Lack of efficacy

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.

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).

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.