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

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

Study Description

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).

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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 ]

Eligibility Criteria

• 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.

Contacts and Locations

Contacts

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

Locations

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

• Study Chair: A. Dimitrios Colevas, MD; Stanford Cancer Institute

More Information

Publications:

Young LS. Epstein-Barr virus at 50-future perspectives. Chin J Cancer. 2014 Nov;33(11):527-8. doi: 10.5732/cjc.014.10208.

Young LS, Dawson CW. Epstein-Barr virus and nasopharyngeal carcinoma. Chin J Cancer. 2014 Dec;33(12):581-90. doi: 10.5732/cjc.014.10197. Epub 2014 Nov 21.

Tsao SW, Tsang CM, Lo KW. Epstein-Barr virus infection and nasopharyngeal carcinoma. Philos Trans R Soc Lond B Biol Sci. 2017 Oct 19;372(1732). pii: 20160270. doi: 10.1098/rstb.2016.0270. Review.

• Responsible Party: Cullinan Apollo Corporation
• ClinicalTrials.gov Identifier: NCT03682055 History of Changes
• Other Study ID Numbers: VK-2019-001
• First Posted: September 24, 2018
• Last Update Posted: September 27, 2019
• Last Verified: September 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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:

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