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Safety and Efficacy Study of PDR001 in Patients With Recurrent or Metastatic Nasopharyngeal Carcinoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02605967
Recruitment Status : Completed
First Posted : November 17, 2015
Results First Posted : August 12, 2021
Last Update Posted : February 10, 2022
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE October 15, 2015
First Posted Date  ICMJE November 17, 2015
Results First Submitted Date  ICMJE April 21, 2021
Results First Posted Date  ICMJE August 12, 2021
Last Update Posted Date February 10, 2022
Actual Study Start Date  ICMJE April 20, 2016
Actual Primary Completion Date November 5, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 17, 2022)
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: November 16, 2015)
Progression free survival [ Time Frame: approximately 20 months after FPFV ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 17, 2022)
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 16, 2015)
  • Overall Survival (OS) [ Time Frame: 2 years ]
    evaluate the anti-tumor activity of PDR001 versus investigator choice of chemotherapy in NPC patients
  • Composite serum pharmacokinetics (PK) parameters [ Time Frame: 1 year ]
    characterize the pharmacokinetics profiles of PDR001; PK parameters area under the curve (AUC)
  • Presence and /or concentration of anti-PDR001 antibodies [ Time Frame: 1 year ]
    Assess immunogenicity serum concentration
  • Overall response rate (ORR) [ Time Frame: 1 year ]
    evaluate the anti-tumor activity of PDR001 versus investigator choice of chemotherapy in NPC patients
  • Duration of response (DOR) [ Time Frame: 1 year ]
    evaluate the anti-tumor activity of PDR001 versus investigator choice of chemotherapy in NPC patients
  • Time to progression (TTP) [ Time Frame: 1 year ]
    evaluate the anti-tumor activity of PDR001 versus investigator choice of chemotherapy in NPC patients
  • immune related progression free survival (irPFS) using central assessment [ Time Frame: 2 years ]
    evaluate the anti-tumor activity of PDR001 versus investigator choice of chemotherapy in NPC patients
  • serum concentration vs.time profiles [ Time Frame: 1 year ]
    serum concentration of PDR001 on D1,D8,D15,D29,D36,D43,D57,D58,D64,D71,D85,D140
  • Potential associations between expression of PD-L1, CD8 and other immunological markers with anti-tumor activity [ Time Frame: 2 years ]
    assess changes in expression of immunological markers such as CD8 and PD-L1 in tumor biopsies
  • expression of immune-related genes (RNA/protein in tumor sample [ Time Frame: 2 years ]
    assess changes in immune-related gene signature
  • Peripheral, soluble ligands and cytokine levels [ Time Frame: 2 years ]
    assess plasma concentration levels of cytokines interferon-gamma ( IFN-γ) in pg/ml
  • Composite serum pharmacokinetics (PK) parameters [ Time Frame: 1 year ]
    characterize the pharmacokinetics profiles of PDR001; PK parameters maximum plasma concentration(Cmax)
  • Composite serum pharmacokinetics (PK) parameters [ Time Frame: 1 year ]
    characterize the pharmacokinetics profiles of PDR001; PK parameter as the time to reach maximum peak plasma (Tmax)
  • Composite serum pharmacokinetics (PK) parameters [ Time Frame: 1 year ]
    characterize the pharmacokinetics profiles of PDR001; PK parameters include the elimination half-life (T1/2)
  • Peripheral, soluble ligands and cytokine levels [ Time Frame: 2 years ]
    assess plasma concentration levels of cytokines as tumor necrosis factor-alpha (TNF-α) in pg/ml
  • Peripheral, soluble ligands and cytokine levels [ Time Frame: 2 years ]
    assess plasma concentration levels of cytokines as Interleukin-6 ( IL-6) in pg/ml
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Efficacy Study of PDR001 in Patients With Recurrent or Metastatic Nasopharyngeal Carcinoma
Official Title  ICMJE 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
Brief Summary

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.

Detailed Description

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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Nasopharyngeal Carcinoma
Intervention  ICMJE
  • 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
  • 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.
Study Arms  ICMJE
  • Experimental: Spartalizumab 400 mg Q4W
    anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab
    Intervention: Drug: Spartalizumab
  • Active Comparator: Chemotherapy
    commonly used chemotherapy as per investigator's choice
    Intervention: Drug: Investigator choice of chemotherapy
Publications * Even C, Wang HM, Li SH, Ngan RK, Dechaphunkul A, Zhang L, Yen CJ, Chan PC, Chakrabandhu S, Ma BBY, Tanasanvimon S, Lee VHF, Lou PJ, Li Z, Spira AI, Sukari A, Guigay J, McCune S, Gonzalez-Maffe J, Szpakowski S, Yao Y, Liang H, Mataraza J, Séchaud R, Manenti L, Lim DW. Phase II, Randomized Study of Spartalizumab (PDR001), an Anti-PD-1 Antibody, versus Chemotherapy in Patients with Recurrent/Metastatic Nasopharyngeal Cancer. Clin Cancer Res. 2021 Dec 1;27(23):6413-6423. doi: 10.1158/1078-0432.CCR-21-0822. Epub 2021 Aug 25.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 19, 2020)
122
Original Estimated Enrollment  ICMJE
 (submitted: November 16, 2015)
114
Actual Study Completion Date  ICMJE February 19, 2021
Actual Primary Completion Date November 5, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE China,   France,   Hong Kong,   Singapore,   Taiwan,   Thailand,   United States
Removed Location Countries Canada
 
Administrative Information
NCT Number  ICMJE NCT02605967
Other Study ID Numbers  ICMJE CPDR001X2201
2015-000454-38 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
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

Current Responsible Party Novartis ( Novartis Pharmaceuticals )
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Novartis Pharmaceuticals
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date January 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP