NCT04969315招募中1 期
A Phase 1/1b, Open-Label, First-in-Human Multicenter Study to Assess the Safety, Tolerability, Preliminary Efficacy, Pharmacokinetics, and Pharmacodynamics of Oral TT-10 (an Adenosine 2A Receptor Antagonist), and TT-4 Diacid (an Adenosine 2B Receptor Antagonist), as Single Agents and in Combination in Participants With Advanced Selected Solid Tumors
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
- 35
- 试验地点
- 5
- 主要终点
- Number of subjects with Dose Limiting Toxicities (DLTs) of TT-10, TT-4 and TT-10 + TT-4 during the dose escalation phase
研究概览
简要总结
The goal of this clinical trial is to evaluate TT-10, TT-4 and TT-10 + TT-4, (Dual Blockade) in participants with advanced selected solid tumors, who have failed or are not eligible for standard of care. The main questions it aims to answer are:
- To evaluate the safety and tolerability of TT-10, TT-4 Diacid, and combination therapy (TT-10 + TT-4 Diacid).
- To determine the maximum tolerated dose (MTD) or phase 2 recommended dose of TT-10, TT-4 Diacid, and combination therapy (TT-10 + TT-4 Diacid).
- To evaluate safety of combination therapy (TT-10 + TT-4 Diacid).
详细描述
This is a Phase 1/1b, multicenter, open-label, non-randomized, multi-cohort study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of TT-10 (A2A receptor antagonist) and TT-4 Diacid (A2B receptor antagonist) administered orally as single agents and, in selected participants, as a sequential add-on combination regimen in participants with advanced selected solid tumors.
This study is planned to be conducted at approximately 5 sites in Unites States.
The study consists of a Phase 1 dose escalation/safety lead-in and a Phase 1b dose/regimen optimization (and limited expansion, if applicable).
All participants will undergo pre-treatment screening, on-study assessments for safety and clinical activity, and post-treatment follow-up for at least 30 days (+7 days) after the final dose. A treatment cycle is defined as 28 days.
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
- •To be eligible for inclusion in the dose escalation cohorts or expansion cohorts in this study, participants must meet all of the following criteria:
- •Male or female participants must be ≥18 years of age on the day of signing the ICF.
- •Participants or their legal representative must be able to provide written informed consent to participate in the study prior to the performance of any study-specific procedures.
- •Diagnosis of histologically or cytologically confirmed advanced selected solid tumors:
- •All Cohorts
- •RCC: Participants with locally advanced or metastatic RCC who have previously received at least two prior standard of care systemic regimens for advanced disease. Prior exposure to a checkpoint inhibitor and/or vascular endothelial growth factor (VEGF) targeted therapy is permitted but not required. Prior HIF-2α inhibitor therapy is permitted and may count toward the number of prior systemic regimens.
- •CRPC: Participants with metastatic CRPC who have previously received a second-generation hormonal agent (unless contraindicated) and a taxane-based chemotherapy.
- •Non-small cell lung cancer (NSCLC): Participants with metastatic NSCLC that are intolerant or resistant to standard systemic therapy or for whom no standard therapy is available. Prior exposure to platinum-based chemotherapy should be limited to no more than two prior cytotoxic chemotherapy regimens (e.g. platinum doublets, docetaxel, gemcitabine, vinorelbine, taxanes) administered for advanced/metastatic disease. Adjuvant or neoadjuvant chemotherapy does not count toward this limit.
- •Cohort C Only d. PM: Participants with unresectable, metastatic PM with any subtype that have progressed after, or are intolerant to, at least one line of standard systemic therapy (e.g., platinum-pemetrexed ± immune checkpoint inhibitor) and ≤3 prior lines of systemic therapy (biologic or chemotherapy are allowed). Maintenance therapy after 4-6 cycles of front-line chemotherapy is still considered 1 line of therapy and is not considered 2 separate therapies.
- •Eastern Cooperative Oncology Group (ECOG) performance status (PS) score 0 - 2
- •a. Participants with ECOG PS 2 must have performance decline attributable to cancer rather than comorbid conditions, in the judgment of the investigator.
- •Have measurable disease per RECIST 1.1 (Eisenhauer et al 2009) except as specified below and as assessed by the local site investigator/radiology. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
- •PM: modified RECIST (mRECIST) (Nowak et al 2018) will be applied for malignant pleural mesothelioma
- •Measurable CRPC: Prostate Cancer Working Group 3 (PCWG3; Scher et al 2016). Participants with CRPC who have metastatic disease that is non-measurable are eligible if screening PSA ≥2.0 ng/mL and with Sponsor approval
- •Failure to respond to standard therapy, or for whom no appropriate therapies are available (based on the judgment of the investigator)
- •Consent to baseline biopsy, with the following exceptions:
- •Participants whose only site(s) of disease are in areas considered moderate or high risk, as defined in Section 7.2.9 may be enrolled without a fresh biopsy with Sponsor approval;
- •Archival tissue may be submitted in lieu of a fresh biopsy if collected within 6 months of screening and without intervening systemic therapy.
- •Participants must have adequate hematologic function based on the following:
- •ANC ≥1.5 × 109/L
- •Platelet count ≥100 × 109/L
- •Hemoglobin ≥9.0 g/dL
- •Participants must have adequate hepatic function based on the following:
- •Total bilirubin <1.5 × upper limit of normal (ULN) (unless elevated due to Gilbert's syndrome)
- •ALT/AST ≤2.5 × ULN (≤5 × ULN for participants with known hepatic metastases)
- •Participants must have adequate renal function, defined as serum creatinine clearance ≥30 mL/min per Cockcroft-Gault formula.
- •For women of childbearing potential (WCBP): negative urine pregnancy test (UPT) within 1 week before first treatment (WCBP defined as a sexually mature woman who has not undergone surgical sterilization or who has not been naturally post-menopausal for at least 12 consecutive months for women >55 years of age). WCBP should be placed on effective birth control directly after testing negative for pregnancy; if not, then WCBP should have a UPT on Day 1 of every cycle, prior to study intervention administration. Any positive or indeterminant UPT result must be confirmed by serum.
- •a. Female participants of childbearing potential must use a highly effective mode of contraception or abstain from heterosexual activity for the duration of the study and for 120 days following the last dose of study intervention. A female is NOT of childbearing potential if she has undergone bilateral salpingoophorectomy or is menopausal, defined as an absence of menses for 12 consecutive months. Male participants must agree to use highly effective contraception.
- •Ability to adhere to the study visit schedule and all protocol requirements
- •Any gastrointestinal condition that would preclude the use of oral medications (e.g. difficulty swallowing, nausea, vomiting or malabsorption).
排除标准
- •Participants will be excluded from the study if they satisfy any of the following criteria at the Screening visit unless otherwise stated:
- •Participants are to be excluded from the study if they meet any of the following criteria:
- •Major surgery within 4 weeks prior to Screening
- •Participants with active CNS metastases are excluded.
- •a. Participants with treated CNS metastases are eligible provided all of the following are met: i. Definitive local therapy completed (surgery and/or radiotherapy, including SRS or WBRT) ≥4 weeks before first dose; ii. Neurologically stable (no new/worsening neurologic signs/symptoms attributable to CNS disease) for ≥2 weeks prior to first dose; iii. No evidence of progression of CNS lesions on screening brain MRI (baseline MRI required at Screening); iv. Off corticosteroids, or on a stable/decreasing dose not exceeding ≤10 mg prednisone equivalent/day for ≥7 days prior to first dose (physiologic replacement permitted); v. No leptomeningeal metastases (LMD excluded). b. Leptomeningeal metastases are not eligible.
- •Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
- •Prior anti-cancer therapy within 4 weeks prior to the start of study intervention. A 2 week washout is acceptable for short-acting drugs (e.g., tyrosine kinase inhibitors). Any treatment-related toxicities must be resolved to Grade 0 -
- •Human immunodeficiency virus (HIV)-infected participants
- •Participants who are hepatitis B surface antigen positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to enrollment (Note: Participants should remain on antiviral therapy throughout study intervention and follow local guidelines for HBV antiviral therapy post completion of study intervention). Hepatitis B screening tests are not required unless:
- •Known history of HBV infection
- •As mandated by local health authority
- •Participants with a history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at Screening. Note: Participants must have completed curative antiviral therapy at least 4 weeks prior to enrollment. Hepatitis C screening tests are not required unless:
- •Known history of HCV infection
- •As mandated by local health authority
- •Participants requiring immunosuppressive therapy: Participants who require systemic immunosuppressive therapy at Screening or within 14 days prior to first dose are excluded. Systemic immunosuppressive therapy includes, but is not limited to, chronic corticosteroids at >10 mg/day prednisone equivalent, and other systemic immunosuppressants or biologic agents (e.g., cyclosporine, mycophenolate, azathioprine, methotrexate, TNF inhibitors such as adalimumab/infliximab, vedolizumab, JAK inhibitors such as tofacitinib, dupilumab, rituximab, or similar agents).
- •a. Permitted exceptions: i. Physiologic corticosteroid replacement for documented adrenal insufficiency (e.g., hydrocortisone replacement) is permitted.
- •ii. Inhaled, intranasal, topical steroids, and short courses of systemic steroids for non-immune indications (e.g., premedication for imaging contrast, antiemetic prophylaxis) may be permitted at the Investigator's discretion.
- •iii. Local steroid injections (e.g., intra-articular) may be permitted if not expected to result in systemic immunosuppression.
- •b. Washout: A minimum 14-day washout from systemic immunosuppressive therapy prior to first dose may be permitted based on Investigator judgment and Medical Monitor approval, provided the underlying condition is stable and the participant does not require ongoing immunosuppression.
- •Participants requiring administration of drugs known to be strong inhibitors or inducers of CYP3A4, 2C9 or 2C19
- •Participants requiring drugs that modify gastric pH, such as proton-pump inhibitors (PPIs) or H2 blockers. Antacids, such as calcium carbonate or aluminum hydroxide-based products, will be allowed during the study, but are recommended to be taken either 4 hours before or 2 hours after dosing of TT-10 or TT-4 Diacid.
- •Ongoing systemic bacterial, fungal or viral infections at Screening Note: Participants on antimicrobial, antifungal or antiviral prophylaxis are not specifically excluded if all other inclusion/exclusion criteria are met
- •Administration of a live vaccine within 6 weeks of first dose of study intervention. Messenger ribonucleic acid (mRNA) vaccines for the prevention of Coronavirus Disease 2019 (COVID-19) infection are permitted.
- •Baseline QT interval corrected with Fridericia's method (QTcF) >470 ms (average of triplicate readings) Note: Criterion does not apply to participants with a right or left bundle branch block.
- •Prior surgery or gastrointestinal dysfunction that may affect drug absorption (e.g., gastric bypass surgery, gastrectomy)
- •Female participants who are pregnant or breastfeeding
- •Concurrent active malignancy other than non-melanoma skin cancer, carcinoma in situ of the cervix or prostate intraepithelial neoplasia
- •Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease
- •History of peptic ulcer and/or gastrointestinal bleed within the past 6 months prior to Screening
- •History of stroke, unstable angina, myocardial infarction or ventricular arrhythmia requiring medication or mechanical control within the last 6 months prior to Screening
- •Unstable or severe uncontrolled medical condition (e.g., unstable cardiac function, unstable pulmonary condition including pneumonitis and/or interstitial lung disease, uncontrolled diabetes), current evidence of uncontrolled hypertension despite optimal medical management at screening, or any important medical illness or abnormal laboratory finding that would, in the investigator's judgment, increase the risk to the participant associated with his or her participation in the study
研究组 & 干预措施
Cohort A: Dose Escalation
Experimental
Drug: TT-10 (A2A Receptor Antagonist)
-
Supplied in capsules for daily oral administration twice a day (BID)
-
One cycle is considered 28 days
-
Ascending Dose levels are being explored
-
Dose Level 1
-
Dose Level 2
-
Dose Level 3
-
Dose Level 4* *Additional dose levels may be explored, if appropriate based on emerging safety, PK or pharmacodynamic data
干预措施: TT-10 (Drug)
Cohort-C TT-4 Accelerated Titration w/Optional Intra-Participant Escalation MPM
Experimental
TT-4 diacid will be administered orally once daily (QD) in 28-day treatment cycles. Dose Levels evaluated in Cohort C are 200 mg QD (Dose Level 0), 400 mg QD (Dose Level 1), and 800 mg QD (Dose Level 2; target dose).
干预措施: TT-10 (Drug)
Cohort-C TT-4 Accelerated Titration w/Optional Intra-Participant Escalation MPM
Experimental
TT-4 diacid will be administered orally once daily (QD) in 28-day treatment cycles. Dose Levels evaluated in Cohort C are 200 mg QD (Dose Level 0), 400 mg QD (Dose Level 1), and 800 mg QD (Dose Level 2; target dose).
干预措施: TT-4 (Drug)
Cohort B: Dose Escalation/Safety Lead-In
Experimental
Drug: TT-4 (A2B Receptor Antagonist)
-
Supplied in capsules for daily oral administration once a day (QD)
-
One cycle is considered 28 days
-
During Cycle 1 (28 days), participants will receive TT-4 monotherapy at the assigned dose level for safety evaluation
-
Ascending Dose levels are being explored
-
Dose Level 1
-
Dose Level 2
-
Dose Level 3*
-
*Additional dose levels or frequency may be explored, if appropriate based on emerging safety, PK or pharmacodynamic data
Drug: TT-10 (A2A Receptor Antagonist)
- Supplied in capsules for daily oral administration once a day (QD)
- One cycle is considered 28 days
- During Cycle 2 (28 days), participants may initiate TT-10 + TT-4 at the assigned dose level from Cycle 1 for safety evaluation
干预措施: TT-4 (Drug)
结局指标
主要结局
Number of subjects with Dose Limiting Toxicities (DLTs) of TT-10, TT-4 and TT-10 + TT-4 during the dose escalation phase
时间窗: 28 Days
All toxicities will be graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0
Define the maximum tolerated dose (MTD) or phase 2 recommended dose of TT-10, TT-4 and TT-10 + TT-4 during the dose escalation phase
时间窗: Through study completion, an average of 1 year
To confirm the maximum tolerated dose (MTD) of TT-10, TT-4 and TT-10 + TT-4, defined as the highest dose level at which \<2 out of 6 participants experience a dose-limiting toxicity
Expansion cohort primary objective - safety
时间窗: Through study completion, an average of 1 year
Incidence and severity of treatment-related adverse events (TRAEs) in participants treated at the recommended phase 2 dose in the expansion phase
次要结局
- Overall Response Rate (ORR)(From study enrollment until participant discontinuation, first occurrence of progressive disease, or death from any cause, whichever occurs first (approximately 2 years))
- Duration of Response (DoR)(From study enrollment until participant discontinuation, first occurrence of progressive disease, or death from any cause, whichever occurs first (approximately 2 years))
- Progression Free Survival (PFS)(From study enrollment until participant discontinuation, first occurrence of progressive disease, or death from any cause, whichever occurs first (approximately 2 years))
- Peak serum concentration (Cmax) of TT-10(Predose, 0.5, 1, 2, 4, 6, 8, 24 hours post-dose)
- Area under the serum concentration versus time curve (AUC) of TT-10(Predose, 0.5, 1, 2, 4, 6, 8, 24 hours post-dose)
- Half-life of TT-10(Predose, 0.5, 1, 2, 4, 6, 8, 24 hours post-dose)
研究者
研究点 (5)
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