A Phase II Single Arm Trial Evaluating the Preliminary Efficacy of the Combination of 177Lu-DOTATATE and Nivolumab in Grade 3 Well-differentiated Neuroendocrine Tumours (NET) or Poorly Differentiated Neuroendocrine Carcinomas (NEC)
Overview
- Phase
- Phase 2
- Intervention
- 177Lu-Dotatate
- Conditions
- Neuroendocrine Tumours (NET)
- Sponsor
- Fundación de investigación HM
- Enrollment
- 30
- Locations
- 5
- Primary Endpoint
- Overall Response Rate (ORR)
- Status
- Recruiting
- Last Updated
- 3 years ago
Overview
Brief Summary
This is a prospective, multi-centre, open-label, single-arm, stratified, exploratory, Phase 2 study evaluating the efficacy and safety of 177Lu-DOTATATE in combination with nivolumab in adult patients with Grade 3 neuroendocrine tumours (NET) or neuroendocrine carcinomas (NEC).
Detailed Description
Patients will have unresectable advanced, recurrent or metastatic, histologically confirmed, well-differentiated Grade 3 NET or poorly-differentiated NEC of the pancreas, gastrointestinal tract lung and unknown primary site. Thirty patients will be included in this trial, of which 15 will not have received prior chemotherapy (Cohort 1) and 15 will have received at least one prior line of chemotherapy (Cohort 2). Patient will receive 240 mg flat dose of nivolumab intravenously as a 30-minutes infusion and 7.4 GBq 177Lu-DOTATATE intravenously as a 4-hours infusion. Nivolumab will be administered at Day 1 and Day 15 of a 28-days cycle, starting on Cycle 1 Day 1. Patients will receive the study drugs while it is considered to be in their best interest, 177Lu-DOTATATE being administered at a maximum of 4 injection cycle. Treatment discontinuation criteria include, among others, progression, unacceptable toxicity or patient study withdrawal
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients having voluntarily signed and dated IRB/IEC-approved written informed consent form in accordance with regulatory and institutional guidelines before the performance of any protocol-related procedures.
- •Patients with advanced/metastatic, histologically confirmed, well-differentiated Grade 3 NET or poorly-differentiated NEC of the pancreas, gastrointestinal tract, lung and unknown primary site at diagnosis or after progression to one systemic treatment. Patients will be enrolled in two cohorts based on the therapy of their aforementioned cancer: Cohort 1: Patients with no previous chemotherapy. Cohort 2: Patients who have received one line of chemotherapy.
- •Age ≥18 years.
- •Patients must have measurable disease based on RECIST v.1.1 meeting the following criteria:
- •Lesions that have had external beam radiotherapy or loco-regional therapies such as radiofrequency ablation or liver embolization must show evidence of progressive disease based on RECIST v.1.1 to be deemed a target lesion.
- •Patients in cohort 2 must show evidence of disease progression by radiologic image techniques according to RECIST v.1.1 within 3 months prior to signing informed consent.
- •Confirmed presence of somatostatin receptors on tumour lesions based on positive PET-Gallium (SomaKit) imaging within 8 weeks prior to enrolment in the study. At least one lesion should have an uptake of 64-Gallium higher than the normal liver according to investigator judgement.
- •Karnofsky Performance Score ≥ 60 and Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤
- •Life expectancy of ≥ 6 months.
- •Adequate normal organ and marrow function as defined below:
Exclusion Criteria
- •Treatment with \>30 mg Octreotide LAR at 3-4 weeks intervals within 12 weeks prior to enrolment in the study.
- •Peptide receptor radionuclide therapy (PRRT) at any time prior to enrolment in the study.
- •Targeted surgery, radiotherapy (external beam), chemotherapy, embolization, interferons, mTOR-inhibitors or other investigational therapy within 12 weeks prior to enrolment in the study. In Cohort 2, chemotherapy should be administered at least 4 weeks prior to first dose of the treatment.
- •Prior treatment with anti-PDL-1/anti-PD-1 or anti-CTL-4 therapy.
- •Known brain metastases, unless these metastases have been treated and stabilized for at least 24 weeks prior to enrolment in the study. Patients with a history of brain metastases must have a head CT with contrast to document stable disease prior to enrolment in the study.
- •Uncontrolled congestive heart failure (NYHA II-IV).
- •Uncontrolled diabetes mellitus as defined by a fasting blood glucose \>2 ULN.
- •Any patient receiving treatment with short-acting Octreotide, which cannot be interrupted for 24 h before and 24 h after the administration of 177Lu-DOTATATE , or any patient receiving treatment with Octreotide LAR, which cannot be interrupted for at least 6 weeks before the administration of 177Lu-DOTATATE, unless the tumour uptake observed by Somakit imaging during continued Octreotide treatment is at least as high as normal liver uptake observed by planar imaging.
- •Acute or chronic hepatitis B (e.g., Hepatitis B surface antigen reactive), hepatitis C (e.g., HCV RNA \[qualitative\] is detected) or known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
- •Active, known, or suspected autoimmune disease within the past 2 years. NOTE: Patients with Type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) and Grave's disease not requiring systemic treatment within the past 2 years are not excluded.
Arms & Interventions
177Lu-DOTATATE + Nivolumab
Patients will receive 240 mg flat dose of nivolumab intravenously as a 30-minutes infusion and 7.4 GBq 177Lu-DOTATATE intravenously as a 4-hours infusion
Intervention: 177Lu-Dotatate
177Lu-DOTATATE + Nivolumab
Patients will receive 240 mg flat dose of nivolumab intravenously as a 30-minutes infusion and 7.4 GBq 177Lu-DOTATATE intravenously as a 4-hours infusion
Intervention: Nivolumab
Outcomes
Primary Outcomes
Overall Response Rate (ORR)
Time Frame: Week 15 (+/-1) of treatment
ORR assessed by RECIST v.1.1
Secondary Outcomes
- Number and Grade of Adverse Events(Week 31 (+/-1) of treatment)
- Overall Survival (OS)(Week 31 (+/-1) of treatment)
- Overall Response Rate (ORR)(Week 31 (+/-1) of treatment)
- Progression-free Survival (PFS)(Week 31 (+/-1) of treatment)