Tabelecleucel in Combination With Pembrolizumab in Subjects With Epstein-Barr Virus-associated Nasopharyngeal Carcinoma (EBV+ NPC)

NCT03769467 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: ATA129-NPC-202KEYNOTE PN597
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 7

Brief Summary

This is a multicenter, open-label, single-arm Phase 1B/2 study to assess the safety and efficacy of tabelecleucel in combination with pembrolizumab for the treatment of subjects with platinum-pretreated, recurrent/metastatic Epstein-Barr Virus-associated Nasopharyngeal Carcinoma (EBV+ NPC).

Conditions

Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Epstein-Barr Virus Infections; Epstein-Barr Viraemia; Epstein-Barr Virus-associated Nasopharyngeal Carcinoma (EBV+ NPC)

Keywords

Nasopharyngeal Carcinoma (NPC); NPC; Nasopharyngeal Cancer; Nose Cancer; Epstein-Barr Virus (EBV); Epstein-Barr Virus Viremia; EBV-associated NPC; Allogeneic, off-the-shelf T-cell; immunotherapy; Head and Neck Cancer; Carcinoma; Nasopharyngeal Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Head and Neck Neoplasms; Neoplasms by Site; Nasopharyngeal Diseases; Pharyngeal Diseases; Stomatognathic Diseases; Otorhinolaryngologic Diseases; Pembrolizumab; Programmed death-1 (PD-1); Programmed death-ligand 1(PD-L1)

Outcome Measures

Primary Outcomes (6)

• Cohort 1B: Number of Participants With Dose-Limiting Toxicities (DLTs)

  The occurrence of any of the following toxicities during Treatment Cycle 1 will be considered a DLT, if assessed by the investigator to be possibly related or related to investigational product administration (either tabelecleucel and/or pembrolizumab): Grade (G) 4 nonhematologic toxicity; G4 hematologic toxicity lasting \>=7 days, except thrombocytopenia; any nonhematologic AE \>=G3, except G3 fatigue lasting =\<3 days; G3 diarrhea, nausea, or vomiting; G3 rash; Any G3/4 non-hematologic laboratory value if clinically significant medical intervention is required to treat the participant, abnormality leads to hospitalization, abnormality persists for \> 1 week, abnormality results in a Drug-induced Liver Injury (DILI); G3/4 febrile neutropenia; \> 2 weeks delay in initiating Cycle 2; discontinue treatment during Cycle 1; missing \> 25% of study drugs doses as a result of investigational product-related AEs during the first cycle;G5 toxicity.

  From Day 1 through Day 21 of Cycle 1

• Cohort 1B: Maximum Tolerated Dose (MTD)

  The MTD is defined as the highest dose level at which the subject incidence of a DLTs during the first 21-day cycle of investigational product dosing is \< 33%

  From Day 1 through Day 21 of Cycle 21

• Cohort 1B: Recommended Phase 2 Dose (RP2D) of Tabelecleucel in Combination With Pembrolizumab

  The RP2D is no higher than the maximum tolerated dose (highest dose level at which the number of participants with a DLTs during the first 21-day cycle of investigational product dosing is \< 33%) and is based on optimal benefit-risk, as determined by the Safety Data Review Committee (SDRC).

  From Day 1 through Day 21 of Cycle 1

• Cohort 1B: Characterization of the Safety Profile: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

  An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as any AE occurring after initiation of the first dose of study treatment through 30 days after the last administration of study drugs or any pre-existing AE (ie, started prior to the first dose of study drugs) that worsened after the first dose through 30 days after the last administration of study drugs or any related AE on or after first dose.

  From Day 1 to end of study (1 year after the last dose or until disease progression, whichever occurred first) (approximately 27 months)

• Cohort 2: Characterization of the Safety Profile: Number of Participants With TEAEs and TESAEs

  An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as any AE occurring after initiation of the first dose of study treatment through 30 days after the last administration of study drugs or any pre-existing AE (ie, started prior to the first dose of study drugs) that worsened after the first dose through 30 days after the last administration of study drugs or any related AE on or after first dose

  From Day 1 to end of study (1 year after the last dose or until disease progression, whichever occurred first) (approximately 27 months)

• Cohort 2: Objective Response Rate (ORR)

  For this study, radiographic tumor assessment was performed by computed tomography (CT) or magnetic resonance imaging (MRI) scan based on Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1) and immune RECIST (iRECIST) criteria. Per RECIST v1.1, ORR is defined as percentage of participants with complete response (CR) (disappearance of all extranodal target lesions and all pathological lymph nodes must have decreased to \<10 mm in short axis) or partial response (PR) (at least a 30% decrease in sum of the longest diameters of target lesions taking as reference baseline sum diameters). Per iRECIST, immune complete response (iCR) is defined as resolution of all lesions and immune partial response (iPR) is defined as the target lesion sum of diameters (initial target lesions) not above initial progressive disease threshold, no significant growth in non-target lesion overall, and no new lesion or appearance of any new factor.

  From Day 1 to end of study (1 year after the last dose or until disease progression, whichever occurred first) (approximately 27 months)

Secondary Outcomes (6)

• Cohort 2: Complete Response (CR) Rate

  From Day 1 to end of study (1 year after the last dose or until disease progression, whichever occurred first) (approximately 27 months)

• Cohort 2: Duration of Response (DOR)

  From Day 1 to end of study (1 year after the last dose or until disease progression, whichever occurred first) (approximately 27 months)

• Cohort 2: Progression Free Survival (PFS)

  From Day 1 to end of study (1 year after the last dose or until disease progression, whichever occurred first) (approximately 27 months)

• Cohort 2: Overall Survival (OS)

  From Day 1 to end of study (1 year after the last dose or until disease progression, whichever occurred first) (approximately 27 months)

• Cohort 2: Immune Response Rate (iRR)

  From Day 1 to end of study (1 year after the last dose or until disease progression, whichever occurred first) (approximately 27 months)

Study Arms (3)

Cohort 1B: Checkpoint Inhibitor Naïve

EXPERIMENTAL

Checkpoint inhibitor naive subjects during the treatment phase will receive intravenous (IV) infusion of pembrolizumab at 200 mg for adults (≥ 18 years of age) or 2 mg/kg for adolescents (12 to \< 18 years of age) prior to the administration of tabelecleucel on Day 1; and IV infusion of tabelecleucel (tab-cel) at 2 × 10\^6 T-cells/kg on Days 1, 8, and 15 of each 21-day treatment/consolidation cycles (at least 2 cycles or up to 4 cycles). From the Maintenance Phase, subjects with stable disease or better will receive tabelecleucel on Day 1 and pembrolizumab on Day 1, Day 21, Day 42, and Day 63 of each 84- day maintenance cycle, which was continued until disease progression, unacceptable toxicity, or a total of 35 pembrolizumab infusions (including for treatment, consolidation, and maintenance) had been administered, whichever occurred first.

Biological: Tabelecleucel; Biological: Pembrolizumab

Cohort 1B: Checkpoint Inhibitor PD-1/PD-L1 Failure

EXPERIMENTAL

Checkpoint inhibitor PD-1/PD-L1 failure subjects during the treatment phase will receive IV infusion of pembrolizumab at 200 mg for adults (≥ 18 years of age) or 2 mg/kg for adolescents (12 to \< 18 years of age) prior to the administration of tabelecleucel on Day 1; and IV infusion of tabelecleucel (tab-cel) at 2 × 10\^6 T-cells/kg on Days 1, 8, and 15 of each 21-day treatment/consolidation cycles (at least 2 cycles or up to 4 cycles).). From the Maintenance Phase, subjects with stable disease or better will receive tabelecleucel on Day 1 and pembrolizumab on Day 1, Day 21, Day 42, and Day 63 of each 84-day maintenance cycle, which was continued until disease progression, unacceptable toxicity, or a total of 35 pembrolizumab infusions (including for treatment, consolidation, and maintenance) had been administered, whichever occurred first.

Biological: Tabelecleucel; Biological: Pembrolizumab

Cohort 2: Checkpoint Inhibitor Naïve

EXPERIMENTAL

Checkpoint inhibitor naive subjects during the treatment phase will receive IV infusion of pembrolizumab at 200 mg for adults (≥ 18 years of age) or 2 mg/kg for adolescents (12 to \< 18 years of age) prior to the administration of tabelecleucel on Day 1; and IV infusion of tabelecleucel (tab-cel) at 2 × 10\^6 T-cells/kg on Days 1, 8, and 15 of each 21-day treatment/consolidation cycles (at least 2 cycles or up to 4 cycles). From the Maintenance Phase, subjects with stable disease or better will receive tabelecleucel on Day 1 and pembrolizumab on Day 1, Day 21, Day 42, and Day 63 of each 84- day maintenance cycle, which was continued until disease progression, unacceptable toxicity, or a total of 35 pembrolizumab infusions (including for treatment, consolidation, and maintenance) had been administered, whichever occurred first.

Biological: Tabelecleucel; Biological: Pembrolizumab

Interventions

Tabelecleucel BIOLOGICAL

Tabelecleucel is an off-the-shelf, allogeneic T-cell immunotherapy for the treatment of EBV+ malignancies and diseases.

Also known as: tab-cel®, ATA129, Epstein-Barr Virus-specific Cytotoxic T Lymphocytes (EBV-CTL)

Cohort 1B: Checkpoint Inhibitor Naïve; Cohort 1B: Checkpoint Inhibitor PD-1/PD-L1 Failure; Cohort 2: Checkpoint Inhibitor Naïve

Pembrolizumab BIOLOGICAL

pembrolizumab IV infusion

Also known as: MK-3475

Cohort 1B: Checkpoint Inhibitor Naïve; Cohort 1B: Checkpoint Inhibitor PD-1/PD-L1 Failure; Cohort 2: Checkpoint Inhibitor Naïve

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female ≥ 12 years of age.
• Incurable, locally recurrent or metastatic Epstein-Barr virus (EBV)+NPC (World Health Organization type II/III) in whom the EBV nucleic acid or antigens have been demonstrated in tissue biopsy samples.
• Subjects must have had prior receipt of platinum-containing regimen either:
• For the treatment of recurrent or metastatic disease, or
• Experienced progression of disease within 6 months following completion of a platinum-based combination therapy as part of (neo)adjuvant chemotherapy. Note: Subject who had only concurrent chemoradiation therapy without (neo)adjuvant therapy and then recurred/metastasized must have progressed on at least 1 platinum-containing regimen for their recurrent/metastatic disease before study entry.
• Phase 1B (Cohort 1):
• Checkpoint inhibitor naïve (have never received pembrolizumab or any other anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-OX40 or anti-CTLA-4 antibodies) OR
• Refractory to an anti-programmed cell death protein-1 (PD-1) or anti-programmed death-ligand1 (PD-L1) monoclonal antibody approved by the local regulatory agency either as monotherapy or in combination with other checkpoint inhibitors or therapies according to their approved label. To be considered refractory to an anti-PD-1 or anti-PD-L1 monoclonal antibody, all of the following criteria must be met:
• i. Received at least 2 doses of anti-PD-1 or anti-PD-L1 monoclonal antibody at a local regulatory agency-approved dose and schedule. ii. Have progressive disease after anti-PD-1 or anti-PD-L1 monoclonal antibody as defined according to Response Evaluation Criteria in Solid Tumors) RECIST 1.1. The initial evidence of progressive disease is to be confirmed by a second assessment, no less than 4 weeks from the date of the first documented progressive disease, in the absence of rapid clinical progression. (The eligibility determination will be made by the investigator and then the sponsor will collect for retrospective analysis at a central vendor. Once progressive disease is confirmed, the initial date of progressive disease documentation will be considered the date of disease progression).
• iii. Documented disease progression within 24 weeks of the last dose of anti-PD-1 or anti-PD-L1 monoclonal antibody. A subject who was re-treated with anti-PD-1 or anti-PD-L1 monoclonal antibody and a subject who was on maintenance with an anti-PD-1 or anti-PD-L1 monoclonal antibody will be allowed to enter the study as long as there is documented PD within 24 weeks of the last treatment date (with the anti-PD-1 or anti-PD-L1 monoclonal antibody).
• Phase 1B (Cohort 1): If PD-1/PD-L1 failure (ie, refractory to or relapsed after PD-1/PD-L1 treatment), must have a lesion that can be biopsied after administration of tabelecleucel with acceptable clinical risk (as judged by the investigator) and must agree to undergo biopsy before Cycle 1 Day 1.
• Phase 2 (Cohort 2): Checkpoint inhibitor naïve (have never received pembrolizumab or any other anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-OX40 or anti-CTLA-4 antibodies).
• For all subjects: Agree to submit prior biopsy material, if available, for biomarker assessment.
• Life expectancy ≥ 4 months at time of screening.
• Measurable disease using RECIST 1.1. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been documented in such lesions.

You may not qualify if:

• Disease that is suitable for local therapy administered with curative intent.
• Requires vasopressor or ventilator support.
• Received antithymocyte globulin or similar anti-T-cell antibody therapy ≤ 4 weeks prior to Cycle 1 Day 1.
• Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to Cycle 1 Day 1 of study treatment. The use of physiologic doses of corticosteroids may be approved after consultation with the sponsor's medical monitor.
• Active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
• History or evidence of interstitial lung disease.
• History of severe hypersensitivity (Grade ≥ 3) to pembrolizumab and/or any of its excipients.
• Active infection requiring systemic therapy.
• History of (non-infectious) pneumonitis that required steroids or current pneumonitis.
• Received transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including granulocyte-colony stimulating factor, granulocyte macrophage-colony stimulating factor or recombinant erythropoetin) within 4 weeks prior to study Day 1.
• Unresolved immunotherapy-related AEs or treatment for these events within 4 weeks prior to enrollment.
• History of severe immunotherapy-related adverse effects (Common Terminology Criteria for Adverse Events \[CTCAE\] grade 4 or CTCAE grade 3 requiring treatment \> 4 weeks).
• Received any non-oncology vaccine therapy used for prevention of infectious diseases for up to 30 days prior to enrollment. Examples include, but are not limited to: measures, mumps, rubella, chicken pox, yellow fever, rabies, bacille Calmette-Guerin, and typhoid vaccine. Seasonal flu vaccines that do not contain live virus are acceptable.
• Known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
• Pregnancy or breastfeeding: females of childbearing potential must have a negative serum pregnancy test. The serum pregnancy must be confirmed negative within 72 hours of Cycle 1 Day 1 (first dose of investigational product) for the subject to be eligible.

Sponsors & Collaborators

• Atara Biotherapeutics: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (7)

City of Hope

Duarte, California, 91010, United States

Location

Stanford Hospital and Clinics

Palo Alto, California, 94305, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Atlantic Health System / Morristown Medical Center

Morristown, New Jersey, 07962, United States

Location

Laura & Isaac Perlmutter Cancer Center at NYU Langone Health

New York, New York, 10016, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

University of Pennsylvania (Adults and Pediatrics)

Philadelphia, Pennsylvania, 19104, United States

Location

MeSH Terms

Conditions

Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Epstein-Barr Virus Infections; Nose Neoplasms; Head and Neck Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Neoplasms by Site; Nasopharyngeal Diseases; Pharyngeal Diseases; Stomatognathic Diseases; Otorhinolaryngologic Diseases

Interventions

pembrolizumab

Condition Hierarchy (Ancestors)

Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections; Tumor Virus Infections; Skull Neoplasms; Bone Neoplasms; Bone Diseases; Musculoskeletal Diseases; Nose Diseases; Respiratory Tract Diseases; Respiratory Tract Neoplasms

Limitations and Caveats

Post-Hoc efficacy outcomes (ORR and CBR) were analyzed for Cohort 1B (phase 1); however, Cohort 1B was not powered for efficacy. The study was deprioritized and terminated early, and did not proceed to Cohort 2 (Phase 2).

Results Point of Contact

• Title: Study Director
• Organization: Atara Biotherapeutics

clinicalstudies@atarabio.com

650-278-8930

Study Officials

• Aditi Mehta, DO

  Atara Biotherapeutics

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 29, 2018
• First Posted: December 7, 2018
• Study Start: February 19, 2019
• Primary Completion: August 19, 2021
• Study Completion: August 19, 2021
• Last Updated: November 14, 2024
• Results First Posted: November 14, 2024

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (7)