Description:
This is an open-label, randomized, active comparator, multicenter, international Phase 3
study of NKTR-102 versus TPC in patients with metastatic breast cancer who have stable brain
metastases and have been previously treated with an anthracycline, a taxane, and capecitabine
in either the adjuvant or metastatic setting (prior anthracycline may be omitted if medically
appropriate or contraindicated for the patient).
Title
- Brief Title: A Study of Etirinotecan Pegol (NKTR-102) Versus Treatment of Physician's Choice (TPC) in Patients With Metastatic Breast Cancer Who Have Stable Brain Metastases and Have Been Previously Treated With an Anthracycline, a Taxane, and Capecitabine
- Official Title: A Phase 3 Open-Label, Randomized, Multicenter Study of NKTR-102 Versus Treatment of Physician's Choice (TPC) in Patients With Metastatic Breast Cancer Who Have Stable Brain Metastases and Have Been Previously Treated With an Anthracycline, a Taxane, and Capecitabine
Clinical Trial IDs
- ORG STUDY ID:
15-102-14
- NCT ID:
NCT02915744
Conditions
Interventions
| Drug | Synonyms | Arms |
|---|
| NKTR-102 | | NKTR-102 |
| Eribulin | | Treatment of Physician's Choice (TPC) |
| Ixabepilone | | Treatment of Physician's Choice (TPC) |
| Vinorelbine | | Treatment of Physician's Choice (TPC) |
| Gemcitabine | | Treatment of Physician's Choice (TPC) |
| Paclitaxel | | Treatment of Physician's Choice (TPC) |
| Docetaxel | | Treatment of Physician's Choice (TPC) |
| Nab-paclitaxel | | Treatment of Physician's Choice (TPC) |
Purpose
This is an open-label, randomized, active comparator, multicenter, international Phase 3
study of NKTR-102 versus TPC in patients with metastatic breast cancer who have stable brain
metastases and have been previously treated with an anthracycline, a taxane, and capecitabine
in either the adjuvant or metastatic setting (prior anthracycline may be omitted if medically
appropriate or contraindicated for the patient).
Detailed Description
This is an open-label, randomized, active comparator, multicenter, international Phase 3
study of NKTR-102 versus TPC in patients with metastatic breast cancer who have stable brain
metastases and have been previously treated with an anthracycline, a taxane, and capecitabine
in either the adjuvant or metastatic setting (prior anthracycline may be omitted if medically
appropriate or contraindicated for the patient).
In Group A, NKTR-102 will be administered at a dose level of 145 mg/m2 on a q21d schedule as
a 90-minute intravenous (IV) infusion on Day 1 of each treatment cycle. In Group B, TPC will
be administered per standard of care. Patients randomized to TPC will receive single-agent IV
chemotherapy, limited to choice of one of the following 7 agents: eribulin, ixabepilone,
vinorelbine, gemcitabine, paclitaxel, docetaxel, or nab-paclitaxel.
This study will randomize approximately 220 patients using a 1:1 randomization ratio and
stratification based on geographic region, tumor receptor status, and Eastern Cooperative
Oncology Group (ECOG) status. At Screening, the Investigator must determine which TPC will be
offered to the patient.
Data will be collected on subsequent anticancer therapies in both treatment groups from the
time patients come off the study treatment until the time of primary data analysis for
Overall Survival (OS).
An independent data monitoring committee (DMC) will assess interim safety and efficacy data
and determine final number of death events needed to provide 80% conditional power based on
the zone adaptive design.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| NKTR-102 | Experimental | In Group A, NKTR-102 will be administered at a dose level of 145 mg/m2 on a q21d schedule as a 90-minute intravenous (IV) infusion on Day 1 of each treatment cycle. | |
| Treatment of Physician's Choice (TPC) | Active Comparator | In Group B, TPC will be administered per standard of care. Patients randomized to TPC will receive single-agent IV chemotherapy, limited to choice of one of the following 7 agents: eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel, or nab-paclitaxel. | - Eribulin
- Ixabepilone
- Vinorelbine
- Gemcitabine
- Paclitaxel
- Docetaxel
- Nab-paclitaxel
|
Eligibility Criteria
Inclusion Criteria:
- 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.
- Patients must have a history of brain metastases that are non-progressing.
- For triple-negative breast cancer, a minimum of 1 prior cytotoxic chemotherapy regimen
must have been administered for the indication of metastatic disease.Depending on
receptor status, 1 or 2 prior cytotoxic regimens are required prior to enrollment in
this trial; hormonal and/or human epidermal growth factor receptor 2 (HER2) -targeted
agents may be required.
- 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 to Grade 1 or less (neuropathy may be Grade 2 or less).
- Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- Demonstrate 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.
- 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.
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.
- Concomitant use of any anticancer therapy or use of any investigational agent(s).
- Received prior treatment for cancer with a camptothecin-derived agent.
- 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.
- 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.
- Daily use of oxygen supplementation.
- Significant known cardiovascular impairment.
- Prior treatment with NKTR-102.
- Psychiatric illness, social situation, or geographical situation that preclude
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.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Overall Survival (OS) of Patients |
| Time Frame: | Within 3 years from study start |
| Safety Issue: | |
| Description: | 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). Overall survival is defined as the time from the date of randomization to the date of death from any cause. Patients will be followed until their date of death or until final database closure. Patients who are lost-to-follow-up or are alive at the time of analysis will be censored at the time they were last known to be alive or at the date of event cut-off for OS analysis. |
Secondary Outcome Measures
| Measure: | Progression-Free Survival (Outside the Central Nervous System) |
| Time Frame: | Through study completion, an expected average of 1 year |
| Safety Issue: | |
| Description: | Progression-Free Survival (PFS) is defined as the time from the date of randomization to the earliest evidence of documented Progressive Disease (PD) or of death from any cause. The date of global deterioration or symptomatic deterioration will not be used as the date of PD. The assessment of PFS outside the CNS will utilize RECIST criteria v1.1. |
| Measure: | Progression-Free Survival in Brain Metastasis (PFS-BM) |
| Time Frame: | Through study completion, an expected average of 1 year |
| Safety Issue: | |
| Description: | Progression-Free Survival in Brain Metastasis (PFS-BM) is defined as the time from the date of randomization to the earliest evidence of documented Progressive Disease (PD) per Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) in brain metastases or death from any cause. The PD will also be determined by the investigator's assessments. |
| Measure: | Progression-Free Survival (Overall) |
| Time Frame: | Through study completion, an expected average of 1 year |
| Safety Issue: | |
| Description: | Progression-free survival (CNS and peripheral) is defined as the time from the date of randomization to the earliest evidence of documented PD in either the CNS or peripheral (using RANO-BM) or death from any cause. The PD will be determined by both the investigator's and the central imaging facility assessments. The same statistical methods that were used for PFS and PFS-BM will be used for PFS (Overall). |
| Measure: | Objective Response Rates (ORR) of the NKTR-102 Treatment and the Treatment of Physician's Choice (TPC) |
| Time Frame: | Through study completion, an expected average of 1 year |
| Safety Issue: | |
| Description: | RECIST criteria for lesions outside the Central Nervous System (CNS); RANO-BM criteria for CNS lesions) based upon the best response as assessed by the central imaging facility. CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had to have reduction in short axis to < 10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. ORR is calculated as the sum of CR and PR. Progressive Disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that was the smallest on study). Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. |
| Measure: | Clinical Benefit Rate (CBR) |
| Time Frame: | For at least 4 months, with an expected average of 1 year |
| Safety Issue: | |
| Description: | Clinical Benefit Rate will be defined as the proportion of patients having a Complete Response (CR), Partial Response (PR), or Stable Disease (SD) for at least 4 months (≥ 120 days). The SD duration of 4 months is selected to reflect the shorter life expectancy of study population. CBR will be calculated based on both the central imaging facility assessment of response, progression and stability of disease, as well as the investigator's assessment of these parameters. |
| Measure: | Duration of Response (DoR) |
| Time Frame: | Through study completion, an expected average of 1 year |
| Safety Issue: | |
| Description: | Duration of response (DoR) outside the CNS will be defined as the time from first documented CR or PR until the earliest evidence of disease progression per RECIST v1.1 or death from any cause. DoR will be calculated based on the central imaging facility assessment of response and progression as well as the investigator's assessment of response and progression. |
| Measure: | Whole Brain Radiotherapy (WBRT) |
| Time Frame: | Through study completion, an expected average of 1 year |
| Safety Issue: | |
| Description: | To compare the incidence of WBRT after date of randomization by treatment group. |
| Measure: | Compare Health-Related Quality of Life (HRQoL) Using the European Organisation for Treatment of Cancer (EORTC) Quality of Life Core 30 (QLQ-C30) Module With the Brain Neoplasms 20-question (BN-20) Subscale. |
| Time Frame: | Through study completion, an expected average of 1 year |
| Safety Issue: | |
| Description: | The EORTC QLQ-BN20 Scale has a series of 20 questions each of which involve reporting a scale from 1-4. It is an increasing scale where a score of one indicates "not at all" while a score of four indicates "very much". The minimum score is 20 and the maximum score is 80. The higher the score the worse the outcome. |
| Measure: | Compare Health-Related Quality of Life (HRQoL) Using the the EuroQoL 5D (EQ-5D-5L™) |
| Time Frame: | Through study completion, an expected average of 1 year |
| Safety Issue: | |
| Description: | The EQ-5D-5L scale is used to measure health by having a patient answer a series of questions. There are a series of 5 questions each of which is scaled from a score of 4-20 in increasing increments of 4. The scale is numbered from 0 to 100 where 100 means the beast health you can imagine and 0 means the worst health. |
| Measure: | Compare Health-Related Quality of Life (HRQoL) Using the Brief Fatigue Inventory (BFI) |
| Time Frame: | Through study completion, an expected average of 1 year |
| Safety Issue: | |
| Description: | The Brief Fatigue Inventory scale utilizes a series of 4 questions. The first three are scored with a scale from 1-10. The fourth question has 6 six sub components each of which are scored with a scale of 1-10. For every scale, a score of 0 indicates no fatigue/interference where a score of 10 indicates as bad as you can imagine. A patient's score can range from 0 to 100 where 0 indicates the best outcome and 100 indicates the worst. |
| Measure: | Magnitude of Clinical Benefit |
| Time Frame: | Through study completion, an expected average of 1 year |
| Safety Issue: | |
| Description: | The magnitude of clinical benefit of NKTR-102 will be assessed by the European Society for Medical Oncology magnitude of clinical benefit scale (ESMO-MCBS) (v1.0). |
| Measure: | Maximum Observed Serum Concentration (Cmax) of NKTR-102 |
| Time Frame: | Through study completion, an expected average of 1 year |
| Safety Issue: | |
| Description: | The maximum concentration of NKTR-102 reached in the bloodstream post administration. |
| Measure: | Time of Maximum Observed Serum Concentration (Tmax) of NKTR-102 |
| Time Frame: | Through study completion, an expected average of 1 year |
| Safety Issue: | |
| Description: | The time it takes to reach the maximum concentration of NKTR-102 in the bloodstream. |
| Measure: | Area Under Serum Concentration Time Curve |
| Time Frame: | Through study completion, an expected average of 1 year |
| Safety Issue: | |
| Description: | The area under the curve of a concentration vs. time graph in the dosing interval (AUCtau) of NKTR-102 |
| Measure: | Half-life of (t1/2) of NKTR-102 |
| Time Frame: | Through study completion, an expected average of 1 year |
| Safety Issue: | |
| Description: | The amount of time necessary to degrade 50% of the NKTR-102 administered. |
| Measure: | Number of Participants With Adverse Events as Assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.3 |
| Time Frame: | Through study completion, an expected average of 1 year |
| Safety Issue: | |
| Description: | The number of participants with adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.3 |
Details
| Phase: | Phase 3 |
| Primary Purpose: | Interventional |
| Overall Status: | Completed |
| Lead Sponsor: | Nektar Therapeutics |
Trial Keywords
- Breast Cancer Brain Metastases (BCBM)
- Carcinoma
Last Updated
August 27, 2021
