Ipilimumab With or Without Talimogene Laherparepvec in Unresected Melanoma

Phase 1

Completed

Conditions: Melanoma

Interventions: Drug: Talimogene laherparepvec
Drug: Ipilimumab

Registration Number: NCT01740297

Lead Sponsor: Amgen

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.

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).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 217

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Phase 1b: Talimogene Laherparepvec + Ipilimumab	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).
Phase 2: Ipilimumab	Ipilimumab	Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1.
Phase 2: Talimogene Laherparepvec + Ipilimumab	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).
Phase 1b: Talimogene Laherparepvec + Ipilimumab	Talimogene laherparepvec	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).
Phase 2: Talimogene Laherparepvec + Ipilimumab	Talimogene laherparepvec	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).

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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 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: 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).