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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 (ATTAIN)

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ClinicalTrials.gov Identifier: NCT02915744
Recruitment Status : Recruiting
First Posted : September 27, 2016
Last Update Posted : March 6, 2019
Sponsor:
Information provided by (Responsible Party):
Nektar Therapeutics

Tracking Information
First Submitted Date  ICMJE September 22, 2016
First Posted Date  ICMJE September 27, 2016
Last Update Posted Date March 6, 2019
Study Start Date  ICMJE November 2016
Estimated Primary Completion Date July 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 23, 2016)
Overall Survival (OS) of Patients [ Time Frame: Within 3 years from study start ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02915744 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 30, 2017)
  • Progression-Free Survival (Outside the Central Nervous System) [ Time Frame: Through study completion, an expected average of 1 year ]
    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.
  • Progression-Free Survival in Brain Metastasis (PFS-BM) [ Time Frame: Through study completion, an expected average of 1 year ]
    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.
  • Progression-Free Survival (Overall) [ Time Frame: Through study completion, an expected average of 1 year ]
    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).
  • 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 ]
    Objective Response Rate (ORR) will be defined as the proportion of patients with a confirmed Complete Response (CR) or Partial Response (PR) (RECIST for lesions outside the Central Nervous System (CNS); RANO-BM for CNS lesions) based upon the best response as assessed by the central imaging facility. As a secondary analysis, ORR will be calculated based on the Investigator assessment of response.
  • Clinical Benefit Rate (CBR) [ Time Frame: For at least 4 months, with an expected average of 1 year ]
    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.
  • Duration of Response (DoR) [ Time Frame: Through study completion, an expected average of 1 year ]
    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.
  • WBRT [ Time Frame: Through study completion, an expected average of 1 year ]
    To compare the incidence and cumulative frequency of WBRT after date of randomization by treatment group. The protocol will also compare time-to-WBRT (defined as the date of first whole-brain radiation fraction) in those patients who received WBRT after the date of randomization by treatment group.
  • 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 ]
  • 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 ]
  • Compare Health-Related Quality of Life (HRQoL) using the Brief Fatigue Inventory (BFI) [ Time Frame: Through study completion, an expected average of 1 year ]
  • Magnitude of Clinical Benefit [ Time Frame: Through study completion, an expected average of 1 year ]
    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).
  • Maximum observed serum concentration (Cmax) of NKTR-102 [ Time Frame: Through study completion, an expected average of 1 year ]
  • Time of maximum observed serum concentration (Tmax) of NKTR-102 [ Time Frame: Through study completion, an expected average of 1 year ]
  • Area Under the serum Concentration time curve in the dosing interval (AUCtau) of NKTR-102 [ Time Frame: Through study completion, an expected average of 1 year ]
  • Half-life of (t1/2) of NKTR-102 [ Time Frame: Through study completion, an expected average of 1 year ]
  • 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 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: September 23, 2016)
  • Progression-Free Survival (Outside the Central Nervous System) [ Time Frame: Through study completion, an expected average of 1 year ]
    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.
  • Progression-Free Survival in Brain Metastasis (PFS-BM) [ Time Frame: Through study completion, an expected average of 1 year ]
    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.
  • To compare the Objective Response Rates (ORR) from NKTR-102 treatment with that of TPC [ Time Frame: Through study completion, an expected average of 1 year ]
    Objective Response Rate (ORR) will be defined as the proportion of patients with a confirmed Complete Response (CR) or Partial Response (PR) (RECIST for lesions outside the Central Nervous System (CNS); RANO-BM for CNS lesions) based upon the best response as assessed by the Investigator.
  • To compare the Clinical Benefit Rate (CBR) [ Time Frame: For at least 4 months, with an expected average of 1 year ]
    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.
  • To compare the Duration of Response (DoR) [ Time Frame: Through study completion, an expected average of 1 year ]
    Duration of response (DoR) will be defined as the time from first documented CR or PR until the earliest evidence of disease progression or death from any cause.
  • 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 ]
  • 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 ]
  • Compare Health-Related Quality of Life (HRQoL) using the Brief Fatigue Inventory (BFI) [ Time Frame: Through study completion, an expected average of 1 year ]
  • Magnitude of Clinical Benefit [ Time Frame: Through study completion, an expected average of 1 year ]
    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).
  • Maximum observed serum concentration (Cmax) of NKTR-102 [ Time Frame: Through study completion, an expected average of 1 year ]
  • Time of maximum observed serum concentration (Tmax) of NKTR-102 [ Time Frame: Through study completion, an expected average of 1 year ]
  • Area Under the serum Concentration time curve in the dosing interval (AUCtau) of NKTR-102 [ Time Frame: Through study completion, an expected average of 1 year ]
  • Half-life of (t1/2) of NKTR-102 [ Time Frame: Through study completion, an expected average of 1 year ]
  • 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 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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
Brief Summary 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 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Metastasis
  • Breast Cancer
Intervention  ICMJE
  • Drug: NKTR-102
  • Drug: Eribulin
  • Drug: Ixabepilone
  • Drug: Vinorelbine
  • Drug: Gemcitabine
  • Drug: Paclitaxel
  • Drug: Docetaxel
  • Drug: Nab-paclitaxel
Study Arms  ICMJE
  • Experimental: NKTR-102
    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.
    Intervention: Drug: NKTR-102
  • Active Comparator: Treatment of Physician's Choice (TPC)
    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.
    Interventions:
    • Drug: Eribulin
    • Drug: Ixabepilone
    • Drug: Vinorelbine
    • Drug: Gemcitabine
    • Drug: Paclitaxel
    • Drug: Docetaxel
    • Drug: Nab-paclitaxel
Publications * Tripathy D, Tolaney SM, Seidman AD, Anders CK, Ibrahim N, Rugo HS, Twelves C, Dieras V, Müller V, Tagliaferri M, Hannah AL, Cortés J. ATTAIN: Phase III study of etirinotecan pegol versus treatment of physician's choice in patients with metastatic breast cancer and brain metastases. Future Oncol. 2019 May 10. doi: 10.2217/fon-2019-0180. [Epub ahead of print]

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 24, 2018)
220
Original Estimated Enrollment  ICMJE
 (submitted: September 23, 2016)
350
Estimated Study Completion Date  ICMJE March 2021
Estimated Primary Completion Date July 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Nektar Recruitment 855-482-8676 StudyInquiry@nektar.com
Listed Location Countries  ICMJE Australia,   Belgium,   Canada,   Czechia,   France,   Israel,   Italy,   New Zealand,   Portugal,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02915744
Other Study ID Numbers  ICMJE 15-102-14
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Nektar Therapeutics
Study Sponsor  ICMJE Nektar Therapeutics
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Nektar Therapeutics
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP