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Phase 1/2a Study of VK-2019 in Patients With Epstein-Barr Virus (EBV)-Positive Nasopharyngeal Carcinoma (NPC)

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ClinicalTrials.gov Identifier: NCT03682055
Recruitment Status : Recruiting
First Posted : September 24, 2018
Last Update Posted : September 27, 2019
Sponsor:
Information provided by (Responsible Party):
Cullinan Apollo Corporation

Brief Summary:
VK-2019-001 is a 1/2a trial of the oral EBNA-1 targeting agent VK-2019 in patients with EBV-positive recurrent or metastatic NPC to determine the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D), as well as to evaluate the PK profile of VK-2019.

Condition or disease Intervention/treatment Phase
Nasopharyngeal Carcinoma Nasopharyngeal Cancer Drug: VK-2019 Phase 1 Phase 2

Detailed Description:

This is a Phase 1/2a, open-label, multicenter, first-in-human trial to evaluate the safety and tolerability, PK, PD, and preliminary efficacy of VK-2019 in patients with EBV-positive NPC.

This trial is divided into three parts: Phase 1 Dose Escalation, Phase 1 Dose Expansion, and Phase 2s Dose Expansion.

The objectives of the dose escalation part are to determine the safety, tolerability, MTD, recommended Phase 2 dose (RP2D), and to evaluate the anti-tumor activity of orally administered VK-2019 monotherapy. Additional objectives are to determine the pharmacokinetic (PK) profile of VK-2019.

VK-2019 will be dosed once daily (QD).


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1/2a Open Label, Multicenter Clinical Trial of a Novel Small Molecule EBNA1 Inhibitor, VK 2019, in Patients With Epstein Barr Virus Positive Nasopharyngeal Cancer, With Pharmacokinetic and Pharmacodynamic Correlative Studies
Actual Study Start Date : April 4, 2019
Estimated Primary Completion Date : October 31, 2021
Estimated Study Completion Date : January 31, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Phase 1 Dose Escalation (Accelerated Titration)
VK-2019 QD in Accelerated Titration dose escalation cohorts enrolling EBV+ NPC
Drug: VK-2019
EBNA1 inhibitor

Experimental: Phase 1 Dose Escalation (Rolling Six)
VK-2019 QD in Rolling Six dose escalation cohorts enrolling EBV+ NPC.
Drug: VK-2019
EBNA1 inhibitor

Experimental: Phase 1 Dose Expansion(s)
VK-2019 QD in expansion cohorts that may be opened at doses that meet pre-specified criteria for clinical and/or biological activity.
Drug: VK-2019
EBNA1 inhibitor

Experimental: Phase 2a Dose Expansion(s)
VK-2019 QD in expansion cohorts that may be opened at doses that meet pre-specified efficacy criteria in Phase 1 Dose Escalation cohorts.
Drug: VK-2019
EBNA1 inhibitor




Primary Outcome Measures :
  1. All Cohorts: The frequency, severity, and duration of AEs and DLTs, AEs leading to discontinuation, and AEs leading to death. [ Time Frame: 24 months ]
  2. Phase 2a Dose Expansion Cohorts: The durable overall response rate (ORR). [ Time Frame: 24 months ]
  3. Phase 2a Dose Expansion Cohorts: ORR [ Time Frame: 24 months ]
  4. Phase 2a Dose Expansion Cohorts: Duration of response (DOR) [ Time Frame: 24 months ]
  5. Phase 2a Dose Expansion Cohorts: Six month disease control rate (DCR-6) [ Time Frame: 30 months ]
  6. Phase 2a Dose Expansion Cohorts: Twelve month disease control rate (DCR-12) [ Time Frame: 36 months ]
  7. Phase 2a Dose Expansion Cohorts: Progression Free Survival (PFS) [ Time Frame: 24 months ]
  8. Phase 2a Dose Expansion Cohorts: Rate of survival [ Time Frame: 24 months ]
  9. Phase 2a Dose Expansion Cohorts: Overall survival (OS) [ Time Frame: 24 months ]

Secondary Outcome Measures :
  1. All Cohorts: Incidence of safety laboratory assessment abnormalities [ Time Frame: 24 months ]
  2. All Cohorts: Incidence of abnormalities in vital signs or other clinical safety assessments. [ Time Frame: 24 months ]
  3. Phase 1 Dose Escalation and Dose Expansion Cohorts: ORR [ Time Frame: 24 months ]
  4. Phase 1 Dose Escalation and Dose Expansion Cohorts: DOR [ Time Frame: 24 months ]
  5. Phase 1 Dose Escalation and Dose Expansion Cohorts: DCR [ Time Frame: 24 months ]
  6. All Cohorts: Rate of partial or complete plasma EBV DNA antiviral response during treatment (assessed as 3xlog10 reduction or a drop below the lower limit of detection of the assay [LLOD], respectively). [ Time Frame: 24 months ]
  7. All Cohorts: Maximum measured concentration in serum (Cmax) [ Time Frame: 24 months ]
  8. All Cohorts: Minimum measured concentration in serum (Cmin) [ Time Frame: 24 months ]
  9. All Cohorts: Time from dosing to maximum measured concentration (tmax) [ Time Frame: 24 months ]
  10. All Cohorts: Area under the serum concentration-time curve (AUC) [ Time Frame: 24 months ]
  11. All Cohorts: Terminal half-life (t1/2) [ Time Frame: 24 months ]

Other Outcome Measures:
  1. Phase 2a Dose Expansion Cohorts: Exploratory PD assay for EBER in situ hybridization levels in baseline and on treatment tumor biopsies in a limited number of patients at MTD. [ Time Frame: 24 months ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Informed consent obtained prior to any protocol mandated assessment.
  2. Age ≥ 18.
  3. Either loco regionally recurrent or metastatic EBV positive nasopharyngeal carcinoma not amenable to curative treatment. EBV positivity is defined as high EBV viral load in plasma (> 4000 genomes per µg plasma DNA) and/or biopsy tissue positive for EBV.
  4. Prior palliative radiation must have been completed at least 2 weeks prior to study Cycle 1 Day 0.
  5. Prior anti cancer systemic treatment must have been completed greater than 4 weeks prior to study Cycle 1 Day 0.
  6. Toxicities related to prior anti-cancer therapy must have returned to Grade 1 or less. Peripheral neuropathy must be Grade 2 or less. Chronic but stable toxicities Grade > 1 (e.g., dysphasia, G tube dependence, etc.) may be allowed after agreement between the Investigator and Sponsor.
  7. For the dose expansion phase only: Patients must have RECIST v1.1 measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non nodal lesions and short axis for nodal lesions) as ≥ 10 mM with spiral CT scan, MRI, or calipers by clinical exam.
  8. ECOG performance status score of ≤ 2 at study entry.
  9. Absolute neutrophil count > 1500/µL (stable off any growth factor within 1 week of study drug administration).
  10. Hemoglobin > 9g/dL (transfusion to achieve this level is permitted).
  11. Platelet count > 75 x 103/ µL (transfusion to achieve this level is NOT permitted).
  12. Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤ 2.5 x upper limit of normal (ULN).
  13. Total serum bilirubin ≤ 1.5 x ULN.
  14. Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min as calculated per Cockcroft Gault equation.
  15. Urinary protein < 2+ by dipstick. If dipstick ≥ 2+, then a 24 hour urine collection can be done and the patient may enter only if urinary protein is < 1 g/24 hour.
  16. Sexually active patients must agree to utilize birth control method during the study and for 18 weeks after the study is concluded, using effective birth control methods as defined in https://www.cdc.gov/reproductivehealth/unintendedpregnancy/pdf/contraceptive_methods_508.pdf.
  17. Willingness and ability to comply with the study scheduled visits, treatment plans, laboratory tests and other procedures.

Exclusion Criteria:

  1. Severe or active symptomatic cardiopulmonary diseases (unstable angina and/or congestive heart failure or peripheral vascular disease within the last 12 months; chronic obstructive pulmonary disease exacerbation other respiratory illness requiring hospitalization) or clinically significant psychiatric disorders; patients with effectively treated conditions (eg, stenting for CAD) are eligible.
  2. Metastatic disease with active central nervous system (CNS) involvement, defined as parenchymal brain involvement. Patients with cranial nerve or base of skull involvement without the above are eligible; Patients with CNS metastases stable 1 month following focal treatment with radiation are eligible.
  3. Concurrent treatment with systemic cancer directed therapy including complementary, alternative, herbal or nutritional supplement based treatments whose purpose is for anti cancer effect.
  4. Positive for human immunodeficiency virus (HIV) are not excluded from this study, but HIV positive patients must have:

    • A stable regimen of highly active anti retroviral therapy (HAART)
    • No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections
    • A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard PCR based test
  5. Serious uncontrolled medical disorder or active infection which would, in the opinion of the Investigator, impair the ability of the subject to receive protocol therapy or whose control may be jeopardized by the complications of this therapy.
  6. Currently taking drugs that inhibit or induce OATP1B1 or OATP1B3 within 5 half lives of that agent. Examples are included in Appendix 2.
  7. Have received a prior organ allograft or allogeneic bone marrow transplant.
  8. Current non prescription drug or alcohol dependence.
  9. For all female patients, pregnancy or breastfeeding.
  10. All female patients with reproductive potential must have a negative pregnancy test (serum or urine) prior to enrollment.
  11. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, or in the judgment of the investigator would make the patient inappropriate for entry into the study.
  12. Corrected QT by Fridericia's formula (QTcF) of > 470 ms.

Information from the National Library of Medicine

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): NCT03682055


Contacts
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Contact: Myles Clancy 617-410-4650 VK2019001trial@cullinanoncology.com

Locations
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United States, California
Stanford University, School of Medicine, Stanford Cancer Institute Recruiting
Stanford, California, United States, 94305
Contact: Elizabeth Winters    650-721-6509    ewinters@stanford.edu   
Principal Investigator: A. Dimitrios Colevas, MD         
United States, Texas
The University of Texas - MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: LaKeisha DeBose    713-745-1024    lsdebose@mdanderson.org   
Principal Investigator: Maura Gillison, MD, PhD         
France
Institut Gustave Roussy Not yet recruiting
Villejuif, France, 94800
Principal Investigator: Caroline Even, MD         
Hong Kong
Hong Kong University - Queen Mary Hospital Not yet recruiting
Hong Kong, Hong Kong
Contact: Victor Ho-Fun Lee, MBBS       vhflee@hku.hk   
Principal Investigator: Victor Ho-Fun Lee, MBBS         
Sponsors and Collaborators
Cullinan Apollo Corporation
Investigators
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Study Chair: A. Dimitrios Colevas, MD Stanford Cancer Institute

Publications:
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Responsible Party: Cullinan Apollo Corporation
ClinicalTrials.gov Identifier: NCT03682055     History of Changes
Other Study ID Numbers: VK-2019-001
First Posted: September 24, 2018    Key Record Dates
Last Update Posted: September 27, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Cullinan Apollo Corporation:
Epstein-Barr Virus
Nasopharyngeal Carcinoma
NPC
EBV
EBNA1 inhibitor
VK-2019
Nasopharynx cancer
Nasopharynx carcinoma
Additional relevant MeSH terms:
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Carcinoma
Nasopharyngeal 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