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

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.

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.

Study Overview

• Status: Terminated
• Conditions: Acute Myeloid Leukemia, in Relapse; Therapy-related Acute Myeloid Leukemia and Myelodysplastic Syndrome; de Novo Acute Myeloid Leukemia at Diagnostic
• Intervention / Treatment: Drug: PF-05212384

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

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Ile De France
    • Paris, Ile De France, France, 75475
      • Hôpital Saint-Louis
    • Paris, Ile De France, France, 75679
      • Hopital Cochin
    • Saint-Cloud, Ile De France, France, 92210
      • Institut Curie - Hôpital René Huguenin
  • Midi-Pyrénées
    • Toulouse, Midi-Pyrénées, France, 31059
      • CHU de Toulouse
  • Paca
    • Marseille, Paca, France, 13009
      • Institut Paoli Calmette

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PF-05212384; 150 mg Intra-venous every week	Drug: PF-05212384; 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.; Other Names: PKI-587

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Institut Curie
• Collaborators: National Cancer Institute, France; Fondation ARC
• Investigators: Principal Investigator: Jacques Vargaftig, MD, Institut Curie - Hôpital René Huguenin

Study record dates

Study Major Dates

• Study Start (Actual): August 31, 2015
• Primary Completion (Actual): May 10, 2017
• Study Completion (Actual): April 23, 2018

Study Registration Dates

• First Submitted: May 6, 2015
• First Submitted That Met QC Criteria: May 6, 2015
• First Posted (Estimate): May 8, 2015

Study Record Updates

• Last Update Posted (Actual): February 6, 2019
• Last Update Submitted That Met QC Criteria: February 4, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: Acute Myeloid Leukemia; Myelodysplastic Syndrome; PIK/Akt/mTor
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Gedatolisib
• Other Study ID Numbers: IC 2014-10 LAM-PIK