Brief Summary
This study aimed to investigate the efficacy and safety of PDR001 in patients with advanced or metastatic, well-differentiated, non-functional neuroendocrine tumors of pancreatic, gastrointestinal (GI), or thoracic origin or poorly-differentiated gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) that progressed on prior treatment.
Brief Title
Study of Efficacy and Safety of PDR001 in Patients With Advanced or Metastatic, Well-differentiated, Non-functional Neuroendocrine Tumors of Pancreatic, Gastrointestinal (GI), or Thoracic Origin or Poorly-differentiated Gastroenteropancreatic Neuroendocrine Carcinoma (GEP-NEC)
Detailed Description
Two groups of adult patients with advanced (unresectable or metastatic) were included in this study:
* Well-differentiated (G1/2), non-functional, neuroendocrine tumor of GI, pancreatic or thoracic (lung/thymus) origin who have progressed on prior treatment
* Poorly-differentiated GEP-NEC who have progressed on or after one prior chemotherapy regimen.
The study was comprised of the following periods: screening, treatment, end of treatment (EOT), safety follow-up (30-Days, 60-Days, 90-Days, 120-Days, and 150-Days after the last dose of PDR001) and post-treatment efficacy follow-up. Subjects were treated with PDR001 as an infusion at a flat dose of 400 mg every 4 weeks (Q4W). Subjects were to continue study treatment beyond disease progression by RECIST 1.1 until disease progression as per irRECIST, as per BIRC, unacceptable toxicity, start of new antineoplastic therapy, withdrawal of consent, physician's decision, lost to follow-up, death, or study termination by the Sponsor.
* Well-differentiated (G1/2), non-functional, neuroendocrine tumor of GI, pancreatic or thoracic (lung/thymus) origin who have progressed on prior treatment
* Poorly-differentiated GEP-NEC who have progressed on or after one prior chemotherapy regimen.
The study was comprised of the following periods: screening, treatment, end of treatment (EOT), safety follow-up (30-Days, 60-Days, 90-Days, 120-Days, and 150-Days after the last dose of PDR001) and post-treatment efficacy follow-up. Subjects were treated with PDR001 as an infusion at a flat dose of 400 mg every 4 weeks (Q4W). Subjects were to continue study treatment beyond disease progression by RECIST 1.1 until disease progression as per irRECIST, as per BIRC, unacceptable toxicity, start of new antineoplastic therapy, withdrawal of consent, physician's decision, lost to follow-up, death, or study termination by the Sponsor.
Categories
Completion Date
Completion Date Type
Actual
Conditions
Well-differentiated Non-functional NET of Thoracic Origin
Well-differentiated Non-functional NET of Gastrointestinal Origin
Well-differentiated Non-functional NET of Pancreatic Origin
Poorly-differentiated Gastroenteropancreatic Neuroendocrine Carcinoma
Eligibility Criteria
Inclusion Criteria:
* Pathologically confirmed, advanced (unresectable or metastatic):
* Well-differentiated (G1 or G2) based on local pathology report, non-functional neuroendocrine tumor of GI, pancreatic or thoracic (including lung and thymus) origin.
* Poorly-differentiated GEP-NEC based on local pathology report
* No active symptoms related to carcinoid syndrome during the last 3 months prior to start of study treatment.
* Patients must have been pretreated for advanced disease - the number of prior systemic therapy/regimen depended on which origin for NET and for GEP-NEC
* Tumor biopsy material must be provided for all patients for the purpose of biomarker analysis
* Radiological documentation of disease progression:
* Well-differentiated NET group: Disease progression while on/or after the last treatment, and this progression must have been observed within 6 months prior to start of study treatment (i.e. maximum of 24 weeks from documentation of progression until study entry). Disease must show evidence of radiological disease progression based on scans performed not more than 12 months apart.
* Poorly-differentiated GEP-NEC group: Disease progression while on or after prior treatment.
Exclusion Criteria:
* Well-differentiated grade 3 neuroendocrine tumors; poorly-differentiated neuroendocrine carcinoma of any origin (other than GEP-NEC); including NEC of unknown origin, adenocarcinoid, and goblet cell carcinoid
* Pretreatment with interferon as last treatment prior to start of study treatment.
* Prior treatment for study indication with:
* Antibodies or immunotherapy within 6 weeks before the first dose of study treatment.
* Peptide Radionuclide Receptor Therapy (PRRT) administered within 6 months of the first dose.
* Systemic antineoplastic therapy
* Tyrosine kinase inhibitors within 14 days or 5 half-lives, whichever is longer, before the first dose of study treatment.
* Prior Programmed Death-1 (PD-1) or Programmed Death-Ligand 1 (PD-L1) directed therapy.
* Cryoablation, radiofrequency ablation, or trans-arterial embolization of hepatic metastases
* History of severe hypersensitivity reactions to other monoclonal antibodies which in the opinion of the investigator may pose an increased risk of a serious infusion reaction.
Other inclusion/exclusion criteria might apply
* Pathologically confirmed, advanced (unresectable or metastatic):
* Well-differentiated (G1 or G2) based on local pathology report, non-functional neuroendocrine tumor of GI, pancreatic or thoracic (including lung and thymus) origin.
* Poorly-differentiated GEP-NEC based on local pathology report
* No active symptoms related to carcinoid syndrome during the last 3 months prior to start of study treatment.
* Patients must have been pretreated for advanced disease - the number of prior systemic therapy/regimen depended on which origin for NET and for GEP-NEC
* Tumor biopsy material must be provided for all patients for the purpose of biomarker analysis
* Radiological documentation of disease progression:
* Well-differentiated NET group: Disease progression while on/or after the last treatment, and this progression must have been observed within 6 months prior to start of study treatment (i.e. maximum of 24 weeks from documentation of progression until study entry). Disease must show evidence of radiological disease progression based on scans performed not more than 12 months apart.
* Poorly-differentiated GEP-NEC group: Disease progression while on or after prior treatment.
Exclusion Criteria:
* Well-differentiated grade 3 neuroendocrine tumors; poorly-differentiated neuroendocrine carcinoma of any origin (other than GEP-NEC); including NEC of unknown origin, adenocarcinoid, and goblet cell carcinoid
* Pretreatment with interferon as last treatment prior to start of study treatment.
* Prior treatment for study indication with:
* Antibodies or immunotherapy within 6 weeks before the first dose of study treatment.
* Peptide Radionuclide Receptor Therapy (PRRT) administered within 6 months of the first dose.
* Systemic antineoplastic therapy
* Tyrosine kinase inhibitors within 14 days or 5 half-lives, whichever is longer, before the first dose of study treatment.
* Prior Programmed Death-1 (PD-1) or Programmed Death-Ligand 1 (PD-L1) directed therapy.
* Cryoablation, radiofrequency ablation, or trans-arterial embolization of hepatic metastases
* History of severe hypersensitivity reactions to other monoclonal antibodies which in the opinion of the investigator may pose an increased risk of a serious infusion reaction.
Other inclusion/exclusion criteria might apply
Inclusion Criteria
Inclusion Criteria:
* Pathologically confirmed, advanced (unresectable or metastatic):
* Well-differentiated (G1 or G2) based on local pathology report, non-functional neuroendocrine tumor of GI, pancreatic or thoracic (including lung and thymus) origin.
* Poorly-differentiated GEP-NEC based on local pathology report
* No active symptoms related to carcinoid syndrome during the last 3 months prior to start of study treatment.
* Patients must have been pretreated for advanced disease - the number of prior systemic therapy/regimen depended on which origin for NET and for GEP-NEC
* Tumor biopsy material must be provided for all patients for the purpose of biomarker analysis
* Radiological documentation of disease progression:
* Well-differentiated NET group: Disease progression while on/or after the last treatment, and this progression must have been observed within 6 months prior to start of study treatment (i.e. maximum of 24 weeks from documentation of progression until study entry). Disease must show evidence of radiological disease progression based on scans performed not more than 12 months apart.
* Poorly-differentiated GEP-NEC group: Disease progression while on or after prior treatment.
inclusion/
* Pathologically confirmed, advanced (unresectable or metastatic):
* Well-differentiated (G1 or G2) based on local pathology report, non-functional neuroendocrine tumor of GI, pancreatic or thoracic (including lung and thymus) origin.
* Poorly-differentiated GEP-NEC based on local pathology report
* No active symptoms related to carcinoid syndrome during the last 3 months prior to start of study treatment.
* Patients must have been pretreated for advanced disease - the number of prior systemic therapy/regimen depended on which origin for NET and for GEP-NEC
* Tumor biopsy material must be provided for all patients for the purpose of biomarker analysis
* Radiological documentation of disease progression:
* Well-differentiated NET group: Disease progression while on/or after the last treatment, and this progression must have been observed within 6 months prior to start of study treatment (i.e. maximum of 24 weeks from documentation of progression until study entry). Disease must show evidence of radiological disease progression based on scans performed not more than 12 months apart.
* Poorly-differentiated GEP-NEC group: Disease progression while on or after prior treatment.
inclusion/
Gender
All
Gender Based
false
Keywords
Advanced or metastatic
NET
pNET
GI NET
thoracic NET
GEP-NEC
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT02955069
Org Class
Industry
Org Full Name
Novartis
Org Study Id
CPDR001E2201
Overall Status
Completed
Phases
Phase 2
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
An Open Label Phase II Study to Evaluate the Efficacy and Safety of PDR001 in Patients With Advanced or Metastatic, Well-differentiated, Non-functional Neuroendocrine Tumors of Pancreatic, Gastrointestinal (GI), or Thoracic Origin or Poorly-differentiated Gastroenteropancreatic Neuroendocrine Carcinoma (GEP-NEC), That Have Progressed on Prior Treatment.
Primary Outcomes
Outcome Description
ORR is defined as the proportion of patients with best overall response (BOR) of complete response (CR) or partial response (PR), according to BIRC radiological assessment by RECIST 1.1.
CR: disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm.
PR: at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
CR: disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm.
PR: at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Outcome Measure
Overall Response Rate (ORR) by RECIST 1.1 and as Per Blinded Independent Central Review (BIRC).
Outcome Time Frame
From baseline up to approximately 1.5 years
Secondary Ids
Secondary Id
2016-002522-36
Secondary Outcomes
Outcome Description
DOR is defined as the time between the date of first documented response (CR or PR) and the date of first documented disease progression by RECIST 1.1 and as per BIRC or death due to underlying cancer. For DOR analysis, participants continuing without progression or death due to underlying cancer were censored at the date of their last adequate tumor assessment. An adequate tumour assessment is a tumour assessment with an overall response other than unknown.
CR: disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm.
PR: at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
CR: disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm.
PR: at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Outcome Time Frame
From the date of first documented response (CR or PR) until the first documented disease progression or death, whichever comes first, assessed up to approximately 1.5 years
Outcome Measure
Duration of Response (DOR) by RECIST 1.1 and as Per BIRC
Outcome Description
Disease control rate is defined as the proportion of patients with best overall response of CR, PR or stable disease (SD) according to RECIST 1.1 criteria and as per BIRC.
CR: disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm.
PR: at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
SD: neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.
CR: disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm.
PR: at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
SD: neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.
Outcome Time Frame
From baseline up to approximately 1.5 years
Outcome Measure
Disease Control Rate by RECIST 1.1 and as Per BIRC
Outcome Description
TTR is defined as the time from the date of start of treatment to the first documented response of either CR or PR, which must be subsequently confirmed. TTR was evaluated according to RECIST 1.1 and as per BIRC.
CR: disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm.
PR: at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
CR: disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm.
PR: at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Outcome Time Frame
From baseline to the first documented response, assessed up to approximately 1.5 years
Outcome Measure
Time to Response (TTR) by RECIST 1.1 and as Per BIRC
Outcome Description
PFS is defined as the time from the date of first dose to the date of the first documented radiological progression or death due to any cause. PFS was evaluated according to RECIST 1.1 and as per BIRC. For participants who had not progressed or died at the analysis cut-off date, PFS was censored at the date of the last adequate tumor evaluation date. An adequate tumour assessment is a tumour assessment with an overall response other than unknown.
Outcome Time Frame
From baseline until the date of the first documented radiological progression or death due to any cause, whichever comes first, assessed up to approximately 1.5 years
Outcome Measure
Progression-free Survival (PFS) by RECIST 1.1 and as Per BIRC
Outcome Description
irORR is the proportion of patients with a best overall response of immune related Complete Response (irCR) or immune related partial response (irPR), according to BIRC assessment by irRECIST.
irCR: Complete disappearance of all measurable and non-measurable lesions. In addition, any pathological lymph nodes must have a reduction in short axis to \< 10 mm.
irPR: At least 30% decrease in the total measurable tumor burden (TMTB) compared to baseline and not qualifying for irCR or immune related progressive disease (irPD).
irCR: Complete disappearance of all measurable and non-measurable lesions. In addition, any pathological lymph nodes must have a reduction in short axis to \< 10 mm.
irPR: At least 30% decrease in the total measurable tumor burden (TMTB) compared to baseline and not qualifying for irCR or immune related progressive disease (irPD).
Outcome Time Frame
From baseline up to approximately 1.5 years
Outcome Measure
Immune Related Overall Response Rate (irORR) by irRECIST and as Per BIRC
Outcome Description
irDOR is defined as the time from first documentation of irCR or irPR until the time of first documentation of progression per irRECIST based on BIRC assessment. Participants continuing without progression or death due to underlying cancer were censored at the date of their last adequate tumor assessment. An adequate tumour assessment is a tumour assessment with an overall response other than unknown for irRECIST.
irCR: Complete disappearance of all measurable and non-measurable lesions. In addition, any pathological lymph nodes must have a reduction in short axis to \< 10 mm.
irPR: At least 30% decrease in the TMTB compared to baseline and not qualifying for irPD or irCR
irCR: Complete disappearance of all measurable and non-measurable lesions. In addition, any pathological lymph nodes must have a reduction in short axis to \< 10 mm.
irPR: At least 30% decrease in the TMTB compared to baseline and not qualifying for irPD or irCR
Outcome Time Frame
From the date of first documented confirmed response (irCR or irPR) until the first documented progression, assessed up to approximately 1.5 years
Outcome Measure
Immune Related Duration of Response (irDoR) by irRECIST and as Per BIRC.
Outcome Description
irTTR is defined as the time between date of start of treatment until first documented response (confirmed irCR or irPR) by irRECIST and as per BIRC.
irCR: Complete disappearance of all measurable and non-measurable lesions. In addition, any pathological lymph nodes must have a reduction in short axis to \< 10 mm.
irPR: At least 30% decrease in the TMTB compared to baseline and not qualifying for irPD or irCR.
irCR: Complete disappearance of all measurable and non-measurable lesions. In addition, any pathological lymph nodes must have a reduction in short axis to \< 10 mm.
irPR: At least 30% decrease in the TMTB compared to baseline and not qualifying for irPD or irCR.
Outcome Time Frame
From baseline to the first documented response, assessed up to approximately 1.5 years
Outcome Measure
Immune Related Time to Response (irTTR) by irRECIST and as Per BIRC
Outcome Description
irDCR is defined as the proportion of patients with a best overall response of irCR or irPR or immune related stable disease (irSD) according to irRECIST and as per BIRC.
irCR: Complete disappearance of all measurable and non-measurable lesions. In addition, any pathological lymph nodes must have a reduction in short axis to \< 10 mm.
irPR: At least 30% decrease in the TMTB compared to baseline and not qualifying for irPD or irCR.
irSD: Neither a sufficient shrinkage to qualify for irPR or irCR, nor an increase in lesions, or a clear and unequivocal progression of existing nontarget or new non-measurable lesions that would qualify for irPD.
irCR: Complete disappearance of all measurable and non-measurable lesions. In addition, any pathological lymph nodes must have a reduction in short axis to \< 10 mm.
irPR: At least 30% decrease in the TMTB compared to baseline and not qualifying for irPD or irCR.
irSD: Neither a sufficient shrinkage to qualify for irPR or irCR, nor an increase in lesions, or a clear and unequivocal progression of existing nontarget or new non-measurable lesions that would qualify for irPD.
Outcome Time Frame
From baseline up to approximately 1.5 years
Outcome Measure
Immune Related Disease Control Rate (irDCR) by irRECIST and as Per BIRC
Outcome Description
irPFS is defined as the time from date of start of treatment to the date of event defined as the first documented assessment of immune related progression that is confirmed or death due to any cause. If a patient has not had an event, immune related progression-free survival was censored at the date of last adequate tumor assessment. An adequate tumor assessment is a tumor assessment with overall response other than unknown for irRECIST.
Outcome Time Frame
From baseline until the date of the first documented immune related progression or death due to any cause, whichever comes first, assessed up to approximately 1.5 years
Outcome Measure
Immune Related Progression Free Survival (irPFS) by irRECIST and as Per BIRC
Outcome Description
OS is defined as the time from the start of treatment date to the date of death, due to any cause. If a patient was not known to have died, then OS was censored at the latest date the patient was known to be alive.
Outcome Time Frame
From baseline until death due to any cause, assessed up to approx. 3 years
Outcome Measure
Overall Survival (OS)
Outcome Description
Blood samples were collected for assessment of CgA level. Change from Baseline at a particular visit was calculated as the CgA level at that visit minus Baseline.
Outcome Time Frame
Baseline, day 1 of each cycle from Cycle 2 to end of treatment, assessed up to approx. 1.5 years. Cycle=28 days.
Outcome Measure
Changes From Baseline in Chromogranin A (CgA) Levels
Outcome Description
Blood samples were collected for assessment of NSE level. Change from Baseline at a particular visit was calculated as the NSE level at that visit minus Baseline.
Outcome Time Frame
Baseline, day 1 of each cycle from Cycle 2 to end of treatment, assessed up to approx. 1.5 years. Cycle= 28days
Outcome Measure
Change From Baseline in Neuron Specific Enolase (NSE) Levels
Outcome Description
Blood samples will be taken to evaluate the pharmacokinetics by assessing plasma concentration of PDR001 at selected time points
Outcome Time Frame
Cycle(C)1 Day(D)1 pre-dose and 30min post-infusion,C2D1 Pre-dose,C3D1 Pre-dose and 30min post-infusion,D1 pre-dose from C4 to C13, assessed up to approx. 1.5 years.Cycle=28 days
Outcome Measure
PDR001 Plasma Concentration
Outcome Description
The EORTC QLQ-C30 is a patient completed 30 item questionnaire that is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, six single items and a global health status/QoL scale. Global health status/QoL response options are 1 to 4. Scores were averaged and transformed to 0 to 100. Higher scores indicate better functioning.
Change from Baseline was calculated by subtracting Baseline value from the selected visit value. A positive change from Baseline indicates improvement.
Change from Baseline was calculated by subtracting Baseline value from the selected visit value. A positive change from Baseline indicates improvement.
Outcome Time Frame
Baseline, every 8 weeks from Cycle 3 Day 1 for the first 13 cycles and every 12 weeks from Cycle 13 Day 1 thereafter and end of treatment, assessed up to approx. 1.5 years. Cycle=28 days
Outcome Measure
Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life Score
Outcome Description
The EQ-5D-5L descriptive system provides a profile of the participant's health state in 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each of these dimensions, the participant self-assigned a score: from 1 (no problems) to 5 (extreme problems). The 5 digit health states obtained for each dimension was converted into a single mean index value based on the EQ-5D crosswalk value set for the UK using the time trade-off method. This index ranges from -0.594 (worst health) to 1.0 (best health). Change from Baseline was calculated by subtracting Baseline value from the selected visit value. A positive change from baseline indicates improvement.
Outcome Time Frame
Baseline, every 8 weeks from Cycle 3 Day 1 for the first 13 cycles and every 12 weeks from Cycle 13 Day 1 thereafter, and end of treatment, assessed up to approx.1.5 year. Cycle=28 days
Outcome Measure
Change From Baseline in EQ-5D-5L Index Score
Outcome Description
ADA prevalence at baseline was calculated as the proportion of participants who had an ADA positive result at baseline
Outcome Time Frame
Baseline
Outcome Measure
PDR001 Anti-drug Antibodies (ADA) Prevalence at Baseline
Outcome Description
ADA incidence on treatment was calculated as the proportion of participants who were treatment-induced ADA positive (post-baseline ADA positive with ADA-negative sample at baseline) and treatment-boosted ADA positive (post-baseline ADA positive with titer that is at least the fold titer change greater than the ADA-positive baseline titer)
Outcome Time Frame
Cycle(C)1 Day(D)1 pre-dose and 30min post-infusion,C2D1 Pre-dose,C3D1 Pre-dose and 30min post-infusion,D1 pre-dose from C4 to C13 and every 6 cycles until C25, and end of treatment, assessed up to approx. 1.5 years. Cycle=28 days
Outcome Measure
PDR001 ADA Incidence On-treatment
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Jennifer Chuy
Investigator Email
jchuy@montefiore.org
Investigator Phone