Evaluation of a New Anti-cancer Immunotherapy in Adult Acute Myeloid Leukemia Patients With a Suboptimal Clinical Response to Induction Chemotherapy

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the clinical activity and safety of a WT1 Antigen-Specific Cancer Immunotherapeutic (WT1 ASCI) as post-induction therapy in adult patients with WT1-positive AML presenting a suboptimal clinical response to induction chemotherapy. The study will also assess whether this treatment induces a specific immune response to the malignancy.

Detailed Description
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At least 40 patients will be enrolled in this study, divided in two cohorts of 20 patients each. One cohort will include patients in partial remission after induction therapy and one cohort will include patients in complete remission but with incomplete blood count recovery. Patients in both cohorts will receive the same study treatment according to the same administration schedule. This protocol summary has been updated according to the Protocol Amendment 3 (dated 10 Sept 2014). All active follow-up visits and procedures after the concluding visit, 30 days after the last treatment administration, will be stopped In addition, no more biological samples will be collected for protocol research purposes. For each biological sample already collected in the scope of this study and not tested yet, testing will not be performed by default, except if a scientific rationale remains relevant.Blood sampling for safety monitoring as per protocol will continue.

Official Title
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Study of GSK2130579A Tumor-Antigen-Specific Cancer Immunotherapeutic in Adult Acute Myeloid Leukemia Patients With a Suboptimal Clinical Response to Induction Chemotherapy

Conditions
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Leukaemia, Myelocytic, Acute

Intervention / Treatment
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* Biological: GSK Biologicals' recombinant WT1 Antigen-Specific Cancer Immunotherapeutic (ASCI) GSK2130579A


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient has cytologically proven AML as defined by the World Health Organization (WHO) classification. The pretreatment AML karyotype should be documented. The leukemia is a de novo or secondary AML. The patient's blasts cells show expression of WT1 transcript, detected by quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR).The patient received the following therapy according to the Institution's standard of care. For patients < 60 years old: at least two induction chemotherapy treatments. For patients >= 60 years old: at least one induction chemotherapy treatment or alternative treatment. The first ASCI administration should be given within one year after the last chemotherapy administration. All screening procedures should be completed within seven weeks before the first ASCI administration. In the investigator's opinion and in compliance with the Institution Hematology Tumor Board's guidances, the patient should not be eligible for any additional chemotherapy treatment before the ASCI treatment. The clinical status of the patient at inclusion is one of the following: Partial Remission (PR) Morphologic complete remission with incomplete blood count recovery (CRi) Written informed consent has been obtained prior to the performance of any protocol-specific procedure. The patient is >= 18 years of age at the time of signature of the first informed consent form. Eastern Cooperative Oncology Group performance status of 0, 1 or 2. Adequate hepatic and renal function defined as: Serum bilirubin < 1.5 times the Upper Limit of Nor-mal (ULN). Serum ALT < 2.5 times the ULN. Calculated creatinine clearance > 50 mL/min. In the view of the investigator, the patient can and will comply with the requirements of the protocol. If the patient is female, she must be of non-childbearing potential, i.e. have a current tubal ligation, hysterectomy, ovariectomy or be post-menopausal, or if she is of childbearing potential, then she must practice adequate contraception for 30 days prior to treatment administration, have a negative pregnancy test and continue such precautions for 2 months after completion of the treatment administration series. Exclusion Criteria: The patient was diagnosed with leukemic Central Nervous System (CNS) disease (e.g. before chemotherapy) or presents neurological symptoms at baseline suggestive of a CNS involvement. The patient has acute promyelocytic leukemia with t(15;17) (q22;q12), (PML/RARα) or variants. The patient has received, or is receiving, allogeneic Stem Cell Transplantation (SCT). The patient has received Fludarabine, Clofarabine or Cloretazine within 12 months preceding the ASCI treat-ment. The patient has hypercalcemia. The patient is known to be HIV-positive. The patient has symptomatic autoimmune disease such as, but not limited to multiple sclerosis, lupus, and in-flammatory bowel disease. Patients with vitiligo are not excluded. The patient has a history of allergic reactions likely to be exacerbated by any component of the study investigational product. The patient has other concurrent severe medical prob-lems, unrelated to the malignancy, that would significantly limit full compliance with the study or expose the patient to unacceptable risk. The patient has another metastatic cancer disease. The patient has a history of congestive heart failure, coronary artery disease or previous myocardial infarction. 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 medicinal product other than the study treat-ment within 30 days preceding the first dose of study treatment or plans to receive such a drug during the study period. The patient requires concomitant chronic treatment (more than 7 consecutive days) with systemic corticosteroids or any other immunosuppressive agents. The patient is receiving full dose subcutaneous heparins or is under anti-coagulation treatment. For female patients: the patient is pregnant or lactating.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Partial Remission Group<br>Adult patients in partial remission post-induction chemotherapy, who received the GSK2130579A study product, administered sequentially, as follows: Cycle 1: 6 doses, each given at 2-week intervals; Cycle 2: 6 doses, each given at 3-week intervals; Cycle 3: 4 doses, each given at 6-week intervals; Cycle 4: 4 doses, each given at 3-month intervals, followed by 4 doses each given at 6-month intervals. | Biological: GSK Biologicals' recombinant WT1 Antigen-Specific Cancer Immunotherapeutic (ASCI) GSK2130579A<br>* Intramuscular injection<br>* Other names: WT1 ASCI;|
| Experimental: Complete Remission Group<br>Adult patients in complete remission with incomplete blood count recovery post-induction chemotherapy, who received the GSK2130579A study product, administered sequentially, as follows: Cycle 1: 6 doses, each given at 2-week intervals; Cycle 2: 6 doses, each given at 3-week intervals; Cycle 3: 4 doses, each given at 6-week intervals; Cycle 4: 4 doses, each given at 3-month intervals, followed by 4 doses each given at 6-month intervals. | Biological: GSK Biologicals' recombinant WT1 Antigen-Specific Cancer Immunotherapeutic (ASCI) GSK2130579A<br>* Intramuscular injection<br>* Other names: WT1 ASCI;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Severe Toxicities | Severe toxicities (as classified according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0) during the study treatment period defined as a study product-related or possibly study product-related: Grade 4 toxicity (exception: study product-related or possibly study product-related Grade 4 fatigue - including lethargy, asthenia, and malaise - had to have a duration of at least 48 hours to be taken into account). Grade 3 toxicity lasting for at least 48 hours (exceptions: myalgia, arthralgia, headache, and fever, regardless of duration). Grade 2 toxicity (i.e., rash, flushing, urticaria, and dyspnea). Drug fever was not part of this definition. Decrease in renal function, with a calculated creatinine clearance < 40 mL/min. Grade 2 cardiac ischemia/infarction (i.e., asymptomatic and testing suggesting ischemia; stable angina). | During the entire study (from Month 0 to Month 49) | 
| Number of Patients With Best Overall Response, Defined by Either Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progressive Disease (PD) | CR = having < 5% blasts in aspirate sample with marrow spicules and with a count of ≥ 200 nucleated cells, no blasts with Auer rods or persistence of extramedullary disease; different phenotype (by flow cytometry) to the pre-treatment specimen; absolute neutrophil count > 1000/mm3; platelet count ≥ 100 000/mm3 and being independent of red blood cell (RBC) transfusions. PR = a decrease of ≤ 50% in the % of blasts in bone marrow aspirate compared to Visit 4; being independent of RBC transfusions and the absolute neutrophil ≥ 1000/mm3 and platelet counts and ≥ 100 000/mm3. SD = no sufficient criteria for CR, a PR or Progressive disease (PD = Reappearance of leukemic blasts in the peripheral blood; Reappearance/development of cytologically proven extramedullary disease, Appearance of new dysplastic changes, or in a bone marrow aspirate sample (with marrow spicules and with a count of ≥200 nucleated cells) of ≥5% blasts; or, in case of early progression, a higher blast % than at Visit 4). | During the entire study (from Month 0 to Month 49) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-WT1 Seropositivity Rate | Seropositivity rate was defined as the number of patients with anti-WT1 antibody concentrations greater than or equal to (≥) 9 Enzyme-Linked Immunosorbent Assay (ELISA) units per milliliter (EU/mL). | At baseline (PRE), weeks (W) 5, 9, 13, 15, 21, 32, 40, 54, at months 15, 18, 21, 24, 30, 36, 42 and 49 (concluding visit), as well as follow-up visits 1 to 4 | 
| Anti-WT1 Antibody Concentrations | Antibody concentrations were expressed as geometric mean concentrations, measured in ELISA units per milliliter (EU/mL). | At baseline (PRE), weeks (W) 5, 9, 13, 15, 21, 32, 40, 54, at months 15, 18, 21, 24, 30, 36, 42 and 49 (concluding visit), as well as follow-up visits 1 to 4 | 
| Anti-WT1 Antibody Response | The anti-WT1 antibody response was defined as: For initially seronegative patients, post-vaccination antibody concentration ≥ 9 EU/mL; For initially seropositive patients, post-vaccination antibody concentration ≥ 2 fold the pre-vaccination antibody concentration. | At baseline (PRE), weeks (W) 5, 9, 13, 15, 21, 32, 40, 54, at months 15, 18, 21, 24, 30, 36, 42 and 49 (concluding visit), as well as follow-up visits 1 to 4 | 
| Number of Subjects With Any and Related Unsolicited Adverse Events (AEs) | An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. Related = AE assessed by the investigator as causally related to the study treatment. | Starting with the first administration of study treatment and ending 30 days after the last study treatment administration | 
| Number of Subjects With Study Treatment Failure | Study treatment failure was defined as withdrawal from investigational product because of disease progression or death. Among the characteristics evaluated were: Progression, Death in absence of Relapse, Relapse or progression or Death (Progression Free Survival event), Death [An event that 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 did not need to be reported as an SAE], Autopsy performed and Cause of death. | During the entire study (from Month 0 to Month 49) | 
| Number of Subjects With Any or Related Serious Adverse Events (SAEs) | SAEs assessed include medical occurrences that result in death, are life-threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. Related = SAE assessed by the investigator as causally related to the study treatment. An event that 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 did not need to be reported as an SAE. Death due to progressive disease was recorded on a specific form in the CRF, but not as an SAE. | During the entire study (from Month 0 to Month 49) | 
| Number of Patients With Abnormal Hematological and Biochemical Parameters | Haematological and biochemical parameters assessed were Alanine aminotransferase, Aspartate aminotransferase, Alkaline Phosphatase, Bilirubin, Creatinine, Gamma-glutamyl transpeptidase, Hemoglobin, Hypercalcemia, Hyperkalemia, Hypernatremia, Hypoalbuminemia, Hypocalcemia, Hypokalemia, Hyponatremia, Leukocytes, Lymphopenia, Neutrophils, Platelets and Proteinuria. Parameters were assessed as per the Common Terminology Criteria for adverse events (CTCAE), where Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe but not life-threatening and Grade 4 = life-threatening. | During the entire study (Month 0 to Month 49) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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partial remission, WT1, adult, ASCI, complete remission with incomplete blood count recovery, post-induction therapy, tumor antigen, Acute Myeloid Leukemia, Immunotherapy