Clinical trial NCT02438761: PF-05212384 (PKI-587) for t-AML/MDS or de Novo Relapsed or Refractory Acute Myeloid Leukemia (AML)
Official title: 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.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Therapy-related Acute Myeloid Leukemia and Myelodysplastic Syndrome
Acute Myeloid Leukemia, in Relapse
de Novo Acute Myeloid Leukemia at Diagnostic
Keywords: Acute Myeloid Leukemia
Myelodysplastic Syndrome
PIK/Akt/mTor
Lead sponsor: Institut Curie
Sponsor class: OTHER
Collaborators: name: Fondation ARC
name: National Cancer Institute, France
First posted: 2015-05-08
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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

Eligibility criteria: Inclusion Criteria:

1. 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)
2. Adequate glycemic balance defined by glycated hemoglobin ≤ 8%
3. Females of childbearing potential (FCBP) should receive effective contraception: a negative pregnancy blood test is required within 2 weeks before starting experimental treatment.
4. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2
5. Absence of severe or active infection
6. Adequate systolic cardiac function : Left Ventricular Ejection Fraction (LVEF) ≥ 50%
7. 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
8. Adequate renal function: serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance \> 60 ml/min.
9. Signed informed consent

Exclusion Criteria:

1. Glucose intolerance or diabetes mellitus, treated or untreated
2. 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
3. AML secondary to MDS or myeloproliferative syndrome (WHO 2008 definitions)
4. Acute Promyelocytic Leukaemia (APL or AML French American British (FAB) classification 3) de novo or secondary to treatment (t-APL)
5. de novo or secondary Core Binding Factor (CBF)/AML
6. 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
7. Leukocytes above 30.000/mm3 (30 G/L) at enrollment
8. Antileukemic treatment within 15 days before enrollment, with the exception of hydroxyurea
9. Central nervous system leukemic involvement
10. Pregnant or lactating women, or women of childbearing potential without effective contraception
11. Prior history of allogeneic bone marrow transplantation
12. Prior history of organ transplantation or other cause of severe or chronic immunodeficiency Human
13. Seropositivity for Human Immunodeficiency Virus (HIV) or Human T-Lymphotropic Virus-1 (HTLV-1) viruses, active B or C hepatitis
14. Inclusion in another experimental anti-cancer clinical trial\*
15. Patients unable to undergo medical monitoring for geographical, social or psychological issues
16. Patient under measure of legal protection
17. 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.

Primary outcomes:
measure: To evaluate the efficacy of PF-05212384
timeFrame: 4 months after treatment
Secondary outcomes:
measure: Tolerance and toxicity during treatment
timeFrame: 4 months
measure: Treatment compliance
timeFrame: 4 months
measure: Progressive Free Survival (PFS)
timeFrame: one year
measure: Overall survival
timeFrame: 48 months
measure: Evaluation of Quality of life
timeFrame: 4 months
Other outcomes:
Locations:
city: Paris
country: France
facility: Hôpital Saint-Louis
state: Ile De France
city: Paris
country: France
facility: Hôpital Cochin
state: Ile De France
city: Saint-Cloud
country: France
facility: Institut Curie - Hôpital René Huguenin
state: Ile De France
city: Toulouse
country: France
facility: CHU de Toulouse
state: Midi-Pyrénées
city: Marseille
country: France
facility: Institut Paoli Calmette
state: Paca
Study officials:
affiliation: Institut Curie - Hôpital René Huguenin
name: Jacques Vargaftig, MD
role: PRINCIPAL_INVESTIGATOR
References: