| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Triple Negative Breast Cancer (advanced breast cancer that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Triple Negative (ER-, PR-, HER2-) Breast Cancer |
|
| 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 | 16.0 |
| 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 the progression-free survival of vintafolide monotherapy relative to paclitaxel and the progression-free survival of vintafolide + paclitaxel combination therapy relative to paclitaxel in subjects with advanced triple negative breast cancer whose target lesions are 100% positive for folate receptor expression using etarfolatide scans. |
|
| E.2.2 | Secondary objectives of the trial |
1. To assess the frequency of triple negative breast cancer subjects whose target tumors express FR(100%) versus FR(10-90%) versus FR(0%) using etarfolatide scans. 2. To determine the correlation between FOLR1 mRNA expression in tumors in subjects with advanced triple negative breast cancer and subject etarfolatide target lesion scores (FR[100%], FR[10-90%], FR[0%]) measured by etarfolatide.
3. To compare the clinical activity of vintafolide monotherapy versus paclitaxel and the clinical activity of vintafolide + paclitaxel combination therapy versus paclitaxel in subjects with advanced triple negative breast cancer as measured by Overall Response Rate, Clinical Benefit Rate, and Overall Survival.
4. To assess the safety and tolerability of vintafolide monotherapy versus the combination of vintafolide and paclitaxel versus paclitaxel monotherapy in subjects with advanced triple negative breast cancer.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Female subjects must have histologically or cytologically confirmed ER-, PR-, HER2 – advanced breast cancer that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective
- Have developed progressive disease following at least 1 (and not more than 4) prior chemotherapeutic regimens for breast cancer, which was administered for treatment of locally recurrent and/or metastatic disease
- At least 1 regimen must have included a taxane (e.g. paclitaxel or docetaxel) in any combination or order. Prior taxane may have been administered as adjuvant and/or neoadjuvant therapy.
- Subject is ≥ 18 years of age on day of signing informed consent
- Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Have at least a single (RECIST 1.1 defined) measurable lesion
- All tumor target lesions characterized as FR(100%) using etarfolatide screened assessed by central core facility.
|
|
| E.4 | Principal exclusion criteria |
Has had chemotherapy, radiotherapy, or biological therapy (including monoclonal antibodies) within 4 weeks prior to drug administration or who has not recovered (≤Grade 1 or baseline) from adverse events due to agents administered more than 4 weeks earlier.
- Is currently participating or has participated in a study with an investigational compound or device within 28 days of initial dosing on this study.
- Has received more than 4 prior cytotoxic regimens for metastatic disease.
- Has a primary central nervous system (CNS) tumor.
- Has active CNS metastases and/or carcinomatous meningitis. However, subjects with CNS metastases who have completed a course of therapy would be eligible for the study provided they are clinically stable for 1 month prior to entry as defined as: (1) no evidence of new or enlarging CNS metastasis (2) off steroids or on a stable dose of steroids for at least 2 weeks.
- Has had prior therapy with vinorelbine (Navelbine®) or vinca-containing compounds.
- Has known hypersensitivity to the components of the study therapy or its analogs. This includes paclitaxel, docetaxel, other taxane therapies, drugs formulated with polyoxyethylated castor oil (Cremphor EL), vinlastine, or other vinca-derived therapies.
- Has pre-existing neuropathy > Grade 2. Subjects with residual drug-induced neuropathy of ≤2 will be eligible if it has stable, and not worsening, for at least 30 days.
- Has a bowel occlusion or subocclusion.
- Has had prior abdominal or pelvis radiation therapy or radiation therapy to > 10% of the bone marrow at any time in the past or prior radiation therapy within the last three years to the breast/sternum, dermal lesions, head, or neck.
- Requires anti-folate therapy for the management of co-morbid conditions (e.g., rheumatoid arthritis).
- Has symptomatic ascites or pleural effusion. A subject who is clinically stable following treatment for these conditions is eligible for the study however.
- Has had a prior stem cell or bone marrow transplant
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary analysis will be to evaluate PFS which is generally accepted as an endpoint (or the closely related time to progression [TTP] endpoint) for clinical trials in patients with breast cancer. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| PFS will be assessed throughout the study and measured as the time from randomization to the time of disease progression or death. Patients will receive imaging assessments at 8 week intervals throughout the study to assess response. |
|
| E.5.2 | Secondary end point(s) |
1. Overall Response Rate (ORR): Disease response will be assessed throughout the study by anatomic imaging evaluation and physical exam of visible/palpable tumor. Overall tumor response will be assessed using Enhanced RECIST 1.1 at the designated time points. The portion of patients with tumor size reduction predefined by RECIST 1.1, including patients with complete response (CR) and partial response (PR), will be evaluated.
2. Clinical Benefit Rate (CBR): Disease control rates (DCR), which include stable disase (SD) as a response measure offer additional advantages over ORRs, since they are also associated with overall survival (OS) in breast cancer. During clinical development of Eribulin, SD lasting > 6 months was used to assess CBR as CR + PR + SD (≥6 months). Since the same criteria were used to assess vintafolide activity in initial monotherapy trials in ovarian cancer, the CBR for this trial will be defined as CR + PR + SD (≥6 months).
3.Overall Survival (OS): OS data defined as the time from randomization until death from any cause will be collected as a universally accepted direct measure of benefit.
4. Safety: The study will use standard endpoints that allow one to see results in context for comparison with large historical databases. Safety and tolerability of vintafolide in multiple indications will be assessed in advanced cancer subjects. Monitoring will include complete blood counts, serum chemistry, vital signs, physical exam, ECGs, and ECOG performance status.
5. Pharmackokinetic Endpoints: For the initial dose of vintafolide and paclitaxel for each subject, plasma concentration-time profiles will be determined following IV administration. The following PK parameters will be determined for vintafolide and paclitaxel: maximum observed plasma concentration (Cmax); area under the plasma concentration-time curve (AUC); and if feasible, half-life (t1/2); total body clearance (CL) and volume of distribution (Vd). In addition, descriptive statistics of plasma concentrations at designated time points will be provided.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
ORR and CBR will be assessed throughout the study through physical exams performed at the beginning of each cycle and by anatomic imaging performed every 8 weeks throughout the study.
Subjects will be followed for OS at 3 month intervals via telephone contact for a minimum of 24 months and a maximum of 60 months from randomization.
Safety: Complete blood counts will be monitored weekly throughout the study, serum chemistry assessment at week 1 and week 3 of every cycle, vital signs (prior to each dose), physical examination,ECGs, and ECOG performance status (once per cycle) . All toxicity will be graded and recorded according to National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events-CTCAE, Version 4.
"Refer to protocol for complete list." |
|
| 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 | Yes |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| 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 |
|
| 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
|
| The overall trial ends when the last subject completes the last trial visit, a minimum of 6 months post initial study medication administration have elapsed, or the last subject either discontinues from the trial or is lost to follow-up (i.e., the subject is unable to be contacted by the investigator), whichever comes first. |
|
| 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 | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
