MelanomaPhase 1/2NCT01740297
Ipilimumab With or Without Talimogene Laherparepvec in Unresected Melanoma
A Phase 1/2 study testing Talimogene laherparepvec and Ipilimumab in people with Melanoma, run by Amgen at 40 sites in 3 countries.
Trial summary
Phase 1b of the study will evaluate the safety of talimogene laherparepvec in combination with ipilimumab. Phase 2 is a randomized study that will evaluate the safety and efficacy of talimogene laherparepvec in combination with ipilimumab versus ipilumumab alone. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Melanoma
- What is being tested?
- Talimogene laherparepvec and Ipilimumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 217 participants
- Where
- 40 sitesin 3 countries
- Study dates
- 7 Feb 2013to 9 Mar 2021
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Histologically confirmed diagnosis of malignant melanoma.
- Stage IIIB, IIIC, IVM1a, IVM1b, or IVM1c disease that is not suitable for surgical resection
- Phase1: Treatment naïve: Must not have received any prior systemic anticancer treatment consisting of chemotherapy, immunotherapy, or targeted therapy for unresected stage IIIB to IV melanoma.
- Phase 2:
- Either treatment naïve or received only one line of systemic anticancer therapy if v-raf murine sarcoma viral oncogene homolog B1 (BRAF) wild-type or up to two lines of systemic anticancer therapy including one BRAF inhibitor-containing regimen if BRAF mutant. Treatments given in an adjuvant setting (eg, interferon, radiotherapy, isolated limb perfusion, or investigational agents) are not considered as prior lines of therapy. No prior talimogene laherparepvec, other oncolytic virus therapies, or tumor vaccines are allowed, even if given in the adjuvant setting.
- Subjects treated with prior ipilimumab must have had partial response (PR), complete response (CR), or at least 6 months of stable disease followed by disease progression.
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- Subjects previously treated with anti-program death-1 (PD1) or anti-cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) antibodies must not have discontinued therapy due to any treatment-related adverse events including immune-related adverse events. Prior treatment-related adverse events should also be fully resolved and not requiring treatment for at least 28 days prior to randomization.
- Measurable disease defined as one or both of the following
- at least 1 melanoma lesion that can be accurately and serially measured in at least 2 dimensions and for which the longest diameter is ≥ 10 mm and with perpendicular diameter ≥ 5 mm as measured by contrast-enhanced or spiral computed tomography (CT) scan for visceral or nodal/soft tissue disease. Lymph nodes must measure > 15 mm in their short axis to be considered measurable by CT scan.
- at least 1 superficial cutaneous or subcutaneous melanoma lesion that can be accurately and serially measured in at least 2 dimensions and for which the short axis is ≥ 5 mm as measured by calipers
- Injectable disease (ie, suitable for direct injection or through the use of ultrasound [US] guidance) defined as follows:
- at least 1 injectable cutaneous, subcutaneous, or nodal melanoma lesion ≥ 5 mm in longest diameter
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- Adequate hematologic, hepatic, renal, and coagulation functions
Who cannot join
- Primary uveal or mucosal melanoma
- History or evidence of melanoma associated with immunodeficiency states (eg, hereditary immune deficiency, organ transplant, or leukemia)
- Phase 1b: History or evidence of central nervous system (CNS) metastases
- Phase 2: Clinically active cerebral melanoma metastases. Subjects with up to 3 cerebral metastases, and neurological performance status of 0 may be enrolled, provided that all lesions have been adequately treated with stereotactic radiation therapy, craniotomy, or Gamma knife therapy, with no evidence of progression, and have not required steroids, for at least 2 months prior to enrollment.
- History or evidence of symptomatic autoimmune disease (such as pneumonitis, glomerulonephritis, vasculitis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, scleroderma, or other), or history of autoimmune disease that required systemic treatment (ie, use of corticosteroids, immunosuppressive drugs or biological agents used for treatment of autoimmune diseases) in past 2 months prior to enrollment. Replacement therapy (eg, thyroxine for hypothyroidism, insulin for diabetes mellitus) is not considered a form of systemic treatment for autoimmune disease.
- History of or plan for splenectomy or splenic irradiation
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- Active herpetic skin lesions or prior complications of herpes simplex type-1 virus (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
- Known human immunodeficiency virus (HIV) disease
- Known acute or chronic hepatitis B or hepatitis C infection
- Phase 1b: Prior talimogene laherparepvec, ipilimumab, other CTLA-4 inhibitors, PD-1 inhibitors, or tumor vaccine
- Phase 2: Prior talimogene laherparepvec, other oncolytic virus therapies, or tumor vaccines
- Currently receiving or less than 28 days since ending systemic anticancer treatment for unresected stage IIIB to IV melanoma
Trial locations and contacts
40 sites in 3 countries.
40 sites in 3 countries
United States32 sites
Research Site
Aurora, Colorado, 80045
Research Site
Beverly Hills, California, 90211
Research Site
Canton, Ohio, 44718
Research Site
Chapel Hill, North Carolina, 27599
Research Site
Charleston, South Carolina, 29425
Research Site
Chicago, Illinois, 60612
Research Site
Cincinnati, Ohio, 45267
Research Site
Houston, Texas, 77030
Research Site
Indianapolis, Indiana, 46202
Research Site
Indianapolis, Indiana, 46260
Research Site
Iowa City, Iowa, 52242
Research Site
Jacksonville, Florida, 32207
Research Site
Jacksonville, Florida, 32224
Research Site
Lakeland, Florida, 33805
Research Site
Los Angeles, California, 90025
Research Site
Los Angeles, California, 90089-2211
Research Site
Los Angeles, California, 90095
Research Site
Louisville, Kentucky, 40202
Research Site
Miami, Florida, 33140
Research Site
Milwaukee, Wisconsin, 53226
Research Site
Minneapolis, Minnesota, 55407
Research Site
Morristown, New Jersey, 07962
Research Site
Nashville, Tennessee, 37232
Research Site
New Brunswick, New Jersey, 08903
Research Site
New York, New York, 10029
Research Site
New York, New York, 10032
Research Site
Richmond, Virginia, 23298-0037
Research Site
Salt Lake City, Utah, 84112
Research Site
San Francisco, California, 94115
Research Site
Santa Rosa, California, 95403
Research Site
St Louis, Missouri, 63110
Research Site
Tucson, Arizona, 85724
France5 sites
Research Site
Bordeaux, 33075
Research Site
Grenoble, 38043
Research Site
Lille, 59037
Research Site
Nantes, 44093
Research Site
Paris, 75010
Germany3 sites
Research Site
Göttingen, 37075
Research Site
Kiel, 24105
Research Site
Tübingen, 72076
About this study
Official title: Phase 1b/2, Multicenter, Open-label Trial to Evaluate the Safety and Efficacy of Talimogene Laherparepvec and Ipilimumab Compared to Ipilimumab Alone in Subjects With Unresected, Stage IIIB-IV Melanoma
Phase 1b of the study will evaluate the safety of talimogene laherparepvec in combination with ipilimumab. Phase 2 is a randomized study that will evaluate the safety and efficacy of talimogene laherparepvec in combination with ipilimumab versus ipilumumab alone.
Read the detailed description
The phase 1b part is an open-label, multicenter, single-arm study where all participants will receive talimogene laherparepvec in combination with ipilimumab.
The phase 2 part of the study is an open-label, multicenter, randomized study to further assess the safety and to evaluate the efficacy of talimogene laherparepvec in combination with ipilimumab. Participants will be randomized 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone.
Participants randomized before amendment 2 will be stratified by stage of disease (stage IIIB/C, IVM1a, and stage IVM1b vs IVM1c) and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E (a mutation resulting in a substitution of glutamic acid for valine at codon 600) (mutation vs mutation not present). Participants randomized after amendment 2 will be stratified by stage of disease (stage IIIB/C and IVM1a vs stage IVM1b and IVM1c) and prior therapy (treatment naïve vs previously treated with systemic anticancer immunotherapy vs previously treated with systemic anticancer treatment other than immunotherapy).
- Conditions
- Melanoma
- Being tested
- Talimogene laherparepvec, Ipilimumab
- Keywords
- melanoma, talimogene laherparepvec, ipilimumab, immunotherapy
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Talimogene laherparepvecDrug
Also called IMLYGIC®, OncoVEX^GM-CSF, T-VEC
Talimogene laherparepvec administered by intratumoral injection on Day 1 of Week 1, Day 1 of Week 4, then every two weeks thereafter.
IpilimumabDrug
Also called Yervoy®
Ipilimumab administered intravenously every 3 weeks for a total of 4 infusions.
| Study group | Role | What they receive |
|---|---|---|
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Experimental | Participants received talimogene laherparepvec at an initial dose of 10⁶ plaque-forming units (PFU)/mL injected into 1 or more skin, nodal, or subcutaneous tumors. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until complete response (CR), all injectable tumors had disappeared, confirmed disease progression per the modified immune-related response criteria (irRC), or intolerance of study treatment, whichever occurred first. Participants also received 3 mg/kg ipilimumab administered intravenously every 3 weeks for a total of 4 infusions starting at the time of the third dose of talimogene laherparepvec (week 6). Receives: Drug: Talimogene laherparepvec; Drug: Ipilimumab |
| Phase 2: Ipilimumab | Active comparator | Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1. Receives: Drug: Ipilimumab |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Experimental | Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until CR, all injectable tumors had disappeared, confirmed disease progression per the modified irRC, or intolerance of study treatment, whichever occurred first. Participants also received 3 mg/kg ipilimumab intravenously every 3 weeks for a total of 4 infusions starting at the time of the third dose of talimogene laherparepvec (week 6). Receives: Drug: Talimogene laherparepvec; Drug: Ipilimumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Phase 1b: Number of Participants With Dose-limiting Toxicities
A DLT was defined as any toxicity related to study drug which met any of the following criteria based on Common Terminology Criteria for Adverse Events version 3.0:
- treatment-related non-laboratory adverse events (AE) ≥ grade 4
- ≥ grade 4 immune-mediated dermatitis
- ≥ grade 4 immune-mediated endocrinopathy (except autoimmune thyroiditis)
- ≥ grade 3 immune-mediated enterocolitis
- ≥ grade 3 immune-mediated hepatitis (except grade 3 that resolved to grade 1 or baseline within 28 days of onset)
- ≥ grade 3 immune-mediated neuropathy
- ≥ grade 3 other immune-mediated AEs including hemolytic anemia, angiopathy, myocarditis, pericarditis, temporal arteritis, or vasculitis, autoimmune thyroiditis (except grade 3 that resolved to grade 1 or baseline within 28 days of onset), blepharitis, conjunctivitis, episcleritis, iritis, scleritis, or uveitis, pancreatitis, meningitis, arthritis or polymyalgia rheumatic, nephritis, pneumonitis, psoriasis or leukocytoclastic vasculitis.
Measured: The DLT evaluation period was 6 weeks from the initial administration of ipilimumab (week 6 to 12).
Phase 2: Objective Response Rate
Objective response rate is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) according to the modified immune-related response criteria (irRC) assessed by the investigator. Tumors were examined clinically and by computed tomography (CT) or magnetic resonance imaging (MRI).
CR: Complete disappearance of all lesions and no new lesions; Any pathological lymph nodes reduced in short axis to <10 mm.
PR: Decrease in tumor burden ≥ 50% relative to baseline. Response must have been confirmed by a repeat, consecutive assessment ≥ 4 weeks from the date first documented. Participants who did not have any follow-up tumor assessments were regarded as non-responders.
Measured: Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Secondary outcomes (14)
Phase 1b: Objective Response Rate
Objective response rate is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) according to the modified immune-related response criteria (irRC) assessed by the investigator. Tumors were examined clinically and by computed tomography (CT) or magnetic resonance imaging (MRI).
CR: Complete disappearance of all lesions and no new lesions; Any pathological lymph nodes reduced in short axis to <10 mm.
PR: Decrease in tumor burden ≥ 50% relative to baseline. Response must have been confirmed by a repeat, consecutive assessment ≥ 4 weeks from the date first documented. Participants who did not have any follow-up tumor assessments were regarded as non-responders.
Measured: Tumor response was assesed every 12 weeks until disease progression; median follow-up time at the primary analysis was 148.4 weeks.
Phase 2: Best Overall Response
Best overall response was categorized in descending order as a complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD) or unevaluable (UE) based on investigator assessment according to the modified irRC.
CR: Complete disappearance of all lesions and no new lesions; Any pathological lymph nodes reduced in short axis to <10 mm.
PR: Decrease in tumor burden ≥ 50% relative to baseline. PD: Increase in tumor burden ≥ 25% relative to nadir. SD: Not meeting criteria for CR or PR, in absence of PD and no earlier than 77 days after the date of enrollment/randomization.
CR, PR and PD must have been confirmed at 2 consecutive assessment ≥ 4 weeks apart.
Assessments occurring after the start of the first subsequent anticancer therapy or removal of a lesion were not included.
Measured: Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Phase 2: Disease Control Rate
Disease control rate (DCR) was defined as the percentage of participants with a best overall response of CR, PR or SD based on investigator assessment according to the modified irRC.
CR: Complete disappearance of all lesions and no new lesions; any pathological lymph nodes reduced in short axis to <10 mm.
PR: Decrease in tumor burden ≥ 50% relative to baseline. SD: Not meeting criteria for CR or PR, in absence of PD and no earlier than 77 days after the date of enrollment/randomization.
CR and PR must have been confirmed at 2 consecutive assessments ≥ 4 weeks apart.
Measured: Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Phase 2: Durable Response Rate
Durable response rate (DRR) was defined as the percentage of participants with a duration of response (best response of CR or PR) per modified irRC of at least 6 months. Duration of response is the time from the first confirmed CR or PR to confirmed disease progression per the modified irRC or death, whichever occurs earlier.
Measured: Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Phase 2: Time to Response
Time to confirmed response (TTR) was defined as the time from randomization to the date of the first confirmed CR or PR per modified irRC criteria. Participants who did not have a confirmed CR or PR were censored at their last evaluable tumor assessment date.
Measured: Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Phase 2: Duration of Response
Duration of response was calculated only for participants with an objective response per modified irRC and was defined as the time from first confirmed objective response (CR or PR) to confirmed disease progression per the modified irRC or death, whichever was earlier. Responders who did not have an event of death or disease progression were censored at their last evaluable tumor assessment date.
Measured: Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Phase 2: Progression-free Survival
Progression-free survival was measured from the date of randomization to the date of disease progression (as measured by modified irRC) or death on or before the data cutoff date, whichever occurred first. Participants who had no disease progression and did not die while on study were censored at the last disease assessment date.
Measured: From randomization until the primary analysis data cut-off date of 23 August 2016; median follow-up time was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Phase 2: Resection Rate
Resection rate was defined as the percentage of participants who had surgical procedures for melanoma that resulted in a partial reduction or complete eradication of all previously unresectable cutaneous or visceral metastatic disease. Surgical procedures for melanoma with palliative intent (eg, for pain control) in the presence of disease progression were not considered resection.
Measured: From randomization until the primary analysis data cut-off date of 23 August 2016; median follow-up time was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Phase 2: Overall Survival
Overall survival was defined as the time from the date of randomization to the date of death from any cause. Participants without an event were censored at the last date they were known to be alive. Participants with a vital status obtained after the data cut-off were censored at the date cut-off date.
Measured: From randomization until the primary analysis data cut-off date of 23 August 2016; median follow-up time was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Phase 2: Kaplan-Meier Estimate of Percentage of Participants Alive at Month 12 and 24
The overall survival estimates at month 24 data were not mature as most participants had not been followed for 24 months at the time of data cutoff.
Measured: Months 12 and 24; The median (Q1, Q3) follow-up time from randomization to the primary analysis data cutoff date was 80.6 (58.3, 106.3) weeks.
Phase 2: Progression-free Survival - Final Analysis
Progression-free survival was measured from the date of randomization to the date of disease progression (as measured by modified irRC) or death, whichever occurred first. Participants who had no disease progression and did not die while on study were censored at the last disease assessment date.
Measured: From randomization until the end of study (09 March 2021); median follow-up time was 155 weeks in the Ipilimumab group and 214 weeks in the Talimogene Laherparepvec + Ipilimumab group.
Phase 2: Overall Survival - Final Analysis
Overall survival was defined as the time from the date of randomization to the date of death from any cause. Participants without an event were censored at the last date they were known to be alive.
Measured: From randomization until the end of study (09 March 2021); median follow-up time was 155 weeks in the Ipilimumab group and 214 weeks in the Talimogene Laherparepvec + Ipilimumab group.
Phase 2: Kaplan-Meier Estimate of Percentage of Participants Alive at Month 12 and 24 - Final Analysis
Measured: Months 12 and 24
Number of Participants With Adverse Events
Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, where grade 1 = mild AE, grade 2 = moderate AE, grade 3 = severe AE, grade 4 = life-threatening or disabling AE and grade 5 = death related to AE.
The investigator assessed whether each AE was possibly related to talimogene laherparepvec (T-VEC) and/or ipilimumab (Ipi).
Measured: From first dose of study drug to 30 days after last dose of T-VEC or 60 days after last dose of Ipi, whichever was later; median duration of treatment was 14.7 weeks in Phase 1b T-VEC + Ipi, 9.1 weeks in Phase 2 Ipi, and 21.1 weeks in Phase 2 T-VEC + Ipi.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Dec 2012 (estimated)
- Study start7 Feb 2013
- Primary completion23 Aug 2016
- Study completion9 Mar 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for MelanomaStudies of the same condition, open and under way.
- More trials run by AmgenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Phase 1b was an open-label, multicenter single-arm part of the study to evaluate safety of talimogene laherparepvec in combination with ipilimumab. Phase 2 was an open-label multicenter, randomized design to further assess safety and to evaluate efficacy of talimogene laherparepvec in combination with ipilimumab.
- Masking
- None (open label)
- Enrolment
- 217 participants (actual)
Sponsor and investigators
- Lead sponsor
- Amgen
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- MD, Study director, Amgen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01740297
- Sponsor's protocol ID
- 20110264
- Other IDs
- 2012-000307-32
- Status last verified
- May 2024
- First submitted
- 14 Nov 2012
- Last updated
- 14 May 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- Individual data sharing
- Yes: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
Publications
Chesney J, Puzanov I, Collichio F, Singh P, Milhem MM, Glaspy J, Hamid O, Ross M, Friedlander P, Garbe C, Logan TF, Hauschild A, Lebbe C, Chen L, Kim JJ, Gansert J, Andtbacka RHI, Kaufman HL. Randomized, Open-Label Phase II Study Evaluating the Efficacy and Safety of Talimogene Laherparepvec in Combination With Ipilimumab Versus Ipilimumab Alone in Patients With Advanced, Unresectable Melanoma. J Clin Oncol. 2018 Jun 10;36(17):1658-1667. doi: 10.1200/JCO.2017.73.7379. Epub 2017 Oct 5.
PubMed 28981385Puzanov I, Milhem MM, Minor D, Hamid O, Li A, Chen L, Chastain M, Gorski KS, Anderson A, Chou J, Kaufman HL, Andtbacka RH. Talimogene Laherparepvec in Combination With Ipilimumab in Previously Untreated, Unresectable Stage IIIB-IV Melanoma. J Clin Oncol. 2016 Aug 1;34(22):2619-26. doi: 10.1200/JCO.2016.67.1529. Epub 2016 Jun 13.
PubMed 27298410Chesney J, Puzanov I, Collichio F, Milhem MM, Hauschild A, Chen L, Sharma A, Garbe C, Singh P, Mehnert JM. Patterns of response with talimogene laherparepvec in combination with ipilimumab or ipilimumab alone in metastatic unresectable melanoma. Br J Cancer. 2019 Aug;121(5):417-420. doi: 10.1038/s41416-019-0530-6. Epub 2019 Jul 29.
PubMed 31353364Dummer R, Hoeller C, Gruter IP, Michielin O. Combining talimogene laherparepvec with immunotherapies in melanoma and other solid tumors. Cancer Immunol Immunother. 2017 Jun;66(6):683-695. doi: 10.1007/s00262-017-1967-1. Epub 2017 Feb 25.
PubMed 28238174Chesney JA, Puzanov I, Collichio FA, Singh P, Milhem MM, Glaspy J, Hamid O, Ross M, Friedlander P, Garbe C, Logan T, Hauschild A, Lebbe C, Joshi H, Snyder W, Mehnert JM. Talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone for advanced melanoma: 5-year final analysis of a multicenter, randomized, open-label, phase II trial. J Immunother Cancer. 2023 May;11(5):e006270. doi: 10.1136/jitc-2022-006270.
PubMed 37142291
Study at a glance
From the registry record, last updated by the sponsor on 14 May 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase 1b/2, Multicenter, Open-label Trial to Evaluate the Safety and Efficacy of Talimogene Laherparepvec and Ipilimumab Compared to Ipilimumab Alone in Subjects With Unresected, Stage IIIB-IV Melanoma
- ClinicalTrials.gov ID
- NCT01740297
- Acronym / sponsor ID
- 20110264
- Conditions
- Melanoma
- Keywords
- melanoma, talimogene laherparepvec, ipilimumab, immunotherapy
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 217 participants (actual)
- Lead sponsor
- AmgenIndustry (pharma, biotech, devices)
- Study start
- 7 Feb 2013 (actual)
- Primary completion
- 23 Aug 2016 (actual)
- Study completion
- 9 Mar 2021 (actual)
- First posted
- 4 Dec 2012 (estimated)
- Results
- Posted 9 Oct 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Phase 1b of the study will evaluate the safety of talimogene laherparepvec in combination with ipilimumab. Phase 2 is a randomized study that will evaluate the safety and efficacy of talimogene laherparepvec in combination with ipilimumab versus ipilumumab alone.
Detailed description
The phase 1b part is an open-label, multicenter, single-arm study where all participants will receive talimogene laherparepvec in combination with ipilimumab.
The phase 2 part of the study is an open-label, multicenter, randomized study to further assess the safety and to evaluate the efficacy of talimogene laherparepvec in combination with ipilimumab. Participants will be randomized 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone.
Participants randomized before amendment 2 will be stratified by stage of disease (stage IIIB/C, IVM1a, and stage IVM1b vs IVM1c) and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E (a mutation resulting in a substitution of glutamic acid for valine at codon 600) (mutation vs mutation not present). Participants randomized after amendment 2 will be stratified by stage of disease (stage IIIB/C and IVM1a vs stage IVM1b and IVM1c) and prior therapy (treatment naïve vs previously treated with systemic anticancer immunotherapy vs previously treated with systemic anticancer treatment other than immunotherapy).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
- Model description
- Phase 1b was an open-label, multicenter single-arm part of the study to evaluate safety of talimogene laherparepvec in combination with ipilimumab. Phase 2 was an open-label multicenter, randomized design to further assess safety and to evaluate efficacy of talimogene laherparepvec in combination with ipilimumab.
| Arm | Type | Receives |
|---|---|---|
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Experimental | Drug: Talimogene laherparepvec, Drug: IpilimumabParticipants received talimogene laherparepvec at an initial dose of 10⁶ plaque-forming units (PFU)/mL injected into 1 or more skin, nodal, or subcutaneous tumors. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until complete response (CR), all injectable tumors had disappeared, confirmed disease progression per the modified immune-related response criteria (irRC), or intolerance of study treatment, whichever occurred first. Participants also received 3 mg/kg ipilimumab administered intravenously every 3 weeks for a total of 4 infusions starting at the time of the third dose of talimogene laherparepvec (week 6). |
| Phase 2: Ipilimumab | Active comparator | Drug: IpilimumabParticipants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1. |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Experimental | Drug: Talimogene laherparepvec, Drug: IpilimumabParticipants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until CR, all injectable tumors had disappeared, confirmed disease progression per the modified irRC, or intolerance of study treatment, whichever occurred first. Participants also received 3 mg/kg ipilimumab intravenously every 3 weeks for a total of 4 infusions starting at the time of the third dose of talimogene laherparepvec (week 6). |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- Histologically confirmed diagnosis of malignant melanoma.
- Stage IIIB, IIIC, IVM1a, IVM1b, or IVM1c disease that is not suitable for surgical resection
- Phase1: Treatment naïve: Must not have received any prior systemic anticancer treatment consisting of chemotherapy, immunotherapy, or targeted therapy for unresected stage IIIB to IV melanoma.
- Phase 2:
- Measurable disease defined as one or both of the following
Key exclusion criteria (13 listed)
- Primary uveal or mucosal melanoma
- History or evidence of melanoma associated with immunodeficiency states (eg, hereditary immune deficiency, organ transplant, or leukemia)
- Phase 1b: History or evidence of central nervous system (CNS) metastases
- Phase 2: Clinically active cerebral melanoma metastases. Subjects with up to 3 cerebral metastases, and neurological performance status of 0 may be enrolled, provided that all lesions have been adequately treated with stereotactic radiation therapy, craniotomy, or Gamma knife therapy, with no evidence of progression, and have not required steroids, for at least 2 months prior to enrollment.
- History or evidence of symptomatic autoimmune disease (such as pneumonitis, glomerulonephritis, vasculitis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, scleroderma, or other), or history of autoimmune disease that required systemic treatment (ie, use of corticosteroids, immunosuppressive drugs or biological agents used for treatment of autoimmune diseases) in past 2 months prior to enrollment. Replacement therapy (eg, thyroxine for hypothyroidism, insulin for diabetes mellitus) is not considered a form of systemic treatment for autoimmune disease.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Talimogene laherparepvecAlso: IMLYGIC®, OncoVEX^GM-CSF, T-VECTalimogene laherparepvec administered by intratumoral injection on Day 1 of Week 1, Day 1 of Week 4, then every two weeks thereafter. | Drug | Phase 1b: Talimogene Laherparepvec + Ipilimumab, Phase 2: Talimogene Laherparepvec + Ipilimumab |
| IpilimumabAlso: Yervoy®Ipilimumab administered intravenously every 3 weeks for a total of 4 infusions. | Drug | Phase 1b: Talimogene Laherparepvec + Ipilimumab, Phase 2: Ipilimumab, Phase 2: Talimogene Laherparepvec + Ipilimumab |
Primary outcome
Phase 1b: Number of Participants With Dose-limiting Toxicities
Time frame: The DLT evaluation period was 6 weeks from the initial administration of ipilimumab (week 6 to 12).
A DLT was defined as any toxicity related to study drug which met any of the following criteria based on Common Terminology Criteria for Adverse Events version 3.0: * treatment-related non-laboratory adverse events (AE) ≥ grade 4 * ≥ grade 4 immune-mediated dermatitis * ≥ grade 4 immune-mediated endocrinopathy (except autoimmune thyroiditis) * ≥ grade 3 immune-mediated enterocolitis * ≥ grade 3 immune-mediated hepatitis (except grade 3 that resolved to grade 1 or baseline within 28 days of onset) * ≥ grade 3 immune-mediated neuropathy * ≥ grade 3 other immune-mediated AEs including hemolytic anemia, angiopathy, myocarditis, pericarditis, temporal arteritis, or vasculitis, autoimmune thyroiditis (except grade 3 that resolved to grade 1 or baseline within 28 days of onset), blepharitis, conjunctivitis, episcleritis, iritis, scleritis, or uveitis, pancreatitis, meningitis, arthritis or polymyalgia rheumatic, nephritis, pneumonitis, psoriasis or leukocytoclastic vasculitis.
Phase 2: Objective Response Rate
Time frame: Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Objective response rate is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) according to the modified immune-related response criteria (irRC) assessed by the investigator. Tumors were examined clinically and by computed tomography (CT) or magnetic resonance imaging (MRI). CR: Complete disappearance of all lesions and no new lesions; Any pathological lymph nodes reduced in short axis to <10 mm. PR: Decrease in tumor burden ≥ 50% relative to baseline. Response must have been confirmed by a repeat, consecutive assessment ≥ 4 weeks from the date first documented. Participants who did not have any follow-up tumor assessments were regarded as non-responders.
14 secondary outcomes
Phase 1b: Objective Response Rate
Time frame: Tumor response was assesed every 12 weeks until disease progression; median follow-up time at the primary analysis was 148.4 weeks.
Phase 2: Best Overall Response
Time frame: Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Phase 2: Disease Control Rate
Time frame: Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Phase 2: Durable Response Rate
Time frame: Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Phase 2: Time to Response
Time frame: Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Phase 2: Duration of Response
Time frame: Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Phase 2: Progression-free Survival
Time frame: From randomization until the primary analysis data cut-off date of 23 August 2016; median follow-up time was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Phase 2: Resection Rate
Time frame: From randomization until the primary analysis data cut-off date of 23 August 2016; median follow-up time was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Phase 2: Overall Survival
Time frame: From randomization until the primary analysis data cut-off date of 23 August 2016; median follow-up time was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Phase 2: Kaplan-Meier Estimate of Percentage of Participants Alive at Month 12 and 24
Time frame: Months 12 and 24; The median (Q1, Q3) follow-up time from randomization to the primary analysis data cutoff date was 80.6 (58.3, 106.3) weeks.
Phase 2: Progression-free Survival - Final Analysis
Time frame: From randomization until the end of study (09 March 2021); median follow-up time was 155 weeks in the Ipilimumab group and 214 weeks in the Talimogene Laherparepvec + Ipilimumab group.
Phase 2: Overall Survival - Final Analysis
Time frame: From randomization until the end of study (09 March 2021); median follow-up time was 155 weeks in the Ipilimumab group and 214 weeks in the Talimogene Laherparepvec + Ipilimumab group.
Phase 2: Kaplan-Meier Estimate of Percentage of Participants Alive at Month 12 and 24 - Final Analysis
Time frame: Months 12 and 24
Number of Participants With Adverse Events
Time frame: From first dose of study drug to 30 days after last dose of T-VEC or 60 days after last dose of Ipi, whichever was later; median duration of treatment was 14.7 weeks in Phase 1b T-VEC + Ipi, 9.1 weeks in Phase 2 Ipi, and 21.1 weeks in Phase 2 T-VEC + Ipi.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 May 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 28981385Chesney J, Puzanov I, Collichio F, Singh P, Milhem MM, Glaspy J, Hamid O, Ross M, Friedlander P, Garbe C, Logan TF, Hauschild A, Lebbe C, Chen L, Kim JJ, Gansert J, Andtbacka RHI, Kaufman HL. Randomized, Open-Label Phase II Study Evaluating the Efficacy and Safety of Talimogene Laherparepvec in Combination With Ipilimumab Versus Ipilimumab Alone in Patients With Advanced, Unresectable Melanoma. J Clin Oncol. 2018 Jun 10;36(17):1658-1667. doi: 10.1200/JCO.2017.73.7379. Epub 2017 Oct 5.
- Background: PubMed 27298410Puzanov I, Milhem MM, Minor D, Hamid O, Li A, Chen L, Chastain M, Gorski KS, Anderson A, Chou J, Kaufman HL, Andtbacka RH. Talimogene Laherparepvec in Combination With Ipilimumab in Previously Untreated, Unresectable Stage IIIB-IV Melanoma. J Clin Oncol. 2016 Aug 1;34(22):2619-26. doi: 10.1200/JCO.2016.67.1529. Epub 2016 Jun 13.
- Background: PubMed 31353364Chesney J, Puzanov I, Collichio F, Milhem MM, Hauschild A, Chen L, Sharma A, Garbe C, Singh P, Mehnert JM. Patterns of response with talimogene laherparepvec in combination with ipilimumab or ipilimumab alone in metastatic unresectable melanoma. Br J Cancer. 2019 Aug;121(5):417-420. doi: 10.1038/s41416-019-0530-6. Epub 2019 Jul 29.
- Background: PubMed 28238174Dummer R, Hoeller C, Gruter IP, Michielin O. Combining talimogene laherparepvec with immunotherapies in melanoma and other solid tumors. Cancer Immunol Immunother. 2017 Jun;66(6):683-695. doi: 10.1007/s00262-017-1967-1. Epub 2017 Feb 25.
- Background: PubMed 37142291Chesney JA, Puzanov I, Collichio FA, Singh P, Milhem MM, Glaspy J, Hamid O, Ross M, Friedlander P, Garbe C, Logan T, Hauschild A, Lebbe C, Joshi H, Snyder W, Mehnert JM. Talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone for advanced melanoma: 5-year final analysis of a multicenter, randomized, open-label, phase II trial. J Immunother Cancer. 2023 May;11(5):e006270. doi: 10.1136/jitc-2022-006270.
- AmgenTrials clinical trials websiteLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
MD study director
Amgen
40 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Talimogene laherparepvec and Ipilimumab in people with Melanoma, run by Amgen at 40 sites in 3 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 14 May 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 40 sites in United States, France, Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 9 Oct 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Phase 1b: Number of Participants With Dose-limiting Toxicities (time frame: The DLT evaluation period was 6 weeks from the initial administration of ipilimumab (week 6 to 12).). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01740297, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 May 2024.