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

Sponsor

Mayo Clinic (Other)

Overall Status

Recruiting

CT.gov ID

NCT05005182

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Arms

27.4

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic/Myeloproliferative Neoplasm With Ring Sideroblasts and Thrombocytosis Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable	Drug: Hydroxyurea Biological: Luspatercept	Phase 2

Detailed Description

PRIMARY OBJECTIVE:

To document the erythroid response rate assessed as per the 2015 International Working Group (IWG) myelodysplastic (MDS)/myeloproliferative neoplasms (MPN) response criteria.

SECONDARY OBJECTIVES:

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.
To document safety of luspatercept (luspatercept-aamt) in patients with MDS/MPN-RS-T and MDS/MPN-U with RS.

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.

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.

After completion of study treatment, patients are followed up every 3 months.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

54 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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)

Actual Study Start Date :

Jan 17, 2022

Anticipated Primary Completion Date :

May 1, 2023

Anticipated Study Completion Date :

May 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort A (luspatercept) Patients receive luspatercept SC on day 1. Cycles repeat every 21 days for 6 months in the absence of disease progression or unacceptable toxicity.	Biological: Luspatercept Given SC Other Names: ACE-536 Luspatercept-aamt Reblozyl
Experimental: Cohort A (luspatercept, hydroxyurea) 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.	Drug: Hydroxyurea Given PO Other Names: Droxia Hydrea Hydroxycarbamide Litalir Onco-Carbide Oncocarbide Oxeron SQ 1089 SQ-1089 Syrea WR 83799 Biological: Luspatercept Given SC Other Names: ACE-536 Luspatercept-aamt Reblozyl

Arm

Intervention/Treatment

Experimental: Cohort A (luspatercept)

Patients receive luspatercept SC on day 1. Cycles repeat every 21 days for 6 months in the absence of disease progression or unacceptable toxicity.

Biological: Luspatercept

Given SC

Other Names:

ACE-536

Luspatercept-aamt

Reblozyl

Experimental: Cohort A (luspatercept, hydroxyurea)

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.

Drug: Hydroxyurea

Given PO

Other Names:

Droxia

Hydrea

Hydroxycarbamide

Litalir

Onco-Carbide

Oncocarbide

Oxeron

SQ 1089

SQ-1089

Syrea

WR 83799

Biological: Luspatercept

Given SC

Other Names:

ACE-536

Luspatercept-aamt

Reblozyl

Outcome Measures

Primary Outcome Measures

Erythroid response rate [Up to 8 weeks]
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) [Up to 6 months]
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 [From first documented erythroid response to the time of progression and/or relapse, assessed up to 6 months]
Will be evaluated and characterized within each cohort using the methods of Kaplan and Meier.
Time to leukemic transformation [From study entry to the time of transformation to acute myeloid leukemia (AML), assessed up to 6 months]
Will be evaluated and characterized within each cohort using the methods of Kaplan and Meier.
Leukemia-free survival [From time of treatment to progression to acute myeloid leukemia or death from any cause, assessed up to 6 months]
Will be evaluated and characterized within each cohort using the methods of Kaplan and Meier.
Overall survival [From study entry to the time of death due to any cause, assessed up to 6 months]
Will be evaluated and characterized within each cohort using the methods of Kaplan and Meier.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts 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