Efficacy and Safety Study of Talimogene Laherparepvec Compared to Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) in Melanoma

A Randomized Phase 3 Clinical Trial to Evaluate the Efficacy and Safety of Treatment With OncoVEX^GM-CSF Compared to Subcutaneously Administered GM-CSF in Melanoma Patients With Unresectable Stage IIIb, IIIc and IV Disease

The objective of this study is to evaluate the efficacy and safety of treatment with talimogene laherparepvec compared to subcutaneously administered GM-CSF in patients with unresectable Stage IIIb, IIIc and Stage IV melanoma. The efficacy endpoints of the study aim to demonstrate overall clinical benefit for patients treated with talimogene laherparepvec as compared to GM-CSF.

Study Overview

• Status: Completed
• Conditions: Melanoma
• Intervention / Treatment: Biological: GM-CSF; Biological: Talimogene laherparepvec

• Study Type: Interventional
• Enrollment (Actual): 437
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Cross Cancer Institute
  • Ontario
    • Toronto, Ontario, Canada, M5G2M9
      • Princess Margaret Hospital
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital
• South Africa
  • Eastern Cape
    • Port Elizabeth, Eastern Cape, South Africa, 6045
      • GVI Oncology
  • Free State
    • Bloemfontein, Free State, South Africa, 9301
      • Dr. Fourie & Bonnet
  • Gauteng
    • Johannesburg, Gauteng, South Africa, 2196
      • Medical Oncology Centre of Rosebank
  • Guateng
    • Parktown, Guateng, South Africa, 2193
      • Wits Donald Gordon Clinical Trial Site
    • Pretoria, Guateng, South Africa, 0001
      • University of Pretoria
    • Pretoria, Guateng, South Africa, 0075
      • Mary Potter Oncology Centre
  • Kwa-Zulu Natal
    • Pietermaritzburg, Kwa-Zulu Natal, South Africa, 3201
      • Hopelands Cancer Centre
  • Pretoria
    • Hatfield, Pretoria, South Africa, 0028
      • Wilgers Oncology Center
  • Western Cape
    • Cape Town, Western Cape, South Africa, 7500
      • GVI Onocology Clinical Trials Unit
    • Cape Town, Western Cape, South Africa
      • GVI Oncology Centre
• United Kingdom
  • Birmingham, United Kingdom, B15 2TT
    • University of Birmingham
  • Cambridge, United Kingdom, CB2 0QQ
    • Addenbrookes Hospital
  • Chelmsford, United Kingdom, CM1 7ET
    • Broomfield Hospital
  • Leeds, United Kingdom, LS9 7TF
    • St. James's University Hospital
  • Leicester, United Kingdom, LE1 5WW
    • Leicester Royal Infirmary
  • London, United Kingdom, SW3 6JJ
    • Royal Marsden Hospital
  • London, United Kingdom, NW3 2QG
    • Royal Free Hospital
  • London, United Kingdom, SW17 0RE
    • St. George's University of London
  • Newcastle upon Tyne, United Kingdom, NE7 7DN
    • Freeman Hospital
  • Nottingham, United Kingdom, NG5 1PB
    • Nottingham City Hospital
  • Oxford, United Kingdom, OX3 7LJ
    • Churchill Hospital
  • Southampton, United Kingdom, SO16 6YD
    • Southampton General Hospital
  • Wirral, United Kingdom, CH63 4JY
    • Clatterbridge Centre for Oncology
• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona Cancer Center
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences
  • California
    • La Jolla, California, United States, 92093
      • University of California San Diego, Moores Cancer Center
    • Los Angeles, California, United States, 90095
      • UCLA Medical Center
    • San Francisco, California, United States, 94115
      • San Francisco Oncology Associates
    • San Francisco, California, United States, 94117
      • Northern California Melanoma Center, St. Mary's Medical Center
    • Santa Monica, California, United States, 90404
      • John Wayne Cancer Institute
    • Sebastopol, California, United States, 95472
      • Redwood Regional Medical Group Inc, North Bay Melanoma Program
  • Colorado
    • Aurora, Colorado, United States, 80014
      • University of Colorado Cancer Center
  • Florida
    • Jacksonville, Florida, United States, 32207
      • Baptist Cancer Institute
    • Lakeland, Florida, United States, 33805
      • Lakeland Regional Cancer Center
    • Miami, Florida, United States, 33136
      • University of Miami
    • Miami Beach, Florida, United States, 33140
      • Mount Sinai Medical Center CCOP
    • Orlando, Florida, United States, 32806
      • MD Anderson Cancer Center Orlando
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center
    • West Palm Beach, Florida, United States, 33401
      • Palm Beach Cancer Institute
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Park Ridge, Illinois, United States, 60068
      • Cancer Care Center at Lutheran General Hospital
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
    • Indianapolis, Indiana, United States, 46254
      • Investigative Clinical Research of Indiana
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals & Clinics
  • Kansas
    • Kansas City, Kansas, United States, 66205
      • University of Kansas Medical Center
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • James Graham Brown Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Cancer Center
  • Minnesota
    • Robbinsdale, Minnesota, United States, 55422
      • Hubert H Humphrey Cancer Center
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Kansas City, Missouri, United States, 66210
      • Kansas City Cancer Center
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
    • St. Louis, Missouri, United States, 63110
      • St. Louis University Hospital
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Methodist Estabrook Cancer Center
  • New Jersey
    • Morristown, New Jersey, United States, 07962
      • Mountainside Hospital
  • New Mexico
    • Albuquerque, New Mexico, United States, 87109
      • New Mexico Cancer Care Alliance
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • New York, New York, United States, 10032
      • Mount Sinai School of Medicine
    • New York, New York, United States, 10032
      • Columbia Medical University
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina at Chapel Hill School of Medicine
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Winston Salem, North Carolina, United States, 27157
      • Wake Forest University School of Medicine
  • Ohio
    • Canton, Ohio, United States, 44718
      • Gabrail Cancer Center
    • Cincinnati, Ohio, United States, 45267
      • Barrett Cancer Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation, Taussig Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97213
      • Earle A Chiles Research Institute, Providence Cancer Center
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18015
      • St Luke's Hospital & Health Network
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Rhode Island Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
    • Greenville, South Carolina, United States, 29605
      • Institute for Translational Oncology Research
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt Ingram Cancer Center
  • Texas
    • Abilene, Texas, United States, 79701
      • Texas Cancer Center, Abilene
    • Dallas, Texas, United States, 75246
      • Mary Crowley Medical Research Center
    • Houston, Texas, United States, 77030
      • University of Texas - MD Anderson
    • Midland, Texas, United States, 79701
      • Texas Oncology, Allison Cancer Center
  • Utah
    • Murray, Utah, United States, 84107
      • Intermountain Medical Center
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute
  • Virginia
    • Salem, Virginia, United States, 24153
      • Oncology and Hematology Associates of Southwest Virginia, Inc.
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53215
      • Aurora/St. Luke's Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Males or females age ≥ 18 years
• Stage IIIb, IIIc or stage IV disease that is not surgically resectable
• Injectable disease (i.e. suitable for direct injection or through the use of ultrasound guidance)
• At least 1 injectable cutaneous, subcutaneous or nodal melanoma lesion >= 10 mm in longest diameter or, multiple injectable melanoma lesions which in aggregate have a longest diameter of >= 10 mm
• Serum lactate dehydrogenase (LDH) levels less than 1.5 x upper limit of normal (ULN)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Prolongation in International Normalized Ratio (INR), Prothrombin Time (PT), and Partial Thromboplastin Time (PTT) when the result is from therapeutic anticoagulation treatment are permitted for patients whose injectable lesions are cutaneous and/or subcutaneous such that direct pressure could be applied in the event of excessive bleeding

Exclusion Criteria:

• Clinically active cerebral or any bone metastases. Patients with up to 3 (neurological performance status of 0) cerebral metastases may be enrolled, provided that all lesions have been adequately treated with stereotactic radiation therapy, craniotomy, gammaknife therapy, with no evidence of progression, and have not required steroids, for at least two (2) months prior to randomization
• Greater than 3 visceral metastases (this does not include lung metastases or nodal metastases associated with visceral organs). For patients with < 3 visceral metastases, no lesion > 3 cm, and liver lesions must meet Response Evaluation Criteria In Solid Tumors (RECIST) criteria for stable disease for at least 1 month prior to randomization

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: GM-CSF; Granulocyte macrophage colony-stimulating factor (GM-CSF) was administered at a dose of 125 μg/m²/day subcutaneously for 14 days, followed by a 14-day rest period for 24 weeks. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, or lack of response by 12 months, for a maximum of 18 months.	Biological: GM-CSF; 125 µg/m² subcutaneous injection; Other Names: Leukine; Sargramostim
Experimental: Talimogene Laherparepvec; Participants received talimogene laherparepvec on Days 1 and 15 of each 28-day cycle for 24 weeks. The initial dose of talimogene laherparepvec was at a concentration of 10⁶ plaque forming units (PFU)/mL, injected into 1 or more skin, subcutaneous or nodal tumors. Subsequent doses began at least 3 weeks after the first dose and consisted of talimogene laherparepvec at a concentration of 10⁸ PFU/mL. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, lack of response by 12 months, or disappearance of all injectable lesions, for a maximum of 18 months.	Biological: Talimogene laherparepvec; Up to 4 mL of 10⁸ pfu/mL/per intratumoral injection; Other Names: OncoVEX^GM-CSF; IMLYGIC™

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Durable Response Rate	Durable response rate was defined as the percentage of participants with a complete response (CR) or partial response (PR) maintained continuously for at least 6 months from the time the objective response was first observed and initiating within 12 months of starting therapy as assessed by the Endpoint Assessment Committee (EAC). This reflects all new sites of disease as well as disease sites identified at baseline. Disease assessments were performed at the beginning of each treatment cycle in accordance with modified World Health Organization criteria. CR: Disappearance of all clinical evidence of tumor (both measurable and non-measurable but evaluable disease); PR: ≥ 50% reduction in the sum of the products of the perpendicular diameters of all measurable tumors at the time of assessment as compared to baseline.	From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Overall survival was defined as the time from the date of randomization to the date of death from any cause. Overall survival time was censored at the last date the patient was known to be alive when the confirmation of death was absent or unknown. Participants were censored at the date of randomization if no additional follow-up data were obtained.	From randomization until the first 290 survival events had occurred (data cut-off date of 31 March 2014); median time on follow-up was 44 months.
Objective Response Rate	Objective response rate was defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) assessed by the Endpoint Assessment Committee (EAC). Best overall response for a patient is the best overall response observed across all time points. Disease assessments were performed at the beginning of each treatment cycle and assessed in accordance with modified World Health Organization criteria. CR: Disappearance of all clinical evidence of tumor (both measurable and non-measurable but evaluable disease); PR: ≥ 50% reduction in the sum of the products of the perpendicular diameters of all measurable tumors at the time of assessment as compared to baseline.	From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months.
Duration of Response	The duration of response is defined as the longest individual period from entering response (CR or PR as assessed by the EAC) to the first documented evidence of the patient no longer meeting the criteria for being in response or death, whichever is earlier. Responses were censored at the last assessment showing response.	From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months.
Response Onset	Response onset is defined as the time from the date of randomization to the date of the first documented evidence of response (CR or PR) per EAC assessment.	From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months.
Time to Treatment Failure	Time to treatment failure was assessed by the investigator, and calculated from randomization until the first clinically relevant disease progression where there is no response achieved after the progression, or until death if no such progression occurs. Participants who did not have clinically relevant progression or did not die were censored at the time of the their last tumor assessment. Participants who withdrew from treatment due to a clinically unacceptable toxicity were not considered as an event in the analysis. Progressive disease (PD) is defined as a ≥ 25% increase in the sum of the products of the perpendicular diameters of all measurable tumors since baseline, or the unequivocal appearance of a new tumor since the last response assessment time point. Clinically relevant progressive disease is PD that is associated with a decline in performance status and/or in the opinion of the investigator the patient requires alternative therapy.	From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months.
Response Interval	Response interval is defined as the interval between the date of randomization and the date of the last documented evidence of response (CR or PR as assessed by the Investigator) prior to any new anti-cancer therapy. Response Interval post response onset was censored if a patient was still in response at the last observation.	From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months.

Collaborators and Investigators

• Sponsor: BioVex Limited
• Collaborators: Amgen

Publications and helpful links

General Publications

• Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, Delman KA, Spitler LE, Puzanov I, Agarwala SS, Milhem M, Cranmer L, Curti B, Lewis K, Ross M, Guthrie T, Linette GP, Daniels GA, Harrington K, Middleton MR, Miller WH Jr, Zager JS, Ye Y, Yao B, Li A, Doleman S, VanderWalde A, Gansert J, Coffin RS. Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. J Clin Oncol. 2015 Sep 1;33(25):2780-8. doi: 10.1200/JCO.2014.58.3377. Epub 2015 May 26.
• Andtbacka RHI, Collichio F, Harrington KJ, Middleton MR, Downey G, Ӧhrling K, Kaufman HL. Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III-IV melanoma. J Immunother Cancer. 2019 Jun 6;7(1):145. doi: 10.1186/s40425-019-0623-z.
• Kaufman HL, Andtbacka RHI, Collichio FA, Wolf M, Zhao Z, Shilkrut M, Puzanov I, Ross M. Durable response rate as an endpoint in cancer immunotherapy: insights from oncolytic virus clinical trials. J Immunother Cancer. 2017 Sep 19;5(1):72. doi: 10.1186/s40425-017-0276-8.

Study record dates

Study Major Dates

• Study Start: April 1, 2009
• Primary Completion (Actual): February 1, 2013
• Study Completion (Actual): September 1, 2014

Study Registration Dates

• First Submitted: October 7, 2008
• First Submitted That Met QC Criteria: October 8, 2008
• First Posted (Estimate): October 9, 2008

Study Record Updates

• Last Update Posted (Estimate): July 13, 2016
• Last Update Submitted That Met QC Criteria: June 14, 2016
• Last Verified: June 1, 2016

More Information

Terms related to this study

• Keywords: Melanoma; talimogene laherparepvec; GM-CSF; OncoVEX^GM-CSF; Stage IIIb, IIIc and IV Disease; oncolytic; OncoVex; T-Vec
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Sargramostim; Molgramostim; Talimogene laherparepvec
• Other Study ID Numbers: 005/05; 20110263 (Other Identifier: Sponsor); 2008-006140-20 (EudraCT Number)