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出境医 / 临床实验 / A Phase I Pilot Study of Abaloparatide + Bevacizumab in Myelodysplastic Syndromes

A Phase I Pilot Study of Abaloparatide + Bevacizumab in Myelodysplastic Syndromes

Study Description
Brief Summary:
The primary objective of this study is to determine the safety and tolerability of combined abaloparatide and bevacizumab in patients with Myelodysplastic Syndromes (MDS). A secondary objective is to determine the response to treatment (based on bone marrow and peripheral blood findings). A tertiary objective is to determine the impact of therapy on health-related quality of life (HRQOL) and patient-reported outcomes (PRO). A quaternary (scientific) objective is to determine the impact of treatment on both hematopoietic and stromal cell populations within the bone marrow of MDS patients.

Condition or disease Intervention/treatment Phase
Myelodysplastic Syndromes Chronic Myelomonocytic Leukemia Drug: abaloparatide Drug: bevacizumab Phase 1

Detailed Description:
The main objective of this study is to determine the safety and tolerability of combined abaloparatide + bevacizumab in MDS patients. This will be a single center, single arm, phase 1 trial in MDS patients. In cycle 1, patients will be treated with single-agent, subcutaneous (SQ) abaloparatide at a dose of 80 mcg/day for 28 days. This will enable the investigator to monitor for any potential toxicities of single-agent abaloparatide in the MDS patient population. Following cycle 1, patients will have a bone marrow aspirate to determine the impact of abaloparatide treatment on bone marrow stromal cell and hematopoietic cell populations. In cycles 2-4 (each cycle is 28 days), patients will be treated with SQ abaloparatide at a dose of 80 mcg/day and intravenous (IV) bevacizumab 5 mg/kg on days 1 and 15. At the end of study, patients will have a bone marrow aspirate and biopsy to assess disease response and to determine the impact of combined abaloparatide + bevacizumab on bone marrow stromal cell and hematopoietic cell populations. After completion of trial therapy, another bone marrow aspirate and biopsy will be done 3 months later to assess the delayed impact of treatment. The investigator has chosen a phase 1 trial design because this combination has not been previously evaluated for toxicity. Since safe and effective doses of both abaloparatide and bevacizumab have already been identified and both drugs are Food and Drug Administration (FDA)-approved, the investigator does not feel there is a need to dose-escalate. The investigator will carefully monitor for therapy-limiting toxicities (TLTs) throughout the course of the study and impose an early stopping rule for toxicity. To monitor for TLTs, patients will have laboratory tests weekly and clinic visits every other week throughout the course of the trial. TLT is defined in the protocol with grading of adverse events defined by the NCI Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0. Response will be defined according to 2006 IWG working criteria for MDS. Patients who have achieved complete remission (CR), partial remission (PR), marrow CR, and/or hematologic improvement at any time during the 7 month trial period will be considered responders. Eligible subjects will have a diagnosis of MDS or non-proliferative chronic myelomonocytic leukemia (CMML) based on 2016 world health organization (WHO) criteria, and associated signs of bone marrow failure characterized by at least some degree of cytopenia involving at least one cell line such as anemia, thrombocytopenia or leukopenia. Patients will not be allowed to receive concurrent active chemotherapy or growth factors.
Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 19 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Pilot Study of Abaloparatide + Bevacizumab in Myelodysplastic Syndromes
Actual Study Start Date : February 14, 2019
Estimated Primary Completion Date : November 1, 2021
Estimated Study Completion Date : January 1, 2022
Arms and Interventions
Arm Intervention/treatment
Experimental: abaloparatide and bevacizumab treatment
In cycle 1, patients will be treated with single-agent, subcutaneous (SQ) abaloparatide at a dose of 80 mcg/day for 28 days. In cycles 2-4 (each cycle is 28 days), patients will be treated with SQ abaloparatide at a dose of 80 mcg/day and intravenous (IV) bevacizumab 5 mg/kg on days 1 and 15.
 Drug: abaloparatide
In cycle 1, patients will be treated with single-agent, subcutaneous (SQ) abaloparatide at a dose of 80 mcg/day for 28 days.

Drug: bevacizumab
In cycles 2-4 (each cycle is 28 days), patients will be treated with SQ abaloparatide at a dose of 80 mcg/day and intravenous (IV) bevacizumab 5 mg/kg on days 1 and 15.
Outcome Measures
Primary Outcome Measures :
  1. Proportion of patients who experience a therapy-limiting Toxicity (TLT) [ Time Frame: 7 months ]
    Safety of this therapy will be based on subjects who complete at least two cycles, experiencing both study drugs for at least one cycle. TLT is defined as any serious AEs considered at least possibly due to abaloparatide and/or bevacizumab, occurring at any time from the initial dose of study treatment, with severity graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 5.


Secondary Outcome Measures :
  1. Proportion of patients who responded to therapy [ Time Frame: 7 months ]
    In this study, patients who have achieved complete remission (CR), partial remission (PR), marrow CR, and/or hematologic improvement will be considered responders according to the International Working Group (IWG) Response Criteria and Modified IWG Response Criteria for Hematological Improvement. The overall rate of response will be estimated among all subjects who received at least one dose of any study drug.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age equal to or greater than 18
  • Patients must have a documented diagnosis of MDS or non-proliferative chronic myelomonocytic leukemia (CMML) (WBC < 12,000/mcL) according to World Health Organization (WHO) criteria (27)

  • Patients can be treatment-naïve or have received prior MDS-directed chemotherapy.

    • Treatment-naïve MDS patients (or those previously treated with growth factors alone) must have Revised International Prognostic Scoring System (IPSS-R) categories of Very Low-, Low- or Intermediate-risk disease (see Appendix A for Revised International Prognostic Scoring System for MDS).
    • MDS patients previously treated with disease-modifying chemotherapy (i.e. azacitidine, decitabine, lenalidomide, intensive chemotherapy, and/or an investigational agent) are eligible irrespective of IPSS-R score.
  • Patients must be off all non-transfusion therapy for MDS for 28 days prior to initiation of study treatment, including all types of growth factors.
  • Bone marrow biopsy (BMBx) within 30 days prior to first study treatment.

  • Cytopenia involving at least one cell line such as anemia, thrombocytopenia or leukopenia at the time of study enrollment. Cytopenias should be present on at least 2 different blood draws within 8 weeks of study enrollment. Definitions of cytopenias for the purposes of this study are as follows:

    • Anemia: Patients must be symptomatic in the opinion of the treating physician with a hemoglobin ≤ 10.0 g/dL
    • Thrombocytopenia: Platelet count < 100,000/microliter
    • Neutropenia: Absolute neutrophil count < 1000/microliter
  • ECOG Performance Status 0-2

  • Adequate organ function as evidenced by:

    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × the upper limit of normal (ULN).
    • Total bilirubin ≤2 mg/dL
    • Serum creatinine <2 mg/dL, or creatinine clearance (calculated by the Cockcroft-Gault formula) ≤1.5 × ULN.
  • Urine dipstick for proteinuria < 2+. Patients discovered to have ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate ≤ 1 g of protein in 24 hours
  • International normalised ratio (INR) ≤1.5 and prothrombin time (PT) ≤ 1.5 x ULN
  • Women with an intact uterus (unless amenorrheic for the last 24 months) must have a negative serum pregnancy test within 30 days prior to enrollment into the study.
  • Females of childbearing potential and sexually active males must use effective contraception during the trial and for 6 months after the last dose of bevacizumab.
  • Written informed consent.

Exclusion Criteria:

  • Bone marrow blasts equal to or greater than 20%
  • Patients actively receiving either abaloparatide, teriparatide or bisphosphonate therapy for other indications
  • Cumulative prior use of abaloparatide and/or any other parathyroid hormone analogs for > 20 months
  • History of allogeneic stem cell transplant
  • Pregnant or breast feeding female subjects
  • Platelets < 50,000/mm3
  • Major surgery (including open biopsy), significant traumatic injury within 28 days prior to enrollment or anticipation of the need for major surgery during study treatment
  • Prior malignancy (excluding localized cervical carcinoma or cutaneous basal cell/squamous cell carcinoma) unless in remission for at least 2 years.
  • Concurrent malignancy (excluding localized cervical carcinoma or cutaneous basal cell/squamous cell carcinoma)
  • Need for aspirin at a dose of ≥ 325 mg/day; if aspirin can be safely stopped or dose dropped to < 325 mg/day ≥ 10 days before the first dose of bevacizumab, then patient will remain eligible
  • Uncontrolled hypertension (blood pressures: systolic > 150 mmHg and/or diastolic > 100 mmHg)

  • Clinically significant cardiovascular disease present ≤6 months before enrollment as judged by the treating physician. Examples include:

    1. Myocardial infarction
    2. Unstable angina
    3. Congestive heart failure NYHA Class ≥ II
    4. Serious cardiac arrhythmia
    5. Cerebrovascular accident and/or transient ischemic attack
    6. Severe peripheral vascular disease (ischemic rest pain, non-healing wound or ulcer, or tissue loss)
  • Pulmonary embolus, deep venous thrombosis, or arterial thrombosis currently requiring anticoagulation
  • < 10 days since prior anticoagulants
  • Non-healing wound, active peptic ulcer or bone fracture
  • History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months of enrollment
  • Clinically significant hemorrhagic illness within the past 3 weeks
  • History of osteosarcoma
  • History of hyperparathyroidism
  • Elevated (>ULN) serum calcium level
  • Patients at increased risk for osteosarcoma, including those with Paget's disease of bone, unexplained elevations of alkaline phosphatase, and/or prior external beam or implant radiation therapy involving the skeleton.
  • Psychiatric illness or social situation that would preclude study compliance
  • Patients unable to give informed consent or to be followed up adequately
  • Known hypersensitivity to a product from Chinese Hamster Ovary mammalian cell or to a recombinant humanized monoclonal antibody
  • Other investigational treatments within 28 days of the start of study therapy
Contacts and Locations

Contacts
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Contact: Katherine Nedrow 585-273-3893 Katherine_Nedrow@URMC.Rochester.edu

Locations
Layout table for location information
United States, New York
University of Rochester Recruiting
Rochester, New York, United States, 14623
Contact: Katherine Nedrow         
Sponsors and Collaborators
University of Rochester
Investigators
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Principal Investigator: Jason Mendler, M.D. University of Rochester
Tracking Information
First Submitted Date  ICMJE November 15, 2018
First Posted Date  ICMJE November 19, 2018
Last Update Posted Date March 3, 2021
Actual Study Start Date  ICMJE February 14, 2019
Estimated Primary Completion Date November 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 15, 2018) 		Proportion of patients who experience a therapy-limiting Toxicity (TLT) [ Time Frame: 7 months ]
Safety of this therapy will be based on subjects who complete at least two cycles, experiencing both study drugs for at least one cycle. TLT is defined as any serious AEs considered at least possibly due to abaloparatide and/or bevacizumab, occurring at any time from the initial dose of study treatment, with severity graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 5.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 15, 2018) 		Proportion of patients who responded to therapy [ Time Frame: 7 months ]
In this study, patients who have achieved complete remission (CR), partial remission (PR), marrow CR, and/or hematologic improvement will be considered responders according to the International Working Group (IWG) Response Criteria and Modified IWG Response Criteria for Hematological Improvement. The overall rate of response will be estimated among all subjects who received at least one dose of any study drug.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Phase I Pilot Study of Abaloparatide + Bevacizumab in Myelodysplastic Syndromes
Official Title  ICMJE A Phase I Pilot Study of Abaloparatide + Bevacizumab in Myelodysplastic Syndromes
Brief Summary The primary objective of this study is to determine the safety and tolerability of combined abaloparatide and bevacizumab in patients with Myelodysplastic Syndromes (MDS). A secondary objective is to determine the response to treatment (based on bone marrow and peripheral blood findings). A tertiary objective is to determine the impact of therapy on health-related quality of life (HRQOL) and patient-reported outcomes (PRO). A quaternary (scientific) objective is to determine the impact of treatment on both hematopoietic and stromal cell populations within the bone marrow of MDS patients.
Detailed Description The main objective of this study is to determine the safety and tolerability of combined abaloparatide + bevacizumab in MDS patients. This will be a single center, single arm, phase 1 trial in MDS patients. In cycle 1, patients will be treated with single-agent, subcutaneous (SQ) abaloparatide at a dose of 80 mcg/day for 28 days. This will enable the investigator to monitor for any potential toxicities of single-agent abaloparatide in the MDS patient population. Following cycle 1, patients will have a bone marrow aspirate to determine the impact of abaloparatide treatment on bone marrow stromal cell and hematopoietic cell populations. In cycles 2-4 (each cycle is 28 days), patients will be treated with SQ abaloparatide at a dose of 80 mcg/day and intravenous (IV) bevacizumab 5 mg/kg on days 1 and 15. At the end of study, patients will have a bone marrow aspirate and biopsy to assess disease response and to determine the impact of combined abaloparatide + bevacizumab on bone marrow stromal cell and hematopoietic cell populations. After completion of trial therapy, another bone marrow aspirate and biopsy will be done 3 months later to assess the delayed impact of treatment. The investigator has chosen a phase 1 trial design because this combination has not been previously evaluated for toxicity. Since safe and effective doses of both abaloparatide and bevacizumab have already been identified and both drugs are Food and Drug Administration (FDA)-approved, the investigator does not feel there is a need to dose-escalate. The investigator will carefully monitor for therapy-limiting toxicities (TLTs) throughout the course of the study and impose an early stopping rule for toxicity. To monitor for TLTs, patients will have laboratory tests weekly and clinic visits every other week throughout the course of the trial. TLT is defined in the protocol with grading of adverse events defined by the NCI Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0. Response will be defined according to 2006 IWG working criteria for MDS. Patients who have achieved complete remission (CR), partial remission (PR), marrow CR, and/or hematologic improvement at any time during the 7 month trial period will be considered responders. Eligible subjects will have a diagnosis of MDS or non-proliferative chronic myelomonocytic leukemia (CMML) based on 2016 world health organization (WHO) criteria, and associated signs of bone marrow failure characterized by at least some degree of cytopenia involving at least one cell line such as anemia, thrombocytopenia or leukopenia. Patients will not be allowed to receive concurrent active chemotherapy or growth factors.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Myelodysplastic Syndromes
  • Chronic Myelomonocytic Leukemia
Intervention  ICMJE
  • Drug: abaloparatide
    In cycle 1, patients will be treated with single-agent, subcutaneous (SQ) abaloparatide at a dose of 80 mcg/day for 28 days.
  • Drug: bevacizumab
    In cycles 2-4 (each cycle is 28 days), patients will be treated with SQ abaloparatide at a dose of 80 mcg/day and intravenous (IV) bevacizumab 5 mg/kg on days 1 and 15.
Study Arms  ICMJE Experimental: abaloparatide and bevacizumab treatment
In cycle 1, patients will be treated with single-agent, subcutaneous (SQ) abaloparatide at a dose of 80 mcg/day for 28 days. In cycles 2-4 (each cycle is 28 days), patients will be treated with SQ abaloparatide at a dose of 80 mcg/day and intravenous (IV) bevacizumab 5 mg/kg on days 1 and 15.
Interventions:
  • Drug: abaloparatide
  • Drug: bevacizumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 15, 2018) 		19
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 1, 2022
Estimated Primary Completion Date November 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age equal to or greater than 18
  • Patients must have a documented diagnosis of MDS or non-proliferative chronic myelomonocytic leukemia (CMML) (WBC < 12,000/mcL) according to World Health Organization (WHO) criteria (27)

  • Patients can be treatment-naïve or have received prior MDS-directed chemotherapy.

    • Treatment-naïve MDS patients (or those previously treated with growth factors alone) must have Revised International Prognostic Scoring System (IPSS-R) categories of Very Low-, Low- or Intermediate-risk disease (see Appendix A for Revised International Prognostic Scoring System for MDS).
    • MDS patients previously treated with disease-modifying chemotherapy (i.e. azacitidine, decitabine, lenalidomide, intensive chemotherapy, and/or an investigational agent) are eligible irrespective of IPSS-R score.
  • Patients must be off all non-transfusion therapy for MDS for 28 days prior to initiation of study treatment, including all types of growth factors.
  • Bone marrow biopsy (BMBx) within 30 days prior to first study treatment.

  • Cytopenia involving at least one cell line such as anemia, thrombocytopenia or leukopenia at the time of study enrollment. Cytopenias should be present on at least 2 different blood draws within 8 weeks of study enrollment. Definitions of cytopenias for the purposes of this study are as follows:

    • Anemia: Patients must be symptomatic in the opinion of the treating physician with a hemoglobin ≤ 10.0 g/dL
    • Thrombocytopenia: Platelet count < 100,000/microliter
    • Neutropenia: Absolute neutrophil count < 1000/microliter
  • ECOG Performance Status 0-2

  • Adequate organ function as evidenced by:

    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × the upper limit of normal (ULN).
    • Total bilirubin ≤2 mg/dL
    • Serum creatinine <2 mg/dL, or creatinine clearance (calculated by the Cockcroft-Gault formula) ≤1.5 × ULN.
  • Urine dipstick for proteinuria < 2+. Patients discovered to have ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate ≤ 1 g of protein in 24 hours
  • International normalised ratio (INR) ≤1.5 and prothrombin time (PT) ≤ 1.5 x ULN
  • Women with an intact uterus (unless amenorrheic for the last 24 months) must have a negative serum pregnancy test within 30 days prior to enrollment into the study.
  • Females of childbearing potential and sexually active males must use effective contraception during the trial and for 6 months after the last dose of bevacizumab.
  • Written informed consent.

Exclusion Criteria:

  • Bone marrow blasts equal to or greater than 20%
  • Patients actively receiving either abaloparatide, teriparatide or bisphosphonate therapy for other indications
  • Cumulative prior use of abaloparatide and/or any other parathyroid hormone analogs for > 20 months
  • History of allogeneic stem cell transplant
  • Pregnant or breast feeding female subjects
  • Platelets < 50,000/mm3
  • Major surgery (including open biopsy), significant traumatic injury within 28 days prior to enrollment or anticipation of the need for major surgery during study treatment
  • Prior malignancy (excluding localized cervical carcinoma or cutaneous basal cell/squamous cell carcinoma) unless in remission for at least 2 years.
  • Concurrent malignancy (excluding localized cervical carcinoma or cutaneous basal cell/squamous cell carcinoma)
  • Need for aspirin at a dose of ≥ 325 mg/day; if aspirin can be safely stopped or dose dropped to < 325 mg/day ≥ 10 days before the first dose of bevacizumab, then patient will remain eligible
  • Uncontrolled hypertension (blood pressures: systolic > 150 mmHg and/or diastolic > 100 mmHg)

  • Clinically significant cardiovascular disease present ≤6 months before enrollment as judged by the treating physician. Examples include:

    1. Myocardial infarction
    2. Unstable angina
    3. Congestive heart failure NYHA Class ≥ II
    4. Serious cardiac arrhythmia
    5. Cerebrovascular accident and/or transient ischemic attack
    6. Severe peripheral vascular disease (ischemic rest pain, non-healing wound or ulcer, or tissue loss)
  • Pulmonary embolus, deep venous thrombosis, or arterial thrombosis currently requiring anticoagulation
  • < 10 days since prior anticoagulants
  • Non-healing wound, active peptic ulcer or bone fracture
  • History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months of enrollment
  • Clinically significant hemorrhagic illness within the past 3 weeks
  • History of osteosarcoma
  • History of hyperparathyroidism
  • Elevated (>ULN) serum calcium level
  • Patients at increased risk for osteosarcoma, including those with Paget's disease of bone, unexplained elevations of alkaline phosphatase, and/or prior external beam or implant radiation therapy involving the skeleton.
  • Psychiatric illness or social situation that would preclude study compliance
  • Patients unable to give informed consent or to be followed up adequately
  • Known hypersensitivity to a product from Chinese Hamster Ovary mammalian cell or to a recombinant humanized monoclonal antibody
  • Other investigational treatments within 28 days of the start of study therapy
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Katherine Nedrow 585-273-3893 Katherine_Nedrow@URMC.Rochester.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03746041
Other Study ID Numbers  ICMJE 00003054
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Jason Mendler, University of Rochester
Study Sponsor  ICMJE University of Rochester
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Jason Mendler, M.D. University of Rochester
PRS Account University of Rochester
Verification Date March 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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