| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic or advanced HER-2 negative breast cancer patients who have already received treatment with anthracyclines and paclitaxel. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced breast cancer patients who have already received first line treatment |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10072737 |
| E.1.2 | Term | Advanced breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate and compare the OS of subjects with advanced or metastatic HER2 negative breast cancer when treated with ruxolitinib in combination with capecitabine versus capecitabine alone. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate and compare the efficacy of the 2 treatment groups with respect to PFS.
To evaluate and compare the efficacy of the 2 treatment groups with respect to overall tumor response and duration of response.
To evaluate and compare the efficacy of the 2 treatment groups with respect to clinical benefit rate.
To evaluate and compare the safety and tolerability of ruxolitinib in combination with capecitabine versus capecitabine alone.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Women aged 18 years or older.
2.Histologically or cytologically confirmed HER2-negative adenocarcinoma of the breast, including ER+, PR+, and TNBC.
3.Locally advanced or metastatic disease; locally advanced disease must not be amenable to resection with curative intent.
4.Modified GPS of 1 or 2 as defined below:
a. mGPS of 1: CRP > 10 mg/L and albumin ≥ 35 g/L
b. mGPS of 2: CRP > 10 mg/L and albumin < 35 g/L
5.ECOG performance status 0 to 2 (see Appendix D).
6.Received up to 2 prior chemotherapy regimens (not including neoadjuvant/adjuvant therapy) for advanced or metastatic disease.
7.Subjects with hormone-receptor positive tumors (ER+ and/or PR+) must have failed available appropriate lines of hormonal therapy, unless intolerant to hormonal therapy or hormonal therapy is not considered to be clinically appropriate.
8.≥ 2 weeks elapsed from the completion of previous treatment regimen and subjects must have recovered (eg, ≤ Grade 2), or be at a new stable baseline from any related toxicities.
9.Radiographically measurable or evaluable disease (based on local evaluation), per RECIST (v1.1).
a.Measurable lesions (eg, target lesions) may be in the field of prior radiation; however, there must be at least a 4-week period between the last radiation treatment and demonstration of interval progression of the lesion compared with the baseline scan documenting disease status for the lesion to be considered measurable.
b.Palliative radiotherapy to other disease sites (eg, nontarget lesions) is allowed provided there are other sites of disease or subsequent progression of the disease in the radiation field, and ≥ 2 weeks have elapsed since the completion of radiotherapy and all treatment-related toxicities have resolved or are at a new stable baseline.
10.Able to swallow and retain oral medication.
11. Female subjects of childbearing potential (defined as women who have not undergone surgical sterilization with a hysterectomy and/or bilateral oophorectomy, and are not postmenopausal, defined as ≥ 12 months of amenorrhea) must have a negative serum pregnancy test at screening. All female subjects of childbearing potential must agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening through follow-up. Permitted methods that are at least 99% effective in preventing pregnancy (Appendix A) should be communicated to the subjects and their understanding confirmed. Male subjects must agree to take appropriate precautions to avoid fathering children (with at least 99% certainty) from screening through follow-up. Permitted methods that are at least 99% effective in preventing pregnancy (Appendix A) should be communicated to the subjects and their understanding confirmed.
12.Ability to comprehend and willingness to sign an informed consent form (ICF).
|
|
| E.4 | Principal exclusion criteria |
1.Received prior treatment with capecitabine or fluoropyrimidine for advanced or metastatic disease.
2.Received more than 2 prior regimens for advanced or metastatic disease (not including hormonal therapy in the metastatic setting, or neoadjuvant and adjuvant therapies).
3.Unknown hormone-receptor status (ER and PR).
6.Untreated brain metastases, or brain metastases that have progressed Subjects with treated and clinically stable brain metastases and off all corticosteroids for at least 4 weeks are eligible.
7.Inadequate renal, hepatic, and bone marrow function as evidenced by:
a.Absolute neutrophil count < 1.5 × 109/L.
b.Platelets < 75 × 109/L.
c.Hemoglobin < 9 g/dL (transfusions are permitted to achieve baseline hemoglobin level).
d.ALT/AST > 2.5 × upper limit of normal (ULN); or > 5 × ULN in the presence of liver metastases.
e.Total bilirubin > 1.5 × ULN (if total bilirubin is > 1.5 × ULN then direct bilirubin must be ≤ 1.5 × ULN).
f.Creatinine clearance < 50 mL/min measured or calculated by Cockroft-Gault equation or the estimated glomerular filtration rate < 50 mL/min/1.73 m2 using the Modification of Diet in Renal Disease formula.
8.Significant concurrent, uncontrolled medical condition, including, but not limited to, renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, cardiac, neurological, cerebral or psychiatric disease.
9.Chronic or current active infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment.
10.Clinically significant or uncontrolled cardiac disease including unstable angina, acute myocardial infarction within 6 months from Day 1 of study drug administration, New York Heart Association Class III or IV congestive heart failure, and arrhythmia requiring therapy.
11.Ongoing radiation therapy or radiation therapy administered within 2 weeks of enrollment.
12.Concurrent anticancer therapy
13.Subjects who participated in any other study in which receipt of an investigational study drug occurred within 28 days or 5 half-lives (whichever is longer) before first dose. For investigational agents with long half-lives, enrollment before the fifth half-life requires medical monitor approval.
14.Current or previous other malignancy within 2 years of study entry, except cured basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix, or other noninvasive or indolent malignancy without sponsor approval.
15.Recent (≤ 3 months) history or ongoing partial or complete bowel obstruction.
16.Prior severe reaction to fluoropyrimidines, known dihydropyrimidine dehydrogenase deficiency, or other known hypersensitivity to active substances, including 5 FU, ruxolitinib, or any of their excipients.
17.Known history of human immunodeficiency virus infection.
18.Active hepatitis B or C infection that requires treatment.
19.Unwilling to be transfused with blood components.
20.Prior treatment with a JAK-inhibitor for any indication.
21. Pregnant or breastfeeding women. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall survival as determined from the date of randomization until death due to any cause. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary endpoint is overall survival, defined as number of days from randomization to death. This analysis will be based on the ITT population, according to treatment assignment. |
|
| E.5.2 | Secondary end point(s) |
•Progression-free survival defined as the time from randomization until the earliest date of disease progression determined by investigator assessment of objective radiographic disease assessments per RECIST (v1.1), or death due to any cause, if sooner.
•Objective response rate and duration of response determined by radiographic disease assessments per RECIST (v1.1), by investigator assessment.
•Clinical benefit rate defined as a complete response, partial response, or stable disease, determined by investigator assessment of objective radiographic disease assessments per RECIST (v1.1) that lasts for ≥ 6 months.
•Safety and tolerability of the treatment regimens through assessment of AEs and changes in safety assessments, including laboratory parameters.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Progression-free survival will be determined from the randomization date until the earliest date of disease progression, as measured by investigator assessment of objective radiographic disease assessments per RECIST (v1.1), or death due to any cause if earlier.
For the analysis of objective response, each subject will be considered a responder if his or her best overall response is a PR or better based on RECIST (v1.1). The duration of response is defined as the difference of the end of response and the start of response for subjects who have at least 1 response measurement. The start of a response will be the first visit where the subject achieves a PR or better based on RECIST (v1.1). The end of response will be the first visit after PD based on RECIST (v1.1). |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 29 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| European Union |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
Print
