Lutetium DOTATATE plus capecitabine in advanced neuroendocrine tumours
- Conditions
- Malignant carcinoid tumors,
- Registration Number
- CTRI/2020/01/022636
- Lead Sponsor
- Postgraduate Institute of Medical Education and Research Chandigarh
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Closed to Recruitment of Participants
- Sex
- All
- Target Recruitment
- 50
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.
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.
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method 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 At around 8 weeks after 2nd cycle and completion of treatment
- Secondary Outcome Measures
Name Time Method 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
Trial Locations
- Locations (1)
Postgraduate Institute of Medical Education and Research, Chandigarh
🇮🇳Chandigarh, CHANDIGARH, India
Postgraduate Institute of Medical Education and Research, Chandigarh🇮🇳Chandigarh, CHANDIGARH, IndiaDr Ashwani SoodPrincipal investigator9781814203sood99@yahoo.com