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Single-arm Trial to Evaluate the Role of the Immune Response to Talimogene Laherparepvec in Unresected Melanoma (TVEC-325)

Primary Purpose

Unresected Stage IIIb to IVM1c Melanoma

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Talimogene Laherparepvec

About this trial

This is an interventional treatment trial for Unresected Stage IIIb to IVM1c Melanoma focused on measuring T-VEC, CD8+ cell density, objective response rate, unresected, Melanoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Provided informed consent prior to initiation of any study-specific activities/procedures
Subject with stage IIIB to IVM1c melanoma for whom surgery is not recommended
Candidate for intralesional therapy
Measurable disease with greatest diameter ≥ 10 mm
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Adequate organ function

Other Inclusion Criteria May Apply

Exclusion Criteria:

Clinically active cerebral metastases.
Bone metastases
Primary ocular or mucosal melanoma
Active herpetic skin lesions or prior complications of herpes simplex virus type 1 (HSV-1) infection (eg, herpetic keratitis or encephalitis)
Requires intermittent or chronic systemic (intravenous or oral) treatment with an antiherpetic drug (eg, acyclovir), other than intermittent topical use
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
Female subject of childbearing potential who is unwilling to use acceptable method(s) of effective contraception

Other Exclusion Criteria May Apply

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Talimogene Laherparepvec

Arm Description

Talimogene laherparepvec was administered by intralesional injection into injectable cutaneous, subcutaneous, and nodal lesions at an initial dose of 10⁶ plaque-forming units (PFU) per mL on day 1 followed by a dose of 10⁸ PFU/mL 21 days after the initial dose and every 14 days thereafter. Participants were treated with talimogene laherparepvec until they achieved a complete response, all injectable tumors had disappeared, clinically significant (resulting in clinical deterioration or requiring change of therapy) disease progression beyond 6 months of treatment, per modified World Health Organization (WHO) response criteria, or intolerance of study treatment, whichever occurred first.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Full Information

NCT ID

NCT02366195

First Posted

November 11, 2014

Last Updated

November 26, 2021

Sponsor

Amgen

1. Study Identification

Unique Protocol Identification Number

NCT02366195

Brief Title

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

Acronym

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

Study Type

Interventional

2. Study Status

Record Verification Date

November 2021

Overall Recruitment Status

Completed

Study Start Date

April 7, 2015 (Actual)

Primary Completion Date

June 26, 2017 (Actual)

Study Completion Date

December 25, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Amgen

4. Oversight

Data Monitoring Committee

5. Study Description

Brief 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.

Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Unresected Stage IIIb to IVM1c Melanoma

Keywords

T-VEC, CD8+ cell density, objective response rate, unresected, Melanoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

112 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Talimogene Laherparepvec

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Talimogene Laherparepvec

Other Intervention Name(s)

IMLYGIC®

Intervention Description

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.

Primary Outcome Measure Information:

Title

Odds Ratio of Baseline Intratumoral CD8+ Cell Density and Objective Response Rate

Description

Time Frame

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 Outcome Measure Information:

Title

Odds Ratio of Baseline Intratumoral CD8+ Cell Density and Durable Response Rate

Description

Time Frame

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)

Title

Hazards Ratio of Baseline Intratumoral CD8+ Cell Density and Duration of Response

Description

Time Frame

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)

Title

Correlation Between Baseline Intratumoral CD8+ Cell Density and Changes in Tumor Burden

Description

Time Frame

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)

Title

Odds Ratio of Change From Baseline Intratumoral CD8+ Cell Density and Objective Response Rate

Description

Time Frame

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)

Title

Odds Ratio of Change From Baseline in Intratumoral CD8+ Cell Density and Durable Response Rate

Description

Time Frame

Title

Hazard Ratio of Change From Baseline in Intratumoral CD8+ Cell Density and Duration of Response

Description

Time Frame

Title

Correlation Between Change From Baseline in Intratumoral CD8+ Cell Density and Changes in Tumor Burden

Description

Time Frame

Title

Objective Response Rate

Description

Time Frame

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)

Title

Duration of Response

Description

Time Frame

Title

Time to Treatment Failure

Description

Time Frame

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)

Title

Durable Response Rate

Description

Time Frame

Title

Overall Survival

Description

Time Frame

Title

Change From Baseline in Tumor Burden

Description

Time Frame

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.

Title

Number of Participants With Adverse Events

Description

Time Frame

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)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Provided informed consent prior to initiation of any study-specific activities/procedures Subject with stage IIIB to IVM1c melanoma for whom surgery is not recommended Candidate for intralesional therapy Measurable disease with greatest diameter ≥ 10 mm Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Adequate organ function Other Inclusion Criteria May Apply Exclusion Criteria: Clinically active cerebral metastases. Bone metastases Primary ocular or mucosal melanoma Active herpetic skin lesions or prior complications of herpes simplex virus type 1 (HSV-1) infection (eg, herpetic keratitis or encephalitis) Requires intermittent or chronic systemic (intravenous or oral) treatment with an antiherpetic drug (eg, acyclovir), other than intermittent topical use 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 Female subject of childbearing potential who is unwilling to use acceptable method(s) of effective contraception Other Exclusion Criteria May Apply

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Organizational Affiliation

Amgen

Official's Role

Study Director

Facility Information:

Facility Name

Research Site

City

Salt Lake City

State/Province

Utah

ZIP/Postal Code

84112

Country

United States

Facility Name

Research Site

City

Salzburg

ZIP/Postal Code

5020

Country

Austria

Facility Name

Research Site

City

Wien

ZIP/Postal Code

1090

Country

Austria

Facility Name

Research Site

City

Bruxelles

ZIP/Postal Code

1000

Country

Belgium

Facility Name

Research Site

City

Bruxelles

ZIP/Postal Code

1200

Country

Belgium

Facility Name

Research Site

City

Liege

ZIP/Postal Code

4000

Country

Belgium

Facility Name

Research Site

City

Boulogne Billancourt

ZIP/Postal Code

92100

Country

France

Facility Name

Research Site

City

Marseille cedex 05

ZIP/Postal Code

13385

Country

France

Facility Name

Research Site

City

Nantes Cedex 1

ZIP/Postal Code

44093

Country

France

Facility Name

Research Site

City

Paris

ZIP/Postal Code

75010

Country

France

Facility Name

Research Site

City

Poitiers Cedex

ZIP/Postal Code

86021

Country

France

Facility Name

Research Site

City

Essen

ZIP/Postal Code

45147

Country

Germany

Facility Name

Research Site

City

Frankfurt am Main

ZIP/Postal Code

60590

Country

Germany

Facility Name

Research Site

City

Hannover

ZIP/Postal Code

30625

Country

Germany

Facility Name

Research Site

City

Heidelberg

ZIP/Postal Code

69120

Country

Germany

Facility Name

Research Site

City

Athens

ZIP/Postal Code

11527

Country

Greece

Facility Name

Research Site

City

Athens

ZIP/Postal Code

18547

Country

Greece

Facility Name

Research Site

City

Heraklion - Crete

ZIP/Postal Code

71110

Country

Greece

Facility Name

Research Site

City

Patra

ZIP/Postal Code

26504

Country

Greece

Facility Name

Research Site

City

Thessaloniki

ZIP/Postal Code

54622

Country

Greece

Facility Name

Research Site

City

Budapest

ZIP/Postal Code

1085

Country

Hungary

Facility Name

Research Site

City

Budapest

ZIP/Postal Code

1122

Country

Hungary

Facility Name

Research Site

City

Debrecen

ZIP/Postal Code

4032

Country

Hungary

Facility Name

Research Site

City

Pecs

ZIP/Postal Code

7632

Country

Hungary

Facility Name

Research Site

City

Szeged

ZIP/Postal Code

6720

Country

Hungary

Facility Name

Research Site

City

Bergamo

ZIP/Postal Code

24127

Country

Italy

Facility Name

Research Site

City

Milano

ZIP/Postal Code

20141

Country

Italy

Facility Name

Research Site

City

Siena

ZIP/Postal Code

53100

Country

Italy

Facility Name

Research Site

City

Amsterdam

ZIP/Postal Code

1081 HV

Country

Netherlands

Facility Name

Research Site

City

Groningen

ZIP/Postal Code

9713 GZ

Country

Netherlands

Facility Name

Research Site

City

Konin

ZIP/Postal Code

62-500

Country

Poland

Facility Name

Research Site

City

Warszawa

ZIP/Postal Code

02-781

Country

Poland

Facility Name

Research Site

City

Moscow

ZIP/Postal Code

115478

Country

Russian Federation

Facility Name

Research Site

City

Saint-Petersburg

ZIP/Postal Code

197758

Country

Russian Federation

Facility Name

Research Site

City

Badalona

State/Province

Cataluña

ZIP/Postal Code

08916

Country

Spain

Facility Name

Research Site

City

Barcelona

State/Province

Cataluña

ZIP/Postal Code

08036

Country

Spain

Facility Name

Research Site

City

Valencia

State/Province

Comunidad Valenciana

ZIP/Postal Code

46014

Country

Spain

Facility Name

Research Site

City

San Sebastian

State/Province

País Vasco

ZIP/Postal Code

20014

Country

Spain

Facility Name

Research Site

City

Madrid

ZIP/Postal Code

28009

Country

Spain

Facility Name

Research Site

City

Madrid

ZIP/Postal Code

28041

Country

Spain

Facility Name

Research Site

City

London

ZIP/Postal Code

SE1 9RT

Country

United Kingdom

Facility Name

Research Site

City

Wirral

ZIP/Postal Code

CH63 4JY

Country

United Kingdom

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request

IPD Sharing Time Frame

Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.

IPD Sharing Access Criteria

Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.

IPD Sharing URL

https://www.amgen.com/datasharing

Citations:

PubMed Identifier

33785610

Citation

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):e001621. doi: 10.1136/jitc-2020-001621.

Results Reference

background

Links:

URL

http://www.amgentrials.com

Description

AmgenTrials clinical trials website

Learn more about this trial

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

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Single-arm Trial to Evaluate the Role of the Immune Response to Talimogene Laherparepvec in Unresected Melanoma (TVEC-325)

Unresected Stage IIIb to IVM1c Melanoma

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial