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

• ClinicalTrials.gov Identifier: NCT00769704
• Recruitment Status: Completed
• First Posted: October 9, 2008
• Results First Posted: December 17, 2015
• Last Update Posted: July 13, 2016
• Sponsor: BioVex Limited
• Collaborator: Amgen
• Information provided by (Responsible Party): BioVex Limited

Tracking Information

• First Submitted Date: October 7, 2008
• First Posted Date: October 9, 2008
• Results First Submitted Date: September 22, 2015
• Results First Posted Date: December 17, 2015
• Last Update Posted Date: July 13, 2016
• Study Start Date: April 2009
• Actual Primary Completion Date: February 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 12, 2015)

Durable Response Rate [ Time Frame: From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months. ]

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.

• Original Primary Outcome Measures (submitted: October 8, 2008): Achieving a statistically significant improvement in durable response rate, defined as the rate of CR or PR lasting continuously for 6 or more months, as compared to control therapy. [ Time Frame: Every 12 weeks ]

Current Secondary Outcome Measures (submitted: November 12, 2015)

• Overall Survival [ Time Frame: 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. ]
  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.
• Objective Response Rate [ Time Frame: From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months. ]
  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.
• Duration of Response [ Time Frame: From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months. ]
  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.
• Response Onset [ Time Frame: From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months. ]
  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.
• Time to Treatment Failure [ Time Frame: From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months. ]
  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.
• Response Interval [ Time Frame: From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months. ]
  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.

• Original Secondary Outcome Measures (submitted: October 8, 2008): To evaluate overall survival in patients treated with OncoVEXGM-CSF as compared to control therapy. [ Time Frame: Every 3 months ]
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy and Safety Study of Talimogene Laherparepvec Compared to Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) in Melanoma
• Official Title: 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
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Melanoma

Intervention

• Biological: Talimogene laherparepvec
  Up to 4 mL of 10⁸ pfu/mL/per intratumoral injection
  Other Names:

  • OncoVEX^GM-CSF
  • IMLYGIC™
• Biological: GM-CSF
  125 µg/m² subcutaneous injection
  Other Names:

  • Leukine
  • Sargramostim

Study Arms

• 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.
  Intervention: Biological: GM-CSF
• 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.
  Intervention: Biological: Talimogene laherparepvec

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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 12, 2015): 437
• Original Estimated Enrollment (submitted: October 8, 2008): 430
• Actual Study Completion Date: September 2014
• Actual Primary Completion Date: February 2013 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, South Africa, United Kingdom, United States

Administrative Information

• NCT Number: NCT00769704
• Other Study ID Numbers: 005/05; 20110263 ( Other Identifier: Sponsor ); 2008-006140-20 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: BioVex Limited
• Original Responsible Party: Robert Coffin, PhD, BioVex
• Current Study Sponsor: BioVex Limited
• Original Study Sponsor: Same as current
• Collaborators: Amgen

Investigators

• Study Director: MD; Amgen

• PRS Account: BioVex Limited
• Verification Date: June 2016