Phase 1 Open-Label Study of Autologous M-CENK in Subjects With Locally Advanced or Metastatic Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 50
- 试验地点
- 2
- 主要终点
- Primary Objective (cohort 1 and cohort 2, part A subjects): Determine the safety of mononuclear cell (MNC) apheresis collection by number of participants with abnormal vital signs.
研究概览
简要总结
This is a two-part, open-label phase 1 study to evaluate safety and preliminary efficacy of M-CENK Suspension for Infusion, Cryopreserved, and N-803 for subcutaneous administration in subjects with locally advanced or metastatic solid tumors. The study consists of two cohorts: cohort 1 includes subjects with either newly diagnosed solid tumors who have not received prior therapy or subjects who have received prior first line treatment; and cohort 2 that includes subjects with relapsed/refractory (r/r) solid tumors who have progressive disease after receiving ≥ 2 prior therapies. The two cohorts will be conducted simultaneously.
详细描述
Both cohorts will be enrolled simultaneously. Both cohorts have a part A (apheresis) and cohort 2 has a part B (M-CENK treatment [one bag has a 100 mL cell suspension containing 0.25 to 0.75 x 109 cells] and N-803 treatment).
Up to 40 subjects may be enrolled in cohort 1. Subjects in cohort 1 will participate in apheresis collection of MNCs prior to receiving disease specific first-line therapy per primary oncologists' recommendations. Subjects who have completed apheresis in cohort 1 may subsequently enroll in cohort 2 part B if they have progressive disease after ≥ 2 prior therapies or if they have progressive disease within 12 months of receiving neoadjuvant or adjuvant chemotherapy.
They must also meet the inclusion criteria to participate in the treatment phase (cohort 2 part B). Additionally, all subjects will be re-evaluated to confirm that they still meet the specified eligibility criteria once the M-CENK cells are manufactured and prior to the first administration of M-CENK. The Sponsor will approve the subject's continued eligibility prior to receiving the manufactured M-CENK cells.
Up to 21 subjects may be enrolled in cohort 2 part A so that up to 11 subjects receive at least 1 dose of M-CENK. A dose is a single administration of M-CENK cells or a single administration of N-803. Subjects in cohort 2 part A will undergo an apheresis collection of MNCs prior to receiving approximately 4 weeks of disease-specific therapy per oncologists' recommendations while the M-CENK cells are being manufactured for use in the treatment phase (cohort 2 part B). Subjects will be evaluated for eligibility in inclusion/exclusion criteria prior to enrollment into part B. Additionally, all subjects will be re-evaluated to confirm that they still meet the specified eligibility criteria once the M-CENK cells are manufactured and prior to the first administration of M-CENK. The Sponsor will approve the subject's continued eligibility prior to receiving the manufactured M-CENK cells.
M-CENK cells, manufactured from the autologous apheresis product, may be administered up to 10 times weekly starting on study day 1 with a minimum of 7 days between each M-CENK dose depending on the availability of cells and that there is no contra-indication to administer cells. Subjects will receive up to 5 doses of N-803 SC every 2 weeks prior to every other dose of M-CENK (ie, odd number M-CENK doses).The treatment may be administered for up to 10 doses of M-CENK, if the subject tolerates treatment, the doses of M-CENK cells are available, and the Investigator believes there may be potential benefit to the subject.
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 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Cohorts 1 and 2, Part A:
- •Age ≥ 18 years old.
- •Able to understand and provide a signed informed consent that fulfills the relevant Institutional Review Board (IRB) or Independent Ethics Committee (IEC) guidelines.
- •Have histologically confirmed locally advanced, unresectable, or metastatic solid tumor.
- •For subjects with genetic mutations or alterations in solid tumors (e.g. NSCLC, pancreatic cancer, melanoma), the subjects must have received prior appropriate disease specific targeted therapy and have progressed.
- •Have at least 1 measurable lesion and/or non-measurable disease evaluable in accordance with RECIST Version 1.
- •For subjects with a history of human immunodeficiency virus (HIV)
- •Subjects with CD4+ T-cell (CD4+) counts ≥ 350 cells/uL and without a history of AIDS defining opportunistic infections.
- •For subjects with a history of hepatitis B virus (HBV)
- •Subjects who are chronic carriers of HBV infection (HBsAg-positive, undetectable or low HBV DNA, and normal ALT) who are not on HBV therapy, or in individuals who have serologic evidence of a resolved prior HBV infection (i.e., HBsAg-negative and anti-HBc-positive), anti-HBV prophylaxis should be assessed prior to enrollment.
- •Subjects with chronic HBV infection with active disease who meet the criteria for anti HBV therapy should be on a suppressive antiviral therapy prior to enrollment.
- •For subjects with a history of hepatitis C virus (HCV)
- •Subjects with a history of HCV infection should have completed curative antiviral treatment and have a HCV viral load below the limit of quantification are eligible.
- •Subjects who are HCV Ab positive but HCV RNA negative due to prior treatment or natural resolution are eligible.
- •Subjects on concurrent HCV treatment and have HCV below the limit of quantification are eligible.
- •Note: Subjects who have a history of HIV/HBV/HCV or are seropositive will require Infectious Disease Marker (IDM) testing prior to apheresis collection.
- •Subjects who currently have non-progressive brain metastasis and were previously treated with surgical resection/debulking, radiation, and stereotactic radiosurgery.
- •Able to undergo an Apheresis procedure:
- •Have adequate venous access
- •Able to sit or recline for 5-6 hours with limited movement
- •Hemoglobin must be ≥ 9.0 g/dL
- •Platelet count must be ≥ 100,000 cells/mm3
- •Vital signs must be within normal range
- •Negative serum pregnancy test for females of childbearing potential.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 to
- •Ability to attend required study visits and return for adequate follow-up, as required by this protocol.
- •Agreement to practice effective contraception for female subjects of child-bearing potential and non-sterile males. Female subjects of child-bearing potential must agree to use effective contraception for up to 30 days after completion of therapy, and non- sterile male subjects must agree to use a condom for up to 30 days after treatment. Effective contraception includes surgical sterilization (eg, vasectomy, tubal ligation), 2 forms of barrier methods (eg, condom, diaphragm) used with spermicide, and intrauterine devices (IUDs).
- •Cohort 2, Part B subjects only:
- •Have documented progressive disease after receiving treatment with at least 2 prior lines of therapy or not be a candidate for therapy of proven efficacy for their disease. Prior immune therapy and prior treatment with a checkpoint inhibitor as per FDA indication for current standard of care therapy is allowed.
- •Subjects cannot receive M-CENK before a 14-day washout period following treatment with an approved chemotherapy and approved or investigational immunotherapy (eg PD-1/PD-L1 inhibitors, CAR NK cells [PD-L1 t-haNK], N-803). A repeat lab at least 14 days after completion of the washout period is required.
- •Subjects cannot receive M-CENK before a 30-day washout period following treatment with investigational chemotherapy. A repeat lab at least 30 days after completion of the washout period is required.
- •Ability to attend required study visits and return for adequate follow-up, as required by this protocol.
- •Agreement to practice effective contraception for female subjects of child-bearing potential and nonsterile males. Female subjects of child-bearing potential must agree to use effective contraception for up to 30 days after completion of therapy, and non- sterile male subjects must agree to use a condom for up to 30 days after treatment. Effective contraception includes surgical sterilization (eg, vasectomy, tubal ligation), 2 forms of barrier methods (eg, condom, diaphragm) used with spermicide, and intrauterine devices (IUDs).
- •Exclusion Criteria (Cohorts 1 and 2, Part A):
- •There is no exclusion criteria for cohorts 1 and 2, part A.
- •Exclusion Criteria (Cohort 2, Part B only):
- •*Note: All subjects must meet eligibility criteria at the time of enrollment. Additionally, all subjects will be re-evaluated to confirm that they still meet the eligibility criteria specified with an asterisk below once the M-CENK cells are manufactured and prior to to the first administration of M-CENK. The Sponsor will approve the subject's continued eligibility prior to receiving the manufactured M-CENK cells.
- •*Life expectancy < 16 weeks based on the best judgment of the Investigator.
- •*Involuntary weight loss of > 10% usual body weight between the time of enrollment and at the time of administration of M-CENK cells
- •*Calorie or protein restrictive dietary regimen.
- •*Serious uncontrolled concomitant disease that would contraindicate the use of the investigational drug used in this study or that would put the subject at high risk for treatment- related complications.
- •Systemic autoimmune disease (eg, lupus erythematosus, rheumatoid arthritis, Addison's disease, autoimmune disease associated with lymphoma) requiring medical treatment.
- •*Currently receiving or has received antibiotics since enrolling in the study or documented infection.
- •History of organ transplant requiring immunosuppression.
- •History of or active inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis), unless the inflammation is well controlled.
- •*Inadequate organ function, evidenced by the following laboratory results:
- •Absolute neutrophil count (ANC) < 1000 cells/mm
- •Platelet count < 100,000 cells/mm
- •Hemoglobin < 9 g/dL.
- •Total bilirubin > 1.5 x the upper limit of normal (ULN; unless the subject has documented Gilbert's syndrome).
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排除标准
- 未提供
研究组 & 干预措施
Cohort 1: Subjects newly diagnosed no prior therapy or prior first line treatment
Cohort 1: Subjects with either newly diagnosed solid tumors who have not received prior therapy or subjects who have received prior first line treatment. Cohort 1 may subsequently enroll in cohort 2 part B if they have progressive disease after ≥ 2 prior therapies or if they have progressive disease within 12 months of receiving neoadjuvant or adjuvant chemotherapy and meet the inclusion criteria for cohort 2 part B.
干预措施: Apheresis collection of MNCs (part A) (Other)
Cohort 2: Subjects with relapsed/refractory (r/r) solid tumors
Cohort 2: Subjects with relapsed/refractory (r/r) solid tumors who have progressive disease after receiving ≥ 2 prior therapies or not a candidate for therapy of proven efficacy for their disease.
干预措施: M-CENK, Suspension for Infusion, Cryopreserved (M-CENK) (Cohort 2 part B) (Biological)
Cohort 2: Subjects with relapsed/refractory (r/r) solid tumors
Cohort 2: Subjects with relapsed/refractory (r/r) solid tumors who have progressive disease after receiving ≥ 2 prior therapies or not a candidate for therapy of proven efficacy for their disease.
干预措施: N-803 (Cohort 2 part B) (Biological)
结局指标
主要结局
Primary Objective (cohort 1 and cohort 2, part A subjects): Determine the safety of mononuclear cell (MNC) apheresis collection by number of participants with abnormal vital signs.
时间窗: From Baseline/Screening through Study Day 1, assessed for up to 28 days
\- Vital signs to include temperature, respiratory rate, heart rate, blood pressure, and oxygen saturation
Primary Objective (cohort 2, part B subjects): Evaluate the overall safety profile of M-CENK and N-803 for SC administration by the number of participants with abnormal vital signs
时间窗: From M-CENK Dose Number 1, assessed for up to 1 day
\- Vital signs to include temperature, respiratory rate, heart rate, blood pressure, and oxygen saturation
Primary Objective (cohort 1 and cohort 2, part A subjects): Determine the safety of mononuclear cell (MNC) apheresis collection by the number of participants with clinically significant laboratory tests.
时间窗: From Baseline/Screening through Study Day 1, assessed for up to 1 day
\- Clinical lab tests include hematology (CBC w/ differential (5 part) including platelet count) and chemistry panel (BUN, blood urea nitrogen; CBC, complete blood count; RBC, red blood cells; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase) performed within 1 calendar day prior to apheresis collection. Hematology test will be performed pre- and post- apheresis collection.
Primary Objective (cohort 2, part B subjects): Evaluate the overall safety profile of M-CENK and N-803 for SC administration by the number of participants with clinically significant laboratory tests
时间窗: From M-CENK Dose Number 1, assessed for up to 1 day
\- Clinical lab tests include hematology (CBC w/ differential (5 part) including platelet count) and chemistry panel (BUN, blood urea nitrogen; CBC, complete blood count; RBC, red blood cells; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase) performed within 1 calendar day prior to first dose.
Primary Objective (cohort 1 and cohort 2, part A subjects): Determine the safety of mononuclear cell (MNC) apheresis collection by the number of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) related to apheresis.
时间窗: Study Day 1, assessed for up to 1 week
\- Safety of apheresis collection as indicated by incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) related to apheresis, graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, or in the case of cytokine release syndrome (CRS), using the specified grading system.
Primary Objective (cohort 2, part B subjects): Evaluate the overall safety profile of M-CENK and N-803 for SC administration by the number of TEAEs and SAEs after the first dose of M-CENK and the first dose of N-803 (M-CENK Dose Number 1)
时间窗: From M-CENK Dose Number 1 up to 30 days, assessed for up to 30 days
\- Incidence of TEAEs and SAEs, graded using the NCI CTCAE Version 5.0, or in the case of CRS using the specified grading system.
次要结局
- Secondary Objective (cohort 1 and cohort 2, part A subjects): Evaluate the quantity and quality of the manufactured investigational cells from subjects in cohort 1 vs. cohort 2 by the number of MNCs for manufacturing M-CENK cells.(Study Day 1)
- Cohort 1 and cohort 2, part A subjects: Evaluate the quantity and quality of the manufactured cells from subjects in cohort 1 vs. cohort 2 by the number of MNCs collected and the % of natural killer (NK) cells.(Study Day 1)
- Secondary Objective (cohort 2, part B): Evaluate the overall safety profile of up to 10 doses of M-CENK and up to 5 doses of N-803 for SC administration in subjects with relapsed or refractory (R/R) solid tumors by the number of TEAEs and SAEs.(From M-CENK Dose Number 1 through End of Study (up to 12 months from first dose), assessed for up to 12 months)
- Cohort 2, part B subjects: Evaluate overall safety profile of up to 10 doses of M-CENK and up to 5 doses of N-803 in subjects with relapsed or refractory (R/R) solid tumors by the number of participants with clinically significant laboratory tests.(From M-CENK Dose Number 1 through End of Study (up to 12 months from first dose), assessed for up to 12 months)
- Cohort 1 and cohort 2, part A subjects: Evaluate the quantity and quality of the manufactured cells from subjects in cohort 1 vs. cohort 2 by the number, phenotype (CD56/CD16 positive and CD3 positive cells), and function of M-CENK cells.(Study Day 1)
- Secondary Objective (cohort 2, part B subjects): Obtain preliminary estimates of efficacy by measuring the progression-free survival (PFS) by the(From M-CENK Dose Number 1 to the date of disease progression or death (any cause), assessed for up to 12 months)
- Secondary Objective (cohort 1 and cohort 2, part A subjects): Evaluate the quantity and quality of the manufactured investigational cells from subjects in cohort 1 vs. cohort 2 by the number of cryopreserved aliquots of manufactured M-CENK cells.(Study Day 1)
- Cohort 2, part B: Evaluate the overall safety profile of up to 10 doses of M-CENK and up to 5 doses of N-803 for SC administration in subjects with relapsed or refractory (R/R) solid tumors by the number of of participants with abnormal vital si(From M-CENK Dose Number 1 through End of Study (up to 12 months from first dose), assessed for up to 12 months)
- Secondary Objective (cohort 2, part B subjects): Obtain preliminary estimates of efficacy by measuring the overall survival (OS) from the first date of treatment to the date of death.(From M-CENK Dose Number 1 to the date of death (any cause), assessed for up to 12 months)
- Secondary Objective (cohort 2, part B subjects): Obtain preliminary estimates of efficacy by measuring the objective response rate (ORR) by the percentage of subjects that achieve a confirmed complete or partial overall response(From Baseline/Screening through End of Study (up to 12 months from first dose), measured at 4 weeks, every 8 weeks, EOT, EOS)