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MPN-RC 118 AVID200 in Myelofibrosis

Primary Purpose

Primary Myelofibrosis, Post-essential Thrombocythemia Myelofibrosis, Post-polycythemia Vera Myelofibrosis

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
AVID200
Sponsored by
John Mascarenhas
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Primary Myelofibrosis focused on measuring Therapeutic, Fibrosis, Splenomegaly, Myeloproliferative neoplasms research consortium, Intravenous Infusion, Phase 1

Eligibility Criteria

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

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

Sites / Locations

  • Icahn School of Medicine at Mount Sinai

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

AVID200

Arm Description

intravenous in dose cohorts of 70mg/m2 or 180 mg/m2

Outcomes

Primary Outcome Measures

Maximally tolerated dose (MTD) of AVID200
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.
Number of patients with response eligibility for Phase 1b
Subjects attaining at least a CI (clinical improvement) by IWG/ELN criteria, or a decrease in bone marrow fibrosis by ≥1 grade with otherwise stable disease, will be allowed to continue AVID200 in the extension phase of the trial.

Secondary Outcome Measures

IWG/ELN criteria
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
Bone marrow fibrosis grade
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.
Myelofibrosis Symptom Assessment Form (MFSAF)
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.
EORTC QLQ-C30
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

Full Information

First Posted
March 22, 2019
Last Updated
February 9, 2023
Sponsor
John Mascarenhas
Collaborators
Formation Biologics, National Cancer Institute (NCI), Myeloproliferative Neoplasm Research Consortium (MPN-RC)
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1. Study Identification

Unique Protocol Identification Number
NCT03895112
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)
Study Type
Interventional

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Completed
Study Start Date
February 15, 2019 (Actual)
Primary Completion Date
May 16, 2022 (Actual)
Study Completion Date
May 16, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
John Mascarenhas
Collaborators
Formation Biologics, National Cancer Institute (NCI), Myeloproliferative Neoplasm Research Consortium (MPN-RC)

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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Primary Myelofibrosis, Post-essential Thrombocythemia Myelofibrosis, Post-polycythemia Vera Myelofibrosis, Post ET MF, Post PV MF
Keywords
Therapeutic, Fibrosis, Splenomegaly, Myeloproliferative neoplasms research consortium, Intravenous Infusion, Phase 1

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
21 (Actual)

8. Arms, Groups, and Interventions

Arm Title
AVID200
Arm Type
Experimental
Arm Description
intravenous in dose cohorts of 70mg/m2 or 180 mg/m2
Intervention Type
Drug
Intervention Name(s)
AVID200
Intervention Description
dose cohorts of 21-day cycles
Primary Outcome Measure Information:
Title
Maximally tolerated dose (MTD) of AVID200
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.
Time Frame
After 6 cycles (Each cycle is 21 days)
Title
Number of patients with response eligibility for Phase 1b
Description
Subjects attaining at least a CI (clinical improvement) by IWG/ELN criteria, or a decrease in bone marrow fibrosis by ≥1 grade with otherwise stable disease, will be allowed to continue AVID200 in the extension phase of the trial.
Time Frame
After 6 cycles
Secondary Outcome Measure Information:
Title
IWG/ELN criteria
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
Time Frame
After 6 cycles and after 12 cycles (Each cycle is 21 days)
Title
Bone marrow fibrosis grade
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.
Time Frame
up to 37 days after 13 cycles (Each cycle is 21 days)
Title
Myelofibrosis Symptom Assessment Form (MFSAF)
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.
Time Frame
up to 37 days after 13 cycles (Each cycle is 21 days)
Title
EORTC QLQ-C30
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
Time Frame
up to 37 days after 13 cycles (Each cycle is 21 days)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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: 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 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: 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); 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); Serum creatinine ≤ 2.0 mg/dL; 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: 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 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
John Mascarenhas, MD
Organizational Affiliation
Icahn School of Medicine at Mount Sinai
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Ruben Mesa, MD
Organizational Affiliation
Mays Cancer Center at UT Health
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Ronald Hoffman, MD
Organizational Affiliation
Icahn School of Medicine at Mount Sinai
Official's Role
Study Director
Facility Information:
Facility Name
Icahn School of Medicine at Mount Sinai
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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MPN-RC 118 AVID200 in Myelofibrosis

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