Natural Killer Cell Therapy (UD TGFbetai NK Cells) and Temozolomide for the Treatment of Stage IV Melanoma Metastatic to the Brain

PRIMARY OBJECTIVES:

I. To confirm the safety and tolerability of UD TGFbetai NK cells in combination with temozolomide as a lymphodepleting agent in patients with melanoma metastatic to the brain and to determine the recommended phase 2 dose (RP2D). (Phase 1) II. To determine the intracranial response rate. (Phase 2)

SECONDARY OBJECTIVES:

I. To define the toxicities of UD TGFbetai NK cells when delivered with temozolomide as a lymphodepleting agent. (Phase 1) II. To define the pharmacokinetics (pK) associated with UD TGFbetai NK cells when used in combination with temozolomide as a lymphodepleting agent in patients with metastatic melanoma. (Phase 1) III. To determine the extracranial response rate. (Phase 2) IV. To determine progression free survival (PFS) (intracranial, extracranial, overall). (Phase 2) V. To assess overall survival (OS). (Phase 2) VI. To continue to assess the safety of temozolomide in combination with UD TGFbetai NK cells in a patient with melanoma metastatic to the brain. (Phase 2)

EXPLORATORY/CORRELATIVE OBJECTIVES:

I. To assess the phenotype and function of the UD TGFbetai NK cells and correlate with clinical outcomes.

II. To assess in vivo persistence of UD TGFbetai NK cells after adoptive transfer and correlate with clinical outcomes.

III. To assess immune status, inflammatory cytokine levels, and anti-melanoma cell activity.

OUTLINE: This is a phase I, dose-escalation study of UD TGFbetai NK cells followed by a phase II study.

Patients receive UD TGFbetai NK cells intravenously (IV) over 30 minutes on day 1 and temozolomide orally (PO) daily on days 1-5. Treatment with UD TGFbetai NK cells repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Cycles of temozolomide repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for up to 5 years.

Inclusion criteria

• Histologically confirmed melanoma with stage IV disease
• Radiologically confirmed brain metastasis (n >= 1) with at least one measurable central nervous system (CNS) lesion >= 10 mm on T1-weighted gadolinium enhanced magnetic resonance imaging (MRI) and unequivocal evidence of progression
• No indication for stereotactic radiotherapy
• At least 4 weeks from any anticancer treatment (cytotoxic chemotherapy, signal transduction inhibitors, immunotherapy or radiation)
• Absolute neutrophil count (ANC) 1 x 10^9/L
• Platelets > 100,000/L
• Hemoglobin (Hgb) >= 10 g/dL
• Creatinine =< 1.5 x upper limit of normal (ULN)
• Albumin >= 2.5 g/dL
• Serum bilirubin < 1.5 x ULN unless due to Gilbert's syndrome
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 5 x ULN if documented liver metastases or < 3 X ULN without liver metastasis
• > 18 years old (y/o)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Females of reproductive age must agree to the use of an effective contraceptive method while on treatment, beginning 2 weeks before the first dose of investigational product and for 28 days after the final dose of investigational product for women. Males able to father a child must practice adequate methods of contraception or completely abstain from intercourse from the first dose of investigational treatment until one week after the final dose of investigational treatment
• Women of childbearing potential must have a negative serum pregnancy test within 14 days of enrollment and/or urine pregnancy test 48 hours prior to the administration of the first study treatment
• Patient information and written informed consent form signed

Exclusion criteria

• Planned or concurrent systemic treatment or radiation therapy
• If requiring corticosteroids for cerebral edema, patients must be on a stable dose. Lowest dose of steroids needed to control CNS edema is recommended. Doses above 4 mg daily need to be cleared by principal investigator (PI) of the study
• Known contra-indication to MRI
• Patients with non-melanoma malignancies are excluded unless a complete remission has been achieved at least 3 years prior to study entry and no additional therapy is required or anticipated during the study period (exceptions include: non-melanoma skin cancers, in situ bladder cancer, in situ gastric cancer, in situ colon cancers, in situ cervical cancers/dysplasia, or in situ breast carcinoma)
• Patients with other concurrent severe and/or uncontrolled medical disease which could compromise participation in the study, such as:

• Active infection
• Current active hepatic or renal disease
• Pregnant women, women who are likely to become pregnant or are breastfeeding
• Patients with significantly altered mental status prohibiting the understanding of the study or with psychological, familial, sociological, or geographical conditions potentially hampering ability to consent, compliance with the study protocol, and follow-up schedule; those conditions should be discussed with the patient before remigration in the trial
• Patients who received any other investigational drugs within the 30 days prior to screening visit
• Leptomeningeal metastases diagnosed by MRI
• Inclusion in another therapeutic protocol within 30 days
• If steroids are necessary to control symptoms related to CNS metastases, patients should be on the lowest dose of steroids necessary to control symptoms