Efficacy and Safety of Talimogene Laherparepvec Neoadjuvant Treatment Plus Surgery Versus Surgery Alone for Melanoma

• ClinicalTrials.gov Identifier: NCT02211131
• Recruitment Status: Completed
• First Posted: August 7, 2014
• Results First Posted: May 28, 2020
• Last Update Posted: June 5, 2023
• Sponsor: Amgen
• Information provided by (Responsible Party): Amgen

Tracking Information

• First Submitted Date: August 5, 2014
• First Posted Date: August 7, 2014
• Results First Submitted Date: April 21, 2020
• Results First Posted Date: May 28, 2020
• Last Update Posted Date: June 5, 2023
• Actual Study Start Date: February 3, 2015
• Actual Primary Completion Date: April 30, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 9, 2023)

Recurrence-Free Survival (RFS) [ Time Frame: 24 months after last participant was randomized (data cutoff date of 30 April 2019) ]

Recurrence free survival (RFS) is defined as the time from randomization to the date of event, and is presented as a Kaplan Meier estimate of time to events. The event for RFS is defined as the first of local, regional, or distant recurrence of melanoma or death due to any cause. Participants without a histopathology tumor-free margin (R0) surgical outcome or those who withdrew prior to surgery were considered an event at randomization. Participants without an event were censored at their last evaluable tumor assessment.

Original Primary Outcome Measures (submitted: August 5, 2014)

Efficacy [ Time Frame: 24 months after last patient randomized ]

Estimate the efficacy of neoadjuvant talimogene laherparepvec plus surgery versus surgery alone on recurrence-free survivial (RFS)

Current Secondary Outcome Measures (submitted: May 9, 2023)

• RFS [ Time Frame: 5 years after the last participant was randomized (last subject last visit occurred 28 April 2022) ]
  Recurrence free survival (RFS) is defined as the time from randomization to the date of event, and is presented as a Kaplan Meier estimate of time to events. The event for RFS is defined as the first of local, regional, or distant recurrence of melanoma or death due to any cause. Participants without a histopathology tumor-free margin (R0) surgical outcome or those who withdrew prior to surgery were considered an event at randomization. Participants without an event were censored at their last evaluable tumor assessment.
• Kaplan-Meier (K-M) Estimate of RFS Rate at 1 Year, 2 Years, 3 Years, and 5 Years [ Time Frame: 5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022) ]
  Kaplan-Meier estimates of the percentage of participants with RFS at 1 year, 2 years, 3 years, and 5 years from randomization. The event for RFS is defined as the first of local, regional, or distant recurrence of melanoma or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Participants without an event were censored at their last evaluable tumor assessment. Rate is presented as the percentage of participants with RFS at given time point.
• Histopathology Tumor-Free Margin (R0) Surgical Resection Rate [ Time Frame: 18 weeks after last participant randomized (data cutoff date of 30 April 2019) ]
  Histopathology tumor-free margin (R0) surgical resection is defined by pathologist as absence of ink on the tumor for all disease. Rate is presented as the percentage of participants with histopathology tumor-free margin (R0) surgical resection.
• Pathological Complete Response (pCR) Rate [ Time Frame: 18 weeks after last participant randomized (data cutoff date of 30 April 2019) ]
  Pathological Complete Response (pCR) is defined as no evidence of viable tumor cells on complete pathological evaluation of the surgical specimen per institutional standards of care. Rate is presented as the percentage of participants with pCR.
• Local Recurrence-Free Survival (LRFS) [ Time Frame: 5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022) ]
  Local recurrence-free survival (LRFS) is defined as the time from randomization to the earlier date of the first of local disease recurrence or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Local recurrence is defined as histologically or cytologically confirmed reappearance of melanoma in the area of up to 2 cm from the scar from the surgical excision or at the edge of the skin graft if that was used for closure.
• Regional Recurrence-Free Survival (RRFS) [ Time Frame: 5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022) ]
  Regional recurrence-free survival (RRFS) is defined as the time from randomization to the date of the first of regional disease recurrence or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Regional recurrence excludes local recurrence and is defined as histologically, cytologically, or radiographically confirmed reappearance of melanoma in the regional lymph node basin.
• Distant Metastases-Free Survival (DMFS) [ Time Frame: 5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022) ]
  Distant metastases-free survival (DMFS) is defined as the time from randomization to the date of the first of distant metastases or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Distant metastases exclude local and regional recurrence and will include distant cutaneous/subcutaneous metastases, distant nodal metastases, or visceral, central nervous system, brain, or bone metastases.
• Overall Survival (Kaplan-Meier) [ Time Frame: 5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022) ]
  Overall Survival (OS) is defined as the time from randomization to the date of death due to any cause.
• Kaplan-Meier Estimate of OS at 1 Year, 2 Years, 3 Years, and 5 Years [ Time Frame: 5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022) ]
  Kaplan-Meier estimates of the percentage of participants alive at 1 year, 2 years, 3 years, and 5 years from randomization.
• Best Overall Tumor Response Per Investigator Response Rate (Talimogene Laherparepvec Arm Only) [ Time Frame: 18 months after last participant randomized (data cutoff date of 30 April 2019). ]
  Response was assessed based on the response of the index lesions and nonindex lesions as described in protocol-defined World Health Organization (WHO) criteria (for complete response [CR], partial response [PR], stable disease [SD], progressive disease [PD]), and presence or absence of new lesions. Best response for a participant is the best overall response observed across all time points. Response rate is reported as the percentage of participants with the best overall response (per investigator) of CR or PR. CR: complete disappearance of all index lesions, including any new measurable tumor lesions which might have appeared. PR: ≥ 50% reduction in the sum of the products of the 2 largest perpendicular diameters of all index lesions and new measurable lesions, if applicable, at the time of assessment as compared to the sum of the products of the perpendicular diameters of all index lesions at baseline.
• Lesion Objective Response Rate: Injected Lesions (Talimogene Laherparepvec Arm Only) [ Time Frame: 18 months after last participant randomized (data cutoff date of 30 April 2019). ]
  The investigator-assessed tumor response rate for injected lesions, reported as the percentage of evaluable lesions in response. A lesion is in response if the decrease in tumor area is ≥ 50%.
• Lesion Objective Response Rate: Uninjected Lesions (Talimogene Laherparepvec Arm Only) [ Time Frame: 18 months after last participant randomized (data cutoff date of 30 April 2019). ]
  The investigator-assessed tumor response rate for uninjected lesions, reported as the percentage of evaluable lesions in response. A lesion is in response if the decrease in tumor area is ≥ 50%.
• Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Fatal Adverse Events (AEs), and TEAEs Leading to Discontinuations or Interruptions [ Time Frame: Adverse Events are reported from first day of study drug or the surgery through 30 days after the last dose of study drug or 30 days after the surgery, whichever is later. Median duration of treatment was 11.14 weeks (range 0.1 to 12.3 weeks). ]
  Adverse event (AE): any untoward medical occurrence that does not necessarily have a causal relationship with study treatment. SAE: AE meeting at least 1 of the following serious criteria: fatal; life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious event. Event severity grades: 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). Treatment begins when the first dose of protocol-required therapies is administered to a participant (Talimogene Laherparepvec Arm) or the participant undergoes surgery (Surgery Arm). Events are reported from first day of study drug or the surgery through 30 days after the last administration of talimogene laherparepvec or 30 days after the surgical resection of melanoma tumor lesion(s), whichever is later.
• Number of Participants With Talimogene Laherparepvec-Related TEAEs, SAEs, Fatal AEs, and TEAEs Leading to Discontinuations or Interruptions [ Time Frame: Adverse Events are reported from first day of study drug or the surgery through 30 days after the last administration of talimogene laherparepvec or 30 days after the surgical resection of melanoma tumor lesion(s), whichever is later. ]
  Adverse event (AE): any untoward medical occurrence that does not necessarily have a causal relationship with study treatment. SAE: AE meeting at least 1 of the following serious criteria: fatal; life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious event. Event severity grades: 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). Treatment begins when the first dose of protocol-required therapies is administered to a participant (Talimogene Laherparepvec Arm) or the participant undergoes surgery (Surgery Arm). Events are reported from first day of study drug or the surgery through 30 days after the last administration of talimogene laherparepvec or 30 days after the surgical resection of melanoma tumor lesion(s), whichever is later.

Original Secondary Outcome Measures (submitted: August 5, 2014)

• Efficacy [ Time Frame: Primary analysis for 2-year RFS will occur approximately 2 years after the end of randomisation. Additional analysis for 3-year RFS and final analysis for 5-year RFS will occur approximately 3 and 5 years after the end of randomization ]
  Estimate the efficacy of neoadjuvant talimogene laherparepvec plus surgery compared to surgery alone on 2-year, 3-year and 5-year RFS
• Efficacy [ Time Frame: 16 weeks after last patient randomized ]
  Estimate the efficacy of neoadjuvant talimogene laherparepvec plus surgery compared to surgery alone on rate of histopathological tumor-free margin (R0) surgical resection
• Efficacy [ Time Frame: 16 weeks after last patient randomized ]
  Estimate the effect of neoadjuvant talimogene laherparepvec on rate of pathological complete response (pCR)
• Efficacy [ Time Frame: 24 months after last patient randomized ]
  Estimate the effect of neoadjuvant talimogene laherparepvec plus surgery compared to surgery alone on local recurrence-free survival (LRFS) and distant metastases-free survival (DMFS)
• Efficacy [ Time Frame: Primary analysis for 2 year overall survival will occur approximately 2 years after the end of randomisation. Additional analysis for 3-year OS and final analysis for 5-year OS will occur approximately 3 and 5 years after the end of randomization ]
  Estimate the effect of neoadjuvant talimogene laherparepvec plus surgery compared to surgery alone on 2-year, 3-year, 5-year and overall survival (OS)
• Overall Response [ Time Frame: 16 weeks after last patient randomized ]
  Estimate response to neoadjuvant talimogene laherparepvec overall and seperately in injected and uninjected lesions during treatment (Arm 1 only)
• Safety [ Time Frame: 16 weeks after 40tth, 75th and last patient randomized ]
  Evaluate the safety of neoadjuvant talimogene laherparepvec plus surgery commpared to surgery alone

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy and Safety of Talimogene Laherparepvec Neoadjuvant Treatment Plus Surgery Versus Surgery Alone for Melanoma
• Official Title: A Phase 2, Multicenter, Randomized, Open-label Trial Assessing the Efficacy and Safety of Talimogene Laherparepvec Neoadjuvant Treatment Plus Surgery Versus Surgery Alone for Resectable, Stage IIIB to IVM1a Melanoma
• Brief Summary: This is a phase 2, multicenter, randomized, open-label study to estimate the efficacy of talimogene laherparepvec as a neoadjuvant treatment followed by surgery compared to surgery alone in subjects with completely resectable stage IIIB, IIIC, or IVM1a melanoma.

Detailed Description

This is a phase 2, multicenter, randomized, open-label study to estimate the efficacy of talimogene laherparepvec as a neoadjuvant treatment followed by surgery compared to surgery alone in subjects with completely resectable stage IIIB, IIIC, or IVM1a melanoma.

Arm 1: Talimogene laherparepvec for 6 doses followed by surgical resection of melanoma tumor lesion(s).

Arm 2: Immediate surgical resection of melanoma tumor lesion(s) Following surgery, adjuvant systemic therapy and/or radiotherapy may be administered at the investigator's discretion and per the institutional standard of care.

Subjects will be followed for safety approximately 30 (+15) days after surgery and for disease recurrence, subsequent anticancer therapy, and survival every 3 months (±30 days) for first 3 years after the end of the safety follow-up period and then every 6 months (±30 days) until death, subject withdraws full consent, or up to 5 years after the last subject is randomized.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Completely Resectable Stage IIIB, IIIC, or IVM1a Melanoma

Intervention

• Drug: Talimogene Laherparepvec
  Talimogene laherparepvec will be administered by intralesional injection into the injectable cutaneous, subcutaneous, and nodal tumors initially at a dose of 10^6 plaque forming units (PFU)/mL at day 1 of week 1 followed by a dose of 10^8 PFU/mL at day 1 (±3 days) of week 4, 6, 8, 10 and 12 or until all injectable tumors have disappeared, or intolerance of study treatment or in the opinion of the investigator, immediate surgical resection or any other treatment for melanoma is warranted, whichever occurs first.
• Procedure: Immediate surgical resection of melanoma lesion(s)
  Surgical resection of melanoma tumor lesion(s) will be performed after randomization any time during weeks 1 to 6.

Study Arms

• Surgery
  Surgical resection of melanoma tumor lesion(s)
  Intervention: Procedure: Immediate surgical resection of melanoma lesion(s)
• Experimental: Talimogene Laherparepvec
  Talimogene laherparepvec for 6 doses followed by surgical resection of melanoma tumor lesion(s).
  Intervention: Drug: Talimogene Laherparepvec

• Publications *: Dummer R, Gyorki DE, Hyngstrom J, Berger AC, Conry R, Demidov L, Sharma A, Treichel SA, Radcliffe H, Gorski KS, Anderson A, Chan E, Faries M, Ross MI. Neoadjuvant talimogene laherparepvec plus surgery versus surgery alone for resectable stage IIIB-IVM1a melanoma: a randomized, open-label, phase 2 trial. Nat Med. 2021 Oct;27(10):1789-1796. doi: 10.1038/s41591-021-01510-7. Epub 2021 Oct 4.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 5, 2014): 150
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: April 28, 2022
• Actual Primary Completion Date: April 30, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Histologically confirmed diagnosis of stage IIIB, IIIC or IVM1a melanoma eligible for complete surgical resection.
• Prior systemic, regional and radiation anticancer therapies for melanoma must have been completed at least 3 months prior to randomization.
• Subject must have measurable disease and must be a candidate for intralesional therapy with at least one injectable cutaneous, subcutaneous, or nodal melanoma lesion (≥ 10 mm in longest diameter) or with multiple injectable lesions that in aggregate have a longest diameter of ≥ 10 mm.
• Subject must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and must have a serum lactate dehydrogenase (LDH) ≤ 1.0 X upper limit of normal and adequate hematologic, hepatic, renal, and coagulation organ function- Other criteria may apply

Exclusion Criteria:

• Subject must not have primary ocular or mucosal melanoma, or history or evidence of melanoma associated with immunodeficiency states (eg, hereditary immune deficiency, organ transplant, or leukemia).
• Subject must not have history or evidence of symptomatic autoimmune pneumonitis, glomerulonephritis, vasculitis, or other symptomatic autoimmune disease.
• Subject must not have evidence of clinically significant immunosuppression or active herpetic skin lesions or prior complications of herpes simplex type 1 (HSV-1) infection (eg, herpetic keratitis or encephalitis) and must not require intermittent or chronic systemic treatment with an antiherpetic drug (eg, acyclovir), other than intermittent topical use.
• Subject known to have acute or chronic active hepatitis B, hepatitis C, or human immunodeficiency virus infection will also be excluded.
• Subject must not have been treated previously with talimogene laherparepvec or tumor vaccine.

Other criteria may apply

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: Australia, Brazil, France, Greece, Poland, Russian Federation, Spain, Switzerland, United States

Administrative Information

• NCT Number: NCT02211131
• Other Study ID Numbers: 20110266; 2014-001146-13 ( EudraCT Number )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• 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.
• 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.
• URL: https://www.amgen.com/datasharing

• Current Responsible Party: Amgen
• Original Responsible Party: Same as current
• Current Study Sponsor: Amgen
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: MD; Amgen

• PRS Account: Amgen
• Verification Date: May 2023