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A Study of HDC/IL-2 Treatment in Chronic Myelomonocytic Leukemia (CMML)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03040401
Recruitment Status : Recruiting
First Posted : February 2, 2017
Last Update Posted : December 19, 2017
Sponsor:
Collaborators:
Sahlgrenska University Hospital, Sweden
Karolinska University Hospital
Nordic MDS Group
Information provided by (Responsible Party):
Vastra Gotaland Region

Tracking Information
First Submitted Date  ICMJE January 24, 2017
First Posted Date  ICMJE February 2, 2017
Last Update Posted Date December 19, 2017
Actual Study Start Date  ICMJE February 15, 2017
Estimated Primary Completion Date December 15, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 31, 2017)
Adverse events as defined by CTCAE v4.03. [ Time Frame: 3 weeks after last treatment cycle ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03040401 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 31, 2017)
  • Disease progression according to IWG criteria for MDS/MPN [ Time Frame: 3 weeks after last treatment cycle ]
  • Percentage of blasts in peripheral blood [ Time Frame: 3 weeks after last treatment cycle ]
    Percentage of blasts (CD34+ cells and promonocytes) will be assessed by flow cytometry. End-of-treatment percentage will be compared to values pre-study.
  • Percentage of monocytes in peripheral blood [ Time Frame: 3 weeks after last treatment cycle ]
    Percentage of CD14+ monocytes will be assessed by flow cytometry. End-of-treatment percentage will be compared to values pre-study.
  • Number of treated patients that transform to AML [ Time Frame: 2 years after last treatment cycle ]
  • Percentage of circulating NK cells i peripheral blood [ Time Frame: 3 weeks after last treatment cycle ]
    Percentage of NK cells in peripheral blood will be assessed by flow cytometry. End-of-treatment percentage will be compared to values pre-study.
  • Percentage of circulating CD4+ T cells i peripheral blood [ Time Frame: 3 weeks after last treatment cycle ]
    Percentage of CD4+ T cells in peripheral blood will be assessed by flow cytometry. End-of-treatment percentage will be compared to values pre-study.
  • Percentage of circulating CD8+ T cells i peripheral blood [ Time Frame: 3 weeks after last treatment cycle ]
    Percentage of CD8+ T cells in peripheral blood will be assessed by flow cytometry. End-of-treatment percentage will be compared to values pre-study.
  • Proportion of participants with overall survival at 2 years. [ Time Frame: 2 years after last treatment cycle ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of HDC/IL-2 Treatment in Chronic Myelomonocytic Leukemia (CMML)
Official Title  ICMJE A Phase I/II, Open-Label, Multicenter Study of the Safety, Efficacy and Immune Response of Histamine Dihydrochloride and Low-dose Interleukin-2 in Chronic Myelomonocytic Leukemia (CMML)
Brief Summary

Enrolled subjects will receive histamine dihydrochloride (HDC; Ceplene®) and/or IL-2 (Proleukin®) subcutaneously (s.c.) twice daily (BID) in 3-week periods followed by 3- or 6 week rest periods.

All subjects will be assigned to one of three consecutive cohorts, each comprising five patients.

Cohort 1 will receive HDC without IL-2 for the first treatment cycle, to enable the assessment of short-term impact of HDC alone on clonal and immunological markers. For all remaining cycles the combination of HDC and IL-2 will be given.

Cohort 2 will receive the combination of Ceplene and Proleukin in all cycles. After all patients in cohorts 1 and 2 have completed 4 treatment cycles, immunological and clinical response and toxicity will be evaluated. On the basis of the results for the first 4 cycles of cohorts 1 and 2, a third cohort of 5 patients will be enrolled receiving either the combination of HDC/IL-2 or HDC alone.

In case of a beneficial response* after 4 cycles, treatment may be continued to a total of 10 cycles. Treatment cycles 5-10 will comprise 3 weeks of treatment and 6-week rest periods.

IL-2 will be administered s.c., 1 µg/kg (=16400 IU/kg) body weight twice daily (BID) during treatment periods. Ceplene® will be administered s.c. 0.5 mg BID after IL-2. The patient or a family member/significant other will be instructed to administer injections of both study drugs to allow safe treatment at home.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Leukemia, Myelomonocytic, Chronic
Intervention  ICMJE
  • Drug: Cohort 1, Ceplene® and Proleukin®

    Patients in Cohort 1 will be administered only Ceplene® during the first treatment cycles and Ceplene® in combination with Proleukin® during treatment cycles 2-4.

    IL-2 will be administered s.c., 1 µg/kg (=16400 IU/kg) body weight twice daily (BID) during treatment periods. Ceplene® will be administered s.c. 0.5 mg BID after IL-2.

  • Drug: Cohort 2, Ceplene® and Proleukin®

    Patients in Cohort 2 will be administered Ceplene® in combination with Proleukin® during all treatment cycles 1-4.

    IL-2 will be administered s.c., 1 µg/kg (=16400 IU/kg) body weight twice daily (BID) during treatment periods. Ceplene® will be administered s.c. 0.5 mg BID after IL-2.

  • Drug: Cohort 3, Ceplene® and Proleukin®

    Cohort 3 will receive either only Ceplene® during treatment cycles 1-4 or Ceplene® in combination with Proleukin® during treatment cycles 1-4. Treatment will be decided by the study committee based on the safety profile of treatment administered to cohort 1 and 2.

    IL-2 will be administered s.c., 1 µg/kg (=16400 IU/kg) body weight twice daily (BID) during treatment periods. Ceplene® will be administered s.c. 0.5 mg BID after IL-2.

Study Arms  ICMJE
  • Experimental: Cohort 1: Ceplene® and Proleukin®

    Enrolled subjects will receive histamine dihydrochloride (HDC; Ceplene®) and IL-2 (Proleukin®) subcutaneously (s.c.) twice daily (BID) in 3-week periods followed by 3 week rest periods for a total of 4 treatment cycles.

    IL-2 will be administered s.c., 1 µg/kg (=16400 IU/kg) body weight twice daily (BID) during treatment periods. Ceplene® will be administered s.c. 0.5 mg BID after IL-2 injections.

    Cohort 1 will receive only Ceplene® during the first treatment cycles and Ceplene® in combination with Proleukin® during treatment cycles 2-4.

    Intervention: Drug: Cohort 1, Ceplene® and Proleukin®
  • Experimental: Cohort 2: Ceplene® and Proleukin®

    Enrolled subjects will receive histamine dihydrochloride (HDC; Ceplene®) and IL-2 (Proleukin®) subcutaneously (s.c.) twice daily (BID) in 3-week periods followed by 3 week rest periods for a total of 4 treatment cycles.

    IL-2 will be administered s.c., 1 µg/kg (=16400 IU/kg) body weight twice daily (BID) during treatment periods. Ceplene® will be administered s.c. 0.5 mg BID after IL-2 injections.

    Cohort 2 will receive Ceplene® in combination with Proleukin® during all treatment cycles (1-4).

    Intervention: Drug: Cohort 2, Ceplene® and Proleukin®
  • Experimental: Cohort 3: Ceplene® and Proleukin®

    Enrolled subjects will receive histamine dihydrochloride (HDC; Ceplene®) and IL-2 (Proleukin®) subcutaneously (s.c.) twice daily (BID) in 3-week periods followed by 3 week rest periods for a total of 4 treatment cycles.

    IL-2 will be administered s.c., 1 µg/kg (=16400 IU/kg) body weight twice daily (BID) during treatment periods. Ceplene® will be administered s.c. 0.5 mg BID after IL-2 injections.

    Cohort 3 will receive either only Ceplene® during treatment cycles 1-4 or Ceplene® in combination with Proleukin® during treatment cycles 1-4. Treatment will be decided by the study committee based on the safety profile of treatment administered to cohort 1 and 2.

    Intervention: Drug: Cohort 3, Ceplene® and Proleukin®
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 31, 2017)
15
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 15, 2019
Estimated Primary Completion Date December 15, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • ≥18 years of age at the time of signing the informed consent form.
  • CMML-1 with indication for treatment according to NMDSG guidelines*.
  • Life expectancy of more than three months and ability to undergo routine outpatient evaluations for efficacy, safety, and compliance.
  • The patient must be informed of the investigational nature of the study and written informed consent obtained and signed.

    • including, but not limited to increasing WBC, transfusion dependence, B-symptoms, splenomegaly.

Exclusion Criteria:

  • Acute myeloid leukemia.
  • CMML-2 according to WHO criteria.
  • Systemic mastocytosis.
  • Previous or intended allogeneic stem cell transplantation.
  • Concomitant or intended cytostatic or cytoreductive therapy other than hydroxyurea (HU) *.
  • ECOG performance status ≥3.
  • Platelet count (TPK) <30x109/L
  • NYHA 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, 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.
  • Serum creatinine > 1.5 times the upper normal limit.
  • Serum aminotransferase (AST), alanine transaminase (ALT) and bilirubin >2.0 times the upper normal limit
  • 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.
  • 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.
  • Pregnancy. Women of childbearing potential (WCBP) and males having intercourse with WCBP must agree to comply with using an effective contraceptive method for the duration of the treatment (WCBP is a sexually mature woman who is not surgically sterile or has not been naturally postmenopausal for at least 12 consecutive months).
  • Nursing

    • Note that treatment with HU is allowed if treatment has been ongoing for at least 3 months prior to enrollment. The use of HU is also allowed to control myeloproliferation after starting study treatment, preferably during resting periods.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Lars Möllgård, PhD, MD +46 (0)31 3427344 lars.mollgard@vgregion.se
Contact: Johan Aurelius, PhD +46 (0)31 7866677 johan.aurelius@gu.se
Listed Location Countries  ICMJE Sweden
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03040401
Other Study ID Numbers  ICMJE NMDSG14A
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Vastra Gotaland Region
Study Sponsor  ICMJE Vastra Gotaland Region
Collaborators  ICMJE
  • Sahlgrenska University Hospital, Sweden
  • Karolinska University Hospital
  • Nordic MDS Group
Investigators  ICMJE
Principal Investigator: Lars Möllgård, PhD, MD Sahlgrenska University Hospital, Sweden
PRS Account Vastra Gotaland Region
Verification Date December 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP