A Phase Ib Study of TGFbi NK Cells and Isatuximab for Myeloma Relapsed/Refractory to BCMA Targeting Therapy
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 3
- 试验地点
- 1
- 主要终点
- Incidence and severity of adverse events (AE)
研究概览
简要总结
This phase I trial tests the side effects and best dose of TGFbi natural killer (NK) cells (TiNK) when given together with isatuximab for the treatment of patients with multiple myeloma that has come back after a period of improvement (relapsed) or that has not responded to treatment (refractory). NK cells are a type of white blood cell that are known to spontaneously attack cancer cells. TiNK are NK cells made in a laboratory to have a higher response to tumor cells. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Immunotherapy with monoclonal antibodies, such as isatuximab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Patients also receive standard treatment (cyclophosphamide and dexamethasone) on this trial. Cyclophosphamide is in a class of medications called alkylating agents. It works by damaging the cell's DNA and may kill cancer cells. It may also lower the body's immune response. Dexamethasone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Giving TiNK and isatuximab with standard treatment may be a safe and effective treatment for relapsed or refractory multiple myeloma.
详细描述
PRIMARY OBJECTIVE:
I. To evaluate the safety and tolerability of transforming growth factor beta imprinted natural killer cells (TiNK) and isatuximab in patients with multiple myeloma (MM) relapsed or refractory (R/R) to BCMA-targeting therapy.
SECONDARY OBJECTIVES:
I. To evaluate the objective response rate (ORR) by International Myeloma Working Group (IMWG) criteria of TiNK and isatuximab in patients with MM R/R to BCMA-targeting therapy.
II. To determine the time to response (TTR), time to next therapy (TTNT), the duration of response (DOR), progression free survival (PFS), and overall survival (OS) at 1 year.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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 or older with evidence of relapsed or refractory disease as defined by IMWG criteria and measurable disease as defined by any of the following:
- •Serum M-protein ≥ 0.5 g/dl
- •Urine monoclonal protein ≥ 200 mg/24h
- •Involved free light chain (FLC) level ≥ 10mg/dl (≥ 100mg/l) and an abnormal serum free light chain ratio (< 0.26, or > 1.65)
- •Patients must have had at least 3 prior lines of therapy including lenalidomide, proteasome inhibitor (PI), anti-CD38 or anti-SLAMF7 directed antibody, and BCMA-targeting therapy.
- •Prior daratumumab or isatuximab is permitted but not in the immediate line prior to study entry
- •Prior autologous hematopoietic cell transplant is permitted
- •Prior allogeneic transplant is excluded
- •Refractory (progressed on or within 60 days of treatment) to their last treatment
- •If chimeric antigen receptor t cell (CAR-T) therapy was the immediately prior therapy, then the definition of refractory disease will not be limited to within 60 days
- •Patients must be off last treatment for at least 2 weeks by the beginning of treatment on this protocol
- •Hemoglobin ≥ 7g/dL
- •Absolute neutrophil count (ANC) ≥ 1000/µL
- •Platelets ≥ 70,000/µL
- •If plasma cell percentage on bone marrow biopsy core is > 30%, platelet requirement will be adjusted to 50,000/µl
- •Total bilirubin < 2 mg/dL
- •Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT)/ alkaline phosphatase < 2.5 X the upper limit of normal (ULN)
- •Calculated creatinine clearance of ≥ 30ml/min using Modification of Diet in Renal Disease (MDRD) formula
- •Left ventricular ejection fraction ≥ 30%; baseline echocardiography (ECHO) is not required if ECHO was done within the preceding one year and patients do not have new signs/symptoms suggestive of heart failure
- •No uncontrolled arrhythmias
- •No New York Heart Association class III-IV heart failure
- •12-lead electrocardiogram (ECG) with QT interval calculated by Fridericia Formula (QTcF) interval of ≤ 470 msec
- •Patients must provide informed consent
- •Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of ≤ 2
- •Fertility requirements:
- •Women of child bearing potential (WOCBP) must commit to either abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously. This includes one highly effective form of contraception (tubal ligation, intrauterine device [IUD], hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants] or partner's vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prior to dosing and continue to 6 months after study treatment ending. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy.
- •Investigators shall counsel WOCBP and male participants who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy
- •A negative pregnancy test will be required for all WOCBP within 24 hours before starting treatment drugs
- •Breast feeding is not permitted
- •Male patients must agree to use an adequate method of contraception (latex or synthetic condom) for the duration of the study and up to 6 months after study treatment ending
- •Criteria also applies to azoospermic males
- •Males should refrain from sperm donation during this time and continue for 6 months after study treatment ending
排除标准
- •Patients with active (untreated or relapsed) central nervous system (CNS) MM
- •Patients with Waldenstrom macroglobulinemia, primary AL amyloidosis, primary plasma cell leukemia, or polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome
- •Patients with secondary plasma cell leukemia are permitted
- •Patients receiving concurrent corticosteroids at the time protocol therapy is initiated other than for physiologic maintenance treatment
- •Concurrent use of complementary or alternative medicines that would confound the interpretation of toxicities and antitumor activity of the study drugs
- •Patients with contraindications or allergy to cyclophosphamide and/or daratumumab/isatuximab
- •Unacceptable respiratory risk factors defined by any one of the following criteria:
- •Chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) less than 50% of predicted normal
- •Moderate or severe persistent asthma within the past 2 years, or currently has uncontrolled asthma of any classification
- •Unacceptable cardiac risk factors defined by any of the following criteria:
- •Complete left bundle branch, bifascicular block or clinically significant abnormal electrocardiogram (EKG) finding at screening
- •Congenital long QT Syndrome
- •Myocardial infarction or unstable angina within 6 months
- •Patients who have received targeted or investigational agents within 2 weeks or within 5 half-lives of the agent and active metabolites (whichever is shorter) and who have not recovered from side effects of those therapies
- •Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from the side-effects of surgery
- •Patients with known positivity for human immunodeficiency virus (HIV) or active hepatitis B/C
- •Patients with chronic hepatitis B infection may be enrolled but must be provided prophylaxis (ex. entecavir for one year from start of therapy)
- •Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention, other than non-melanoma skin cancer and carcinoma in situ of the cervix or breast, should not be enrolled
- •Patients with any significant history of non-compliance to medical regimens or unwilling or unable to comply with the instructions given to them by the study staff
- •Any other medical condition, including mental illness or substance abuse, deemed by the investigator(s) to likely interfere with the patient's ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results
- •Life expectancy of 6 months or less
研究组 & 干预措施
Treatment (cyclophosphamide, dexamethasone, TiNK, isatuximab)
Patients receive cyclophosphamide IV on day 1, dexamethasone PO on days 1-4, TiNK IV on day 8, and isatuximab IV on days 8 and 15 of each cycle. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow aspiration and biopsy during screening and on study, as well as optionally during follow up. Patients undergo ECHO during screening and blood sample collection throughout the study.
干预措施: Cyclophosphamide (Drug)
Treatment (cyclophosphamide, dexamethasone, TiNK, isatuximab)
Patients receive cyclophosphamide IV on day 1, dexamethasone PO on days 1-4, TiNK IV on day 8, and isatuximab IV on days 8 and 15 of each cycle. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow aspiration and biopsy during screening and on study, as well as optionally during follow up. Patients undergo ECHO during screening and blood sample collection throughout the study.
干预措施: Questionnaire Administration (Other)
Treatment (cyclophosphamide, dexamethasone, TiNK, isatuximab)
Patients receive cyclophosphamide IV on day 1, dexamethasone PO on days 1-4, TiNK IV on day 8, and isatuximab IV on days 8 and 15 of each cycle. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow aspiration and biopsy during screening and on study, as well as optionally during follow up. Patients undergo ECHO during screening and blood sample collection throughout the study.
干预措施: Bone Marrow Aspiration and Biopsy (Procedure)
Treatment (cyclophosphamide, dexamethasone, TiNK, isatuximab)
Patients receive cyclophosphamide IV on day 1, dexamethasone PO on days 1-4, TiNK IV on day 8, and isatuximab IV on days 8 and 15 of each cycle. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow aspiration and biopsy during screening and on study, as well as optionally during follow up. Patients undergo ECHO during screening and blood sample collection throughout the study.
干预措施: Universal Donor Expanded TGF-beta-imprinted NK Cells (Biological)
Treatment (cyclophosphamide, dexamethasone, TiNK, isatuximab)
Patients receive cyclophosphamide IV on day 1, dexamethasone PO on days 1-4, TiNK IV on day 8, and isatuximab IV on days 8 and 15 of each cycle. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow aspiration and biopsy during screening and on study, as well as optionally during follow up. Patients undergo ECHO during screening and blood sample collection throughout the study.
干预措施: Isatuximab (Biological)
Treatment (cyclophosphamide, dexamethasone, TiNK, isatuximab)
Patients receive cyclophosphamide IV on day 1, dexamethasone PO on days 1-4, TiNK IV on day 8, and isatuximab IV on days 8 and 15 of each cycle. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow aspiration and biopsy during screening and on study, as well as optionally during follow up. Patients undergo ECHO during screening and blood sample collection throughout the study.
干预措施: Biospecimen Collection (Procedure)
Treatment (cyclophosphamide, dexamethasone, TiNK, isatuximab)
Patients receive cyclophosphamide IV on day 1, dexamethasone PO on days 1-4, TiNK IV on day 8, and isatuximab IV on days 8 and 15 of each cycle. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow aspiration and biopsy during screening and on study, as well as optionally during follow up. Patients undergo ECHO during screening and blood sample collection throughout the study.
干预措施: Echocardiography (Procedure)
Treatment (cyclophosphamide, dexamethasone, TiNK, isatuximab)
Patients receive cyclophosphamide IV on day 1, dexamethasone PO on days 1-4, TiNK IV on day 8, and isatuximab IV on days 8 and 15 of each cycle. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow aspiration and biopsy during screening and on study, as well as optionally during follow up. Patients undergo ECHO during screening and blood sample collection throughout the study.
干预措施: Dexamethasone (Drug)
结局指标
主要结局
Incidence and severity of adverse events (AE)
时间窗: Up to 60 days after completion of study treatment
Will use the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 for AE collection. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. The incidence of severe (grade 3+) adverse events or toxicities will be described. We will also assess tolerability of the regimen through assessing the number of patients who required dose modifications and/or dose delays. In addition, we will capture the proportion of patients who go off treatment due to adverse reactions.
次要结局
- Overall survival(From start of treatment to the date of his or her death, at 1 year)
- Overall response rate (ORR)(Up to 2 years after completion of study treatment)
- Time to response(From start of treatment until measurement criteria are first met for PR, very good partial response (VGPR), or complete response (CR), assessed up to 2 years after completion of study treatment)
- Change in quality of life (QOL) using PROMIS G10(Baseline up to 60 days after completion of study treatment)
- Change in quality of life (QOL) using EORTC QLQ-MY20(Baseline up to 60 days after completion of study treatment)
- Time to next therapy(From start of treatment until initiation of the next line of therapy, assessed up to 2 years after completion of study treatment)
- Duration of response(From the time measurement criteria are first met for PR or better (whichever status is recorded first) until the first date of progressive disease or death, assessed up to 2 years after completion of study)
- Progression free survival(From start of treatment until disease progression or death, at 1 year)
研究者
Elvira Umyarova
Principal Investigator
Ohio State University Comprehensive Cancer Center