Ipilimumab With or Without Talimogene Laherparepvec in Unresected Melanoma

NCT01740297 | Completed Phase 1 Results

• 2 other identifiers: 201102642012-000307-32
• Study Type: interventional
• Target: 217
• Locations: 3 countries
• Sites: 40

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.

Conditions

Melanoma

Keywords

melanoma; talimogene laherparepvec; ipilimumab; immunotherapy

Outcome Measures

Primary Outcomes (2)

• Phase 1b: Number of Participants With Dose-limiting Toxicities

  A DLT was defined as any toxicity related to study drug which met any of the following criteria based on Common Terminology Criteria for Adverse Events version 3.0: * treatment-related non-laboratory adverse events (AE) ≥ grade 4 * ≥ grade 4 immune-mediated dermatitis * ≥ grade 4 immune-mediated endocrinopathy (except autoimmune thyroiditis) * ≥ grade 3 immune-mediated enterocolitis * ≥ grade 3 immune-mediated hepatitis (except grade 3 that resolved to grade 1 or baseline within 28 days of onset) * ≥ grade 3 immune-mediated neuropathy * ≥ grade 3 other immune-mediated AEs including hemolytic anemia, angiopathy, myocarditis, pericarditis, temporal arteritis, or vasculitis, autoimmune thyroiditis (except grade 3 that resolved to grade 1 or baseline within 28 days of onset), blepharitis, conjunctivitis, episcleritis, iritis, scleritis, or uveitis, pancreatitis, meningitis, arthritis or polymyalgia rheumatic, nephritis, pneumonitis, psoriasis or leukocytoclastic vasculitis.

  The DLT evaluation period was 6 weeks from the initial administration of ipilimumab (week 6 to 12).

• Phase 2: Objective Response Rate

  Objective response rate is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) according to the modified immune-related response criteria (irRC) assessed by the investigator. Tumors were examined clinically and by computed tomography (CT) or magnetic resonance imaging (MRI). CR: Complete disappearance of all lesions and no new lesions; Any pathological lymph nodes reduced in short axis to \<10 mm. PR: Decrease in tumor burden ≥ 50% relative to baseline. Response must have been confirmed by a repeat, consecutive assessment ≥ 4 weeks from the date first documented. Participants who did not have any follow-up tumor assessments were regarded as non-responders.

  Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively.

Secondary Outcomes (14)

• Phase 1b: Objective Response Rate

  Tumor response was assesed every 12 weeks until disease progression; median follow-up time at the primary analysis was 148.4 weeks.

• Phase 2: Best Overall Response

  Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively.

• Phase 2: Disease Control Rate

  Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively.

• Phase 2: Durable Response Rate

  Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively.

• Phase 2: Time to Response

  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.

Study Arms (3)

Phase 1b: Talimogene Laherparepvec + Ipilimumab

EXPERIMENTAL

Participants received talimogene laherparepvec at an initial dose of 10⁶ plaque-forming units (PFU)/mL injected into 1 or more skin, nodal, or subcutaneous tumors. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until complete response (CR), all injectable tumors had disappeared, confirmed disease progression per the modified immune-related response criteria (irRC), or intolerance of study treatment, whichever occurred first. Participants also received 3 mg/kg ipilimumab administered intravenously every 3 weeks for a total of 4 infusions starting at the time of the third dose of talimogene laherparepvec (week 6).

Drug: Talimogene laherparepvec; Drug: Ipilimumab

Phase 2: Ipilimumab

ACTIVE COMPARATOR

Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1.

Drug: Ipilimumab

Phase 2: Talimogene Laherparepvec + Ipilimumab

EXPERIMENTAL

Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until CR, all injectable tumors had disappeared, confirmed disease progression per the modified irRC, or intolerance of study treatment, whichever occurred first. Participants also received 3 mg/kg ipilimumab intravenously every 3 weeks for a total of 4 infusions starting at the time of the third dose of talimogene laherparepvec (week 6).

Drug: Talimogene laherparepvec; Drug: Ipilimumab

Interventions

Talimogene laherparepvec DRUG

Talimogene laherparepvec administered by intratumoral injection on Day 1 of Week 1, Day 1 of Week 4, then every two weeks thereafter.

Also known as: IMLYGIC®, OncoVEX^GM-CSF, T-VEC

Phase 1b: Talimogene Laherparepvec + Ipilimumab; Phase 2: Talimogene Laherparepvec + Ipilimumab

Ipilimumab DRUG

Ipilimumab administered intravenously every 3 weeks for a total of 4 infusions.

Also known as: Yervoy®

Phase 1b: Talimogene Laherparepvec + Ipilimumab; Phase 2: Ipilimumab; Phase 2: Talimogene Laherparepvec + Ipilimumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Amgen: lead

Study Sites (40)

Research Site

Tucson, Arizona, 85724, United States

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Beverly Hills, California, 90211, United States

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Los Angeles, California, 90025, United States

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Los Angeles, California, 90089-2211, United States

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Los Angeles, California, 90095, United States

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San Francisco, California, 94115, United States

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Santa Rosa, California, 95403, United States

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Aurora, Colorado, 80045, United States

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Jacksonville, Florida, 32207, United States

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Jacksonville, Florida, 32224, United States

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Lakeland, Florida, 33805, United States

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Miami, Florida, 33140, United States

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Chicago, Illinois, 60612, United States

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Indianapolis, Indiana, 46202, United States

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Indianapolis, Indiana, 46260, United States

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Iowa City, Iowa, 52242, United States

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Louisville, Kentucky, 40202, United States

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Minneapolis, Minnesota, 55407, United States

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St Louis, Missouri, 63110, United States

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Morristown, New Jersey, 07962, United States

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New Brunswick, New Jersey, 08903, United States

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New York, New York, 10029, United States

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New York, New York, 10032, United States

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Chapel Hill, North Carolina, 27599, United States

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Canton, Ohio, 44718, United States

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Cincinnati, Ohio, 45267, United States

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Charleston, South Carolina, 29425, United States

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Nashville, Tennessee, 37232, United States

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Houston, Texas, 77030, United States

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Salt Lake City, Utah, 84112, United States

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Richmond, Virginia, 23298-0037, United States

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Milwaukee, Wisconsin, 53226, United States

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Bordeaux, 33075, France

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Grenoble, 38043, France

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Lille, 59037, France

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Nantes, 44093, France

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Paris, 75010, France

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Göttingen, 37075, Germany

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Kiel, 24105, Germany

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Tübingen, 72076, Germany

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Related Publications (5)

• Chesney J, Puzanov I, Collichio F, Singh P, Milhem MM, Glaspy J, Hamid O, Ross M, Friedlander P, Garbe C, Logan TF, Hauschild A, Lebbe C, Chen L, Kim JJ, Gansert J, Andtbacka RHI, Kaufman HL. Randomized, Open-Label Phase II Study Evaluating the Efficacy and Safety of Talimogene Laherparepvec in Combination With Ipilimumab Versus Ipilimumab Alone in Patients With Advanced, Unresectable Melanoma. J Clin Oncol. 2018 Jun 10;36(17):1658-1667. doi: 10.1200/JCO.2017.73.7379. Epub 2017 Oct 5.

  PMID: 28981385 BACKGROUND

• 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.

  PMID: 27298410 BACKGROUND

• 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.

  PMID: 31353364 BACKGROUND

• 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.

  PMID: 28238174 BACKGROUND

• Chesney JA, Puzanov I, Collichio FA, Singh P, Milhem MM, Glaspy J, Hamid O, Ross M, Friedlander P, Garbe C, Logan T, Hauschild A, Lebbe C, Joshi H, Snyder W, Mehnert JM. Talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone for advanced melanoma: 5-year final analysis of a multicenter, randomized, open-label, phase II trial. J Immunother Cancer. 2023 May;11(5):e006270. doi: 10.1136/jitc-2022-006270.

  PMID: 37142291 BACKGROUND

Related Links

• AmgenTrials clinical trials website

MeSH Terms

Conditions

Melanoma

Interventions

talimogene laherparepvec; Ipilimumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Study Director
• Organization: Amgen Inc.

medinfo@amgen.com

866-572-6436

Study Officials

• MD

  Amgen

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: November 14, 2012
• First Posted: December 4, 2012
• Study Start: February 7, 2013
• Primary Completion: August 23, 2016
• Study Completion: March 9, 2021
• Last Updated: May 14, 2024
• Results First Posted: October 9, 2017

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
• Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.

Locations

DE (3); US (32); FR (5)