A Multicenter, Open-Label, First-In-Human, Multiple Expansion Cohort, Phase 1/2 Study to Evaluate the Safety and Efficacy of DR-01 in Adult Subjects With Large Granular Lymphocytic Leukemia or Cytotoxic Lymphomas
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 200
- 试验地点
- 39
- 主要终点
- Part A: Safety and Tolerability. To determine the incidence and severity of adverse events as assessed by CTCAE v5.0.
研究概览
简要总结
This is a multicenter, first-in-human, Phase 1/2 study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and anti-tumor activity of DR-01 in adult patients with large granular lymphocytic leukemia or cytotoxic lymphomas
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
- •(All Subjects):
- •≥18 years of age.
- •Able to understand and comply with protocol-required study procedures and voluntarily sign a written informed consent document.
- •Sufficient key organ performance and coagulation.
- •Female subjects of childbearing potential (postmenarcheal, has an intact uterus and at least one ovary, and is <1 year postmenopausal) must agree to use a highly effective method of contraception from enrollment through at least 12 months after last dose of DR-
- •Male subjects must agree to use acceptable effective method(s) of contraception.
- •Subjects with LGLL must also meet inclusion criteria 6 and
- •Must have discontinued at least one prior line of systemic therapy.
- •Additional immunophenotypic and symptomatic criteria must be met.
- •Disease-specific Inclusion Criteria (Cytotoxic Lymphomas):
- •Subjects with cytotoxic lymphomas must also meet inclusion criteria 8,9, and
- •Subjects must have failed at least one prior systemic regimens.
- •Availability of post-progression tissue sample or willingness to consent to a baseline biopsy.
- •Histologically confirmed diagnosis of a cytotoxic lymphoma by a hematopathologist (according to the WHO 2016 classification [Swerdlow 2016]).
- •For Part A only, evaluable disease is acceptable.
- •For Part B2 only, evaluable by the following response criteria as documented during Screening:
- •For cytotoxic PTCL-NOS, ENKTL, MEITL, EATL, SPTCL - Subjects must have radiographically measurable disease by computed tomography (CT) or CT/positron emission tomography (PET) scan defined as at least one node measuring >1.5 cm or measurable extranodal lesion of at least 1.0 cm in longest diameter to be evaluated by Lugano criteria (Cheson 2014).
- •For PCGDTCL, ET-CTCL, HVLPD, cytotoxic CuPTCL-NOS - Subjects with primary cutaneous variants must have at least 1 measurable lesion that is evaluable using the Olsen criteria (Olsen 2021) or have leukemic involvement that can be evaluated using modified TPLL response criteria (Staber 2019).
- •For HSTCL, ANKL, SysEBV TCL - Subjects with hepatosplenic disease without measurable disease by Lugano criteria (Cheson 2014) or leukemic involvement in BM or peripheral blood that is evaluable for response using a modified TPLL response criteria (Staber 2019).
排除标准
- •Disease-specific Exclusion Criteria; LGLL and ANKL:
- •A reactive LGL lymphocytosis to a viral infection or LGL associated with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
- •The following exclusion criteria apply to all subjects:
- •Active systemic infection or severe localized infection requiring systemic antibiotics, antivirals or antifungals.
- •Active or suspected malignant central nervous system involvement.
- •Life-threatening, severe complications of malignancy (e.g., uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation).
- •Active known second malignancy.
- •Infection with human immunodeficiency virus (HIV) type 1 or 2 (HIV-1 or HIV-2).
- •Hepatitis B infection (hepatitis B virus surface antigen [HBsAg] positive), or hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by HCV ribonucleic acid). Subjects with HCV with undetectable virus after treatment are eligible.
- •History of clinically significant cardiac disease or congestive heart failure greater than New York Heart Association (NYHA) Class II.
- •Use of systemic corticosteroids at prohibited dose levels within 15 days prior to C1D1 (except for prophylaxis for radiodiagnostic contrast reactions and study-defined premedication) or use of other non-biological immunosuppressive drugs within 15 days or 5 half-lives (whichever is less) prior to C1D
- •Any condition requiring hormonal therapy (except for contraception, hormone replacement therapy and hormonal prophylaxis for a prior malignancy).
- •Any other medical or psychiatric condition, or laboratory abnormality that would increase the risk associated with study participation, in the opinion of the Investigator or Medical Monitor.
- •Toxicities from previous anticancer therapies must have resolved to baseline levels or to Grade 1 (except for alopecia, peripheral neuropathy, or hematologic parameters meeting inclusion criteria).
- •Autologous HSCT within 40 days of C1D1, allogeneic HSCT within 90 days
- •Any immunosuppressive therapy for GVHD for subjects who are post allogeneic HSCT.
- •Major surgery within 28 days of C1D1 (requires more than local anesthesia or plexus blockade).
研究组 & 干预措施
Part A Dose Escalation 6 mg/kg of DR-01
Subjects in this arm will initially receive 6 mg/kg at either the Primary regimen (bi-weekly dosing for fist month), Secondary regimen (doses at Days 1, 8, 15, 29 during first month), or Tertiary regimen (dosing days 1-5, 15, 29 during first month), followed by monthly dosing (up to 10 mg/kg) thereafter for up to 25 cycles total.
干预措施: DR-01 (Drug)
Part A Dose De-escalation 0.3 to <1 mg/kg of DR-01
This cohort would only be triggered should a DLT occur at Dose Level 1 or if recommended by the Safety Review Committee. Subjects in this arm would initially receive 0.3 to <1 mg/kg at either the Primary regimen (bi-weekly dosing for fist month), Secondary regimen (doses at Days 1, 8, 15, 29 during first month), or Tertiary regimen (dosing days 1-5, 15, 29 during first month), followed by monthly dosing (up to 3 mg/kg) thereafter for up to 25 cycles total.
干预措施: DR-01 (Drug)
Part A Dose Escalation 1 mg/kg of DR-01
Subjects in this arm will initially receive 1 mg/kg at either the Primary regimen (bi-weekly dosing for fist month), Secondary regimen (doses at Days 1, 8, 15, 29 during first month), or Tertiary regimen (dosing days 1-5, 15, 29 during first month), followed by monthly dosing (up to 6 mg/kg) thereafter for up to 25 cycles total.
干预措施: DR-01 (Drug)
Part A Dose Escalation 3 mg/kg of DR-01
Subjects in this arm will initially receive 3 mg/kg at either the Primary regimen (bi-weekly dosing for fist month), Secondary regimen (doses at Days 1, 8, 15, 29 during first month), or Tertiary regimen (dosing days 1-5, 15, 29 during first month), followed by monthly dosing (up to 10 mg/kg) thereafter for up to 25 cycles total.
干预措施: DR-01 (Drug)
Part A Dose Escalation 10 mg/kg of DR-01
Subjects in this arm will initially receive 10 mg/kg at either the Primary regimen (bi-weekly dosing for fist month), Secondary regimen (doses at Days 1, 8, 15, 29 during first month), or Tertiary regimen (dosing days 1-5, 15, 29 during first month), followed by monthly dosing (up to 10 mg/kg) thereafter for up to 25 cycles total.
干预措施: DR-01 (Drug)
Part B Dose Expansion (Cohort B1) Optimized Dose/Regimen of DR-01
Subjects in this arm will receive the pharmacologically optimized dose/regimen for LGL leukemia subjects determined in Part A. Depending on the selected dose/regimen, subjects will receive target dose at either the Primary regimen (bi-weekly dosing for fist month), Secondary regimen (doses at Days 1, 8, 15, 29 during first month), or Tertiary regimen (dosing days 1-5, 15, 29 during first month), followed by monthly dosing thereafter for up to 25 doses total.
干预措施: DR-01 (Drug)
Part B Dose Expansion (Cohort B2) Optimized Dose/Regimen of DR-01
Subjects in this arm will receive the pharmacologically optimized dose/regimen for cytotoxic lymphoma subjects determined in Part A. Depending on the selected dose/regimen, subjects will receive target dose at either the Primary regimen (bi-weekly dosing for fist month), Secondary regimen (doses at Days 1, 8, 15, 29 during first month), or Tertiary regimen (dosing days 1-5, 15, 29 during first month), followed by monthly dosing thereafter for up to 25 doses total.
干预措施: DR-01 (Drug)
结局指标
主要结局
Part A: Safety and Tolerability. To determine the incidence and severity of adverse events as assessed by CTCAE v5.0.
时间窗: Up to 25 months
Part A: Safety and Tolerability. To determine the incidence and severity of dose limiting toxicities (DLTs) as defined by protocol specified DLT criteria.
时间窗: During First 28 days (Cycle 1)
Part A: To determine potential pharmacologically optimized dose/regimen for DR-01 in LGL leukemia and cytotoxic lymphoma populations as determined using an integrated assessment of efficacy, safety, PK/PD, and exposure-response relationships.
时间窗: Up to 6 months
Part B: Overall Response Rate (ORR), defined as the proportion of subjects with Complete Response (CR) or Partial Response (PR) based on disease-specific response criteria.
时间窗: Up to 24 months
次要结局
未报告次要终点