Phase 1 Study of Intratumoral Administration of VAX014 With Expansion in Combination With a Checkpoint Inhibitor in Subjects With Advanced Solid Tumors

Phase 1 Study of Intratumoral Administration of VAX014 With Expansion in Combination With a Checkpoint Inhibitor in Subjects With Advanced Solid Tumors

The purpose of this research study is to evaluate the safety, tolerability and activity of VAX014 for intratumoral injections (VAX014) as a single agent as well as in combination with Investigator's choice of nivolumab or pembrolizumab in patients with advanced solid tumors. VAX014 is a targeted oncolytic agent designed to kill tumor cells following intratumoral injection into advanced solid tumors.

This study will evaluate the safety and tolerability of VAX014 using a 3+3 dose escalation design to determine a maximum tolerated dose (MTD) or maximum practical dose (MPD) of single agent VAX014. The DLT assessment period will be the initial 21-days of injections. Subjects will receive weekly injections for the initial 8 weeks. Up to six dose levels will be evaluated (i.e., [starting dose], [starting dose] x 3, [starting dose] x 10, [starting dose] x 30, [starting dose] x 100, [starting dose] x 300).

Subjects may continue on treatment following discussion between the Principal Investigator and Sponsor/Medical Monitor.

After the determination of a single agent RP2D by the SRC for single agent intratumoral VAX014, an Expansion Phase will be conducted combining intratumoral VAX014 with Investigator's choice of nivolumab or pembrolizumab. The SRC may adjust the RP2D of VAX014 used during the Expansion Phase based on accumulating safety data.

The Expansion Phase will consist of up to 25 subjects. For the first 3 subjects treated with the combination of VAX014 and either nivolumab or pembrolizumab, the initial 2 doses of intratumoral VAX014 will be reduced by one dose level from the VAX014 RP2D. If the initial 3 subjects are able to escalate to the RP2D for VAX014, all subsequent subjects will then receive VAX014 at the RP2D starting with the first dose of VAX014.

Inclusion Criteria:

1. Age 18+

2. Informed consent

3. Histological or cytopathological confirmed diagnosis of a locally advanced or metastatic solid tumor

4. Progression following at least one prior standard treatment or intolerant of standard treatments.

5. [Dose Escalation] Availability of archival or fresh tumor tissue

6. [Expansion] Willing to undergo biopsy of the tumor to be injected prior to the initial VAX014 injection (may provide archival tissue instead if approved by Medical Monitor)

7. No available SOC therapy that would confer clinical benefit

8. [Dose escalation] At least one cutaneous, subcutaneous, or nodal injectable tumor (between 1 and 10 cm in largest diameter) that can be injected by direct palpation or with the assistance of ultrasound without the need for interventional radiology

9. [Expansion] At least one injectable tumor (>=0.5cm in largest diameter) that can be injected either with or without the need for interventional radiology

10. [Expansion] Appropriate for treatment with either nivolumab or pembrolizumab

11. [Expansion] Progression following at least one prior regimen containing PD-1 directed immune checkpoint blockade

12. Measurable disease by RECIST v1.1

13. ECOG Performance Status of 0, 1, or 2

14. Resolution of any toxicity associated with prior therapy to ≤ Grade 1 (Residual toxicity of Grade 2 may be allowed following discussion with Medical Monitor)

15. Adequate hematologic function defined as:

    1. Absolute neutrophil count >=1,500/uL
    2. Platelet count >=100,000/uL
    3. [Expansion] Hemoglobin >=9 gm/dL

16. Adequate hepatic function defined as:

    1. Total bilirubin ≤ 1.5 x ULN
    2. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN

17. Adequate coagulation defined as:

    1. International normalized ratio (INR) ≤ 1.5 x ULN or prothrombin time (PT) ≤ 1.5 x ULN
    2. Partial thromboplastin time (PTT) or activated PTT (aPTT) ≤ 1.5 x ULN

18. Serum creatinine ≤ 1.5 x ULN or estimated GFR ≥ 60 mL/min/1.73 m2 (per MDRD GFR formula)

19. Women of childbearing potential must have a negative serum pregnancy test

20. All subjects of childbearing potential must be willing to consent to using effective contraception (as determined by the Investigator) while on treatment and for 3 months after their participation in the study ends

Exclusion Criteria:

1. Injectable tumor not sufficiently distanced from critical structures (e.g., major airway, neurovascular structure) where post injection swelling may place the subject at unacceptable risk

2. ≤ 21 days or ≤ five half-lives (whichever is shorter) between any prior anticancer therapy (e.g., chemotherapy, immunotherapy, intralesional therapy, irradiation) and the first injection of VAX014

3. Known CNS metastases or leptomeningeal carcinomatosis, unless adequately treated and clinically stable off steroids for ≥ 14 days from the first injection of VAX014

4. Severe infection requiring systemic antibiotic therapy or hospitalization for treatment of injection

5. Need for systemic immunosuppressive therapy (≤10 mg of prednisone equivalent, or one time pulse steroids excepted)

6. Active autoimmune disease requiring systemic immunosuppressive therapy

7. Active lung disease or pneumonitis

8. History of Grade 4 toxicity in response to prior PD-1 blockade

9. Any other malignancy likely to require treatment in the next 2 years (exceptions include cancer such as basal or squamous cell skin cancers, noninvasive cancer of the cervix, and local prostate cancer)

10. Known active infection with tuberculosis or HIV

11. Active Hepatitis B or C

12. [Females] pregnant or breastfeeding

13. Clinically significant cardiovascular abnormalities including:

    1. ≤ 12 months from prior MI
    2. Unstable angina pectoris
    3. ≤ 6 months from NYHA classification >=3 CHF

14. Electrocardiogram (ECG) with QTcF > 450 msec (males) and QTcF > 470 msec (females) based on an average of triplicate ECGs (triplicate ECGs performed only if initial QTcF exceeds male/female limits)

15. Medical or psychological condition that places the subject at undue risk with study participation