An Open-Label Phase Ib, Multicenter Study To Evaluate The Safety And Efficacy Of Belantamab Mafodotin Plus Cevostamab And Pomalidomide In Participants With Relapsed/Refractory Multiple Myeloma (RRMM)
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 108
- 试验地点
- 7
- 主要终点
- Recommended Phase 2 Dose (RP2D)
研究概览
简要总结
This study will evaluate efficacy and tolerability various doses of belantamab mafodotin in combination with cevostamab and pomalidomide in patients with multiple myeloma who have relapsed disease after two or more lines of therapy and/or have refractory to treatment disease.
详细描述
This is a phase Ib, multicenter, open-label study to evaluate the safety and efficacy various doses of belantamab mafodotin (belamaf) in combination with cevostamab and pomalidomide in patients with relapsed and/or refractory multiple myeloma (RRMM). The study consists of 2 parts.
Part 1 will evaluate the clinical activity and safety of up to three dose combinations of belamaf and cevostamab in patients who have relapsed and refractory multiple myeloma after receiving 2 or more prior lines of therapy and having previously received lenalidomide, a proteosome inhibitor, and/or anti-CD38 mAb. Their disease must be refractory to the last line of therapy. The doses will be evaluated in cohorts: Cohort 1a - belamaf 1.9 mg/kg + cevostamab 90 mg; Cohort 1b - belamaf 1.9 mg/kg + cevostamab 160 mg; and Cohort 1c - belamaf 2.5 mg/kg + cevostamab 160 mg. In this part I the recommended phase 2 dose (RP2D) of the combination will be determined.
Part 2 will evaluate the clinical activity and safety of the recommended phase 2 dose (RP2D) in patients who have relapsed multiple myeloma having previously received 1-3 prior line of therapy including lenalidomide, a proteosome inhibitor, and/or an anti-CD38 mAb.
In addition, a cohort exploring the safety and efficacy of the combination of cevostamab and belamaf at the recommended phase 2 dose (RP2D) with low dose pomalidomide (2 mg ) will be considered.
This study will have an induction phase (cycle 1-6) and a maintenance phase (cycle 7 onwards). Participants will receive study treatment until progression is documented. Participants will be followed for up to 24 months after confirmation of progressive disease or until death, whichever is reached earlier.
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 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Must be able to understand and voluntarily sign an informed consent form (ICF).
- •Must be ≥ 18 years of age at the time of signing the ICF.
- •Must be able to adhere to the study visit schedule and other protocol requirements.
- •Documented diagnosis of MM and must have:
- •(Part 1) relapsed and refractory disease having previously received 2 or more prior lines and having previously received lenalidomide, a proteosome inhibitor and/or anti-CD38 mAb (triple class exposed) and must be refractory to the last line of therapy.
- •(Part 2) relapsed disease having previously received 1-3 prior line of therapy including lenalidomide, a proteosome inhibitor, and/or an anti-CD38 mAb .
- •Lines of therapy are defined as per the consensus panel of the International Myeloma Workshop and include induction therapy followed by ASCT and consolidation/maintenance as one line.
- •Relapse is defined as documented evidence of progressive disease (PD) after achieving at least stable disease (SD) for ≥ 1 cycle during a previous MM treatment (i.e., relapsed MM). and refractory is defined as disease progression during or within 60 days from the end of the most recent MM treatment.
- •Subjects with measurable disease defined as at least one of the following (these baseline laboratory studies for determining eligibility must be obtained within 28 days prior to start of study drug):
- •Serum M-protein ≥ 5 g/l
- •Urine M-protein ≥ 200 mg/24 h
- •Serum free light chains (FLC) assay: Involved FLC level ≥ 100 mg/l and an abnormal serum free light chain ratio (< 0.26 or > 1.65).
- •Subjects with a history of autologous stem cell transplant are eligible for study participation provided the following eligibility criteria are met:
- •- Transplant was > 100 days prior to study enrollment
- •Must have Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or
- •Adequate organ system function defined as:
- •Absolute neutrophil count (ANC) > 1.0 x 109/L. Granulocyte colony-stimulating factor (G-CSF) cannot be given within 7 days prior to first study drug administration.
- •Hemoglobin ≥ 8.0 g/dL.
- •Platelet count >75 x 109/L.
- •Serum alanine transaminase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN).
- •Total bilirubin ≤ 1.5 x ULN, unless known to have Gilbert's disease. If Gilberts, isolated bilirubin >1.5 and <3xULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%.
- •Estimated glomerular filtration rate (eGFR) (MDRD) ≥ 30 mL/min.
- •Albumin/creatinine ratios (spot urine) <500mg/g (56 mg/mmol).
- •Albumin ≥ 2.0 g/dL (20 g/L).
- •Left ventricular ejection fraction (LVEF) >50%.
- •Serum calcium (corrected for albumin) level ≤11.5 mg/dL (treatment of hypercalcemia is allowed and patient may enroll if hypercalcemia returns to Grade ≤1 with standard treatment).
- •All prior treatment-related toxicities must be Grade <1 at the time of screening except for alopecia (any grade), neuropathy (Grade <2), cataracts or endocrinopathy managed with replacement therapy (any grade).
- •For women of childbearing potential and males: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception.
- •Male Participants:
- •Male participants are eligible to participate if they agree to the following during the intervention period and for at 6 months after the last dose of study intervention to allow for clearance of any altered sperm:
- •Refrain from donating sperm.
- •PLUS, either:
- •Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent.
- •OR c. Must agree to use contraception/barrier as detailed below: d. Agree to use a male condom, even if they have undergone a successful vasectomy, and female partner to use an additional highly effective contraceptive method with a failure rate of <1% per year when having sexual intercourse with a woman of childbearing potential who is not currently pregnant.
- •Female Participants:
- •A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
- •a. Is not a woman of childbearing potential (WOCBP). OR Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during the intervention period and for at least 5 months after the last dose of study intervention.
- •A WOCBP must have a negative highly sensitive pregnancy test [serum] as required by local regulations) within 72 hours before the first dose of study intervention and agree to use effective contraception during the study and for 5 months after the last dose of cevostamab, 3 months after the last dose of tocilizumab and 4 months after the last dose of belamaf.
排除标准
- •Prior treatment with bispecific or BCMA targeted antibody drug conjugate. Note prior anti-BCMA CAR T-cell therapy is permitted provided that the subject achieved a response of partial response (PR) or better and did not progress within 12 months of CAR T-cell infusion.
- •Prior exposure to FcRH5 targeted therapy.
- •Life-expectancy less than or equal to 12 weeks.
- •WOCBP who are pregnant or lactating.
- •Known history of amyloidosis, POEMS syndrome, active plasma cell leukemia (defined as circulating plasma cell count exceeding 500/uL or 5% of the peripheral blood white cells) at the time of screening.
- •Inability to comply with protocol-mandated hospitalization and activities restrictions.
- •History of allogeneic stem cell transplant.
- •Any serious and/or unstable pre-existing medical, psychiatric disorder, or other conditions (including lab abnormalities) that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures.
- •Evidence of active mucosal or internal bleeding.
- •Presence of active renal condition (infection, requirement for dialysis or any other condition that could affect participant's safety).
- •Subjects with previous or concurrent malignancies are allowed only if the second tumor is not contributing to the subject's illness and deemed to be at negligible risk of metastasis or death (e.g., expected 5-year OS ≥90%). Examples include ductal carcinoma in situ not requiring chemotherapy, appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, low-grade, localized prostate cancer (Gleason score ≤7) not requiring treatment or appropriately treated Stage I uterine cancer. Subjects must be appropriately observed or managed/controlled are permitted onto study. The subject must not be receiving active therapy, other than hormonal therapy for this disease and the disease must be considered medically stable for at least 2 years.
- •Current corneal epithelial disease except mild punctate keratopathy.
- •History of autoimmune disease, including, but not limited to, 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.
- •- Note that patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for this study.
- •Patients with history of confirmed progressive multifocal leukoencephalopathy (PML).
- •Prior solid organ transplantation.
- •Treatment with radiotherapy (with the exception of local, palliative radiotherapy for management of pain or for stabilization of an extensive bone lesion at risk of pathologic fracture or damage to surrounding tissue), any chemotherapeutic agent, or treatment with systemic therapy (systemic or biologic agent) 14 days. Prior treatment with a monoclonal antibody within 28 days of receiving the first dose of study drug.
- •Prior treatment with a monoclonal antibody, denosumab for hypercalcaemia is allowed.
- •Use of an investigational drug within five half-lives or 28 days if the half-life of the investigational agent is unknown, preceding the first dose of study drug.
- •Any major surgery within the last ≤ 4 weeks prior to initiating study treatment.
- •Current unstable liver or biliary disease defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis. Note: Stable chronic liver disease (including Gilbert's syndrome or asymptomatic gallstones) or hepatobiliary involvement of malignancy is acceptable if participant otherwise meets entry criteria.
- •Evidence of cardiovascular risk including any of the following:
- •Evidence of current clinically significant untreated arrhythmias, including clinically significant ECG abnormalities such as 2nd degree (Mobiz Type II) or 3rd degree atrioventricular (AV) block.
- •QTc interval ≥ 470 msecs. NOTE: The QT interval should be corrected for the heart rate by Fridericia's formula (QTcF)
- •History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, stenting or bypass grafting, all within 6 months of Screening.
- •Class III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.
- •Uncontrolled hypertension
- •Current or past history of central nervous system (CNS) disease, such as stroke, epilepsy, CNS vasculitis, neurodegenerative disease, or CNS involvement by MM
- •Note that patients with a history of stroke who have not experienced a stroke or transient ischemic attack in the past 2 years and have no residual neurologic deficits as judged by the investigator are allowed.
- •Note that patients with a history of epilepsy who have had no seizures in the past 2 years while not receiving any anti-epileptic medications are allowed.
- •Significant active pulmonary disease (e.g., bronchospasm and/or obstructive pulmonary disease)
- •Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to belamaf and/or cevostamab any of the components of the study treatment. History of severe hypersensitivity to other mAbs.
- •Known history of HLH/IEH-HS or macrophage activation syndrome (MAS).
- •Prior treatment with systemic immunotherapeutic agents, including, but not limited to cytokine therapy and anti-CTLA4, anti-PD-1, and anti-PD-L1 therapeutic antibodies, within 12 weeks or 5 half-lives of the drug, whichever is shorter, before first dose of study drugs.
- •Active infection requiring antibiotic, antiviral, or antifungal treatment.
- •Known HIV infection.
- •Recent history (within the past 6 months) of acute diverticulitis, inflammatory bowel disease, intra-abdominal abscess, or gastrointestinal obstruction.
- •Known or suspected chronic active Epstein-Bar Virus (EBV) infection. Guidelines for diagnosing chronic active EBV infection are provided by Okano et al.
- •Presence of hepatitis B (HBV) surface antigen (HBsAg) or positive HBV PCR test at screening or within 3 months prior to first dose of study treatment. Participants with positive hepatitis B core antibody (HBcAb) can be enrolled, only if confirmatory negative Hepatitis B DNA is obtained AND patient is on hepatitis B prophylaxis (eg tenofovir or entecavir) before first dose of study drugs. Presence of isolated Hep B surface antigen (HBsAb) indicating previous vaccination will not exclude a participant.
- •Positive hepatitis C (HCV) antibody test result or positive hepatitis C RNA test result at screening or within 3 months prior to first dose of study treatment.
- •Note: Participants with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained. Hepatitis RNA testing is optional and participants with negative Hepatitis C antibody test are not required to also undergo Hepatitis C RNA testing.
- •History of receiving systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents), with the exception of corticosteroid treatment ≤10mg/day prednisone or equivalent within 2 weeks prior to first dose of study drugs.
- •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 however the dose should not exceed 10 mg prednisone a day.
- •Intolerance to prednisone or dexamethasone that would preclude the patient from taking the full starting dose of dexamethasone or prednisone as described in the protocol.
研究组 & 干预措施
Belamaf + Cevostamab
Belamaf + Cevostamab will be administrated on the dose escalation schedule in cycles: induction phase cycles are 21 days (Q3W) for 6 cycles followed by maintenance phase cycles, which are 42 days (Q6W). Up to 3 cohorts (Cohorts 1a-c) evaluating escalating doses of belamaf and cevostamab will be evaluated. (Cohort 1a - belamaf 1.9 mg/kg + cevostamab 90 mg; Cohort 1b - belamaf 1.9 mg/kg + cevostamab 160 mg; and Cohort 1c - belamaf 2.5 mg/kg + cevostamab 160 mg.) Treatment will continue until progression or unacceptable toxicity.
Then, after the recommended phase 2 dose (RP2D) is determined, Cohort 2 will receive Belamaf + Cevostamab at the RP2D schedule in cycles: induction phase cycles are 21 days (Q3W) for 6 cycles followed by maintenance phase cycles, which are 42 days (Q6W). Treatment will continue until progression or unacceptable toxicity.
干预措施: Belamaf (Drug)
Belamaf + Cevostamab
Belamaf + Cevostamab will be administrated on the dose escalation schedule in cycles: induction phase cycles are 21 days (Q3W) for 6 cycles followed by maintenance phase cycles, which are 42 days (Q6W). Up to 3 cohorts (Cohorts 1a-c) evaluating escalating doses of belamaf and cevostamab will be evaluated. (Cohort 1a - belamaf 1.9 mg/kg + cevostamab 90 mg; Cohort 1b - belamaf 1.9 mg/kg + cevostamab 160 mg; and Cohort 1c - belamaf 2.5 mg/kg + cevostamab 160 mg.) Treatment will continue until progression or unacceptable toxicity.
Then, after the recommended phase 2 dose (RP2D) is determined, Cohort 2 will receive Belamaf + Cevostamab at the RP2D schedule in cycles: induction phase cycles are 21 days (Q3W) for 6 cycles followed by maintenance phase cycles, which are 42 days (Q6W). Treatment will continue until progression or unacceptable toxicity.
干预措施: Cevostamab (Biological)
Belamaf + Cevostamab+ Pomalidomide
Belamaf + Cevostamab at RP2D with pomalidomide at 2 mg at 14/21 schedule in cycles: induction phase cycles are 21 days (Q3W) for 6 cycles followed by maintenance phase cycles, which are are 42 days (Q6W). pomalidomide on 14/21 schedule. Treatment will continue until progression or unacceptable toxicity.
干预措施: Belamaf (Drug)
Belamaf + Cevostamab+ Pomalidomide
Belamaf + Cevostamab at RP2D with pomalidomide at 2 mg at 14/21 schedule in cycles: induction phase cycles are 21 days (Q3W) for 6 cycles followed by maintenance phase cycles, which are are 42 days (Q6W). pomalidomide on 14/21 schedule. Treatment will continue until progression or unacceptable toxicity.
干预措施: Pomalidomide (Drug)
Belamaf + Cevostamab+ Pomalidomide
Belamaf + Cevostamab at RP2D with pomalidomide at 2 mg at 14/21 schedule in cycles: induction phase cycles are 21 days (Q3W) for 6 cycles followed by maintenance phase cycles, which are are 42 days (Q6W). pomalidomide on 14/21 schedule. Treatment will continue until progression or unacceptable toxicity.
干预措施: Cevostamab (Biological)
结局指标
主要结局
Recommended Phase 2 Dose (RP2D)
时间窗: From the first dose of study drugs until the end of 3 cycles of therapy (up to 9 weeks; each cycle is 21 days) in the last dose-escalation cohort, or until study therapy is discontinued due to disease progression or toxicity, whichever occurs first.
The Recommended Phase 2 Dose (RP2D) will be determined based on the incidence of dose-limiting toxicities (DLTs), overall tolerability, and preliminary antitumor activity. DLTs will be evaluated based on adverse events, clinical assessments, and laboratory test results.
Overall Response Rate (ORR)
时间窗: From 3 weeks after the first dose of study therapy (end of Cycle 1; Cycle 1 is 21 days) until the date of documented disease progression or death from any cause, whichever occurs first, assessed up to 24 months.
Overall Response Rate (ORR) is defined as the proportion of participants who achieved a stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) according to International Myeloma Working Group (IMWG) criteria.
次要结局
- Progression Free Survival (PFS)(From the date of the first dose of study therapy until the date of documented disease progression or death from any cause, whichever occurs first, assessed up to 24 months.)
- Duration of Response (DOR)(From the date of first documented partial response or better to the date of documented disease progression or death, whichever occurs first, assessed up to 24 months.)
- Overall Survival (OS)(From the date of the first dose of therapy until the date of death from any cause, assessed up to 24 months.)
- Rates of Corneal Adverse Events(From 1 day before receiving belamaf until the end of treatment or, if corneal findings are present, until corneal findings return to pre-treatment (baseline) condition or become stable, assessed up to 12 months.)
- Number of Participants with Adverse Events (AEs), Serious Adverse Events (SAEs)(From 1 day before receiving study therapy until death from any cause or 90 days after discontinuation of study therapy, whichever occurs first.)
- Number of Adverse Events of Special Interest (AESI)(From 1 day before receiving the study therapy until the date of death from any cause or 90 days following last date of study therapy, whichever occurs first.)
- Change from Baseline in Health-Related Quality of Life as Assessed by EORTC QLQ-C30(From 1 day before receiving study therapy to the end of study treatment, including the last day of treatment, assessed up to approximate 73 months.)
- Change From Baseline in Patient-Reported Outcomes as Assessed by PRO-CTCAE(From 1 day before receiving study therapy to the end of study treatment, including the last day of treatment, assessed up to approximate 73 months.)