A Modular, Multipart, Multiarm, Open-label, Phase I/II Study to Evaluate the Safety and Tolerability of CT7001 Alone and in Combination With Anti-cancer Treatments in Patients With Advanced Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 124
- 试验地点
- 46
- 主要终点
- Treatment-Emergent Adverse Events and Laboratory Abnormalities (Safety and Tolerability)
研究概览
简要总结
This is a modular, Phase I/II, multicentre study to investigate CT7001 monotherapy in advanced solid malignancies and to further investigate CT7001 as monotherapy or in combination with standard therapy in specific participant groups with Triple Negative Breast Cancer (TNBC), Castrate Resistant Prostate Cancer (CRPC) and in combination with fulvestrant for patients with hormone receptor-positive (HR+ve) / human epidermal growth factor-2 negative (HER2-ve) breast cancer.
详细描述
Module 1 comprises two sequential parts:
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Part A: First-in-human (FiH) dose escalation investigating the safety and tolerability of CT7001 to identify the minimum biologically active dose (MBAD) and maximum tolerated dose (MTD). Part A also includes a cohort expansion for breast cancer participants only: this includes sequential tumour biopsies for evaluation of pharmacokinetic (PK), pharmacodynamic (PD) and tumour responses. The module is completed.
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Part B: To refine the safety, tolerability, and PK and PD profiles of CT7001 monotherapy in participants with advanced solid malignancies from up to four tumour- specific cohorts, which may include, but is not limited to, triple-negative breast cancer, ovarian cancer, small-cell lung cancer and prostate cancer.
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Part B, Cohort 1, Triple-Negative Breast Cancer (M1B-1 TNBC) treated with CT7001 as monotherapy. The module is completed.
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Part B, Cohort 2, Prostate Cancer (M1B-2 CRPC) treated with CT7001 as monotherapy. The module is completed.
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Module 2 is a Phase Ib/II, 3-part safety and efficacy study in participants with hormone- receptor positive (HR+ve) and human epidermal growth factor-2 negative (HER2-ve) breast cancer. This module includes dosing CT7001 in combination with fulvestrant. Module 2 was planned to comprise of 3 parts; Part A (open-label, single-arm, ascending dose study), Part B (double blinded, randomised, placebo-controlled study) and Part C (crossover from Part B). However, only Module 2 Part A was initiated and completed. Therefore, further sections of this record only reflect Module 2 Part A information.
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Module 4 is a study investigating the effect of food on the PK of CT7001 monotherapy in participants with advanced solid malignancies. The module is completed.
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Module 6 was planned as a Phase 1 study to explore the tolerability of, and the total and peak exposure of, an enteric capsule formulation of CT7001 [CT7001(EC)], when given as monotherapy to patients with advanced solid malignancies. Module 6 was not initiated.
研究设计
- 研究类型
- Interventional
- 分配方式
- 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
- •Core Inclusion Criteria:
- •ECOG performance status 0 or 1 with no deterioration over the previous 2 weeks
- •Estimated life expectancy of greater than 12 weeks
- •Ability to swallow and retain oral medication
- •Women either of non-childbearing potential or of childbearing potential willing to practice effective contraception for the duration of the study and for 6 months (Module 1, Module 4) and 24 months (Module 2) after the last dose of CT7001
- •Sexually active male patients must be willing to use condoms with all sexual partners for the duration of the study and for 3 months after the last dose of CT
- •Provision of signed and dated, written informed consent
排除标准
- •Any other malignancy that has been active or treated within the past 3 years, with the exception of cervical intraepithelial neoplasia and non-melanoma skin cancer
- •Any unresolved toxicity (except alopecia) from prior therapy of ≥ CTCAE Grade 2
- •Spinal cord compression or brain metastases, unless asymptomatic, stable, and not requiring steroids for at least 4 weeks before the first dose of investigational product (IP)
- •Refractory nausea and vomiting, chronic gastrointestinal (GI) disease or previous significant bowel resection, with clinically significant sequelae that would preclude adequate absorption of CT7001
- •Uncontrolled seizures
- •Active infection requiring systemic antibiotic, antifungal, or antiviral medication
- •Severe or uncontrolled medical condition or psychiatric condition
- •Active bleeding diatheses
- •Renal transplant
- •Known hepatitis B, hepatitis C, or human immunodeficiency virus infection
- •Breastfeeding or pregnancy
- •Receipt of systemic cytotoxic treatment for the malignancy within 28 days or ≤ 5 half-lives, whichever is shorter before the first dose of IP
- •Receipt of non-cytotoxic treatment for the malignancy within 5 half-lives of the drug before the first dose of IP
- •Receipt of corticosteroids (at a dose > 10 mg prednisone/day or equivalent) within 14 days before the first dose of IP
- •Receipt of any small-molecule investigational medicinal product (IMP) within 28 days or ≤ 5 half-lives, whichever is shorter before the first dose of IP
- •Receipt of any biological IMP (e.g., immune checkpoint blockers, antibodies, nanoparticles) within 42 days before the first dose of IP
- •Receipt of St John's Wort within 21 days before the first dose of IP or of another concomitant medication, herbal supplement, or food that is a strong inhibitor or inducer of CYP3A4, CYP2C19, CYP2D6, or P-glycoprotein (PGP) activity within 14 days before the first dose of CT7001
- •Receipt of a blood transfusion (blood or blood products) within 14 days before the first dose of IP
- •Known hypersensitivity to CT7001 or any excipient of the product
- •Impaired hepatic or renal function as demonstrated by any of the following laboratory values:
- •Albumin < 30 g/L
- •Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × the upper limit of normal (ULN)
- •> 5.0 × ULN for patients with liver metastases
- •Total bilirubin > 1.5 × ULN
- •Serum creatinine > 1.5 × ULN
- •Liver function deteriorating in a manner that would likely make the participant meet the AST, ALT, or bilirubin levels specified above at the time of the first dose of IP
- •Other evidence of impaired hepatic synthesis function
- •Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:
- •Absolute neutrophil count (ANC) < 1.5 × 10^9/L
- •Platelet count < 100 × 10^9/L
- •Haemoglobin < 90 g/L
- •Persistent (> 4 weeks) severe pancytopenia due to previous therapy rather than to disease (ANC < 0.5 × 10^9/L or platelets < 50 x 10^9/L)
- •Cardiac dysfunction (defined as myocardial infarction within 6 months of study entry, New York Heart Association Class II/III/IV heart failure, unstable angina, unstable cardiac arrhythmias, or left ventricular ejection fraction < 55 percent)
- •Mean resting QT interval corrected for heart rate by the Fridericia formula (QTcF) > 470 msec obtained from 3 electrocardiograms (ECGs) obtained within 5 minutes of each other prior to the first dose
- •Any clinically important abnormalities in rhythm, conduction, or morphology on resting ECG (e.g., complete left bundle branch block, third degree heart block). Controlled atrial fibrillation (AF) is permitted
- •Any factor that increases the risk of QTc prolongation or of arrhythmic events (e.g., heart failure, hypokalaemia, congenital long QT syndrome, immediate family history of long QT syndrome or unexplained sudden death under 40 years of age)
- •In the opinion of the Investigator, unlikely to comply with study procedures, restrictions, or requirements
- •A history of haemolytic anaemia or marrow aplasia
- •Has received a live-virus vaccination within 28 days or less of planned treatment start
- •Additional Module 1A Inclusion Criteria:
- •Histological, radiological or cytological confirmation of an advanced non-haematological malignancy not considered to be appropriate for further standard treatment
- •Module 1A biopsy cohort only : at least one tumour suitable for repeat biopsy
- •Additional Module 1A Exclusion Criteria:
- •1. International normalised ratio (INR) ≥1.5
- •Additional Module 1B Inclusion Criteria
- •Histological or cytological confirmation of metastasis or locally advanced tumour
- •At least one line of systemic anti-cancer therapy
- •Disease measurable by RECIST v1.1
- •Additional Module 1B-1 (TNBC Expansion) Inclusion Criteria:
- •Histologically-confirmed carcinoma of breast not expressing oestrogen receptor (ER) or progesterone receptor (PR) and negative for human epidermal growth factor receptor 2 (HER2)
- 另有 28 项未显示
研究组 & 干预措施
Module 1 Part B-1 Triple-negative breast cancer (TNBC) Expansion
Participants with locally advanced or metastatic triple-negative breast cancer (TNBC) will receive CT7001(samuraciclib) as oral monotherapy at the dose, frequency and schedule recommended from Module 1 Part A.
干预措施: CT7001 (Drug)
Module 1 Part B-2 Castrate resistant prostate Cancer (CRPC) Expansion
Participants with castrate resistant prostate cancer will receive CT7001(samuraciclib) as oral monotherapy at the dose, frequency and schedule recommended from Module 1 Part A.
干预措施: CT7001 (Drug)
Module 2 Part A
Participants with locally advanced or metastatic HR+ve and HER2-ve breast cancer will receive CT7001 (samuraciclib) at the dose, frequency and schedule recommended from Module 1 part A and will receive Fulvestrant solution in pre-filled syringe for intramuscular (IM) injection
干预措施: CT7001 (Drug)
Module 2 Part A
Participants with locally advanced or metastatic HR+ve and HER2-ve breast cancer will receive CT7001 (samuraciclib) at the dose, frequency and schedule recommended from Module 1 part A and will receive Fulvestrant solution in pre-filled syringe for intramuscular (IM) injection
干预措施: Fulvestrant (Drug)
Module 4
Participants with advanced solid tumours will receive CT7001(samuraciclib) oral monotherapy in a randomized, balanced, single-dose, two-treatment (fed v fasting), two-period, two-sequence crossover study followed by once daily continuous dosing.
干预措施: CT7001 (Drug)
Module 1 Part A Multiple ascending dose cohort and Paired Biopsy Breast Cancer Expansion Cohort
Module 1 Part A Multiple ascending dose cohort: Participants with advanced solid tumours receive CT7001 (samuraciclib) as oral monotherapy, in ascending dose cohorts, to identify the maximum tolerated dose (MTD), minimally biologically active dose (MBAD) and recommended dose for Phase II testing (RP2D).
Following completion of the dose escalation part of Module 1A, participants to receive safe, tolerable and MBAD of CT7001 for the paired biopsy expansion cohort.
Module 1 Part A Paired Biopsy Breast Cancer Expansion Cohort: Participants with locally advanced or metastatic breast cancer will receive CT7001 (samuraciclib) as oral monotherapy at the minimally biologically active dose (MBAD) and recommended dose for Phase II testing (RP2D).
干预措施: CT7001 (Drug)
结局指标
主要结局
Treatment-Emergent Adverse Events and Laboratory Abnormalities (Safety and Tolerability)
时间窗: Screening to end of study
Type, incidence and severity
次要结局
- Maximum Plasma Concentration of CT7001 (and Fulvestrant, where applicable) (Cmax)(After the first dose and during the dosing period)
- Area Under the Curve (AUC)(After the first dose and during the dosing period)
- Anti-tumour Activity according to RECIST v1.1(Baseline until disease progression or withdrawal from the study)