Phase 1b/2 Study of Axatilimab (SNDX-6352) + Azacitidine (AZA) in Advanced Phase MPN, MPN/MDS Overlap or High-Risk CMML
概览
- 阶段
- 1 期
- 干预措施
- Axatilimab
- 疾病 / 适应症
- Atypical Chronic Myeloid Leukemia
- 发起方
- Uma Borate
- 入组人数
- 52
- 试验地点
- 1
- 主要终点
- Incidence of dose limiting toxicities
- 状态
- 招募中
- 最后更新
- 上个月
概览
简要总结
This phase Ib/II trial tests the best dose of axatilimab and effectiveness of axatilimab with or without azacitidine for the treatment of patients with advanced phase myeloproliferative neoplasms (MPN), myeloproliferative neoplasm/myelodysplastic syndrome (MPN/MDS) overlap or high risk chronic myelomonocytic leukemia (CMML). Axatilimab is an antibody that is cloned from a single white blood cell that is known to be able to recognize cancer cells and block a protein on the surface of the white blood cells that may be involved in cancer cell growth. By blocking the proteins, this may slow or halt the growth of the cancer. Azacitidine is in a class of medications called antimetabolites. It works by stopping or slowing the growth of cancer cells. Giving axatilimab with or without azacitidine may be safe and effective in treating patients with advanced phase MPN, MPN/MDS overlap or high risk CMML.
详细描述
PRIMARY OBJECTIVES: I. To determine the recommended phase 2 dose (RP2D) of axatilimab in relapsed or refractory patients with advanced phase MPN, MPN/MDS overlap or high-risk CMML. II. To evaluate the overall response rate of axatilimab + azacitidine (AZA) in newly diagnosed patients with advanced phase MPN, MPN/MDS overlap or high-risk CMML using Savona response criteria. SECONDARY OBJECTIVES: I. Determine the safety and tolerability of axatilimab + azacitidine combination therapy in those with newly diagnosed advanced phase MPN, MPN/MDS overlap or high-risk CMML. II. Determine the quality of life in patients receiving axatilimab + AZA using a Modified Myeloproliferative Neoplasm Symptom Assessment Form (MPNSAF). III. Determine the effect of axatilimab + azacitidine on symptom relief which will be measured by transfusion burden (platelet and/or packed red blood cell), time in hospital, and immune related side effects specifically reactivation of tuberculosis (TB), infusion-related reactions, hepatotoxicity, pneumonia, pyrexia, sepsis, shortness of breath (SBO), hemoptysis, periorbital edema, fatigue, and pancreatitis. EXPLORATORY OBJECTIVES: I. To assess the pharmacokinetics of axatilimab in combination with AZA. II. To describe the prevalence and trajectories of patients' physical activity during treatment. III. To perform detailed correlative studies related to genetic, biochemical, and immunologic changes that occur with axatilimab in combination with AZA. OUTLINE: This is a phase I, dose-escalation study of axatilimab followed by a phase II study. PHASE I: Patients receive axatilimab intravenously (IV) over 30 minutes on days 1 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. At time of phase Ib completion, patients with clinical improvement may transition to phase II. Patients undergo bone marrow biopsy and aspiration and blood sample collection throughout the study. PHASE II: Patients receive axatilimab IV over 30 minutes on days 1 and 15 and azacitidine IV over 10-40 minutes or subcutaneously (SC) on days 1-7 of each cycle. Cycles repeat every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients who achieve partial response (PR) or better may continue for up to 24 total cycles. Patients who achieve less than PR receive 2 additional cycles and, if PR or better is achieved, may complete up to 24 total cycles. Patients undergo bone marrow biopsy and aspiration and blood sample collection throughout the study. After completion of study treatment, patients are followed up at 30 days and then every 6 months for up to 24 months after last dose of study medication.
研究者
Uma Borate
Principal Investigator
Ohio State University Comprehensive Cancer Center
入排标准
入选标准
- •Signed informed consent must be obtained prior to participation in the study
- •Age ≥ 18 years at the date of signing the informed consent form (ICF)
- •Morphologically confirmed diagnosis of the following based on 2016 World Health Organization (WHO) classification (Arber et al 2016): Phase 1b, patients with relapsed or refractory of any of the following; phase 2, patients with newly diagnosed of any of the following:
- •Chronic myelomonocytic leukemia (CMML), classified as intermediate-2, OR high-risk per the CMML Specific Prognostic Scoring System (CPSS) Molecular Model
- •Atypical chronic myelocytic leukemia (aCML)
- •MDS/MPN unclassified (MDS/MPN-U)
- •Myeloproliferative neoplasm accelerated phase (MPN-AP)
- •MPN-AP requires a previous diagnosis of polycythemia vera (PV), essential thrombocythemia (ET), or primary myelofibrosis (PMF) with intermediate-2 or high risk disease according to International Prostate Symptom Score (IPSS) as well as progression on or failure to respond to at least one line of therapy.
- •Myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) or MDS/MPN with SF3B1 mutation and thrombocytosis (MDS/MPN-SF3B1-T).
- •Not suitable for immediate myeloablative/intensive chemotherapy based on investigator assessment of age, comorbidities, local guidelines, institutional practice (any or all of these)
排除标准
- •Previous treatment for MPN or MDS/MPN overlap with chemotherapy or other antineoplastic agents including lenalidomide and hypomethylating agent (HMAs) such as decitabine or azacitidine or INQOVI (oral decitabine) (patients who had up to 2 cycles of hypomethylating agents \[HMAs\] can be included). However, previous treatment with hydroxyurea and/or ruxolitinib is permitted
- •Diagnosis of acute myeloid leukemia (AML) including acute promyelocytic leukemia and extra-medullary AML based on WHO 2016 classification (Arber et al 2016)
- •Patients who are candidates for myeloablative or intensive chemotherapy treatment or who do not provide consent for this treatment
- •History of organ transplant or allogenic hematopoietic stem cell transplant
- •Participants with prior malignancy, except:
- •Participants with history of adequately treated malignancy for which no anticancer systemic therapy (namely chemotherapy, radiotherapy or surgery) is ongoing or required during the course of the study.
- •Participants who are receiving adjuvant therapy such as hormone therapy are eligible. However, participants who developed therapy related neoplasms are not eligible
- •Previous known allergy/sensitivity to components of axatilimab
- •History of acute or chronic pancreatitis
- •History of myositis
研究组 & 干预措施
Phase I (Axatilimab)
Patients receive axatilimab IV over 30 minutes on days 1 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. At time of phase Ib completion, patients with clinical improvement may transition to phase II. Patients undergo bone marrow biopsy and aspiration and blood sample collection throughout the study.
干预措施: Axatilimab
Phase I (Axatilimab)
Patients receive axatilimab IV over 30 minutes on days 1 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. At time of phase Ib completion, patients with clinical improvement may transition to phase II. Patients undergo bone marrow biopsy and aspiration and blood sample collection throughout the study.
干预措施: Biospecimen Collection
Phase I (Axatilimab)
Patients receive axatilimab IV over 30 minutes on days 1 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. At time of phase Ib completion, patients with clinical improvement may transition to phase II. Patients undergo bone marrow biopsy and aspiration and blood sample collection throughout the study.
干预措施: Bone Marrow Aspiration and Biopsy
Phase II (Axatilimab and azacitidine)
Patients receive axatilimab IV over 30 minutes on days 1 and 15 and azacitidine IV over 10-40 minutes or SC on days 1-7 of each cycle. Cycles repeat every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients who achieve PR or better may continue for up to 24 total cycles. Patients who achieve less than PR receive 2 additional cycles and, if PR or better is achieved, may complete up to 24 total cycles. Patients undergo bone marrow biopsy and aspiration and blood sample collection throughout the study.
干预措施: Axatilimab
Phase II (Axatilimab and azacitidine)
Patients receive axatilimab IV over 30 minutes on days 1 and 15 and azacitidine IV over 10-40 minutes or SC on days 1-7 of each cycle. Cycles repeat every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients who achieve PR or better may continue for up to 24 total cycles. Patients who achieve less than PR receive 2 additional cycles and, if PR or better is achieved, may complete up to 24 total cycles. Patients undergo bone marrow biopsy and aspiration and blood sample collection throughout the study.
干预措施: Azacitidine
Phase II (Axatilimab and azacitidine)
Patients receive axatilimab IV over 30 minutes on days 1 and 15 and azacitidine IV over 10-40 minutes or SC on days 1-7 of each cycle. Cycles repeat every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients who achieve PR or better may continue for up to 24 total cycles. Patients who achieve less than PR receive 2 additional cycles and, if PR or better is achieved, may complete up to 24 total cycles. Patients undergo bone marrow biopsy and aspiration and blood sample collection throughout the study.
干预措施: Biospecimen Collection
Phase II (Axatilimab and azacitidine)
Patients receive axatilimab IV over 30 minutes on days 1 and 15 and azacitidine IV over 10-40 minutes or SC on days 1-7 of each cycle. Cycles repeat every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients who achieve PR or better may continue for up to 24 total cycles. Patients who achieve less than PR receive 2 additional cycles and, if PR or better is achieved, may complete up to 24 total cycles. Patients undergo bone marrow biopsy and aspiration and blood sample collection throughout the study.
干预措施: Bone Marrow Aspiration and Biopsy
Phase II (Axatilimab and azacitidine)
Patients receive axatilimab IV over 30 minutes on days 1 and 15 and azacitidine IV over 10-40 minutes or SC on days 1-7 of each cycle. Cycles repeat every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients who achieve PR or better may continue for up to 24 total cycles. Patients who achieve less than PR receive 2 additional cycles and, if PR or better is achieved, may complete up to 24 total cycles. Patients undergo bone marrow biopsy and aspiration and blood sample collection throughout the study.
干预措施: Survey Administration
结局指标
主要结局
Incidence of dose limiting toxicities
时间窗: Up to 42 days after the first dose of study medication
Includes hematologic and non-hematologic toxicities
Overall response rate
时间窗: Up to 5 years
The number of participants whose best response (according to the 2006 International Working Group response criteria) over the efficacy analysis period is a complete response or partial response will be tallied to estimate the overall response rate and provide a 95% exact confidence interval, according to the Clopper-Pearson method.
次要结局
- Number of packed red blood cell transfusions(Up to 5 years)
- Number of platelet transfusions(Up to 5 years)
- Quality of life measured by Modified Myeloproliferative Neoplasm Symptom Assessment Form (MPNSAF)(Up to 5 years)
- Incidence of adverse events(Up to 30 days after end of treatment)
- Time in hospital(Up to 5 years)