Single-arm Trial to Evaluate the Role of the Immune Response to Talimogene Laherparepvec in Unresected Melanoma

Unresected Stage IIIb to IVM1c Melanoma Clinical Trial

— TVEC-325  

Official title:

A Phase 2, Multicenter, Open-label, Single-arm Trial to Evaluate the Correlation Between Objective Response Rate and Baseline Intratumoral CD8+ Cell Density in Subjects With Unresected Stage IIIB to IVM1c Melanoma Treated With Talimogene Laherparepvec

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02366195
• Other study ID #: 20120325
• Secondary ID: 2013-005552-15
• Status: Completed
• Phase: Phase 2
• Start date: April 7, 2015
• Est. completion date: December 25, 2020

Study information

• Verified date: November 2021
• Source: Amgen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The study is a phase 2, multi centered, single arm study designed to evaluate the correlation between cluster of differentiation 8-positive (CD8+) cell density and objective response rate in adults with unresected stage IIIB to IVM1c melanoma. This study will also evaluate the safety and tolerability profile of talimogene laherparepvec.

Description:

The study will explore the hypothesis that intratumoral CD8+ cell density at baseline correlates with objective response rate in adults with unresected stage IIIB to IVMIc melanoma treated with talimogene laherparepvec.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 112
• Est. completion date: December 25, 2020
• Est. primary completion date: June 26, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Provided informed consent prior to initiation of any study-specific activities/procedures

2. Subject with stage IIIB to IVM1c melanoma for whom surgery is not recommended

3. Candidate for intralesional therapy

4. Measurable disease with greatest diameter = 10 mm

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

6. Adequate organ function

Other Inclusion Criteria May Apply

Exclusion Criteria:

1. Clinically active cerebral metastases.

2. Bone metastases

3. Primary ocular or mucosal melanoma

4. Active herpetic skin lesions or prior complications of herpes simplex virus type 1 (HSV-1) infection (eg, herpetic keratitis or encephalitis)

5. Requires intermittent or chronic systemic (intravenous or oral) treatment with an antiherpetic drug (eg, acyclovir), other than intermittent topical use

6. Female subject is pregnant or breast-feeding, or planning to become pregnant during study treatment and through 3 months after the last dose of talimogene laherparepvec

7. Female subject of childbearing potential who is unwilling to use acceptable method(s) of effective contraception

Other Exclusion Criteria May Apply

Related Conditions & MeSH terms

• Melanoma
• Unresected Stage IIIb to IVM1c Melanoma

Intervention

Drug:
• Talimogene Laherparepvec
The initial dose of talimogene laherparepvec is up to 4.0 mL of 10^6 PFU/mL. Subsequent doses of talimogene laherparepvec are up to 4.0 mL of 10^8 PFU/mL.

Locations

Country	Name	City	State
Austria	Research Site	Salzburg
Austria	Research Site	Wien
Belgium	Research Site	Bruxelles
Belgium	Research Site	Bruxelles
Belgium	Research Site	Liege
France	Research Site	Boulogne Billancourt
France	Research Site	Marseille cedex 05
France	Research Site	Nantes Cedex 1
France	Research Site	Paris
France	Research Site	Poitiers Cedex
Germany	Research Site	Essen
Germany	Research Site	Frankfurt am Main
Germany	Research Site	Hannover
Germany	Research Site	Heidelberg
Greece	Research Site	Athens
Greece	Research Site	Athens
Greece	Research Site	Heraklion - Crete
Greece	Research Site	Patra
Greece	Research Site	Thessaloniki
Hungary	Research Site	Budapest
Hungary	Research Site	Budapest
Hungary	Research Site	Debrecen
Hungary	Research Site	Pecs
Hungary	Research Site	Szeged
Italy	Research Site	Bergamo
Italy	Research Site	Milano
Italy	Research Site	Siena
Netherlands	Research Site	Amsterdam
Netherlands	Research Site	Groningen
Poland	Research Site	Konin
Poland	Research Site	Warszawa
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Saint-Petersburg
Spain	Research Site	Badalona	Cataluña
Spain	Research Site	Barcelona	Cataluña
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	San Sebastian	País Vasco
Spain	Research Site	Valencia	Comunidad Valenciana
United Kingdom	Research Site	London
United Kingdom	Research Site	Wirral
United States	Research Site	Salt Lake City	Utah

Sponsors (1)

Lead Sponsor	Collaborator
Amgen

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  France,  Germany,  Greece,  Hungary,  Italy,  Netherlands,  Poland,  Russian Federation,  Spain,  United Kingdom, 

References & Publications (1)

Malvehy J, Samoylenko I, Schadendorf D, Gutzmer R, Grob JJ, Sacco JJ, Gorski KS, Anderson A, Pickett CA, Liu K, Gogas H. Talimogene laherparepvec upregulates immune-cell populations in non-injected lesions: findings from a phase II, multicenter, open-label study in patients with stage IIIB-IVM1c melanoma. J Immunother Cancer. 2021 Mar;9(3). pii: e001621. doi: 10.1136/jitc-2020-001621. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Odds Ratio of Baseline Intratumoral CD8+ Cell Density and Objective Response Rate	A univariate logistic regression model was performed to evaluate baseline log2(CD8+ cell density) as a predictor of objective response.; Response was assessed according to the modified version of the World Health Organization (WHO) response criteria. Objective response rate (ORR) was defined as the percentage of participants with a complete response (CR) or partial response (PR) according to the modified WHO criteria.; The unadjusted odds ratio of log2(baseline intratumoral CD8+ cell density) for objective response rate is reported.	Intratumoral CD8+ cell density: Baseline. Response: every 12 weeks until disease progression beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up at primary completion = 59 weeks (min 3 to max 116 weeks)
Secondary	Odds Ratio of Baseline Intratumoral CD8+ Cell Density and Durable Response Rate	A univariate logistic regression model was performed to evaluate baseline log2(CD8+ cell density) as a predictor of durable response.; Response was assessed according to the modified version of the World Health Organization (WHO) response criteria. Durable response rate (DRR) was defined as the percentage of participants with an objective response lasting continuously for 6 months and starting any time within 12 months of initiating therapy.; The unadjusted odds ratio of log2(baseline intratumoral CD8+ cell density) for durable response rate is reported.; Primary completion is defined as PC and final analysis is defined as FA.	Intratumoral CD8+ cell density: Baseline. Response: every 12 weeks until disease progression beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up: PC: 59 weeks (3 to 116 weeks); FA: 108 weeks (2.7 to 245.6)
Secondary	Hazards Ratio of Baseline Intratumoral CD8+ Cell Density and Duration of Response	A Cox proportional hazards regression model was performed to evaluate baseline log2(CD8+ cell density) as a predictor of duration of response.; Response was assessed according to the modified version of the World Health Organization (WHO) response criteria. Duration of response (DOR) is defined as the longest individual period from entering an objective response (CR/PR) to the first documented evidence of the participant no longer meeting the criteria for being in the response (i.e. an overall response of either stable disease [SD] as compared with baseline or progressive disease [PD]).; The unadjusted hazard ratio of log2(baseline intratumoral CD8+ cell density) for duration of response is reported.	Intratumoral CD8+ cell density: Baseline. Response: every 12 weeks until disease progression beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up: PC: 59 weeks (3 to 116 weeks); FA: 108 weeks (2.7 to 245.6 weeks)
Secondary	Correlation Between Baseline Intratumoral CD8+ Cell Density and Changes in Tumor Burden	Pearson's correlation coefficient (r) was estimated to assess the relationship between baseline log2(CD8+ cell density) and the maximum decrease in measurable tumor burden.; Tumor burden is the sum of the products of the 2 largest perpendicular diameters (SPD) for all index lesions selected at baseline.; The Pearson's correlation coefficient (r) of log2(baseline intratumoral CD8+ cell density) and the maximum decrease in tumor burden is reported.; Primary completion is defined as PC and final analysis is defined as FA.	Intratumoral CD8+ cell density: Baseline; Tumor burden: First dose of study drug until primary completion date (26 June 2017) or end of follow-up; median time on follow-up: PC: 59 weeks (3 to 116 weeks); FA: 108 weeks (2.7 to 245.6 weeks)
Secondary	Odds Ratio of Change From Baseline Intratumoral CD8+ Cell Density and Objective Response Rate	A univariate logistic regression model was performed to evaluate change from baseline to week 6 in log2(CD8+ cell density) in uninjected tumors as a predictor of objective response.; Response was assessed according to the modified version of the World Health Organization (WHO) response criteria. Objective response rate (ORR) was defined as the percentage of participants with a complete response or partial response according to the modified WHO criteria.; The unadjusted odds ratio of log2(change from baseline intratumoral CD8+ cell density) for objective response rate is reported.; Intratumoral CD8+ Cell density has been shortened to "CD8+ cell density" in the time frame due to character limit. Primary completion is defined as PC and final analysis is defined as FA.	CD8+ cell density: Baseline & Week 6. Response: every 12 weeks until disease progression beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up: PC: 59 weeks (3 to 116 weeks); FA: 108 weeks (2.7 to 245.6 weeks)
Secondary	Odds Ratio of Change From Baseline in Intratumoral CD8+ Cell Density and Durable Response Rate	A univariate logistic regression model was performed to evaluate change from baseline to week 6 in log2(CD8+ cell density) in uninjected lesions as a predictor of durable response.; Response was assessed according to the modified version of the World Health Organization (WHO) response criteria. Durable response rate (DRR) was defined as the percentage of participants with an objective response lasting continuously for 6 months and starting any time within 12 months of initiating therapy.; The unadjusted odds ratio of log2(change from baseline in intratumoral CD8+ cell density) for durable response rate is reported.; Intratumoral CD8+ Cell density has been shortened to "CD8+ cell density" in the time frame due to character limit. Primary completion is defined as PC and final analysis is defined as FA.	CD8+ cell density: Baseline & Week 6. Response: every 12 weeks until disease progression beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up: PC: 59 weeks (3 to 116 weeks); FA: 108 weeks (2.7 to 245.6 weeks)
Secondary	Hazard Ratio of Change From Baseline in Intratumoral CD8+ Cell Density and Duration of Response	A Cox proportional hazards regression model was performed to evaluate change from baseline in log2(CD8+ cell density) as a predictor of duration of response.; Response was assessed according to the modified version of the World Health Organization (WHO) response criteria. Duration of response (DOR) is defined as the longest individual period from entering an objective response (CR/PR) to the first documented evidence of the participant no longer meeting the criteria for being in the response (i.e. an overall response of either stable disease [SD] as compared with baseline or progressive disease [PD]).; The unadjusted hazard ratio of log2(change from baseline intratumoral CD8+ cell density) for duration of response is reported.; Intratumoral CD8+ Cell density has been shortened to "CD8+ cell density" in the time frame due to character limit. Primary completion is defined as PC and final analysis is defined as FA.	CD8+ cell density: Baseline & Week 6. Response: every 12 weeks until disease progression beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up: PC: 59 weeks (3 to 116 weeks); FA: 108 weeks (2.7 to 245.6 weeks)
Secondary	Correlation Between Change From Baseline in Intratumoral CD8+ Cell Density and Changes in Tumor Burden	Pearson's correlation coefficient (r) was estimated to assess the relationship between change from baseline in log2(CD8+ cell density) in uninjected lesions and the maximum decrease in measurable tumor burden.; Tumor burden is the sum of the products of the 2 largest perpendicular diameters (SPD) for all index lesions selected at baseline.; The Pearson's correlation coefficient (r) of log2(change from baseline intratumoral CD8+ cell density) and the maximum decrease in tumor burden is reported.; Intratumoral CD8+ Cell density has been shortened to "CD8+ cell density" in the time frame due to character limit. Primary completion is defined as PC and final analysis is defined as FA.	CD8+ cell density: Baseline & Week 6. Response: every 12 weeks until disease progression beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up: PC: 59 weeks (3 to 116 weeks); FA: 108 weeks (2.7 to 245.6 weeks)
Secondary	Objective Response Rate	Objective Response rate is defined as the percentage of participants with either a CR or PR based on Modified WHO Response Criteria.; CR: Complete disappearance of all index lesions, all non-index lesions, and any new tumors which might have appeared. Any residual cutaneous or subcutaneous index lesions must be documented by representative biopsy to not contain viable tumor.; PR: Disappearance of all index lesions with persistence of one or more non-index tumor(s), or, 50% or greater reduction in the 2 largest perpendicular diameters (SPD) of all index lesions as compared to baseline, and disappearance or persistence of non-index lesions.	Response was assessed every 12 weeks until PD beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up at time of primary completion: 59 weeks (3 to 116 weeks); final analysis: 108 weeks (2.7 to 245.6 weeks)
Secondary	Duration of Response	Duration of response (DOR) was defined as the longest individual period from entering an objective response (CR/PR) to the first documented evidence of the participant no longer meeting the criteria for objective response (i.e. an overall response of either stable disease [SD] as compared with baseline or progressive disease [PD]).; SD: Neither sufficient tumor shrinkage of index lesion to qualify for response (PR or CR) nor sufficient tumor increase of index lesion to qualify for PD, with no increase in size of non-index lesions.; PD: A > 25% increase in the sum of the SPD of all index tumors since baseline, or the unequivocal appearance of a new tumor since the last response assessment time point, or unequivocal progression of one or more non-index lesions.; Participants last reported to be either a CR or PR were censored at that time point.	Response was assessed every 12 weeks until PD beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up at time of primary completion: 59 weeks (3 to 116 weeks); final analysis: 108 weeks (2.7 to 245.6 weeks)
Secondary	Time to Treatment Failure	Time to treatment failure (TTF) was calculated from first dosing until one or more of the following: (1) clinically relevant disease progression (PDr); (2) death from any cause; (3) non clinically relevant disease progression (PDn) associated with a requirement for alternative therapy as the reason for ending treatment or start of new anti-cancer therapy. Participants with no event were censored at their last evaluable tumor assessment.	From first dose of study drug until primary completion date of 26 June 2017, or end of follow-up; median time on follow-up at primary completion was 59 weeks (3 to 116 weeks); final analysis was 108 weeks (2.7 to 245.6 weeks)
Secondary	Durable Response Rate	Durable response rate (DRR) was defined as the percentage of participants with an objective response (CR or PR) based on modified WHO response criteria lasting continuously for 6 months and starting any time within 12 months of initiating therapy.	Response was assessed every 12 weeks until PD beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up at time of primary completion: 59 weeks (3 to 116 weeks); final analysis: 108 weeks (2.7 to 245.6 weeks)
Secondary	Overall Survival	Overall survival (OS) was defined as the time from the date of first dose to the date of death from any cause.; OS time was censored at the last date the participant was known to be alive when the confirmation of death is absent or unknown.	From first dose of study drug until primary completion date of 26 June 2017, or end of follow-up; median time on follow-up at primary completion was 59 weeks (3 to 116 weeks); final analysis was 108 weeks (2.7 to 245.6 weeks)
Secondary	Change From Baseline in Tumor Burden	Tumor burden is the sum of the products of the 2 largest perpendicular diameters (SPD) for all index lesions selected at baseline.; Change from baseline in tumor burden was assessed in participants with an objective response.	Baseline and Day 1 of cycle 6, 12 , 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90, 96, 102, 108, 114, and 120. The first cycle was 21 days and all subsequent cycles were 14 days.
Secondary	Number of Participants With Adverse Events	The severity of each adverse event (AE) was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 grading scale, where Grade 1 = Mild AE Grade 2 = Moderate AE Grade 3 = Severe AE Grade 4 = Life-threatening or disabling AE Grade 5 = Death related to AE Treatment-related adverse events (TRAE) were those assessed by the investigator as possibly related to talimogene laherparepvec.	From first dose through 30 days after last dose of talimogene laherparepvec; median duration of treatment was 25.143 weeks (range 0.14 to 241.43 weeks)

External Links

•   AmgenTrials clinical trials website