A Clinical Study to Assess the Combination of Two Drugs (177Lu-DOTATATE and Nivolumab) in Neuroendocrine Tumours
Primary Purpose
Neuroendocrine Tumours (NET), Neuroendocrine Carcinomas (NEC)
Status
Recruiting
Phase
Phase 2
Locations
Spain
Study Type
Interventional
Intervention
177Lu-Dotatate
Nivolumab
Sponsored by
About this trial
This is an interventional treatment trial for Neuroendocrine Tumours (NET)
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) ≤ 2.
- Life expectancy of ≥ 6 months.
Adequate normal organ and marrow function as defined below:
- Haemoglobin concentration ≥ 8.0 g/dL (5.0 mmol/L).
- WBC ≥ 2x10 9/L (2000/mm3).
- Platelets ≥75x10 9/L (75x103/mm3).
- Adequate renal function defined as serum creatinine ≤150 μmol/L or 1.7 mg/dL, or a creatinine clearance or measured glomerular filtration rate (using plasma clearance methods) of ≥ 50 mL/min.
- Adequate hepatic function defined as total bilirubin ≤3 x ULN and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases are present).
- Serum albumin ≥ 3.0 g/dL (or serum albumin < 3.0 g/dL if prothrombin time is within the normal range).
- Female patients must either be of non-reproductive potential (i.e., post-menopausal by history: ≥60 years old and no menses for ≥1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry. Both women and men must agree to use a medically acceptable method of contraception throughout the treatment period and for six months after discontinuation of treatment. Acceptable methods of contraception include intrauterine device, oral contraceptive, subdermal implant and/or double barrier.
- Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow-up.
- Recovery to Grade ≤ 1 from any adverse event (AE) derived from previous treatment (excluding alopecia and/or cutaneous toxicity and/or asthenia).
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.
- Patients with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of start of study treatment. NOTE: Inhaled or topical steroids, and systemic steroid doses > 10 mg daily prednisone equivalent for adrenal replacement are permitted in the absence of active autoimmune disease.
- Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).
- History of allogeneic organ transplant.
- Known hypersensitivity to nivolumab, 177Lu-DOTATATE or its excipients.
- Patients with any other significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with completion of the study. Patients must have recovered from the effects of major surgery or significant traumatic injury at least 14 days before starting treatment.
- Prior external beam radiation therapy to more than 25% of the bone marrow.
- Urinary incontinence.
- Subjects with previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, esophageal, colon, endometrial, cervical/dysplasia, melanoma, or breast) unless a complete remission was achieved at least 5 years prior to study entry AND no additional therapy is required during the study period
- Prisoners or patients who are compulsory detained.
- Established or suspected pregnancy or when pregnancy has not been excluded
- Kidney failure with creatinine clearance < 30 mL/min
Sites / Locations
- Complexo Hospitalario Universitario de SantiagoRecruiting
- Hospital Universitario Puerta de Hierro MajadahondaRecruiting
- Hospital Universitario Madrid SanchinarroRecruiting
- Hospital Unviersitario Ramón y CajalRecruiting
- Hospital Universitario 12 de OctubreRecruiting
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
177Lu-DOTATATE + Nivolumab
Arm Description
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
Outcomes
Primary Outcome Measures
Overall Response Rate (ORR)
ORR assessed by RECIST v.1.1
Secondary Outcome Measures
Overall Response Rate (ORR)
ORR assessed by RECIST v.1.1
ORR assessed by Choi and modified RECIST for immune based therapeutics (iRECIST)
Progression-free Survival (PFS)
Number and Grade of Adverse Events
by CTCAE v.5 criteria
Overall Survival (OS)
Full Information
NCT ID
NCT04525638
First Posted
August 21, 2020
Last Updated
August 1, 2022
Sponsor
Fundación de investigación HM
Collaborators
Syntax for Science, S.L
1. Study Identification
Unique Protocol Identification Number
NCT04525638
Brief Title
A Clinical Study to Assess the Combination of Two Drugs (177Lu-DOTATATE and Nivolumab) in Neuroendocrine Tumours
Official Title
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)
Study Type
Interventional
2. Study Status
Record Verification Date
July 2022
Overall Recruitment Status
Recruiting
Study Start Date
June 29, 2020 (Actual)
Primary Completion Date
September 30, 2024 (Anticipated)
Study Completion Date
September 30, 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Fundación de investigación HM
Collaborators
Syntax for Science, S.L
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
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
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neuroendocrine Tumours (NET), Neuroendocrine Carcinomas (NEC)
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
open-label, single-arm
Masking
None (Open Label)
Allocation
N/A
Enrollment
30 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
177Lu-DOTATATE + Nivolumab
Arm Type
Experimental
Arm Description
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 Type
Drug
Intervention Name(s)
177Lu-Dotatate
Intervention Description
7.4 GBq 177Lu-DOTATATE intravenously as a 4-hours infusion
Intervention Type
Drug
Intervention Name(s)
Nivolumab
Intervention Description
240 mg flat dose of nivolumab intravenously as a 30-minutes infusion
Primary Outcome Measure Information:
Title
Overall Response Rate (ORR)
Description
ORR assessed by RECIST v.1.1
Time Frame
Week 15 (+/-1) of treatment
Secondary Outcome Measure Information:
Title
Overall Response Rate (ORR)
Description
ORR assessed by RECIST v.1.1
ORR assessed by Choi and modified RECIST for immune based therapeutics (iRECIST)
Time Frame
Week 31 (+/-1) of treatment
Title
Progression-free Survival (PFS)
Time Frame
Week 31 (+/-1) of treatment
Title
Number and Grade of Adverse Events
Description
by CTCAE v.5 criteria
Time Frame
Week 31 (+/-1) of treatment
Title
Overall Survival (OS)
Time Frame
Week 31 (+/-1) of treatment
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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) ≤ 2.
Life expectancy of ≥ 6 months.
Adequate normal organ and marrow function as defined below:
Haemoglobin concentration ≥ 8.0 g/dL (5.0 mmol/L).
WBC ≥ 2x10 9/L (2000/mm3).
Platelets ≥75x10 9/L (75x103/mm3).
Adequate renal function defined as serum creatinine ≤150 μmol/L or 1.7 mg/dL, or a creatinine clearance or measured glomerular filtration rate (using plasma clearance methods) of ≥ 50 mL/min.
Adequate hepatic function defined as total bilirubin ≤3 x ULN and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases are present).
Serum albumin ≥ 3.0 g/dL (or serum albumin < 3.0 g/dL if prothrombin time is within the normal range).
Female patients must either be of non-reproductive potential (i.e., post-menopausal by history: ≥60 years old and no menses for ≥1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry. Both women and men must agree to use a medically acceptable method of contraception throughout the treatment period and for six months after discontinuation of treatment. Acceptable methods of contraception include intrauterine device, oral contraceptive, subdermal implant and/or double barrier.
Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow-up.
Recovery to Grade ≤ 1 from any adverse event (AE) derived from previous treatment (excluding alopecia and/or cutaneous toxicity and/or asthenia).
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.
Patients with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of start of study treatment. NOTE: Inhaled or topical steroids, and systemic steroid doses > 10 mg daily prednisone equivalent for adrenal replacement are permitted in the absence of active autoimmune disease.
Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).
History of allogeneic organ transplant.
Known hypersensitivity to nivolumab, 177Lu-DOTATATE or its excipients.
Patients with any other significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with completion of the study. Patients must have recovered from the effects of major surgery or significant traumatic injury at least 14 days before starting treatment.
Prior external beam radiation therapy to more than 25% of the bone marrow.
Urinary incontinence.
Subjects with previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, esophageal, colon, endometrial, cervical/dysplasia, melanoma, or breast) unless a complete remission was achieved at least 5 years prior to study entry AND no additional therapy is required during the study period
Prisoners or patients who are compulsory detained.
Established or suspected pregnancy or when pregnancy has not been excluded
Kidney failure with creatinine clearance < 30 mL/min
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Antonio Cubillo, MD
Phone
+34 917567800
Email
secretaria@fundacionhm.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Antonio Cubillo, MD
Organizational Affiliation
Director
Official's Role
Study Director
Facility Information:
Facility Name
Complexo Hospitalario Universitario de Santiago
City
Santiago De Compostela
State/Province
Galicia
ZIP/Postal Code
15706
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Urbano Anido, MD
Phone
+34981950535
First Name & Middle Initial & Last Name & Degree
Urbano Anido, MD
Facility Name
Hospital Universitario Puerta de Hierro Majadahonda
City
Majadahonda
State/Province
Madrid
ZIP/Postal Code
28022
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Juan Cristobal Sanchez, MD
Phone
+34911917147
First Name & Middle Initial & Last Name & Degree
Juan Cristobal Sanchez
Facility Name
Hospital Universitario Madrid Sanchinarro
City
Sanchinarro
State/Province
Madrid
ZIP/Postal Code
28050
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Rafael Álvarez, MD
First Name & Middle Initial & Last Name & Degree
Rafael Alvarez
Facility Name
Hospital Unviersitario Ramón y Cajal
City
Madrid
ZIP/Postal Code
28029
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Teresa Alonso Gordoa, MD
First Name & Middle Initial & Last Name & Degree
Teresa Alonso Gordoa
Facility Name
Hospital Universitario 12 de Octubre
City
Madrid
ZIP/Postal Code
28041
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Rocio García Carbonero, MD
Phone
+34913908003
Email
rgcarbonero.ensayos@gmail.com
First Name & Middle Initial & Last Name & Degree
Rocio García Carbonero
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
A Clinical Study to Assess the Combination of Two Drugs (177Lu-DOTATATE and Nivolumab) in Neuroendocrine Tumours
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