A Study Comparing Treatment With Lutetium[177Lu] Oxodotreotide Injection to Octreotide LAR in Patients With Inoperable, Progressive, Well Differentiated, Somatostatin Receptor Positive Gastroenteropancreatic Neuroendocrine Tumours
Overview
- Phase
- Phase 3
- Status
- Active, not recruiting
- Sponsor
- Sinotau Pharmaceutical Group
- Enrollment
- 196
- Locations
- 23
- Primary Endpoint
- Progression Free Survival (PFS) assessed by BIRC
Overview
Brief Summary
This was a multicenter, stratified, open, randomized, comparator-controlled, parallel-group phase III study comparing treatment with Lutetium[177Lu] Oxodotreotide Injection to high dose (60 mg) Octreotide LAR in patients with unresectable or metastatic, progressive, well differentiated (G1 and G2), somatostatin receptor positive gastroenteropancreatic neuroendocrine tumours.
Detailed Description
After the screening period, participants who signed the ICF and were eligible for the study in accordance with the entry criteria were randomly assigned to treatment either Lutetium[177Lu] Oxodotreotide Injection or Octreotide LAR. Participant randomization was performed according to a centralized permuted block randomization scheme with a balanced ratio (1:1) between the 2 treatment groups, stratified by primary site of tumor (pancreatic or non-pancreatic), NET pathological grading (G1 or G2) and by the length of time that a participant was on a constant dose of Octreotide (=< 6 versus > 6 months). Objective tumor assessment in both groups was performed every 12+/-1 weeks from the randomization date according to RECIST Criteria until progression was centrally confirmed: any participants with progressive disease ceased the treatment/assessment period and proceeded to the long-term follow-up period for evaluation of survival and long-term safety.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Ability to understand and willingness to sign a written informed consent document.
- •Aged 18 years or older.
- •Histopathologically confirmed low and moderate grade (G1 or G2) unresectable locally advanced or metastatic GEP-NET (based on the fifth edition of the WHO classification and grading criteria for neuroendocrine tumors of the digestive system in 2019, to be centrally confirmed).
- •Previously received fixed-dose Octreotide LAR (20-30 mg/3-4 weeks) for at least 12 weeks of continuous treatment with disease progression.
- •Presence of disease progression prior to randomization (time point of disease progression limited to 1 year prior to randomization and no other antitumor therapy received after progression).
- •Presence of at least 1 measurable site of disease (based on RECIST 1.1).
- •All target lesions (based on RECIST 1.1) at baseline must be confirmed as somatostatin receptor positive by 68Ga-Dotatate PET/CT .
- •ECOG score of 0 or
- •Subjects of childbearing potential voluntarily use an effective method of contraception, such as condoms, oral or injectable contraceptives, IUDs, etc., during treatment and within 4 months (men) or 7 months (women) of the last use of the trial drug.
Exclusion Criteria
- •Serum creatinine \>150 μmol/L (1.7 mg/dL) or creatinine clearance \<50 ml/min (Cockcroft Gault formula).
- •Hemoglobin \<80g/L, or white blood cell count \<2.0×10\^9/L, or platelets \<75×10\^9/L.
- •Serum total bilirubin \> 3 × upper limit of normal (ULN).
- •Serum albumin \<30g/L.
- •alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 2.5×ULN.
- •international normalized ratio (INR) \> 1.5 or partially activated prothrombin time (APTT) \> 1.5 x ULN.
- •Positive human immunodeficiency virus (HIV) antibody.
- •Positive for hepatitis B virus (HBV) surface antigen (HBsAg) and positive for HBV DNA (≥1×10\^4 copies/ml or judged positive by research center criteria), or positive for hepatitis C virus (HCV) antibodies.
- •Pregnant or lactating females.
- •Received peptide receptor radionuclide therapy(PRRT) prior to randomization.
Arms & Interventions
Lutetium[177Lu] Oxodotreotide Injection
Treatment consisted of a cumulative administered radioactivity of 29.6 Giga Becquerel (GBq) (800 mCi) Lutetium[177Lu] Oxodotreotide Injection: Four administrations of 7.4 GBq (200 mCi).
Concomitant amino acids were given with each administration for kidney protection.
Lutetium[177Lu] Oxodotreotide Injection was administered at 8 +/- 1-week intervals, which could be extended up to 16 weeks to accommodate resolving acute toxicity.
In case participants experienced clinical symptoms (i.e. diarrhoea and flushing) associated with their carcinoid tumours, Octreotide s.c. rescue injections were allowed.
Intervention: Lutetium[177Lu] Oxodotreotide Injection (Drug)
Octreotide LAR
60 mg Octreotide LAR treatment every 4 weeks (i.m. injections) until the end of the study, unless the participant progressed or died.
In case participants experienced clinical symptoms (i.e. diarrhoea and flushing) associated with their carcinoid tumours, s.c. Octreotide rescue injections were allowed.
Intervention: Octreotide LAR (Drug)
Outcomes
Primary Outcomes
Progression Free Survival (PFS) assessed by BIRC
Time Frame: From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first until Primary Analysis cutoff date reached，assessed up to approximately 34 months
Progression Free Survival (PFS) was defined as the time from randomization to documented centrally assessed disease progression, as evaluated by the Blinded Independent Review Committee (BIRC), or death due to any cause. If a participant had no centrally assessed progression and had not died at the time of the primary endpoint analysis, the participant was regarded as censored in the context of a time to event analysis at the date of last evaluable tumor assessment. Disease progression was determined by objective tumor response status using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1).
Secondary Outcomes
- Progression Free Survival (PFS) assessed by investigator(From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first until Primary Analysis cutoff date reached，assessed up to approximately 34 months)
- Objective Response Rate (ORR) assessed by investigator(From date of randomization until date of progression or date of death from any cause, whichever comes first until Primary Analysis cutoff date reached，assessed up to approximately 34 months)
- Objective Response Rate (ORR) assessed by BIRC(From date of randomization until date of progression or date of death from any cause, whichever comes first until Primary Analysis cutoff date reached，assessed up to approximately 34 months)
- Duration of Response (DoR) assessed by investigator(From date of randomization until date of progression or date of death from any cause, whichever comes first until Primary Analysis cutoff date reached，assessed up to approximately 34 months)
- Duration of Response (DoR) assessed by BIRC(From date of randomization until date of progression or date of death from any cause, whichever comes first until Primary Analysis cutoff date reached，assessed up to approximately 34 months)
- Time to Tumour Progression (TTP) assessed by investigator(From date of randomization until date of progression or date of death from any cause, whichever comes first until Primary Analysis cutoff date reached，assessed up to approximately 34 months)
- Time to Tumour Progression (TTP) assessed by BIRC(From date of randomization until date of progression or date of death from any cause, whichever comes first until Primary Analysis cutoff date reached，assessed up to approximately 34 months)
- Disease Control Rate (DCR) assessed by investigator(From date of randomization until date of progression or date of death from any cause, whichever comes first until Primary Analysis cutoff date reached，assessed up to approximately 34 months)
- Disease Control Rate (DCR) assessed by BIRC(From date of randomization until date of progression or date of death from any cause, whichever comes first until Primary Analysis cutoff date reached，assessed up to approximately 34 months)
- 20-month Progression-Free Survival rate assessed by BIRC(From date of randomization until date of progression or date of death from any cause, whichever comes first until Primary Analysis cutoff date reached，assessed up to approximately 34 months)
- 20-month Progression-Free Survival rate assessed by investigator(From date of randomization until date of progression or date of death from any cause, whichever comes first until Primary Analysis cutoff date reached，assessed up to approximately 34 months)
- Overall Survival (OS)(From date of randomization until date of death from any cause up to final safety cut-off date reached，assessed up to approximately 60 months)
- Change From Baseline in the EORTC QLQ-C30 Questionnaire(From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first until Primary Analysis cutoff date reached，assessed up to approximately 34 months)
- Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21)(From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first until Primary Analysis cutoff date reached，assessed up to approximately 34 months)
- Number of Participants With Adverse Events(From informed consent signature through study completion reached at final safety cutoff date，assessed up to approximately 60 months)