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

Nasopharyngeal Carcinoma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02605967
• Other study ID #: CPDR001X2201
• Secondary ID: 2015-000454-38
• Status: Completed
• Phase: Phase 2
• Start date: April 20, 2016
• Est. completion date: February 19, 2021

Study information

• Verified date: January 2022
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 122
• Est. completion date: February 19, 2021
• Est. primary completion date: November 5, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma
• Nasopharyngeal Carcinoma

Intervention

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.
• 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.

Locations

Country	Name	City	State
China	Novartis Investigative Site	Guangzhou
France	Novartis Investigative Site	Nice Cedex 2	Alpes Maritimes
France	Novartis Investigative Site	Villejuif Cedex	Villejuif
Hong Kong	Novartis Investigative Site	Hong Kong
Hong Kong	Novartis Investigative Site	Kowloon
Hong Kong	Novartis Investigative Site	Tuen Mun
Singapore	Novartis Investigative Site	Singapore
Taiwan	Novartis Investigative Site	Kaohsiung City
Taiwan	Novartis Investigative Site	Tainan	Taiwan ROC
Taiwan	Novartis Investigative Site	Taipei
Taiwan	Novartis Investigative Site	Taoyuan
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Chiang Mai
Thailand	Novartis Investigative Site	Songkhla	Hat Yai
United States	Karmanos Cancer Institute	Detroit	Michigan
United States	Virginia Cancer Specialists	Fairfax	Virginia
United States	Northwest Georgia Oncology Center NWGA Onc - Carrollton	Marietta	Georgia
United States	NYU Laura and Isaac Perlmutter Cancer Center Laura & Isaac Perlmutter Ctr	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  China,  France,  Hong Kong,  Singapore,  Taiwan,  Thailand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free Survival (PFS) as Per RECIST v 1.1 Using Central Assessment - Number of Participants With Progression or Death	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.	From randomization up to maximum 3.3 years
Primary	Progression-free Survival (PFS) as Per RECIST v 1.1 Using Central Assessment - Median PFS	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.	From randomization up to maximum 3.3 years
Secondary	Overall Survival (OS)	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.	From randomization up to maximum 4.8 years.
Secondary	Overall Response Rate (ORR) as Per RECIST v 1.1	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.	From randomization up to maximum 3.3 years
Secondary	Duration of Response (DOR) as Per RECIST v 1.1	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.	From randomization up to maximum 3.3 years
Secondary	Time to Progression (TTP) as Per RECIST v 1.1	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.	From randomization up to maximum 3.3 years
Secondary	Immune-related Progression-free Survival (irPFS) as Per irRC	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.	From randomization up to maximum 3.3 years
Secondary	Maximum Observed Serum Concentration (Cmax) of Spartalizumab	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.	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.
Secondary	Time to Reach Maximum Serum Concentration (Tmax) of Spartalizumab	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.	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.
Secondary	Area Under the Serum Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) of Spartalizumab	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.	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.
Secondary	Area Under the Serum Concentration-time Curve From Time Zero to Infinity (AUCinf) of Spartalizumab	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.	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.
Secondary	Accumulation Ratio (Racc) of Spartalizumab	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.	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.
Secondary	Terminal Elimination Half-life (T1/2) of Spartalizumab	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.	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.
Secondary	Number of Participants With Anti-spartalizumab Antibodies	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.	Baseline (pre-dose on Cycle 1 Day 1) and post-baseline (assessed throughout the treatment up to maximum 655 days).
Secondary	PD-L1 Percent Positive Tumor	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.	Baseline (screening), Cycle 3 Day 1. The duration of one cycle was 28 days.
Secondary	Percent Marker Area for CD8 Expression in Tumor Samples	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.	Baseline (screening), Cycle 3 Day 1. The duration of one cycle was 28 days.
Secondary	TIL Count in Tumor Samples	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.	Baseline (screening), Cycle 3 Day 1. The duration of one cycle was 28 days.
Secondary	Fold Change From Baseline in IFN-gamma Levels in Plasma	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.	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.
Secondary	Fold Change From Baseline in IL-6 Levels in Plasma	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.	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.
Secondary	Fold Change From Baseline in TNF-alfa Levels in Plasma	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.	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.