PF-05212384 (PKI-587) for t-AML/MDS or de Novo Relapsed or Refractory Acute Myeloid Leukemia (AML)

Study Overview
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Brief Summary
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Phase II open-label single-arm prospective multicentric clinical trial of PF-05212384 (PKI-587) delivered by intravenous route. A 2-stage Fleming design will be employed.

Detailed Description
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The treatment is administered in cycles of 28 days for a period of 4 cycles. Patients will be treated on a weekly basis continuously during 112 days or until progression. Blood tests (hemogram) are assessed weekly before each injection of PF-05212384 (PKI-587). Bone marrow aspiration (myelogram) is performed to evaluate the response before starting treatment and before the start of cycle 3 (after two cycles) and at the end of the study (after four cycles). Good responders who continue treatment after four cycles will be evaluated by bone marrow aspiration (myelogram) every two cycles and after the end of treatment

Official Title
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Phase II Evaluating the Efficacy of the Dual Inhibition of Phosphoinositide 3 Kinase (PI3K)/Akt /Mammalian Target Of Rapamycine (mTOR) Signaling Pathway by PF-05212384 (PKI-587) for Patients With Myeloid Neoplasm Secondary to Chemo-radiotherapy (t-AML/MDS) or de Novo Relapsed or Refractory AML.

Conditions
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Therapy-related Acute Myeloid Leukemia and Myelodysplastic Syndrome, Acute Myeloid Leukemia, in Relapse, de Novo Acute Myeloid Leukemia at Diagnostic

Intervention / Treatment
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* Drug: PF-05212384


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients belong to one of three categories: Myeloid neoplasm secondary to chemo-radiotherapy (t-AML/MDS) aged 60 and over with unfavorable cytogenetics (European Leukemia Network definition 2010), the first cancer must have been in remission for more than two years, except in situ carcinoma, basal cell carcinoma and squamous cell carcinoma Relapsed or refractory de novo AML aged 18 and over (multiple relapses allowed), regardless of the risk group, provided not being eligible for allogeneic bone marrow transplantation de novo AML at diagnosis, aged 60 and over and considered unfit to benefit from induction chemotherapy associated with aplasia (at the discretion of the investigator) Adequate glycemic balance defined by glycated hemoglobin ≤ 8% Females of childbearing potential (FCBP) should receive effective contraception: a negative pregnancy blood test is required within 2 weeks before starting experimental treatment. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2 Absence of severe or active infection Adequate systolic cardiac function : Left Ventricular Ejection Fraction (LVEF) ≥ 50% Adequate hepatic function: Aspartate Aminotransferase Test (AST) and Alanine Aminotransferase Test (ALT) ≤ 3 times the upper limit of normal (ULN), bilirubin ≤ 1.5 x ULN Adequate renal function: serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance > 60 ml/min. Signed informed consent Exclusion Criteria: Glucose intolerance or diabetes mellitus, treated or untreated First cancer in evolution(solid tumor or lymphoma) or in remission for less than two years, except in situ carcinoma, basal cell carcinoma and squamous cell carcinoma AML secondary to MDS or myeloproliferative syndrome (WHO 2008 definitions) Acute Promyelocytic Leukaemia (APL or AML French American British (FAB) classification 3) de novo or secondary to treatment (t-APL) de novo or secondary Core Binding Factor (CBF)/AML de novo or secondary Philadelphia Chromosome (Ph) 1 positive AML defined by the presence of a t(9.22) or a Breakpoint Cluster Region-Abelson Murine Leukemia Viral Oncogene Homolog (BCR-ABL) transcript Leukocytes above 30.000/mm3 (30 G/L) at enrollment Antileukemic treatment within 15 days before enrollment, with the exception of hydroxyurea Central nervous system leukemic involvement Pregnant or lactating women, or women of childbearing potential without effective contraception Prior history of allogeneic bone marrow transplantation Prior history of organ transplantation or other cause of severe or chronic immunodeficiency Human Seropositivity for Human Immunodeficiency Virus (HIV) or Human T-Lymphotropic Virus-1 (HTLV-1) viruses, active B or C hepatitis Inclusion in another experimental anti-cancer clinical trial* Patients unable to undergo medical monitoring for geographical, social or psychological issues Patient under measure of legal protection No social security For ethical reasons, the exclusion period before considering the possibility of participating in another clinical study with a new experimental molecule cannot be determined, yet each case will be discussed on an individual basis with the study coordinator.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-05212384<br>150 mg Intra-venous every week | Drug: PF-05212384<br>* PF-05212384 will be delivered by intra-venous route at a fixed dose of 150 mg per week. Each treatment cycle includes four weekly injections The treatment is administered in cycles of 28 days for a period of 4 cycles. Patients will be treated on a weekly basis continuously during 112 days or until progression.<br>* Other names: PKI-587;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the efficacy of PF-05212384 | The overall response rate will be assessed according to the International Working Group (IWG) AML and MDS criteria (by B.D. Cheson). | 4 months after treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerance and toxicity during treatment | Issued the Common Terminology Criteria for Adverse Events (CTCAE) version 4 National Cancer Institute (NCI) | 4 months | 
| Treatment compliance | Treatment compliance will be assessed by the ratio between the number of cycles administered on the expected number of cycles, and on time between treatment cycles | 4 months | 
| Progressive Free Survival (PFS) | Progressive Free Survival at one year from the date of inclusion to the date of progression of the disease or death | one year | 
| Overall survival | Overall Survival from the date of inclusion to the date of death | 48 months | 
| Evaluation of Quality of life | Quality of life (QLQ-C30) questionnaire according to European Organisation for Research and Treatment of Cancer (EORTC) | 4 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myeloid Leukemia, Myelodysplastic Syndrome, PIK/Akt/mTor