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

• Status: Recruiting
• Trial end date: 2022-01-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Rochester
• Treatments: Abaloparatide; Bevacizumab

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