Clinical trial NCT02915744: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Metastasis
Breast Cancer
Keywords: Breast Cancer Brain Metastases (BCBM)
Carcinoma
Lead sponsor: Nektar Therapeutics
Sponsor class: INDUSTRY
First posted: 2016-09-27
Enrollment: 178
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 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.

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.

Primary outcomes:
measure: Overall Survival (OS) of Patients
timeFrame: Within 3 years from study start
Secondary outcomes:
measure: Progression-Free Survival (Outside the Central Nervous System)
timeFrame: Through study completion, an expected average of 1 year
measure: Progression-Free Survival in Brain Metastasis (PFS-BM)
timeFrame: Through study completion, an expected average of 1 year
measure: Progression-Free Survival (Overall)
timeFrame: Through study completion, an expected average of 1 year
measure: Objective Response Rates (ORR) of the NKTR-102 Treatment and the Treatment of Physician's Choice (TPC)
timeFrame: Through study completion, an expected average of 1 year
measure: Clinical Benefit Rate (CBR)
timeFrame: For at least 4 months, with an expected average of 1 year
measure: Duration of Response (DoR)
timeFrame: Through study completion, an expected average of 1 year
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.
timeFrame: 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.
measure: Compare Health-Related Quality of Life (HRQoL) Using the the EuroQoL 5D (EQ-5D-5L™)
timeFrame: 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
measure: Compare Health-Related Quality of Life (HRQoL) Using the Brief Fatigue Inventory (BFI)
timeFrame: 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
measure: Magnitude of Clinical Benefit Assessed by ESMO-MCBS Derived From Overall Survival
timeFrame: Through study completion, within 3 years from study start
measure: Number of Participants With Adverse Events as Assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.3
timeFrame: Through study completion, an expected average of 1 year
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Investigator Site - Tucson
state: Arizona
city: Orange
country: United States
facility: Investigator Site - Orange
state: California
city: San Francisco
country: United States
facility: Investigator Site - San Francisco
state: California
city: Miami
country: United States
facility: Investigator Site - Miami
state: Florida
city: Plantation
country: United States
facility: Investigator Site - Plantation
state: Florida
city: West Palm Beach
country: United States
facility: Investigator Site - West Palm Beach
state: Florida
city: Athens
country: United States
facility: Investigator Site - Athens
state: Georgia
city: Baltimore
country: United States
facility: Investigator Site - Baltimore
state: Maryland
city: Boston
country: United States
facility: Investigator Site - Boston
state: Massachusetts
city: Minneapolis
country: United States
facility: Investigator Site - Minneapolis
state: Minnesota
city: Saint Louis
country: United States
facility: Investigator Site - Saint Louis
state: Missouri
city: New York
country: United States
facility: Investigator Site - New York
state: New York
city: Chapel Hill
country: United States
facility: Investigator Site - Chapel Hill
state: North Carolina
city: Columbus
country: United States
facility: Investigator Site - Columbus
state: Ohio
city: Germantown
country: United States
facility: Investigator Site - Germantown
state: Tennessee
city: Fort Worth
country: United States
facility: Investigator Site - Fort Worth
state: Texas
city: Houston
country: United States
facility: Investigator Site - Houston
state: Texas
city: Salt Lake City
country: United States
facility: Investigator Site - Salt Lake City
state: Utah
city: Seattle
country: United States
facility: Investigator Site - Seattle
state: Washington
city: Albury
country: Australia
facility: Investigatory Site - Albury
state: New South Wales
city: Darlinghurst
country: Australia
facility: Investigator Site - Darlinghurst
state: New South Wales
city: Wollongong
country: Australia
facility: Investigator Site - Wollongong
state: New South Wales
city: Subiaco
country: Australia
facility: Investigator Site - Subiaco
state: Western Australia
city: Box Hill
country: Australia
facility: Investigator Site - Box Hill
city: Nedlands
country: Australia
facility: Investigator Site - Nedlands
city: Brussels
country: Belgium
facility: Investigator Site - Brussels
city: Brussels
country: Belgium
facility: Investigator Site - Brussels
city: Brussels
country: Belgium
facility: Investigator Site - Brussels
city: Charleroi
country: Belgium
facility: Investigator Site - Charleroi
city: Edegem
country: Belgium
facility: Investigator Site - Edegem
city: Liège
country: Belgium
facility: Investigator Site - Liege
city: Woluwe-Saint-Lambert
country: Belgium
facility: Investigator Site - Woluwe- Saint-Lambert
city: Montréal
country: Canada
facility: Investigator Site - Montreal
state: Quebec
city: Le Mans
country: France
facility: Investigator Site - Le Mans
city: Nîmes
country: France
facility: Investigator Site - Nimes
city: Paris
country: France
facility: Investigator Site - Paris
city: Rennes
country: France
facility: Investigator Site - Rennes
city: Rouen
country: France
facility: Investigator Site - Rouen
city: Strasbourg
country: France
facility: Investigator Site - Strasbourg
city: Beersheba
country: Israel
facility: Investigator Site - Beersheba
city: Haifa
country: Israel
facility: Investigator Site - Haifa
city: Tel Aviv
country: Israel
facility: Investigator Site - Tel Aviv
city: Milano
country: Italy
facility: Investigator Site - Milano
city: Milan
country: Italy
facility: Investigator Site - Milan
city: Napoli
country: Italy
facility: Investigator Site - Napoli
city: Roma
country: Italy
facility: Investigator Site - Roma
city: Lisboa
country: Portugal
facility: Investigator Site - Lisboa
city: Porto
country: Portugal
facility: Investigator Site - Porto
city: Barcelona
country: Spain
facility: Investigator Site - Barcelona
city: Barcelona
country: Spain
facility: Investigator Site - Barcelona
city: Madrid
country: Spain
facility: Investigator Site - Madrid
city: Santa Cruz de Tenerife
country: Spain
facility: Investigator Site - Santa Cruz de Tenerife
city: Sevilla
country: Spain
facility: Investigator Site - Sevilla
city: Bradford
country: United Kingdom
facility: Investigator Site - Bradford
city: Manchester
country: United Kingdom
facility: Investigator Site - Manchester
city: Nottingham
country: United Kingdom
facility: Investigator Site - Nottingham
Study officials:
References:
citation: 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.
citation: 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.