Phase II study to determine the effects of aNK infusions in combination with ALT-803 in patients with stage III (IIIB) or stage (IV) merkel cell carcinoma (MCC).

This is a multi-center, non-randomized, open-label, phase 2 trial to determine the effects of aNK in combination with ALT-803 in patients with stage III (IIIB) or stage IV MCC. The study will use an adaptive Simon optimal two-stage design, which detects efficacy signals, allows for early assessment, and avoids enrolling larger numbers of patients in case of inefficacy.

In the original protocol, an initial cohort of up to 12 patients with stage III (IIIB) or stage IV MCC were to be enrolled and treated with aNK monotherapy (first stage). If the treatment in the first stage improved the 4-month progression free survival (PFS) rate from 4% to 20% (e.g. at least 1 patient out of 12 patients has PFS ≥ 16 weeks [4 months]), then the study would proceed to the second stage, in which 12 more patients were planned to be enrolled and treated. As of July 2016, the trial has met the required efficacy signal defined for the first stage and will continue to enroll a planned total of 24 patients who will receive the combination of aNK and ALT-803. Any patients who are already receiving aNK cells as monotherapy will receive aNK cells in combination with ALT-803 in subsequent cycles.

aNK will be given via IV infusion at a dose of 2 x 10^9 cells/m^2 on two consecutive days (= 1 cycle) every 2 weeks. In addition, ALT-803 will be administered SC at 10 μg/kg on the first day of every aNK infusion (before the aNK infusion) every 2 weeks.

Inclusion Criteria:

1. Male or female patients 18 years of age or older.
2. Patients must have histologically confirmed MCC that is Stage III (IIIB) or Stage IV, as defined by the 2010 AJCC staging criteria for MCC. MCC of unknown primary is allowed.
3. Prior systemic cytotoxic chemotherapies and/or novel immunotherapy treatments for MCC are allowed. A wash-out period of 2 weeks prior to aNK treatment will be required.
4. ECOG performance status of 0-2.
5. Voluntary written informed consent must be given before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
6. Mandatory diagnostic biopsy and whole blood sample are required. The tumor biopsy tissue will be analyzed for the presence of immune cells and will also undergo genomic, transcriptomic, and proteomic profiling.

Exclusion Criteria:

1. Major surgery within 30 days before study entry.

2. Any of the following clinical laboratory values at the time of enrollment:

   1. Absolute neutrophil count (ANC) < 1,000 cells/mm^3.
   2. Platelets < 50,000 x 10^9/L.

3. Liver function abnormalities as indicated by ongoing hepatic enzyme elevation (e.g. AST, ALT, GGT) > 2 x the ULN. Elevation related to direct tumor infiltration is allowed.

4. Renal insufficiency as indicated by a creatinine level > 2 x the ULN.

5. Myocardial infarction within 6 months prior to enrollment or New York Hospital Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled arrhythmias, or electrocardiographic evidence of acute ischemia or significant conduction system abnormalities in the opinion of the Investigator. Prior to study entry any known abnormality on an electrocardiogram (ECG) must be determined and documented by the Investigator to be not clinically significant to the patient participation in this study.

6. Any condition, including laboratory abnormalities, that in the opinion of the Investigator places the patient at unacceptable risk if he/she were to participate in the study. This includes, but is not limited to, serious medical conditions or psychiatric illness likely to interfere with participation in this clinical study.

7. Female patients who are pregnant or breastfeeding. Female patients of childbearing potential must have a negative pregnancy test and agree to use adequate contraception for the duration of the trial.

8. Patients with other malignancies or brain metastasis are not eligible; however, given the frequent coexistence of MCC with other malignancies, the following exceptions are allowed:

   1. Patients who have been continuously disease-free for any solid tumor malignancy >3 years prior to the time of enrollment.
   2. Patients with basal cell carcinoma or squamous cell carcinoma.
   3. Patients with prior history of in situ cancer (e.g., breast, melanoma, squamous cells carcinoma of the skin, cervical).
   4. Patients with prior history of prostate cancer that is not under active systemic treatment (except hormonal therapy), but with undetectable PSA (<0.2 ng/mL).
   5. Patients with chronic non-T-cell-based lymphocytic leukemia are eligible if they have isolated lymphocytosis (Rai stage O) on the condition that they do not require systemic treatment for their disease ["B" symptoms, Richter's transformation, lymphocyte doubling time (<6 months) and they do not have lymphadenopathy of hepatosplenomegaly].
   6. Patients with non-T-cell-based lymphoma of any type or hairy cell leukemia are eligible on the condition that they do not receive active systemic treatment for their hematologic disease and are in complete remission as evidenced by PET/CT scans and bone marrow biopsies for at least 3 months.

9. Patients on immunosuppressants, systemic corticosteroids, or any other investigational product.

10. Patients unwilling to consent to analysis of their tumor tissue.

30 days past treatment completion, up to 5 months

There is an insufficient number of subjects enrolled in order to evaluate efficacy.