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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02211131
Recruitment Status : Active, not recruiting
First Posted : August 7, 2014
Results First Posted : May 28, 2020
Last Update Posted : May 28, 2020
Sponsor:
Information provided by (Responsible Party):
Amgen

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.

Condition or disease Intervention/treatment Phase
Completely Resectable Stage IIIB, IIIC, or IVM1a Melanoma Drug: Talimogene Laherparepvec Procedure: Immediate surgical resection of melanoma lesion(s) Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 150 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : February 3, 2015
Actual Primary Completion Date : April 30, 2019
Estimated Study Completion Date : April 30, 2022

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma
MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Surgery
Surgical resection of melanoma tumor lesion(s)
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.

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




Primary Outcome Measures :
  1. Recurrence-Free Survival (RFS) [ Time Frame: 24 months after last participant 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.


Secondary Outcome Measures :
  1. Kaplan-Meier (K-M) Estimate of RFS Rate at 1 Year and 2 Years [ Time Frame: 1 year (Month 12), 2 years (Month 24) ]
    Kaplan-Meier estimates of the percentage of participants with RFS events at 1 year and 2 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.

  2. 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.

  3. 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.

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

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

  6. Distant Metastases-Free Survival (DMFS) [ Time Frame: 24 months after last participant randomized (data cutoff date of 30 April 2019) ]
    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.

  7. Overall Survival (OS) [ Time Frame: 24 months after last participant randomized (data cutoff date of 30 April 2019) ]
    Overall survival (OS) is defined as the time from randomization to the date of death due to any cause.

  8. Kaplan-Meier (K-M) Estimate of OS at 1 Year and 2 Years [ Time Frame: 1 year (Month 12), 2 years (Month 24) ]
    Kaplan-Meier estimates of the percentage of participants with OS events at 1 year and 2 years from randomization. An OS event is defined as death due to any cause.

  9. 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.

  10. 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%.

  11. 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%.

  12. 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: Up to data cutoff date of 30 April 2019. Median duration of treatment for participants in the talimogene laherparepvec plus surgery group 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 subject (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.

  13. Number of Participants With Talimogene Laherparepvec-Related TEAEs, SAEs, Fatal AEs, and TEAEs Leading to Discontinuations or Interruptions [ Time Frame: Up to data cutoff date of 30 April 2019. Median duration of treatment for participants in the talimogene laherparepvec plus surgery group 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 subject (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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02211131


Locations
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United States, Alabama
Research Site
Birmingham, Alabama, United States, 35249
United States, California
Research Site
Duarte, California, United States, 91010
Research Site
Orange, California, United States, 92868
Research Site
San Francisco, California, United States, 94115
Research Site
Santa Monica, California, United States, 90404
United States, Florida
Research Site
Daytona Beach, Florida, United States, 32117
Research Site
Gainesville, Florida, United States, 32610
Research Site
Tampa, Florida, United States, 33612
United States, Kentucky
Research Site
Louisville, Kentucky, United States, 40202
United States, Massachusetts
Research Site
Worcester, Massachusetts, United States, 01655
United States, Nebraska
Research Site
Omaha, Nebraska, United States, 68130
United States, New Jersey
Research Site
New Brunswick, New Jersey, United States, 08903
United States, New York
Research Site
New York, New York, United States, 10029
Research Site
New York, New York, United States, 10032
United States, North Carolina
Research Site
Chapel Hill, North Carolina, United States, 27599
United States, Ohio
Research Site
Columbus, Ohio, United States, 43210
United States, Pennsylvania
Research Site
Philadelphia, Pennsylvania, United States, 19107
United States, Tennessee
Research Site
Memphis, Tennessee, United States, 38163
United States, Texas
Research Site
Dallas, Texas, United States, 75230
Research Site
Dallas, Texas, United States, 75390
Research Site
Houston, Texas, United States, 77030
United States, Utah
Research Site
Salt Lake City, Utah, United States, 84112
Australia, New South Wales
Research Site
North Sydney, New South Wales, Australia, 2060
Australia, South Australia
Research Site
Woodville South, South Australia, Australia, 5011
Australia, Victoria
Research Site
Heidelberg, Victoria, Australia, 3084
Brazil
Research Site
Florianopolis, Santa Catarina, Brazil, 88034-000
Research Site
Barretos, São Paulo, Brazil, 14784-400
Research Site
Rio de Janeiro, Brazil, 20220-410
France
Research Site
Dijon, France, 21034
Research Site
Marseille cedex 05, France, 13385
Research Site
Paris, France, 75010
Research Site
Pierre Benite Cedex, France, 69495
Research Site
Toulouse cedex 9, France, 31059
Greece
Research Site
Athens, Greece, 11527
Research Site
Heraklion - Crete, Greece, 71110
Poland
Research Site
Poznan, Poland, 60-856
Research Site
Warszawa, Poland, 02-781
Research Site
Wroclaw, Poland, 50-368
Russian Federation
Research Site
Moscow, Russian Federation, 115478
Research Site
Saint-Petersburg, Russian Federation, 197022
Research Site
Saint-Petersburg, Russian Federation, 197758
Spain
Research Site
Malaga, Andalucía, Spain, 29010
Research Site
Pamplona, Navarra, Spain, 31008
Research Site
Madrid, Spain, 28009
Switzerland
Research Site
Chur, Switzerland, 7000
Research Site
Zürich, Switzerland, 8091
Sponsors and Collaborators
Amgen
Investigators
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Study Director: MD Amgen
  Study Documents (Full-Text)

Documents provided by Amgen:
Study Protocol  [PDF] March 23, 2018
Statistical Analysis Plan  [PDF] May 14, 2019

Additional Information:
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Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT02211131    
Other Study ID Numbers: 20110266
2014-001146-13 ( EudraCT Number )
First Posted: August 7, 2014    Key Record Dates
Results First Posted: May 28, 2020
Last Update Posted: May 28, 2020
Last Verified: May 2020
Individual Participant Data (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
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
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
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Talimogene laherparepvec
Antineoplastic Agents, Immunological
Antineoplastic Agents