Concomitant 177Lu-DOTATATE low dose capecitabine versus 177Lu - DOTATATE alone in patients with advanced well-differentiated gastroenteropancreatic neuroendocrine tumours-randomized controlled trial.
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- Objective response rate, i.e. proportion of patients with complete response plus partial response (as per RECIST 1.1), assessed by 68Ga-DOTANOC PET/CT
研究概览
简要总结
Gastroenteropancreaticneuroendocrine tumours (GEP-NETs) are a rare group of malignancies that haveshown an increased global burden over the recent decades with an incidence of3.56 per 1,00,000 persons. The 2017 WHO classification categorizedpancreatic neuroendocrine neoplasms (NENs) into two broad types: well-differentiatedpancreatic NEN, also referred as neuroendocrine tumour (NET) and poorly-differentiatedNEN, otherwise known as neuroendocrine carcinoma (NEC). NETs were furthersubcategorized into grades depending on the Ki-67 proliferation index andmitotic index: G1 (Ki-67 index < 3% and mitotic index < 2/10 high-powerfields); G2 (Ki-67 index 3-20 % and mitotic index 2-20/10 high-power fields); andG3 (Ki-67 index > 20% and mitotic index > 20/10 high-power fields).
Most of the NETsprogress slowly over the years, however, the aggressiveness varies according tothe primary site. While smallintestinal NETs tend to progress indolently in the metastatic setting, gastricand rectal NETs often have a rapid progression once they become metastatic.Treatment options for advanced inoperable or metastatic GEP-NETs are currentlylimited. While somatostatin analogues viz. octreotideand lanreotide are widely used as first-line treatment for advanced GEP-NETs, targetedand cytotoxic chemotherapy are reserved for progressive disease. However,more often than not, disease progression eventually ensues and there exists alack of therapeutic alternatives. Further, the adverse effects and costsassociated with these treatment modalities often limit their practical utilityfor patients especially in low to middle income countries. In this setting,Peptide Receptor Radionuclide Therapy (PRRT) offers an attractive option withencouraging results over several retrospective and prospective studies.
Increasedsomatostatin receptor (SSTR) expression in NETs as demonstrated by high-gradeuptake on SSTR scintigraphy provides the rationale for the use of PRRT in NETs,especially G1 and G2. The PRRT agents consist of a radionuclide (90Y-Yttrium90 or 177Lu-Lutetium 177) linked to a peptide (SSTR agonist either TOC-Tyr3Octreotide or TATE-Tyr3Octreotate or TATE ) by means of a chelator (DOTA). Thebinding of the agents to the SSTRs on the tumour cell membrane enables thedelivery of the beta emitting radionuclides, thereby leading to cellular damage. Of the PRRTs, 177Lu-DOTATATE is the only FDA approved agentfor advanced/unresectable GEP-NETs. The approval was based on the NETTER-1trial comprising 229 patients with progressive, well-differentiated, locallyadvanced/inoperable or metastatic SSTR positive mid gut NET.
In recent times, fewretrospective studies have shown combination therapies of PRRT withcapecitabine to be effective in advanced NETs. In a retrospective studyby Ballal et al., patients treated with concomitant 177Lu – DOTATATEand capecitabine had better objective response and overall survival as comparedto those treated with 177Lu – DOTATATE alone. Capecitabine,administered in suboptimal doses in this setting as a radiosensitizer, acts byinducing DNA damage and inhibiting cell repair and thereby is suggested to havea synergistic role with PRRT. Few other studies have also demonstrated thesafety of this combination approach. However, no prospective study hasyet been conducted to establish the added benefit associated with thiscombination approach over standalone PRRT. In this prospective phase 2 study,we intend to compare the efficacy and safety of concomitant 177Lu-DOTATATEplus capecitabine and 177Lu – DOTATATE alone in patients withadvanced inoperable/metastatic well differentiated GEP-NETs.
研究设计
- 研究类型
- Interventional
- 分配方式
- Computer generated randomization
- 盲法
- Open Label
入排标准
- 年龄范围
- 18.00 Year(s) 至 80.00 Year(s)（—）
- 性别
- All
入选标准
- •Adults ≥ 18 years with histopathologically proven, well-differentiated grade 1/2 gastroenteropancreatic neuroendocrine tumours Progressive inoperable/metastatic disease during or after ≤ 2 prior systemic therapies Significant somatostatin receptor (SSTR) expression in 68Ga-DOTANOC PET/CT defined as SUVmax of lesion being significantly (1.5 x) greater than that of normal liver Dedifferentiation excluded using 18F-FDG PET/CT as per the NETPET score ECOG performance 0-2 Estimated life expectancy of at least 8 months Adequate renal function – GFR ≥ 50 mL/min (as estimated by 99mTc DTPA GFR) Stable haematological parameters: Haemoglobin ≥ 8 g/dL Total leucocyte count ≥ 2000/mcL Platelets ≥ 70000/mcL Adequate liver function: Bilirubin ≤ 3 x upper limit of normal (ULN) AST, ALT, ALP ≤ 2.5 x ULN (or ≤ 5.0 x ULN in the presence of liver metastases) Albumin ≥ 3.0 g/dL.
排除标准
- •Patient not willing to give the consent Primary tumours other than gastroenteropancreatic neuroendocrine tumours Grade 3 neuroendocrine tumours Cytotoxic chemotherapy or targeted therapy including somatostatin analogues within the last four weeks Prior Peptide Receptor Radionuclide Therapy Prior Selective Internal Radiation Therapy with 90Y microspheres for liver lesions Any other active malignancy Poorly controlled concurrent medical illness e.g. uncontrolled diabetes, cardiac disease, severe infection Malabsorption syndromes that might impair absorption of Capecitabine Pregnant and lactating female patients.
结局指标
主要结局
Objective response rate, i.e. proportion of patients with complete response plus partial response (as per RECIST 1.1), assessed by 68Ga-DOTANOC PET/CT
时间窗: At around 8 weeks after 2nd cycle and completion of treatment
次要结局
- Biochemical response rate i.e proportion of patients achieving ≥50% reduction in serum chromogranin A level(At around 8 weeks after 2nd cycle and completion of treatment)
- Disease Control Rate(At around 8 weeks after 2nd cycle and completion of treatment)
- Health related quality of life assessed using EORTC QLQ – C30 questionnaire(At around 8 weeks after 2nd cycle and completion of treatment)
- Proportion of serious adverse events, assessed using CTCAE version 5.0(Every 3 weeks post each treatment cycle)
- Progression free survival(Estimated from the first PRRT cycle till documented radiological disease progression (as per RECIST 1.1). Patients will be followed up for a minimum of 2 years)