QUILT-3.063: A Study of N-803, haNK and Avelumab in Patients With Merkel Cell Carcinoma That Has Progressed After Checkpoint Therapy

QUILT-3.063: A Phase 2 Study of Combination Therapy With an IL-15 Superagonist (N-803), Off-the-shelf CD16-targeted Natural Killer Cells (haNK), and Avelumab Without Cytotoxic Chemotherapy in Subjects With Merkel Cell Carcinoma (MCC) That Has Progressed on or After Treatment With a Checkpoint Inhibitor.

Phase 2, single-arm study to evaluate combination therapy of avelumab, haNK and N-803 in patients with Merkel Cell Carcinoma who have progressed on or after checkpoint inhibitor therapy as assessed by ORR. Patients will receive treatment for a maximum of two years.

This is a phase II, single-arm study of combination therapy of avelumab, haNK, and N-803 in patients with Merkel Cell Carcinoma who have progressed on or after checkpoint inhibitor therapy as assessed by ORR. Patients must have progressed on or within six months of completing treatment with either avelumab or pembrolizumab. Patients will received treatment for a maximum of two years, with avelumab and haNK administered every two weeks, and N-803 administered every three weeks. Radiologic evaluation will occur every eight weeks during the first year of treatment, and every twelve weeks during the second year of treatment.

Inclusion Criteria:

1. Age ≥ 18 years on day of signing informed consent.
2. Able to understand and provide a signed informed consent that fulfills the relevant IRB or IEC guidelines.
3. Histologically-confirmed metastatic MCC that has progressed during treatment or within 6 months after completing treatment with single-agent avelumab or pembrolizumab therapy, as per FDA indication.
4. ECOG performance status of 0 to 2.
5. Have at least 1 measurable lesion of ≥ 1.0 cm.
6. Must have a recent FFPE tumor biopsy specimen following the conclusion of the most recent anticancer treatment and be willing to release the specimen for exploratory tumor molecular profiling. If an historic specimen is not available, the subject must be willing to undergo a biopsy during the screening period, if considered safe by the Investigator. If safety concerns preclude collection of a biopsy during the screening period, a tumor biopsy specimen collected prior to the conclusion of the most recent anticancer treatment may be used.
7. Must be willing to provide blood samples for exploratory analyses.
8. Must be willing to provide a tumor biopsy specimen 8 weeks after the start of treatment for exploratory analyses, if considered safe by the Investigator.
9. Ability to attend required study visits and return for adequate follow-up, as required by this protocol.
10. Agreement to practice effective contraception for female subjects of child-bearing potential and non-sterile males. Female subjects of child-bearing potential must agree to use effective contraception for up to 1 year after completion of therapy, and non-sterile male subjects must agree to use a condom for up to 4 months after treatment. Effective contraception includes surgical sterilization (eg, vasectomy, tubal ligation), two forms of barrier methods (eg, condom, diaphragm) used with spermicide, intrauterine devices (IUDs), and abstinence.

Exclusion Criteria:

1. Serious uncontrolled concomitant disease that would contraindicate the use of the investigational drug used in this study or that would put the subject at high risk for treatment-related complications.

2. Systemic autoimmune disease (eg, lupus erythematosus, rheumatoid arthritis, [subjects with mild rheumatoid arthritis that aren't currently receiving treatment for their disease are eligible for enrollment], Addison's disease, or autoimmune disease associated with lymphoma).

3. History of organ transplant requiring immunosuppression.

4. History of or active inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis).

5. Inadequate organ function, evidenced by the following laboratory results:

   1. ANC < 900 cells/mm3.
   2. Platelet count < 75,000 cells/mm3
   3. Total bilirubin greater than twice the ULN (unless the subject has documented Gilbert's syndrome).
   4. AST (SGOT) or ALT (SGPT) > 2.5 × ULN (> 5 × ULN in subjects with liver metastases).
   5. ALP levels > 2.5 × ULN (> 5 × ULN in subjects with liver metastases, or >10 × ULN in subjects with bone metastases).

6. Uncontrolled hypertension (systolic > 160 mm Hg and/or diastolic > 110 mm Hg) or clinically significant (ie, active) cardiovascular disease, cerebrovascular accident/stroke, or myocardial infarction within 6 months prior to first study medication; unstable angina; congestive heart failure of New York Heart Association grade 2 or higher; or serious cardiac arrhythmia requiring medication.

7. Dyspnea at rest due to complications of advanced malignancy or other disease requiring continuous oxygen therapy.

8. Current chronic daily treatment (continuous for > 3 months) with systemic corticosteroids (dose equivalent to or greater than 10 mg/day methylprednisolone), excluding inhaled steroids. Short-term steroid use to prevent IV contrast allergic reaction or anaphylaxis in subjects who have known contrast allergies is allowed.

9. Known hypersensitivity to any component of the study medication(s), including anaphylactic reaction to sulfur-containing medications.

10. Subjects taking any medication(s) (herbal or prescribed) known to have an adverse drug reaction with any of the study medications.

11. Participation in an investigational drug study or history of receiving any investigational treatment within 14 days prior to the start of treatment on this study, except for testosterone-lowering therapy in men with prostate cancer.

12. Assessed by the Investigator to be unable or unwilling to comply with the requirements of the protocol.

13. Concurrent participation in any interventional clinical trial.

14. Pregnant and nursing women.