A Phase 1 Study of the Clinical and Immunologic Effects of ALT-803 in Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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The proposed clinical trial is a phase I, open-label, multi-center, dose-escalation study of ALT-803 in patients with surgically incurable advanced solid tumors: melanoma, renal cell, non-small cell lung and squamous cell head and neck cancer

Detailed Description
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This trial will investigate the safety and immunogenicity, immunomodulatory properties, and clinical benefits of treatment with weekly doses of ALT-803 in patients with advanced solid tumors.

Official Title
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A Phase 1 Study of the Clinical and Immunologic Effects of ALT-803, a Novel Recombinant IL-15 Complex in Patients With Advanced Solid Tumors: Melanoma, Renal Cell, Non-Small Cell Lung and Squamous Cell Head and Neck Cancer

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Biological: ALT-803


Participation Criteria
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Eligibility Criteria
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ENTRY CRITERIA: DISEASE CHARACTERISTICS: Histological or cytological confirmed malignancy in the following disease groups: melanoma that is metastatic or unresectable, non-small cell lung carcinoma, renal cell carcinoma or squamous cell head and neck carcinoma, for which standard curative or palliative measures do not exist or are no longer effective. Primary site may be cutaneous or unknown, but mucosal and ocular primaries are excluded. Patients with non-small lung cancer must have had prior EGFR and ALK testing. Patients with sensitizing mutations in EGFR or ALK rearrangements should have been treated with prior targeted agents and have had progression or discontinued due to toxicity from these agents. No patients with known brain metastases. PRIOR/CONCURRENT THERAPY: At least one prior therapy using an agent with the potential for prolonged remission. Patients with BRAF v600 mutation should be excluded or may be included after experiencing progression following treatment with BRAF inhibitor regimen or if they consent to forgo FDA-approved therapies that increase median survival. At least 4 weeks from last dose of prior chemotherapy or immunomodulator therapy with full recovery of acute toxicities. For patients coming off molecularly-targeted therapy, at least 2 weeks since last dose and recovery from laboratory and constitutional toxicities. At least 2 weeks from completion of prior radiation therapy with full recovery from toxicities. At least 4 weeks from last dose of prior investigational therapy with recovery to meet baseline eligibility criteria. Not receiving any current anticancer therapy No patients who have had chemotherapy, targeted therapy, or radiotherapy and have not recovered from acute toxicity to their pretreatment baseline or to a grade 1 level within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study. For resolution of autoimmune toxicity from prior immune therapy, patients must be off steroids for at least 30 days without relapse of autoimmune toxicity, or it must be at least 30 days from their last dose of infliximab or related immunosuppressive therapy without relapse of autoimmune toxicity. No patients who are receiving any other investigational agents. No patients who are receiving chronic systemic or regular inhaled corticosteroid use within 7 days prior to initiation of protocol therapy. No immunosuppressive therapy within 30 days prior to treatment start. PATIENT CHARACTERISTICS Age >18 years Both men and women of all races and ethnic groups are eligible. Performance Status ECOG performance status ≤1 Life expectancy of greater than 6 months. Bone Marrow Function leukocytes ≥3,000/mcL absolute lymphocyte count ≥500/mcL absolute neutrophil count ≥1,000/mcL (without hematopoietic growth factors) platelets ≥100,000/mcL (without transfusion) hemoglobin ≥ 10 gm/dL (may be transfused but must be stable without clinical evidence of ongoing blood loss or hemolysis) Hepatic Function total bilirubin within normal institutional limits AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal Kidney Function Creatinine within normal institutional limits OR Creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal. Pulmonary Function • No history of severe COPD or emphysema or interstitial lung disease currently on home supplemental oxygen. Patients with NSCLC with stable COPD or emphysema not requiring supplemental oxygen are eligible. Cardiac Function No symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia. Patients who have underlying risk factors for cardiac disease should be excluded or undergo clearance stress-based cardiac function testing. The pre-treatment QTc must be <500 msec. No class II or greater congestive heart failure as described in the New York Heart Association Functional Classification criteria or serious arrhythmias likely to increase the risk of cardiac complications of cytokine therapy. Other Women of child-bearing potential and men must agree to use adequate contraception. Ability to understand and the willingness to sign a written informed consent document. No uncontrolled inter-current illness or psychiatric illness/social situations that would limit compliance with study requirements. No pregnant women. No HIV-positive patients. No positive hepatitis C serology or active hepatitis B infection. No active bacterial or fungal infection. No inability to home monitor blood pressure. Patients with thyroid disease should be excluded unless euthyroid on suppressive or replacement therapy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ALT-803<br> | Biological: ALT-803<br>* Intravenous infusion for dose level 1-5; subcutaneous injection for dose level 5a-8; two 6-week treatment cycles: ALT-803 on Day 1, 8, 15, 22; stable or benefitting patients may receive up to two additional 6-week cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety profile and effectiveness of escalating doses of ALT-803 | Safety and effectiveness of ALT-803 on the peripheral blood white blood cell (WBC) and absolute lymphocyte (ALC) counts. Defined by the increase in the total number of peripheral lymphocytes during the first cycle. The safety endpoint is the MTD of ALT-803, defined as the dose level below that at which ≥2 of 6 patients experience a DLT. The efficacy endpoint is the OBD, defined as that which produces an ALC ≥25,000/µL and/or a total WBC ≥35,000/µL among 2/3 of patients. For safety, we have also defined an exceeding OBD as the occurrence of ALC ≥35,000/µL and/or WBC ≥50,000/µL. | 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the effect of escalating doses of ALT-803 | On the number and phenotype of peripheral blood mononuclear cells (PBMCs)by multiparameter blood flow, the level of immune response to autochthonous viral and tumor antigens by interferon gamma (IFN-γ) ELISPOT, immunogenicity and pharmacokinetics of ALT-803 assessed by ELISA and overall objective response rate (ORR) and response duration assessed by evidence of antitumor activity as defined by objective responses and the pharmacokinetic and pharmacodynamic profiles of ALT-803 | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cancer, IL-15, melanoma, metastatic, unresectable, solid tumors, renal cell, non-small cell lung, squamous cell head and neck