A Phase 1 Study of AG-270 in the Treatment of Subjects With Advanced Solid Tumors or Lymphoma With Homozygous Deletion of MTAP
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 123
- 试验地点
- 8
- 主要终点
- Percentage of Participants with DLTs Associated with the Combination of AG-270 and Docetaxel Administration During the First Cycle (First 28 Days) of Treatment
研究概览
简要总结
This study will evaluate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of AG-270 in participants with advanced solid tumors or lymphoma with homozygous MTAP deletion.
详细描述
The purpose of this Phase 1, multicenter, open-label study is to determine the maximum tolerated dose (MTD) of AG-270, administered as a single agent or in combination with taxane-based chemotherapy, and to characterize its dose-limiting toxicities (DLTs) when given daily by mouth to participants with advanced solid tumors or lymphoma with homozygous deletion of methylthioadenosine phosphorylase (MTAP).
In each arm of the study, successive cohorts of participants will receive increasing oral doses of AG-270 to determine the MTD, the dose with maximum pharmacologic activity or the maximum feasible dose, as a single agent and in combination with taxane-based chemotherapy. In the subsequent dose-expansion parts of the study, additional participants in each treatment arm will be treated at the MTD (or one of the described alternative doses) to further characterize that dose's safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD), and to detect preliminary evidence of anti-tumor activity.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- •AG-270 Monotherapy
- •Be ≥18 years of age;
- •Have a histologically confirmed diagnosis of an advanced solid tumor or lymphoma that has progressed in spite of at least one prior line of treatment, and for which additional effective standard therapy is not available. For this study, effective standard therapy is defined as treatment that has been shown to be curative and/or to prolong survival. In addition, participants who are considered to not be candidates for standard therapy or who decline standard therapy are eligible for this study; in such cases, documentation of the reason for omitting or declining a standard therapy is required;
- •Have evidence of homozygous loss of cyclin-dependent kinase inhibitor 2A (CDKN2A) and/or MTAP in the participant's tumor tissue;
- •Have disease that can be clinically evaluated for improvement or progression. In the dose-expansion phase of the study arm, participants must have disease that is measurable, as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria for solid tumors (Eisenhauer et al, 2009) or the Lugano criteria for lymphoma (Cheson et al, 2014);
- •Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤2;
- •Have a hemoglobin ≥9.0 grams per deciliter (g/dL) without red blood cell transfusion for ≥1 month;
- •Have an absolute neutrophil count (ANC) ≥1.0 × 10^9/liter (L);
- •Have a platelet count ≥75 × 10^9/L;
- •Have a serum total bilirubin ≤1.5 × upper limit of normal (ULN);
- •Have an alanine aminotransferase (ALT) ≤3.0 × ULN. (Note: There are no specific requirements for aspartate aminotransferase (AST) or Alkaline phosphatase [ALP]);
- •Have a serum creatinine ≤1.5 × ULN;
- •Be fully recovered from major surgery and from the acute toxic effects of prior chemotherapy and radiotherapy. Residual chronic toxicities of prior therapy ≤Grade 2 (eg, peripheral neuropathy, residual alopecia) are allowed;
- •Female participants who are pre-menopausal or have experienced menopause for less than 2 years and who have not undergone a hysterectomy, bilateral oophorectomy, or tubal occlusion must have a negative serum pregnancy test during screening and a serum or urine pregnancy test must be re-confirmed as negative no more than 72 hours before starting AG-
- •Females of reproductive potential as well as fertile men with partners who are female of reproductive potential must agree to abstain from sexual intercourse or to use 2 effective forms of contraception (including at least 1 barrier form) from the time of giving informed consent, during the study, and for 6 months (for females) and for 3 months (for males) following the last dose of AG-
- •Effective forms of contraception are defined as hormonal oral contraceptives, injectables, patches, intrauterine devices, double-barrier methods (eg, synthetic condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel), or male partner sterilization;
- •Able to understand and has provided written informed consent. A legally authorized representative may consent on behalf of a participant who is otherwise unable to provide informed consent, if acceptable to and approved by the site and/or site's Institutional Review Board (IRB)/Independent Ethics Committee (IEC).
- •AG-270 in Combination with Docetaxel
- •a. Be ≥18 years of age;
- •a. Have histologically confirmed diagnosis of non-small cell lung cancer (NSCLC) that has been treated with no more than 2 prior lines of cytotoxic chemotherapy in the setting of metastatic (Stage 4) disease. Three prior lines of cytotoxic chemotherapy for metastatic disease are allowed if one of the 3 lines was a maintenance treatment. Participants with solid tumors other than NSCLC for which docetaxel is indicated are eligible for the dose-escalation arm, but they also must have received no more than 2 prior lines of cytotoxic chemotherapy in the setting of metastatic disease; For both participants with NSCLC and participants with other malignancies prior treatment with taxanes is permitted, but prior treatment with docetaxel is not allowed. There is no limitation on the number of non-cytotoxic therapies that a participant with NSCLC or with another malignancy may have received;
- •a. Have evidence of homozygous loss of CDKN2A and/or MTAP in the participant's tumor tissue. In the dose expansion phase of the combination, participants must have homozygous MTAP deletion;
- •a. Have disease that can be clinically evaluated for improvement or progression. In the dose-expansion phase of this study arm, participants must have disease that is measurable, as defined by the RECIST Version 1.1 criteria for solid tumors (Eisenhauer et al, 2009);
- •a. Have an ECOG PS of ≤1;
- •a. Have a hemoglobin ≥9.0 g/dL without red blood cell transfusion for ≥1 month;
- •a. Have an ANC ≥1.5 × 10^9/L;
- •a. Have a platelet count ≥100 × 10^9/L;
- •a. Have a serum total bilirubin ≤1.5 × ULN;
- •a. Have an ALT ≤3.0 × ULN. If ALP is >2.5 × ULN and the increase in ALP cannot be attributed to bone metastases or other bone disease then the participant must have ALT and AST values that are both <1.0 × ULN; this requirement conforms with the current label for Taxotere®;
- •a. Have a serum creatinine ≤1.5 × ULN;
- •a. Meet any criteria necessary for the safe and proper use of docetaxel;
- •a. Be fully recovered from major surgery and from the acute toxic effects of prior chemotherapy and radiotherapy. Residual chronic toxicities of prior therapy ≤ Grade 2 (eg, peripheral neuropathy, residual alopecia) are allowed;
- •a. Female participants who are pre-menopausal or have experienced menopause for less than 2 years and who have not undergone a hysterectomy, bilateral oophorectomy, or tubal occlusion must have a negative serum pregnancy test during Screening and a serum or urine pregnancy test must be re-confirmed as negative no more than 72 hours before starting AG-
- •Females of reproductive potential as well as fertile men with partners who are female of reproductive potential must agree to abstain from sexual intercourse or to use 2 effective forms of contraception (including at least 1 barrier form) from the time of giving informed consent, during the study, and for 6 months (for females) and for 3 months (for males) following the last dose of AG-
- •Effective forms of contraception are defined as hormonal oral contraceptives, injectables, patches, intrauterine devices, double-barrier methods (eg, synthetic condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel), or male partner sterilization;
- •a. Able to understand and has provided written informed consent. A legally authorized representative may consent on behalf of a participant who is otherwise unable to provide informed consent, if acceptable to and approved by the site and/or site's IRB/IEC.
- •AG-270 in Combination with nab-Paclitaxel and Gemcitabine
- •b. Be ≥18 years of age;
- •b. Have locally advanced or metastatic pancreatic ductal adenocarcinoma characterized by CDKN2A deletion and/or MTAP deletion;
- •b. Have evidence of homozygous loss of CDKN2A and/or MTAP in the participant's tumor tissue. In the dose expansion phase of the combination, participants must have homozygous MTAP deletion;
- •b. Have received no more than 1 previous line of cytotoxic chemotherapy for advanced or metastatic disease. Participants may have been treated with cytotoxic chemotherapy in the adjuvant setting if the final dose of such adjuvant treatment was given at least 6 months before administration of the first doses of AG-270, nab-paclitaxel, and gemcitabine; treatment with cytotoxic chemotherapy in the adjuvant setting will not be counted in the lines of previous cytotoxic chemotherapy for advanced or metastatic disease. There is no limitation on the number of non-cytotoxic therapies that a participant may have received;
- •b. Have an ECOG PS of ≤1;
- •b. Have a hemoglobin ≥9.0 g/dL without red blood cell transfusion for ≥1 month;
- •b. Have an ANC ≥1.5 × 10^9/L;
- •b. Have a platelet count ≥100 × 10^9/L;
- •b. Have a serum total bilirubin ≤1.5 × ULN;
- •b. Have an ALT ≤3.0 × ULN. (Note: There are no specific requirements for AST or ALP.);
- •b. Have a serum creatinine ≤1.5 × ULN;
- •b. Meet any criteria necessary for the safe and proper use of nab-paclitaxel and gemcitabine;
- •b. Be fully recovered from major surgery and from the acute toxic effects of prior chemotherapy and radiotherapy. Residual chronic toxicities of prior therapy ≤ Grade 2 (eg, peripheral neuropathy, residual alopecia) are allowed;
- •b. Female participants who are pre-menopausal or have experienced menopause for less than 2 years and who have not undergone a hysterectomy, bilateral oophorectomy, or tubal occlusion must have a negative serum pregnancy test during Screening and a serum or urine pregnancy test must be re-confirmed as negative no more than 72 hours before starting AG-
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排除标准
- 未提供
研究组 & 干预措施
AG-270
AG-270 will be administered on Days 1 to 28 of each 28-day cycle. Treatment will continue until disease progression or unacceptable toxicity.
干预措施: AG-270 (Drug)
AG-270/docetaxel
AG-270 will be administered daily, starting 1 week prior to docetaxel infusion. Starting on Cycle 1 Day 1, docetaxel (by intravenous infusion [IV]) will be administered once during each 21-day cycle. Treatment with AG-270 and docetaxel will continue until disease progression or unacceptable toxicity.
干预措施: AG-270 (Drug)
AG-270/docetaxel
AG-270 will be administered daily, starting 1 week prior to docetaxel infusion. Starting on Cycle 1 Day 1, docetaxel (by intravenous infusion [IV]) will be administered once during each 21-day cycle. Treatment with AG-270 and docetaxel will continue until disease progression or unacceptable toxicity.
干预措施: docetaxel (Drug)
AG-270/nab-paclitaxel/gemcitabine
AG-270 will be administered daily, starting 1 week prior to nab-paclitaxel and gemcitabine infusion. Starting on Cycle 1 Day 1, nab-paclitaxel and gemcitabine IV will be administered on Days 1,8, and 15 during each 28-day cycle. Treatment with AG-270, nab-paclitaxel, and gemcitabine will continue until disease progression or unacceptable toxicity.
干预措施: AG-270 (Drug)
AG-270/nab-paclitaxel/gemcitabine
AG-270 will be administered daily, starting 1 week prior to nab-paclitaxel and gemcitabine infusion. Starting on Cycle 1 Day 1, nab-paclitaxel and gemcitabine IV will be administered on Days 1,8, and 15 during each 28-day cycle. Treatment with AG-270, nab-paclitaxel, and gemcitabine will continue until disease progression or unacceptable toxicity.
干预措施: nab-paclitaxel (Drug)
AG-270/nab-paclitaxel/gemcitabine
AG-270 will be administered daily, starting 1 week prior to nab-paclitaxel and gemcitabine infusion. Starting on Cycle 1 Day 1, nab-paclitaxel and gemcitabine IV will be administered on Days 1,8, and 15 during each 28-day cycle. Treatment with AG-270, nab-paclitaxel, and gemcitabine will continue until disease progression or unacceptable toxicity.
干预措施: gemcitabine (Drug)
结局指标
主要结局
Percentage of Participants with DLTs Associated with the Combination of AG-270 and Docetaxel Administration During the First Cycle (First 28 Days) of Treatment
时间窗: Up to 28 days, on average
Percentage of Participants with DLTs Associated with AG-270 Administration During the First Cycle (First 28 Days) of Treatment
时间窗: Up to 28 days, on average
Percentage of Participants with DLTs Associated with the Combination of AG-270, nab-paclitaxel, and Gemcitabine Administration During the First Cycle (First 28 Days) of Treatment
时间窗: Up to 28 days, on average
次要结局
- Maximum Concentration (Cmax) of AG-270(At multiple time points up to 30 weeks, on average)
- Time to Maximum Concentration (Tmax) of AG-270(At multiple time points up to 30 weeks, on average)
- AUC from 0 to Infinity (AUC0-∞) of AG-270(At multiple time points up to 30 weeks, on average)
- Trough Concentration (Ctrough) of AG-270(At multiple time points up to 30 weeks, on average)
- Apparent Volume of Distribution (Vd/F) of AG-270(At multiple time points up to 30 weeks, on average)
- Apparent Clearance (CL/F) of AG-270(At multiple time points up to 30 weeks, on average)
- Duration of Response (DOR)(Up to 30 weeks, on average)
- Percentage of Participants with Treatment-related Adverse Events and Serious Adverse Events(Up to 30 weeks, on average)
- Changes in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Score(Up to 30 weeks, on average)
- Half-life (t1/2) of AG-270(At multiple time points up to 30 weeks, on average)
- Change from Baseline in Circulating Concentration of Methionine(Up to 30 weeks, on average)
- Clinical Activity of AG-270 in Solid Tumors as Assessed by RECIST V1.1(Up to 30 weeks, on average)
- Progression-free Survival (PFS)(Up to 30 weeks, on average)
- Area under the Concentration-versus-time Curve (AUC) from 0 to Time of Last Measurable Concentration (AUC0-t) of AG-270(At multiple time points up to 30 weeks, on average)
- AUC over One Dosing Interval at Steady State (AUCtau,ss) of AG-270(At multiple time points up to 30 weeks, on average)
- Change from Baseline in Circulating Concentration of S-adenosylmethionine (SAM)(Up to 30 weeks, on average)
- Clinical Activity of AG-270 in Lymphoma as Assessed by Lugano Criteria(Up to 30 weeks, on average)