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Luspatercept With or Without Hydroxyurea for the Treatment of Myelodysplastic/Myeloproliferative Neoplasms With Ring Sideroblasts and Thrombocytosis or Unclassifiable With Ring Sideroblasts

Primary Purpose

Myelodysplastic/Myeloproliferative Neoplasm With Ring Sideroblasts and Thrombocytosis, Not Otherwise Specified, Myelodysplastic/Myeloproliferative Neoplasm, Not Otherwise Specified

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Biospecimen Collection
Bone Marrow Aspiration
Bone Marrow Biopsy
Hydroxyurea
Luspatercept
Questionnaire Administration
Sponsored by
Mayo Clinic
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Myelodysplastic/Myeloproliferative Neoplasm With Ring Sideroblasts and Thrombocytosis, Not Otherwise Specified

Eligibility Criteria

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

Criteria:

  • Refractory or unlikely to respond (erythropoietin [EPO] >= 200 U/L) or documented intolerance to erythropoiesis stimulating agent (ESA). Patients should have either a documented intolerance or contraindication to ESA or a lack of response after ESA therapy trial of at least four weeks; and ESA therapy should be stopped four weeks prior to trial enrollment

Inclusion Criteria:

  • Age >= 18 years
  • Patients with a World Health Organization(WHO)-defined diagnosis of MDS/MPN-RS-T or MDS/MPN-U with >= 15% RS
  • Prior treatment with lenalidomide, hypomethylating agents, immunosuppressive therapy or investigational agent is allowed as long as patients have not received luspatercept-aamt or sotatercept. If there is prior history of investigational agent, there should be an interval equivalent to at least four elimination half-lives of the agent prior to enrollment. Note: For patients who have received prior lenalidomide, hypomethylating agents, or immunosuppressive therapy, there must be >= 6 weeks since the last dose before luspatercept-aamt treatment is started
  • Eastern Cooperative Oncology Group (ECOG) performance score of 0, 1 or 2
  • Requirement of red blood cell transfusions (>= 2 unit =< 8-weeks prior to registration) OR symptomatic anemia with hemoglobin < 9.5 g/dL OR hematocrit < 30% (as long as there is documentation of adequate iron stores (ferritin > 50 mg/L) =< 5 weeks prior to registration). Symptomatic anemia is defined as fatigue with or without exertion, shortness of breath with or without exertion, or decrease in exercise tolerance
  • Hemoglobin =< 9.5 g/dL (obtained =< 14 days prior to registration)
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 14 days prior to registration)
  • Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 3 x ULN (=< 5 x ULN for patients with liver involvement) (obtained =< 14 days prior to registration)
  • Calculated creatinine clearance >= 30 ml/min using the Cockcroft-Gault (obtained =< 14 days prior to registration)
  • Females of childbearing potential (FCBP) defined as a sexually mature woman who:

    • Has achieved menarche at some point
    • Has not undergone a hysterectomy or bilateral oophorectomy, or
    • Has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months) and must:

      • Must have two negative urine or serum pregnancy tests as verified by the investigator prior to starting study therapy. A negative pregnancy test must be done =< 7 days prior to registration. Patient must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy. This applies even if the subject practices true abstinence from heterosexual contact
      • Either commit to true abstinence*from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with highly effective, contraception without interruption during the study therapy (including dose interruptions), and for 84 days after discontinuation of study therapy

        • True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception)
  • Male participants must:

    • Practice true abstinence (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 84 days following investigational product discontinuation even if he has undergone a successful vasectomy

      • True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception)
  • Provide written informed consent
  • Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study)
  • Willingness to provide mandatory blood specimens for correlative research

Exclusion Criteria:

  • Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects:

    • Pregnant persons
    • Nursing persons
    • Persons of childbearing potential who are unwilling to employ highly effective contraception
  • Any of the following prior therapies:

    • Surgery =< 3 weeks prior to registration
    • Chemotherapy or other agents =< 2 weeks prior to registration
  • Uncontrolled intercurrent non-cardiac illness including, but not limited to:

    • Ongoing or active infection
    • Uncontrolled hypertension (defined as systolic blood pressure >= 140 mmHg or diagnostic blood pressure >= 90 mmHg despite use of >= 3 anti-hypertensive drugs at optimal doses)
    • Psychiatric illness/social situations
    • Dyspnea at rest due to complications of advanced malignancy or other disease that requires continuous oxygen therapy
    • Clinically significant (symptomatic) anemia either due to nutritional deficiencies or iron, vitamin B12, folate or gastrointestinal (GI) bleeding
    • Any other conditions that would limit compliance with study requirements
  • Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy

    • NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state (CD4 =< 200 x 10^6/L), are eligible for this trial
  • Receiving any other drug (except hydroxyurea) or investigational agent which would be considered as a treatment for the primary disease, that is, MDS/MPN-RS-T or MDS/MPN-U with RS =< 2 weeks prior to registration
  • Other active malignancy =< 3 years prior to registration. Patients on hormonal therapy for treated breast or prostate cancer are permitted if they meet other eligibility criteria

    • EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix. NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment (luteinizing hormone-releasing hormone (LHRH) agonists for prostate cancer, and treatment with bisphosphonates and receptor activator of nuclear factor kappa-B ligand [RANKL] inhibitors) for their cancer
  • History of myocardial infarction, stroke, embolism, deep vein or arterial thrombosis =< 6 months prior to registration, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias

Sites / Locations

  • Mayo Clinic Hospital in ArizonaRecruiting
  • Mayo Clinic in FloridaRecruiting
  • Mayo Clinic in RochesterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Cohort A (luspatercept)

Cohort A (luspatercept, hydroxyurea)

Arm Description

Patients receive luspatercept SC on day 1. Cycles repeat every 21 days for 6 months in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, bone marrow biopsy and aspirate at baseline and on study.

Patients receive luspatercept SC on day 1 and hydroxyurea PO on days 1-21. Cycles repeat every 21 days for 6 months in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, bone marrow biopsy and aspirate at baseline and on study.

Outcomes

Primary Outcome Measures

Erythroid response rate
Defined as the proportion of patients who achieve an erythroid response out of the total number of evaluable patients (i.e. eligible patients who received at least one dose of treatment on study).

Secondary Outcome Measures

Incidence of adverse events (AEs)
AEs as well as toxicities (AEs felt to be at least possibly related to study treatment) will be tabulated and evaluated in each cohort along with tabulation of specific types of AEs. Time to end of active treatment will be evaluated as the time from treatment start date to the time patients go off treatment for any reason. This will be summarized within and across cohorts using the methods of Kaplan and Meier, and the reasons patients discontinue treatment will be summarized.
Duration of response
Will be evaluated and characterized within each cohort using the methods of Kaplan and Meier.
Time to leukemic transformation
Will be evaluated and characterized within each cohort using the methods of Kaplan and Meier.
Leukemia-free survival
Will be evaluated and characterized within each cohort using the methods of Kaplan and Meier.
Overall survival
Will be evaluated and characterized within each cohort using the methods of Kaplan and Meier.

Full Information

First Posted
August 9, 2021
Last Updated
August 3, 2023
Sponsor
Mayo Clinic
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1. Study Identification

Unique Protocol Identification Number
NCT05005182
Brief Title
Luspatercept With or Without Hydroxyurea for the Treatment of Myelodysplastic/Myeloproliferative Neoplasms With Ring Sideroblasts and Thrombocytosis or Unclassifiable With Ring Sideroblasts
Official Title
Phase II Study to Determine the Efficacy and Safety of Luspatercept (ACE-536) in Patients With Myelodysplastic/Myeloproliferative Neoplasms With Ring Sideroblasts and Thrombocytosis (MDS/MPN-RS-T) and Myelodysplastic/Myeloproliferative Neoplasms, Unclassifiable With Ring Sideroblasts (MDS/MPN-U With RS)
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
February 20, 2023 (Actual)
Primary Completion Date
May 1, 2024 (Anticipated)
Study Completion Date
May 1, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Mayo Clinic

4. Oversight

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

5. Study Description

Brief Summary
This phase II trial studies the effects of luspatercept with or without hydroxyurea in treating patients with myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis or unclassifiable with ring sideroblasts. Biological therapies, such as luspatercept, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Hydroxyurea may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving luspatercept with or without hydroxyurea may help doctors determine what doses of the combination is safe for patients to take and how the disease responds to the treatment.
Detailed Description
PRIMARY OBJECTIVE: I. To document the erythroid response rate assessed as per the 2015 International Working Group (IWG) myelodysplastic (MDS)/myeloproliferative neoplasms (MPN) response criteria. SECONDARY OBJECTIVES: I. To document response duration, time to acute myeloid leukemia (AML) transformation, AML-free survival (LFS) and overall survival (OS) in patients with MDS/MPN-with ring sideroblasts (RS) and thrombocytosis (T) and MDS/MPN-unclassifiable (U)U with RS. II. To document safety of luspatercept (luspatercept-aamt) in patients with MDS/MPN-RS-T and MDS/MPN-U with RS. EXPLORATORY OBJECTIVE: I. To assess overall health-related quality of life as measured by Hematological Malignancy Specific Patient-Reported Outcome Measure (HM-PRO). CORRELATIVE RESEARCH OBJECTIVE: I: To find an effective biomarker of response to luspatercept-aamt. OUTLINE: Patients are assigned to 1 of 2 cohorts. COHORT A: Patients receive luspatercept subcutaneously (SC) on day 1. Cycles repeat every 21 days for 6 months in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, bone marrow biopsy and aspirate at baseline and on study. COHORT B: Patients receive luspatercept SC on day 1 and hydroxyurea orally (PO) on days 1-21. Cycles repeat every 21 days for 6 months in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, bone marrow biopsy and aspirate at baseline and on study. After completion of study treatment, patients are followed up every 3 months.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myelodysplastic/Myeloproliferative Neoplasm With Ring Sideroblasts and Thrombocytosis, Not Otherwise Specified, Myelodysplastic/Myeloproliferative Neoplasm, Not Otherwise Specified

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Cohort A (luspatercept)
Arm Type
Experimental
Arm Description
Patients receive luspatercept SC on day 1. Cycles repeat every 21 days for 6 months in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, bone marrow biopsy and aspirate at baseline and on study.
Arm Title
Cohort A (luspatercept, hydroxyurea)
Arm Type
Experimental
Arm Description
Patients receive luspatercept SC on day 1 and hydroxyurea PO on days 1-21. Cycles repeat every 21 days for 6 months in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, bone marrow biopsy and aspirate at baseline and on study.
Intervention Type
Procedure
Intervention Name(s)
Biospecimen Collection
Other Intervention Name(s)
Biological Sample Collection, Biospecimen Collected, Specimen Collection
Intervention Description
Undergo blood sample collection
Intervention Type
Procedure
Intervention Name(s)
Bone Marrow Aspiration
Intervention Description
Undergo bone marrow biopsy and aspirate
Intervention Type
Procedure
Intervention Name(s)
Bone Marrow Biopsy
Other Intervention Name(s)
Biopsy of Bone Marrow, Biopsy, Bone Marrow
Intervention Description
Undergo bone marrow biopsy and aspirate
Intervention Type
Drug
Intervention Name(s)
Hydroxyurea
Other Intervention Name(s)
Droxia, Hydrea, Hydroxycarbamide, Litalir, Onco-Carbide, Oncocarbide, Oxeron, SQ 1089, SQ-1089, Syrea, WR 83799
Intervention Description
Given PO
Intervention Type
Biological
Intervention Name(s)
Luspatercept
Other Intervention Name(s)
ACE-536, Luspatercept-aamt, Reblozyl
Intervention Description
Given SC
Intervention Type
Other
Intervention Name(s)
Questionnaire Administration
Intervention Description
Ancillary studies
Primary Outcome Measure Information:
Title
Erythroid response rate
Description
Defined as the proportion of patients who achieve an erythroid response out of the total number of evaluable patients (i.e. eligible patients who received at least one dose of treatment on study).
Time Frame
Up to 8 weeks
Secondary Outcome Measure Information:
Title
Incidence of adverse events (AEs)
Description
AEs as well as toxicities (AEs felt to be at least possibly related to study treatment) will be tabulated and evaluated in each cohort along with tabulation of specific types of AEs. Time to end of active treatment will be evaluated as the time from treatment start date to the time patients go off treatment for any reason. This will be summarized within and across cohorts using the methods of Kaplan and Meier, and the reasons patients discontinue treatment will be summarized.
Time Frame
Up to 6 months
Title
Duration of response
Description
Will be evaluated and characterized within each cohort using the methods of Kaplan and Meier.
Time Frame
From first documented erythroid response to the time of progression and/or relapse, assessed up to 6 months
Title
Time to leukemic transformation
Description
Will be evaluated and characterized within each cohort using the methods of Kaplan and Meier.
Time Frame
From study entry to the time of transformation to acute myeloid leukemia (AML), assessed up to 6 months
Title
Leukemia-free survival
Description
Will be evaluated and characterized within each cohort using the methods of Kaplan and Meier.
Time Frame
From time of treatment to progression to acute myeloid leukemia or death from any cause, assessed up to 6 months
Title
Overall survival
Description
Will be evaluated and characterized within each cohort using the methods of Kaplan and Meier.
Time Frame
From study entry to the time of death due to any cause, assessed up to 6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age >= 18 years Patients with a World Health Organization(WHO)-defined diagnosis of MDS/MPN-RS-T or MDS/MPN-U with >= 15% RS Prior treatment with lenalidomide, hypomethylating agents, immunosuppressive therapy, erythropoietin stimulating agents (ESA) or investigational agent is allowed as long as patients have not received luspatercept-aamt or sotatercept. If there is prior history of investigational agent, there should be an interval equivalent to at least four elimination half-lives of the agent prior to enrollment. Note: For patients who have received prior lenalidomide, hypomethylating agents, or immunosuppressive therapy, there must be >= 6 weeks since the last dose before luspatercept-aamt treatment is started Eastern Cooperative Oncology Group (ECOG) performance score of 0, 1 or 2 Requirement of red blood cell transfusions (>= 2 unit =< 8-weeks prior to registration) OR symptomatic anemia with hemoglobin < 9.5 g/dL OR hematocrit < 30% (as long as there is documentation of adequate iron stores (ferritin > 50 mg/L) =< 5 weeks prior to registration). Symptomatic anemia is defined as fatigue with or without exertion, shortness of breath with or without exertion, or decrease in exercise tolerance Hemoglobin =< 9.5 g/dL (obtained =< 14 days prior to registration) Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 14 days prior to registration) Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 3 x ULN (=< 5 x ULN for patients with liver involvement) (obtained =< 14 days prior to registration) Calculated creatinine clearance >= 30 ml/min using the Cockcroft-Gault (obtained =< 14 days prior to registration) Females of childbearing potential (FCBP) defined as a sexually mature woman who: Has achieved menarche at some point Has not undergone a hysterectomy or bilateral oophorectomy, or Has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months) and must: Must have two negative urine or serum pregnancy tests as verified by the investigator prior to starting study therapy. A negative pregnancy test must be done =< 7 days prior to registration. Patient must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy. This applies even if the subject practices true abstinence from heterosexual contact Either commit to true abstinence*from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with highly effective, contraception without interruption during the study therapy (including dose interruptions), and for 84 days after discontinuation of study therapy True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception) Male participants must: Practice true abstinence (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 84 days following investigational product discontinuation even if he has undergone a successful vasectomy True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception) Provide written informed consent Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study) Willingness to provide mandatory blood specimens for correlative research Exclusion Criteria: Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects: Pregnant persons Nursing persons Persons of childbearing potential who are unwilling to employ highly effective contraception Any of the following prior therapies: Surgery =< 3 weeks prior to registration Chemotherapy or other agents =< 2 weeks prior to registration Uncontrolled intercurrent non-cardiac illness including, but not limited to: Ongoing or active infection Uncontrolled hypertension (defined as systolic blood pressure >= 140 mmHg or diagnostic blood pressure >= 90 mmHg despite use of >= 3 anti-hypertensive drugs at optimal doses) Psychiatric illness/social situations Dyspnea at rest due to complications of advanced malignancy or other disease that requires continuous oxygen therapy Clinically significant (symptomatic) anemia either due to nutritional deficiencies or iron, vitamin B12, folate or gastrointestinal (GI) bleeding Any other conditions that would limit compliance with study requirements Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state (CD4 =< 200 x 10^6/L), are eligible for this trial Receiving any other drug (except hydroxyurea) or investigational agent which would be considered as a treatment for the primary disease, that is, MDS/MPN-RS-T or MDS/MPN-U with RS =< 2 weeks prior to registration Other active malignancy =< 3 years prior to registration. Patients on hormonal therapy for treated breast or prostate cancer are permitted if they meet other eligibility criteria EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix. NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment (luteinizing hormone-releasing hormone (LHRH) agonists for prostate cancer, and treatment with bisphosphonates and receptor activator of nuclear factor kappa-B ligand [RANKL] inhibitors) for their cancer History of myocardial infarction, stroke, embolism, deep vein or arterial thrombosis =< 6 months prior to registration, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Abhishek Mangaonkar
Organizational Affiliation
Mayo Clinic in Rochester
Official's Role
Principal Investigator
Facility Information:
Facility Name
Mayo Clinic Hospital in Arizona
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85054
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Clinical Trials Referral Office
Phone
855-776-0015
Email
mayocliniccancerstudies@mayo.edu
First Name & Middle Initial & Last Name & Degree
Cecilia Y. Arana Yi, M.D.
Facility Name
Mayo Clinic in Florida
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32224-9980
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Clinical Trials Referral Office
Phone
855-776-0015
Email
mayocliniccancerstudies@mayo.edu
First Name & Middle Initial & Last Name & Degree
Hemant S. Murthy, M.D.
Facility Name
Mayo Clinic in Rochester
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Clinical Trials Referral Office
Phone
855-776-0015
Email
mayocliniccancerstudies@mayo.edu
First Name & Middle Initial & Last Name & Degree
Abhishek Mangaonkar, M.D.

12. IPD Sharing Statement

Learn more about this trial

Luspatercept With or Without Hydroxyurea for the Treatment of Myelodysplastic/Myeloproliferative Neoplasms With Ring Sideroblasts and Thrombocytosis or Unclassifiable With Ring Sideroblasts

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