| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed/Refractory Triple-Negative Breast Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Triple-Negative breast cancer who has progressed or returned |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10075566 |
| E.1.2 | Term | Triple negative breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10055113 |
| E.1.2 | Term | Breast cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006198 |
| E.1.2 | Term | Breast cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| The primary objective of this study is to compare the efficacy of sacituzumab govitecan to the treatment of physician’s choice (TPC) as measured by independently reviewed (IRC) progression-free survival (PFS) in patients with locally advanced or metastatic TNBC previously treated with at least two systemic chemotherapy regimens for unresectable, locally advanced or metastatic disease, and without brain metastasis at baseline. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are to compare between the two treatment groups for:
- PFS for the ITT population
- Overall Survival (OS) in both the ITT population and in the subgroup with brain metastasis.
- Independently-determined Objective Response Rate (ORR), duration of response and time to onset of response per RECIST 1.1 criteria
- Quality of life
- Safety (adverse events, safety laboratories, incidence of dose delays and dose reductions, treatment discontinuations due to adverse events) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Female or male patients, ≥18 years of age, able to understand and give written informed consent.
2. Histologically or cytologically confirmed TNBC per ASCO/CAP criteria, based on the most recent analyzed biopsy or other pathology specimen. Triple negative is defined as <1% expression for estrogen receptor (ER) and progesterone receptor (PR) and negative for human epidermal growth factor receptor 2 (HER2) by in-situ hybridization.
3. Metastatic disease documented by CT or MRI imaging.
4. Measurable disease by CT or MRI as per RECIST 1.1. Bone-only disease is not permitted.
5. Brain MRI must be done for patients with brain metastasis and patient must have had stable CNS* disease for at least 4 weeks. A maximum of 15% (N=74) of patients with brain metastases will be included in this trial.
“Stable” brain mets may be defined as:
• Prior local treatment by radiation, surgery, or stereotactic surgery
• Imaging – stable or decreasing size after such local treatment
• Clinically stable signs and symptoms
• ≥2 weeks from discontinuation of anti-seizure medication.
• Corticosteroid (if needed) - dose should be stable, or decreasing for at least 2 weeks before randomization. Steroid dose should be 20 mg or less of prednisone/prednisolone daily, or equivalent of a different steroid.
6. At least 2 weeks beyond high dose systemic corticosteroids (however, low dose corticosteroids ≤ 20 mg prednisone or equivalent daily are permitted provided the dose is stable for 4 weeks).
7. Refractory to or relapsed after at least two prior standard of care chemotherapy regimens for unresectable, locally advanced or metastatic breast cancer. (These regimens will qualify regardless of triple-negative status at the time they were given. There is no cap on the number of prior chemotherapies for locally advanced or metastatic disease and earlier adjuvant or neoadjuvant therapy for more limited disease will qualify as one of the required prior regimens if the development of unresectable, locally advanced or metastatic disease occurred within a 12-month period of time after completion of chemotherapy).
a. For patients with a documented germ-line BRCA1/BRCA2 mutation who received an approved PARP inhibitor, the PARP inhibitor can be used to meet the criteria for one of two prior standard of care chemotherapies.
All patients must have been previously treated with a taxane regardless of disease stage (adjuvant, neoadjuvant or advanced) when it was given.
Patients who have contra-indications or are intolerant to taxanes are eligible provided that they received at least one cycle of a taxane and showed contra-indications or intolerance during or at the end of that cycle.
8. Eligible for one of the chemotherapy options listed as TPC (Eribulin, capecitabine, gemcitabine, or vinorelbine) as per investigator assessment.
9. ECOG performance score of 0 or 1 (Appendix 2).
10. Adequate hematology without transfusional support (hemoglobin > 9 g/dL, ANC > 1,500 per mm3, platelets > 100,000 per mm3). Blood transfusion or growth factor support is not allowed within 14 days prior to screening labs.
11. Adequate renal and hepatic function (creatinine clearance of > 60 ml/min, may be calculated using Cockcroft-Gault equation; bilirubin ≤ 1.5 IULN, AST and ALT ≤ 2.5 x IULN or ≤ 5 x IULN if known liver metastases) and serum albumin ≥3 g/dL).
12. Recovered from all toxicities to Grade 1 or less by NCI CTCAE v4.03 (except alopecia or peripheral neuropathy that may be Grade 2 or less) at the time of randomization. Patients with Grade 2 neuropathy are eligible but may not receive vinorelbine as TPC.
13. Patients must have completed all prior cancer treatments at least 2 weeks prior to randomization including chemotherapy (includes also endrocrine treatment), radiotherapy and major surgery. Note: Prior antibody treatment for cancer must have been completed at least 3 weeks prior to randomization. 14. Prior investigational agents are permitted, provided completion according to the timeframes above.
15. Patients must have a life expectancy of 3-months or greater, in the opinion of the investigator. |
|
| E.4 | Principal exclusion criteria |
1. Women who are pregnant or lactating.
2. Women of childbearing potential or fertile men unwilling to use highly effective * contraception during study and up to three months after treatment discontinuation in women of child-bearing potential and six months in males post last study drug.
3. Patients with Gilbert’s disease.
4. Patients with non-melanoma skin cancer or carcinoma in situ of the cervix are eligible, while patients with other prior malignancies must have had at least a 3-year disease-free interval.
5. Patients known to be HIV positive.
6. Patients with hepatitis B positive, or hepatitis C positive infection**.
7. Known history of unstable angina, MI, or CHF present within 6 months of randomization or clinically significant cardiac arrhythmia (other than stable atrial fibrillation) requiring anti-arrhythmia therapy.
8. Known history of clinically significant active COPD, or other moderate-to-severe chronic respiratory illness present within 6 months of randomization.
9. Prior history of clinically significant bleeding, intestinal obstruction, or GI perforation within 6 months of randomization.
10. Infection requiring antibiotic use within one week of randomization.
11. Patients with active chronic inflammatory bowel disease (ulcerative colitis, Crohn disease) and patients with a history of bowel obstruction
12. Patients who have received a live vaccine within 30 days of randomization
13. Patients who previously received irinotecan.
14. Rapid deterioration during screening prior to randomization, e.g. significant change in performance status, ≥ 20% decrease in serum albumin levels, unstable pain symptoms requiring modifications in analgesic management.
15. Other concurrent medical or psychiatric conditions that, in the Investigator’s opinion, may be likely to confound study interpretation or prevent completion of study procedures and follow-up examinations.
*Highly effective is defined as i.e. Combined (estrogen and progestogen containing) hormonal contraception: oral, intravaginal, transdermal, progestin -only hormonal contraception associated with inhibition of ovulation: oral, injectable, implantable, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner, sexual abstinence). Abstinence refers to ‘True abstinence’ which means it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptotherma, post-ovulation methods), declaration of abstinence for the duration of exposure to study treatment, and withdrawal are not acceptable methods of contraception.
** In patients with a history of HBV, hepatitis B core antibody (HBcAb) testing is required and if positive, then HB DNA testing will be performed and if positive the patient will be excluded. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Progression-free survival (PFS) as determined by an independent centralized blinded assessment.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Monitored throughout the study |
|
| E.5.2 | Secondary end point(s) |
- Overall survival (OS)
- Progression Free Survival (PFS) in the ITT population.
- Objective response rate (ORR), duration of response, and time to onset of response
- Quality of life
- Safety, including: adverse events; safety laboratories and evaluations; incidence of dose delays and dose reductions; and treatment discontinuations due to adverse events |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Monitored throughout the study |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| 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 |
| Belgium |
| Canada |
| France |
| Germany |
| Ireland |
| Italy |
| Spain |
| United Kingdom |
| 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
|
End of study is defined as the point in time when the number of progression events required for the primary analysis have been reached or if the sponsor terminates the study, whichever comes first.
The primary analysis is expected to occur minimally 9 months after the
last patient is randomized to the study. Survival data may continue to
be collected after End of Study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 16 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 16 |
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