A Phase 3, Multicenter, Open-label Trial of Talimogene Laherparepvec in Combination With Pembrolizumab (MK-3475), as compared with Pembrolizumab with placebo, for Treatment of Unresected, Stage IIIB to IVM1c Melanoma.
The Phase 3 study is a blinded, multicenter, randomized trial to evaluate the efficacy, as assessed by PFS and OS of treatment with talimogene laherparepvec in combination with pembrolizumab, as compared to pembrolizumab with placebo, in subjects with unresected, stage IIIB to IVM1c melanoma. Approximately 660 subjects will be randomized 1:1 to receive the following:
Arm 1: talimogene laherparepvec plus pembrolizumab
Arm 2: pembrolizumab plus placebo. Randomization will be stratified by stage of disease: less advanced stages (IIIB, IIIC, and IVM1a) versus more advanced stages (IVM1b and IVM1c) and by prior BRAF inhibitor therapy: no prior BRAF inhibitor versus BRAF inhibitor with or without MEK inhibitor. Subjects will be treated with talimogene laherparepvec in combination with pembrolizumab (arm 1) or pembrolizumab with placebo (arm 2) until 24 months from the date of the first dose of pembrolizumab or end of treatment for other reasons as described in full protocol, whichever happens first.
For more information: https://clinicaltrials.gov/ct2/show/NCT02626000
Key Inclusion Criteria:
- Subject has provided informed consent prior to initiation of any study-specific activities/procedures.
- Male or female age ≥ 18 years at the time of informed consent Histologically confirmed diagnosis of melanoma
- Disease stage: Subject with stage IIIB, IIIC, IVM1a, IVM1b, or IVM1c melanoma for whom surgery is not recommended
- Treatment naïve : Must not have received any prior systemic anticancer treatment consisting of chemotherapy, immunotherapy, or targeted therapy for unresected stage IIIB to IVM1c melanoma Note: Subjects who received prior adjuvant therapy for melanoma will not be excluded (including, but not limited to radiotherapy, interferon, limb infusion/perfusion, or use of investigational agents in the adjuvant setting). Amendment 2 allows for patients who have received adjuvant ipilimumab 28+ days prior to beginning therapy to be enrolled. No prior pembrolizumab, other anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, other CTLA-4 inhibitor, talimogene laherparepvec, tumor vaccine, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways is allowed, even if given in the adjuvant setting.
- Prior therapy for melanoma inclusion requirement du: BRAFV600 wild-type: Subjects with BRAF V600 wild-type tumors must not have received any prior systemic anticancer treatment consisting of chemotherapy, immunotherapy, or targeted therapy for unresected stage IIIB to IVM1c melanoma.
- BRAFV600 mutation: Subjects with BRAFV600 mutated tumors who have received prior BRAF inhibitor therapy either alone or in combination with MEK inhibitor as their only prior systemic therapy are eligible for this study. However, the subject must have ended BRAF inhibitor therapy either alone or in combination with MEK inhibitor at least 14 days prior to enrollment. At the discretion of the investigator, subjects with BRAFV600 mutant melanoma or those subjects whose BRAF mutation status is unknown at the time of randomization who have not received a BRAF inhibitor are also eligible for the phase 3 of this study as their only prior treatment if they meet the following criteria: LDH < upper limit normal (ULN), No clinically significant tumor related symptoms in the judgment of the investigator , absence of rapidly progressing metastatic melanoma in the judgment of the investigator ,
- Note: Subjects who received prior adjuvant therapy for melanoma will not be excluded (including, but not limited to radiotherapy, interferon, limb infusion/perfusion, or use of investigational agents in the adjuvant setting). However, the subject must have ended therapy at least 3 months prior to enrollment. No prior pembrolizumab, other anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, other CTLA-4 inhibitor, talimogene laherparepvec, tumor vaccine, or any other oncolytic viruses or drugs specifically targeting T-cell co-stimulation or checkpoint pathways are allowed, even if given in the adjuvant setting.
- Subjects must have measurable disease and be a candidate for intralesional therapy administration into cutaneous, subcutaneous, or nodal lesions.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Adequate hematologic, hepatic, renal, and coagulation function.
- Female subjects of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to enrollment. If urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
- Tumor sample during phase 3: Subject has a tumor sample (archival sample obtained within 3 months prior to day 1 and no systemic therapy given 3 months prior biopsy or newly obtained biopsy) that is submitted for PD-L1 assessment prior to randomization. Subject must submit the tumor sample during screening for PD-L1 expression testing at a central laboratory. Subjects will be eligible to participate regardless of the level of PD-L1 expression. Subjects with an unevaluable archival sample may obtain a new biopsy and subjects with an unevaluable newly obtained biopsy may undergo re-biopsy at the discretion of the investigator.
Key Exclusion Criteria:
- Subjects must not have clinically active cerebral melanoma metastases. Subjects with up to 3 cerebral metastases 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.
- Primary uveal or mucosal melanoma
- History or evidence of melanoma associated with immunodeficiency states (eg, hereditary immune deficiency, organ transplant, or leukemia)
- History of other malignancy within the past 3 years with the following exceptions:
- Malignancy treated with curative intent and with no known active disease present and has not received chemotherapy for 3 years before enrollment and felt to be at low risk for recurrence by the treating physician.
- Adequately treated non-melanoma skin cancer without evidence of disease at the time of enrollment.
- Adequately treated cervical carcinoma in situ without evidence of disease at the time of enrollment .
- Adequately treated breast ductal carcinoma in situ without evidence of disease at the time of enrollment .
- Prostatic intraepithelial neoplasia without evidence of prostate cancer at the time of enrollment
- Adequately treated superficial or in-situ carcinoma of the bladder without evidence of disease at the time of enrollment
- Prior therapy with talimogene laherparepvec or any other oncolytic viruses
- Prior therapy with tumor vaccine
- Prior therapy with pembrolizumab, other anti-PD-1, anti-PD-L1, anti-CD137, or anti-CTLA-4 antibody (excluding ipilimumab)
- Prior monoclonal antibody therapy within 28 days prior to enrollment or who has not recovered (ie, ? grade 1 or at baseline) from adverse events due to agents administered more than 28 days earlier
- Currently receiving treatment in another investigational device or drug study, or less than 28 days since ending treatment on another investigational device or drug study
- Expected to require other cancer therapy while on study with the exception of local radiation treatment to the site of bone and other metastasis for palliative pain management
- Other investigational procedures while participating in this study are excluded.
- History or evidence of symptomatic autoimmune pneumonitis, glomerulonephritis, vasculitis, or other symptomatic autoimmune disease, or active autoimmune disease or syndrome that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs) except vitiligo or resolved childhood asthma/atopy. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc) is not considered a form of systemic treatment.
- Evidence of clinically significant immunosuppression such as the following:
- diagnosis of immunodeficiency
- concurrent opportunistic infection
- receiving systemic immunosuppressive therapy (> 2 weeks) or within 7 days prior to the first dose of study treatment, including oral steroid doses > 10 mg/day of prednisone or equivalent except for management of adverse events and central nervous system (CNS) metastases during the course of the study. Subjects that require intermittent use of bronchodilators or local steroid injection will not be excluded from the study.
- Active herpetic skin lesions or prior complications of herpetic infection (eg, herpetic keratitis or encephalitis)
- Require intermittent or chronic 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
- Received live vaccine within 28 days prior to enrollment
- Female subject is pregnant or breast-feeding, or planning to become pregnant during study treatment and through 3 months after the last dose of talimogene laherparepvec or 4 months after the last dose of pembrolizumab, whichever is later
- Female subject of childbearing potential who is unwilling to use acceptable method(s) of effective contraception during study treatment and through 3 months after the last dose of talimogene laherparepvec or 4 months after the last dose of pembrolizumab, whichever is later. (Note: Women not of childbearing potential are defined as: Any female who is post-menopausal [age > 55 years with cessation of menses for 12 or more months or less than 55 years but not spontaneous menses for at least 2 years or less than 55 years and spontaneous menses within the past 1 year, but currently amenorrheic (eg, spontaneous or secondary to hysterectomy), and with postmenopausal gonadotropin levels (luteinizing hormone and follicle-stimulating hormone levels > 40 IU/L) or postmenopausal estradiol levels (< 5 ng/dL) or according to the definition of "postmenopausal range" for the laboratory involved] or who have had a hysterectomy, bilateral salpingectomy, or bilateral oophorectomy). Note: Acceptable methods of effective contraception are defined in the informed consent form. Where required by local laws and regulations, additional country-specific contraception requirements may be outlined in a country-specific protocol supplement at the end of the Appendix Section of protocol. Or Male subject who is unwilling to use acceptable method of effective contraception during pembrolizumab treatment and through 4 months after the last dose of pembrolizumab. Note: Acceptable methods of effective contraception are defined in the informed consent form. Additional country-specific contraception requirements may be defined in a country-specific protocol supplement at the end of the Appendix Section of protocol as required by local laws and regulations.
- Subject has known sensitivity to any of the products or components to be administered during dosing
- Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the subject and investigator’s knowledge
- History or evidence of psychiatric, substance abuse, or any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion
- Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or child) who is investigational site or sponsor staff directly involved in the this trial, unless prospective institutional review board (IRB)/independent ethics committee (IEC) approval (by chair or designee) is given allowing exception to this criterion for a specific subject
- Sexually active subject who is unwilling to use a barrier method (male or female condom) to avoid potential viral transmission during sexual contact during and within 30 days after treatment with talimogene laherparepvec.
- Subject who is unwilling to minimize exposure with his/her blood or other body fluids to individuals who are at higher risks for HSV-1 induced complications (immunosuppressed individuals, HIV-positive individuals, pregnant women, or children under the age of 1 year) during talimogene laherparepvec treatment and through 28 days after the last dose of talimogene laherparepvec.Type your paragraph here.