A Study to Evaluate the Safety and Efficacy of the CD40 Agonistic Antibody APX005M Administered in Combination With Nivolumab in Subjects With Non-small Cell Lung Cancer and Subjects With Metastatic Melanoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 140
- 试验地点
- 23
- 主要终点
- Number of Participants Experiencing Dose-limiting Toxicities (DLTs)
研究概览
简要总结
This study is a Phase 1-2 open-label dose escalation study of the immuno-activating monoclonal antibody APX005M administered in combination with nivolumab to adult subjects with non-small cell lung cancer or metastatic melanoma. The Phase 1 portion is intended to establish the maximum tolerated dose and the recommended phase 2 dose of APX005M when administered in combination with nivolumab. The Phase 2 portion of the study will evaluate safety and efficacy of the combination.
详细描述
APX005M-002 is an open-label Phase 1-2 study and comprises a dose-escalation portion (Phase 1) followed by a Phase 2 tumor specific portion.
Eligible subjects with non-small cell lung cancer or metastatic melanoma will receive intravenous APX005M in combination with nivolumab until disease progression, unacceptable toxicity or death, whichever occurs first.
Study objectives include:
- Determine the maximum tolerated dose and the recommended phase 2 dose of APX005M when given in combination with nivolumab
- Evaluate safety of the APX005M and nivolumab combination
- Evaluate the objective response rate, duration of response and median PFS by RECIST 1.1 in subjects with non-small cell lung cancer or metastatic melanoma receiving APX005M in combination with nivolumab
- Determine the PK of APX005M
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically or cytologically confirmed, immunotherapy naïve or PD-1/PD-L1 pre-treated, metastatic or locally advanced non-small cell lung cancer not amenable to curative treatment. Subjects may be treatment naive or could have received one prior platinum based chemotherapy for non-small cell lung cancer and subjects with a documented activating mutation (e.g., EGFR, ALK, ROS) must also have received the appropriate therapy and progressed
- •Histologically or cytologically confirmed unresectable or metastatic melanoma that progressed during treatment with an anti-PD-1/PD-L1 therapy and had confirmation of PD>=4 weeks later. Subjects with BRAF activating mutation could have also received a BRAF inhibitor and/or MEK inhibitor regimen prior to anti-PD-1/PD-L1 therapy.
- •Measurable disease by RECIST 1.1
- •ECOG performance status of 0 or 1
- •Adequate bone marrow, liver and kidney function
- •Negative pregnancy test for women of child bearing potential
- •Agreement to use effective methods of contraception per the protocol requirements
排除标准
- •Previous exposure to any immunomodulatory agents (e.g., anti- CD40, anti-PD-1/PD-L1, anti-CTLA-4, IDO inhibitors) except PD-1/PD-L1 targeting agents in the subsets of patients that must have previous treatment with anti-PD-1/PD-L1 therapy
- •Second malignancy (solid or hematologic) within the past 3 years except locally curable cancers that have been apparently cured
- •Active, known, clinically serious infections within the 14 days prior to first dose of investigational product
- •Use of systemic corticosteroids or other systemic immunosuppressive drugs
- •Active, known or suspected autoimmune disease
- •History of (non-infectious) pneumonitis that required corticosteroids or current pneumonitis
- •History of interstitial lung disease
- •History of life-threatening toxicity related to prior anti-PD-1/PD-L1 treatment for subjects with metastatic melanoma or NSCLC.
研究组 & 干预措施
Phase 1b escalation 0.03 mg/kg
Non-small cell lung cancer (NSCLC) or metastatic melanoma
APX005M 0.03 mg/kg and nivolumab 360 mg every 3 weeks
干预措施: APX005M (Drug)
Phase 1b escalation 0.03 mg/kg
Non-small cell lung cancer (NSCLC) or metastatic melanoma
APX005M 0.03 mg/kg and nivolumab 360 mg every 3 weeks
干预措施: Nivolumab (Drug)
Phase 1b escalation 0.1 mg/kg
Non-small cell lung cancer (NSCLC) or metastatic melanoma
APX005M 0.1 mg/kg and nivolumab 360 mg every 3 weeks
干预措施: APX005M (Drug)
Phase 1b escalation 0.1 mg/kg
Non-small cell lung cancer (NSCLC) or metastatic melanoma
APX005M 0.1 mg/kg and nivolumab 360 mg every 3 weeks
干预措施: Nivolumab (Drug)
Phase 1b escalation 0.3 mg/kg
Non-small cell lung cancer (NSCLC) or metastatic melanoma
APX005M 0.3 mg/kg and nivolumab 360 mg every 3 weeks
干预措施: APX005M (Drug)
Phase 1b escalation 0.3 mg/kg
Non-small cell lung cancer (NSCLC) or metastatic melanoma
APX005M 0.3 mg/kg and nivolumab 360 mg every 3 weeks
干预措施: Nivolumab (Drug)
Phase 2 expansion Cohort 1
Immunotherapy naïve, metastatic or locally advanced NSCLC
APX005M 0.3 mg/kg and nivolumab 360 mg every 3 weeks
干预措施: APX005M (Drug)
Phase 2 expansion Cohort 1
Immunotherapy naïve, metastatic or locally advanced NSCLC
APX005M 0.3 mg/kg and nivolumab 360 mg every 3 weeks
干预措施: Nivolumab (Drug)
Phase 2 expansion Cohort 2
Metastatic melanoma progressing during treatment with anti-PD-1/PD-L1 therapy
APX005M 0.3 mg/kg and nivolumab 360 mg every 3 weeks
干预措施: APX005M (Drug)
Phase 2 expansion Cohort 2
Metastatic melanoma progressing during treatment with anti-PD-1/PD-L1 therapy
APX005M 0.3 mg/kg and nivolumab 360 mg every 3 weeks
干预措施: Nivolumab (Drug)
Phase 2 expansion Cohort 3
Metastatic or locally advanced NSCLC progressing during treatment with anti-PD-1/PD-L1:
- Group A: best response of progressive disease or with stable disease < 16 weeks
- Group B: tumor response or with stable disease ≥ 16 weeks
干预措施: APX005M (Drug)
Phase 2 expansion Cohort 3
Metastatic or locally advanced NSCLC progressing during treatment with anti-PD-1/PD-L1:
- Group A: best response of progressive disease or with stable disease < 16 weeks
- Group B: tumor response or with stable disease ≥ 16 weeks
干预措施: Nivolumab (Drug)
结局指标
主要结局
Number of Participants Experiencing Dose-limiting Toxicities (DLTs)
时间窗: Up to 21 days following first dose of APX005M and nivolumab
All toxicities were graded according to the NCI-CTCAE version 4.03. DLT was defined as any of the following events attributed to APX005M and nivolumab combination: * Grade 4 hematologic toxicity lasting ≥ 7 days (except asymptomatic lymphopenia) * Grade 3 or 4 neutropenia with a single temperature of \>38.3◦ C (101◦ F) or a sustained temperature of ≥38◦ C (100.4◦ F) for more than one hour * Grade 4 thrombocytopenia or Grade ≥3 thrombocytopenia with signs or symptoms of bleeding or requiring platelet transfusion * Grade 4 non-hematologic toxicity * Grade 3 non-hematologic toxicity lasting \>3 days despite optimal supportive care * Any Grade ≥ 3 non-hematologic laboratory value if: medical intervention is required to treat the subject, abnormality leads to hospitalization, or abnormality persists for \>1 week * Failure to recover from a treatment-related AE to baseline or ≤ Grade 1 within 12 weeks of last dose of investigational product * Grade 5 toxicity.
Phase 2 Evaluate the Objective Response Rate (ORR) by RECIST 1.1 and iRECIST in Each Cohort / Group
时间窗: From start of the treatment (Day 1) until disease progression, withdrawal of consent, death, initiation of any anticancer therapy, lost to follow-up, or termination by the Sponsor, whichever comes first (for Phase 2: maximum up to 27 months)
ORR defined as the rate of patients who show as best overall response; either a complete response (CR) or a partial response (PR). The ORR can be evaluated by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. using computed tomography (CT) scans/magnetic resonance imaging (MRI). Per RECIST v1.1, for target lesions and assessed by imaging: Complete Response, (CR), Disappearance of all target lesions and nontarget (NT) lesions; Partial Response (PR), \>30% decrease in the sum of the longest diameter of target lesions and no PD in NT lesions or new lesions; Objective Response Rate (ORR)=CR + PR.
Maximum Tolerated Dose (MTD) of APX005M + Nivolumab (Phase 1b)
时间窗: Up to 21 days following first dose of APX005M and nivolumab
Establish the MTD dose of APX005M combined with 360 mg of nivolumab for which for which \< 33% of DLT- evaluable participants experience a DLT. In Phase 1b, the RP2D was based on the overall safety and tolerability of the combination of APX005M and nivolumab by testing increasing doses up to 0.3 mg/kg APX005M + nivolumab.
次要结局
- 6-month PFS Rate (Phase 2)(* Outcome Measure Time Frame From start of treatment (Day 1) to 6 months)
- Duration of Response (DOR) as Per RECIST 1.1(Phase 2)(Maximum up to 25 months)
- Safety of the APX005M and Nivolumab Combination (Phase 2)(Day 1 up to 30 days (or 100 days for SAEs and AEs with potential immunologic etiology) following the after the last dose of APX005M and/or nivolumab (from start of treatment up to 27 months))
- Median Progression-free Survival (PFS) (Phase 2)(From start of treatment (Day 1) up to 27 months)