A Phase I/Ib Study of NIZ985 in Combination With PDR001 in Adults With Metastatic Cancers

Study Overview
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Brief Summary
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Phase I/Ib multicenter clinical trial. Single agent dose escalation of NIZ985 followed by expansion. Second escalation of NIZ985 in combination with PDR001 followed by expansion

Official Title
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A Phase 1 Study of Subcutaneous Recombinant Human NIZ985 ((hetIL-15) (IL15/sIL-15Ra)) Alone and in Combination With PDR001 in Adults With Metastatic Cancers

Conditions
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Metastatic and Advanced Solid Tumors

Intervention / Treatment
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* Drug: NIZ985
* Drug: PDR001


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed solid tumor malignancy that is metastatic or unresectable and have progressed on at least 1 prior therapy and for whom standard curative or palliative measures do not exist or are associated with minimal subject survival benefit. Evaluable or measurable disease, defined as by Response Evaluation Criteria in Solid Tumors (RECIST). Recovered to ≤ grade 1 NCI CTCAE version 4.0 from toxicity of prior chemotherapy or biologic therapy administered more than 4 weeks earlier. Subjects on bisphosphonates for any cancer or on hormone therapy for prostate cancer may continue this therapy. However, subjects with prostate cancer must have confirmed metastatic disease that has progressed despite hormonal therapy producing castrate levels of testosterone. Age ≥18 years. ECOG performance status ≤1 (Karnofsky ≥70%). Normal organ and marrow function: leukocytes ≥3,000/mcL absolute neutrophil count (ANC) ≥1,500/mcL platelets ≥100,000/mcL total bilirubin within normal institutional limits AST/ALT ≤2.5 × ULN creatinine <1.5 × institutional ULN OR creatinine clearance ≥60 mL/min/1.73 m2 for subjects with serum creatinine levels >1.5 × higher than ULN. DLCO/VA and FEV1 ≥ 50% of predicted on PFTs. Subjects with inactive central nervous system (CNS) metastasis are eligible.. Women of child-bearing potential and men must agree to use adequate contraception prior to study entry, during the treatment portion of the study and for 4 months after completion of hetIL-15 administration. Able to provide written informed consent. Life expectancy > 3 months. Exclusion Criteria: Prior IL-15 treatment or cytotoxic therapy, immunotherapy, radiotherapy, major surgery, antitumor vaccines or monoclonal antibodies in the 4 weeks prior or for checkpoint inhibitors such as anti-CTLA-4 or anti PD1/PD-L1 or nitrosoureas or mitomycin C for 6 weeks prior to C1D1. Primary brain cancers or active CNS metastases should be excluded from this clinical trial History of allergic reactions attributed to compounds of similar chemical or biologic composition to hetIL-15. Concurrent anticancer therapy (including other investigational agents) with the exception of hormone therapy for prostate cancer. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, cognitive impairment, active substance abuse, or psychiatric illness/social situations that, in the view of the Investigator, would preclude safe treatment or the ability to give informed consent and limit compliance with study requirements. HIV positive patients. Positive hepatitis B or C serology. History of severe asthma or absolute requirement for chronic inhaled corticosteroid medications. History of autoimmune disease, with the exception of an autoimmune event associated with prior ipilimumab (anti-CTLA-4) therapy that has been completely resolved for more than 4 weeks prior to C1D1.

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NIZ985<br>Single treatment arm, dose escalation administered subcutaneously (SC) on MWF for 2 consecutive weeks. Cycle length 28 days. Occurrence of a dose-limiting toxicity (DLT) leads to the expansion to 6 subjects. MTD is the dose prior to the dose level where ≥ 2/6 subjects have a DLT. Following identification of the MTD / RDE, dose expansion will follow. | Drug: NIZ985<br>* Subcutaneous administration of hetIL-15 three times a week for two consecutive weeks<br>* Other names: IL-15/sIL-15Ra, heterodimeric IL-15;|
| Experimental: NIZ985 + PDR001<br>The phase Ib dose escalation portion of the study will consist of a fixed dose (400 mg, IV infusion, Q4W) of PDR001 and escalating doses of NIZ985 (hetIL-15) to evaluate safety, tolerability and determine the MTD and/or RDE of the combination to be used in expansion cohorts. On days when PDR001 and NIZ985 are administered on the same day, PDR001 will be administered first. NIZ985 will be administered after the PDR001 infusion has been completed. Information on the preparation and administration of PDR001 is found in the PDR001 pharmacy manual. | Drug: PDR001<br>* • PDR001 is a human monoclonal antibody (MAb) administered day 1 of each cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the dose-limiting toxicity of the single agent NIZ985 and the combination of PDR001 |  | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the maximum tolerated dose (MTD) of hetIL-15 as determined by DLTs during Cycle 1. |  | 28 days | 
| Determine the pharmacokinetic (PK) profile of hetIL-15, including T½ |  | 28 days | 
| Determine the pharmacokinetic (PK) profile of hetIL-15, including Cmax. |  | 28 Days | 
| Determine the preliminary anti-tumor activity of hetIL-15 | Best overall response (BOR) per RECIST and irRC | 8 weeks |