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)

• ClinicalTrials.gov Identifier: NCT02915744
• Recruitment Status: Completed
• First Posted: September 27, 2016
• Results First Posted: August 27, 2021
• Last Update Posted: April 14, 2023
• Sponsor: Nektar Therapeutics
• Information provided by (Responsible Party): Nektar Therapeutics

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Metastasis; Breast Cancer	Drug: NKTR-102; Drug: Eribulin; Drug: Ixabepilone; Drug: Vinorelbine; Drug: Gemcitabine; Drug: Paclitaxel; Drug: Docetaxel; Drug: Nab-paclitaxel	Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 178 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Study Start Date: November 2016
• Actual Primary Completion Date: July 2020
• Actual Study Completion Date: July 2020

Arms and Interventions

Arm	Intervention/treatment
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.	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.	Drug: Eribulin; Drug: Ixabepilone; Drug: Vinorelbine; Drug: Gemcitabine; Drug: Paclitaxel; Drug: Docetaxel; Drug: Nab-paclitaxel

Outcome Measures

Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

1. 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. The assessment of PFS outside the CNS will utilize RECIST criteria v1.1.
2. 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. Progressive Disease (PD) is defined as at least a 20% increase in the sum of longest diameters of CNS target lesions, taking as reference the smallest sum on study. This included the baseline sum if that was the smallest on study. In addition to the relative increase of 20%, at least 1 lesion had to increase by an absolute value of 5 mm or more to be considered progression.
3. 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). Progressive Disease (PD) is defined as at least a 20% increase in the sum of longest diameters of CNS target lesions, taking as reference the smallest sum on study. This included the baseline sum if that was the smallest on study. In addition to the relative increase of 20%, at least 1 lesion had to increase by an absolute value of 5 mm or more to be considered progression.
4. 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 ]
   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.
5. 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). CR is defined as disappearance of all target lesions for at least 4 weeks with no new lesions, not use of corticosteroids, and patient was stable or improved clinically. PR is defined as at least a 30% decrease in the sum of longest diameters sustained for at least 4 weeks, no new lesions; stable to decreased corticosteroid dose; stable or improved clinically. 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.
6. 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. CR is defined as disappearance of all target lesions for at least 4 weeks with no new lesions, not use of corticosteroids, and patient was stable or improved clinically. PR is defined as at least a 30% decrease in the sum of longest diameters sustained for at least 4 weeks, no new lesions; stable to decreased corticosteroid dose; stable or improved clinically. 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.
7. 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: Baseline (prior to first dose of study treatment in Cycle 1 [cycle length = 21 for NKTR-102 or 28 days for TPC] and end of Cycle 44. ]
   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.
8. Compare Health-Related Quality of Life (HRQoL) Using the the EuroQoL 5D (EQ-5D-5L™) [ Time Frame: Baseline (prior to first dose of study treatment in Cycle 1 [cycle length = 21 for NKTR-102 or 28 days for TPC] and end of Cycle 44 ]
   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.
9. Compare Health-Related Quality of Life (HRQoL) Using the Brief Fatigue Inventory (BFI) [ Time Frame: Baseline (prior to first dose of study treatment in Cycle 1 [cycle length = 21 for NKTR-102 or 28 days for TPC] and end of Cycle 44 ]
   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.
10. Magnitude of Clinical Benefit Assessed by ESMO-MCBS Derived From Overall Survival [ Time Frame: Through study completion, within 3 years from study start ]
    The magnitude of clinical benefit of NKTR-102 is assessed by the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) (v1.0). The scale is graded 5, 4, 3, 2, 1, where grades 5 and 4 represent a high level of proven clinical benefit, and grade 1 represents no clinical benefit. To determine the magnitude of clinical benefit when the median OS with the standard of treatment is ≤ 1 year, the score is derived from the Hazard Ratio (HR) of Overall Survival, overall survival gain, and QoL improvement between two treatment arms. Values reported in the data table are Overall Survival values.
11. 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 ]
    The number of participants with adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.3

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Arizona

Investigator Site - Tucson

Tucson, Arizona, United States, 85724

United States, California

Investigator Site - Orange

Orange, California, United States, 92868

Investigator Site - San Francisco

San Francisco, California, United States, 94115

United States, Florida

Investigator Site - Miami

Miami, Florida, United States, 33136

Investigator Site - Plantation

Plantation, Florida, United States, 33324

Investigator Site - West Palm Beach

West Palm Beach, Florida, United States, 33401

United States, Georgia

Investigator Site - Athens

Athens, Georgia, United States, 30607

United States, Maryland

Investigator Site - Baltimore

Baltimore, Maryland, United States, 21201

United States, Massachusetts

Investigator Site - Boston

Boston, Massachusetts, United States, 02115

United States, Minnesota

Investigator Site - Minneapolis

Minneapolis, Minnesota, United States, 55455

United States, Missouri

Investigator Site - Saint Louis

Saint Louis, Missouri, United States, 63110

United States, New York

Investigator Site - New York

New York, New York, United States, 10065

United States, North Carolina

Investigator Site - Chapel Hill

Chapel Hill, North Carolina, United States, 27599

United States, Ohio

Investigator Site - Columbus

Columbus, Ohio, United States, 43210

United States, Tennessee

Investigator Site - Germantown

Germantown, Tennessee, United States, 38138

United States, Texas

Investigator Site - Fort Worth

Fort Worth, Texas, United States, 76104

Investigator Site - Houston

Houston, Texas, United States, 77030

United States, Utah

Investigator Site - Salt Lake City

Salt Lake City, Utah, United States, 84106

United States, Washington

Investigator Site - Seattle

Seattle, Washington, United States, 98109

Australia, New South Wales

Investigatory Site - Albury

Albury, New South Wales, Australia, 2640

Investigator Site - Darlinghurst

Darlinghurst, New South Wales, Australia, 2010

Investigator Site - Wollongong

Wollongong, New South Wales, Australia, 2500

Australia, Western Australia

Investigator Site - Subiaco

Subiaco, Western Australia, Australia, 6008

Australia

Investigator Site - Box Hill

Box Hill, Australia, 3128

Investigator Site - Nedlands

Nedlands, Australia, 6009

Belgium

Investigator Site - Brussels

Brussels, Belgium, 1000

Investigator Site - Brussels

Brussels, Belgium, 1180

Investigator Site - Brussels

Brussels, Belgium, 1200

Investigator Site - Charleroi

Charleroi, Belgium, 6000

Investigator Site - Edegem

Edegem, Belgium, 2650

Investigator Site - Liege

Liège, Belgium, 4000

Investigator Site - Woluwe- Saint-Lambert

Woluwe-Saint-Lambert, Belgium, 1200

Canada, Quebec

Investigator Site - Montreal

Montréal, Quebec, Canada, H4A 3J1

France

Investigator Site - Le Mans

Le Mans, France, 72000

Investigator Site - Nimes

Nîmes, France, 30029

Investigator Site - Paris

Paris, France, 75248

Investigator Site - Rennes

Rennes, France, 35042

Investigator Site - Rouen

Rouen, France, 76038

Investigator Site - Strasbourg

Strasbourg, France, 67091

Israel

Investigator Site - Beersheba

Beersheba, Israel, 84101

Investigator Site - Haifa

Haifa, Israel, 31096

Investigator Site - Tel Aviv

Tel Aviv, Israel, 64239

Italy

Investigator Site - Milano

Milano, Italy, 20141

Investigator Site - Milan

Milan, Italy, 20132

Investigator Site - Napoli

Napoli, Italy, 80131

Investigator Site - Roma

Roma, Italy, 144

Portugal

Investigator Site - Lisboa

Lisboa, Portugal, 1649-035

Investigator Site - Porto

Porto, Portugal, 4200-072

Spain

Investigator Site - Barcelona

Barcelona, Spain, 8023

Investigator Site - Barcelona

Barcelona, Spain, 8035

Investigator Site - Madrid

Madrid, Spain, 28040

Investigator Site - Santa Cruz de Tenerife

Santa Cruz de Tenerife, Spain, 38320

Investigator Site - Sevilla

Sevilla, Spain, 41013

United Kingdom

Investigator Site - Bradford

Bradford, United Kingdom, BD7 1DP

Investigator Site - Manchester

Manchester, United Kingdom, M20 4BX

Investigator Site - Nottingham

Nottingham, United Kingdom, NG5 1PB

Sponsors and Collaborators

Nektar Therapeutics

  Study Documents (Full-Text)

Documents provided by Nektar Therapeutics:

Study Protocol  [PDF] January 14, 2016

Statistical Analysis Plan  [PDF] April 10, 2015

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Tripathy D, Tolaney SM, Seidman AD, Anders CK, Ibrahim N, Rugo HS, Twelves C, Dieras V, Muller V, Du Y, Currie SL, Hoch U, Tagliaferri M, Hannah AL, Cortes J; ATTAIN Investigators. Treatment With Etirinotecan Pegol for Patients With Metastatic Breast Cancer and Brain Metastases: Final Results From the Phase 3 ATTAIN Randomized Clinical Trial. JAMA Oncol. 2022 Jul 1;8(7):1047-1052. doi: 10.1001/jamaoncol.2022.0514.

Tripathy D, Tolaney SM, Seidman AD, Anders CK, Ibrahim N, Rugo HS, Twelves C, Dieras V, Muller V, Tagliaferri M, Hannah AL, Cortes 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 Jul;15(19):2211-2225. doi: 10.2217/fon-2019-0180. Epub 2019 May 10.

• Responsible Party: Nektar Therapeutics
• ClinicalTrials.gov Identifier: NCT02915744
• Other Study ID Numbers: 15-102-14
• First Posted: September 27, 2016
• Results First Posted: August 27, 2021
• Last Update Posted: April 14, 2023
• Last Verified: April 2023

Keywords provided by Nektar Therapeutics:

Breast Cancer Brain Metastases (BCBM); Carcinoma

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasm Metastasis; Brain Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Neoplastic Processes; Pathologic Processes; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Paclitaxel; Vinorelbine; Docetaxel; Albumin-Bound Paclitaxel; Gemcitabine; Etirinotecan pegol; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Topoisomerase II Inhibitors; Topoisomerase Inhibitors