Clinical Trials /

Luspatercept and Lenalidomide (L2) in Lower-risk, Non-del(5q) MDS Patients

NCT04539236

Description:

The purpose of this study is to evaluate if the combination of drugs, Lenalidomide and Luspatercept, will help improve the treatment of anemia in people with lower-risk MDS. Anemia is a condition in which the blood does not have enough healthy red blood cells. Red blood cells are made in an area of the bone called the bone marrow. Anemia is a common side effect in people who have MDS because this cancer disrupts the production of red blood cells in the bone marrow. Sometimes anemia can be treated successfully with a therapy known as an erythropoiesis-stimulating agent (ESA). The ESA medication tries to help the bone marrow make more red blood cells. However, some people do not respond to this treatment and have limited options. This research study is to improve anemia treatment options for people with MDS who have not responded, or are unlikely to respond to ESAs.

Related Conditions:
  • Myelodysplastic Syndromes
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Luspatercept and Lenalidomide (L2) in Lower-risk, Non-del(5q) MDS Patients
  • Official Title: A Multicenter, Phase Ib/II Study That Combines Luspatercept and Lenalidomide (L2) in Lower-risk, Non-del(5q) MDS Patients

Clinical Trial IDs

  • ORG STUDY ID: CASE2920
  • NCT ID: NCT04539236

Conditions

  • Myelodysplastic Syndromes

Interventions

DrugSynonymsArms
LenalidomideRevlimidLuspatercept + Lenalidomide
LuspaterceptReblozyl, ActRIIB-IgG, ACE-536, 1373715-00-4Luspatercept + Lenalidomide

Purpose

The purpose of this study is to evaluate if the combination of drugs, Lenalidomide and Luspatercept, will help improve the treatment of anemia in people with lower-risk MDS. Anemia is a condition in which the blood does not have enough healthy red blood cells. Red blood cells are made in an area of the bone called the bone marrow. Anemia is a common side effect in people who have MDS because this cancer disrupts the production of red blood cells in the bone marrow. Sometimes anemia can be treated successfully with a therapy known as an erythropoiesis-stimulating agent (ESA). The ESA medication tries to help the bone marrow make more red blood cells. However, some people do not respond to this treatment and have limited options. This research study is to improve anemia treatment options for people with MDS who have not responded, or are unlikely to respond to ESAs.

Detailed Description

      This is a multicenter, Phase Ib/II study that combines Luspatercept and Lenalidomide in
      people with lower-risk, non-del(5q) MDS for whom ESAs were ineffective or who are unlikely to
      respond to ESAs, with a baseline serum EPO level >200.

      Lenalidomide, also known as Revlimid® is an FDA approved drug for some types of lymphoma and
      for those who have a different type of MDS than what is being looked at in this study.
      Lenalidomide is considered investigational (experimental) in this study because it is being
      used in a different setting than the FDA approval. Lenalidomide blocks the development of
      abnormal cells, prevents the growth of blood vessels within tumors, and also stimulates
      specialized cells of the immune system to attack the abnormal cells.

      Luspatercept, also known as Reblozyl, has been recently approved by the FDA for those with
      lower-risk MDS. Luspatercept works by helping red blood cells grow and mature.

      There are 2 parts to this study: part 1 is referred to as phase I and part 2 is referred to
      as phase II.

        -  The goal of phase I is to find the safest dosing schedule of Luspatercept in combination
           with Lenalidomide

        -  The goal of phase II is to use the safest dosing schedule (found in phase I) to assess
           the independence a patient can have from receiving red blood cell transfusions.
    

Trial Arms

NameTypeDescriptionInterventions
Luspatercept + LenalidomideExperimentalLenalidomide (LEN) administered at a fixed dose of 5mg PO daily for 21 days of a 21 day cycle and Luspatercept at 1.0 mg/kg subcutaneously on Day 1 of each cycle, escalated to 1.75 mg/kg with a safety assessment for dose limiting toxicities (DLTs) (assessment period of first 28 days of treatment). A standard "3+3" design will be used to identify the MTD of Luspatercept in combination with LEN. The Phase II portion will involve an expansion cohort with LEN dosed at 5mg PO daily for 21 days of the 21-day cycle, and Luspatercept at the MTD determined from the Phase Ib. Treatment with LEN and luspatercept will continue as long as a participant is deriving benefit from the drugs, defined as hematologic improvement.
  • Lenalidomide
  • Luspatercept

Eligibility Criteria

        Inclusion Criteria:

          -  Participant must understand and voluntarily sign an ICF prior to any study related
             assessments/procedures being conducted.

          -  Documented diagnosis of MDS according to WHO/FAB classification that meets IPSS-R
             classification (Greenberg, 2012; Appendix D) of very low, low, or intermediate risk
             disease

          -  Refractory or intolerant to, or ineligible for, prior ESA treatment, as defined by any
             one of the following:

               -  Refractory to prior ESA treatment - documentation of non-response or response
                  that is no longer maintained to prior ESA-containing regimen, either as single
                  agent or combination (eg, with G-CSF); ESA regimen must have been either:

                    -  recombinant human erythropoietin (rHu EPO) ≥ 40,000 IU/wk for at least 8
                       doses or equivalent; OR

                    -  darbepoetin alpha ≥ 200-500 μg Q1-3W for at least 4 doses or equivalent;

               -  Intolerant to prior ESA treatment - documentation of discontinuation of prior
                  ESA-containing regimen, either as single agent or combination (eg, with GCSF), at
                  any time after introduction due to intolerance or an adverse event

               -  ESA ineligible - Low chance of response to ESA based on endogenous serum
                  erythropoietin level > 200 U/L for subjects not previously treated with ESAs

          -  If previously treated with ESAs or granulocyte colony-stimulating factor (G-CSF),
             granulocyte-macrophage colony-stimulating factor (GM-CSF), both agents must have been
             discontinued ≥ 4 weeks prior to date of randomization.

          -  Requires RBC transfusions, as documented by the following criteria:

               -  Average transfusion requirement of ≥ 2 units/8 weeks of pRBCs confirmed for a
                  minimum of 16 weeks immediately preceding randomization.

               -  Hemoglobin levels at the time of or within 7 days prior to administration of a
                  RBC transfusion must have been ≤ 10.0 g/dL for the transfusion to be counted
                  towards meeting eligibility criteria. Red blood cell transfusions administered
                  when Hgb levels were > 10.0 g/dL and/or RBC transfusions administered for
                  elective surgery will not qualify as a required transfusion for the purpose of
                  meeting eligibility criteria.

               -  No consecutive 56-day period that was RBC transfusion-free during the 16 weeks
                  immediately preceding randomization

          -  Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2

          -  Females of childbearing potential (FCBP), defined as a sexually mature woman who: 1)
             has not undergone a hysterectomy or bilateral oophorectomy or 2) 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), must:

               -  Have two negative pregnancy tests as verified by the Investigator prior to
                  starting study therapy (unless the screening pregnancy test was done within 72
                  hours of C1D1). She must agree to ongoing pregnancy testing during the course of
                  the study, and after end of study treatment.

               -  If sexually active, agree to use, and be able to comply with, highly effective
                  contraception without interruption, 5 weeks prior to starting investigational
                  product, during the study therapy (including dose interruptions), and for 12
                  weeks after discontinuation of study therapy.

          -  Male subjects must:

             --Agree to use a condom, defined as a male latex condom or nonlatex condom NOT made
             out of natural (animal) membrane (for example, polyurethane), 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 12 weeks following
             investigational product discontinuation, even if he has undergone a successful
             vasectomy.

          -  Subject is willing and able to adhere to the study visit schedule and other protocol
             requirements.

        Exclusion Criteria:

          -  Prior therapy with Lenalidomide.

          -  Previously treated with either luspatercept (ACE-536) or sotatercept (ACE011)

          -  MDS associated with del 5q cytogenetic abnormality

          -  Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies,
             or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding

             --iron deficiency to be determined by serum ferritin ≤ 15 μg/L and additional testing
             if clinically indicated (eg, calculated transferrin saturation [iron/total iron
             binding capacity ≤ 20%] or bone marrow aspirate stain for iron).

          -  Prior allogeneic stem cell transplant

          -  Known history of diagnosis of AML

          -  Use of any of the following within 4 weeks prior to randomization:

               -  Anticancer cytotoxic chemotherapeutic agent or treatment

               -  Other RBC hematopoietic growth factors (eg, Interleukin-3)

               -  Investigational drug or device, or approved therapy for investigational use. If
                  the half-life of the previous investigational product is known, use within 5
                  times the half-life prior to randomization or within 5 weeks, whichever is longer
                  is excluded.

          -  Uncontrolled hypertension, defined as repeated elevations of diastolic blood pressure
             (DBP) ≥ 100 mmHg despite adequate treatment.

          -  Prior history of malignancies, other than MDS, unless the subject has been free of the
             disease (including completion of any active or adjuvant treatment for prior
             malignancy) for ≥ 1 year. However, subjects with the following history/concurrent
             conditions involving in situ cancer (or similar) are allowed:

               -  Basal or squamous cell carcinoma of the skin

               -  Carcinoma in situ of the cervix

               -  Carcinoma in situ of the breast

               -  Incidental histologic finding of prostate cancer (T1a or T1b using the tumor,
                  nodes, metastasis [TNM] clinical staging system)

          -  Major surgery within 4 weeks prior to randomization. Subjects must have completely
             recovered from any previous surgery prior to randomization

          -  History of stroke, deep venous thrombosis (DVT), pulmonary or arterial embolism within
             6 months prior to randomization

          -  Pregnant or breastfeeding females

          -  Subject has any significant medical condition, laboratory abnormality, psychiatric
             illness, or is considered vulnerable by local regulations (eg, imprisoned or
             institutionalized) that would prevent the subject from participating in the study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD) of Luspatercept
Time Frame:Up to 30 days after treatment
Safety Issue:
Description:MTD of Luspatercept from phase Ib portion of study, reported in mg/kg

Secondary Outcome Measures

Measure:Percent of patients experiencing a grade 3 or higher adverse event
Time Frame:Up to 30 days after treatment
Safety Issue:
Description:Safety of intervention, as assessed by percent of patients experiencing a grade 3 or higher adverse event for combination therapy compared to either agent alone
Measure:DLT rate within the first cycle for phase Ib portion of study
Time Frame:Up to 30 days after treatment
Safety Issue:
Description:Tolerability of intervention, as assessed by DLT rate within the first cycle for phase Ib portion of study
Measure:Number of participants with relevant reduction in RBC transfusion
Time Frame:Up to 30 days after treatment
Safety Issue:
Description:For participants who were RBC transfusion dependent and received ≥ 4 units during the 8 weeks before registration on study - If, during a 8-week period after entering the study, the total number of RBC units transfused has decreased by at least 4 units compared to the number transfused during the 8 weeks before registration, then the participant will have a relevant reduction in RBC transfusion requirement. Numbers of RBC units and platelet transfusions during the 8 weeks before registration on the study will be recorded for use as baselines. Only RBC transfusions given for hemoglobin ≤ 9 g/dL or platelet transfusions for platelets < 50,000/mm3 before registration will be considered in the RBC transfusion response evaluation.
Measure:Percent of participants with hemoglobin improvement
Time Frame:Baseline, day 1 of each 21-day cycle, and 30 day follow-up
Safety Issue:
Description:Percent of participants with hemoglobin improvement, defined as at least a 1.5 g/dl increase in hemoglobin from pretreatment; and, for RBC transfusion-dependent participants, achievement of transfusion independence or a relevant reduction in the RBC transfusion requirement.
Measure:Duration of RBC-TI
Time Frame:Up to 30 days after treatment
Safety Issue:
Description:Duration of RBC-TI - Participants who receive one or more RBC or platelet transfusions will be considered RBC or platelet transfusion dependent, respectively, in the absence of another explanation such as gastrointestinal bleeding, hemolysis, etc.
Measure:Percent of participants with by platelet response (HI-P)
Time Frame:Baseline, day 1 of each 21-day cycle, and 30 day follow-up
Safety Issue:
Description:Hematologic improvement of platelets assessed by platelet response (HI-P): Defined only for participants with platelet count < 100,000/mm3 prior to treatment, who have improved. Criteria must be satisfied for all blood examinations performed during a period of at least 8 weeks. HI-P defined as an absolute increase of ≥ 30,000/mm3 from pretreatment for participants with a platelet count > 20,000/mm3 at pretreatment. For participants with a platelet count ≤ 20,000/mm3 at pretreatment, an increase of at least 100% from pretreatment counts to a platelet count > 20,000/mm3. For platelet transfusion-dependent participants, platelet transfusion independence is also required.
Measure:Percent of participants with a neutrophil response (HI-N)
Time Frame:Baseline, day 1 of each 21-day cycle, and 30 day follow-up
Safety Issue:
Description:Hematologic improvement of neutrophils assessed by neutrophil response (HI-N): Defined only for participants with ANC < 1,000/mm3 prior to treatment. ANC increase from pre-treatment of at least 100%, and an absolute increase of > 500/mm3 from pre-treatment
Measure:Rate of progression to higher-risk MDS or AML
Time Frame:Up to 30 days after treatment
Safety Issue:
Description:Percent of participants experiencing a progression to higher-risk MDS or AML
Measure:Overall Survival (OS)
Time Frame:Every 6 months +/- 30 days for 3 years
Safety Issue:
Description:OS is calculated for all participants from the date of initial registration to date of death due to any cause. The follow-up for participants last known to be alive is censored at the date of last contact.
Measure:RBC-TI > 16 weeks
Time Frame:Week 1 through week 24
Safety Issue:
Description:Proportion of subjects who are red blood cell (RBC) transfusion free over any consecutive 112-day period.
Measure:Percent of participants experiencing hematologic improvement, CR, or PR within first 2 years
Time Frame:Up to 2 years from start of treatment
Safety Issue:
Description:Response is defined as Hematologic improvement, Complete hematological remission (CR) or partial remission (PR). For CR & PR, participant satisfied all criteria and did not receive RBC or platelet transfusions, erythropoietin, myeloid growth factor, or thrombopoietic agent within 28 days prior to assessment. CR: Bone marrow evaluation: Myeloblasts must be ≤ 5% of total nucleated cells, and normal maturation of all cell lines Peripheral blood evaluation: Satisfied all of the following for examinations performed during at least a 4 week period: Hemoglobin ≥ 11.0 g/dl, Neutrophils ≥ 1,000/mm3, Platelets ≥ 100,000/mm3, Blasts = 0%, No evidence for dysplasia. PR: Bone marrow evaluation: Blasts > 5% but decreased by ≥ 50% from pretreatment or a WHO subtype of MDS that is less advanced than pretreatment, Cellularity and morphology are not relevant. Peripheral blood evaluation: All peripheral blood results required for CR during at least a 4 week period.
Measure:Proportion of of participants with high baseline transfusion burden who achieve Erythroid response (HI-E) per 2006 International Working Group (IWG) response criteria
Time Frame:Week 1 through week 24
Safety Issue:
Description:Proportion of of participants with high baseline transfusion burden (hemoglobin < 11 g/dl prior to treatment) who achieve HI-E per 2006 IWG response criteria, representing a secondary efficacy endpoint. HI-E is defined as at least a 1.5 g/dl increase in hemoglobin from pre-treatment; and achievement of transfusion independence or a relevant reduction in the RBC transfusion requirement

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Mikkael Sekeres MD

Trial Keywords

  • non-del(5q) MDS

Last Updated

September 3, 2020