Clinical trial NCT01220128: Evaluation of an Anti-cancer Immunotherapy Combined With Standard Neoadjuvant Treatment in Patients With WT1-positive Primary Invasive Breast Cancer
Official title: Study of GSK2302024A Antigen-Specific Cancer Immunotherapeutic Combined With Standard Neoadjuvant Treatment in Patients With WT1-positive Primary Invasive Breast Cancer
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Neoplasms, Breast
Keywords: WT1
neoadjuvant
tumor antigen
immunotherapy
breast cancer
adult
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2010-10-13
Enrollment: 66
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: The purpose of this study is to evaluate the safety, immunogenicity and clinical activity of a new WT1 anti-cancer immunotherapy in patients with WT1-positive Stage II or III breast cancer. The treatment will be given before surgery in combination with standard therapy.

Detailed description: The study will be conducted in two consecutive segments (Phase I and Phase II), each with specific objectives. Active follow-up will be for three years.

Patients in this study will be allocated to cohorts as below. Cohort A will include postmenopausal patients with hormone receptor-positive breast cancer who receive aromatase inhibitor (AI) as neoadjuvant therapy concurrently with administration of 6 or 8 doses of WT1 anti-cancer immunotherapy (WT1 ASCI)/placebo starting on Day 0. AI treatment will be administered daily for duration of either 18 (if 6 doses of WT1 ASCI/placebo) or 24 weeks (if 8 doses of WT1 ASCI/placebo).

Cohort B will include breast cancer patients who will receive neoadjuvant chemotherapy concurrently with administration of WT1 ASCI/placebo starting on Day 0. Neoadjuvant chemotherapy in Cohort B will consist either 1) if 6 doses of WT1 ASCI/placebo: 6 cycle-treatment chemotherapy regimens consist of 6, three-weekly cycles of anthracycline/taxane-based therapy, or 2) if 8 doses of WT1 ASCI/placebo: 8 cycle-treatment regimens consisting of 4 three-weekly cycles of anthracycline-based therapy followed by 4 three-weekly or 12-weekly taxane administrations without trastuzumab.

Cohort C will include patients with Human Epidermal Growth Factor Receptor 2 (HER2)-overexpressing breast cancer who will receive neoadjuvant trastuzumab (Herceptin) therapy combined with chemotherapy concurrently with administration of WT1 ASCI/placebo starting on Day 0. Neoadjuvant chemotherapy in Cohort C will consist either 1) if 6 doses of WT1 ASCI/placebo: 6 cycle-treatment chemotherapy regimens consist of 6, three-weekly cycles of anthracycline/taxane-based therapy, or 2) if 8 doses of WT1 ASCI/placebo: 8 cycle-treatment regimens consisting of 4 three-weekly cycles of anthracycline-based therapy followed by 4 three-weekly or 12-weekly taxane administrations with trastuzumab.

Cohorts D and E will include patients with hormone receptor-positive and HER2 non-overexpressing breast cancer who will receive neoadjuvant chemotherapy. For patients in these Cohorts D and E, WT1 ASCI/placebo (placebo applicable only for Cohort E patients) will be administered on Day 14 of each three-weekly cycle of chemotherapy. Neoadjuvant chemotherapy in Cohorts D and E will consist either 1) if 6 doses of WT1 ASCI/placebo: 6 cycle-treatment chemotherapy regimens consist of 6, three-weekly cycles of anthracycline/taxane-based therapy, or 2) if 8 doses of WT1 ASCI/placebo: 8 cycle-treatment regimens consisting of 4 three-weekly cycles of anthracycline-based therapy followed by 4 three-weekly taxane administrations without trastuzumab. Enrolment in Cohort E will be conditional on the absence of a safety signal and on the adequate induction of an immune response by the WT1 ASCI in Cohort D (defined as \>= 40% response rate based on post-Dose 4 anti-WT1 antibody responses in at least six patients). If this criterion is met, 60 patients (40 receiving WT1 ASCI and 20 placebo) with identical eligibility criteria will be enrolled into Cohort E. In case no adequate safety and/or immunogenicity will be obtained in Cohort D, recruitment in Cohort E will not be initiated.

The protocol has been updated following Protocol Amendment 4, April 2013, leading to the update of the study design.

Eligibility criteria: Inclusion Criteria:

* The patient is ≥ 18 years of age at the time the informed consent to screening has been obtained.
* The patient has proven T1 with lymph node involvement or T2-T4c, any N, M0 primary invasive breast cancer, histologically confirmed by core needle biopsy.

Isolated supraclavicular lymph node involvement is allowed.

* The patient's tumor shows WT1 antigen expression.
* The patient has one of the following histologically confirmed breast cancer subtypes:

  * Estrogen receptor and/or progesterone positive tumor.
  * Human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer.
  * HER2-negative breast cancer.
* Eastern Cooperative Oncology Group (performance status of 0 or 1 at the time of study treatment allocation.
* Baseline left ventricular ejection fraction of ≥ 50% as measured within six weeks prior to study treatment allocation by echocardiography or multi-gated acquisition(MUGA)scan.
* The patient shows normal organ function according to the following parameters(as measured within six weeks prior to treatment allocation)::

  * Hemoglobin: Within normal range according to institutional standards.
  * Absolute leukocyte count: Within normal range according to institutional standards.
  * Absolute lymphocyte count: Within normal range according to institutional standards.
  * Platelet count: Within normal range according to institutional standards
  * Alanine aminotransferase: ≤ 2.5 x Upper Limit of Normal (ULN)
  * Aspartate aminotransferase: ≤ 2.5 x ULN
  * Total bilirubin: ≤ 1.5 x ULN. In the case of known Gilbert's syndrome ≤ 2 x ULN
  * Serum creatinine: 1.5 x ULN
  * Calculated creatinine clearance: \> 50 mL/min
* A female patient of childbearing potential may be enrolled in the study, if the patient:

  * has practiced adequate contraception for 30 days prior to study product administration, and
  * has a negative pregnancy test within one week prior to treatment allocation and
  * has agreed to continue adequate contraception during the entire treatment period and for 2 months after completion of the study product administration series.In view of the investigator, the patient can and will comply with the requirements of the protocol.
* Written informed consent has been obtained from the patient prior to performance of any study specific procedure.

Exclusion Criteria:

* The patient has inflammatory breast cancer, which is defined as clinically significant erythema of the breast and/or documented dermal lymphatic invasion.
* Diagnosis established by incisional biopsy.
* Prior and concomitant neoadjuvant anti-breast-cancer treatments such as chemotherapy, immunotherapy / biological response modifiers, endocrine therapy, and radiotherapy, unless authorized specifically by the protocol.
* The patient is known to be human immunodeficiency virus -positive.
* The patient has symptomatic autoimmune disease such as, but not limited to multiple sclerosis, lupus, and inflammatory bowel disease. Patients with vitiligo are not excluded.
* The patient is known to have difficult-to-control hypertension, coronary artery disease, arrhythmia requiring treatment, clinically significant valvular disease, cardiomegaly on chest X-ray, ventricular hypertrophy on electrocardiogram or previous myocardial infarction or congestive heart failure.
* The patient has a history of allergic reactions likely to be exacerbated by any component of the investigational product used in the study.
* The patient has other concurrent severe medical problems, unrelated to the malignancy, that would significantly limit full compliance with the study or expose the patient to unacceptable risk.
* The patient has (or has had) previous or concomitant malignancies at other sites, except effectively treated malignancy that is considered by the investigator highly likely to have been cured.
* The patient has psychiatric or addictive disorders that may compromise his/her ability to give informed consent or to comply with the study procedures.
* The patient has received any investigational or non-registered product within 30 days preceding the first dose of study products or planned use during the study period.
* The patient requires concomitant treatment with any immunosuppressive agents or with systemic corticosteroids prescribed for chronic treatment.
* The patient has a significant disorder of coagulation or receives treatment with warfarin derivatives or heparin. Patients receiving individual doses of low molecular weight heparin outside of 24 hours prior to WT1-A10 + AS15 ASCI/placebo administration are eligible. Patients receiving prophylactic antiplatelet medications e.g. low-dose aspirin, and without a clinically-apparent bleeding tendency are eligible.

Primary outcomes:
measure: Number of Subjects With Severe Toxicities
timeFrame: From Week 0 to Week 26/32 (period starting from GSK2302024A/placebo treatment allocation and ending with the concluding Visit i.e.: Week 26 for patients receiving 6 injections and Week 32 for patients receiving 8 injections)
measure: Number of Patients With an Anti-Wilm's Tumor Gene (Anti-WT1) Humoral Response
timeFrame: At post-GSK2302024A/placebo Dose 4 (Week 13)
measure: Number of Patients With Adverse Events (AEs)
timeFrame: During the treatment period and up to 30 days post last administration
measure: Number of Subjects With Serious Adverse Events SAE(s)
timeFrame: From Week 0 to Week 26/32 (period starting from GSK2302024A/placebo treatment allocation and ending with the concluding Visit i.e.: Week 26 for patients receiving 6 injections and Week 32 for patients receiving 8 injections)
measure: Number of Subjects With Alanine Aminotransferase Increased Abnormality, by Common Terminology Criteria for Adverse Events (CTCAE) Maximum Grade
timeFrame: During the treatment period and up to 30 days post last administration
measure: Number of Subjects With Alkaline Phosphatase Increased Abnormality, by CTCAE Maximum Grade
timeFrame: During the treatment period and up to 30 days post last administration
measure: Number of Subjects With Anemia, by CTCAE Maximum Grade
timeFrame: During the treatment period and up to 30 days post last administration
measure: Number of Subjects With Aspartate Aminotransferase Increased Abnormality, by CTCAE Maximum Grade
timeFrame: During the treatment period and up to 30 days post last administration
measure: Number of Subjects With Blood Bilirubin Increased Abnormality, by CTCAE Maximum Grade
timeFrame: During the treatment period and up to 30 days post last administration
measure: Number of Subjects With Creatine Increased Abnormality, by CTCAE Maximum Grade
timeFrame: During the treatment period and up to 30 days post last administration
measure: Number of Subjects With Hemoglobin Increased Abnormality, by CTCAE Maximum Grade
timeFrame: During the treatment period and up to 30 days post last administration
measure: Number of Subjects With Hypercalcemia Abnormality, by CTCAE Maximum Grade
timeFrame: During the treatment period and up to 30 days post last administration
measure: Number of Subjects With Hyperkalemia Abnormality, by CTCAE Maximum Grade
timeFrame: During the treatment period and up to 30 days post last administration
measure: Number of Subjects With Hypernatremia Abnormality, by CTCAE Maximum Grade
timeFrame: During the treatment period and up to 30 days post last administration
measure: Number of Subjects With Hypoalbuminemia Abnormality, by CTCAE Maximum Grade
timeFrame: During the treatment period and up to 30 days post last administration
measure: Number of Subjects With Hypocalcemia Abnormality, by CTCAE Maximum Grade
timeFrame: During the treatment period and up to 30 days post last administration
measure: Number of Subjects With Hypokalemia Abnormality, by CTCAE Maximum Grade
timeFrame: During the treatment period and up to 30 days post last administration
measure: Number of Subjects With Hyponatremia Abnormality, by CTCAE Maximum Grade
timeFrame: During the treatment period and post 30 days post last administration
measure: Number of Subjects With Lymphocyte Count Decreased Abnormality, by CTCAE Maximum Grade
timeFrame: During the treatment period and up to 30 days post last administration
measure: Number of Subjects With Lymphocyte Count Increased Abnormality, by CTCAE Maximum Grade
timeFrame: During the treatment period and up to 30 days post last administration
measure: Number of Subjects With Neutrophil Count Decreased Abnormality, by CTCAE Maximum Grade
timeFrame: During the treatment period and up to 30 days post last administration
measure: Number of Subjects With Platelet Count Decreased Abnormality, by CTCAE Maximum Grade
timeFrame: During the treatment period and up to 30 days post last administration
measure: Number of Subjects With White Blood Cell Decreased Abnormality, by CTCAE Maximum Grade
timeFrame: During the treatment period and up to 30 days post last administration
measure: Number of Patients With Adverse Events (AEs), by CTCAE Maximum Grade Reported
timeFrame: During the treatment period and up to 30 days post last administration
measure: Number of Subjects With Adverse Events (AEs) Assessed by the Investigators as Causally Related to GSK2302024A Treatment, by CTCAE Maximum Grade Reported
timeFrame: During the treatment period and up to 30 days post last administration
measure: Number of Subjects With Serious Adverse Events (SAEs), by CTCAE Maximum Grade Reported
timeFrame: During the treatment period and up to 30 days post last administration
measure: Number of Subjects With Serious Adverse Events (SAEs), Assessed by the Investigators as Causally Related to GSK2302024A Treatment, by CTCAE Maximum Grade Reported
timeFrame: During the treatment period and up to 30 days post last administration
measure: Number of Subjects With Breast Cancer Pathological Response
timeFrame: During the treatment period, up to Week 26/32
Secondary outcomes:
Other outcomes:
Locations:
city: Newark
country: United States
facility: GSK Investigational Site
state: Delaware
city: Plantation
country: United States
facility: GSK Investigational Site
state: Florida
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Ann Arbor
country: United States
facility: GSK Investigational Site
state: Michigan
city: Bend
country: United States
facility: GSK Investigational Site
state: Oregon
city: Memphis
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Amarillo
country: United States
facility: GSK Investigational Site
state: Texas
city: Spokane
country: United States
facility: GSK Investigational Site
state: Washington
city: Brussels
country: Belgium
facility: GSK Investigational Site
city: Leuven
country: Belgium
facility: GSK Investigational Site
city: Namur
country: Belgium
facility: GSK Investigational Site
city: Lyon Cedex 08
country: France
facility: GSK Investigational Site
city: Saint-Herblain
country: France
facility: GSK Investigational Site
city: Tuebingen
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Erlangen
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Frankfurt
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Rostock
country: Germany
facility: GSK Investigational Site
state: Mecklenburg-Vorpommern
city: Dortmund
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Essen
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Chemnitz
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Kiel
country: Germany
facility: GSK Investigational Site
state: Schleswig-Holstein
city: Napoli
country: Italy
facility: GSK Investigational Site
state: Campania
city: Aviano (PN)
country: Italy
facility: GSK Investigational Site
state: Friuli-Venezia-Giulia
city: Genova
country: Italy
facility: GSK Investigational Site
state: Liguria
city: Milano
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Pavia
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Torino
country: Italy
facility: GSK Investigational Site
state: Piemonte
city: Trento
country: Italy
facility: GSK Investigational Site
state: Trentino-Alto Adige
city: Ryazan
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Belfast
country: United Kingdom
facility: GSK Investigational Site
city: Bournemouth
country: United Kingdom
facility: GSK Investigational Site
city: Derby
country: United Kingdom
facility: GSK Investigational Site
city: Edinburgh
country: United Kingdom
facility: GSK Investigational Site
city: Nottingham
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Higgins M, Curigliano G, Dieras V, Kuemmel S, Kunz G, Fasching PA, Campone M, Bachelot T, Krivorotko P, Chan S, Ferro A, Schwartzberg L, Gillet M, De Sousa Alves PM, Wascotte V, Lehmann FF, Goss P. Safety and immunogenicity of neoadjuvant treatment using WT1-immunotherapeutic in combination with standard therapy in patients with WT1-positive Stage II/III breast cancer: a randomized Phase I study. Breast Cancer Res Treat. 2017 Apr;162(3):479-488. doi: 10.1007/s10549-017-4130-y. Epub 2017 Feb 7.