Maintenance Therapy With Ceplene® (Histamine) and IL-2 on Immune Response and MRD in Acute Myeloid Leukemia

November 27, 2017 updated by: Cytovia, Inc.

Open-Label, Multicenter, Effects of Remission Maintenance Therapy With Ceplene® , Given in Conjunction With Low-Dose Interleukin-2, on Immune Response and Minimal Residual Disease in Adult Patients With AML in First Complete Remission

Ceplene/IL-2 remission maintenance therapy has been shown to significantly prolong Leukemia Free Survival in patients with Acute Myeloid Leukemia (AML) in first complete remission. This is an international, multicenter, open-label study to evaluate the effects of remission maintenance therapy with Ceplene/IL-2 in adult patients with AML in CR1 on specific immune system cells (T and NK cells) and prospectively defined markers of immune response that are known to reflect T and NK cell ability to combat AML.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Outcome Measures:

Primary:

  1. To assess the quantitative and qualitative pharmacodynamic effects of Ceplene plus low-dose IL-2 (Ceplene/IL-2) by monitoring T and natural killer (NK) cell phenotypes and their functionality after the first and third treatment cycles in adult patients with acute myeloid leukemia (AML) in first complete remission (CR1).
  2. To evaluate minimal residual disease (MRD) in AML patients receiving Ceplene/IL-2.

Secondary:

To document, in adult AML patients in CR1 treated with Ceplene/IL-2:

  1. Leukemia-free survival (LFS) after a follow-up period of up to two years.
  2. The safety of Ceplene/IL-2 therapy.
  3. The potential relationship of Ceplene/IL-2 effects on T and NK cell phenotypes and their functionality to MRD.

Study Type

Interventional

Enrollment (Actual)

84

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Sweden
      • Gothenburg, Sweden
        • Sahlgrenska academy, University of Gothenburg

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

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:

  • AML patients in CR1 whose AML subtype has been well-characterized using conventional karyotyping and molecular genetic techniques (eg, RQ-PCR) at diagnosis. Patients may be considered eligible if they have not had this assessment performed at diagnosis provided that stored samples of diagnostic genetic material (DNA/RNA) from blood and BM are available that can be assayed for the presence of markers such as WT1 and/or AML-specific genetic markers.
  • Bone marrow examination confirming CR (defined as less than 5% blasts in a normocellular bone marrow).
  • Eighteen years of age or older.
  • Patients have received any form of induction and consolidation therapy as per standard practice at the institution, including autologous stem cell transplantation (ASCT).
  • Within 8 weeks following the date of the last dose of consolidation or conditioning chemotherapy for AML, or following ASCT.
  • Patients not undergoing consolidation therapy must have been in CR1 for at least one month prior to enrollment.
  • Platelet count recovered after chemotherapy to ≥75 x 109/L, and Partial Thromboplastin Time (PTT) within normal limits.
  • WBC ≥1.5 x 109/L and LFTs (to include SGPT [ALAT] or SGOT [AST] and bilirubin) should not exceed twice the upper limit of normal.
  • Serum creatinine less than or equal to 1.5 times the upper normal limit.
  • Able to function without significant decrease in daily activities (WHO Performance Status 0 - 1 or Karnofsky ≥70).
  • Life expectancy of more than three months and able to undergo routine outpatient evaluations for efficacy, safety, and/or compliance.
  • Women of childbearing potential must be practicing barrier or oral contraception, for the duration of the treatment, or documented as surgically sterile or one year post-menopausal.
  • If female, be non-nursing, non-pregnant and have a negative pregnancy test within two weeks of starting study drug.
  • The patient must be informed of the investigational nature of the study and written informed consent obtained.

Exclusion Criteria:

  • Patients who have undergone or are planned for allogeneic stem cell transplantation.
  • Patients with M3 as an AML subtype.
  • Class III or IV cardiac disease, hypotension or severe hypertension, vasomotor instability, serious or uncontrolled cardiac dysrhythmias (including ventricular arrhythmias) at any time, acute myocardial infarction within the past 12 months, active uncontrolled angina pectoris or symptomatic arteriosclerotic blood vessel disease.
  • Other active malignancies except in situ carcinoma of the cervix, localized squamous or basal cell carcinoma of the skin.
  • Serious concurrent or recent non-malignant medical conditions which, in the opinion of the Investigator, makes the patient unsuitable for participation in this study.
  • History of seizures, central nervous system disorders, stroke within the last 12 months, or psychiatric disability thought to be clinically significant in the opinion of the Investigator and adversely affecting compliance to protocol.
  • Patients unable to undergo repeat treatments, clinical evaluations and other diagnostic procedures required by the protocol.
  • Active autoimmune disease (including but not limited to systemic lupus, inflammatory bowel disease, and psoriasis).
  • Patients with active peptic or esophageal ulcer disease or with past peptic ulcer or esophageal disease with a history or bleeding.
  • Patients requiring active treatment for hypotension.
  • Medical, sociologic, or psychological impediment to probable compliance with the protocol.
  • Patients continuing systemic treatment with clonidine, steroids, and/or H2 receptor blocking agents.
  • Patients with a history of histamine hypersensitivity, severe allergies to food or contrast media requiring treatment within the last five years.
  • Patients unable to provide written consent.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: histamine dihydrochloride and IL-2
histamine and IL-2 subcutaneous injections
Drug: histamine dihydrochloride and IL-2
Ceplene 0.5 mg subcutaneously twice daily and IL-2 1 µg/kg [16,400 IU/kg] body weight twice daily for 10, 21 day cycles
Other Names:
  • Proleukin
  • IL-2
  • interleukin-2
  • histamine
  • Ceplene

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Minimal residual disease (MRD) in AML patients receiving Ceplene/IL-2
Time Frame: Comparison at baseline and various time points up to 2 years
A second primary objective of this study is to evaluate MRD in patients who are receiving remission maintenance therapy with Ceplene/IL-2. MRD will be evaluated using RQ-PCR for molecular detection of genetic markers of AML. Patients' MRD status will be quantified at the time of enrollment (baseline) and within ten days after completion of Cycles 3, 5, 6, 7, 9 and 10 of Ceplene/IL-2 therapy, corresponding to approximately every 3 months during this immunotherapy.
Comparison at baseline and various time points up to 2 years
Pharmacodynamic effects of Ceplene plus low dose IL-2 (Ceplene/IL-2) by monitoring T and NK cell phenotypes and their functionality after the first and third cycles of treatment
Time Frame: Baseline vs Cycle 1 and 3

The quantitative and qualitative pharmacodynamic effects of Ceplene/IL-2 on the immune responses of T and NK cells will be assessed as follows:

  1. Changes in T and NK cell phenotypes (CD56, CD3, CD4, CD8) in peripheral blood from Day 1 (baseline) to Day 21‡ of Cycle 1 and from Day 1 (pre-treatment Cycle 3) to Day 21‡ of Cycle 3.
  2. Changes in immune response markers (CD3, NKp46 [and other NCRs], CD25, CD69, and IFN-γ) in peripheral blood from Day 1 (baseline) to Day 21‡ of Cycle 1 and from Day 1 (pre-treatment Cycle 3) to Day 21‡ of Cycle 3
Baseline vs Cycle 1 and 3

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Duration of LFS
Time Frame: up to 2 years
Duration of LFS: LFS will be defined as the time from achieving CR after successful induction therapy until relapse of AML (defined as 5% or more blast cells in the bone marrow).
up to 2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Cytovia, Inc.

Collaborators

EpiCept Corporation

Investigators

  • Study Chair: Robin FOA, MD, PhD, Università degli Studi di Roma "La Sapienza" Dipartimento di Biotecnologie Cellulari ed Ematolgia
  • Principal Investigator: Mats L Brune, MD, PhD, Sahlgrenska Academy University of Gothenburg, Gothenburg, Sweden

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2009

Primary Completion (Actual)

June 1, 2014

Study Completion (Actual)

June 1, 2014

Study Registration Dates

First Submitted

May 2, 2011

First Submitted That Met QC Criteria

May 4, 2011

First Posted (Estimate)

May 5, 2011

Study Record Updates

Last Update Posted (Actual)

November 29, 2017

Last Update Submitted That Met QC Criteria

November 27, 2017

Last Verified

November 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • EPC2008-02

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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