A Phase 1b Study of Cytokine-Induced Memory Like (CIML) Natural Killer (NK) Cell Therapy in Recurrent Ovarian Cancer
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 18
- 试验地点
- 4
- 主要终点
- Maximum Tolerated Dose (MTD) (Cohort 1)
研究概览
简要总结
The goal of this research study is to evaluate the safety and effectiveness of the use of cytokine-induced memory-like (CIML) natural killer (NK) cell therapy in recurrent, high grade ovarian cancer (HGOC).
Names of the study therapies involved in this study are:
CIML NK (cellular therapy) Interleukin-2 (IL-2)
详细描述
This is an open-label, single site, phase 1b study to evaluate the safety and effectiveness of the use of cytokine-induced memory-like (CIML) natural killer (NK) cell therapy in recurrent, high grade ovarian cancer.
Participants will be enrolled to test the safety of intraperitoneal CIML NK cell therapy
The U.S. Food and Drug Administration (FDA) has not approved CIML NK cell therapy as a treatment for recurrent, high grade ovarian cancer.
The research study procedures include screening for eligibility, collection of natural killer (NK) cells in a process called leukapheresis, lymphodepleting chemotherapy, infusion of CIML NK cell therapy into the abdominal cavity (intraperitoneal), administration of low-dose IL-2, Computerized Tomography (CT) scans, Magnetic Resonance Imaging (MRI), or Positron Emission Tomography (PET) scans, blood tests, urine tests, electrocardiograms (ECGs), and echocardiograms.
Participants in this research study will be followed for up to for 5 years after start of study treatment.
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 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants must have histologically or cytologically confirmed recurrent epithelial ovarian cancer. Eligible histologies include high grade serous, high grade endometrioid and clear cell ovarian carcinoma.
- •Participants must have measurable cancer defined by RECIST 1.1 criteria.
- •Patients must have received at least 1 lines of prior systemic therapy and be deemed platinum resistant/intolerant by their treating oncologist. Patients with germline or somatic BRCA1 or BRCA2 mutations must have received prior PARP inhibitor therapy as maintenance or treatment. Prior receipt of immune checkpoint blockade is allowed if grade 3 or higher toxicities were not experienced.
- •Age ≥18 years and <85 years old.
- •ECOG performance status of 0 or
- •Participants must meet the following organ and marrow function as defined below:
- •Absolute neutrophil count ≥1,000/mcL
- •Platelets ≥75,000/mcL
- •AST(SGOT)/ALT(SGPT) ≤3 x institutional ULN
- •Total bilirubin ≤1.5 x institutional upper limit of normal (ULN) (except Gilbert's or disease-related hemolysis, then < 3 x ULN)
- •Serum creatinine ≤ 2.0 mg/dL OR glomerular filtration rate (GFR) ≥40 mL/min/1.73 m2
- •Oxygen saturation: ≥ 90% on room air
- •Left ventricular ejection fraction (cardiac function) ≥ 40%
- •No laboratory evidence of ongoing hemolysis in opinion of investigator
- •Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
- •Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants should be class 2B or better.
- •Physician assessment indicating the patient would be able to tolerate undergoing a brief procedure for placement of an intraperitoneal port for NK cell infusion.
- •Ability to understand and the willingness to sign a written informed consent document.
- •The effects of CIML NK cells and IL-2 on the developing human fetus are unknown. For this reason and because CIML NK cells and IL-2 may be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation.
排除标准
- •Participants who have had anti-tumor chemotherapy or other investigational agents within two weeks prior to NK cell infusion (6 weeks for nitrosoureas or mitomycin C), or immunotherapy within 6 weeks prior, or those who have not recovered from adverse events due to agents administered more than two weeks prior.
- •Participants with a bowel obstruction within the last 3 months or high risk for bowel obstruction (in the opinion of the investigator) or current need for parenteral nutrition or dependence on intravenous fluids.
- •Participants who are receiving any other investigational agents.
- •Solid organ transplant (allograft) recipients.
- •Participants with known additional malignancy that is progressing or requires active treatment, or history of other malignancy within 2 years of the first dose of study treatment with the exception of cured basal cell or squamous cell carcinoma of the skin, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in situ of the cervix, or other non-invasive or indolent malignancy, or cancers from which the patient has been disease-free for > 1 year after treatment with curative intent.
- •History of severe or anaphylactic allergic reactions attributed to compounds of similar chemical or biologic composition to CIML NK cells or IL-2 or any of the other agents used in study.
- •For patients with prior exposure to check point inhibitor therapy, those with a prior history of immune-related toxicity during immune therapy that resulted in permanent discontinuation of therapy (as recommended per product label or consensus guidelines) OR any immune-related toxicity requiring intensive or prolonged immunosuppression to manage (with the exception of endocrinopathy that is well-controlled on replacement hormones) are excluded.
- •Autoimmune disease: patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's disease, are excluded from this study, as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [Wegener's granulomatosis]) and motor neuropathy considered of autoimmune origin (e.g., GuillainBarre syndrome and myasthenia gravis). Patients with Hashimoto thyroiditis are eligible.
- •Systemic corticosteroid therapy (> 10 mg of prednisone or equivalent dose of systemic steroids for at least 4 weeks prior to NK cell infusion).
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
- •Pregnant women are excluded from this study because of the unknown teratogenic risk of CIML NK cells and IL-2 and with the potential for teratogenic or abortifacient effects by fludarabine/cyclophosphamide chemotherapy regimen. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with CIML NK cells and IL-2, breastfeeding should be discontinued if the mother is treated on this study.
- •HIV-positive participants are ineligible because of the potential for pharmacokinetic interactions with anti-retroviral agents used in this study. In addition, these participants are at increased risk of lethal infections when treated with marrow-suppressive therapy.
- •Individuals with active uncontrolled hepatitis B or C are ineligible as they are at high-risk of lethal treatment-related hepatotoxicity in the setting of marrow suppression. Known non-infectious pneumonitis or any history of interstitial lung disease.
- •Receipt of a live vaccine within 30 days of start of study treatment. During eligibility confirmation the study team is requested to confirm that according to the planned NK cell dosing schedule, the washout period should be completed.
- •Anaphylactic reactions to murine-based antibody therapy or iron dextran as the CIML NK cell product contains similar reagents at end of manufacturing/infusion.
- •Prior history of Grade 2 or higher hemolytic anemia (>/= 2g decrease in hemoglobin plus laboratory evidence of hemolysis) from any cause.
研究组 & 干预措施
Dose Level 0
Participants will be enrolled in a staggered fashion into a 3+3 dose de-escalation per protocol to establish a maximum tolerated dose (MTD). Dosage will start at dose level 0.
-
Baseline visit.
-
MRIs, PET scans, and/or CT scans every 8 weeks.
-
Cycle 0:
-
Day -7 of 8 day cycle: Apheresis for autologous NK cell collection.
-
Days -6 through -2 of 8 day cycle: Predetermined dose of lymphodepleting chemotherapy per protocol.
-
Days -5 through -4 of 8 day cycle:
-
Predetermined dose of lymphodepleting chemotherapy per protocol.
-
Predetermined dose of premedication per institutional standards.
-
Day 0 of 8 day cycle:
-
Predetermined dose of CIML NK cells once
-
Subcutaneous low-dose IL-2 once
-
Cycle 1:
- Days 2-8: Subcutaneous low-dose IL-2 every other day for 4 additional doses
-
Off-Treatment:
-
Long-term follow up for 5 years after last CIML NK cell infusion.
干预措施: Cytokine-Induced Memory-like Natural Killer Cells (Biological)
Dose Level -1
3+3 de-escalation to dose level -1 per protocol if DLTs occur in Cohort 1 dose Level 0.
-
Baseline visit.
-
MRIs, PET scans, and/or CT scans every 8 weeks.
-
Cycle 0:
-
Day -7 of 8 day cycle: Apheresis for autologous NK cell collection.
-
Days -6 through -2 of 8 day cycle: Predetermined dose of lymphodepleting chemotherapy per protocol.
-
Days -5 through -4 of 8 day cycle:
-
Predetermined dose of lymphodepleting chemotherapy per protocol.
-
Predetermined dose of premedication per institutional standards.
-
Day 0 of 8 day cycle:
-
Predetermined dose of CIML NK cells once
-
Subcutaneous low-dose IL-2 once
-
Cycle 1:
- Days 2-8: Subcutaneous low-dose IL-2 every other day for 4 additional doses
-
Off-Treatment:
-
Long-term follow up for 5 years after last CIML NK cell infusion.
干预措施: Cytokine-Induced Memory-like Natural Killer Cells (Biological)
Dose Level 0
Participants will be enrolled in a staggered fashion into a 3+3 dose de-escalation per protocol to establish a maximum tolerated dose (MTD). Dosage will start at dose level 0.
-
Baseline visit.
-
MRIs, PET scans, and/or CT scans every 8 weeks.
-
Cycle 0:
-
Day -7 of 8 day cycle: Apheresis for autologous NK cell collection.
-
Days -6 through -2 of 8 day cycle: Predetermined dose of lymphodepleting chemotherapy per protocol.
-
Days -5 through -4 of 8 day cycle:
-
Predetermined dose of lymphodepleting chemotherapy per protocol.
-
Predetermined dose of premedication per institutional standards.
-
Day 0 of 8 day cycle:
-
Predetermined dose of CIML NK cells once
-
Subcutaneous low-dose IL-2 once
-
Cycle 1:
- Days 2-8: Subcutaneous low-dose IL-2 every other day for 4 additional doses
-
Off-Treatment:
-
Long-term follow up for 5 years after last CIML NK cell infusion.
干预措施: Interleukin 2 (Drug)
Dose Level -1
3+3 de-escalation to dose level -1 per protocol if DLTs occur in Cohort 1 dose Level 0.
-
Baseline visit.
-
MRIs, PET scans, and/or CT scans every 8 weeks.
-
Cycle 0:
-
Day -7 of 8 day cycle: Apheresis for autologous NK cell collection.
-
Days -6 through -2 of 8 day cycle: Predetermined dose of lymphodepleting chemotherapy per protocol.
-
Days -5 through -4 of 8 day cycle:
-
Predetermined dose of lymphodepleting chemotherapy per protocol.
-
Predetermined dose of premedication per institutional standards.
-
Day 0 of 8 day cycle:
-
Predetermined dose of CIML NK cells once
-
Subcutaneous low-dose IL-2 once
-
Cycle 1:
- Days 2-8: Subcutaneous low-dose IL-2 every other day for 4 additional doses
-
Off-Treatment:
-
Long-term follow up for 5 years after last CIML NK cell infusion.
干预措施: Interleukin 2 (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD) (Cohort 1)
时间窗: 60 days
The MTD of the use of cytokine induced memory-like natural killer (CIML NK) cell therapy is determined by the number of participants who experience a dose limiting toxicity (DLT). See subsequent primary outcome measure for DLT definition.
Dose Limiting Toxicity (DLT) (Cohort 1)
时间窗: 60 days
A DLT is defined as an adverse event that is related to CIML NK cell therapy with an attribution of possible, probable, or definite, and meets the criteria defined in protocol section 5.4.
次要结局
- Overall Response Rate (ORR)(Up to 5 years)
- Median Progression Free Survival (PFS)(Up to 5 years)
- Clinical Benefit Rate (CBR)(Up to 5 years)
- Duration of Response (DOR)(Up to 5 years)
- 6 months Progression Free Survival (PFS6)(6 months)
研究者
Rebecca Porter, MD, PhD
Principal Investigator
Dana-Farber Cancer Institute