Phase Ib, Open-label, Multi-center Study to Characterize the Safety, Tolerability and Pharmacodynamics (PD) of PDR001 in Combination With CJM112, EGF816, Ilaris® (Canakinumab) or Mekinist® (Trametinib)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 283
- 试验地点
- 5
- 主要终点
- Frequency of dose interruptions
研究概览
简要总结
The purpose of this study was to combine the PDR001 checkpoint inhibitor with each of four agents with immunomodulatory activity to identify the doses and schedule for combination therapy and to preliminarily assess the safety, tolerability, pharmacological and clinical activity of these combinations.
详细描述
This was a Phase Ib, multi-center, open-label study, to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of PDR001 in combination with canakinumab, CJM112, trametinib and EGF816 and single agent (s.a.) canakinumab in subjects with Triple Negative Breast Cancer (TNBC), Non-Small Cell Lung Cancer (NSCLC) and Colorectal Cancer (CRC). The study comprised a dose escalation part for combination treatments only, followed by a dose expansion part.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 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
- •Patients with advanced/metastatic cancer, with measurable disease as determined by RECIST version 1.1, who have progressed despite standard therapy or are intolerant to standard therapy, and for whom no effective therapy is available.
- •Patients must fit into one of the following groups:
- •Colorectal cancer (CRC) (not mismatch repair deficient by local assay including PCR and/or immunohistochemistry)
- •Non-small cell lung cancer (NSCLC) (adenocarcinoma)
- •Triple Negative Breast Cancer (TNBC) (D
- •ECOG Performance Status ≤ 2
- •Patient must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institution's guidelines. Patient must be willing to undergo a new tumor biopsy at baseline, and again during therapy on this study.
- •Prior therapy with PD-1/PDL-1 inhibitors is allowed provided any toxicity attributed to prior PD-1- or PD-L1-directed therapy did not lead to discontinuation of therapy.
- •Written informed consent must be obtained prior to any screening procedures other than procedures performed as part of standard of care.
排除标准
- •Presence of symptomatic central nervous system (CNS) metastases, or CNS metastases that require local CNS-directed therapy, or increasing doses of corticosteroids within the prior 2 weeks.
- •History of severe hypersensitivity reactions to other monoclonal antibodies.
- •Out of range laboratory values for measures of hepatic and renal function, electrolytes and blood counts
- •Impaired cardiac function or clinically significant cardiac disease.
- •Patients with active, known or suspected autoimmune disease.
- •Human Immunodeficiency Virus infection at screening.
- •Escalation part: Active Hepatitis B (HBV) or Hepatitis C (HCV) virus infection at screening.
- •Expansion part: Patients with active HBV or HCV are excluded, excepting those patients undergoing treatment for HBV or HCV.
- •Malignant disease, other than that being treated in this study.
- •Recent systemic anti-cancer therapy
- •Active infection requiring systemic antibiotic therapy.
- •Patients requiring chronic treatment with systemic steroid therapy, other than replacement dose steroids in the setting of adrenal insufficiency or treatment with low, stable dose of steroid (<10mg/ day prednisone or equivalent) for stable CNS metastatic disease.
- •Patients receiving systemic treatment with any immunosuppressive medication, excepting the above
- •Use of any live vaccines against infectious diseases (e.g. influenza, varicella, pneumococcus) within 4 weeks of initiation of study treatment.
- •Participation in an interventional, investigational study within 2 weeks of the first dose of study treatment.
- •Presence of ≥ CTCAE grade 2 toxicity (except alopecia and ototoxicity, which are excluded if ≥ CTCAE grade 3) due to prior cancer therapy.
- •Recent use of hematopoietic colony-stimulating growth factors (e.g. G-CSF, GMCSF, M-CSF)
- •Additional exclusion criteria for Combination arm PDR001+canakinumab and single-agent canakinumab
- •Patients with tuberculosis (TB). Note: Patient with latent TB may be eligible based on the investigator's benefit-risk assessment.
- •Patients who have been infected with HBV or HCV including those with inactive disease.
- •Additional exclusion criteria for Combination arm PDR001+CJM112
- •Patients with TB. Note: Patient with latent TB may be eligible based on the investigator's benefit-risk assessment.
- •Patients with history of and/or active inflammatory bowel disease.
- •Active skin or soft tissue infection including cellulitis, erysipelas, impetigo, furuncle,carbuncle, abscess, or fasciitis.
- •Active candida infection, including mucocutaneous infection or history of invasive candidiasis.
- •Additional exclusion criteria for Combination arm PDR001+trametinib
- •Patients with history of retinal vein oclusion.
- •Patients with history of interstitial lung disease or pneumonitis.
- •Patients with cardiomyopathy and/or LVEF < LLN.
- •Impairment of gastrointestinal function or GI disease that may significantly alter the absorption of oral combination partners.
- •Hemoglobin (Hgb) < 9 g/dL without growth factor or transfusion support
- •Women of child-bearing potential using hormonal contraception, unless an additional contraception method is also used according to the Mekinist® label.
- •Additional exclusion criteria for Combination arm PDR001+EGF816
- •NSCLC patients with EGFR mutant tumors.
- •Strong inhibitors and strong inducers of CYP3A4 should not be used concomitantly.
- •Patients with history of interstitial lung disease.
- •Patients who have been infected with HBV or HCV including those with inactive disease.
- •Impairment of gastrointestinal function or GI disease that may significantly alter the absorption of oral combination partners
- •Patients cannot have received radiotherapy to lung fields within 6 months of study treatment start.
研究组 & 干预措施
PDR + CJM 900mg Q4W
PDR + CJM 900mg Q4W
干预措施: PDR001 (Biological)
PDR + ACZ 100mg Q8W
PDR + ACZ 100mg Q8W
干预措施: PDR001 (Biological)
PDR + ACZ 100mg Q8W
PDR + ACZ 100mg Q8W
干预措施: ACZ885 (Biological)
PDR + ACZ 300mg Q8W
PDR + ACZ 300mg Q8W
干预措施: PDR001 (Biological)
PDR + ACZ 300mg Q8W
PDR + ACZ 300mg Q8W
干预措施: ACZ885 (Biological)
PDR + ACZ RDE TNBC
PDR + ACZ Recommended Dose for Expansion (RDE) Triple Negative Breast Cancer (TNBC)
干预措施: PDR001 (Biological)
PDR + ACZ RDE TNBC
PDR + ACZ Recommended Dose for Expansion (RDE) Triple Negative Breast Cancer (TNBC)
干预措施: ACZ885 (Biological)
PDR + ACZ RDE NSCLC
PDR + ACZ Recommended Dose for Expansion (RDE) Non-Small Cell Lung Cancer (NSCLC)
干预措施: PDR001 (Biological)
PDR + ACZ RDE NSCLC
PDR + ACZ Recommended Dose for Expansion (RDE) Non-Small Cell Lung Cancer (NSCLC)
干预措施: ACZ885 (Biological)
PDR + ACZ RDE CRC
PDR + ACZ Recommended Dose for Expansion (RDE) Colorectal Cancer (CRC)
干预措施: PDR001 (Biological)
PDR + ACZ RDE CRC
PDR + ACZ Recommended Dose for Expansion (RDE) Colorectal Cancer (CRC)
干预措施: ACZ885 (Biological)
PDR + CJM 25mg Q4W
PDR + CJM 25mg Q4W
干预措施: PDR001 (Biological)
PDR + CJM 25mg Q4W
PDR + CJM 25mg Q4W
干预措施: CJM112 (Biological)
PDR + CJM 75mg Q4W
PDR + CJM 75mg Q4W
干预措施: PDR001 (Biological)
PDR + CJM 75mg Q4W
PDR + CJM 75mg Q4W
干预措施: CJM112 (Biological)
PDR + CJM 225mg Q4W
PDR + CJM 225mg Q4W
干预措施: PDR001 (Biological)
PDR + CJM 225mg Q4W
PDR + CJM 225mg Q4W
干预措施: CJM112 (Biological)
PDR + CJM 450mg Q4W
PDR + CJM 450mg Q4W
干预措施: PDR001 (Biological)
PDR + CJM 450mg Q4W
PDR + CJM 450mg Q4W
干预措施: CJM112 (Biological)
PDR + CJM 450mg Q2W
PDR + CJM 450mg Q2W
干预措施: PDR001 (Biological)
PDR + CJM 450mg Q2W
PDR + CJM 450mg Q2W
干预措施: CJM112 (Biological)
PDR + CJM 900mg Q4W
PDR + CJM 900mg Q4W
干预措施: CJM112 (Biological)
PDR + CJM 900mg Q2W
PDR + CJM 900mg Q2W
干预措施: PDR001 (Biological)
PDR + CJM 900mg Q2W
PDR + CJM 900mg Q2W
干预措施: CJM112 (Biological)
PDR + CJM 1200mg Q4W
PDR + CJM 1200mg Q4W
干预措施: PDR001 (Biological)
PDR + CJM 1200mg Q4W
PDR + CJM 1200mg Q4W
干预措施: CJM112 (Biological)
PDR + TMT 0.5mg QD
PDR + TMT 0.5mg QD
干预措施: PDR001 (Biological)
PDR + TMT 0.5mg QD
PDR + TMT 0.5mg QD
干预措施: TMT212 (Drug)
PDR + TMT 1mg QD
PDR + TMT 1mg QD
干预措施: PDR001 (Biological)
PDR + TMT 1mg QD
PDR + TMT 1mg QD
干预措施: TMT212 (Drug)
PDR + TMT 1mg QD, 3 Weeks on/1 Week off
PDR + TMT 1mg QD, 3 Weeks on/1 Week off
干预措施: PDR001 (Biological)
PDR + TMT 1mg QD, 3 Weeks on/1 Week off
PDR + TMT 1mg QD, 3 Weeks on/1 Week off
干预措施: TMT212 (Drug)
PDR + TMT 1.5 mg QD, 2 Weeks on/2 Weeks off
PDR + TMT 1.5 mg QD, 2 Weeks on/2 Weeks off
干预措施: PDR001 (Biological)
PDR + TMT 1.5 mg QD, 2 Weeks on/2 Weeks off
PDR + TMT 1.5 mg QD, 2 Weeks on/2 Weeks off
干预措施: TMT212 (Drug)
PDR + TMT 1.5 mg QD, 3 Weeks on/1 Week off
PDR + TMT 1.5 mg QD, 3 Weeks on/1 Week off
干预措施: PDR001 (Biological)
PDR + TMT 1.5 mg QD, 3 Weeks on/1 Week off
PDR + TMT 1.5 mg QD, 3 Weeks on/1 Week off
干预措施: TMT212 (Drug)
s.a. ACZ RDE NSCLC
Single agent (s.a.) ACZ Recommended Dose for Expansion (RDE) Non-Small Cell Lung Cancer (NSCLC)
干预措施: ACZ885 (Biological)
PDR + EGF816 25mg QD
PDR + EGF816 25mg QD
干预措施: EGF816 (Drug)
PDR + EGF816 50mg QD
PDR + EGF816 50mg QD
干预措施: EGF816 (Drug)
s.a. ACZ RDE TNBC
Single agent (s.a.) ACZ Recommended Dose for Expansion (RDE) Triple Negative Breast Cancer (TNBC)
干预措施: ACZ885 (Biological)
s.a. ACZ RDE CRC
Single agent (s.a.) ACZ Recommended Dose for Expansion (RDE) Colorectal Cancer (CRC)
干预措施: ACZ885 (Biological)
结局指标
主要结局
Frequency of dose interruptions
时间窗: Throughout the study at every visit, an average of 1 year
Frequency of dose reductions
时间窗: Throughout the study at every visit, an average of 1 year
Frequency of treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) as a measure of safety
时间窗: Throughout the study at every visit, an average of 1 year
Changes between baseline and post-baseline laboratory parameters and vital signs.
时间窗: Baseline and throughout the study at every visit, an average of 1 year
Incidence of dose limiting toxicities (DLTs) of treatment (Escalation only)
时间窗: During the first two cycles; Cycle = 28 days
Dose intensities
时间窗: Throughout the study at every visit, an average of 1 year
Severity of treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) as a measure of safety
时间窗: Throughout the study at every visit, an average of 1 year
次要结局
- Serum concentration of PDR001, canakinumab, CJM112(Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year))
- Key secondary: Histopathology of tumor infiltrating lymphocytes (TILs)(Baseline and approximately after 2 cycles of treatment and at disease progression; Cycle = 28 days)
- Changes from baseline in electrocardiogram (ECG) parameters(Baseline and end of treatment, an average of 1 year)
- Best overall response (BOR)(T1: Every 2 cycles until the start of T2. T2: Every 2 cycles until cycle 3 and then every 3 cycles until PD; cycle = 28 days)
- Progression free survival (PFS) per irRC and RECIST v1.1(T1: Every 2 cycles until the start of T2. T2: Every 2 cycles until cycle 3 and then every 3 cycles until PD; cycle = 28 days)
- Treatment Free Survival (TFS)(T1: Every 2 cycles until the start of T2. T2: Every 2 cycles until cycle 3 and then every 3 cycles until PD; cycle = 28 days)
- Presence and/or concentration of anti-PDR001 antibodies.(Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year))
- Plasma concentrations of trametinib and EGF816(Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year))
- Key secondary: Histopathology of myeloid cell infiltrate by IHC (such as CD8, FoxP3 and myeloid markers as appropriate).(Baseline and approximately after 3 cycles of treatment and at disease progression; cycle = 28 days)
- PK parameters (Eg. TMax) of EGF816(Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year))
- PK parameter (Eg. TMax) of PDR001(Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year))
- PK parameters (Eg. TMax) of CJM112(Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year))
- PK parameters (Eg. TMax) of trametinib(Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year))
- PK parameters (Eg. TMax) of canakinumab(Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year))
- Presence and/or concentration of anti-canakinumab antibodies.(Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year))
- Presence and/or concentration of anti-CJM112 antibodies.(Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year))