Ipilimumab With or Without Talimogene Laherparepvec in Unresected Melanoma
Sponsor
Amgen (Industry)
Overall Status
Completed
CT.gov ID
NCT01740297
Collaborator
(none)
217
40
3
97
5.4
0.1
Study Details
Study Description
Brief 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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
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
Study Type:
Interventional
Actual Enrollment
:
217 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention 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.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)
Primary Purpose:
Treatment
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
Actual Study Start Date
:
Feb 7, 2013
Actual Primary Completion Date
:
Aug 23, 2016
Actual Study Completion Date
:
Mar 9, 2021
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Phase 1b: Talimogene Laherparepvec + Ipilimumab 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). |
Drug: Talimogene laherparepvec
Talimogene laherparepvec administered by intratumoral injection on Day 1 of Week 1, Day 1 of Week 4, then every two weeks thereafter.
Other Names:
Drug: Ipilimumab
Ipilimumab administered intravenously every 3 weeks for a total of 4 infusions.
Other Names:
|
| Active Comparator: Phase 2: Ipilimumab Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1. |
Drug: Ipilimumab
Ipilimumab administered intravenously every 3 weeks for a total of 4 infusions.
Other Names:
|
| Experimental: Phase 2: Talimogene Laherparepvec + Ipilimumab 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). |
Drug: Talimogene laherparepvec
Talimogene laherparepvec administered by intratumoral injection on Day 1 of Week 1, Day 1 of Week 4, then every two weeks thereafter.
Other Names:
Drug: Ipilimumab
Ipilimumab administered intravenously every 3 weeks for a total of 4 infusions.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Phase 1b: Number of Participants With Dose-limiting Toxicities [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 [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.
Secondary Outcome Measures
- Phase 1b: Objective Response Rate [Tumor response was assesed every 12 weeks until disease progression; median follow-up time at the primary analysis was 148.4 weeks.]
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.
- Phase 2: Best Overall Response [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.]
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.
- Phase 2: Disease Control Rate [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.]
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.
- Phase 2: Durable Response Rate [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.]
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.
- Phase 2: Time to Response [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.]
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.
- Phase 2: Duration of Response [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.]
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.
- Phase 2: Progression-free Survival [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.]
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.
- Phase 2: Resection Rate [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.]
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.
- Phase 2: Overall Survival [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.]
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.
- Phase 2: Kaplan-Meier Estimate of Percentage of Participants Alive at Month 12 and 24 [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.]
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.
- Phase 2: Progression-free Survival - Final Analysis [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.]
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.
- Phase 2: Overall Survival - Final Analysis [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.]
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.
- Phase 2: Kaplan-Meier Estimate of Percentage of Participants Alive at Month 12 and 24 - Final Analysis [Months 12 and 24]
- Number of Participants With Adverse Events [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.]
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).
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
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.
-
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
Exclusion Criteria:
-
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
-
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Research Site | Tucson | Arizona | United States | 85724 |
| 2 | Research Site | Beverly Hills | California | United States | 90211 |
| 3 | Research Site | Los Angeles | California | United States | 90025 |
| 4 | Research Site | Los Angeles | California | United States | 90089-2211 |
| 5 | Research Site | Los Angeles | California | United States | 90095 |
| 6 | Research Site | San Francisco | California | United States | 94115 |
| 7 | Research Site | Santa Rosa | California | United States | 95403 |
| 8 | Research Site | Aurora | Colorado | United States | 80045 |
| 9 | Research Site | Jacksonville | Florida | United States | 32207 |
| 10 | Research Site | Jacksonville | Florida | United States | 32224 |
| 11 | Research Site | Lakeland | Florida | United States | 33805 |
| 12 | Research Site | Miami | Florida | United States | 33140 |
| 13 | Research Site | Chicago | Illinois | United States | 60612 |
| 14 | Research Site | Indianapolis | Indiana | United States | 46202 |
| 15 | Research Site | Indianapolis | Indiana | United States | 46260 |
| 16 | Research Site | Iowa City | Iowa | United States | 52242 |
| 17 | Research Site | Louisville | Kentucky | United States | 40202 |
| 18 | Research Site | Minneapolis | Minnesota | United States | 55407 |
| 19 | Research Site | Saint Louis | Missouri | United States | 63110 |
| 20 | Research Site | Morristown | New Jersey | United States | 07962 |
| 21 | Research Site | New Brunswick | New Jersey | United States | 08903 |
| 22 | Research Site | New York | New York | United States | 10029 |
| 23 | Research Site | New York | New York | United States | 10032 |
| 24 | Research Site | Chapel Hill | North Carolina | United States | 27599 |
| 25 | Research Site | Canton | Ohio | United States | 44718 |
| 26 | Research Site | Cincinnati | Ohio | United States | 45267 |
| 27 | Research Site | Charleston | South Carolina | United States | 29425 |
| 28 | Research Site | Nashville | Tennessee | United States | 37232 |
| 29 | Research Site | Houston | Texas | United States | 77030 |
| 30 | Research Site | Salt Lake City | Utah | United States | 84112 |
| 31 | Research Site | Richmond | Virginia | United States | 23298-0037 |
| 32 | Research Site | Milwaukee | Wisconsin | United States | 53226 |
| 33 | Research Site | Bordeaux | France | 33075 | |
| 34 | Research Site | Grenoble Cedex 9 | France | 38043 | |
| 35 | Research Site | Lille | France | 59037 | |
| 36 | Research Site | Nantes Cedex 1 | France | 44093 | |
| 37 | Research Site | Paris | France | 75010 | |
| 38 | Research Site | Göttingen | Germany | 37075 | |
| 39 | Research Site | Kiel | Germany | 24105 | |
| 40 | Research Site | Tübingen | Germany | 72076 |
Sponsors and Collaborators
- Amgen
Investigators
- Study Director: MD, Amgen
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
- Chesney 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.
- Chesney J, Puzanov I, Collichio F, Singh P, Milhem MM, Glaspy J, Hamid O, Ross M, Friedlander P, Garbe C, Logan TF, Hauschild A, Lebbé 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.
- Dummer 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. Review.
- Puzanov 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.
Responsible Party:
Amgen
ClinicalTrials.gov Identifier:
NCT01740297
Other Study ID Numbers:
- 20110264
- 2012-000307-32
First Posted:
Dec 4, 2012
Last Update Posted:
Mar 10, 2022
Last Verified:
Mar 1, 2022
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Keywords provided by Amgen
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | This study was conducted at 33 centers in the United States of America, France, and Germany. Participants were enrolled in Phase 1b from 07 February 2013 to 08 July 2013 and in Phase 2 from 13 August 2013 to 25 February 2016. |
|---|---|
| Pre-assignment Detail | In Phase 1b all participants received talimogene laherparepvec in combination with ipilimumab. In Phase 2 participants were randomized in 1:1 ratio to receive talimogene laherparepvec plus ipilimumab or ipilimumab. Participants randomized prior to Protocol Amendment 2 were stratified by disease stage and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation V600E; participants randomized after Amendment 2 were stratified by disease stage and prior therapy. |
| Arm/Group Title | Phase 1b: Talimogene Laherparepvec + Ipilimumab | Phase 2: Ipilimumab | Phase 2: Talimogene Laherparepvec + Ipilimumab |
|---|---|---|---|
| Arm/Group Description | 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 with maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) 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). | Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1. | Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) 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). |
| Period Title: Overall Study | |||
| STARTED | 19 | 100 | 98 |
| Received Talimogene Laherparepvec | 19 | 0 | 95 |
| Received Ipilimumab | 18 | 95 | 92 |
| COMPLETED | 6 | 36 | 37 |
| NOT COMPLETED | 13 | 64 | 61 |
Baseline Characteristics
| Arm/Group Title | Phase 1b: Talimogene Laherparepvec + Ipilimumab | Phase 2: Ipilimumab | Phase 2: Talimogene Laherparepvec + Ipilimumab | Total |
|---|---|---|---|---|
| Arm/Group Description | 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 with maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) 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). | Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1. | Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) 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). | Total of all reporting groups |
| Overall Participants | 19 | 100 | 98 | 217 |
| Age (years) [Mean (Standard Deviation) ] | ||||
| Mean (Standard Deviation) [years] |
61.1
(12.1)
|
64.2
(13.3)
|
63.6
(14.0)
|
63.6
(13.5)
|
| Age, Customized (Count of Participants) | ||||
| < 65 years |
11
57.9%
|
54
54%
|
46
46.9%
|
111
51.2%
|
| ≥ 65 years |
8
42.1%
|
46
46%
|
52
53.1%
|
106
48.8%
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
11
57.9%
|
45
45%
|
36
36.7%
|
92
42.4%
|
| Male |
8
42.1%
|
55
55%
|
62
63.3%
|
125
57.6%
|
| Ethnicity (NIH/OMB) (Count of Participants) | ||||
| Hispanic or Latino |
1
5.3%
|
4
4%
|
0
0%
|
5
2.3%
|
| Not Hispanic or Latino |
18
94.7%
|
96
96%
|
98
100%
|
212
97.7%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Race/Ethnicity, Customized (Count of Participants) | ||||
| American Indian or Alaska Native |
0
0%
|
1
1%
|
0
0%
|
1
0.5%
|
| Asian |
0
0%
|
1
1%
|
0
0%
|
1
0.5%
|
| Black (or African American) |
0
0%
|
3
3%
|
0
0%
|
3
1.4%
|
| Multiple |
0
0%
|
1
1%
|
1
1%
|
2
0.9%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| White |
18
94.7%
|
92
92%
|
97
99%
|
207
95.4%
|
| Other |
1
5.3%
|
2
2%
|
0
0%
|
3
1.4%
|
| Eastern Cooperative Oncology Group (ECOG) Performance Status (Count of Participants) | ||||
| 0 (Fully active) |
14
73.7%
|
73
73%
|
69
70.4%
|
156
71.9%
|
| 1 (Restrictive but ambulatory) |
5
26.3%
|
27
27%
|
29
29.6%
|
61
28.1%
|
| Tumor, Node, Metastasis (TNM) Disease Stage (Count of Participants) | ||||
| Stage IIIB - IVM1a |
8
42.1%
|
57
57%
|
50
51%
|
115
53%
|
| Stage IVM1b/c |
11
57.9%
|
43
43%
|
48
49%
|
102
47%
|
| BRAF V600 Mutation Status (Count of Participants) | ||||
| Mutation |
12
63.2%
|
34
34%
|
35
35.7%
|
81
37.3%
|
| Wild-type |
7
36.8%
|
60
60%
|
62
63.3%
|
129
59.4%
|
| Missing/Unknown |
0
0%
|
6
6%
|
1
1%
|
7
3.2%
|
Outcome Measures
| Title | Phase 1b: Number of Participants With Dose-limiting Toxicities |
|---|---|
| Description | 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. |
| Time Frame | The DLT evaluation period was 6 weeks from the initial administration of ipilimumab (week 6 to 12). |
Outcome Measure Data
| Analysis Population Description |
|---|
| All phase 1b participants who received ≥ 1 dose of investigational product (talimogene laherparepvec or ipilimumab). |
| Arm/Group Title | Phase 1b: Talimogene Laherparepvec + Ipilimumab |
|---|---|
| Arm/Group Description | 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 with maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) 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). |
| Measure Participants | 19 |
| Count of Participants [Participants] |
0
0%
|
| Title | Phase 2: Objective Response Rate |
|---|---|
| Description | 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. |
| 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants randomized in phase 2 |
| Arm/Group Title | Phase 2: Ipilimumab | Phase 2: Talimogene Laherparepvec + Ipilimumab |
|---|---|---|
| Arm/Group Description | Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1. | Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) 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). |
| Measure Participants | 100 | 98 |
| Number (95% Confidence Interval) [percentage of participants] |
18.0
94.7%
|
38.8
38.8%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1b: Talimogene Laherparepvec + Ipilimumab, Phase 2: Talimogene Laherparepvec + Ipilimumab |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.002 |
| Comments | ||
| Method | Chi-squared, Corrected | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 2.9 | |
| Confidence Interval |
(2-Sided) 95% 1.5 to 5.5 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Obtained from the unstratified logistic regression model. | |
| Title | Phase 1b: Objective Response Rate |
|---|---|
| Description | 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. |
| Time Frame | Tumor response was assesed every 12 weeks until disease progression; median follow-up time at the primary analysis was 148.4 weeks. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All phase 1b participants who received ≥ 1 dose of investigational product (talimogene laherparepvec or ipilimumab). |
| Arm/Group Title | Phase 1b: Talimogene Laherparepvec + Ipilimumab |
|---|---|
| Arm/Group Description | 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 with maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) 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). |
| Measure Participants | 19 |
| Number (95% Confidence Interval) [percentage of participants] |
52.6
276.8%
|
| Title | Phase 2: Best Overall Response |
|---|---|
| Description | 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. |
| 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants randomized in phase 2 |
| Arm/Group Title | Phase 2: Ipilimumab | Phase 2: Talimogene Laherparepvec + Ipilimumab |
|---|---|---|
| Arm/Group Description | Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1. | Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) 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). |
| Measure Participants | 100 | 98 |
| Complete Response (CR) |
7
36.8%
|
13
13%
|
| Partial Response (PR) |
11
57.9%
|
25
25%
|
| Stable Disease (SD) |
24
126.3%
|
19
19%
|
| Progressive Disease (PD) |
33
173.7%
|
31
31%
|
| Unevaluable (UE) |
17
89.5%
|
4
4%
|
| Not Done (ND) |
8
42.1%
|
6
6%
|
| Title | Phase 2: Disease Control Rate |
|---|---|
| Description | 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. |
| 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants randomized in phase 2 |
| Arm/Group Title | Phase 2: Ipilimumab | Phase 2: Talimogene Laherparepvec + Ipilimumab |
|---|---|---|
| Arm/Group Description | Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1. | Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) 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). |
| Measure Participants | 100 | 98 |
| Number (95% Confidence Interval) [percentage of participants] |
42.0
221.1%
|
58.2
58.2%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1b: Talimogene Laherparepvec + Ipilimumab, Phase 2: Talimogene Laherparepvec + Ipilimumab |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.033 |
| Comments | P-value is descriptive | |
| Method | Chi-squared, Corrected | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 1.9 | |
| Confidence Interval |
(2-Sided) 95% 1.1 to 3.4 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Obtained from the unstratified logistic regression model. | |
| Title | Phase 2: Durable Response Rate |
|---|---|
| Description | 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. |
| 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants randomized in phase 2 |
| Arm/Group Title | Phase 2: Ipilimumab | Phase 2: Talimogene Laherparepvec + Ipilimumab |
|---|---|---|
| Arm/Group Description | Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1. | Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) 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). |
| Measure Participants | 100 | 98 |
| Number (95% Confidence Interval) [percentage of participants] |
13.0
68.4%
|
29.6
29.6%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1b: Talimogene Laherparepvec + Ipilimumab, Phase 2: Talimogene Laherparepvec + Ipilimumab |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.007 |
| Comments | P-value is descriptive. | |
| Method | Chi-squared, Corrected | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 2.8 | |
| Confidence Interval |
(2-Sided) 95% 1.4 to 5.8 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Obtained from the unstratified logistic regression model. | |
| Title | Phase 2: Time to Response |
|---|---|
| Description | 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. |
| 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants randomized in phase 2 |
| Arm/Group Title | Phase 2: Ipilimumab | Phase 2: Talimogene Laherparepvec + Ipilimumab |
|---|---|---|
| Arm/Group Description | Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1. | Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) 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). |
| Measure Participants | 100 | 98 |
| Median (95% Confidence Interval) [months] |
NA
|
5.8
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1b: Talimogene Laherparepvec + Ipilimumab, Phase 2: Talimogene Laherparepvec + Ipilimumab |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.228 |
| Comments | P-value is descriptive | |
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 1.41 | |
| Confidence Interval |
(2-Sided) 95% 0.80 to 2.49 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Obtained from unstratified Cox Proportional Hazard Model. | |
| Title | Phase 2: Duration of Response |
|---|---|
| Description | 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. |
| 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants randomized in phase 2 with a confirmed CR or PR. |
| Arm/Group Title | Phase 2: Ipilimumab | Phase 2: Talimogene Laherparepvec + Ipilimumab |
|---|---|---|
| Arm/Group Description | Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1. | Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) 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). |
| Measure Participants | 18 | 38 |
| Median (95% Confidence Interval) [months] |
NA
|
NA
|
| Title | Phase 2: Progression-free Survival |
|---|---|
| Description | 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. |
| 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants randomized in phase 2 |
| Arm/Group Title | Phase 2: Ipilimumab | Phase 2: Talimogene Laherparepvec + Ipilimumab |
|---|---|---|
| Arm/Group Description | Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1. | Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) 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). |
| Measure Participants | 100 | 98 |
| Median (95% Confidence Interval) [months] |
6.4
|
8.2
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1b: Talimogene Laherparepvec + Ipilimumab, Phase 2: Talimogene Laherparepvec + Ipilimumab |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.348 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.83 | |
| Confidence Interval |
(2-Sided) 95% 0.56 to 1.23 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Obtained from unstratified Cox Proportional Hazard Model | |
| Title | Phase 2: Resection Rate |
|---|---|
| Description | 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. |
| 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants randomized in phase 2 |
| Arm/Group Title | Phase 2: Ipilimumab | Phase 2: Talimogene Laherparepvec + Ipilimumab |
|---|---|---|
| Arm/Group Description | Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1. | Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) 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). |
| Measure Participants | 100 | 98 |
| Number (95% Confidence Interval) [percentage of participants] |
3.0
15.8%
|
5.1
5.1%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1b: Talimogene Laherparepvec + Ipilimumab, Phase 2: Talimogene Laherparepvec + Ipilimumab |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.696 |
| Comments | ||
| Method | Chi-squared, Corrected | |
| Comments | ||
| Title | Phase 2: Overall Survival |
|---|---|
| Description | 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. |
| 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants randomized in phase 2 |
| Arm/Group Title | Phase 2: Ipilimumab | Phase 2: Talimogene Laherparepvec + Ipilimumab |
|---|---|---|
| Arm/Group Description | Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1. | Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) 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). |
| Measure Participants | 100 | 98 |
| Median (95% Confidence Interval) [months] |
NA
|
NA
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1b: Talimogene Laherparepvec + Ipilimumab, Phase 2: Talimogene Laherparepvec + Ipilimumab |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.474 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.80 | |
| Confidence Interval |
(2-Sided) 95% 0.44 to 1.46 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Obtained from unstratified Cox Proportional Hazard Model | |
| Title | Phase 2: Kaplan-Meier Estimate of Percentage of Participants Alive at Month 12 and 24 |
|---|---|
| Description | 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. |
| 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants randomized in phase 2 |
| Arm/Group Title | Phase 2: Ipilimumab | Phase 2: Talimogene Laherparepvec + Ipilimumab |
|---|---|---|
| Arm/Group Description | Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1. | Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) 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). |
| Measure Participants | 100 | 98 |
| Month 12 |
81.4
428.4%
|
86.9
86.9%
|
| Month 24 |
67.7
356.3%
|
76.6
76.6%
|
| Title | Phase 2: Progression-free Survival - Final Analysis |
|---|---|
| Description | 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. |
| 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants randomized in phase 2 |
| Arm/Group Title | Phase 2: Ipilimumab | Phase 2: Talimogene Laherparepvec + Ipilimumab |
|---|---|---|
| Arm/Group Description | Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1. | Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) 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). |
| Measure Participants | 100 | 98 |
| Median (95% Confidence Interval) [months] |
6.4
|
13.5
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1b: Talimogene Laherparepvec + Ipilimumab, Phase 2: Talimogene Laherparepvec + Ipilimumab |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.14 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.78 | |
| Confidence Interval |
(2-Sided) 95% 0.55 to 1.09 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Obtained from unstratified Cox Proportional Hazard Model | |
| Title | Phase 2: Overall Survival - Final Analysis |
|---|---|
| Description | 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. |
| 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants randomized in phase 2 |
| Arm/Group Title | Phase 2: Ipilimumab | Phase 2: Talimogene Laherparepvec + Ipilimumab |
|---|---|---|
| Arm/Group Description | Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1. | Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) 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). |
| Measure Participants | 100 | 98 |
| Median (95% Confidence Interval) [months] |
50.1
|
84.9
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1b: Talimogene Laherparepvec + Ipilimumab, Phase 2: Talimogene Laherparepvec + Ipilimumab |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.37 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.83 | |
| Confidence Interval |
(2-Sided) 95% 0.56 to 1.24 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Obtained from unstratified Cox Proportional Hazard Model | |
| Title | Phase 2: Kaplan-Meier Estimate of Percentage of Participants Alive at Month 12 and 24 - Final Analysis |
|---|---|
| Description | |
| Time Frame | Months 12 and 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants randomized in phase 2 |
| Arm/Group Title | Phase 2: Ipilimumab | Phase 2: Talimogene Laherparepvec + Ipilimumab |
|---|---|---|
| Arm/Group Description | Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1. | Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) 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). |
| Measure Participants | 100 | 98 |
| Month 12 |
79.9
420.5%
|
83.3
83.3%
|
| Month 24 |
69.3
364.7%
|
72.7
72.7%
|
| Title | Number of Participants With Adverse Events |
|---|---|
| Description | 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). |
| 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants who received ≥ 1 dose of investigational product (talimogene laherparepvec or ipilimumab). |
| Arm/Group Title | Phase 1b: Talimogene Laherparepvec + Ipilimumab | Phase 2: Ipilimumab | Phase 2: Talimogene Laherparepvec + Ipilimumab |
|---|---|---|---|
| Arm/Group Description | 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 with maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) 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). | Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1. | Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) 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). |
| Measure Participants | 19 | 95 | 95 |
| All adverse events |
19
100%
|
90
90%
|
92
93.9%
|
| Adverse events ≥ grade 2 |
17
89.5%
|
72
72%
|
80
81.6%
|
| Adverse events ≥ grade 3 |
7
36.8%
|
41
41%
|
44
44.9%
|
| Adverse events ≥ grade 4 |
2
10.5%
|
4
4%
|
6
6.1%
|
| Serious adverse events |
6
31.6%
|
34
34%
|
34
34.7%
|
| AEs leading to discontinuation of T-VEC |
0
0%
|
NA
NaN
|
6
6.1%
|
| AEs leading to discontinuation of ipilimumab |
0
0%
|
17
17%
|
13
13.3%
|
| Fatal adverse events |
1
5.3%
|
1
1%
|
5
5.1%
|
| T-VEC-related adverse events |
17
89.5%
|
NA
NaN
|
82
83.7%
|
| T-VEC-related adverse events AEs ≥ grade 2 |
12
63.2%
|
NA
NaN
|
44
44.9%
|
| T-VEC-related adverse events AEs ≥ grade 3 |
3
15.8%
|
NA
NaN
|
15
15.3%
|
| T-VEC-related adverse events ≥ grade 4 |
0
0%
|
NA
NaN
|
1
1%
|
| T-VEC-related serious adverse events |
1
5.3%
|
NA
NaN
|
10
10.2%
|
| T-VEC-related AEs leading to T-VEC discontinuation |
0
0%
|
NA
NaN
|
0
0%
|
| Fatal T-VEC-related adverse events |
0
0%
|
NA
NaN
|
0
0%
|
| Ipilimumab-related adverse events |
15
78.9%
|
78
78%
|
75
76.5%
|
| Ipilimumab-related adverse events ≥ grade 2 |
8
42.1%
|
50
50%
|
48
49%
|
| Ipilimumab-related adverse events ≥ grade 3 |
4
21.1%
|
21
21%
|
19
19.4%
|
| Ipilimumab-related adverse events ≥ grade 4 |
1
5.3%
|
2
2%
|
1
1%
|
| Ipilimumab-related serious adverse events |
4
21.1%
|
19
19%
|
14
14.3%
|
| Ipi-related AEs leading to Ipi discontinuation |
0
0%
|
12
12%
|
11
11.2%
|
| Fatal ipilimumab-related adverse events |
0
0%
|
0
0%
|
1
1%
|
Adverse Events
| Time Frame | All-cause mortality is reported from randomization until the end of study (09 March 2021); median follow-up time was 271 weeks in Phase 1, 155 weeks in the Phase 2 Ipilimumab group and 214 weeks in the Phase 2 T-VEC + Ipilimumab group. AEs are reported from first dose of study drug until 30 days after last dose of talimogene laherparepvec or 60 days after last dose of ipilimumab, whichever was later; median duration of treatment was 14.7, 9.1, and 21.1 weeks in each treatment group respectively. | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | All-cause mortality is reported for all enrolled (Phase 1b) or randomized (Phase 2) participants. Serious adverse events and other adverse events are reported for all participants who received at least one dose of study drug (talimogene laherparepvec or ipilimumab). | |||||
| Arm/Group Title | Phase 1b: Talimogene Laherparepvec + Ipilimumab | Phase 2: Ipilimumab | Phase 2: Talimogene Laherparepvec + Ipilimumab | |||
| Arm/Group Description | 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 with maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) 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). | Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1. | Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) 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). | |||
All Cause Mortality |
||||||
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Phase 2: Ipilimumab | Phase 2: Talimogene Laherparepvec + Ipilimumab | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 9/19 (47.4%) | 52/100 (52%) | 45/98 (45.9%) | |||
Serious Adverse Events |
||||||
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Phase 2: Ipilimumab | Phase 2: Talimogene Laherparepvec + Ipilimumab | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 6/19 (31.6%) | 34/95 (35.8%) | 34/95 (35.8%) | |||
| Blood and lymphatic system disorders | ||||||
| Lymphopenia | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Anaemia | 0/19 (0%) | 1/95 (1.1%) | 0/95 (0%) | |||
| Cardiac disorders | ||||||
| Angina pectoris | 0/19 (0%) | 1/95 (1.1%) | 0/95 (0%) | |||
| Arrhythmia | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Atrial fibrillation | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Myocardial infarction | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Endocrine disorders | ||||||
| Hypophysitis | 0/19 (0%) | 1/95 (1.1%) | 1/95 (1.1%) | |||
| Lymphocytic hypophysitis | 0/19 (0%) | 1/95 (1.1%) | 2/95 (2.1%) | |||
| Adrenocortical insufficiency acute | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Eye disorders | ||||||
| Exophthalmos | 0/19 (0%) | 1/95 (1.1%) | 0/95 (0%) | |||
| Gastrointestinal disorders | ||||||
| Abdominal distension | 1/19 (5.3%) | 0/95 (0%) | 0/95 (0%) | |||
| Abdominal pain | 0/19 (0%) | 1/95 (1.1%) | 1/95 (1.1%) | |||
| Autoimmune colitis | 0/19 (0%) | 3/95 (3.2%) | 3/95 (3.2%) | |||
| Colitis | 0/19 (0%) | 9/95 (9.5%) | 6/95 (6.3%) | |||
| Constipation | 0/19 (0%) | 1/95 (1.1%) | 0/95 (0%) | |||
| Diarrhoea | 0/19 (0%) | 2/95 (2.1%) | 1/95 (1.1%) | |||
| Nausea | 2/19 (10.5%) | 0/95 (0%) | 2/95 (2.1%) | |||
| Anal fissure | 0/19 (0%) | 1/95 (1.1%) | 0/95 (0%) | |||
| General disorders | ||||||
| Asthenia | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Chest pain | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Fatigue | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| General physical health deterioration | 0/19 (0%) | 1/95 (1.1%) | 1/95 (1.1%) | |||
| Influenza like illness | 0/19 (0%) | 0/95 (0%) | 5/95 (5.3%) | |||
| Injection site reaction | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Non-cardiac chest pain | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Pain | 0/19 (0%) | 1/95 (1.1%) | 0/95 (0%) | |||
| Pyrexia | 0/19 (0%) | 0/95 (0%) | 2/95 (2.1%) | |||
| Hepatobiliary disorders | ||||||
| Autoimmune hepatitis | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Infections and infestations | ||||||
| Appendicitis | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Cellulitis | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Cytomegalovirus colitis | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Meningitis aseptic | 0/19 (0%) | 1/95 (1.1%) | 0/95 (0%) | |||
| Sepsis | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Urinary tract infection | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Osteomyelitis | 0/19 (0%) | 1/95 (1.1%) | 0/95 (0%) | |||
| Injury, poisoning and procedural complications | ||||||
| Hip fracture | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Lumbar vertebral fracture | 0/19 (0%) | 1/95 (1.1%) | 0/95 (0%) | |||
| Investigations | ||||||
| Amylase increased | 1/19 (5.3%) | 0/95 (0%) | 0/95 (0%) | |||
| Blood creatinine increased | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Lipase increased | 1/19 (5.3%) | 0/95 (0%) | 0/95 (0%) | |||
| Neutrophil count decreased | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| White blood cell count decreased | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Metabolism and nutrition disorders | ||||||
| Dehydration | 0/19 (0%) | 0/95 (0%) | 2/95 (2.1%) | |||
| Hypercalcaemia | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Hypoglycaemia | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Hyponatraemia | 0/19 (0%) | 2/95 (2.1%) | 0/95 (0%) | |||
| Hyperglycaemia | 0/19 (0%) | 1/95 (1.1%) | 0/95 (0%) | |||
| Musculoskeletal and connective tissue disorders | ||||||
| Arthralgia | 0/19 (0%) | 1/95 (1.1%) | 0/95 (0%) | |||
| Back pain | 1/19 (5.3%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Lumbar spinal stenosis | 0/19 (0%) | 1/95 (1.1%) | 0/95 (0%) | |||
| Musculoskeletal pain | 0/19 (0%) | 1/95 (1.1%) | 0/95 (0%) | |||
| Rhabdomyolysis | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Myositis | 0/19 (0%) | 1/95 (1.1%) | 0/95 (0%) | |||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Malignant melanoma | 0/19 (0%) | 2/95 (2.1%) | 1/95 (1.1%) | |||
| Malignant neoplasm progression | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Malignant pleural effusion | 0/19 (0%) | 0/95 (0%) | 2/95 (2.1%) | |||
| Metastases to central nervous system | 1/19 (5.3%) | 1/95 (1.1%) | 1/95 (1.1%) | |||
| Tumour flare | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Tumour pain | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Nervous system disorders | ||||||
| Dizziness | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Facial paralysis | 1/19 (5.3%) | 0/95 (0%) | 0/95 (0%) | |||
| Intracranial mass | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Seizure | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Transient ischaemic attack | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Encephalopathy | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Psychiatric disorders | ||||||
| Anxiety | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Confusional state | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Renal and urinary disorders | ||||||
| Haematuria | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Respiratory, thoracic and mediastinal disorders | ||||||
| Acute respiratory failure | 0/19 (0%) | 1/95 (1.1%) | 0/95 (0%) | |||
| Dyspnoea | 0/19 (0%) | 0/95 (0%) | 2/95 (2.1%) | |||
| Pleural effusion | 0/19 (0%) | 0/95 (0%) | 2/95 (2.1%) | |||
| Pulmonary embolism | 0/19 (0%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Pneumonitis | 0/19 (0%) | 1/95 (1.1%) | 0/95 (0%) | |||
| Pulmonary oedema | 0/19 (0%) | 1/95 (1.1%) | 0/95 (0%) | |||
| Skin and subcutaneous tissue disorders | ||||||
| Rash maculo-papular | 0/19 (0%) | 1/95 (1.1%) | 0/95 (0%) | |||
| Drug reaction with eosinophilia and systemic symptoms | 0/19 (0%) | 1/95 (1.1%) | 0/95 (0%) | |||
| Vascular disorders | ||||||
| Hypotension | 0/19 (0%) | 1/95 (1.1%) | 1/95 (1.1%) | |||
Other (Not Including Serious) Adverse Events |
||||||
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Phase 2: Ipilimumab | Phase 2: Talimogene Laherparepvec + Ipilimumab | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 19/19 (100%) | 85/95 (89.5%) | 91/95 (95.8%) | |||
| Blood and lymphatic system disorders | ||||||
| Anaemia | 0/19 (0%) | 5/95 (5.3%) | 11/95 (11.6%) | |||
| Lymphopenia | 0/19 (0%) | 3/95 (3.2%) | 10/95 (10.5%) | |||
| Endocrine disorders | ||||||
| Adrenal insufficiency | 1/19 (5.3%) | 3/95 (3.2%) | 2/95 (2.1%) | |||
| Hypothyroidism | 2/19 (10.5%) | 4/95 (4.2%) | 4/95 (4.2%) | |||
| Lymphocytic hypophysitis | 1/19 (5.3%) | 1/95 (1.1%) | 1/95 (1.1%) | |||
| Eye disorders | ||||||
| Eye pain | 1/19 (5.3%) | 0/95 (0%) | 0/95 (0%) | |||
| Uveitis | 1/19 (5.3%) | 0/95 (0%) | 0/95 (0%) | |||
| Vision blurred | 3/19 (15.8%) | 8/95 (8.4%) | 6/95 (6.3%) | |||
| Gastrointestinal disorders | ||||||
| Abdominal pain | 0/19 (0%) | 11/95 (11.6%) | 15/95 (15.8%) | |||
| Constipation | 2/19 (10.5%) | 8/95 (8.4%) | 14/95 (14.7%) | |||
| Diarrhoea | 8/19 (42.1%) | 33/95 (34.7%) | 40/95 (42.1%) | |||
| Dyspepsia | 1/19 (5.3%) | 2/95 (2.1%) | 4/95 (4.2%) | |||
| Nausea | 9/19 (47.4%) | 26/95 (27.4%) | 36/95 (37.9%) | |||
| Vomiting | 5/19 (26.3%) | 13/95 (13.7%) | 19/95 (20%) | |||
| Colitis | 0/19 (0%) | 6/95 (6.3%) | 2/95 (2.1%) | |||
| Haematochezia | 0/19 (0%) | 5/95 (5.3%) | 0/95 (0%) | |||
| General disorders | ||||||
| Application site pain | 1/19 (5.3%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Asthenia | 0/19 (0%) | 10/95 (10.5%) | 7/95 (7.4%) | |||
| Chest pain | 1/19 (5.3%) | 1/95 (1.1%) | 1/95 (1.1%) | |||
| Chills | 11/19 (57.9%) | 4/95 (4.2%) | 50/95 (52.6%) | |||
| Fatigue | 11/19 (57.9%) | 40/95 (42.1%) | 56/95 (58.9%) | |||
| Influenza like illness | 3/19 (15.8%) | 1/95 (1.1%) | 27/95 (28.4%) | |||
| Injection site inflammation | 1/19 (5.3%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Injection site pain | 1/19 (5.3%) | 0/95 (0%) | 27/95 (28.4%) | |||
| Injection site reaction | 2/19 (10.5%) | 0/95 (0%) | 15/95 (15.8%) | |||
| Injection site swelling | 0/19 (0%) | 0/95 (0%) | 5/95 (5.3%) | |||
| Malaise | 1/19 (5.3%) | 2/95 (2.1%) | 7/95 (7.4%) | |||
| Oedema peripheral | 2/19 (10.5%) | 5/95 (5.3%) | 14/95 (14.7%) | |||
| Pain | 3/19 (15.8%) | 4/95 (4.2%) | 11/95 (11.6%) | |||
| Performance status decreased | 1/19 (5.3%) | 0/95 (0%) | 0/95 (0%) | |||
| Peripheral swelling | 1/19 (5.3%) | 1/95 (1.1%) | 3/95 (3.2%) | |||
| Pyrexia | 11/19 (57.9%) | 9/95 (9.5%) | 36/95 (37.9%) | |||
| Infections and infestations | ||||||
| Escherichia infection | 1/19 (5.3%) | 0/95 (0%) | 0/95 (0%) | |||
| Eye infection | 1/19 (5.3%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Influenza | 1/19 (5.3%) | 0/95 (0%) | 0/95 (0%) | |||
| Nasopharyngitis | 1/19 (5.3%) | 0/95 (0%) | 4/95 (4.2%) | |||
| Oral herpes | 0/19 (0%) | 0/95 (0%) | 6/95 (6.3%) | |||
| Sinusitis | 2/19 (10.5%) | 0/95 (0%) | 4/95 (4.2%) | |||
| Upper respiratory tract infection | 1/19 (5.3%) | 5/95 (5.3%) | 6/95 (6.3%) | |||
| Vaginal infection | 1/19 (5.3%) | 0/95 (0%) | 0/95 (0%) | |||
| Vulvovaginal mycotic infection | 2/19 (10.5%) | 0/95 (0%) | 0/95 (0%) | |||
| Wound infection | 1/19 (5.3%) | 0/95 (0%) | 0/95 (0%) | |||
| Injury, poisoning and procedural complications | ||||||
| Radius fracture | 1/19 (5.3%) | 0/95 (0%) | 0/95 (0%) | |||
| Investigations | ||||||
| Alanine aminotransferase increased | 3/19 (15.8%) | 6/95 (6.3%) | 8/95 (8.4%) | |||
| Amylase increased | 1/19 (5.3%) | 1/95 (1.1%) | 1/95 (1.1%) | |||
| Aspartate aminotransferase increased | 0/19 (0%) | 5/95 (5.3%) | 8/95 (8.4%) | |||
| Blood alkaline phosphatase increased | 0/19 (0%) | 2/95 (2.1%) | 5/95 (5.3%) | |||
| Blood lactate dehydrogenase increased | 0/19 (0%) | 3/95 (3.2%) | 5/95 (5.3%) | |||
| Lipase increased | 1/19 (5.3%) | 2/95 (2.1%) | 0/95 (0%) | |||
| Weight decreased | 0/19 (0%) | 6/95 (6.3%) | 2/95 (2.1%) | |||
| Metabolism and nutrition disorders | ||||||
| Decreased appetite | 4/19 (21.1%) | 14/95 (14.7%) | 12/95 (12.6%) | |||
| Dehydration | 2/19 (10.5%) | 5/95 (5.3%) | 3/95 (3.2%) | |||
| Hypercalcaemia | 1/19 (5.3%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Hyperglycaemia | 4/19 (21.1%) | 7/95 (7.4%) | 7/95 (7.4%) | |||
| Hyperuricaemia | 1/19 (5.3%) | 1/95 (1.1%) | 0/95 (0%) | |||
| Hypocalcaemia | 1/19 (5.3%) | 1/95 (1.1%) | 0/95 (0%) | |||
| Hypokalaemia | 2/19 (10.5%) | 8/95 (8.4%) | 6/95 (6.3%) | |||
| Hypomagnesaemia | 1/19 (5.3%) | 2/95 (2.1%) | 3/95 (3.2%) | |||
| Hyponatraemia | 0/19 (0%) | 5/95 (5.3%) | 4/95 (4.2%) | |||
| Musculoskeletal and connective tissue disorders | ||||||
| Arthralgia | 1/19 (5.3%) | 15/95 (15.8%) | 21/95 (22.1%) | |||
| Back pain | 2/19 (10.5%) | 8/95 (8.4%) | 10/95 (10.5%) | |||
| Muscle spasms | 1/19 (5.3%) | 2/95 (2.1%) | 4/95 (4.2%) | |||
| Muscle tightness | 1/19 (5.3%) | 0/95 (0%) | 0/95 (0%) | |||
| Muscular weakness | 1/19 (5.3%) | 4/95 (4.2%) | 4/95 (4.2%) | |||
| Musculoskeletal chest pain | 0/19 (0%) | 0/95 (0%) | 5/95 (5.3%) | |||
| Myalgia | 1/19 (5.3%) | 4/95 (4.2%) | 10/95 (10.5%) | |||
| Pain in extremity | 2/19 (10.5%) | 7/95 (7.4%) | 5/95 (5.3%) | |||
| Pubic pain | 1/19 (5.3%) | 0/95 (0%) | 0/95 (0%) | |||
| Soft tissue mass | 1/19 (5.3%) | 0/95 (0%) | 0/95 (0%) | |||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Tumour pain | 1/19 (5.3%) | 4/95 (4.2%) | 4/95 (4.2%) | |||
| Nervous system disorders | ||||||
| Brain oedema | 1/19 (5.3%) | 1/95 (1.1%) | 0/95 (0%) | |||
| Cluster headache | 1/19 (5.3%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Dizziness | 1/19 (5.3%) | 4/95 (4.2%) | 10/95 (10.5%) | |||
| Headache | 8/19 (42.1%) | 22/95 (23.2%) | 34/95 (35.8%) | |||
| Peripheral motor neuropathy | 1/19 (5.3%) | 0/95 (0%) | 0/95 (0%) | |||
| Peripheral sensory neuropathy | 1/19 (5.3%) | 2/95 (2.1%) | 0/95 (0%) | |||
| Speech disorder | 1/19 (5.3%) | 0/95 (0%) | 0/95 (0%) | |||
| Tension headache | 1/19 (5.3%) | 0/95 (0%) | 0/95 (0%) | |||
| Tremor | 1/19 (5.3%) | 2/95 (2.1%) | 0/95 (0%) | |||
| Psychiatric disorders | ||||||
| Anxiety | 1/19 (5.3%) | 1/95 (1.1%) | 7/95 (7.4%) | |||
| Depression | 0/19 (0%) | 2/95 (2.1%) | 5/95 (5.3%) | |||
| Insomnia | 0/19 (0%) | 16/95 (16.8%) | 10/95 (10.5%) | |||
| Nightmare | 1/19 (5.3%) | 0/95 (0%) | 0/95 (0%) | |||
| Renal and urinary disorders | ||||||
| Acute kidney injury | 1/19 (5.3%) | 0/95 (0%) | 1/95 (1.1%) | |||
| Bladder pain | 1/19 (5.3%) | 0/95 (0%) | 0/95 (0%) | |||
| Dysuria | 1/19 (5.3%) | 0/95 (0%) | 0/95 (0%) | |||
| Pollakiuria | 1/19 (5.3%) | 3/95 (3.2%) | 3/95 (3.2%) | |||
| Respiratory, thoracic and mediastinal disorders | ||||||
| Cough | 1/19 (5.3%) | 11/95 (11.6%) | 21/95 (22.1%) | |||
| Dyspnoea | 1/19 (5.3%) | 10/95 (10.5%) | 8/95 (8.4%) | |||
| Hiccups | 1/19 (5.3%) | 1/95 (1.1%) | 2/95 (2.1%) | |||
| Pleural effusion | 1/19 (5.3%) | 1/95 (1.1%) | 1/95 (1.1%) | |||
| Skin and subcutaneous tissue disorders | ||||||
| Dry skin | 0/19 (0%) | 2/95 (2.1%) | 6/95 (6.3%) | |||
| Erythema | 2/19 (10.5%) | 2/95 (2.1%) | 6/95 (6.3%) | |||
| Hyperhidrosis | 0/19 (0%) | 3/95 (3.2%) | 6/95 (6.3%) | |||
| Night sweats | 2/19 (10.5%) | 2/95 (2.1%) | 2/95 (2.1%) | |||
| Pruritus | 8/19 (42.1%) | 35/95 (36.8%) | 39/95 (41.1%) | |||
| Rash | 9/19 (47.4%) | 29/95 (30.5%) | 40/95 (42.1%) | |||
| Rash erythematous | 2/19 (10.5%) | 1/95 (1.1%) | 3/95 (3.2%) | |||
| Rash maculo-papular | 0/19 (0%) | 2/95 (2.1%) | 6/95 (6.3%) | |||
| Skin disorder | 1/19 (5.3%) | 0/95 (0%) | 0/95 (0%) | |||
| Skin lesion | 1/19 (5.3%) | 2/95 (2.1%) | 4/95 (4.2%) | |||
| Vitiligo | 1/19 (5.3%) | 0/95 (0%) | 4/95 (4.2%) | |||
| Vascular disorders | ||||||
| Embolism | 1/19 (5.3%) | 0/95 (0%) | 0/95 (0%) | |||
| Hot flush | 0/19 (0%) | 1/95 (1.1%) | 6/95 (6.3%) | |||
| Hypertension | 1/19 (5.3%) | 3/95 (3.2%) | 4/95 (4.2%) | |||
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.
Results Point of Contact
| Name/Title | Study Director |
|---|---|
| Organization | Amgen Inc. |
| Phone | 866-572-6436 |
| medinfo@amgen.com |
Responsible Party:
Amgen
ClinicalTrials.gov Identifier:
NCT01740297
Other Study ID Numbers:
- 20110264
- 2012-000307-32
First Posted:
Dec 4, 2012
Last Update Posted:
Mar 10, 2022
Last Verified:
Mar 1, 2022