Nelfinavir and Lenalidomide/Dexamethasone in Patients With Progressive Multiple Myeloma That Have Failed Lenalidomide-containing Therapy - A Single Arm Phase I/II Trial
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 33
- 试验地点
- 11
- 主要终点
- Phase I: Dose limiting toxicity
研究概览
简要总结
There is a great need for treatment options in patients with multiple myeloma (MM) after failure of the lenalidomide/dexamethasone regimen as there is no established standard active therapy for these patients.
Combining nelfinavir, a drug targeting both the proteasome and PI3K/Akt pathway, with lenalidomide, may restore lenalidomide-sensitivity to the disease as has been shown in vivo for the PI3K/Akt inhibitor perifosine and the proteasome inhibitor bortezomib.
Patients expected to be included in the trial are heavily pretreated and might not be candidates for further intensive therapies. The combination of nelfinavir with lenalidomide/dexamethasone offers also to these patients an alternative. Preliminary experiences in another SAKK trial with the combination of bortezomib and nelfinavir are positive with few side effects with nelfinavir doses of up to 1875 mg twice daily (bid). For the phase I part of the trial a starting dose of 1250 mg nelfinavir bid was chosen, since the necessary plasma concentration of nelfinavir will not be reached with lower doses.
In case of progression during or after the trial treatment any other lenalidomide- or bortezomib-based chemotherapy combination could be an option for the patient. However, the addition of a chemotherapeutic drug like cyclophosphamide or doxorubicin has known side effects like hematological toxicities, nausea, vomiting and hair loss.
The aim of this trial is to demonstrate that the combination of nelfinavir with lenalidomide/dexamethasone is safe (phase I, dose escalation of nelfinavir) and active (phase II). Patients who do not respond to trial medication will stop trial treatment after 4 months of therapy at the latest.
If the combination of nelfinavir with lenalidomide/dexamethasone should prove to be safe and efficient in treatment of lenalidomide-refractory MM, this would be the first orally available treatment for these patients and establish a new class of drugs (human immunodeficiency virus (HIV) protease inhibitors) as active antineoplastic agents in MM. In addition this would establish the concept of "re-sensitizing" patients to lenalidomide therapy and demonstrate the effect of nelfinavir on proteasomal degradation and Akt phosphorylation in cancer patients in vivo.
详细描述
Disease background:
MM is a plasma cell tumor. It accounted for an estimated 20,180 new cases of cancer and 11,170 deaths in the United States in 2010. With a prevalence of 23 per 100,000 people, MM is an orphan disease (prevalence <5:10,000). The median age at diagnosis is 60-65 years. Although MM remains incurable, unprecedented gains in survival outcomes have been achieved in the last three decades. Survival has been improved mainly in younger patients below the age of 65 with the advent of high-dose melphalan therapy followed by autologous stem cell transplantation (ASCT). In the last 10 years the introduction of novel therapies, such as thalidomide, lenalidomide and bortezomib have further improved overall survival. However, all patients ultimately relapse and will require salvage therapies.
Therapy background:
The main decision criterion for first-line treatment selection is the patient's eligibility for high-dose chemotherapy with melphalan and subsequent ASCT. Patients who are not eligible for this treatment, due to advanced age, comorbidities or poor performance status, are routinely treated with a combination of melphalan, prednisone and a novel agent such as thalidomide, bortezomib or lenalidomide. Currently, patients will relapse from their first line of therapy at a median of 2-3 years from diagnosis. Achieving a near complete remission and maintaining the residual tumor mass under control is considered as the mainstay in current treatment of MM.
Treatment of relapsed/refractory myeloma is based on double or triple combinations with a novel agent such as lenalidomide or bortezomib with dexamethasone and/or cytotoxic drugs such as alkylators and anthracyclines. The choice of a regimen at relapse depends on the frontline therapy as well as disease- or therapy-related comorbidities. Although patients can achieve long lasting remissions with the novel agents MM remains a chronic disease. Patients will invariably relapse or become refractory to second and later line treatments. Therefore new treatment options for late-line patients are required.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •Patient must have given written informed consent (including the drug-specific informed consent for Revlimid) before registration.
- •Multiple myeloma having progressed after at least two months of lenalidomide-containing therapy (progressive disease during treatment with lenalidomide or <60 days after such treatment).
- •Measurable disease for myeloma defined as one of the following:
- •Serum monoclonal protein (M-protein) ≥10 g/L IgG or ≥5 g/L IgA, IgM, IgD
- •Urine M-protein ≥200 mg/24h
- •To be considered only if patient has no evidence of measurable disease with one of the criteria above: serum free light chain (FLC) ratio of kappa/lambda either >1.65 or <0.26 (baseline level of involved FLC has to be ≥100 mg/L)
- •Adverse events from previous treatment has recovered to grade ≤
- •Age ≥18 years.
- •WHO performance status 0-
- •Adequate hematological values: neutrophils ≥1 x 109/L, platelets ≥75 x 109/L
- •Adequate hepatic function: bilirubin ≤1.5 x ULN, AST and AP ≤2.5 x ULN
- •Adequate renal function: calculated creatinine clearance >50 mL/min, according to the formula of Cockcroft-Gault
- •Adequate cardiac function: EF ≥40% assessed by echocardiography or MUGA scan
- •Negative HIV test.
- •Women are not breastfeeding. Women of child-bearing potential are using effective contraception, are not pregnant and agree not to become pregnant during participation in the trial and during the 12 months thereafter. A negative serum pregnancy test (minimum sensitivity of 25 mIU/ml) before inclusion (within 7 days) into the trial is required for all women of child-bearing potential. Men agree not to father a child during participation in the trial and during 12 months thereafter.
- •Patient compliance and geographic proximity allow proper staging and follow-up.
排除标准
- •Previous malignancy within 2 years with the exception of adequately treated cervical carcinoma in situ or localized non-melanoma skin cancer.
- •Psychiatric disorder precluding understanding of information on trial related topics, giving informed consent, filling patient diary, or interfering with compliance for oral drug intake.
- •Concurrent treatment with other experimental drugs or other anti-cancer therapy (chemotherapeutical/biological agents, radiation therapy). Treatment in a clinical trial within 30 days prior to trial entry.
- •Known hypersensitivity or uncontrolled side effects related to trial drug(s) or hypersensitivity to any other component of the trial drugs.
- •Any concomitant drugs contraindicated for use with the trial drugs according to the approved product information.
- •Any serious underlying medical condition (at the judgment of the investigator) which could impair the ability of the patient to participate in the trial (e.g. active autoimmune disease, uncontrolled diabetes).
- •Unstable cardiovascular disease.
- •Known or clinically suspected myeloma manifestations in the central nervous system.
- •Previous grade 4 adverse events attributable to treatment with lenalidomide.
- •Patients who are on strong CYP3A4 modulators that cannot be replaced at least one week before the first dose of trial drugs and for the period of the trial.
研究组 & 干预措施
Nelfinavir and Lenalidomide/Dexamethasone
Phase I: Cycles 1-4 (1 cycle = 28 days) Lenalidomide: 25 mg per day p.o., day 1 to 21 Dexamethasone: 40/20 mg per day p.o., days 1, 8, 15, 22 Nelfinavir: Dose escalation in cohorts of 3 patients
Phase II: Cycles 1-4 (1 cycle = 28 days) Lenalidomide: 25 mg per day p.o., day 1 to 21 Dexamethasone: 40/20 mg per day p.o., days 1, 8, 15, 22 Nelfinavir: Dose established in phase I twice daily p.o., day 1 to 21
干预措施: Nelfinavir (Drug)
Nelfinavir and Lenalidomide/Dexamethasone
Phase I: Cycles 1-4 (1 cycle = 28 days) Lenalidomide: 25 mg per day p.o., day 1 to 21 Dexamethasone: 40/20 mg per day p.o., days 1, 8, 15, 22 Nelfinavir: Dose escalation in cohorts of 3 patients
Phase II: Cycles 1-4 (1 cycle = 28 days) Lenalidomide: 25 mg per day p.o., day 1 to 21 Dexamethasone: 40/20 mg per day p.o., days 1, 8, 15, 22 Nelfinavir: Dose established in phase I twice daily p.o., day 1 to 21
干预措施: Lenalidomide (Drug)
Nelfinavir and Lenalidomide/Dexamethasone
Phase I: Cycles 1-4 (1 cycle = 28 days) Lenalidomide: 25 mg per day p.o., day 1 to 21 Dexamethasone: 40/20 mg per day p.o., days 1, 8, 15, 22 Nelfinavir: Dose escalation in cohorts of 3 patients
Phase II: Cycles 1-4 (1 cycle = 28 days) Lenalidomide: 25 mg per day p.o., day 1 to 21 Dexamethasone: 40/20 mg per day p.o., days 1, 8, 15, 22 Nelfinavir: Dose established in phase I twice daily p.o., day 1 to 21
干预措施: Dexamethasone (Drug)
结局指标
主要结局
Phase I: Dose limiting toxicity
时间窗: Until up to 4 weeks after start of trial therapy
Phase II: Overall response
时间窗: 16 weeks after the start of trial therapy
次要结局
- Phase I/II: Frequency and percent of occurrence of adverse events during each cycle of treatment, and within patients(Until 30 days after up to 16 weeks of trial therapy)
- Phase I/II: Time to progression(Duration from start of treatment to disease progression, with deaths due to causes other than progression censored, assessed until an expected maximum of 3 years)
- Phase I/II: Duration of response(Duration from first observation of response to the time of disease progression, with deaths due to causes other than progression censored, assessed until an expected maximum of 3 years)
- Phase I/II: Progression free survival(Progression free survial time)
- Phase I: Overall response(16 weeks after the start of trial therapy)
- Phase I/II: Disease control, i.e. no progression at 16 weeks after start of trial therapy(At 16 weeks after the start of trial therapy)
- Phase I/II: Overall survival(At 6 months after start of trial therapy)