Double-blind, Placebo Controlled, Ascending Dose, Randomized Phase 1B/2A Study, Investigating Safety, Tolerability, PK/PD of FE 203799 in Lymphoma Patients, Undergoing Myeloablative Chemotherapy Before Autologous Transplantation
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 发起方
- 主要终点
- Incidence of treatment-emergent adverse events
研究概览
简要总结
RATIONALE:
The integrity of the intestinal mucosa is a key factor for the preservation of a normal gut function. Damage of the epithelium (i.e. by chemotherapy) results in significant cellular and molecular alterations that ultimately lead to intestinal dysfunction/failure. This intestinal dysfunction manifests as several pathological processes, such as inability to absorb nutrients, intestinal inflammation, immune system dysregulation, and disequilibrium of normal intestinal microbiota leading to increased risk of infection due to bacterial translocation and septicaemia. Gastrointestinal (GI) mucositis is a well-known, frequent and debilitating side effect of most anticancer regimens with a very high incidence in hemato-oncology. The most common symptoms are nausea, vomiting, weight loss, abdominal cramps and pain, diarrhea, and electrolyte imbalance. Patients may also experience ulceration/bleeding and injury of the lining of the entire gastrointestinal tract from the esophagus to the colon. Currently no therapy is available for the prevention or treatment of GI intestinal injury. Treatment of related symptoms is limited to supportive measures to decrease diarrhea and to preventive antibiotic therapy. The GLP-2 analogue, FE 203799, has a favorable pharmacology profile for clinical development in the intended therapeutic indication of myeloablative chemotherapy-induced GI damage. The data collected from animal studies has shown that FE 203799 stimulates the proliferation of the intestinal epithelium and protects the GI mucosa from chemotherapy-induced injury. Hence, the primary pharmacologic activity of FE 203799 would promote a healthy GI microenvironment, thus preventing intestinal dysfunction and related complications.
PURPOSE: Prevention by FE 203799 of chemotherapy-induced intestinal damage and related complications in patients with lymphoma receiving Melphalan based (BEAM) myeloablative conditioning regimen followed by hematopoietic stem cell transplantation.
详细描述
OUTLINE:
Multi-center, double-blind, placebo-controlled, ascending dose, randomized Phase IB/2A study to assess the safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) profile of s.c. FE 203799 in patients diagnosed with Hodgkin's lymphoma (HL) or non-Hodgkin's lymphoma (NHL) undergoing Melphalan-based myeloablative chemotherapy (BEAM) followed by autologous human stem cell transplantation (AHSCT). In addition, the impact of FE 203799 on post-transplantation outcomes will be assessed. These outcomes include assessment of intestinal mucosal injury and inflammation, incidence of infection and bacteremia, development of neutropenic fever, assessment of nutritional parameters, modification of the composition of the gut microbiome, recovery of the hematopoietic system and quality of life. More specifically:
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PRIMARY OBJECTIVE: Safety and tolerability of s.c. FE 203799
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SECONDARY OBJECTIVES:
- Determine the PK profile and dose-effect of s.c. FE 203799.
- Determine the PD profile of s.c. FE 203799, based on the plasma concentration of citrulline (indicative of intestinal mass) and of C-Reactive Protein (CRP) (indicative of inflammation).
- Determine the dose/response (PK/PD) relationship of s.c. FE 203799.
- Determine the impact of treatment with s.c. FE 203799 on the incidence and severity of chemotherapy induced intestinal toxicity, as assessed by both symptomatic and visual manifestations of mucosal injury and associated complications.
- Assess the effect of s.c. FE 203799 on the prevention of development of neutropenic fever and bacteremia.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Supportive Care
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Double-blind
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult male and non-pregnant or lactating female patients diagnosed with Hodgkin's lymphoma (HL) or non- Hodgkin's lymphoma (NHL; T- or B-cell variants) based on histological or cytological evidence.
- •Patients are eligible to receive myeloablative chemotherapy as per center eligibility criteria, followed by AHSCT.
- •Patients between 18 years and 65 years of age with a Hematopoietic Cell Transplant- Co-morbidity Index (HCT-CI) ≤
- •Patients between 65 years and 70 years will be eligible if their HCT-CI score is ≤
- •Patients, or their legal representatives, must have the ability to read, understand and provide written informed consent prior to the initiation of any study related procedures.
- •Patients must have chemo-sensitive disease and be in partial or complete remission following the most recent anti-neoplastic therapy regimen, according to the Lugano revision of the International Working Group (IWG) response criteria [1].
- •Patients must have available a cryopreserved autologous hematopoietic stem cell graft containing ≥ 2.0 x 106 cryopreserved CD34+ cells/kg.
- •Patients must have a Karnofsky score ≥ 70%.
- •Patients must have adequate hepatic function as evidenced by bilirubin ≤ upper limit of normal (ULN), unless felt to be related to Gilbert's syndrome or hemolysis; patients must also have AST and ALT ≤ 1.5 x ULN and alkaline phosphatase ≤ 2.5 x ULN.
- •Patients must have an estimated or measured creatinine clearance ≥ 30 ml/min/1.73 m2 by the Cockcroft-Gault equation.
- •Patients must have left ventricular ejection fraction ≥ 50%.
- •Patients must have forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1) and diffusing capacity corrected for hemoglobin (DLCOc) ≥ 50% of predicted.
- •Patients must have recovered from the effects of any prior chemotherapy, radiotherapy or surgery; for patients who have been on monoclonal antibody therapy, at least one half-life or 4 weeks (whichever is longer) should have elapsed prior to the first scheduled day of dosing with FE
- •A female recipient of childbearing potential must meet the following criteria:
- •Participant has a negative pregnancy test at Screening.
- •Participant agrees to use one of the accepted contraceptive regimens from at least 14 days prior to the first administration of the Study Drug, during the study and for at least 90 days after the last dose of the Study Drug. An acceptable method of contraception includes one of the following:
- •Abstinence from heterosexual intercourse
- •Systemic contraceptives (birth control pills, injectable/implant/insertable hormonal birth control products, transdermal patch)
- •Intrauterine device (with or without hormones)
- •Diaphragm with spermicidal gel
- •Condom with spermicide gel
- •A male patient, with sexual partners who are pregnant, possibly pregnant, or who could become pregnant, agrees to use one of the accepted contraceptive regimens throughout the entire duration of the study and until at least 3 months after the last drug administration. An acceptable method of contraception includes one of the following:
- •Abstinence from heterosexual intercourse
- •Condom with spermicide
排除标准
- •Patient is unable or unwilling to give informed consent.
- •Patients who are unable to comply with the treatment protocol including appropriate supportive care, follow-up and tests.
- •Patients with known hypersensitivity to FE 203799, or any related products (including excipients of the formulations) as well as severe hypersensitivity reactions to any drugs.
- •Patients with an active infection or with a fever ≥38.5oC within 3 days of the first scheduled day of dosing.
- •Patients who had an autologous stem cell transplant within 24 months.
- •Patients who had an available cryopreserved autologous graft with a CD34+ cell count of < 2 x 106/kg.
- •Patients undergoing AHSCT for conditions other than lymphoma.
- •Presence of a malignancy other than the one for which the transplant is being performed (except for baso-cellular skin carcinoma).
- •Patients who are receiving investigational therapies or who have been treated with investigational therapies or investigational devices within 30 days prior to the first scheduled day of dosing with FE
- •Patients with cardiovascular congestive heart failure, unstable angina pectoris, cardiac arrhythmias requiring a pacemaker; myocardial infarction within the past six months; stroke within the past 6 months; or uncontrolled hypertension.
- •Patients with mean QTcF values of >450 msec (in males) or >470 msec (in females) following ECGs conducted in triplicate 5 minutes apart from each other; patients who are known to have congenital prolonged QT syndromes, including patients who are already on medication known to cause prolonged QT intervals on ECG.
- •Presence of out-of-range cardiac interval (PR < 110 msec, PR > 220 msec, QRS < 60 msec, QRS >119 msec) on the screening ECG or other clinically significant ECG abnormalities.
- •Patients with history or presence of GI tract cancer, polyps, ulcerative colitis, Crohn's disease, coeliac disease, tropical sprue, etc.
- •Presence of active pancreatic disease.
- •Presence of active liver disease (i.e. cirrhosis; bilirubin > ULN; transaminases > 1.5 x ULN; alkaline phosphatase > 2.5 x ULN).
- •Presence of autoimmune disease.
- •Patients with suicidal tendency or clinically relevant psychiatric diseases or substance abuse.
- •Positive results to HIV Ag/Ab Combo, Hepatitis B surface Antigen (HbsAG (B) (hepatitis B)) or anti-Hepatitis C Virus (HCV (C)) tests.
- •Any abnormal condition or laboratory result that is considered by the PI capable of altering patient's condition or study outcome.
- •Patients who are pregnant or lactating.
- •Patients who are unwilling to use appropriate contraception.
研究组 & 干预措施
Cohort A: 5 mg (FE 203799/Placebo)
Drug: FE 203799 Drug: BEAM Procedure: myeloablative chemotherapy Procedure: autologous stem cell transplantation
干预措施: FE 203799 (Drug)
Cohort B: 10 mg (FE 203799/Placebo)
Drug: FE 203799 Drug: BEAM Procedure: myeloablative chemotherapy Procedure: autologous stem cell transplantation
干预措施: FE 203799 (Drug)
Cohort C: 25 mg (FE 203799/Placebo)
Drug: FE 203799 Drug: BEAM Procedure: myeloablative chemotherapy Procedure: autologous stem cell transplantation
干预措施: FE 203799 (Drug)
结局指标
主要结局
Incidence of treatment-emergent adverse events
时间窗: Day -8 to Day 100
Adverse events as assessed by CTCAE v4.03
次要结局
- Apparent volume of distribution (Vz) of FE 203799 during terminal phase(Day -8 to Day 13)
- Biomarker assessment for gut healing(Day -8 to Day -1, Day 1 to Day 14 and Day 30)
- Assessment of quality of life(Days -8, -1, 6, 13 and 30)
- Maximum observed plasma concentration (Cmax) of FE 203799(Day -8 to Day 13)
- Cumulative area under the plasma concentration (AUC) time curve from 0-168 hours of FE 203799(Day -8 to Day 13)
- Cumulative area under the plasma concentration (AUC) from time zero to infinity of FE 203799(Day -8 to Day 13)
- Terminal elimination half-life (T1/2) of FE 203799(Day -8 to Day 13)
- Apparent total body clearance (CL) of the drug from plasma of FE 203799(Day -8 to Day 13)
- Biomarker assessment for gut inflammation(Day -8 to Day -1, Day 1 to Day 14 and Day 30)
- Assessment of infection - Incidence and duration of fever(Day -8 to Day 20 and Day 30)
- Assessment of gastrointestinal mucositis and related clinical symptoms(Day -8 to Day 20 and Day 30)
- Assessment of gastrointestinal mucositis by video-capsule endoscopy(Day -8, Day 6 and Day 20)
- Assessment of nutrients absorption(Days -8, 0, 3, 6, 9, 12, 15, 18)
- Microbiome composition(Once a week over 4 weeks)
- Time to neutrophil and platelet engraftment(Day-8 and then on Days -2, 5, 12 and 30)
- Assessment of infection - Incidence and duration of neutropenic fever(Day -8 to Day 20 and Day 30)
- Incidence of microbiologically detected infection(Day 5 to Day 15)