| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic breast cancer with stable brain metastases |
|
| E.1.1.1 | Medical condition in easily understood language |
| Breast cancer which has spread to the brain |
|
| 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 | 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 |
| To compare overall survival (OS) of patients who receive 145 mg/m2 NKTR-102 given once every 21 days (q21d) with OS of patients who receive Treatment of Physician’s Choice (TPC) selected from the following list of 7 single-agent intravenous (IV) therapies: eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel, or nab-paclitaxel. TPC drugs will be administered per the standard of care. |
|
| E.2.2 | Secondary objectives of the trial |
• To compare the objective response rate (ORR) from NKTR-102 treatment with that of TPC; assessment of tumor outside the CNS will use the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; assessment of CNS metastases will use the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM)
• To compare progression-free survival (PFS) from NKTR-102 treatment with that of TPC; assessment of tumor outside the CNS will use RECIST version 1.1; assessment of CNS metastases will use RANO-BM
• To compare the clinical benefit rate (CBR) from NKTR-102 treatment with that of TPC (i.e., the proportion of patients having complete response [CR], partial response [PR], or stable disease [SD] for at least 4 months); CBR for peripheral lesions and for CNS lesions will be separately described
• To compare duration of response (DoR) from NKTR-102 treatment with that of TPC
Please see protocol section 3.2 for the full list of secondary objectives |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Each patient must be willing and able to comply with the protocol; the patient or patient’s legal representative must provide written informed consent prior to study-specific screening procedures.
- Female or male, age ≥ 18 years.
- Histologically-confirmed carcinoma of the breast (either the primary or metastatic lesions) for whom single-agent cytotoxic chemotherapy is indicated. Patients may have either measurable or non-measurable disease according to RECIST version 1.1.
- History of brain metastases that are non-progressing. Brain metastases must have been previously treated with either combination therapy (whole-brain radiation with stereotactic radiation and/or surgery) ≥ 14 days prior to randomization, or single-agent modality (WBRT, stereotactic radiation or surgical resection alone, if combination therapy is contraindicated) ≥ 7 days prior to randomization; patients must be sufficiently recovered from whole-brain radiation, or stereotactic radiation and/or surgical resection, with stable signs and symptoms of brain metastases per the investigator to randomize into the study. For patients who have received whole-brain radiation, or stereotactic radiation and/or surgical resection ≥ 28 days prior to randomization, signs or symptoms of brain metastases must be stable for at least 28 days prior to randomization. Corticosteroids for this indication may be used as long as patients are on a stable or decreasing dose for at least 7 days prior to randomization.
- For triple-negative breast cancer, a minimum of 1 prior cytotoxic chemotherapy regimen must have been administered for the indication of metastatic disease. For HER2-positive disease, a minimum of 2 cytotoxic chemotherapy regimens must have been administered for the indication of metastatic disease as well as at least 1 hormonal therapy. For HER2-positive disease, a minimum of 2 cytotoxic chemotherapy regimens must have been administered for the indication of metastatic disease as well as at least 1 HER2 targeted therapy (ado-trastuzumab emtansine is considered a cytotoxic chemotherapy regimen).
- Have had prior therapy (administered in the neoadjuvant, adjuvant, and/or metastatic setting) with an anthracycline, a taxane, and capecitabine (prior anthracycline can be omitted if not medically appropriate or contraindicated for the patient).
- Last dose of anticancer therapy must have been administered within 6 months of the date of randomization into this study.
- All anticancer- and radiation therapy-related toxicities must be completely resolved or downgraded NCI-CTCAE version 4.03 Grade 1.
- ECOG performance status of 0 or 1.
- Adequate organ function obtained within 14 days prior to randomization and analyzed by the central laboratory.
- Women of childbearing potential (WCBP) must agree to use highly effective methods of birth control throughout the duration of the study until 6 months following the last dose of study drug. Acceptable methods are defined as those that result, alone or in combination, in a low failure rate (i.e., less than 1% per year) when used consistently and correctly, such as surgical sterilization, an intrauterine device, or hormonal contraception in combination with a barrier method. It is currently unknown whether NKTR-102 may reduce the effectiveness of systemically acting hormonal contraceptives, and therefore women using systemically acting hormonal contraceptives should add a barrier method. In certain countries (if permitted by law), WCBP may agree to abide by heterosexual sexual abstinence during the time of
participation in this study.
- Males with female partners of child-bearing potential must agree to use a barrier contraception (e.g., condom with spermicidal foam/gel/film/cream/suppository) throughout the duration of the study until 6 months following the last dose of study drug; in addition to their female partner using either an intrauterine device or hormonal contraception and
continuing until 6 months following the last dose of study drug. Male patients should not donate sperm until 6 months following the last dose of study drug. This criterion may be waived for male subjects who have had a vasectomy > 6 months before signing the informed consent form (ICF). |
|
| E.4 | Principal exclusion criteria |
- Last dose of anticancer therapy (including HER2-targeted therapy) within 14 days prior to randomization.
- High-dose chemotherapy followed by stem cell transplantation (autologous or allogeneic).
- Major surgery within 28 days prior to randomization. This does not include surgical resection for CNS lesions, placement of a venous access device or peripherally-inserted central catheter, thoracocentesis, paracentesis, biopsy, and/or abscess drainage.
- Concomitant use of any anticancer therapy or use of any investigational agent(s).
- Received prior treatment for cancer with a camptothecin-derived agent.
- Brain metastases amenable to local therapy but without completion of such therapy. This does not include surgical resection for CNS lesions, placement of a venous access device or peripherally-inserted central catheter, thoracocentesis, paracentesis, biopsy, and/or abscess drainage.
- Lesions on imaging, by cerebrospinal fluid or with neurological findings that are consistent with leptomeningeal disease or meningeal carcinomatosis.
- Chronic or acute GI disorders resulting in diarrhea of any severity grade.
- Patients who are pregnant or lactating, plan to get pregnant, or have a positive serum pregnancy test prior to randomization.
- Enzyme-inducing anti-epileptic drugs (EIAEDs) within 14 days of randomization, including phenytoin, carbamazepine, oxcarbazepine, or phenobarbital.
- Hepatitis B or C, tuberculosis, or HIV.
- Cirrhosis.
- Prior malignancy (other than breast cancer) unless diagnosed and definitively treated more than 5 years prior to randomization. Patients with non-melanoma skin cancer are not excluded.
- Severe/uncontrolled illness within the previous 28 days prior to randomization.
- Daily use of oxygen supplementation
- Significant known cardiovascular impairment
- Prior treatment with NKTR-102.
- Psychiatric illness, social situation, or geographical situation that precludes informed consent or limit compliance.
- Known intolerance or hypersensitivity to any of the products used in this study or their
excipients.
- For patients selecting vinorelbine or gemcitabine as the TPC agent, patients may not receive
yellow fever vaccine in the 28 days prior to randomization. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Monitored throughout the study |
|
| E.5.2 | Secondary end point(s) |
Progression-free survival (outside the CNS)
Progression-free survival in brain metastases
Progression-Free Survival (Overall)
Objective response rate
Clinical benefit rate
Duration of response
WBRT
HRQoL
Magnitude of Clinical Benefit |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
PFS outside the CNS, PFS in brain metastases, PFS (Overall), CBR, WBRT and DoR - monitored throughout the study
ORR - Screening, every 8 weeks through Week 24, then every 12 weeks thereafter
HRQoL - Day 1 of each treatment Cycle prior to infusion and at End of Treatment visit |
|
| 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 | Yes |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 116 |
| 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 |
| Australia |
| Belgium |
| Canada |
| Czech Republic |
| France |
| Greece |
| Hungary |
| Israel |
| Italy |
| New Zealand |
| Poland |
| Portugal |
| Romania |
| 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
|
| The end of study is defined as the date of database lock for all patients. |
|
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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