Evaluation of an Anti-cancer Immunotherapy Combined With Standard Neoadjuvant Treatment in Patients With WT1-positive Primary Invasive Breast Cancer

Phase 2TerminatedNCT01220128

GlaxoSmithKline66 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

Conditions

Neoplasms, Breast

Interventions

GSK Biologicals' recombinant WT1 Antigen-Specific Cancer Immunotherapeutic (ASCI) GSK2302024ABIOLOGICAL

6 or 8 injections at 3 weeks apart, injected intramuscularly in the deltoid or lateral region of the thigh.

PlaceboDRUG

6 or 8 doses at 3 weeks apart of sucrose/mannitol-based formulation reconstituted with an oil-in-water emulsion, injected intramuscularly in the deltoid or lateral region of the thigh.

Aromatase inhibitorDRUG

This treatment consisted of any aromatase inhibitor (e.g. letrozole or exemestane), administered intravenously in Cohort A Groups daily for either 18 (if 6 doses of WT1 ASCI/placebo) or 24 weeks (if 8 doses of WT1 ASCI/placebo).

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (36)

Outcomes

Primary Outcomes

Number of Subjects With Severe Toxicities

Severe toxicity was defined as follows: - A Grade 3 or higher toxicity that is related or possibly related to the combined administration of standard treatment and GSK2302024A/placebo - A decrease in Left Ventricular Ejection Fraction (LVEF) from baseline with ≥ 10 points and at \< 50% that is related or possibly related to the combined administration of treatment and that is confirmed by a second LVEF assessment within approximately 3 weeks. - A Grade 2 or higher cardiac ischemia/infarction that is related or possibly related to the combined administration of standard treatment and GSK2302024A /placebo. - A Grade 2 or higher allergic reaction occurring within 24 hours following the administration. - A Grade 3 or higher blood/bone marrow toxicity that was considered as related or possibly related to the combined Administration. - A decrease in renal function at the time of administration that was considered as related or possibly related.

Time frame: 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)

Number of Patients With an Anti-Wilm's Tumor Gene (Anti-WT1) Humoral Response

For initially seronegative patients: post-administration antibody concentration ≥ 9 EU/mL For initially seropositive patients: post-administration antibody concentration ≥ 2 fold the pre-administration antibody concentration.

Time frame: At post-GSK2302024A/placebo Dose 4 (Week 13)

Number of Patients With Adverse Events (AEs)

An AE is any untoward medical occurrence in a clinical investigation patient, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.

Time frame: During the treatment period and up to 30 days post last administration

Data from ClinicalTrials.gov

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5-FluorouracilDRUG

Administered intravenously in Cohorts A Placebo, B, C and D/E Groups: for the 6 WT1 ASCI-dose schedule 3 doses at 3 weeks apart, and for the 8 WT1 ASCI-dose schedule 4 doses at 3 weeks apart. For Cohorts A Placebo, B and C Groups, the administration was on the same day as the administration of WT1 ASCI/placebo (Day 1 of each cycle). For Cohort D/E Groups, the administration was on Day 14 of each cycle.

Carboplatin AUCDRUG

Administered intravenously in Cohort C Groups in 6 doses at 3 weeks apart, on the same day as WT1 ASCI/placebo administration (Day 1 of each cycle).

CyclophosphamideDRUG

Administered intravenously in Cohorts A Placebo, B, C and D/E Groups: for the 6 WT1 ASCI-dose schedule 3 doses in Cohort C Groups and 6 doses 3 weeks apart in Cohorts A Placebo, B and D Groups, while for the 8 WT1 ASCI-dose schedule 4 doses at 3 weeks apart. For Cohorts A Placebo, B and C Groups, the administration was on the same day as the administration of WT1 ASCI/placebo (Day 1 of each cycle). For Cohort D/E Groups, the administration was on Day 14 of each cycle.

DocetaxelDRUG

Administered intravenously in Cohorts A Placebo, B, C and D/E Groups: for the 6 WT1 ASCI-dose schedule 3 or 6 doses 3 weeks apart, while for the 8 WT1 ASCI-dose schedule 4 doses at 3 weeks apart. For Cohorts A Placebo, B and C Groups, the administration was on the same day as the administration of WT1 ASCI/placebo (Day 1 of each cycle). For Cohort D/E Groups, the administration was on Day 14 of each cycle.

DoxorubicinDRUG

Administered intravenously in Cohorts A Placebo, B, C and D/E Groups: for the 6 WT1 ASCI-dose schedule 6 doses 3 weeks apart (Cohort C patients with this schedule did not receive this treatment), while for the 8 WT1 ASCI-dose schedule 4 doses at 3 weeks apart. For Cohorts A Placebo, B and C Groups, the administration was on the same day as the administration of WT1 ASCI/placebo (Day 1 of each cycle). For Cohort D/E Groups, the administration was on Day 14 of each cycle.

EpirubicinDRUG

Administered intravenously in Cohorts A Placebo, B, C and D/E Groups: for the 6 WT1 ASCI-dose schedule 3 doses 3 weeks apart, while for the 8 WT1 ASCI-dose schedule 4 doses at 3 weeks apart. For Cohorts A Placebo, B and C Groups, the administration was on the same day as the administration of WT1 ASCI/placebo (Day 1 of each cycle). For Cohort D/E Groups, the administration was on Day 14 of each cycle.

PaclitaxelDRUG

Administered intravenously in Cohorts A Placebo, B, C and D/E Groups: only in the 8 WT1 ASCI-dose schedule patients received 4 at 3 weeks apart or 12 weekly doses. For Cohorts A Placebo, B and C Groups, the administration was on the same day as the administration of WT1 ASCI/placebo (Day 1 of each cycle). For Cohort D/E Groups, the administration was on Day 14 of each cycle.

TrastuzumabDRUG

Administered intravenously in Cohort C Groups: for the 6 WT1 ASCI-dose schedule 3 or 6 doses 3 weeks apart, while for the 8 WT1 ASCI-dose schedule 4 doses at 3 weeks apart. For Cohort B and C Groups, the administration was on the same day as the administration of WT1 ASCI/placebo (Day 1 of each cycle). For Cohort D/E Groups, the administration was on Day 14 of each cycle.

GSK Investigational Site

Newark, Delaware, United States

GSK Investigational Site

Plantation, Florida, United States

GSK Investigational Site

Boston, Massachusetts, United States

GSK Investigational Site

Ann Arbor, Michigan, United States

GSK Investigational Site

Bend, Oregon, United States

GSK Investigational Site

Memphis, Tennessee, United States

GSK Investigational Site

Amarillo, Texas, United States

GSK Investigational Site

Spokane, Washington, United States

GSK Investigational Site

Brussels, Belgium

GSK Investigational Site

Leuven, Belgium

...and 26 more locations

Number of Subjects With Serious Adverse Events SAE(s)

A serious adverse event (SAE) is any untoward medical occurrence that: results in death, is life-threatening, requires hospitalization or prolongation of hospitalization, causes disability/incapacity or is a congenital anomaly/birth defect in the offspring of a study patient. In this study, an event which was part of the natural course of the disease under study (i.e., disease progression/recurrence) was captured in the study/as an efficacy measure. Therefore it was not reported as an SAE. Progression/recurrence of the tumor was recorded in the clinical assessments in the electronic case report form (eCRF). Death due to progressive disease was recorded on a specific form in the eCRF but not as an SAE.

Number of Subjects With Alanine Aminotransferase Increased Abnormality, by Common Terminology Criteria for Adverse Events (CTCAE) Maximum Grade

Criteria for Adverse Events (CTCAE), version 4.0 of May 28, 2009. Grades refer to the severity of the AE: mild (grade 1), moderate (grade 2), severe or medically significant (grade 3), life-threatening (grade 4) and death (grade 5).

Time frame: During the treatment period and up to 30 days post last administration

Number of Subjects With Alkaline Phosphatase Increased Abnormality, by CTCAE Maximum Grade

Time frame: During the treatment period and up to 30 days post last administration

Number of Subjects With Anemia, by CTCAE Maximum Grade

Time frame: During the treatment period and up to 30 days post last administration

Number of Subjects With Aspartate Aminotransferase Increased Abnormality, by CTCAE Maximum Grade

Time frame: During the treatment period and up to 30 days post last administration

Number of Subjects With Blood Bilirubin Increased Abnormality, by CTCAE Maximum Grade

Time frame: During the treatment period and up to 30 days post last administration

Number of Subjects With Creatine Increased Abnormality, by CTCAE Maximum Grade

Time frame: During the treatment period and up to 30 days post last administration

Number of Subjects With Hemoglobin Increased Abnormality, by CTCAE Maximum Grade

Time frame: During the treatment period and up to 30 days post last administration

Number of Subjects With Hypercalcemia Abnormality, by CTCAE Maximum Grade

Time frame: During the treatment period and up to 30 days post last administration

Number of Subjects With Hyperkalemia Abnormality, by CTCAE Maximum Grade

Time frame: During the treatment period and up to 30 days post last administration

Number of Subjects With Hypernatremia Abnormality, by CTCAE Maximum Grade

Time frame: During the treatment period and up to 30 days post last administration

Number of Subjects With Hypoalbuminemia Abnormality, by CTCAE Maximum Grade

Time frame: During the treatment period and up to 30 days post last administration

Number of Subjects With Hypocalcemia Abnormality, by CTCAE Maximum Grade

Time frame: During the treatment period and up to 30 days post last administration

Number of Subjects With Hypokalemia Abnormality, by CTCAE Maximum Grade

Time frame: During the treatment period and up to 30 days post last administration

Number of Subjects With Hyponatremia Abnormality, by CTCAE Maximum Grade

Time frame: During the treatment period and post 30 days post last administration

Number of Subjects With Lymphocyte Count Decreased Abnormality, by CTCAE Maximum Grade

Time frame: During the treatment period and up to 30 days post last administration

Number of Subjects With Lymphocyte Count Increased Abnormality, by CTCAE Maximum Grade

Time frame: During the treatment period and up to 30 days post last administration

Number of Subjects With Neutrophil Count Decreased Abnormality, by CTCAE Maximum Grade

Time frame: During the treatment period and up to 30 days post last administration

Number of Subjects With Platelet Count Decreased Abnormality, by CTCAE Maximum Grade

Time frame: During the treatment period and up to 30 days post last administration

Number of Subjects With White Blood Cell Decreased Abnormality, by CTCAE Maximum Grade

Time frame: During the treatment period and up to 30 days post last administration

Number of Patients With Adverse Events (AEs), by CTCAE Maximum Grade Reported

Time frame: During the treatment period and up to 30 days post last administration

Number of Subjects With Adverse Events (AEs) Assessed by the Investigators as Causally Related to GSK2302024A Treatment, by CTCAE Maximum Grade Reported

Time frame: During the treatment period and up to 30 days post last administration

Number of Subjects With Serious Adverse Events (SAEs), by CTCAE Maximum Grade Reported

Time frame: During the treatment period and up to 30 days post last administration

Number of Subjects With Serious Adverse Events (SAEs), Assessed by the Investigators as Causally Related to GSK2302024A Treatment, by CTCAE Maximum Grade Reported

Time frame: During the treatment period and up to 30 days post last administration

Number of Subjects With Breast Cancer Pathological Response

The pathological response in lymph nodes was evaluated by presence or absence of tumor cells by histopathological examination. Partial responses mark the disappearance of tumor cells, with only small clusters or dispersed cells remaining (more than 90% loss) while complete response indicate no identifiable malignant cells. However, ductal carcinoma in situ may be present.

Time frame: During the treatment period, up to Week 26/32