Two Phase I Studies in Patients With Brain Metastases From Any Primary Histology, Followed by a Randomized Phase 2 Study of RO4929097 Combined With CNS Radiotherapy in Patients With Brain Metastases From Breast Cancer Whose Tumors Are Estrogen Receptor Negative
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 5
- 试验地点
- 2
- 主要终点
- Phase 1 Arm I Maximum-tolerated Dose (MTD) of RO4929097 in Combination With Whole-brain Radiotherapy (WBRT)
研究概览
简要总结
This randomized phase I/II trial studies the side effects and the best dose of RO4929097 (gamma-secretase/Notch signalling pathway inhibitor RO4929097) when given together with whole-brain radiation therapy or stereotactic radiosurgery and to see how well it works compared to whole-brain radiation therapy or stereotactic radiosurgery alone in treating patients with breast cancer or other cancers (such as lung cancer or melanoma) that have spread to the brain. RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Whole-brain radiation therapy uses high energy x-rays deliver radiation to the entire brain to treat tumors that can and cannot be seen. Stereotactic radiosurgery may be able to deliver x-rays directly to the tumor and cause less damage to normal tissue. It is not yet known whether giving RO4929097 together with whole-brain radiation therapy or stereotactic radiosurgery may kill more tumor cells.
详细描述
PRIMARY OBJECTIVES:
I. Determine the maximum-tolerated dose (MTD) and phase II dose of RO4929097 when combined with whole-brain radiation therapy (WBRT). (Phase I) II. Determine the safety profile of RO4929097 when combined with WBRT. (Phase I) III. Determine the MTD and phase II dose of RO4929097 when combined with stereotactic radiosurgery (SRS). (Phase I) IV. Determine the safety profile of RO4929097 when combined with SRS. (Phase I) V. Determine whether the addition of RO4929097 to WBRT or SRS significantly increases the percentages of estrogen receptor-negative breast cancer patients with brain metastases who achieve response (complete response [CR] + partial response [PR]) in the brain at the 12-week (3-month) time point after cranial radiotherapy. (Phase II)
SECONDARY OBJECTIVES:
I. Correlate responses and time to progression to: pre- and post-therapy tumor and archived tumor tissue expression of molecular and stem cell markers; pre- and post-therapy plasma biomarkers; changes in pre- and post-therapy tumor and archived tumor tissue expression of molecular and stem cell markers over the first 5 days of therapy and changes of pre- and post-therapy plasma biomarkers over the course of therapy; in Notch positive and Notch negative tumors, over the first 5 days of therapy with RO4929097, compare tumor tissue expression of molecular and stem cell markers. (Phase I and II) II. Determine progression free survival (PFS) in the brain for each treatment arm. (Phase II) III. Determine the percentage of patients alive and disease free (in the brain) at 6 months. (Phase II) IV. Determine local control rate (in the brain) at 24- and 48-week time point after cranial radiotherapy for each treatment arm. (Phase II) V. Determine distant failure rate (in the brain) at 24- and 48-week time point after cranial radiotherapy for each treatment arm. (Phase II) VI. Determine PFS in the body for each treatment arm. (Phase II) VII. Determine systemic response rate. (Phase II) VIII. Determine percentage of patients alive and without progression systemically at 6 months. (Phase II) IX. Further describe the safety profile of each treatment arm. (Phase II) X. Compare neurocognitive outcomes in each treatment arm. (Phase II)
OUTLINE: This is a phase I, dose-escalation study of gamma-secretase/Notch signalling pathway inhibitor RO4929097 followed by a randomized phase II study.
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
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 who have histologically or cytologically confirmed breast cancer or other cancers (such as lung cancer, melanoma, etc) with newly diagnosed metastatic disease to the brain will be eligible for the Phase 1 study only, however, those patients who have available systemic therapeutic options with a demonstrated survival benefit will not be eligible; for Phase 2, patients must have histologically or cytologically confirmed estrogen receptor negative breast cancer with newly diagnosed metastatic disease to the brain
- •Patients must have measurable disease in the brain, defined as at least one lesion that can be accurately measured in at least two dimensions (longest diameter and its longest perpendicular diameter to be recorded)
- •There is no limit on type or number of prior therapies, except that prior therapy with notch inhibitors is not allowed, and patients should not have received prior cranial radiation; therapy naïve patients are eligible; at least 14 days (2 weeks) must have elapsed from any prior experimental therapy, chemotherapy or radiotherapy; toxicities from prior chemotherapy or radiotherapy should have resolved to < grade 2; patients with newly diagnosed brain metastases who have received therapeutic regimens with well-characterized, delayed toxicity (e.g. hematologic toxicity observed following carmustine [BCNU] or mitomycin C) will not receive experimental therapy until the patient has adequately recovered from all drug related toxicities
- •Karnofsky performance status (KPS) >= 70%; Recursive Partitioning Analysis (RPA) class I or II; a small feasibility cohort of 10 RPA class III (KPS < 70%) patients may be enrolled, however these patients, if enrolled will not be included in the efficacy analysis
- •Hemoglobin >= 9g/dL
- •Absolute neutrophil count >= 1,000/mcL
- •Platelets >= 100,000/mcL
- •Total bilirubin within normal institutional limits
- •Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 2.5 x institutional upper limit of normal
- •Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limits of normal
- •Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
- •Tumor HER2/neu status may be positive or negative
- •Women of childbearing potential and men must use two forms of contraception (i.e., barrier contraception and one other method of contraception) for the duration of study participation, and for at least 12 months post-treatment; should a woman become pregnant or suspect she is pregnant while she or her partner are participating in this study and for 12 months after study participation, the patient should inform the treating physician immediately; prior to dispensing RO4929097, the investigator must confirm and document the patient's agreement to the use of two contraceptive methods, dates of negative pregnancy test, and confirm the patient's understanding of the teratogenic potential of RO4929097
- •Ability to understand and the willingness to sign a written informed consent document
- •A tumor site (outside the central nervous system) for needle biopsy for research purposes is preferable
- •Ability to swallow pills
排除标准
- •At least 14 days (2 weeks) must have elapsed from any prior experimental therapy, chemotherapy or radiotherapy; toxicities from prior chemotherapy or radiotherapy should have resolved to < grade 2
- •Patients may not be receiving any other investigational agents
- •Patients with leptomeningeal metastases should be excluded from this clinical trial
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to RO4929097
- •Patients taking medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®) are ineligible
- •Patients taking medications that are generally accepted by the QTdrugs.org Advisory Board to carry a risk of torsades de pointes, including antiemetics, are ineligible
- •Preclinical studies indicate that RO4929097 is a substrate of CYP450 family 3, subfamily A, polypeptide 4 (CYP3A4) and inducer of CYP3A4 enzyme activity; caution should be exercised when dosing RO4929097 concurrently with CYP3A4 substrates, inducers, and/or inhibitors; furthermore, patients who are taking concurrent medications that are strong inducers/inhibitors or substrates of CYP3A4 should be switched to alternative medications to minimize any potential risk; if such patients cannot be switched to alternative medications, they will be ineligible to participate in this study
- •Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption; patients must be able to swallow tablets
- •Patients who are known to be serologically positive for hepatitis A, B or C, or have a history of liver disease, other forms of hepatitis or cirrhosis are ineligible
- •Patients with uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia or hypokalemia defined as less than the lower limit of normal for the institution, despite adequate electrolyte supplementation are excluded from this study
- •Uncontrolled electrolyte abnormalities including hypocalcemia, hypomagnesemia, and hypokalemia; uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (New York Heart Association [NYHA] class III or IV), unstable angina pectoris, a history of torsades de pointes or other significant cardiac arrhythmias, stable atrial fibrillation, or psychiatric illness/social situations that would limit compliance with study requirements
- •Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with RO4929097
- •Cardiovascular: baseline QTcF > 450 msec (male) or QTcF > 470 msec (female)
- •Patients who have not recovered to < Common Terminology Criteria for Adverse Events (CTCAE) grade 2 toxicities related to prior therapy are not eligible to participate in this study
- •A requirement for antiarrhythmics or other medications known to prolong QTc
研究组 & 干预措施
Arm I (WBRT or SRS)
Patients with >= 4 brain lesions undergo WBRT as in phase I and patients with =< 3 brain lesions undergo SRS as in phase I.
干预措施: Cognitive Assessment (Procedure)
Arm I (WBRT or SRS)
Patients with >= 4 brain lesions undergo WBRT as in phase I and patients with =< 3 brain lesions undergo SRS as in phase I.
干预措施: Laboratory Biomarker Analysis (Other)
Arm I (WBRT or SRS)
Patients with >= 4 brain lesions undergo WBRT as in phase I and patients with =< 3 brain lesions undergo SRS as in phase I.
干预措施: Stereotactic Radiosurgery (Radiation)
Arm I (WBRT or SRS)
Patients with >= 4 brain lesions undergo WBRT as in phase I and patients with =< 3 brain lesions undergo SRS as in phase I.
干预措施: Whole-Brain Radiotherapy (Radiation)
Arm II (WBRT or SRS and RO4929097)
Patients with >= 4 brain lesions receive RO4929097 and undergo WBRT as in phase I and patients with =< 3 brain lesions receive RO4929097 and undergo SRS as in phase I.
干预措施: Cognitive Assessment (Procedure)
Arm II (WBRT or SRS and RO4929097)
Patients with >= 4 brain lesions receive RO4929097 and undergo WBRT as in phase I and patients with =< 3 brain lesions receive RO4929097 and undergo SRS as in phase I.
干预措施: Gamma-Secretase Inhibitor RO4929097 (Drug)
Arm II (WBRT or SRS and RO4929097)
Patients with >= 4 brain lesions receive RO4929097 and undergo WBRT as in phase I and patients with =< 3 brain lesions receive RO4929097 and undergo SRS as in phase I.
干预措施: Laboratory Biomarker Analysis (Other)
Arm II (WBRT or SRS and RO4929097)
Patients with >= 4 brain lesions receive RO4929097 and undergo WBRT as in phase I and patients with =< 3 brain lesions receive RO4929097 and undergo SRS as in phase I.
干预措施: Stereotactic Radiosurgery (Radiation)
Arm II (WBRT or SRS and RO4929097)
Patients with >= 4 brain lesions receive RO4929097 and undergo WBRT as in phase I and patients with =< 3 brain lesions receive RO4929097 and undergo SRS as in phase I.
干预措施: Whole-Brain Radiotherapy (Radiation)
结局指标
主要结局
Phase 1 Arm I Maximum-tolerated Dose (MTD) of RO4929097 in Combination With Whole-brain Radiotherapy (WBRT)
时间窗: 4 weeks
Maximum-tolerated dose (MTD) of RO4929097 in combination with WBRT, determined according to incidence of dose limiting toxicity (DLT) graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Phase I)
Phase 1 Arm II MTD of RO4929097 in Combination With Stereotactic Surgery (SRS)
时间窗: 4 weeks
MTD of RO4929097 in combination with SRS, determined according to incidence of DLT graded using the NCI CTCAE version 4.0 (phase I)
Response Rate (Complete or Partial Response)
时间窗: 12 weeks
Only participants with measurable disease present at baseline, received at least 6 weeks of therapy, and had disease re-evaluated considered evaluable for response. Complete Response (CR): Disappearance all lesions; Partial Response (PR): =/\>50% decrease in sum bidimensional products all lesions reference baseline sum of bidimensional products of all lesions; Progressive Disease (PD): \>25% increase in sum bidimensional products of lesions, or progression of any treated lesion not target lesion, or appearance of 1 or \> new lesions at least 6 mm in unidimensional size. Stable Disease (SD): Neither sufficient shrinkage for PR nor increase for PD, reference smallest sum of bidimensional products of all lesions.
次要结局
未报告次要终点