Ipilimumab With or Without Talimogene Laherparepvec in Unresected Melanoma
Describes the nature of a clinical study. Types include:
- Observational study — observes people and measures outcomes without affecting results.
- Interventional study (clinical trial) — studies new tests, treatments, drugs, surgical procedures or devices.
- Medical records research — uses historical information collected from medical records of large groups of people to study how diseases progress and which treatments and surgeries work best.
During the early phases (phases 1 and 2), researchers assess safety, side effects, optimal dosages and risks/benefits. In the later phase (phase 3), researchers study whether the treatment works better than the current standard therapy. They also compare the safety of the new treatment with that of current treatments. Phase 3 trials include large numbers of people to make sure that the result is valid. There are also less common very early (phase 0) and later (phase 4) phases. Phase 0 trials are small trials that help researchers decide if a new agent should be tested in a phase 1 trial. Phase 4 trials look at long-term safety and effectiveness, after a new treatment has been approved and is on the market.
- Jacksonville, Florida: 18-001802
NCT ID: NCT01740297
Sponsor Protocol Number: 20110264
About this study
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.
Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. If you need assistance understanding the eligibility criteria, please contact the study team.See eligibility 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
- 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
Participating Mayo Clinic locations
Study statuses change often. Please contact us for help.
|Mayo Clinic Location
Mayo Clinic principal investigator
Richard Joseph, M.D.
Closed for enrollment
Jason J. Chesney, Igor I. Puzanov, Frances F. Collichio, Parminder P. Singh, Mohammed M MM. Milhem, John J. Glaspy, Omid O. Hamid, Merrick M. Ross, Philip P. Friedlander, Claus C. Garbe, Theodore F TF. Logan, Axel A. Hauschild, Celeste C. Lebbé, Lisa L. Chen, Jenny J JJ. Kim, Jennifer J. Gansert, Robert H I RHI. Andtbacka, Howard L HL. Kaufman.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
2018 Jun; (36):1658-1667 17
Purpose We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. Methods Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, ≤ 4 mL × 10 plaque-forming units/mL; after 3 weeks, ≤ 4 mL × 10 plaque-forming units/mL every 2 weeks). Ipilimumab (3 mg/kg every 3 weeks; up to four doses) began week 1 in the ipilimumab alone arm and week 6 in the combination arm. The primary end point was objective response rate evaluated by investigators per immune-related response criteria. Results One hundred ninety-eight patients were randomly assigned to talimogene laherparepvec plus ipilimumab (n = 98), or ipilimumab alone (n = 100). Thirty-eight patients (39%) in the combination arm and 18 patients (18%) in the ipilimumab arm had an objective response (odds ratio, 2.9; 95% CI, 1.5 to 5.5; P = .002). Responses were not limited to injected lesions; visceral lesion decreases were observed in 52% of patients in the combination arm and 23% of patients in the ipilimumab arm. Frequently occurring adverse events (AEs) included fatigue (combination, 59%; ipilimumab alone, 42%), chills (combination, 53%; ipilimumab alone, 3%), and diarrhea (combination, 42%; ipilimumab alone, 35%). Incidence of grade ≥ 3 AEs was 45% and 35%, respectively. Three patients in the combination arm had fatal AEs; none were treatment related. Conclusion The study met its primary end point; the objective response rate was significantly higher with talimogene laherparepvec plus ipilimumab versus ipilimumab alone. These data indicate that the combination has greater antitumor activity without additional safety concerns versus ipilimumab.
Reinhard R. Dummer, Christoph C. Hoeller, Isabella Pezzani IP. Gruter, Olivier O. Michielin.
Cancer immunology, immunotherapy : CII
2017 Jun; (66):683-695 6
Talimogene laherparepvec is a first-in-class intralesional oncolytic immunotherapy. In a recent Phase III trial (OPTiM), talimogene laherparepvec significantly improved durable response rate compared with subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF). Overall response rate was also higher in the talimogene laherparepvec arm, and the greatest efficacy was demonstrated in patients with earlier-stage (IIIB, IIIC, or IVM1a) melanoma. Talimogene laherparepvec was well tolerated, with the majority (89%) of adverse events being grade 1 or 2. Preclinical studies have shown that talimogene laherparepvec exerts antitumor activity by selectively replicating within and destroying cancer cells, and through the release of tumor-associated antigens and expression of GM-CSF, which facilitates a wider antitumor immune response. It is hypothesized that combining talimogene laherparepvec with a systemic immunotherapy may, by bringing together complementary mechanisms of action, further enhance the efficacy of both agents. Indeed, talimogene laherparepvec is currently being assessed in combination with immune checkpoint inhibitors, including ipilimumab and pembrolizumab, in trials for melanoma and other solid tumors. Early results in melanoma indicate that the combination of talimogene laherparepvec with ipilimumab or pembrolizumab has greater efficacy than either therapy alone, without additional safety concerns above those expected for each monotherapy. In this review, we discuss the latest results from trials assessing talimogene laherparepvec in combination with other immunotherapies, provide an overview of ongoing and upcoming combination trials, and suggest future directions for talimogene laherparepvec in combination therapy for solid tumors.
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