Neratinib and Capmatinib Combination (Phase Ib/II) in Metastatic Breast Cancer and Inflammatory Breast Cancer Patients With Abnormal HER-family and c-Met Pathway Activity as Measured by the CELsignia Signaling Analysis Test
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- To Determine Maximum Tolerated Dose for Use in the Phase II Portion of the Trial
研究概览
简要总结
This study is to learn if the combination therapy of capmatinib and neritinib can help to control metastatic or locally advanced breast cancer. Researchers also want to find the highest tolerable dose of the combination therapy of capmatinib and neritinib that can be used in this study drug combinations. The safety of this drug combination and the CELsignia MP test methodology will also be studied.
详细描述
This is an open-label, phase Ib/II study of neratinib plus Capmatinib in patients with metastatic breast cancer and patients with metastatic IBC.
Phase 1b - Dose Escalation of Neratinib with Capmatinib
This phase of the study will employ the Bayesian optimal interval (BOIN) design with the 3+3 design run-in, to find the MTD. The BOIN design is implemented in a simple way similar to the traditional 3+3 design, but is more flexible and possesses superior operating characteristics that are comparable to those of the more complex model-based designs, such as the continual reassessment method (CRM). The maximum sample size for dose escalation is 18. Patients are treated in cohorts of 3, beginning with Neratinib PO dose level 1 (120 mg, Dose 1-7, 160 mg, through end of treatment, see Table 2) in combination with Capmatinib PO level 1 (400 mg, see Table 3), with a maximum of 12 patients per dose. The target toxicity rate for the maximum tolerable dose (MTD) is 25%.
Phase II
Phase II will be a prospective, open label, interventional study for patients with previously treated HER2-negative metastatic breast cancer or metastatic inflammatory breast cancer. Subjects receive Capmatinib in combination with Neratinib (including an AI for patients with ER+/HER2- breast cancer). The MTD determined during Phase 1b will be used.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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
- 未提供
排除标准
- •Concurrent anticancer therapy within 2 weeks of initiation of study treatment; except:
- •i. Endocrine therapy (SERM, aromatase inhibitor, fulvestrant, medical ovarian suppression therapy) ii. Palliative radiotherapy for bone metastases < 1 week prior to study treatment
- •Unstable and symptomatic brain metastasis (Stable disease is defined as CNS radiographic study ≥ 4 weeks from completion of radiotherapy and ≥ 2 weeks from discontinuation of corticosteroids)
- •Non-hematologic adverse events from prior anticancer therapy that have not resolved to Grade ≤ 1 (CTCAE v 5.0), except for alopecia, vitiligo, pain, constipation if these symptoms existed during screening baseline.
- •i. Grade 3 or above neuropathy induced from prior treatment, that is not resolved to grade 2 or below despite best supportive care
- •Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis
- •Acute exacerbations of underlying condition within the last 12 months (requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids)
- •Patients with known HIV infection. Testing for HIV is not required for study screening: 1) CD4+ count<350 cells/uL; or 2) had AIDS-defining opportunistic infections < 12 months
- •Known active hepatitis B (chronic or acute) or hepatitis C infection. Testing for hepatitis is not required for study screening:
- •i) Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HbsAg] test and a NEGATIVE anti-HBc [antibody to hepatitis B core antigen] antibody test). Patient is eligible if anti-HBc is POSITIVE, but should sample for HBV DNA and referral to virologist to monitor for HBV reactivation ii) Patients with positive for hepatitis C virus (HCV) antibody and have positive polymerase chain reaction (PCR) for HCV RNA.
- •Severe infections within 4 weeks prior to study treatment, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
- •Signs or symptoms of infection within 2 weeks prior to study treatment per treating physician and PI judgement.
- •Concurrent oral or IV antibiotics within 5 days prior to study treatment
- •* Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are allowed and eligible so long as the antibiotic is not prohibited with the study medication (See Tables 8).
- •Major surgical procedure within 28 days prior to study treatment or anticipation of need for a major surgical procedure during the course of the study.
- •Presence or history of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis (i.e., affecting activities of daily living or requiring therapeutic intervention).
- •Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome.
- •Clinically significant, uncontrolled heart diseases.
- •Unstable angina within 6 months prior to screening
- •Myocardial infarction within 6 months prior to screening
- •History of documented congestive heart failure (New York Heart Association functional classification III-IV)
- •Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mm Hg and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without antihypertensive medication. Initiation or adjustment of antihypertensive medication(s) is allowed prior to screening
- •Ventricular arrhythmias
- •Supraventricular and nodal arrhythmias not controlled with medication
- •Other cardiac arrhythmia not controlled with medication
- •QTcF (QT interval corrected by Fridericia's formula) ≥ 470 ms on the screening ECG (as mean of triplicate ECG)
- •Major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks prior (2 weeks for resection of brain metastases) to starting study therapy or who have not recovered from side effects of such procedure.
- •Unable to swallow or absorb study drugs due to impairment of GI function or GI disease e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome
- •Participants receiving treatment with any enzyme-inducing anticonvulsant that cannot be discontinued at least 1 week before first dose of capmatinib, and for the duration of the study.
- •Other severe, acute, or chronic medical or psychotic conditions, substance abuse or laboratory abnormalities that in the opinion of the investigator may increase the risk associated with study participation, or that may interfere with the interpretation of study results.
- •Pregnant or nursing (lactating) women
- •Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for one month after stopping treatment. Highly effective contraception methods include:
- •Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
- •Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
- •Male sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject
- •Use of injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception. Women are considered post-menopausal and not of childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks before study entry. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child-bearing potential.
- •Sexually active males will not be eligible unless they use a condom during intercourse while taking drug and for 3 months after stopping treatment and should not father a child in this period. A condom is required for all sexually active male to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to partner. In addition, male participants must not donate sperm for the time period specified above.
- •Participants receiving treatment with the following medications that cannot be discontinued at least 1 week prior to the start of treatment with study therapy and for the duration of the study:
- •strong inducers of CYP3A
- •moderate inducer of CYP3A4
- •strong CYP3A4 inhibitor
- •concomitant use of a moderate CYP3A4 and P-gp dual inhibitor (verapamil).
- •proton pump inhibitor. Neratinib may be taken at least 2 hours before or 10 hours after an H2-receptor antagonist, and 3 hours after antacids.
- •P-gp substrates (such as digoxin, dabigatran, fexofenadine) or strong P-gp inducers (such as carbamazepine, phenytoin, rifampicin, and St. John's wort).
- •Chronic immunosuppressive therapies including systemic corticosteroids. Steroids given for physiological replacement, as anti-emetics or inhaled as well as short course of oral/topical steroids given for allergic reactions or asthma flares are allowed.
- •No prior treatment with Capmatinib, Neratinib, or other HER2 directed tyrosine kinase inhibitor (for phase II patients only).
研究组 & 干预措施
Part 1b (dose escalation)
This portion of the study will enroll a maximum of 27 patients in the dose-finding trial including the possibility of adding up to 6 additional ER+ patients in a safety assessment of aromatic inhibitor treatment
干预措施: Neratinib (Drug)
Part 1b (dose escalation)
This portion of the study will enroll a maximum of 27 patients in the dose-finding trial including the possibility of adding up to 6 additional ER+ patients in a safety assessment of aromatic inhibitor treatment
干预措施: Capmatinib (Drug)
Part 2 (dose expansion)
This portion of the study will enroll a maximum of 29 patients
干预措施: Neratinib (Drug)
Part 2 (dose expansion)
This portion of the study will enroll a maximum of 29 patients
干预措施: Capmatinib (Drug)
结局指标
主要结局
To Determine Maximum Tolerated Dose for Use in the Phase II Portion of the Trial
时间窗: Cycle1 and 2, total 56 days
This phase of the study uses the Bayesian Optimal Interval (BOIN) design with a 3+3 run-in to identify the maximum tolerable dose (MTD). Patients are treated in cohorts of 3 with a maximum of 27 participants. Starting with Neratinib PO dose level 1 (120 mg for Dose 1-7, then 160 mg) combined with Capmatinib PO level 1 (400 mg), with up to 12 patients per dose. The target toxicity rate for the MTD is 25%.
To Determine Overall Response Rate
时间窗: Up to 3 years
The overall response rate (ORR) for patients treated at the MTD in Phase II was assessed. ORR was defined as the proportion of patients who achieved a partial response or complete response as their best response. All tumor responses were evaluated according to RECIST 1.1 criteria and measured using the QIAC system.
次要结局
- To Further Characterize the Safety and Tolerability of Neratinib + Capmatinib(Up to 3 years)
- To Determine Clinical Benefit Rate (CBR)(Up to 27 months)
- To Determine the Duration of Response (DOR)(Up to 27 months)
- To Determine Progression Free Survival (PFS)(Up to 27 months)
- To Determine 2 Year Overall Survival (OS)(2 years after enrollment)