NCT07548450尚未招募2 期
A Phase II Study of Mosunetuzumab in Combination With Pirtobrutinib in Patients With Relapsed or Refractory Waldenstrom Macroglobulinemia (MPOWER)
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 25
- 试验地点
- 1
- 主要终点
- The recommended phase 2 dose (RP2D) which will be determined based on the rate of dose-limiting toxicities (DLTs) during the DLT evaluation period.
研究概览
简要总结
The purpose of this clinical trial it to test the safety and tolerability of the study drugs mosunetuzumab in combination with pirtobrutinib in patients with relapsed or refractory Waldenstrom's Macroglobulinemia.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subjects aged ≥ 18 years with documented diagnosis of WM with the definition of measurable disease
- •Subjects who are able to comply with the study protocol.
- •Subjects with relapsed or refractory WM who have received at least one prior line of therapy.
- •Must have received prior treatment with covalent BTK inhibitor or have declined such treatment.
- •Prior autologous stem cell transplant is permitted if completed ≥ 100 days prior to treatment.
- •Prior allogeneic transplants are not permitted.
- •Subjects must have an indication for treatment per IWWM
- •ECOG Performance Status ≤ 2
- •Adequate organ function as defined as:
- •Hematologic:
- •Absolute neutrophil count ≥ 1000/mm3 independent of G-CSF support, unless there is documented bone marrow involvement or splenomegaly with ensuing cytopenia in which case ANC of 750 cells/mm3 (0.75 x 10^9/L) is permissible. Also, there should be no evidence of myelodysplasia or hypoplastic bone marrow.
- •Platelet count ≥75,000 cells/mm3 (≥75 x 10^9/L) independent of transfusion support unless there is documented bone marrow involvement in which case platelet count of 50,000 cells/mm3 (50 x 10^9/L) is permissible. Patients must be responsive to transfusion support if given for thrombocytopenia and patients refractory to transfusion support are not eligible. Also, there should be no evidence of myelodysplasia or hypoplastic bone marrow.
- •Hemoglobin of ≥ 8.5 g/dL (≥ 85 g/L) independent of transfusion support unless there is documented bone marrow involvement or splenomegaly with ensuing cytopenia in which case hemoglobin of 7 g/dL (70 g/L) is permissible. Patients must be responsive to transfusion support if given for anemia and patients refractory to transfusion support are not eligible. Also, there should be no evidence of myelodysplasia or hypoplastic bone marrow.
- •Coagulation: Activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) and prothrombin (PT) or (international normalized ratio (INR) not greater than 1.5 x ULN.
- •Total Bilirubin ≤ 1.5x institutional upper limit of normal (ULN) or ≤3 x ULN with document liver involvement and/ or Gilbert's disease
- •AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN
- •Participants with liver metastases will be allowed to enroll with AST and ALT levels ≤ 5 x ULN.
- •Estimated creatinine clearance ≥ 50 mL/min by Cockcroft-Gault formula.
- •Participants must adhere to the following sex and contraceptive/barrier requirements:
- •If participant is of childbearing potential, they must have a negative pregnancy test
- •For participants of non-childbearing potential: The post-menopausal status will be defined as having been amenorrheic for 12 months without an alternative medical cause (or having undergone surgical sterilization (bilateral oophorectomy of hysterectomy). The following age-specific requirements apply:
- •< 50 years of age:
- •Amenorrheic for ≥ 12 months following cessation of exogenous hormonal treatments; and
- •Luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution
- •-≥ 50 years of age:
- •Amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments; or
- •Had radiation-induced menopause with last menses >1 year ago; or
- •Had chemotherapy-induced menopause with last menses >1 year ago
- •Luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution
- •Participants of childbearing potential and participants with a sexual partner of childbearing potential must agree to use a highly effective method of contraception and lactation requirements as described in Sections 5.4.1 and 5.4.
- •Able to swallow oral tablets.
- •Clinically significant adverse effects from any prior oncologic treatment (e.g. prior surgery, radiotherapy, or other antineoplastic therapy) must have recovered to grade 1 or have been determined to be clinically stable per the Investigator.
- •Subject or their legal representative is able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines.
排除标准
- •History of transformation of indolent disease to DLBCL
- •Active or history of CNS lymphoma or leptomeningeal infiltration
- •Prior treatment with a non-covalent BTK inhibitor
- •Prior treatment with CD20-directed bispecific antibody therapy
- •Receiving other investigational agents.
- •Receipt of a live, attenuated vaccine within 4 weeks before first dose of study treatment or anticipation that such a live attenuated vaccine will be required during the study
- •Patients must not receive live, attenuated vaccines (e.g., FluMistâ) while receiving study treatment or after the last dose until B-cell recovery to the normal ranges.
- •Inactivated influenza vaccination should be given during the influenza season only.
- •An approved coronavirus disease 2019 (COVID-19) vaccine (messenger RNA [mRNA], inactivated virus, and replication deficient viral vector vaccines) is allowed, as these are not considered live vaccines.
- •Receipt of systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) with the exception of corticosteroid treatment £ 10 mg/day prednisone or equivalent within 2 weeks prior to the first dose of mosunetuzumab
- •Patients who received acute, low-dose, systemic immunosuppressant medications (e.g., single dose of dexamethasone for nausea or B-symptoms) may be enrolled in the study if deemed appropriate by the investigator.
- •The use of inhaled corticosteroids is permitted.
- •The use of mineralocorticoids for management of orthostatic hypotension is permitted.
- •The use of physiologic doses of corticosteroids for management of adrenal insufficiency is permitted.
- •History of solid organ transplantation
- •History of severe allergic or anaphylactic reaction to humanized, chimeric or murine monoclonal antibodies (MAbs) or known sensitivity or allergy to murine products
- •Known active bacterial, viral (including SARS-CoV-2), fungal, or other infection, or any major episode of infection requiring treatment with IV antibiotics within 4 weeks of Day 1 of Cycle 1
- •Known or suspected chronic active Epstein-Barr virus (EBV) infection
- •Known or suspected history of macrophage activation syndrome (MAS) / hemophagocytic lymphohistiocytosis (HLH)
- •History of confirmed progressive multifocal leukoencephalopathy (PML)
- •Current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease
- •Patients with a history of stroke who have not experienced a stroke or transient ischemic attack in the past 1 year and have no significant residual neurologic deficits as judged by the investigator are allowed.
- •Patients with a history of epilepsy who have had no seizures in the past 1 year while not receiving any anti-epileptic medications are allowed.
- •Clinically significant active malabsorption syndrome or other conditions likely to affect gastrointestinal absorption of the study drug
- •History of bleeding diathesis
- •Major surgery 4 weeks prior to starting study therapy or participant has not fully recovered from major surgery.
- •The diagnosis of another malignancy which, in the opinion of the Investigator, is likely to negatively impact the participant's safety or ability to participate in the study.
- •Current evidence of uncontrolled, significant intercurrent illness including, but not limited to, the following conditions:
- •Cardiovascular disorders:
- •Congestive heart failure New York Heart Association Class III or IV, unstable angina pectoris, serious cardiac arrhythmias.
- •Unstable angina or acute coronary syndrome within 6 months prior to first dose of study therapy.
- •History of myocardial infarction within 6 months prior to first dose of study therapy
- •QTc prolongation defined as a QTcF > 470 ms.
- •Correction of suspected drug induced QTcF prolongation can be attempted at the investigator's discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation.
- •Correction for underlying bundle branch block (BBB) allowed.
- •Note: Patients with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker
- •--Left ventricular ejection fraction < 40% within 12 months prior to first dose of study therapy.
- •Any other condition that would, in the Investigator's judgment, contraindicate the participant's participation in the clinical study due to safety concerns or compliance with clinical study procedures (e.g., infection/inflammation, intestinal obstruction, social/ psychological issues, etc.)
- •Evidence of other clinically significant uncontrolled condition(s) or other clinically significant active disease process which, in the opinion of the investigator, is likely to pose a risk for patient participation.
- •Known HIV infection.
- •Clinically significant history of liver disease, including viral or other hepatitis, or cirrhosis
- •-Note: Participants with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Participants with positive anti-HBc and negative HBV DNA should be on prophylactic nucleo(t)side analogue therapy to prevent reactivation with serial HBV DNA PCR monitoring Participants positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
- •Known active cytomegalovirus (CMV) infection.
- •History of autoimmune disease, including, but not limited to myocarditis, pneumonitis, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis
- •Patients with a remote history of, or well-controlled, autoimmune disease with a treatment-free interval from immunosuppressive therapy for 12 months may be eligible to enroll if judged to be safe by the investigator.
- •Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid-replacement hormone are eligible.
- •Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
- •Patients with a history of disease-related immune thrombocytopenic purpura, or autoimmune hemolytic anemia may be eligible.
- •Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:
- •Rash must cover 10% of body surface area
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研究组 & 干预措施
Dosing Strategy 1-Mosunetuzumab and Pirtobrutinib
Experimental
Participants receive pirtobrutinib daily on days 1-21 of 21 day cycles. Mosunetuzumab will be administered subcutaneously starting on cycle 2, day 1.
If patients have a complete response to treatment, after 9 cycles, they will continue with on pirtobrutinib for a total of 18 cycles.
If patients receive a very good partial or minor response, they will continue to receive Mosunetuzumab and Pirtobrutinib for a total of 18 cycles.
干预措施: Pirtobrutinib (Drug)
Dosing Strategy 1-Mosunetuzumab and Pirtobrutinib
Experimental
Participants receive pirtobrutinib daily on days 1-21 of 21 day cycles. Mosunetuzumab will be administered subcutaneously starting on cycle 2, day 1.
If patients have a complete response to treatment, after 9 cycles, they will continue with on pirtobrutinib for a total of 18 cycles.
If patients receive a very good partial or minor response, they will continue to receive Mosunetuzumab and Pirtobrutinib for a total of 18 cycles.
干预措施: Mosunetuzumab (Drug)
Dosing Strategy 2- Mosunetuzumab and Pirtobrutinib
Experimental
Participants receive pirtobrutinib daily on days 1-21 of 21 day cycles.
Mosunetuzumab will be administered subcutaneously starting on cycle 3, day 1.
If patients have a complete response to treatment, after 9 cycles, they will continue with on pirtobrutinib for a total of 19 cycles.
If patients receive a very good partial or minor response, they will continue to receive Mosunetuzumab and Pirtobrutinib for a total of 19 cycles.
干预措施: Mosunetuzumab (Drug)
Dosing Strategy 2- Mosunetuzumab and Pirtobrutinib
Experimental
Participants receive pirtobrutinib daily on days 1-21 of 21 day cycles.
Mosunetuzumab will be administered subcutaneously starting on cycle 3, day 1.
If patients have a complete response to treatment, after 9 cycles, they will continue with on pirtobrutinib for a total of 19 cycles.
If patients receive a very good partial or minor response, they will continue to receive Mosunetuzumab and Pirtobrutinib for a total of 19 cycles.
干预措施: Pirtobrutinib (Drug)
结局指标
主要结局
The recommended phase 2 dose (RP2D) which will be determined based on the rate of dose-limiting toxicities (DLTs) during the DLT evaluation period.
时间窗: 5 years
To determine the safety and tolerability of mosunetuzumab in combination with pirtobrutinib.
Best very good partial response (VGPR) or better per the modified IWWM6 criteria.1
时间窗: 5 years
To determine the efficacy of the combination of mosunetuzumab and pirtobrutinib.
次要结局
- Best response rates including partial response (PR), Best very good partial response (VGPR), complete response (CR), major response (PR+VGPR+CR) and overall response (minor response + major response).(5 years)
- Best very good partial response (VGPR)/partial response (PR)/minor response conversion rates from Cycle 8 to 18 (dosing strategy 1(DS1)), and Cycle 9 to 19 (dosing strategy 2(DS2)), as applicable.(5 years)
- Duration of response (DoR), defined as the interval of time from the date of initial documented response (minor response or better per modified IWWM6 criteria) to the time of relapse or death from any cause.(5 years)
- Progression free survival (PFS) as defined as the time from study therapy initiation to the time documented disease progression (as assessed by modified IWWM6 criteria) or death from any cause.(5 years)
- Overall survival (OS) as defined as the time from study therapy initiation until death from any cause.(5 years)
研究者
研究点 (1)
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