Safety and Efficacy Study of PDR001 in Patients With Recurrent or Metastatic Nasopharyngeal Carcinoma
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| ClinicalTrials.gov Identifier: NCT02605967 |
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Recruitment Status :
Completed
First Posted : November 17, 2015
Results First Posted : August 12, 2021
Last Update Posted : February 10, 2022
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The purpose of this randomized controlled Phase II study is to assess the efficacy of PDR001 versus investigator's choice of chemotherapy in patients with advanced nasopharyngeal carcinoma (NPC).
By blocking the interaction between PD-1 and its ligands PD-L1 and PD-L2, PDR001 leads to the activation of a T-cell mediated antitumor immune response.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Nasopharyngeal Carcinoma | Drug: Spartalizumab Drug: Investigator choice of chemotherapy | Phase 2 |
This was an open-label, multi-center, randomized, and controlled Phase II study to evaluate the efficacy and safety of spartalizumab versus investigator's choice of treatment in subjects with moderately differentiated/undifferentiated locally advanced recurrent or metastatic NPC who progressed on or after first-line treatment.
Participants who met the inclusion/exclusion criteria were randomized in a 2:1 ratio to either investigational arm (spartalizumab) or control arm (commonly used chemotherapy as per investigator's choice). Participants treated with spartalizumab could continue treatment until confirmed progressive disease as per immune-related response criteria (irRC). Participants in the chemotherapy arm were allowed to crossover to spartalizumab if they had radiological progression as per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1) documented by an independent central review and the Investigator believed this was the best treatment option for the patient.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 122 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | A Phase II, Open-label, Randomized Controlled Study of PDR001 in Patients With Moderately Differentiated/Undifferentiated Locally Advanced Recurrent or Metastatic Nasopharyngeal Carcinoma Who Progressed on Standard Treatment |
| Actual Study Start Date : | April 20, 2016 |
| Actual Primary Completion Date : | November 5, 2019 |
| Actual Study Completion Date : | February 19, 2021 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Spartalizumab 400 mg Q4W
anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab
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Drug: Spartalizumab
Spartalizumab was administered via intravenous infusion at a dose of 400 mg every 4 weeks (Q4W). Spartalizumab is a humanized anti-PD-1 IgG4 antibody which blocks the binding of PD1 to its ligands PD-L1 and PD-L2.
Other Name: PDR001 |
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Active Comparator: Chemotherapy
commonly used chemotherapy as per investigator's choice
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Drug: Investigator choice of chemotherapy
Commonly used chemotherapy as per investigator's choice. The dose and route of administration was the one described in each drug's label. |
- Progression-free Survival (PFS) as Per RECIST v 1.1 Using Central Assessment - Number of Participants With Progression or Death [ Time Frame: From randomization up to maximum 3.3 years ]
PFS is the time from the date of randomization to the date of event defined as the first documented confirmed progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment.
Tumor response was based on central review of tumor scan and the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive disease is at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. Number of participants in each category (progression, death, censored) is reported in this record.
- Progression-free Survival (PFS) as Per RECIST v 1.1 Using Central Assessment - Median PFS [ Time Frame: From randomization up to maximum 3.3 years ]
PFS is the time from the date of randomization to the date of event defined as the first documented confirmed progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment.
Tumor response was based on central review of tumor scan and the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive disease is at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline.
- Overall Survival (OS) [ Time Frame: From randomization up to maximum 4.8 years. ]Overall survival (OS) is defined as the time from date of randomization to date of death due to any cause. If a patient is not known to have died, survival is censored at the date of last known date the patient was alive.
- Overall Response Rate (ORR) as Per RECIST v 1.1 [ Time Frame: From randomization up to maximum 3.3 years ]
ORR is defined as the percentage of participants with a best overall response of Complete Response (CR) or Partial Response (PR). Tumor response was based on central review of overall lesion response according to RECIST 1.1.
For RECIST v1.1, 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) as Per RECIST v 1.1 [ Time Frame: From randomization up to maximum 3.3 years ]DOR only applies to subjects for whom best overall response is complete response (CR) or partial response (PR) based on central review of overall lesion response according to RECIST 1.1. DOR is defined as the time between the date of first documented response (confirmed CR or confirmed PR) and the date of first documented disease progression or death due to underlying cancer. If a patient not had an event, duration was censored at the date of last adequate tumor assessment.
- Time to Progression (TTP) as Per RECIST v 1.1 [ Time Frame: From randomization up to maximum 3.3 years ]
TTP is defined as time from date of randomization to the date of event defined as the first documented progression or death due to underlying cancer. If a subject did not had an event, TTP was censored at the date of last adequate tumor assessment.
Tumor response was based on central review of tumor scan and the assessment criteria was RECIST v1.1. Progressive disease is at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline.
- Immune-related Progression-free Survival (irPFS) as Per irRC [ Time Frame: From randomization up to maximum 3.3 years ]
irPFS is the time from the date of randomization to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment.
Tumor response was based on central review of tumor scan and the assessment criteria was immune-related Response Criteria (irRC). Immune-related progressive disease is at least a 20% increase in the sum of diameters of all measured target lesions including new measurable lesions.
- Maximum Observed Serum Concentration (Cmax) of Spartalizumab [ Time Frame: pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days. ]Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed serum concentration following a dose.
- Time to Reach Maximum Serum Concentration (Tmax) of Spartalizumab [ Time Frame: pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days. ]Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) serum concentration following a dose. Actual recorded sampling times were considered for the calculations.
- Area Under the Serum Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) of Spartalizumab [ Time Frame: pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days. ]Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC calculation. The duration of the dosing interval (tau) was 28 days.
- Area Under the Serum Concentration-time Curve From Time Zero to Infinity (AUCinf) of Spartalizumab [ Time Frame: pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days. ]Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC calculation. The extrapolation of AUC to infinity could be calculated if the percentage of area extrapolated was less than 20% and the regression analysis of the terminal serum elimination phase met a pre-defined criteria of goodness of fit.
- Accumulation Ratio (Racc) of Spartalizumab [ Time Frame: pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days. ]Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Racc was calculated as the ratio between AUCtau Cycle 3 and AUCtau Cycle 1.
- Terminal Elimination Half-life (T1/2) of Spartalizumab [ Time Frame: pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days. ]Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Elimination half-life (T1/2) values were calculated as 0.693/terminal elimination rate constant.
- Number of Participants With Anti-spartalizumab Antibodies [ Time Frame: Baseline (pre-dose on Cycle 1 Day 1) and post-baseline (assessed throughout the treatment up to maximum 655 days). ]Validated immunoassays were used for screening and confirmation of the presence of anti-spartalizumab antibodies (ADA, anti-drug antibodies) in serum. Number of participants with each ADA status is reported in this record.
- PD-L1 Percent Positive Tumor [ Time Frame: Baseline (screening), Cycle 3 Day 1. The duration of one cycle was 28 days. ]The expression of programmed cell death-ligand 1 (PD-L1) was measured in tumor samples by immunohistochemical methods. This record summarizes the PD-L1 positivity percentage in tumor samples.
- Percent Marker Area for CD8 Expression in Tumor Samples [ Time Frame: Baseline (screening), Cycle 3 Day 1. The duration of one cycle was 28 days. ]The expression of CD8 was measured in tumor samples by immunohistochemical methods. This record summarizes the percent marker area for CD8 expression in tumor samples.
- TIL Count in Tumor Samples [ Time Frame: Baseline (screening), Cycle 3 Day 1. The duration of one cycle was 28 days. ]The count of tumor-infiltrating lymphocytes (TILs) was measured in baseline (screening) and post-baseline paired tumor samples by immunohistochemical methods. This record summarizes the TIL count in tumor samples.
- Fold Change From Baseline in IFN-gamma Levels in Plasma [ Time Frame: Baseline (pre-dose on Cycle 1 Day 1), Cycle 1 Day 15, Cycle 2 Day 15 and end of treatment (assessed up to maximum 4 years). The duration of one cycle was 28 days. ]The levels of interferon-gamma (IFN-gamma) were measured in plasma samples by immunoassay methods. This record summarizes the fold change from baseline in IFN-gamma levels in plasma.
- Fold Change From Baseline in IL-6 Levels in Plasma [ Time Frame: Baseline (pre-dose on Cycle 1 Day 1), Cycle 1 Day 15, Cycle 2 Day 15 and end of treatment (assessed up to maximum 4 years). The duration of one cycle was 28 days. ]The levels of interleukin-6 (IL-6) were measured in plasma samples by immunoassay methods. This record summarizes the fold change from baseline in IL-6 levels in plasma.
- Fold Change From Baseline in TNF-alfa Levels in Plasma [ Time Frame: Baseline (pre-dose on Cycle 1 Day 1), Cycle 1 Day 15, Cycle 2 Day 15 and end of treatment (assessed up to maximum 4 years). The duration of one cycle was 28 days. ]The levels of tumor necrosis factor-alpha (TNF-alfa) were measured in plasma samples by immunoassay methods. This record summarizes the fold change from baseline in TNF-alfa levels in plasma.
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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:
- Histologically documented non-keratinizing locally advanced recurrent or metastatic NPC.
- Must be resistant to platinum-based chemotherapy (defined as progression on or after platinum-based chemotherapy given in the recurrent/metastatic setting).
- May have received at least 1 prior therapy for recurrent or metastatic disease, up to 2 prior systemic therapies.
- An archival tumor specimen or newly obtained tumor sample may be submitted at screening/baseline (a fresh tumor sample is preferred), unless agreed differently between Novartis and the Investigator.
- At least 1 measurable lesion (as per RECIST v1.1) progressing or new since last anti-tumor therapy.
- Prior treated brain or meningeal metastases must be without MRI evidence of progression for at least 8 weeks and off systemic steroids for at least 2 weeks prior to screening/baseline.
- Patient must be willing to undergo testing for human immunodeficiency virus (HIV) if not tested within the past 6 months. If HIV+ positive, patient will be eligible if: his/ her CD4+ count ≥ 300/μL; his/her viral load is undetectable; he/she is currently receiving highly active antiretroviral therapy (HAART).
Exclusion Criteria:
- History of severe hypersensitivity reactions to other mAbs
- Active autoimmune disease or a documented history of autoimmune disease, except vitiligo or resolved asthma/atopy that is treated with broncho-dilators.
- Active HBV or HCV infections requiring therapy.
- Prior PD-1- or PD-L1-directed therapy or any therapeutic cancer vaccine.
- Patients receiving systemic treatment with any immunosuppressive medication.
- Use of any vaccines against infectious diseases (e.g. varicella, pneumococcus) within 4 weeks of initiation of study treatment.
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): NCT02605967
| United States, Georgia | |
| Northwest Georgia Oncology Center NWGA Onc - Carrollton | |
| Marietta, Georgia, United States, 30060 | |
| United States, Michigan | |
| Karmanos Cancer Institute | |
| Detroit, Michigan, United States, 48201 | |
| United States, New York | |
| NYU Laura and Isaac Perlmutter Cancer Center Laura & Isaac Perlmutter Ctr | |
| New York, New York, United States, 10016 | |
| United States, Virginia | |
| Virginia Cancer Specialists | |
| Fairfax, Virginia, United States, 22031 | |
| China | |
| Novartis Investigative Site | |
| Guangzhou, China, 510060 | |
| France | |
| Novartis Investigative Site | |
| Nice Cedex 2, Alpes Maritimes, France, 06189 | |
| Novartis Investigative Site | |
| Villejuif Cedex, Villejuif, France, 94800 | |
| Hong Kong | |
| Novartis Investigative Site | |
| Hong Kong, Hong Kong | |
| Novartis Investigative Site | |
| Kowloon, Hong Kong | |
| Novartis Investigative Site | |
| Tuen Mun, Hong Kong | |
| Singapore | |
| Novartis Investigative Site | |
| Singapore, Singapore, 169610 | |
| Taiwan | |
| Novartis Investigative Site | |
| Tainan, Taiwan ROC, Taiwan, 70403 | |
| Novartis Investigative Site | |
| Kaohsiung City, Taiwan, 83301 | |
| Novartis Investigative Site | |
| Taipei, Taiwan, 10002 | |
| Novartis Investigative Site | |
| Taoyuan, Taiwan, 33305 | |
| Thailand | |
| Novartis Investigative Site | |
| Songkhla, Hat Yai, Thailand, 90110 | |
| Novartis Investigative Site | |
| Bangkok, Thailand, 10330 | |
| Novartis Investigative Site | |
| Chiang Mai, Thailand, 50200 | |
| Study Director: | Novartis Pharmaceuticals | Novartis Pharmaceuticals |
Documents provided by Novartis ( Novartis Pharmaceuticals ):
| Responsible Party: | Novartis Pharmaceuticals |
| ClinicalTrials.gov Identifier: | NCT02605967 |
| Other Study ID Numbers: |
CPDR001X2201 2015-000454-38 ( EudraCT Number ) |
| First Posted: | November 17, 2015 Key Record Dates |
| Results First Posted: | August 12, 2021 |
| Last Update Posted: | February 10, 2022 |
| Last Verified: | January 2022 |
| 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 review 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 availability is according to the criteria and 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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PDR001 nasopharyngeal cancer moderately differentiated/undifferentiated |
locally advanced recurrent or metastatic NPC after first- line platinum-based therapy |
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Carcinoma Nasopharyngeal Carcinoma Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Neoplasms Nasopharyngeal Neoplasms Pharyngeal Neoplasms Otorhinolaryngologic Neoplasms Head and Neck Neoplasms Neoplasms by Site |
Nasopharyngeal Diseases Pharyngeal Diseases Stomatognathic Diseases Otorhinolaryngologic Diseases Spartalizumab Immune Checkpoint Inhibitors Molecular Mechanisms of Pharmacological Action Antineoplastic Agents, Immunological Antineoplastic Agents |