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)
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| ClinicalTrials.gov Identifier: NCT02955069 |
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Recruitment Status :
Completed
First Posted : November 4, 2016
Results First Posted : April 12, 2021
Last Update Posted : April 12, 2021
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| 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 | Drug: PDR001 | Phase 2 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 116 participants |
| Allocation: | N/A |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| 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. |
| Actual Study Start Date : | February 14, 2017 |
| Actual Primary Completion Date : | August 10, 2018 |
| Actual Study Completion Date : | May 13, 2020 |
| Arm | Intervention/treatment |
|---|---|
|
Experimental: PDR001
Subjects with advanced or metastatic, well-differentiated, NET of pancreatic, GI, or thoracic origin or poorly-differentiated GEP-NEC, that have progressed on prior treatment were treated with 400mg PDR001 administered via intravenous infusion once every 4 weeks.
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Drug: PDR001
PDR001 was administered at a dose of 400 mg via intravenous infusion once every 4 weeks (Q4W). PDR001 was administered on Day 1 of every cycle. Each cycle was 28 days.
Other Name: Spartalizumab |
- Overall Response Rate (ORR) by RECIST 1.1 and as Per Blinded Independent Central Review (BIRC). [ Time Frame: From baseline up to approximately 1.5 years ]
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.
- Duration of Response (DOR) by RECIST 1.1 and as Per BIRC [ 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 ]
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.
- Disease Control Rate by RECIST 1.1 and as Per BIRC [ Time Frame: From baseline up to approximately 1.5 years ]
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.
- Time to Response (TTR) by RECIST 1.1 and as Per BIRC [ Time Frame: From baseline to the first documented response, assessed up to approximately 1.5 years ]
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.
- Progression-free Survival (PFS) by RECIST 1.1 and as Per BIRC [ 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 ]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.
- Immune Related Overall Response Rate (irORR) by irRECIST and as Per BIRC [ Time Frame: From baseline up to approximately 1.5 years ]
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).
- Immune Related Duration of Response (irDoR) by irRECIST and as Per BIRC. [ 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 ]
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
- Immune Related Time to Response (irTTR) by irRECIST and as Per BIRC [ Time Frame: From baseline to the first documented response, assessed up to approximately 1.5 years ]
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.
- Immune Related Disease Control Rate (irDCR) by irRECIST and as Per BIRC [ Time Frame: From baseline up to approximately 1.5 years ]
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.
- Immune Related Progression Free Survival (irPFS) by irRECIST and as Per BIRC [ 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 ]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.
- Overall Survival (OS) [ Time Frame: From baseline until death due to any cause, assessed up to approx. 3 years ]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.
- Changes From Baseline in Chromogranin A (CgA) Levels [ 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. ]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.
- Change From Baseline in Neuron Specific Enolase (NSE) Levels [ Time Frame: Baseline, day 1 of each cycle from Cycle 2 to end of treatment, assessed up to approx. 1.5 years. Cycle= 28days ]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.
- PDR001 Plasma Concentration [ 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 ]Blood samples will be taken to evaluate the pharmacokinetics by assessing plasma concentration of PDR001 at selected time points
- 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 [ 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 ]
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 in EQ-5D-5L Index Score [ 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 ]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.
- PDR001 Anti-drug Antibodies (ADA) Prevalence at Baseline [ Time Frame: Baseline ]ADA prevalence at baseline was calculated as the proportion of participants who had an ADA positive result at baseline
- PDR001 ADA Incidence On-treatment [ 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 ]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)
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02955069
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| Study Director: | Novartis Pharmaceuticals | Novartis Pharmaceuticals |
Documents provided by Novartis ( Novartis Pharmaceuticals ):
| Responsible Party: | Novartis Pharmaceuticals |
| ClinicalTrials.gov Identifier: | NCT02955069 |
| Other Study ID Numbers: |
CPDR001E2201 2016-002522-36 ( EudraCT Number ) |
| First Posted: | November 4, 2016 Key Record Dates |
| Results First Posted: | April 12, 2021 |
| Last Update Posted: | April 12, 2021 |
| Last Verified: | March 2021 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data is currently available according to the process described on www.clinicalstudydatarequest.com. |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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