Phase 2 Study of Talimogene Laherparepvec in Combination With Pembrolizumab in Subjects With Unresectable/Metastatic Stage IIIB-IVM1d Melanoma Who Have Progressed on Prior Anti PD-1 Based Therapy
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- Amgen
- 入组人数
- 72
- 试验地点
- 46
- 主要终点
- Objective Response Rate (ORR) Per Modified RECIST v1.1
研究概览
简要总结
This is a phase 2, open-label, single-arm, multicenter clinical trial designed to evaluate the efficacy and safety of talimogene laherparepvec in combination with pembrolizumab following disease progression on prior anti-programmed cell death protein (anti-PD-1) therapy in unresectable/metastatic melanoma (stage IIIB-IVM1d) or prior anti-PD-1 therapy in the adjuvant setting. Subjects will be treated with talimogene laherparepvec and pembrolizumab until confirmed complete response, disappearance of all injectable lesions, documented confirmed disease progression per modified immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST), intolerance of study treatment, or 102 weeks from the first dose of talimogene laherparepvec and/or pembrolizumab, whichever occurs first.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 18 years with histologically confirmed diagnosis of stage IIIB to IVM1d melanoma and for whom surgery is not recommended. Subjects with stage IVM1d disease may be enrolled with up to 3 cerebral metastases, provided that all lesions have been adequately treated with stereotactic radiation therapy, craniotomy, or gamma knife therapy, with no evidence of progression and not requiring steroids for at least 2 months prior to enrollment.
- •Subjects must have measurable disease and be a candidate for intralesional therapy administration into cutaneous, subcutaneous, or nodal lesions.
- •Subjects must have had prior treatment (for at least 2 to 3 consecutive cycles within an 8 week period) with a PD-1 inhibitor and have confirmed disease progression (as defined by RECIST v1.1 criteria). The anti-PD-1 therapy must be the immediate prior line of therapy before enrollment and subjects with disease progression on more than 1 line of anti-PD-1 therapy are not eligible.
- •ECOG performance status of 0 or
- •Adequate hematologic, renal, hepatic, and coagulation function.
排除标准
- •Subjects considered by the investigator to have rapid clinical progression due to melanoma
- •Subjects with prior treatment and disease progression on more than 1 line of anti-PD-1 therapy
- •Stage IVM1d subjects must not have greater than 3 cerebral melanoma metastases, or clinically active cerebral melanoma metastases requiring therapy, and/or carcinomatous meningitis regardless of clinical stability.
- •Primary uveal or mucosal melanoma, history or evidence of melanoma associated with immunodeficiency states or history of other malignancy within the past 3 years.
- •Subjects must not have history or evidence of symptomatic autoimmune glomerulonephritis, vasculitis, or other symptomatic autoimmune disease, or active autoimmune disease or syndrome requiring systemic treatment in the past 2 years (ie, with use of disease modifying agents, steroids or immunosuppressive agents) except vitiligo or resolved childhood asthma/atopy, or evidence of clinically significant immunosuppression.
- •Subjects may not have been previously treated with talimogene laherparepvec or any other oncolytic virus.
- •Subjects must not have active herpetic skin lesions or prior complications of herpetic infection and must not require intermittent or chronic treatment with an antiherpetic drug (eg, acyclovir), other than intermittent topical use.
研究组 & 干预措施
Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance
Includes participants who received anti-PD1 therapy in the locally recurrent/metastatic setting and experienced a best overall response of disease progression or stable disease prior to confirmed disease progression.
Participants will receive talimogene laherparepvec at an initial dose of up to 4.0 mL of 10^6 plaque-forming units (PFU)/mL on Day 1. Subsequent doses of up to 4.0 mL of 10^8 PFU/mL will be administered every 3 weeks for up to 35 cycles in total. Participants will also receive pembrolizumab at a dose of 200 mg every 3 weeks for up to 35 cycles.
干预措施: Talimogene laherparepvec (Drug)
Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance
Includes participants who received anti-PD1 therapy in the locally recurrent/metastatic setting and experienced a best overall response of disease progression or stable disease prior to confirmed disease progression.
Participants will receive talimogene laherparepvec at an initial dose of up to 4.0 mL of 10^6 plaque-forming units (PFU)/mL on Day 1. Subsequent doses of up to 4.0 mL of 10^8 PFU/mL will be administered every 3 weeks for up to 35 cycles in total. Participants will also receive pembrolizumab at a dose of 200 mg every 3 weeks for up to 35 cycles.
干预措施: Pembrolizumab (Drug)
Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance
Includes participants who received anti-PD-1 therapy in the locally recurrent/metastatic setting and experienced confirmed disease progression following a complete or partial response on anti-PD-1 therapy.
Participants will receive talimogene laherparepvec at an initial dose of up to 4.0 mL of 10^6 plaque-forming units (PFU)/mL on Day 1. Subsequent doses of up to 4.0 mL of 10^8 PFU/mL will be administered every 3 weeks for up to 35 cycles in total. Participants will also receive pembrolizumab at a dose of 200 mg every 3 weeks for up to 35 cycles.
干预措施: Talimogene laherparepvec (Drug)
Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance
Includes participants who received anti-PD-1 therapy in the locally recurrent/metastatic setting and experienced confirmed disease progression following a complete or partial response on anti-PD-1 therapy.
Participants will receive talimogene laherparepvec at an initial dose of up to 4.0 mL of 10^6 plaque-forming units (PFU)/mL on Day 1. Subsequent doses of up to 4.0 mL of 10^8 PFU/mL will be administered every 3 weeks for up to 35 cycles in total. Participants will also receive pembrolizumab at a dose of 200 mg every 3 weeks for up to 35 cycles.
干预措施: Pembrolizumab (Drug)
Cohort 3 - Adjuvant Setting -Disease Free Interval < 6 months
Includes participants who received anti-PD-1 therapy in the adjuvant setting and experienced confirmed disease progression following a disease-free interval of < 6 months after starting the adjuvant anti-PD-1 therapy.
Participants will receive talimogene laherparepvec at an initial dose of up to 4.0 mL of 10^6 plaque-forming units (PFU)/mL on Day 1. Subsequent doses of up to 4.0 mL of 10^8 PFU/mL will be administered every 3 weeks for up to 35 cycles in total. Participants will also receive pembrolizumab at a dose of 200 mg every 3 weeks for up to 35 cycles.
干预措施: Talimogene laherparepvec (Drug)
Cohort 3 - Adjuvant Setting -Disease Free Interval < 6 months
Includes participants who received anti-PD-1 therapy in the adjuvant setting and experienced confirmed disease progression following a disease-free interval of < 6 months after starting the adjuvant anti-PD-1 therapy.
Participants will receive talimogene laherparepvec at an initial dose of up to 4.0 mL of 10^6 plaque-forming units (PFU)/mL on Day 1. Subsequent doses of up to 4.0 mL of 10^8 PFU/mL will be administered every 3 weeks for up to 35 cycles in total. Participants will also receive pembrolizumab at a dose of 200 mg every 3 weeks for up to 35 cycles.
干预措施: Pembrolizumab (Drug)
Cohort 4 - Adjuvant Setting -Disease Free Interval ≥ 6 months
Includes participants who received anti PD-1 therapy in the adjuvant setting and experienced confirmed disease progression following a disease-free interval of ≥ 6 months after starting the adjuvant PD-1 inhibitor.
Participants will receive talimogene laherparepvec at an initial dose of up to 4.0 mL of 10^6 plaque-forming units (PFU)/mL on Day 1. Subsequent doses of up to 4.0 mL of 10^8 PFU/mL will be administered every 3 weeks for up to 35 cycles in total. Participants will also receive pembrolizumab at a dose of 200 mg every 3 weeks for up to 35 cycles.
干预措施: Talimogene laherparepvec (Drug)
Cohort 4 - Adjuvant Setting -Disease Free Interval ≥ 6 months
Includes participants who received anti PD-1 therapy in the adjuvant setting and experienced confirmed disease progression following a disease-free interval of ≥ 6 months after starting the adjuvant PD-1 inhibitor.
Participants will receive talimogene laherparepvec at an initial dose of up to 4.0 mL of 10^6 plaque-forming units (PFU)/mL on Day 1. Subsequent doses of up to 4.0 mL of 10^8 PFU/mL will be administered every 3 weeks for up to 35 cycles in total. Participants will also receive pembrolizumab at a dose of 200 mg every 3 weeks for up to 35 cycles.
干预措施: Pembrolizumab (Drug)
结局指标
主要结局
Objective Response Rate (ORR) Per Modified RECIST v1.1
时间窗: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
ORR was defined as the incidence of a best overall response (BOR) of complete response (CR) or partial response (PR) per modified RECIST v1.1: * CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to \< 10 mm. All lymph nodes must have been non-pathological in size (\< 10mm short axis). * PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. * Non-CR/Non-progressive disease (PD): Persistence of 1 or more non-target lesion(s).
次要结局
- Complete Response Rate (CRR) Per Modified RECIST v1.1(Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months)
- Complete Response Rate (iCRR) Per Modified Immune-related Response Criteria (irRC) RECIST v1.1(Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months)
- BOR Per Modified RECIST v1.1(Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months)
- Best Overall Response (iBOR) Per Modified irRC-RECIST(Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months)
- Durable Response Rate (DRR) Per Modified RECIST v1.1(Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months)
- Durable Response Rate (iDRR) Per Modified irRC-RECIST(Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months)
- DOR Per Modified RECIST v1.1(Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months)
- iDOR Per Modified irRC-RECIST(Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months)
- Disease Control Rate (DCR) Per Modified RECIST v1.1(Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months)
- Disease Control Rate (iDCR) Per Modified irRC-RECIST(Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months)
- Objective Response Rate (iORR) Per Modified irRC-RECIST(Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months)
- Progression Free Survival (PFS) Per Modified RECIST v1.1(Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months)
- Progression Free Survival (iPFS) Per Modified irRC-RECIST(Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months)
- Overall Survival (OS)(Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months)
- Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)(Serious TEAEs were collected up to 90 days post-last dose of treatment. Non-serious TEAEs were collected up to 30 days post-last dose of treatment. The maximum duration of treatment exposure was 105.9 weeks.)
- Time to First Subsequent Anti-cancer Therapy(Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months)