A Phase 1b Dose-Escalation Study of Cabozantinib (XL184) Administered Alone or in Combination With Atezolizumab to Subjects With Locally Advanced or Metastatic Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- Exelixis
- 入组人数
- 914
- 试验地点
- 124
- 主要终点
- Dose Escalation: MTD/Recommended Dose
研究概览
简要总结
This is a multicenter Phase 1b, open-label study to assess safety, tolerability, preliminary efficacy, and pharmacokinetics (PK) of cabozantinib taken in combination with atezolizumab in subjects with multiple tumor types, including advanced urothelial carcinoma (UC) (including bladder, renal pelvis, ureter, urethra), renal cell carcinoma (RCC), castration-resistant prostate cancer (CRPC), non-small-cell lung cancer (NSCLC), triple negative breast cancer (TNBC), ovarian cancer (OC), endometrial cancer (EC), hepatocellular cancer (HCC), gastric cancer/gastroesophageal junction cancer/lower esophageal cancer (GC/GEJC/LEC), colorectal cancer (CRC), head and neck (H&N) cancer, and differentiated thyroid cancer (DTC). The study consists of two stages: in the Dose Escalation Stage, an appropriate recommended cabozantinib dose for the combination with standard dosing regimen of atezolizumab will be established; in the Expansion Stage, tumor-specific cohorts will be enrolled in order to further evaluate the safety and efficacy of the combination treatment in these tumor indications. Three exploratory single-agent cabozantinib (SAC) cohorts may also be enrolled with UC, NSCLC, or CRPC subjects. One exploratory single-agent atezolizumab (SAA) cohort may also be enrolled with CRPC subjects. Subjects enrolled in the SAC cohorts and SAA cohort may receive combination treatment with both cabozantinib and atezolizumab after they experience radiographic progressive disease per the Investigator per RECIST 1.1. Due to the nature of this study design, some tumor cohorts may complete enrollment earlier than others.
详细描述
- Dose Escalation Stage: to determine the schedule and maximum tolerated dose (MTD) and/or recommended Expansion Stage dose of cabozantinib when taken in combination with a standard dosing regimen of atezolizumab (1200 mg infusion, once every 3 weeks).
- Expansion Stage: to determine the preliminary efficacy (objective response rate [ORR] per RECIST 1.1) and safety of the recommended combination dose of cabozantinib with atezolizumab in eighteen tumor-specific cohorts including subjects with advanced UC, RCC, CRPC, NSCLC, TNBC, OC, EC, HCC, GC/GEJC/LEC, CRC, H&N, and DTC.
- Exploratory SAC Cohorts: Descriptive efficacy, safety, PK, and biomarker analyses of single-agent cabozantinib in UC, NSCLC, and CRPC subjects. Descriptive efficacy and safety analyses of combination therapy after progression on single-agent therapy
- Exploratory SAA Cohort: Descriptive efficacy, safety, PK, and biomarker analyses of single-agent atezolizumab in CRPC subjects. Descriptive efficacy and safety analyses of combination therapy after progression on single-agent therapy
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
- •Cytologically or histologically and radiologically confirmed solid tumor that is inoperable, locally advanced, metastatic, or recurrent:
- •Dose-Escalation Stage:
- •Subjects with UC (including renal pelvis, ureter, bladder, urethra) after prior platinum-based therapy, or
- •Subjects with RCC (clear cell, non-clear cell histology) with or without prior systemic anticancer therapy
- •Expansion Stage:
- •Inoperable locally advanced or metastatic solid tumor (UC, RCC, CRPC, NSCLC, TNBC, OC, EC, HCC, GC/GEJC/LEC, CRC, H&N cancer, and DTC as outlined above)
- •Measurable disease per RECIST 1.1 as determined by the investigator.
- •Tumor tissue material available (archival or recent tumor biopsy)
- •Recovery to baseline or ≤ Grade 1 CTCAE v4 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy.
- •Age eighteen years or older on the day of consent.
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or
- •Adequate organ and marrow function.
- •Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception.
- •Female subjects of childbearing potential must not be pregnant at screening.
排除标准
- •Prior treatment with cabozantinib or immune checkpoint inhibitors including anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PD-L2 therapy except in Expansion Cohorts 5, 7, 9, 11, 17, 19 and
- •Other restrictions regarding prior therapy may apply.
- •Known brain metastases or cranial epidural disease unless adequately treated and stable for at least 4 weeks before first dose of study treatment.
- •Concomitant anticoagulation with oral anticoagulants.
- •Subject is receiving systemic steroid therapy (>10 mg daily prednisone equivalent) or any other form of immunosuppressive therapy within 2 weeks prior to first dose of study treatment.
- •Administration of a live, attenuated vaccine within 30 days before first dose of study treatment.
- •The subject has uncontrolled, significant intercurrent or recent illness, including, but not limited to, an active or history of autoimmune disease or immune deficiency; idiopathic pulmonary fibrosis, organizing pneumonia, pneumonitis; active infection requiring systemic treatment, infection with human immunodeficiency virus (HIV), AIDS-related illness, acute or chronic hepatitis B or C infection, positive test for tuberculosis, moderate to severe hepatic impairment (Child-Pugh B or C).
- •Pregnant or lactating females.
- •Previously identified allergy or hypersensitivity to components of the study treatment formulations.
- •Diagnosis of another malignancy within 2 years before first dose of study treatment.
研究组 & 干预措施
Dose Escalation
Subjects will accrue in cohorts of 3-6 subjects for evaluation of cabozantinib tablet dose of either 20 mg, 40 mg, and 60 mg orally qd in combination with standard dosing regimen of atezolizumab (1200 mg infusion q3w). A standard "3 plus 3" design will be utilized to determine a recommended combination dosing regimen for the Expansion Stage.
干预措施: cabozantinib (Drug)
Dose Escalation
Subjects will accrue in cohorts of 3-6 subjects for evaluation of cabozantinib tablet dose of either 20 mg, 40 mg, and 60 mg orally qd in combination with standard dosing regimen of atezolizumab (1200 mg infusion q3w). A standard "3 plus 3" design will be utilized to determine a recommended combination dosing regimen for the Expansion Stage.
干预措施: atezolizumab (Drug)
Expansion Cohort 1
RCC subjects with clear cell histology who have not received prior systemic anticancer therapy.
干预措施: atezolizumab (Drug)
Expansion Cohort 1
RCC subjects with clear cell histology who have not received prior systemic anticancer therapy.
干预措施: cabozantinib (Drug)
Expansion Cohort 2
UC subjects (including bladder, renal pelvis, ureter, urethra) who have progressed on or after platinum-containing chemotherapy.
干预措施: atezolizumab (Drug)
Expansion Cohort 2
UC subjects (including bladder, renal pelvis, ureter, urethra) who have progressed on or after platinum-containing chemotherapy.
干预措施: cabozantinib (Drug)
Expansion Cohort 3
UC subjects (including bladder, renal pelvis, ureter, urethra) who are ineligible for cisplatin-based chemotherapy and have not received prior systemic chemotherapy.
干预措施: atezolizumab (Drug)
Expansion Cohort 3
UC subjects (including bladder, renal pelvis, ureter, urethra) who are ineligible for cisplatin-based chemotherapy and have not received prior systemic chemotherapy.
干预措施: cabozantinib (Drug)
Expansion Cohort 4
UC subjects (including bladder, renal pelvis, ureter, urethra) eligible for cisplatin-based chemotherapy and have not received prior systemic chemotherapy.
干预措施: atezolizumab (Drug)
Expansion Cohort 4
UC subjects (including bladder, renal pelvis, ureter, urethra) eligible for cisplatin-based chemotherapy and have not received prior systemic chemotherapy.
干预措施: cabozantinib (Drug)
Expansion Cohort 5
UC subjects (including renal pelvis, ureter, urinary bladder, urethra) who have radiographically progressed on or after one prior immune check-point inhibitor (ICI) (anti-PD1 or anti-PD-L1) therapy.
干预措施: atezolizumab (Drug)
Expansion Cohort 5
UC subjects (including renal pelvis, ureter, urinary bladder, urethra) who have radiographically progressed on or after one prior immune check-point inhibitor (ICI) (anti-PD1 or anti-PD-L1) therapy.
干预措施: cabozantinib (Drug)
Expansion Cohort 6
CRPC subjects who have radiographically progressed in soft tissue on or after enzalutamide and/or abiraterone acetate for metastatic disease.
干预措施: atezolizumab (Drug)
Expansion Cohort 6
CRPC subjects who have radiographically progressed in soft tissue on or after enzalutamide and/or abiraterone acetate for metastatic disease.
干预措施: cabozantinib (Drug)
Expansion Cohort 7
Stage IV non-squamous NSCLC subjects who have radiographically progressed on or after treatment with one prior immune checkpoint inhibitor (ICI) (anti-PD-1 or anti-PD-L1) therapy.
干预措施: atezolizumab (Drug)
Expansion Cohort 7
Stage IV non-squamous NSCLC subjects who have radiographically progressed on or after treatment with one prior immune checkpoint inhibitor (ICI) (anti-PD-1 or anti-PD-L1) therapy.
干预措施: cabozantinib (Drug)
Expansion Cohort 8
Stage IV non-squamous NSCLC subjects with positive PD-L1 expression and without prior systemic anticancer therapy.
干预措施: atezolizumab (Drug)
Expansion Cohort 8
Stage IV non-squamous NSCLC subjects with positive PD-L1 expression and without prior systemic anticancer therapy.
干预措施: cabozantinib (Drug)
Expansion Cohort 9
Stage IV nonsquamous NSCLC subjects with sensitizing EGFR mutation who have radiographically progressed during or following prior treatment with an EGFR-targeting TKI. Prior treatment with ICIs (anti-PD1 or anti-PD-L1) is allowed if given in combination with chemotherapy.
干预措施: atezolizumab (Drug)
Expansion Cohort 9
Stage IV nonsquamous NSCLC subjects with sensitizing EGFR mutation who have radiographically progressed during or following prior treatment with an EGFR-targeting TKI. Prior treatment with ICIs (anti-PD1 or anti-PD-L1) is allowed if given in combination with chemotherapy.
干预措施: cabozantinib (Drug)
Expansion Cohort 10
RCC subjects with non-clear cell histology who have had up to one prior VEGFR-targeting TKI therapy.
干预措施: atezolizumab (Drug)
Expansion Cohort 10
RCC subjects with non-clear cell histology who have had up to one prior VEGFR-targeting TKI therapy.
干预措施: cabozantinib (Drug)
Expansion Cohort 11
TNBC subjects who have radiographically progressed during or following treatment with at least one prior systemic anticancer therapy. Prior treatment with ICIs (anti-PD1 or anti-PD-L1) is allowed if given in combination with chemotherapy.
干预措施: atezolizumab (Drug)
Expansion Cohort 11
TNBC subjects who have radiographically progressed during or following treatment with at least one prior systemic anticancer therapy. Prior treatment with ICIs (anti-PD1 or anti-PD-L1) is allowed if given in combination with chemotherapy.
干预措施: cabozantinib (Drug)
Expansion Cohort 12
OC subjects (including primary peritoneal cancer and fallopian tube cancer) who have platinum-resistant or refractory disease who have had up to two lines of prior systemic anticancer therapy.
干预措施: atezolizumab (Drug)
Expansion Cohort 12
OC subjects (including primary peritoneal cancer and fallopian tube cancer) who have platinum-resistant or refractory disease who have had up to two lines of prior systemic anticancer therapy.
干预措施: cabozantinib (Drug)
Expansion Cohort 13
EC subjects (serous or endometrioid histology) who have radiographically progressed during or following treatment with at least one prior systemic anticancer therapy.
干预措施: atezolizumab (Drug)
Expansion Cohort 13
EC subjects (serous or endometrioid histology) who have radiographically progressed during or following treatment with at least one prior systemic anticancer therapy.
干预措施: cabozantinib (Drug)
Expansion Cohort 14
HCC subjects (Child-Pugh score A) who have not received prior systemic anticancer therapy.
干预措施: atezolizumab (Drug)
Expansion Cohort 14
HCC subjects (Child-Pugh score A) who have not received prior systemic anticancer therapy.
干预措施: cabozantinib (Drug)
Expansion Cohort 15
GC/GEJC/LEC subjects who have radiographically progressed during or following platinum-containing or fluoropyrimidine-containing chemotherapy.
干预措施: atezolizumab (Drug)
Expansion Cohort 15
GC/GEJC/LEC subjects who have radiographically progressed during or following platinum-containing or fluoropyrimidine-containing chemotherapy.
干预措施: cabozantinib (Drug)
Expansion Cohort 16
CRC subjects who have radiographically progressed during or following systemic chemotherapy that contained fluoropyrimidine in combination with oxaliplatin or irinotecan.
干预措施: atezolizumab (Drug)
Expansion Cohort 16
CRC subjects who have radiographically progressed during or following systemic chemotherapy that contained fluoropyrimidine in combination with oxaliplatin or irinotecan.
干预措施: cabozantinib (Drug)
Expansion Cohort 17
H&N cancer subjects who have radiographically progressed during or following prior platinum-containing chemotherapy. Prior treatment with ICIs (anti-PD1 or anti-PD-L1) is allowed if given in combination with chemotherapy.
干预措施: atezolizumab (Drug)
Expansion Cohort 17
H&N cancer subjects who have radiographically progressed during or following prior platinum-containing chemotherapy. Prior treatment with ICIs (anti-PD1 or anti-PD-L1) is allowed if given in combination with chemotherapy.
干预措施: cabozantinib (Drug)
Expansion Cohort 18
DTC subjects (follicular, papillary, and poorly differentiated histologies) who are radioactive iodine (RAI) refractory or deemed ineligible for treatment with RAI.
干预措施: atezolizumab (Drug)
Expansion Cohort 18
DTC subjects (follicular, papillary, and poorly differentiated histologies) who are radioactive iodine (RAI) refractory or deemed ineligible for treatment with RAI.
干预措施: cabozantinib (Drug)
Expansion Cohort 19 (SAC)
UC subjects (including renal pelvis, ureter, urinary bladder, urethra) who have radiographically progressed on or after one prior ICI (anti-PD-1 or anti-PD-L1). Subjects may be allowed to receive combination therapy at the Cohort Review Committee recommended dose following radiographic disease progression.
干预措施: cabozantinib (Drug)
Expansion Cohort 20 (SAC)
Stage IV non-squamous NSCLC subjects who have radiographically progressed on or after treatment with one prior ICI (anti-PD-1 or anti-PD-L1). Subjects may be allowed to receive combination therapy at the Cohort Review Committee recommended dose following radiographic disease progression.
干预措施: cabozantinib (Drug)
Expansion Cohort 21 (SAC)
Metastatic CRPC (mCRPC) subjects who have histologically or cytologically confirmed adenocarcinoma of the prostate without small cell features who have had prior treatment with one, and only one, novel hormonal therapy (NHT) (eg, abiraterone, enzalutamide, apalutamide, daralutamide) for CSPC, mCRPC, or non-metastatic CRPC. Subjects may be allowed to receive combination therapy at the Cohort Review Committee recommended dose following radiographic disease progression.
干预措施: cabozantinib (Drug)
Expansion Cohort 22 (SAA)
Metastatic CRPC (mCRPC) subjects who have histologically or cytologically confirmed adenocarcinoma of the prostate without small cell features who have had prior treatment with one, and only one, novel hormonal therapy (NHT) (eg, abiraterone, enzalutamide, apalutamide, daralutamide) for CSPC, mCRPC, or non-metastatic CRPC. Subjects may be allowed to receive combination therapy at the Cohort Review Committee recommended dose following radiographic disease progression.
干预措施: atezolizumab (Drug)
Expansion Cohort 23
Metastatic CRPC (mCRPC) subjects who have histologically or cytologically confirmed adenocarcinoma of the prostate without small cell features who have had prior treatment with one, and only one, novel hormonal therapy (NHT) (eg, abiraterone, enzalutamide, apalutamide, daralutamide) for CSPC, mCRPC, or non-metastatic CRPC
干预措施: atezolizumab (Drug)
Expansion Cohort 23
Metastatic CRPC (mCRPC) subjects who have histologically or cytologically confirmed adenocarcinoma of the prostate without small cell features who have had prior treatment with one, and only one, novel hormonal therapy (NHT) (eg, abiraterone, enzalutamide, apalutamide, daralutamide) for CSPC, mCRPC, or non-metastatic CRPC
干预措施: cabozantinib (Drug)
Expansion Cohort 24
Metastatic CRPC (mCRPC) subjects who have histologically or cytologically confirmed adenocarcinoma of the prostate without small cell features who have had prior treatment with at least one NHT and have received docetaxel for mCRPC
干预措施: atezolizumab (Drug)
Expansion Cohort 24
Metastatic CRPC (mCRPC) subjects who have histologically or cytologically confirmed adenocarcinoma of the prostate without small cell features who have had prior treatment with at least one NHT and have received docetaxel for mCRPC
干预措施: cabozantinib (Drug)
结局指标
主要结局
Dose Escalation: MTD/Recommended Dose
时间窗: Up to Day 21
To determine the maximum tolerated dose (MTD) and/or recommended dose and schedule for the subsequent Expansion Stage of daily oral administration of cabozantinib in subjects with solid tumors when taken in combination with atezolizumab.
Dose Expansion: ORR
时间窗: Up to a maximum of 59 months
To evaluate preliminary efficacy by estimating the Objective Response Rate (ORR) as assessed by the Investigator per RECIST 1.1.
次要结局
- Incidence and severity of nonserious AEs and SAEs (Safety)(From first dose to 30 days following last dose (up to a maximum of 59 months))