A Trial of Pembrolizumab in Combination With Doxorubicin as Treatment for Patients With Advanced Sarcomas
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 37
- 试验地点
- 1
- 主要终点
- Maximum Tolerated Dose (MTD) of Doxorubicin Hydrochloride Plus Pembrolizumab According to the National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) Version 4.0 (Phase I)
研究概览
简要总结
This phase I/II trial studies the side effects and best dose of doxorubicin hydrochloride when given together with pembrolizumab and to see how well they work in treating patients with sarcoma that have spread to other parts of the body or that cannot be removed by surgery. Drugs used in chemotherapy, such as doxorubicin hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving doxorubicin hydrochloride together with pembrolizumab may work better in treating patients with sarcoma.
详细描述
PRIMARY OBJECTIVES:
I. To assess the safety and tolerability of the combination of pembrolizumab and doxorubicin hydrochloride (doxorubicin) in patients with advanced soft tissue sarcoma (STS).
II. To assess the clinical response rate of advanced soft tissue sarcoma (STS) patients receiving the combination of pembrolizumab and doxorubicin.
SECONDARY OBJECTIVES:
I. To explore the clinical activity of pembrolizumab in subjects with advanced STS with respect to time to response.
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
- •Be willing and able to provide written informed consent/assent for the trial
- •Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
- •Have metastatic or unresectable sarcoma
- •Have a performance status of 0 to 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
- •Absolute neutrophil count (ANC) >= 1,500/mcL (within 10 days of treatment initiation)
- •Platelets >= 100,000/mcL (within 10 days of treatment initiation)
- •Hemoglobin >= 9 g/dL (within 10 days of treatment initiation) or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)
- •Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (within 10 days of treatment initiation)
- •Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (within 10 days of treatment initiation)
- •Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases (within 10 days of treatment initiation)
- •Albumin >= 2.5 mg/dL (within 10 days of treatment initiation)
- •International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (within 10 days of treatment initiation)
- •Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (within 10 days of treatment initiation)
- •Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
- •Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
- •Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy
- •Ejection fraction > 45% by either multi-gated acquisition scan (MUGA) scan or echocardiogram
排除标准
- •Has prior treatment using an anthracycline
- •Has one of the following sarcoma subtypes where combining anthracyclines with other chemotherapies is established as the standard of care: osteosarcoma, Ewings sarcoma, embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma
- •Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
- •Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
- •Has a known history of active TB (bacillus tuberculosis)
- •Hypersensitivity to pembrolizumab or any of its excipients
- •Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
- •Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent
- •Note: Subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study
- •Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
- •Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
- •Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
- •Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
- •Has known history of, or any evidence of active, non-infectious pneumonitis
- •Has an active infection requiring systemic therapy
- •Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
- •Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
- •Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
- •Has received prior therapy with an anti-programed death receptor 1 (PD-1), anti-PD-L1, anti-program death receptor ligand 2 (PD-L2) agent or anti-CTLA4
- •Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
- •Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
- •Has received a live vaccine within 30 days of planned start of study therapy
- •Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
研究组 & 干预措施
Treatment (pembrolizumab, doxorubicin hydrochloride)
Patients receive pembrolizumab IV over 30 minutes on day 1 and doxorubicin hydrochloride IV over 1-3 hours on day 1 of courses 2-7 only. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Doxorubicin Hydrochloride (Drug)
Treatment (pembrolizumab, doxorubicin hydrochloride)
Patients receive pembrolizumab IV over 30 minutes on day 1 and doxorubicin hydrochloride IV over 1-3 hours on day 1 of courses 2-7 only. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Laboratory Biomarker Analysis (Other)
Treatment (pembrolizumab, doxorubicin hydrochloride)
Patients receive pembrolizumab IV over 30 minutes on day 1 and doxorubicin hydrochloride IV over 1-3 hours on day 1 of courses 2-7 only. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Pembrolizumab (Biological)
结局指标
主要结局
Maximum Tolerated Dose (MTD) of Doxorubicin Hydrochloride Plus Pembrolizumab According to the National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) Version 4.0 (Phase I)
时间窗: Up to 42 days (6 weeks)
Defined as a dose limiting toxicity (DLT) in less than 2 of 6 subjects. Only Phase 1 subjects will be evaluated for MTD.
Objective Response Rate (ORR) (Phase II)
时间窗: Up to 2 years
Evaluated per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT. Complete Response (CR) is a complete elimination of the tumor; Partial Response (PR) is 30% reduction. If a subject experienced a PR, this was required to be confirmed with a second scan at the next appropriate cycle.
次要结局
- Overall Survival (OS)(Up to 2 years)
- Time to Response(Up to 2 years)
- Duration of Response(Up to 2 years)
- Median Progression-free Survival (PFS)(Up to 2 years)
研究者
Seth Pollack
Steven T. Rosen, MD, Professor of Cancer Biology
Northwestern University