NCT05272709招募中1 期
CURATE: A Cancer Research UK Phase I/II, Dose Escalation and Expansion Trial of TT-702, A Selective Adenosine A2BR Antagonist, Given Orally as a Monotherapy Agent and in Combination, in Patients With Advanced Solid Tumours
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 60
- 试验地点
- 3
- 主要终点
- Number of Dose Limiting Toxicities (DLTs) (Dose Escalation Phase)
研究概览
简要总结
This clinical trial is evaluating the drug candidate TT-702 in patients with advanced solid tumours. The main aims of the trial are to determine the maximum dose of TT-702 that can be given safely to patients alone and in combination with other anti-cancer agents.
详细描述
TT-702 is a 'small molecule prodrug'. TT-702 is converted into TT-478, which then targets and blocks the function of the 'A2B adenosine receptor'. It is hoped that by blocking this receptor the immune system will become more active in recognising and removing tumour cells.
This clinical trial has two phases:
- Phase I, dose escalation phase - groups of patients will receive increasing doses of TT-702 to find an optimal dose that best targets the tumours. This phase will consist of both monotherapy and combination escalation cohorts. In the combination escalation cohorts, TT-702 will be evaluated in combination with an anti-PD-1/PD-L1 agent to be assessed in patients with Mismatch Repair deficiency (MMRd) tumours or patients with non-MMRd tumours in one of the following subtypes: colorectal cancer (CRC), metastatic castration-resistant prostate cancer (mCRPC), non-small cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC), triple-negative breast cancer (TNBC).
- Phase II, expansion phase - larger groups of patients will receive the selected dose of TT-702 considered to be optimal in the Phase I, dose escalation phase. This phase will consist of one monotherapy expansion cohort and one combination expansion cohort. In the combination expansion cohorts, TT-702 will be evaluated in combination with an anti-PD-1/PDL1 agent. Potential agents for further combination expansion cohorts have not yet been defined.
The main aims of this trial are to:
- Find the maximum dose of TT-702 as a monotherapy and in combination with other anti-cancer drugs that can be given safely to patients.
- Define the side effects of TT-702 and how these can be managed.
- Determine the pharmacokinetics (PK) and elimination kinetics of TT-702.
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
- 16 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Be able to provide informed consent and be capable of co-operating with IMP administration, procedures and follow-up.
- •Be willing to provide samples (blood and tissue) as required.
- •Consent to access any available archival tissue.
- •Consent for fresh tumour biopsy samples at baseline and on trial (may be Investigator mandated for patients in the dose escalation phase. Investigators will consider whether a biopsy is feasible for the patient in the dose escalation phase and this will not impede participation in the trial if biopsy is not a suitable option.
- •Life expectancy estimated by the Investigator to be at least 12 weeks.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-
- •Aged 16 years or over at the time consent is given.
- •Haematological and biochemical indices within the protocol specified ranges.
- •Objectively or measurable evaluable disease, radiologically according to RECIST Version 1.1 (and/or, in mCRPC patients, according to PCWG3 criteria). Has radiological disease progression (and/or, in mCRPC patients, PSA progression according to PCWG3 criteria) at the time of trial enrolment.
- •Castrate levels of testosterone (<1.7 nmol/L [50 ng/dL]) (mCRPC patients only).
- •Phase I, dose escalation phase
- •Histologically or cytologically proven advanced solid tumours refractory to conventional treatment, or for which no conventional therapy is considered appropriate by the Investigator or is declined by the patient. Phase I dose escalation cohorts are:
- •Phase I, Cohort 1M (TT-702 monotherapy cohort):
- •MMRd tumour, confirmed by either:
- •i. Loss of MSH2, MSH6, MLH1, PMS2 by ICH (total or near total) OR ii. Loss of function mutation f MMR gene(s) AND iii. High tumour mutation burden (depends on assay but typically >15 mutations/MB sequenced).
- •Non-MMRd tumours:
- •mCRPC: - Prior treatment with a next generation hormonal agent. - Adenocarcinoma without neuroendocrine or small cell features.
- •- Human epidermal growth factor receptor 2 negativity (negative immunohistochemistry [IHC] staining [score 0 or 1] or negative fluorescence in situ hybridisation based on the American Society of Clinical Oncology/College of American Pathologists guidelines and recommendations) and determined through local testing in NHS lab within UKAS/ISO 15198 scope of accreditation.
- •ER and progesterone receptor negativity (<1% positive staining cells in the invasive tumour) determined locally using IHC per American Society of Clinical Oncology/College of American Pathologists criteria.
- •Patients who have received prior anti-PD-1/anti-PD-L1 agent must have experienced Investigator-assessed initial clinical benefit from the most recent anti-PD-1/anti-PD-L1 treatment (either as monotherapy or in combination with other compounds) for at least 10 weeks, followed by subsequent progression. Initial benefit is defined as SD or better with an anti-PD-1/anti-PD-L1 therapy.
- •CRC, NSCLC and PDAC:
- •- Histologically or cytologically proven diagnosis of CRC, NSCLC or PDAC
- •Phase I, Cohort 1P (TT-702 & PD-1/PD-L1 combination cohort): Patients who have had prior treatment with an ICI.
- •Phase II (expansion phase)
- •Histologically or cytologically proven advanced solid tumour of particular interest based on preclinical and clinical data, refractory to conventional treatment or, for which no conventional therapy is considered appropriate by the Investigator or, is declined by the patient. Phase II expansion cohorts are:
- •Cohort 2M (TT-702 Monotherapy expansion cohort) and Cohort 2P (TT-702 & anti-PD-1/PD-L1 combination cohort):
- •Patients must have been previously treated with an ICI
- •MMRd tumour, confirmed by either:
- •i. Loss of MSH2, MSH6, MLH1, PMS2 by IHC (total or near total) OR ii. Loss of function mutation of MMR gene(s) AND iii. High tumour mutation burden (depends on assay but typically >15 mutations/MB sequenced).
排除标准
- •Radiotherapy (except single fractions for palliative reasons), endocrine therapy during the previous four weeks, immunotherapy and chemotherapy during the previous four weeks(previous six weeks for nitrosoureas, Mitomycin-C) before receiving TT-
- •A washout period of eight weeks is required for enzalutamide and apalutamide before the patient receives their first dose of TT-
- •A washout period of 4 weeks or 5 half-lives whichever is shorter for any other previous preceding IMPs is required before the patient receives their first dose of TT-702 (no washout is needed from ICI).
- •Patients with ongoing toxic manifestations of previous treatments greater than NCI CTCAE Version 5.0 Grade
- •Exceptions to this are alopecia and any ongoing toxic manifestation which in the opinion of the Investigator should not exclude the patient.
- •Patients with symptomatic brain or leptomeningeal metastases should be excluded. Asymptomatic patients with previously treated and stable brain metastases (in previous four weeks to trial entry) and not requiring any steroids are eligible for the trial. Patients who are stable on anticonvulsants are also eligible.
- •Women of childbearing potential (or are already pregnant or lactating). However, those patients who meet the following points are considered eligible:
- •Have a negative highly sensitive pregnancy test of a serum sample within 7 days prior to trial inclusion; and
- •Agree to use two forms of medically approved contraception: i. one highly effective form including but not limited to: oral, injected,implanted, transdermal or intravaginal hormonal contraception associated with inhibition of ovulation; intrauterine device; intrauterine hormonereleasing system, bilateral tubal occlusion or vasectomised partner; ii. plus a barrier method (for example, condom plus spermicide); iii. or agree to sexual abstinence. Effective from the first administration of TT-702, throughout the trial and for six months after the last administration of IMP.
- •Male patients with partners of childbearing potential. However, those patients who meet the following points are considered eligible:
- •Agree to take measures not to father children by using a barrier method of contraception [condom plus spermicide] or sexual abstinence effective from the first administration of IMP throughout the trial and for six months after the last administration of IMP.
- •Male patients with pregnant or lactating partners must be advised to use barrier method contraception (for example, condom plus spermicide) to prevent exposure of the foetus or neonate.
- •Non-vasectomised male patients must also be willing to ensure that any partner of childbearing potential uses a highly effective method of contraception (for example, oral, injected, implanted, transdermal or intravaginal hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system or bilateral tubal occlusion) or agree to sexual abstinence for the same duration.
- •Major thoracic or abdominal surgery from which the patient has not yet recovered.
- •At high medical risk because of non-malignant systemic disease including active uncontrolled infection. Patients with previous Hepatitis C exposure but no current infection are eligible to participate.
- •Known to be serologically positive for Hepatitis B, Hepatitis C or Human Immunodeficiency Virus (HIV).
- •Prior bone marrow transplant or have had extensive radiotherapy to greater than 25% of bone marrow within eight weeks.
- •Concurrent congestive heart failure, prior history of class II-IV cardiac disease (New York Heart Association [NYHA]), prior history of clinically significant cardiac ischaemia or prior history of clinically significant cardiac arrhythmia. Patients with significant cardiovascular disease are excluded as defined by:
- •a. History of congestive heart failure requiring therapy (NYHA III or IV); b. History of unstable angina pectoris or myocardial infarction up to six months prior to trial entry (patients with previous cardiac or thrombotic events who are now stable and or recovered are eligible); c. Presence of severe valvular heart disease; d. Presence of a ventricular arrhythmia requiring treatment; e. Left ventricular ejection fraction < 50%; f. Has a QTcF prolongation to >470 milliseconds (ms) based on a 12-lead ECG in triplicate; g. Previous stroke or transient ischaemic attack within 6 months of trial entry; h. History of clinically significant peripheral vascular disease/vasculitis/vasculopathy.
- •Is a participant or plans to participate in another interventional clinical trial, whilst taking part in this Phase I/II trial of TT-
- •Participation in an observational trial or interventional clinical trial which does not involve administration of an IMP and which would not place an unacceptable burden on the patient in the opinion of the Investigator would be acceptable.
- •Previous malignancies of other types, apart from adequately treated in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease for five years or more and are deemed at negligible risk for recurrence, are eligible for the trial.
- •A concomitant significant other illness that might in the opinion of the Investigator affect compliance with the protocol or interpretation of results, examples include but are not limited to autoimmune diseases or immune deficiency, or other disease with ongoing fibrosis (such as scleroderma, pulmonary fibrosis, emphysema, neurofibromatosis, palmar/plantar fibromatosis), alcoholic hepatitis, cirrhosis, and inherited liver disease, previous organ transplantation, uncontrolled or poorly controlled diabetes mellitus (for example HbA1c >10%) and patients with non-alcoholic steatohepatitis.
- •History of an immune-mediated adverse event of Grade 3 or above attributed to prior cancer immunotherapy that resulted in permanent discontinuation of the prior immunotherapeutic agent. Immune-mediated adverse events related to prior immunomodulatory therapy (other than endocrinopathy managed with replacement therapy or stable vitiligo) that have not either resolved completely to baseline or are Grade ≤2 in severity.
- •Patients on systemic corticosteroids (apart from replacement doses for endocrinopathy up to an equivalent of 10 mg QD prednisolone). Topical or inhaled steroids for pre-existent diseases are allowed.
- •Patients who received a live vaccine within 30 days before trial enrolment are excluded.
- •Patients with a known or suspected history of hypersensitivity or allergy to TT-702, or any of its excipients (for any strength) are excluded:
- •TT-702 10 mg strength, excipients: hydroxypropyl cellulose, sodium lauryl sulfate, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium and magnesium stearate;
- •TT-702 40 mg strength, excipients: hydroxypropyl cellulose, sodium lauryl sulfate, mannitol, croscarmellose sodium and magnesium stearate;
- •TT-702 120 mg strength, excipients: poloxamer-188, sodium lauryl sulfate, mannitol, croscarmellose sodium and magnesium stearate in hydroxypropyl methylcellulose (HPMC) capsules;
- •TT-478 (also known as GS-6201 or CVT-6883).
- •Patients who take therapies that inhibit or induce CYP3A must be excluded.
- •Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial.
- •If a patient is taking any dietary supplements or complementary medicines/botanicals, the Sponsor's Centre for Drug Development (CDD) must be informed at the earliest opportunity both prior to enrolment and during the patient's time on trial.
研究组 & 干预措施
Cohort 2M: (Monotherapy expansion cohort)
Experimental
This cohort will recruit patients with MMR defective tumours who have had prior treatment with an immune checkpoint inhibitor (ICI).
干预措施: TT-702 (Drug)
Cohort 1P (Combination escalation cohort)
Experimental
This cohort will recruit patients who have had prior treatment with an ICI.
干预措施: Anti-PD-1 and PD-L1 agent (Drug)
Cohort 2P (Combination expansion cohort)
Experimental
This cohort will recruit patients with MMRd tumours who have had prior treatment with an ICI.
干预措施: Anti-PD-1 and PD-L1 agent (Drug)
Cohort 1M (Monotherapy escalation cohort)
Experimental
This cohort will recruit patients with MMRd tumours or non-MMRd CRC, mCRPC, NSCLC, PDAC, TNBC.
干预措施: TT-702 (Drug)
结局指标
主要结局
Number of Dose Limiting Toxicities (DLTs) (Dose Escalation Phase)
时间窗: From the first dose in Cycle 0, until completion of Cycle 1 (3 weeks [+ 3-9 days to account for initial pharmacokinetic (PK) profiling period following the Cycle 0 dose]).
Dose Limiting Toxicities to TT-702 are determined by testing increasing doses of TT-702 administered once daily in continuous 21-day cycles in escalation cohorts. Dose limiting toxicities are defined per protocol as a highly probably or probably TT-702-related adverse events (AEs) of neutropenia, thrombocytopenia, non-haematological toxicities, photosensitivity, death or other drug-related toxicity causing TT-702 interruption, occurring during Cycle 0 or Cycle 1 administration.
Number of Treatment-Emergent AEs (TEAEs), Related TEAEs and Grade 3, 4 or 5 TEAEs (Dose Escalation Phase)
时间窗: From the time of first dose until the end of the safety follow-up period for TT-702.
Number of TEAEs, TEAEs related to TT-702 and Grade 3, 4 or 5 TEAEs in the dose escalation phase. AEs are categorised according to Medical Dictionary for Regulatory Activities (MedDRA) and graded for severity according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) versions applicable at time of reporting. AEs are assessed by the reporting study doctors for a causal relationship to TT-702. Related are those AEs with a causality of possible, probable or highly probable. All AEs are collected until the off-study visit, approximately 21 (±7) days after the final dose of TT-702 and TT-702-related AEs present at the off-study visit are to be followed up monthly until resolution, return to baseline, stabilisation or initiation of another anti-cancer treatment.
Objective Response Rate (ORR)
时间窗: From the first dose and until the final radiological disease assessment at the off-study visit.
ORR is defined as the proportion of participants with a confirmed Complete Response (CR) or Partial Response (PR) at 6 months (Expansion Phase) and is used to assess antitumour activity according to PCWG3 or RECIST v1.1 criteria. Responses must be confirmed by repeat assessment ≥4 weeks after initial response criteria are met.
Number and Percentage of Participants that Achieved Clinical Benefit Assessed by PCWG3 and RECIST v1.1 (Expansion Phase)
时间窗: From the first dose and until the final radiological disease assessment at the off-study visit.
Antitumour activity measured according to PCWG3 and RECIST version 1.1. Complete Response or PR/remission is confirmed by repeat measurements ≥4 weeks after response criteria are met; participants with SD are to meet criteria at least once ≥6 weeks after first dose of TT-702. Clinical Benefit Rate is defined as the proportion of participants with absence of disease progression (i.e. confirmed CR, PR or SD) for at least 24 weeks from the start of trial treatment.
次要结局
- Measurement of Maximum (or Peak) Plasma Concentration (Cmax) of TT-702 and its Active Product, TT-478, as Appropriate (Dose Escalation and Expansion Phase)(From the first dose of TT-702 until the discontinuation visit (max 12 months).)
- Measurement of Minimal Plasma Concentration (Cmin) of TT-702 and its Active Product, TT-478, as Appropriate (Dose Escalation and Expansion Phase)(From the first dose of TT-702 until the discontinuation visit (max 12 months).)
- Measurement of Time at Cmax (Tmax) of TT-702 and its Active Product, TT-478, as Appropriate (Dose Escalation and Expansion Phase)(From the first dose of TT-702 until the discontinuation visit (max 12 months).)
- Area Under the Curve (AUC) of TT-702 and its active product, TT-478, as appropriate (Dose Escalation and Expansion Phase)(From the first dose of TT-702 until the discontinuation visit (max 12 months).)
- Apparent Clearance of TT-702 and its Active Product, TT-478, as Appropriate (Dose Escalation and Expansion Phase)(From the first dose of TT-702 until the discontinuation visit (max 12 months).)
- Volume of Distribution of TT-702 and its Active Product, TT-478, as Appropriate (Dose Escalation and Expansion Phase)(From the first dose of TT-702 until the discontinuation visit (max 12 months).)
- Terminal Elimination Half-Life (T1/2) of TT-702 and its Active Product, TT-478, as Appropriate (Dose Escalation and Expansion Phase)(From the first dose of TT-702 until the discontinuation visit (max 12 months).)
- Objective Response Rate Defined as the Proportion of Participants with Confirmed CR or PR According to PCWG3 or RECIST v1.1 at 6 Months (Dose Escalation Phase)(From the first dose until the final radiological assessment at the off-study visit.)
- Number and Percentage of Participants that Achieved Clinical Benefit Assessed by PCWG3 or RECIST v1.1 (Dose Escalation Phase)(From the first dose and until the final radiological disease assessment at the off-study visit.)
- Objective Response Rate Defined as the Proportion of Participants with Confirmed CR or PR According to PCWG3 or RECIST v1.1 at Cycles 3, 6, 9, 12 (Dose Escalation and Expansion Phase)(From the first dose and until the final radiological disease assessment at the off-study visit.)
- Objective Response Rate Defined as the Proportion of Participants with Confirmed CR or PR According to PCWG3 or RECIST v1.1 at Any Timepoint (Dose Escalation and Expansion Phase)(From the first dose and until the final radiological disease assessment at the off-study visit.)
- Median Duration of Response and 90% Confidence Interval for Participants that Achieved a Confirmed Response (Dose Escalation and Expansion Phase)(From the first dose and until the final radiological disease assessment at the off-study visit.)
- Median Duration of Clinical Benefit and 90% Confidence Interval for Participants that Achieved Clinical Benefit (Dose Escalation and Expansion Phase)(From the first dose and until the final radiological disease assessment at the off-study visit.)
- Number and Percentage of Participants who Remained Progression Free at 6 Months with 90% Confidence Intervals (Dose Escalation and Expansion Phase)(From the first dose and until confirmation of progression, at the 6-month timepoint.)
- Number and Percentage of Participants who are Alive at 12 Months with Associated 90% Confidence Intervals (Dose Escalation and Expansion Phase)(From the first dose and until confirmation of alive or deceased from any cause, at the 12-month timepoint.)
- Number of TEAEs, related TEAEs, and Grade 3, 4 or 4 TEAEs (Dose Expansion Phase)(From the time of first dose until the end of the safety follow-up period for TT-702.)
研究者
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