An Open-label Phase I/IIa Study to Evaluate the Safety and Efficacy of CCS1477 as Monotherapy and in Combination, in Patients With Advanced Solid/Metastatic Tumours.
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 219
- 试验地点
- 38
- 主要终点
- Number of Participants With Worst Shift in QTcF According to Common Terminology Criteria for Adverse Events (CTCAE)-Version 5 Grades
研究概览
简要总结
A Phase 1/2a study to assess the safety, tolerability, PK and biological activity of CCS1477 in patients with metastatic castration resistant prostate cancer, metastatic breast cancer, non-small cell lung cancer or advanced solid tumours.
详细描述
The Steering Committee closed selected cohorts, in accordance with its responsibilities, after findings from earlier cohorts indicated that further evaluation of those cohorts was no longer warranted. The remaining cohorts were completed as specified in the protocol. Therefore, the study was considered completed.
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
- •Provision of consent
- •ECOG performance status 0-1
- •Assessable disease (by CT, MRI, bone scan or X-ray)
- •Adequate organ function
- •Highly effective contraception measures for duration of study
- •Additional inclusion criteria for mCRPC patients only:
- •Previously received abiraterone and/or enzalutamide (or equivalent anti-androgen), and docetaxel (unless ineligible or refused)
- •Progressive disease documented by one or more of the following:
- •Biochemical progression defined as at least 2 stepwise increases in a series of any 3 PSA values
- •Progression as defined by RECIST v1.1 guideline for assessment of malignant soft tissue disease.
- •Progression defined as two or more new metastatic bone lesions confirmed on bone scan from a previous assessment
- •PSA at screening ≥2 μg/L
- •Serum testosterone concentration ≤50 ng/dL
- •Serum albumin >2.5 g/dL
- •Additional inclusion criteria for patients in CCS1477 plus abiraterone combination arm:
- •Patients must have previously progressed on abiraterone treatment
- •Patients whose last dose of abiraterone is greater than 6 months prior to start of study treatment will receive a 4-week run-in treatment with abiraterone to confirm refractoriness to abiraterone treatment
- •Additional inclusion criteria for patients in CCS1477 plus enzalutamide combination arm:
- •Patients must have previously progressed on enzalutamide treatment
- •Patients whose last dose of enzalutamide is greater than 6 months prior to start of study treatment will receive a 4-week run-in treatment with enzalutamide to confirm refractoriness to enzalutamide treatment
- •Additional inclusion criteria for patients in mutation arm:
- •Advanced solid tumour with identification of markers which may indicate potential for response to p300/CBP inhibition. Markers include loss of function mutations in CREBBP, EP300 or ARID1A, MYC gene amplifications or rearrangements and androgen receptor (AR) gene amplifications or over-expression.
排除标准
- •Intervention with any chemotherapy, investigational agents or other anti-cancer drugs within 14 days or 5 half-lives of the first dose
- •Radiotherapy with a wide field of radiation or to more than 30% of the bone marrow within 4 weeks of the first dose of study treatment
- •Major surgical procedure or significant traumatic injury within 4 weeks of the first dose of study treatment
- •Strong inhibitors of CYP3A4 or CYP3A4 substrates with a narrow therapeutic range taken within 2 weeks of the first dose of study treatment
- •Strong inducers of CYP3A4 within 4 weeks of the first dose of study treatment
- •Statins; patients should discontinue statins prior to starting study treatment
- •Any unresolved reversible toxicities from prior therapy >CTCAE grade 1 at the time of starting study treatment
- •Any evidence of severe or uncontrolled systemic diseases
- •Any known uncontrolled inter-current illness
- •QTcF prolongation (> 480 msec).
- •Primary brain tumours or known or suspected brain metastases.
- •Additional exclusion criteria for patients in CCS1477 plus abiraterone combination arm:
- •Clinically significant cardiac abnormalities
- •Additional exclusion criteria for patients in CCS1477 plus enzalutamide combination arm:
- •History of seizures or other predisposing factors
- •Use of substrates with a narrow therapeutic index metabolised by CYP2C9 or CYP2C19 within 2 weeks of the first dose of study treatment
- •Clinically significant cardiac abnormalities
研究组 & 干预措施
CCS1477 and abiraterone acetate, combination dose finding and expansion - mCRPC
CCS1477 plus abiraterone acetate in patients with mCRPC
干预措施: CCS1477 (Drug)
CCS1477 Monotherapy - Solid tumours
CCS1477 expansion phase in patients with advanced solid tumours with molecular markers which may indicate potential for response to p300/CBP inhibition
干预措施: CCS1477 (Drug)
CCS1477 and olaparib, combination dose finding and expansion - mCRPC and metastatic breast cancer
CCS1477 plus olaparib in patients with mCRPC or metastatic breast cancer.
干预措施: CCS1477 (Drug)
CCS1477 expansion phase - mCRPC
CCS1477 monotherapy in patients with mCRPC
干预措施: CCS1477 (Drug)
CCS1477 and darolutamide, combination dose finding and expansion - mCRPC
CCS1477 plus darolutamide in patients with mCRPC
干预措施: CCS1477 (Drug)
CCS1477 and atezolizumab, combination dose finding and expansion - non-small cell lung cancer
CCS1477 plus atezolizumab in patients with non-small cell lung cancer
干预措施: CCS1477 (Drug)
CCS1477 and abiraterone acetate, combination dose finding and expansion - mCRPC
CCS1477 plus abiraterone acetate in patients with mCRPC
干预措施: Abiraterone acetate (Drug)
CCS1477 and enzalutamide, combination dose finding and expansion - mCRPC
CCS1477 plus enzalutamide in patients with mCRPC
干预措施: Enzalutamide (Drug)
CCS1477 and darolutamide, combination dose finding and expansion - mCRPC
CCS1477 plus darolutamide in patients with mCRPC
干预措施: Darolutamide (Drug)
CCS1477 and olaparib, combination dose finding and expansion - mCRPC and metastatic breast cancer
CCS1477 plus olaparib in patients with mCRPC or metastatic breast cancer.
干预措施: Olaparib (Drug)
CCS1477 and atezolizumab, combination dose finding and expansion - non-small cell lung cancer
CCS1477 plus atezolizumab in patients with non-small cell lung cancer
干预措施: Atezolizumab (Drug)
CCS1477 dose escalation - mCRPC
CCS1477 monotherapy in patients with mCRPC
干预措施: CCS1477 (Drug)
CCS1477 and enzalutamide, combination dose finding and expansion - mCRPC
CCS1477 plus enzalutamide in patients with mCRPC
干预措施: CCS1477 (Drug)
结局指标
主要结局
Number of Participants With Worst Shift in QTcF According to Common Terminology Criteria for Adverse Events (CTCAE)-Version 5 Grades
时间窗: From first dose of study drug in Cycle 1 up to and including 28 days after last dose of study intervention (Up to 363 weeks) (Cycle length was 4 weeks for Cycles 1-6 and 6 weeks for Cycle 7 and subsequent cycles)
Twelve-lead Electrocardiograms (ECGs) were obtained after the participant was in semi-supine for 5 minutes. Three ECGs were taken at each timepoint at about 1-minute intervals. QTcF was calculated using the Fridericia formula: QTcF = QT ÷ RR\^(1/3), where QT is the measured QT interval in milliseconds and RR is the interval between two consecutive R waves on the ECG expressed in seconds. It was categorized as less than equal to (\<=) 450 milliseconds (msec), more than (\>) 450 to \<=480 msec, \> 480 to \<= 500 msec and \> 500 msec.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Withdrawal
时间窗: From signing informed consent until the end of the follow-up period (Up to 363 weeks)
Adverse Event (AE) was defined any untoward medical occurrence in a participant administered with a study intervention, which does not necessarily have a causal relationship with the treatment. Serious AE (SAE) was defined AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs: TEAEs were defined as those events with onset dates/time occurring after study intervention administration or events that worsen after study intervention administration. TEAEs included serious TEAEs and non-serious TEAEs. Number of participants with TEAEs leading to withdrawal of study intervention was also reported.
Number of Participants With Worst Shift in Laboratory Data-Hematology According to Common Terminology Criteria for Adverse Events (CTCAE)-Version 5 Grades
时间窗: From first dose of study drug in Cycle 1 up to and including 28 days after last dose of study intervention (Up to 363 weeks) (Cycle length was 4 weeks for Cycles 1-6 and 6 weeks for Cycle 7 and subsequent cycles.)
Adverse events were graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, where Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life-threatening, and Grade 5 = death related to the adverse event. Number of participants with worst shift in hematology according to Common Terminology Criteria for Adverse Events (CTCAE) grades were reported.
Number of Participants With Worst Shift in Laboratory Data-Biochemistry According to Common Terminology Criteria for Adverse Events (CTCAE)-Version 5 Grades
时间窗: From first dose of study drug in Cycle 1 up to and including 28 days after last dose of study intervention (Up to 363 weeks) (Cycle length was 4 weeks for Cycles 1-6 and 6 weeks for Cycle 7 and subsequent cycles.)
Adverse events were graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, where Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life-threatening, and Grade 5 = death related to the adverse event. Number of participants with worst shift in biochemistry according to Common Terminology Criteria for Adverse Events (CTCAE) grades were reported.
Number of Participants With Clinically Significant Change From Baseline in Laboratory Parameters - Urinalysis
时间窗: From first dose of study drug in Cycle 1 up to and including 28 days after last dose of study intervention (Up to 363 weeks) (Cycle length was 4 weeks for Cycles 1-6 and 6 weeks for Cycle 7 and subsequent cycles.)
The urinalysis measurements included glucose, protein and blood. Number of participants with clinically significant changes from baseline in urinalysis values were reported. Clinically Significance was decided by investigator.
Number of Participants With Clinically Significant Change From Baseline in Vital Signs
时间窗: From first dose of study drug in Cycle 1 up to and including 28 days after last dose of study intervention (Up to 363 weeks) (Cycle length was 4 weeks for Cycles 1-6 and 6 weeks for Cycle 7 and subsequent cycles.)
The vital signs measurements included blood pressure, heart rate, respiration rate and temperature. Number of participants with clinically significant changes from baseline in vital signs values were reported. Clinically Significance was decided by investigator.
Laboratory assessments
时间窗: Up to 12 months
Clinical chemistry and haematology assessments
Incidence of treatment-related adverse events
时间窗: Up to 12 months
Treatment-related adverse events and serious adverse events
次要结局
- Best Percentage Change From Baseline in Prostate Specific Antigen (PSA) Response in Participants With Metastatic Castration Resistant Prostate Cancer (mCRPC)(At Baseline - Cycle 1 - Day 1, Day 8, Day 15, Day 22 and Day 1 of every cycle from cycle 2 onwards until treatment discontinuation (Up to 363 weeks) (Cycle length was 4 weeks for Cycles 1-6 and 6 weeks for Cycle 7 and subsequent cycles.))
- Number of Participants With CTC Response(From Baseline - Day 1 Cycle 1 (Predose), Day 1 Cycle 2, Day 1 Cycle 3, Day 1 Cycle 5 up to disease progression or treatment discontinuation (Up to 363 weeks) (Cycle length was 4 weeks for Cycles 1-6 and 6 weeks for Cycle 7 and subsequent cycles))
- Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1(From day of study intervention in Cycle 1 until progression or censoring date in the absence of progression (Up to 363 weeks) (Cycle length was 4 weeks for Cycles 1-6 and 6 weeks for Cycle 7 and subsequent cycles))
- Radiological Progression Free Survival (rPFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1(From day of study intervention in Cycle 1 until progression or censoring date in the absence of progression (Up to 363 weeks) (Cycle length was 4 weeks for Cycles 1-6 and 6 weeks for Cycle 7 and subsequent cycles))
- Overall Survival (OS)(From start of treatment until death (Up to 363 weeks))
- Maximum Observed Plasma Concentration (Cmax)(Cycle 1 Day 1 and Cycle 2 Day 3 (Cycle length was 4 weeks))
- Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-24)(Cycle 1 Day 1 and Cycle 2 Day 3 (Cycle length was 4 weeks))
- AUC of CCS1477(Up to 30 days after first dose of CCS1477)
- PSA response(Up to 12 months)
- Objective response rate (ORR)(Up to 12 months)
- CTC response(Up to 12 months)
- Radiological progression-free survival (rPFS)(Up to 12 months)
- Cmax of CCS1477(Up to 30 days after first dose of CCS1477)