Austin	Texas
United States	Cleveland Clinic	Cleveland	Ohio
United States	Baylor Scott and White Research Institute	Dallas	Texas
United States	Allina Health Systems dba Virginia Piper Cancer Institute	Fridley	Minnesota
United States	University of Louisville James Graham Brown Cancer Center	Louisville	Kentucky
United States	Medical Oncology Hematology Consultants Helen F Graham Cancer Center	Newark	Delaware
United States	University of Florida Health Cancer Center at Orlando Health	Orlando	Florida
United States	Sansum Clinic	Santa Barbara	California
United States	United States Oncology Regulatory Affairs Corporate Office	The Woodlands	Texas

Sponsors (2)

Lead Sponsor	Collaborator
Amgen	Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Australia,  Canada,  France,  Germany,  Greece,  Italy,  Netherlands,  Poland,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective Response Rate (ORR) Per Modified RECIST v1.1	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).	Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months.
Secondary	Complete Response Rate (CRR) Per Modified RECIST v1.1	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.	Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months.
Secondary	Complete Response Rate (iCRR) Per Modified Immune-related Response Criteria (irRC) RECIST v1.1	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.	Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months.
Secondary	BOR Per Modified RECIST v1.1	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.	Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months.
Secondary	Best Overall Response (iBOR) Per Modified irRC-RECIST	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.	Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months.
Secondary	Durable Response Rate (DRR) Per Modified RECIST v1.1	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.	Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months.
Secondary	Durable Response Rate (iDRR) Per Modified irRC-RECIST	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.	Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months.
Secondary	DOR Per Modified RECIST v1.1	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.	Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months.
Secondary	iDOR Per Modified irRC-RECIST	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.	Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months.
Secondary	Disease Control Rate (DCR) Per Modified RECIST v1.1	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.	Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months.
Secondary	Disease Control Rate (iDCR) Per Modified irRC-RECIST	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.	Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months.
Secondary	Objective Response Rate (iORR) Per Modified irRC-RECIST	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.	Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months.
Secondary	Progression Free Survival (PFS) Per Modified RECIST v1.1	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.	Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months.
Secondary	Progression Free Survival (iPFS) Per Modified irRC-RECIST	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.	Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months.
Secondary	Overall Survival (OS)	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.	Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months.
Secondary	Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)	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.	Day 1 to up to 90 days post-last dose of treatment. The maximum duration of talimogene laherparepvec treatment at data cut off was 74.7 weeks and pembrolizumab treatment at data cut off was 75.9 weeks.
Secondary	Time to First Subsequent Anti-cancer Therapy	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.	Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months.
Secondary	DOR Per Modified RECIST v1.1	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.	Every 12 weeks up to 4 years
Secondary	iDOR Per Modified irRC-RECIST	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.	Every 12 weeks up to 4 years
Secondary	Progression Free Survival (PFS) Per Modified RECIST v1.1	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.	Every 12 weeks up to 4 years
Secondary	Progression Free Survival (iPFS) Per Modified irRC-RECIST	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.	Every 12 weeks up to 4 years
Secondary	Overall Survival (OS)	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.	Every 12 weeks up to 4 years
Secondary	Time to First Subsequent Anti-cancer Therapy	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.	Every 12 weeks up to 4 years

External Links

•   AmgenTrials clinical trials website