A Phase I Trial of Dasatinib in Combination With Crizotinib in Patients With Advanced Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 62
- 试验地点
- 1
- 主要终点
- Maximum tolerated dose (MTD) of Dasatinib plus Crizotinib
研究概览
简要总结
The goal of this clinical research study is to find the highest tolerable dose of the combination of dasatinib and crizotinib that can be given to patients with advanced cancer. The safety of this drug combination will also be studied.
Dasatinib is designed to block certain proteins from causing cancer cells to grow out of control. This may cause the cancer cells to die.
Crizotinib is designed to block certain abnormal genes found in cancer cells. This may cause the cancer cells to die.
This is an investigational study. Dasatinib is FDA approved and commercially available for the treatment of leukemia. Crizotinib is FDA approved and commercially available for the treatment of lung cancer. The combination of dasatinib and crizotinib is currently being used for research purposes only.
Up to 176 participants will take part in this study. All will be enrolled at MD Anderson
详细描述
Study Groups:
Dose Escalation Group:
If you are found to be eligible to take part in this study, you will be assigned to a either Arm A or Arm B based when you joined this study, the disease type, and the drugs you have taken in the past. Up to 5 dose levels of the study drug will be tested in each arm. Up to 6 participants will be enrolled in each dose level of arms A and B. The first group of participants in Arm A will receive the FDA approved dose of crizotinib plus the lowest dose level of dasatinib. The first group of participants in Arm B will receive the FDA approved dose of dasatinib plus the lowest dose level of crizotinib. Each new group will receive a higher dose of the study drug combination than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of the study drug combination is found.
The dose level of the study drug combination that you receive may be lowered if you have intolerable side effects.
Dose Expansion Group:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 16 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must have histologically confirmed solid malignancy that is metastatic or unresectable or lymphoma, for which standard curative or palliative measures that improve survival by at least three months do not exist or are no longer effective. For the purpose of this study patients with leukemia are not eligible.
- •Age >/= 16 years.
- •Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status </=
- •Patients must have normal organ and marrow function as followed defined: ANC >/= 1,000/mcL; Plt >/=75,000/mcL; total bilirubin </=2.0 mg/dL; AST (TGO)/ALT (TGP) </=2.5x upper limit of normal; if liver metastasis are present, then </= 5.0x upper limit; estimated creatinine clearance by Cockcroft-Gault equation > 30 mL/min
- •The effects of Dasatinib and Crizotinib on the developing human fetus are unknown. For this reason 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.
- •Patients receiving palliative radiation will be eligible after a wash-out period of 2 weeks between finishing radiation and initiation of study drugs. Palliative radiation will not be allowed during cycle 1 of treatment but is permitted in this study during following cycles as long as there are evaluable lesions that are not being irradiated
- •Signed informed consent approved by the Institutional Review Board prior to patient entry.
- •Expanded cohort only: Cohort 1: patients with predominant metastatic bone disease; Cohort 2: patients with primary squamous head and neck cancers; Cohort 3: patients presenting any molecular abnormality of interest, which can include an ALK translocation, ALK amplification, ALK mutation and overexpression as determined by FISH, IHC, qPCR, qRT-PCR, array Comparative Genomic Hybridization or direct sequencing (aCGH); a c-MET abnormality, either c-MET amplification by FISH, overexpression by IHC or c-MET mutation; BRAF, DDR2 and CDKN2A mutations; and, finally, TRIM 16 expression and CCN2 expression.
排除标准
- •Patient receiving any concurrent chemotherapy.
- •Concurrent severe and/or uncontrolled medical disease including, but not limited to, ongoing or active infection requiring intravenous antibiotics.
- •Symptomatic congestive heart failure (NYHA Class III or IV), or unstable angina pectoris.
- •Presence of symptomatic pleural and/or pericardial effusion not appropriated treated.
- •Prolonged QTc interval (>/=500 msec), as calculated by Bazett's formula.
- •Psychiatric problems of sufficient severity to limit full compliance with the study or expose patients to undue risk.
- •Known anaphylactic or severe hypersensitivity to Dasatinib or Crizotinib or their analogs.
- •Patient has failed to recover from any prior surgery within 4 weeks of study entry.
- •Patient is pregnant or lactating. Pregnant women are excluded from this study because dasatinib and crizotinib are agents with the potential for teratogenic or abortifacient effects (Pregnancy category D).
- •Patient has had any treatment specific for tumor control within 3 weeks of dosing with investigational drugs and cytotoxic agents, or within 2 weeks of cytotoxic agent given weekly, or within 6 weeks of nitrosoureas or mitomycin C, or within 5 half-lives of biological targeted agents.
- •Patient is not able to swallow oral medication.
- •Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 complex are ineligible.
- •Patients with known pulmonary hypertension.
研究组 & 干预措施
Arm A - Crizotinib + Dasatinib
Arm A: Patients receive dose of crizotinib plus an increasing dose of dasatinib. All participants take dasatinib by mouth 1 time each day. Patients take this drug alone on Day 1 of Cycle 1, before the first day they receive the study drug combination. Final dose level in both arms (dose level number 5) is identical. In the case that both arms define dose level 5 as the MTD, then the expansion cohort for safety will include 10 patients with that dose. If two different MTDs on both arms defined, then both MTDs cohorts expanded with 10 patients and 20 patients included on the safety expansion analysis.
Crizotinib dose: 250 mg by mouth twice a day in a 28 day cycle. Dasatinib starting dose: 50 mg by mouth daily in a 28 day cycle.
Crizotinib Expansion dose: 250 mg by mouth twice a day in a 28 day cycle. Dasatinib Expansion Dose: MTD from dose escalation group.
干预措施: Crizotinib (Drug)
Arm A - Crizotinib + Dasatinib
Arm A: Patients receive dose of crizotinib plus an increasing dose of dasatinib. All participants take dasatinib by mouth 1 time each day. Patients take this drug alone on Day 1 of Cycle 1, before the first day they receive the study drug combination. Final dose level in both arms (dose level number 5) is identical. In the case that both arms define dose level 5 as the MTD, then the expansion cohort for safety will include 10 patients with that dose. If two different MTDs on both arms defined, then both MTDs cohorts expanded with 10 patients and 20 patients included on the safety expansion analysis.
Crizotinib dose: 250 mg by mouth twice a day in a 28 day cycle. Dasatinib starting dose: 50 mg by mouth daily in a 28 day cycle.
Crizotinib Expansion dose: 250 mg by mouth twice a day in a 28 day cycle. Dasatinib Expansion Dose: MTD from dose escalation group.
干预措施: Dasatinib (Drug)
Arm B - Dasatinib + Crizotinib
Arm B: Patients receive dasatinib plus an increasing dose of crizotinib. All participants take dasatinib by mouth 1 time each day. Patients take this drug alone on Day 1 of Cycle 1, before the first day they receive the study drug combination. Final dose level in both arms (dose level number 5) is identical. In the case that both arms define dose level 5 as the MTD, then the expansion cohort for safety will include 10 patients with that dose. If two different MTDs on both arms defined, then both MTDs cohorts expanded with 10 patients and 20 patients included on the safety expansion analysis.
Dasatinib 140 mg by mouth daily in a 28 day cycle. Crizotinib starting dose: 250 mg by mouth every other day in a 28 day cycle.
Dasatinib Expansion Dose: 140 mg by mouth daily in a 28 day cycle. Crizotinib Expansion Dose: MTD from dose escalation group.
干预措施: Crizotinib (Drug)
Arm B - Dasatinib + Crizotinib
Arm B: Patients receive dasatinib plus an increasing dose of crizotinib. All participants take dasatinib by mouth 1 time each day. Patients take this drug alone on Day 1 of Cycle 1, before the first day they receive the study drug combination. Final dose level in both arms (dose level number 5) is identical. In the case that both arms define dose level 5 as the MTD, then the expansion cohort for safety will include 10 patients with that dose. If two different MTDs on both arms defined, then both MTDs cohorts expanded with 10 patients and 20 patients included on the safety expansion analysis.
Dasatinib 140 mg by mouth daily in a 28 day cycle. Crizotinib starting dose: 250 mg by mouth every other day in a 28 day cycle.
Dasatinib Expansion Dose: 140 mg by mouth daily in a 28 day cycle. Crizotinib Expansion Dose: MTD from dose escalation group.
干预措施: Dasatinib (Drug)
结局指标
主要结局
Maximum tolerated dose (MTD) of Dasatinib plus Crizotinib
时间窗: 4 weeks
Maximum tolerated dose (MTD) defined by dose limiting toxicities (DLTs) that occur during the first cycle (first four weeks). MTD defined as the highest dose studied in which the incidence of DLT was less than 33%.
次要结局
- Tumor Response(After 2, 28 day cycles)