ADD-IT1: A Randomized Study of Adjuncts to Immunotherapy in Patients With Advanced Cancers
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 46
- 试验地点
- 1
- 主要终点
- Change in interleukin-8 levels
研究概览
简要总结
This clinical trial tests the effect of multiple therapies (propranolol, desloratadine, and magnesium and vitamin D supplements) added to primary standard of care immunotherapy (adjunct), as well as adjusting the timing of standard immunotherapy to a morning infusion, in treating patients with melanoma that has spread to nearby tissue or lymph nodes (locally advanced) or that has spread from where it first started to other places in the body (metastatic) or hepatocellular cancer that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Propranolol is a medication used for high blood pressure. Desloratadine is a type of drug that blocks the action of histamines, which can cause fever, itching, sneezing, a runny nose, and watery eyes. Immunotherapy has been approved for multiple kinds of advanced cancers, including melanoma, kidney cancer, non-small cell lung cancer and hepatocellular (liver) cancer. Research suggests that giving propranolol and desloratadine, along with ensuring adequate levels of magnesium and vitamin D, as well as administering immunotherapy infusions in the morning may shrink or stop the spread of advanced cancers better than immunotherapy alone.
详细描述
PRIMARY OBJECTIVE:
I. Compare levels of biomarkers of immunomodulation, specifically interleukin (IL)-8, interferon gamma (IFN-y), effector T cells (Teff)/regulatory T cell (Treg) ratio, over a 12-week period, in peripheral blood of patients undergoing standard of care PD-1/PD-L1-containing immunotherapy regimens for advanced cancers randomized to Arm A or Arm B.
SECONDARY OBJECTIVE:
I. Evaluate the safety and tolerability of the combination of: magnesium, vitamin D supplements; desloratadine; propranolol in patients undergoing morning infusion of standard of care PD-1/PD-L1-containing immunotherapy regimens in Arm A.
EXPLORATORY OBJECTIVES:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
盲法说明
Patients will be randomized in a 1:1 ratio to Arm A (Adjuncts/Early ICI Infusion) or Arm B (No Adjuncts/ SOC ICI Infusion).
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
- •Histologically or cytologically confirmed locally advanced or metastatic melanoma or advanced hepatocellular cancer (HCC); histologic/cytologic confirmation not required for HCC
- •Eligible and planned to begin therapy with PD1/PDL-1 inhibitors as standard of care first-line therapy, either as monotherapy or in combination with other approved immune checkpoint inhibitors or bevacizumab
- •Age ≥ 18 years
- •Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- •Absolute neutrophil count ≥ 1,000/mcl
- •Hemoglobin ≥ 8.0 g/dL
- •Platelets ≥ 75,000/mcl
- •Total bilirubin ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 × ULN in Gilbert's syndrome
- •Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/ alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 2.5 × ULN for patients without liver metastasis ≤ 5 × ULN for patients with liver metastasis
- •Creatinine clearance > 30 mL/min per Cockcroft-Gault
- •Females of childbearing potential must agree to sexual abstinence (defined below) or be willing to use a highly effective method of contraception from the start of therapy through 90 days after the completion of therapy.
- •Non-childbearing potential is defined as:
- •Postmenopausal, defined as no menses for 12 months without an alternative medical cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
- •Surgically sterile. Surgical sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.
- •Acceptable highly effective birth control methods include:
- •Oral, intravaginal, or transdermal combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation
- •Oral, injectable, or implantable progestogen-only hormonal contraception associated with inhibition of ovulation
- •Intrauterine device
- •Intrauterine hormone-releasing system
- •Bilateral tubal occlusion
- •Vasectomized partner (provided that partner is the sole sexual partner of the female of reproductive potential and that the vasectomized partner has received medical assessment of the surgical success)
- •Sexual abstinence. In the context of this study sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse from the start of therapy through 90 days after the completion of therapy
- •Males who have female partners of childbearing potential must agree to use a highly effective method of contraception from the start of therapy through 90 days after the completion of therapy
- •Ability to understand and the willingness to sign a written informed consent
排除标准
- •Prior systemic anticancer therapy for locally advanced or metastatic disease. Therapy in the neoadjuvant or adjuvant setting is allowed if the last dose of neo/adjuvant therapy is at least 6 months prior to first dose of study treatment
- •A known history or autoimmune disease requiring systemic immunosuppressive therapy; or any disease process requiring systemic immunosuppressive therapy (e.g. high-dose steroids defined as ≥ 10 mg prednisone or equivalent per day).
- •Note: Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is allowed
- •History of grade ≥ 3 immune-related adverse event(s) associated with prior immunotherapy, unless these events did not require hospitalization, were manageable with medical therapy, and adequately resolved within 14 days
- •Medical requirement for beta blockers or histamine 1 (H1) blockers
- •Has active central nervous system (CNS) metastases and/or any history of leptomeningeal disease
- •Note: Patients with previously treated brain metastases may participate provided they are radiologically stable (i.e. no evidence of progression for ≥ 4 weeks by repeat imaging performed during study screening), clinically stable, and not requiring steroid treatment within 14 days prior to first dose of study treatment
- •Has received a live vaccine administered within 28 days of planned treatment start or while participating in the study
- •Patients must not be pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants
- •History of or current condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate
- •Contraindications to the use of beta-blockers, including but not limited to unstable angina pectoris, uncontrolled heart failure (Grade III or IV), hypotension (systolic blood pressure < 100 mmHg), bradycardia
- •Patients must not be receiving other concomitant biologic therapy, hormonal therapy, chemotherapy, other anti-cancer therapy or any other investigational agents while on this protocol
研究组 & 干预措施
Arm B (Standard interventions)
Patients receive standard of care PD-1/PD-L1-containing immunotherapy, starting at standard of care time. Magnesium and vitamin D levels are checked with any supplementation per investigator discretion and institutional practice, without a prespecified goal level. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI and blood sample collection throughout the study.
干预措施: Immunotherapy (Other)
Arm B (Standard interventions)
Patients receive standard of care PD-1/PD-L1-containing immunotherapy, starting at standard of care time. Magnesium and vitamin D levels are checked with any supplementation per investigator discretion and institutional practice, without a prespecified goal level. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI and blood sample collection throughout the study.
干预措施: Infusion Procedure (Procedure)
Arm A (Adjunct interventions)
Patients receive standard of care PD-1/PD-L1-containing immunotherapy infusion, starting before 12 PM, desloratadine PO QD, propranolol PO BID, magnesium IV if magnesium level is below 1.9, and vitamin D PO QD if vitamin D level is below 30. Additional IV or oral magnesium and vitamin D supplementation may be administered at the investigator's discretion per standard of care. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI and blood sample collection throughout the study.
干预措施: Desloratadine (Drug)
Arm A (Adjunct interventions)
Patients receive standard of care PD-1/PD-L1-containing immunotherapy infusion, starting before 12 PM, desloratadine PO QD, propranolol PO BID, magnesium IV if magnesium level is below 1.9, and vitamin D PO QD if vitamin D level is below 30. Additional IV or oral magnesium and vitamin D supplementation may be administered at the investigator's discretion per standard of care. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI and blood sample collection throughout the study.
干预措施: Biospecimen Collection (Procedure)
Arm A (Adjunct interventions)
Patients receive standard of care PD-1/PD-L1-containing immunotherapy infusion, starting before 12 PM, desloratadine PO QD, propranolol PO BID, magnesium IV if magnesium level is below 1.9, and vitamin D PO QD if vitamin D level is below 30. Additional IV or oral magnesium and vitamin D supplementation may be administered at the investigator's discretion per standard of care. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI and blood sample collection throughout the study.
干预措施: Computed Tomography (Procedure)
Arm A (Adjunct interventions)
Patients receive standard of care PD-1/PD-L1-containing immunotherapy infusion, starting before 12 PM, desloratadine PO QD, propranolol PO BID, magnesium IV if magnesium level is below 1.9, and vitamin D PO QD if vitamin D level is below 30. Additional IV or oral magnesium and vitamin D supplementation may be administered at the investigator's discretion per standard of care. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI and blood sample collection throughout the study.
干预措施: Immunotherapy (Other)
Arm A (Adjunct interventions)
Patients receive standard of care PD-1/PD-L1-containing immunotherapy infusion, starting before 12 PM, desloratadine PO QD, propranolol PO BID, magnesium IV if magnesium level is below 1.9, and vitamin D PO QD if vitamin D level is below 30. Additional IV or oral magnesium and vitamin D supplementation may be administered at the investigator's discretion per standard of care. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI and blood sample collection throughout the study.
干预措施: Infusion Procedure (Procedure)
Arm A (Adjunct interventions)
Patients receive standard of care PD-1/PD-L1-containing immunotherapy infusion, starting before 12 PM, desloratadine PO QD, propranolol PO BID, magnesium IV if magnesium level is below 1.9, and vitamin D PO QD if vitamin D level is below 30. Additional IV or oral magnesium and vitamin D supplementation may be administered at the investigator's discretion per standard of care. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI and blood sample collection throughout the study.
干预措施: Magnetic Resonance Imaging (Procedure)
Arm B (Standard interventions)
Patients receive standard of care PD-1/PD-L1-containing immunotherapy, starting at standard of care time. Magnesium and vitamin D levels are checked with any supplementation per investigator discretion and institutional practice, without a prespecified goal level. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI and blood sample collection throughout the study.
干预措施: Biospecimen Collection (Procedure)
Arm B (Standard interventions)
Patients receive standard of care PD-1/PD-L1-containing immunotherapy, starting at standard of care time. Magnesium and vitamin D levels are checked with any supplementation per investigator discretion and institutional practice, without a prespecified goal level. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI and blood sample collection throughout the study.
干预措施: Computed Tomography (Procedure)
Arm B (Standard interventions)
Patients receive standard of care PD-1/PD-L1-containing immunotherapy, starting at standard of care time. Magnesium and vitamin D levels are checked with any supplementation per investigator discretion and institutional practice, without a prespecified goal level. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI and blood sample collection throughout the study.
干预措施: Magnetic Resonance Imaging (Procedure)
Arm A (Adjunct interventions)
Patients receive standard of care PD-1/PD-L1-containing immunotherapy infusion, starting before 12 PM, desloratadine PO QD, propranolol PO BID, magnesium IV if magnesium level is below 1.9, and vitamin D PO QD if vitamin D level is below 30. Additional IV or oral magnesium and vitamin D supplementation may be administered at the investigator's discretion per standard of care. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI and blood sample collection throughout the study.
干预措施: Magnesium Sulfate (Drug)
Arm A (Adjunct interventions)
Patients receive standard of care PD-1/PD-L1-containing immunotherapy infusion, starting before 12 PM, desloratadine PO QD, propranolol PO BID, magnesium IV if magnesium level is below 1.9, and vitamin D PO QD if vitamin D level is below 30. Additional IV or oral magnesium and vitamin D supplementation may be administered at the investigator's discretion per standard of care. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI and blood sample collection throughout the study.
干预措施: Cholecalciferol (Dietary Supplement)
Arm A (Adjunct interventions)
Patients receive standard of care PD-1/PD-L1-containing immunotherapy infusion, starting before 12 PM, desloratadine PO QD, propranolol PO BID, magnesium IV if magnesium level is below 1.9, and vitamin D PO QD if vitamin D level is below 30. Additional IV or oral magnesium and vitamin D supplementation may be administered at the investigator's discretion per standard of care. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI and blood sample collection throughout the study.
干预措施: Propranolol (Drug)
结局指标
主要结局
Change in interleukin-8 levels
时间窗: From baseline to 12 weeks
The estimand for the null hypothesis will be the estimate of the difference in the average characteristics at week 12 stratified by the disease group. The null hypothesis will be tested at the 0.05 level. Tests of the null hypothesis will be conducted using the t-test. Departures from the normal distribution of the estimand will be assessed using the Shapiro-Wilk test.
Change in interferon-gamma levels
时间窗: From baseline, up to 12 weeks
The estimand for the null hypothesis will be the estimate of the difference in the average characteristics at week 12 stratified by the disease group. The null hypothesis will be tested at the 0.05 level. Tests of the null hypothesis will be conducted using the t-test. Departures from the normal distribution of the estimand will be assessed using the Shapiro-Wilk test.
Change in effector T cells (Teff)/regulatory T cell (Treg) ratio
时间窗: From baseline, up to 12 weeks
The estimand for the null hypothesis will be the estimate of the difference in the average characteristics at week 12 stratified by the disease group. The null hypothesis will be tested at the 0.05 level. Tests of the null hypothesis will be conducted using the t-test. Departures from the normal distribution of the estimand will be assessed using the Shapiro-Wilk test.
次要结局
- Incidence of grade ≥ 3 treatment related adverse events (AEs)(From baseline, up to 12 weeks)
- Incidence of immune related AEs(From baseline, up to 12 weeks)
- Incidence of serious AEs(From baseline, up to 12 weeks)