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

Primary Purpose

Leukemia, Myelomonocytic, Chronic

Status
Unknown status
Phase
Phase 1
Locations
Sweden
Study Type
Interventional
Intervention
Cohort 1, Ceplene® and Proleukin®
Cohort 2, Ceplene® and Proleukin®
Cohort 3, Ceplene® and Proleukin®
Sponsored by
Vastra Gotaland Region
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Leukemia, Myelomonocytic, Chronic focused on measuring CMML, Ceplene, Interleukin-2

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Sahlgrenska University HospitalRecruiting
  • Karolinska University Hospital, HuddingeRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Cohort 1: Ceplene® and Proleukin®

Cohort 2: Ceplene® and Proleukin®

Cohort 3: Ceplene® and Proleukin®

Arm Description

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.

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).

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.

Outcomes

Primary Outcome Measures

Adverse events as defined by CTCAE v4.03.

Secondary Outcome Measures

Disease progression according to IWG criteria for MDS/MPN
Percentage of blasts in peripheral blood
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
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
Percentage of circulating NK cells i peripheral blood
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
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
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.

Full Information

First Posted
January 24, 2017
Last Updated
December 18, 2017
Sponsor
Vastra Gotaland Region
Collaborators
Sahlgrenska University Hospital, Sweden, Karolinska University Hospital, Nordic MDS Group
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1. Study Identification

Unique Protocol Identification Number
NCT03040401
Brief Title
A Study of HDC/IL-2 Treatment in Chronic Myelomonocytic Leukemia (CMML)
Official Title
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)
Study Type
Interventional

2. Study Status

Record Verification Date
December 2017
Overall Recruitment Status
Unknown status
Study Start Date
February 15, 2017 (Actual)
Primary Completion Date
December 15, 2018 (Anticipated)
Study Completion Date
December 15, 2019 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Vastra Gotaland Region
Collaborators
Sahlgrenska University Hospital, Sweden, Karolinska University Hospital, Nordic MDS Group

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leukemia, Myelomonocytic, Chronic
Keywords
CMML, Ceplene, Interleukin-2

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
15 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Cohort 1: Ceplene® and Proleukin®
Arm Type
Experimental
Arm Description
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.
Arm Title
Cohort 2: Ceplene® and Proleukin®
Arm Type
Experimental
Arm Description
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).
Arm Title
Cohort 3: Ceplene® and Proleukin®
Arm Type
Experimental
Arm Description
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 Type
Drug
Intervention Name(s)
Cohort 1, Ceplene® and Proleukin®
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Cohort 2, Ceplene® and Proleukin®
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Cohort 3, Ceplene® and Proleukin®
Intervention Description
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.
Primary Outcome Measure Information:
Title
Adverse events as defined by CTCAE v4.03.
Time Frame
3 weeks after last treatment cycle
Secondary Outcome Measure Information:
Title
Disease progression according to IWG criteria for MDS/MPN
Time Frame
3 weeks after last treatment cycle
Title
Percentage of blasts in peripheral blood
Description
Percentage of blasts (CD34+ cells and promonocytes) will be assessed by flow cytometry. End-of-treatment percentage will be compared to values pre-study.
Time Frame
3 weeks after last treatment cycle
Title
Percentage of monocytes in peripheral blood
Description
Percentage of CD14+ monocytes will be assessed by flow cytometry. End-of-treatment percentage will be compared to values pre-study.
Time Frame
3 weeks after last treatment cycle
Title
Number of treated patients that transform to AML
Time Frame
2 years after last treatment cycle
Title
Percentage of circulating NK cells i peripheral blood
Description
Percentage of NK cells in peripheral blood will be assessed by flow cytometry. End-of-treatment percentage will be compared to values pre-study.
Time Frame
3 weeks after last treatment cycle
Title
Percentage of circulating CD4+ T cells i peripheral blood
Description
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.
Time Frame
3 weeks after last treatment cycle
Title
Percentage of circulating CD8+ T cells i peripheral blood
Description
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.
Time Frame
3 weeks after last treatment cycle
Title
Proportion of participants with overall survival at 2 years.
Time Frame
2 years after last treatment cycle

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Lars Möllgård, PhD, MD
Phone
+46 (0)31 3427344
Email
lars.mollgard@vgregion.se
First Name & Middle Initial & Last Name or Official Title & Degree
Johan Aurelius, PhD
Phone
+46 (0)31 7866677
Email
johan.aurelius@gu.se
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lars Möllgård, PhD, MD
Organizational Affiliation
Sahlgrenska University Hospital, Sweden
Official's Role
Principal Investigator
Facility Information:
Facility Name
Sahlgrenska University Hospital
City
Gothenburg
Country
Sweden
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lars Möllgård, PhD, MD
Phone
+46 (0)31 3427344
Email
lars.mollgard@vgregion.se
First Name & Middle Initial & Last Name & Degree
Olle Werlenius, PhD, MD
Email
olle.werlenius@vgregion.se
Facility Name
Karolinska University Hospital, Huddinge
City
Stockholm
Country
Sweden
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Per Broliden, MD, PhD

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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