Clinical Trials /

MPN-RC 118 AVID200 in Myelofibrosis

NCT03895112

Description:

Increased levels of TGF-β1 were detected in serum, plasma and BM and positively correlated with both grade of BMF and extent of leukemic cell infiltration in the marrow. TGF-β likely plays a dual role in promoting myelofibrosis and myeloproliferation, both of which are the bone marrow morphologic hallmark of MF. AVID200 is a drug that targets TGF-β1 and TGF-β3. The study team hypothesizes that inhibiting the TGF-β signaling pathway in MF will decrease the fibrogenic stimuli leading to myelofibrosis and concomitantly interrupt myeloproliferation and restore normal hematopoiesis. This is a first in human, open-label, multicenter, Phase I/Ib trial of AVID200. Patients must have intermediate-2 or higher primary myelofibrosis (PMF), post-essential thrombocythemia or polycythemia-vera related MF (Post ET/PV MF). This study will enroll up to 24 patients. AVID200 is delivered by IV infusion on day 1 of each 3 week cycle.

Related Conditions:
  • Myelofibrosis
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: MPN-RC 118 AVID200 in Myelofibrosis
  • Official Title: Phase I Study of AVID200 in Patients With Myelofibrosis (Myeloproliferative Neoplasms Research Consortium [MPN-RC] 118)

Clinical Trial IDs

  • ORG STUDY ID: GCO 07-0548-01401
  • SECONDARY ID: P01CA108671
  • SECONDARY ID: MPN-RC 118
  • NCT ID: NCT03895112

Conditions

  • Primary Myelofibrosis
  • Post-essential Thrombocythemia Myelofibrosis
  • Post-polycythemia Vera Myelofibrosis
  • Post ET MF
  • Post PV MF

Interventions

DrugSynonymsArms
AVID200AVID200

Purpose

Increased levels of TGF-β1 were detected in serum, plasma and BM and positively correlated with both grade of BMF and extent of leukemic cell infiltration in the marrow. TGF-β likely plays a dual role in promoting myelofibrosis and myeloproliferation, both of which are the bone marrow morphologic hallmark of MF. AVID200 is a drug that targets TGF-β1 and TGF-β3. The study team hypothesizes that inhibiting the TGF-β signaling pathway in MF will decrease the fibrogenic stimuli leading to myelofibrosis and concomitantly interrupt myeloproliferation and restore normal hematopoiesis. This is a first in human, open-label, multicenter, Phase I/Ib trial of AVID200. Patients must have intermediate-2 or higher primary myelofibrosis (PMF), post-essential thrombocythemia or polycythemia-vera related MF (Post ET/PV MF). This study will enroll up to 24 patients. AVID200 is delivered by IV infusion on day 1 of each 3 week cycle.

Detailed Description

      This is a first in human, open-label, multicenter, Phase I/Ib trial of AVID200. To date,
      there is no therapy for MF evaluated in the clinic that clearly demonstrates the ability to
      target the malignant HSC and result in effective and reproducible bone marrow morphologic,
      cytogenetic and molecular responses. Medicinal therapies that result in disease course
      modification are urgently needed in this chronic and progressive myeloid malignancy. TGF-β
      likely plays a dual role in promoting myelofibrosis and myeloproliferation, both of which are
      the bone marrow morphologic hallmark of MF. The study team proposes that inhibiting the TGF-β
      signaling pathway in MF will decrease the fibrogenic stimuli leading to myelofibrosis and
      concomitantly interrupt myeloproliferation and restore normal hematopoiesis. AVID200 is a
      fusion protein containing TGF-β receptor ectodomains fused to a human Fc IgG domain. AVID200
      is a potent TGFβ trap with antibody-like properties which has pM potency against two of the
      three TGFβ ligands, TGFβ1 and β3.
    

Trial Arms

NameTypeDescriptionInterventions
AVID200Experimentalintravenous in dose cohorts of 180 mg/m2, 550 mg/m2, or 1100 mg/m2
  • AVID200

Eligibility Criteria

        Inclusion Criteria:

          -  Subjects must be ≥18 years of age at the time of signing the Informed Consent Form
             (ICF)

          -  Subjects must voluntarily sign an ICF

          -  Subjects must have a pathologically confirmed diagnosis of PMF as per the WHO
             diagnostic criteria or post ET/PV MF (note that all diagnoses must include the
             presence of at least Grade 2 marrow fibrosis according to the European Consensus on
             Grading of Bone Marrow Fibrosis (see Table 6) with intermediate -2 or high risk
             disease according to the IWG-MRT Dynamic International Prognostic Scoring System
             (DIPSS) (see Table 7)

          -  A bone marrow biopsy must be performed within the 30 day screening period, however, a
             bone marrow biopsy obtained within 90 days of screening without intervening treatments
             and approved by the study chair may suffice.

          -  Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of
             0-2.

          -  Life expectancy of at least six months

          -  At least two weeks must have elapsed between the last dose of any MF-directed drug
             treatments (including investigational therapies and excluding hydroxyurea) and study
             enrollment

          -  Not eligible for ruxolitinib therapy due to a platelet count <50 x 109/L, previously
             treated and lack/loss of response as defined by at least one of the following:

               1. Treatment for ≥3 months with inadequate efficacy response defined as <10% spleen
                  volume reduction by MRI or <30% decrease from baseline in spleen length by
                  physical examination or regrowth to these parameters following an initial
                  response; and/or

               2. Treatment for ≥28 days complicated by either

             i. Development of a red blood cell transfusion requirement (at least 2 units/month for
             2 months) ii. National Cancer Institute (NCI) CTCAE grade ≥ 3 AEs of thrombocytopenia,
             anemia, hematoma, and/or hemorrhage while being treated with a dosage of < 20 mg BID

          -  Recovery to ≤ Grade 1 or baseline of any toxicities due to prior systemic treatments,
             excluding alopecia

          -  Women of child bearing potential (WCBP), defined as a sexually mature woman not
             surgically sterilized or not post-menopausal for at least 24 consecutive months if ≤55
             years or 12 months if >55 years, must have a negative serum pregnancy test at
             screening and cycle 1 day 1 and must agree to use adequate methods of birth control
             throughout the study. Adequate methods of contraception include use of oral
             contraceptives or Depo-Provera, with an additional barrier method (diaphragm with
             spermicidal gel or condoms with spermicide), double-barrier methods (diaphragm with
             spermicidal gel and condoms with spermicide), partner vasectomy, and total abstinence.

          -  Male subjects should agree to use an adequate method of contraception starting with
             the first dose of study therapy through 120 days after the last dose of study therapy.

          -  Must have adequate organ function as demonstrated by the following:

               1. ALT (SGPT) and/or AST (SGOT) ≤ 3x upper limit of normal (ULN), or ≤ 4 x ULN (if
                  upon judgment of the treating physician, it is believed to be due to
                  extramedullary hematopoiesis [EMH] related to MF);

               2. Direct bilirubin ≤ 1.5 x ULN; or ≤ 2x ULN (if upon judgment of the treating
                  physician, it is believed to be due to extra-medullary hematopoiesis related to
                  MF or documented Gilbert's syndrome);

               3. Serum creatinine ≤ 2.0 mg/dL;

               4. Platelet count ≥25 x 109/L

          -  Ability to adhere to the study visit schedule and all protocol requirements

          -  Ability to understand and the willingness to sign a written informed consent

        Exclusion Criteria:

          -  Other invasive malignancies within the last 3 years, except non-melanoma skin cancer
             and localized cured prostate and cervical cancer.

          -  Previous exposure to galunisertib, fresolimumab, sotatercept, or luspatercept.

          -  History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia
             requiring medication or mechanical control within the last 6 months

          -  Have moderate or severe cardiovascular disease:

               1. have the presence of cardiac disease, including a myocardial infarction within 6
                  months prior to study entry, unstable angina pectoris, New York Heart Association
                  Class III/IV congestive heart failure, or uncontrolled hypertension

               2. have documented major ECG abnormalities (not responding to medical treatments)

          -  Have predisposing conditions that are consistent with development of aneurysms of the
             ascending aorta or aortic stress (for example, family history of aneurysms,
             Marfan-Syndrome, bicuspid aortic valve, evidence of damage to the large vessels of the
             heart documented by CT scan/MRI with contrast)

          -  Presence of active serious infection;

          -  Any serious, unstable medical or psychiatric condition that would prevent, (as judged
             by the Investigator) the subject from signing the informed consent form or any
             condition, including the presence of laboratory abnormalities, which places the
             subject at unacceptable risk if he/she were to participate in the study or confounds
             the ability to interpret data from the study

          -  Known history of human immunodeficiency virus (HIV), or known active hepatitis A, B,
             or C infection

          -  Organ transplant recipients other than bone marrow transplant

          -  Women who are pregnant or lactating
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximally tolerated dose (MTD) of AVID200
Time Frame:After 6 cycles (Each cycle is 21 days)
Safety Issue:
Description:Cohorts of 3 patients with a maximum evaluable sample size of 12 patients and a target toxicity rate of 30% to estimate the MTD. Each cycle is 21 days.

Secondary Outcome Measures

Measure:IWG/ELN criteria
Time Frame:After 6 cycles and after 12 cycles (Each cycle is 21 days)
Safety Issue:
Description:response by IWG/ELN criteria at the end of Cycle 6 and Cycle 12. The IWG/ELN criteria: CR (complete remission), PR (partial remission), Clinical improvement, Anemia response, Spleen response, Symptoms response, PD (progressive disease), SD (stable disease), Relapse, Cytogenetic remission, and Molecular remission
Measure:Bone marrow fibrosis grade
Time Frame:up to 37 days after 13 cycles (Each cycle is 21 days)
Safety Issue:
Description:bone marrow fibrosis grade at the end of Cycle 6 and 12. Bone marrow fibrosis (MF) is graded as MF-0 to MF-3, with higher number indicating more disease.
Measure:Myelofibrosis Symptom Assessment Form (MFSAF)
Time Frame:up to 37 days after 13 cycles (Each cycle is 21 days)
Safety Issue:
Description:MF-SAFv4.0,each of the items are scored 0 to 10, with total summation from 0 to 100, with higher score indicating more symptoms.
Measure:EORTC QLQ-C30
Time Frame:up to 37 days after 13 cycles (Each cycle is 21 days)
Safety Issue:
Description:EORTC QLQ-C30, 28 item scored from 1 (not at all) to 4 (very much), and 2 items scored 1 (very poor) to 7 (excellent). Total score from 28 - 126, with higher score indicating poorer health

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Icahn School of Medicine at Mount Sinai

Trial Keywords

  • Therapeutic
  • Fibrosis
  • Splenomegaly
  • Myeloproliferative neoplasms research consortium
  • Intravenous Infusion
  • Phase 1

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