Phase 1 Open Label, Multi-center, Dose-Escalation Study to Assess the Safety, Tolerability and Pharmacokinetics of Orally Administered Fimepinostat (CUDC-907), a PI3K and HDAC Inhibitor, in Subjects With Refractory or Relapsed Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Curis, Inc.
- 入组人数
- 106
- 试验地点
- 11
- 主要终点
- To determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of oral fimepinostat (CUDC-907) in combination with venetoclax and rituximab
研究概览
简要总结
This is a phase 1, open-label, dose-escalation study of fimepinostat (CUDC-907) in patients with relapsed and/or refractory diffuse large B-cell lymphoma (DLBCL), or high-grade B-cell lymphoma (HGBL) with or without MYC and BCL2 alterations. Fimepinostat (CUDC-907) is a multi-targeted agent designed to inhibit phosphoinositide 3-kinase (PI3K)and histone deacetylase (HDAC). The study is designed to assess the safety, the maximum tolerated dose, the recommended phase 2 dose (RP2D), pharmacokinetics and the anti-cancer activity of oral fimepinostat in combination with 1 or more anti-cancer regimens.
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
- •Patients ≥ 18 years of age with any of the following: Histopathologically confirmed DLBCL or HGBL (i.e., HGBL with MYC, BCL2, and/or BCL6 rearrangements, HGBL, not otherwise specified [NOS], or DLBCL, NOS) that is refractory to, or has relapsed after, treatment with at least 1 prior regimen. Eligible sub-types include DHL, THL, or DEL, as well as DLBCL or HGBL without MYC and/or BCL2 alterations. Criteria for DHL are concurrent MYC translocation+ and BCL2 translocation+ by fluorescence in situ hybridization (FISH) (same criteria for THL, which also includes BCL6 translocation+ by FISH); criteria for DEL are concurrent overexpression of MYC (≥ 40%) and BCL2 (> 50%) by immunohistochemistry (IHC).
- •Measurable disease by CT or PET/CT. MRI acceptable as per protocol.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 to
- •Recovery to Grade 1 or baseline of any toxicity due to prior systemic treatments (excluding alopecia).
- •Absolute neutrophil count ≥ 1,000/µL; platelets ≥ 75,000/µL for patients with no bone marrow involvement by malignancy; platelets ≥ 50,000/µL for patients with bone marrow involvement by malignancy.
- •Creatinine ≤ 1.5x upper limit of normal (ULN); total bilirubin ≤ 1.5x ULN; AST/ALT ≤ 2.5x ULN.
- •Life expectancy of at least 3 months.
排除标准
- •Intention to undergo stem cell transplant (SCT) or treatment with chimeric antigen receptor (CAR) T-cell therapy.
- •SCT therapy within 100 days prior to starting study treatment.
- •Systemic anti-cancer therapy or investigational agent within 3 weeks of study entry, except for nitrosoureas or mitomycin C (6 weeks).
- •Other non-cytotoxic anti-cancer therapy or investigational agent within 5 half-lives or 21 days prior to study treatment, whichever is shorter, as long as any drug related toxicities have resolved to Grade 1 or less. Dexamethasone up to 12 mg/d is allowed as supportive therapy and does not exclude participation.
- •Contraindication to venetoclax or rituximab.
- •Progressive disease during treatment or within 3 months of stopping prior treatment with a BCL2 inhibitor, histone deacetylase (HDAC) inhibitor, or phosphoinositide-3 kinase (PI3k) inhibitor, or prior discontinuation of any of these therapies due to clinically significant toxicity.
- •Graft vs. host disease following prior allogeneic transplant within 3 months prior to study treatment.
- •Ongoing treatment with chronic immunosuppressants.
- •Active CNS lymphoma.
- •Known gastrointestinal condition that would interfere with swallowing or the oral absorption or tolerance of fimepinostat.
- •Serious infection requiring systemic antibiotic therapy within 14 days prior to study treatment.
- •Uncontrolled or severe cardiovascular disease
- •Unstable or clinically significant concurrent medical condition.
- •Second primary malignancy within 2 years of study entry other than what is specified in the protocol.
- •Known HIV positive, hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection.
- •Active CMV infection, presence of CMV antigenemia, or evidence of any invasive CMV end organ disease (e.g., CMV colitis).
研究组 & 干预措施
Fimepinostat 30 mg - Combination w/ venetoclax
Fimepinostat 30 mg 5 days on/2 days off plus venetoclax. Different combinations of dose levels for venetoclax will be explored
干预措施: venetoclax (Drug)
Fimepinostat - Continuous Once Daily
Fimepinostat 30-60 mg/day
干预措施: fimepinostat (Drug)
Fimepinostat - 2x/week
Fimepinostat 60-240 mg/day
干预措施: fimepinostat (Drug)
Fimepinostat - 3x/week
Fimepinostat 60-180 mg/day
干预措施: fimepinostat (Drug)
Fimepinostat - 4x/week
Fimepinosta 60-180 mg/day
干预措施: fimepinostat (Drug)
Fimepinostat - 5x/week
Fimepinostat 60-180 mg/day
干预措施: fimepinostat (Drug)
Fimepinostat - Expansion 5x/week
Fimepinostat 60 mg on the 5 days on/2 days off
干预措施: fimepinostat (Drug)
Fimepinostat - Expansion 3x/week
Fimepinostat 120 mg 3 days on/4 days off
干预措施: fimepinostat (Drug)
Fimepinostat 60 mg - Combination w/ rituximab
Fimepinostat 60 mg 5 days on.2 days off plus rituximab
干预措施: fimepinostat (Drug)
Fimepinostat 60 mg - Combination w/ rituximab
Fimepinostat 60 mg 5 days on.2 days off plus rituximab
干预措施: Rituximab (Drug)
Fimepinostat 120 mg - Combination w/ rituximab
Fimepinostat 120 mg 3x/week plus rituximab
干预措施: fimepinostat (Drug)
Fimepinostat 120 mg - Combination w/ rituximab
Fimepinostat 120 mg 3x/week plus rituximab
干预措施: Rituximab (Drug)
Fimepinostat - Biocomparability Arm
Biocomparability Arm
干预措施: fimepinostat (Drug)
Fimepinostat 30 mg - Combination w/ venetoclax
Fimepinostat 30 mg 5 days on/2 days off plus venetoclax. Different combinations of dose levels for venetoclax will be explored
干预措施: fimepinostat (Drug)
Fimepinostat 60 mg - Combination w/ venetoclax
Fimepinostat 60 mg 5 days on/2 days off plus venetoclax. Different combinations of dose levels for venetoclax will be explored
干预措施: fimepinostat (Drug)
Fimepinostat 60 mg - Combination w/ venetoclax
Fimepinostat 60 mg 5 days on/2 days off plus venetoclax. Different combinations of dose levels for venetoclax will be explored
干预措施: venetoclax (Drug)
Fimepinostat - Combination w/ venetoclax and rituximab
Fimepinostat and venetoclax dosed at dose levels determined for that combination. Rituximab dosed at 375 mg/m2 IV on Day 1 of each 21 day cycle
干预措施: fimepinostat (Drug)
Fimepinostat - Combination w/ venetoclax and rituximab
Fimepinostat and venetoclax dosed at dose levels determined for that combination. Rituximab dosed at 375 mg/m2 IV on Day 1 of each 21 day cycle
干预措施: Rituximab (Drug)
结局指标
主要结局
To determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of oral fimepinostat (CUDC-907) in combination with venetoclax and rituximab
时间窗: At the end of cycle 1 or 2 (each cycle is 21 days)
To be evaluated in patients with relapsed and/or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBL). Within any given study arm, the highest dose level studied at which fewer than 2 out of 6 subjects (\< 33%) experience a dose limiting toxicity (DLT).
To assess the safety and tolerability of fimepinostat in combination with anti-cancer regimens by evaluating the number of participants with adverse events assessed using the NCI Common Terminology Criteria for Adverse Events (CTCAE, v4.0).
时间窗: 18 months
Number of participants with adverse events assessed using the NCI Common Terminology Criteria for Adverse Events (CTCAE, v4.0).
To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens by evaluating ORR
时间窗: 24 months
ORR assessments as measured using Lugano criteria.
To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens by evaluating DOR
时间窗: 24 months
DOR assessments as measured using Lugano criteria.
次要结局
- To assess pharmacokinetics (PK) of fimepinostat when administered in combination with anti-cancer regimens as measured by clearance (Cl).(Pre-dose to 21 - 28 days post dose)
- To assess pharmacokinetics (PK) of fimepinostat when administered in combination with anti-cancer regimens as measured by volume of distribution (Vd).(Pre-dose to 21 - 28 days post dose)
- To assess pharmacokinetics (PK) of fimepinostat when administered in combination with anti-cancer regimens as measured by area under the concentration-time curve (AUC).(Pre-dose to 21 - 28 days post dose)
- To assess pharmacokinetics (PK) of fimepinostat when administered in combination with anti-cancer regimens as measured by maximum plasma concentration (Cmax).(Pre-dose to 21 - 28 days post dose)
- To assess pharmacokinetics (PK) of fimepinostat when administered in combination with anti-cancer regimens as measured by half-life (T1/2).(Pre-dose to 21 - 28 days post dose)
- To assess PK of venetoclax when administered in combination with fimepinostat as measured by area under the concentration-time curve (AUC).(Pre-dose to 21 - 28 days post dose)
- To assess PK of venetoclax when administered in combination with fimepinostat as measured by maximum plasma concentration (Cmax).(Pre-dose to 21 - 28 days post dose)
- To assess PK of venetoclax when administered in combination with fimepinostat as measured by half-life (T1/2).(Pre-dose to 21 - 28 days post dose)
- To assess PK of venetoclax when administered in combination with fimepinostat as measured by clearance (Cl).(Pre-dose to 21 - 28 days post dose)
- To assess PK of venetoclax when administered in combination with fimepinostat as measured by volume of distribution (Vd).(Pre-dose to 21 - 28 days post dose)
- To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens as measured by OS.(24 months)
- To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens as measured by PFS.(24 months)
- To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens as measured by ORR.(24 months)
- To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens as measured by DOR.(24 months)
- To evaluate biomarkers of fimepinostat activity(24 months)