A Phase II Study of Cabozantinib and Temozolomide in Patients With Unresectable or Metastatic Leiomyosarcoma and Other Soft Tissue Sarcomas
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 96
- 试验地点
- 10
- 主要终点
- Progression-free survival (PFS)
研究概览
简要总结
This phase II trial studies how well cabozantinib and temozolomide work in treating patients with leiomyosarcoma or other soft tissue sarcoma that cannot be removed by surgery (unresectable) or has spread to other places in the body (metastatic). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, 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. Giving cabozantinib and temozolomide may work better than either one alone in treating patients with leiomyosarcoma or other soft tissue sarcoma. Cabozantinib is an investigational drug, which means that it has not been approved by the United States (US) Food and Drug Administration (FDA) or any other regulatory agencies for sale or use by the public for the indication under investigation in this study.
详细描述
PRIMARY OBJECTIVE:
I. To determine the progression-free survival (defined as complete response [CR]+partial response [PR]+stable disease [SD]) assessed at 12 weeks for subjects in Cohort 1 (Leiomyosarcoma Arm) treated with cabozantinib and temozolomide as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
SECONDARY OBJECTIVES:
I. To determine the overall response rate (defined as CR+PR) for subjects in Cohort 1 treated with a combination of cabozantinib and temozolomide.
II. To determine the clinical benefit rate (CR+PR+SD) for subjects in Cohort 1 treated with a combination of cabozantinib and temozolomide.
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
- •Subjects must have a histologically confirmed diagnosis of unresectable or metastatic:
- •Uterine and non-uterine leiomyosarcoma
- •Other soft tissue sarcoma (non-leiomyosarcoma)
- •Note: Subjects with any one of the following soft tissue sarcoma histological subtypes will not be eligible for participation: alveolar soft-part sarcoma, dermatofibrosarcoma, gastrointestinal stromal tumor (GIST), Kaposi sarcoma, mixed mesodermal tumor/carcinosarcoma, rhabdomyosarcoma (embryonal and alveolar), and low grade (grade 1) sarcomas
- •Subjects must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
- •Subjects with 0 - 5 prior chemotherapy regimens for recurrent/metastatic disease are eligible. It will be up to the investigator to determine what constitutes a regimen in each case
- •Subjects with prior next generation sequencing (NGS) reports completed on their tumor specimen will have this data collected
- •Subjects must have measurable disease by RECIST 1.1
- •Subjects must have adequate organ and bone marrow function, based upon meeting all of the following laboratory:
- •White blood cell count >= 2500/mm^3 (>= 2.5 GI/L)
- •Absolute neutrophil count (ANC) >= 1,500/mm^3 (>= 1.5 GI/L) without granulocyte colony stimulating factor support
- •Hemoglobin >= 9 g/dL (>= 90 g/L)
- •Platelets >= 100,000/mm^3 (>= 100 GI/L) without transfusion
- •Total bilirubin =< 1.5 x upper limit of normal (ULN) (for subjects with Gilbert's disease =< 3 x ULN)
- •Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SPGT]) =< 3 X upper limit of normal (ULN)
- •Alkaline phosphatase (ALP) =< 3 X ULN. ALP =< 5 x ULN with documented bone metastases
- •Serum albumin >= 2.8 g/dl
- •Serum creatinine =< 2.0 x ULN or calculated creatinine clearance >= 30 mL/min (>= 0.5 mL/sec) using the Cockcroft-Gault equation
- •Urine protein/creatinine ratio (UPCR) =< 1 (=< 113.2 mg/mmol)
- •Prothrombin time (PT/institutional normalized ratio [INR]) or partial thromboplastin time (PTT) test =< 1.3 x the laboratory ULN
- •Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (e.g., barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 4 months after the last dose of study treatment
- •Female subjects of childbearing potential must not be pregnant at screening. Females of childbearing potential are defined as premenopausal females capable of becoming pregnant (i.e., females who have had any evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy). However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body weight, ovarian suppression or other reasons
- •Recovery to baseline or =< grade 1 Common Terminology Criteria for Adverse Events (CTCAE) version (v.)5.0 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy
- •Subjects with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression
- •Subjects must be capable of understanding and complying with the protocol requirements and must have signed the informed consent document
排除标准
- •Inability to swallow tablets
- •Previously identified allergy or hypersensitivity to components of the study treatment formulation or dacarbazine
- •Subjects with a prior or concurrent malignancy whose natural history or treatment does have the potential to interfere with the safety or efficacy assessment of the investigational regiment are ineligible for this trial
- •Pregnant or lactating females. Pregnant women are excluded from this study because cabozantinib and temozolomide are antineoplastic agents with potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with cabozantinib and temozolomide, breastfeeding should be discontinued if the mother is treated with cabozantinib and temozolomide
- •Prior treatment with cabozantinib or temozolomide
- •Receipt of any of the following:
- •Any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 14 days before first dose of study treatment
- •Any type of cytotoxic, biologic or other systemic anticancer therapy (including investigational) within 28 days before first dose of study treatment
- •Radiation therapy for bone metastasis within 14 days before first dose of study treatment
- •Any other radiation therapy within 28 days before first dose of study treatment
- •Systemic treatment with radionuclides within 42 days before the first dose of study treatment
- •Note: Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible
- •Major surgery (e.g., GI surgery, removal or biopsy of brain metastasis) within 56 days before the first dose of study treatment
- •Note: Complete wound healing from major surgery must have occurred 28 days before first dose and from minor surgery (e.g., simple excision, tooth extraction) at least 10 days before first dose. Subjects with clinically relevant ongoing complications from prior surgery are not eligible
- •Corrected QT interval calculated by the Bazetts formula (QTcF) > 500 ms per electrocardiogram (ECG) within 28 days before first dose of study treatment
- •Note: If a single electrocardiography (ECG) shows a QTcF with an absolute value > 500 ms, two additional ECGs at intervals of approximately 3 min must be performed within 30 min after the initial ECG, and the average of these three consecutive results for QTcF will be used to determine eligibility
- •The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
- •Cardiovascular disorders:
- •Subjects 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, subjects should be class 2B or better
- •Uncontrolled hypertension defined as sustained blood pressure (BP) ˃ 150 mm Hg systolic or ˃ 100 mm Hg diastolic despite optimal antihypertensive treatment
- •Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic event within 6 months before the first dose
- •Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation:
- •The subject has evidence of tumor invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (e.g., Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction.
- •Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before the first dose
- •Note: Complete healing of an intra-abdominal abscess must be confirmed before the first dose
- •Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding (e.g., pulmonary hemorrhage) within 84 days before the first dose
- •Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation
- •Lesions invading or encasing any major blood vessels
- •Other clinically significant disorders that would preclude safe study participation
- •Serious non-healing wound/ulcer/bone fracture
- •Uncompensated/symptomatic hypothyroidism
- •Moderate to severe hepatic impairment (Child-Pugh B or C)
- •Concomitant anticoagulation with oral anticoagulants (e.g., warfarin, direct thrombin and factor Xa inhibitors) or platelet inhibitors (e.g., clopidogrel). Washout period is considered to be 5 half-lives of the drug. Allowed anticoagulants are the following:
- •Low-dose aspirin for cardio protection (per local applicable guidelines) is permitted.
- •Low-dose low molecular weight heparins (LMWH) are permitted.
- •Anticoagulation with therapeutic doses of LMWH is allowed in subjects without known brain metastases who are on a stable dose of LMWH for at least 42 days before first dose of study treatment, and who have had no clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor
研究组 & 干预措施
Treatment (cabozantinib, temozolomide)
Patients receive cabozantinib PO QD on days 1-28 and temozolomide PO QD on days 1-5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Questionnaire Administration (Other)
Treatment (cabozantinib, temozolomide)
Patients receive cabozantinib PO QD on days 1-28 and temozolomide PO QD on days 1-5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Quality-of-Life Assessment (Other)
Treatment (cabozantinib, temozolomide)
Patients receive cabozantinib PO QD on days 1-28 and temozolomide PO QD on days 1-5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Cabozantinib (Drug)
Treatment (cabozantinib, temozolomide)
Patients receive cabozantinib PO QD on days 1-28 and temozolomide PO QD on days 1-5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Temozolomide (Drug)
结局指标
主要结局
Progression-free survival (PFS)
时间窗: After the first 12 weeks of therapy
PFS will be the time from the start of treatment to the time of progression, with progression defined as changes in Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 defined imaging, progression in non-target lesions as defined by RECIST 1.1, unequivocal clinical deterioration, or death from any cause.
Progression-free Survival (PFS)
时间窗: After the first 12 weeks of therapy
Progression will be evaluated in this study using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1). Per RECIST v1.1 criteria, for target lesions, progression is defined as at least a 20% increase in the sum of the longest diameter or the appearance of one or more new lesions; For non-target lesions, progression is defined as the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. PFS will be the time from the start of treatment to the time of progression, unequivocal clinical deterioration, or death from any cause. The proportion of patients who had a PFS event was calculated.
次要结局
- Clinical benefit rate (Cohort 1)(At weeks 6 and 12, then every 2 cycles up to 5 years)
- Presence of response (Cohort 1)(At weeks 6 and 12, then every 2 cycles up to 5 years)
- Median progression free rate(Up to 5 years)
- Overall survival (OS) (Cohort 1)(Up to 2 years)
- Subject-reported outcomes(5 years)
- Incidence of adverse events(From time of first treatment up to 5 years)
- Presence of Response(At weeks 6 and 12, then every 2 cycles up to 5 years)
- Clinical Benefit Rate(At weeks 6 and 12, then every 2 cycles up to 5 years)
- Median Progression Free Survival(Up to 5 years)
- Overall Survival (OS)(Up to 2 years)
- Number of Participants With Adverse Events(From time of first treatment up to the end of last treatment, up to 5 years)
- Subject-reported Outcomes(Outcomes are measured at Cycle 1 to Cycle 4 between responders and non-responders)