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

• ClinicalTrials.gov Identifier: NCT02452268
• Recruitment Status: Completed
• First Posted: May 22, 2015
• Last Update Posted: March 23, 2022
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Metastatic and Advanced Solid Tumors	Drug: NIZ985; Drug: PDR001	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 74 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: May 8, 2017
• Actual Primary Completion Date: March 7, 2022
• Actual Study Completion Date: March 7, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: NIZ985; 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; Subcutaneous administration of hetIL-15 three times a week for two consecutive weeks; Other Name: IL-15/sIL-15Ra, heterodimeric IL-15
Experimental: NIZ985 + PDR001; 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; • PDR001 is a human monoclonal antibody (MAb) administered day 1 of each cycle

Outcome Measures

Primary Outcome Measures :

1. Assess the dose-limiting toxicity of the single agent NIZ985 and the combination of PDR001 [ Time Frame: 28 days ]

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. 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).

2. Recovered to ≤ grade 1 NCI CTCAE version 4.0 from toxicity of prior chemotherapy or biologic therapy administered more than 4 weeks earlier.
3. 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.
4. Age ≥18 years.
5. ECOG performance status ≤1 (Karnofsky ≥70%).

6. 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.
7. DLCO/VA and FEV1 ≥ 50% of predicted on PFTs.
8. Subjects with inactive central nervous system (CNS) metastasis are eligible..
9. 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.
10. Able to provide written informed consent.
11. Life expectancy > 3 months.

Exclusion Criteria:

1. 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.
2. Primary brain cancers or active CNS metastases should be excluded from this clinical trial
3. History of allergic reactions attributed to compounds of similar chemical or biologic composition to hetIL-15.
4. Concurrent anticancer therapy (including other investigational agents) with the exception of hormone therapy for prostate cancer.
5. 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.
6. HIV positive patients.
7. Positive hepatitis B or C serology.
8. History of severe asthma or absolute requirement for chronic inhaled corticosteroid medications.
9. 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.

Contacts and Locations

Locations

United States, Maryland

National Cancer Institute National Cancer Institute

Bethesda, Maryland, United States, 20892

United States, Missouri

Washington University School of Medicine SC

Saint Louis, Missouri, United States, 63110

United States, Ohio

The Ohio State University Comprehensive Cancer Center

Columbus, Ohio, United States, 43212

United States, Oregon

Providence Portland Medical Center SC

Portland, Oregon, United States, 97123

United States, Utah

Huntsman Cancer Institute

Salt Lake City, Utah, United States, 84112

United States, Washington

Seattle Cancer Care Alliance

Seattle, Washington, United States, 98105

United States, Wisconsin

University of Wisconsin

Madison, Wisconsin, United States, 53792

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Conlon K, Watson DC, Waldmann TA, Valentin A, Bergamaschi C, Felber BK, Peer CJ, Figg WD, Potter EL, Roederer M, McNeel DG, Thompson JA, Gupta S, Leidner R, Wang-Gillam A, Parikh NS, Long D, Kurtulus S, Ho Lee L, Chowdhury NR, Bender F, Pavlakis GN. Phase I study of single agent NIZ985, a recombinant heterodimeric IL-15 agonist, in adult patients with metastatic or unresectable solid tumors. J Immunother Cancer. 2021 Nov;9(11):e003388. doi: 10.1136/jitc-2021-003388.

Watson DC, Moysi E, Valentin A, Bergamaschi C, Devasundaram S, Fortis SP, Bear J, Chertova E, Bess J Jr, Sowder R, Venzon DJ, Deleage C, Estes JD, Lifson JD, Petrovas C, Felber BK, Pavlakis GN. Treatment with native heterodimeric IL-15 increases cytotoxic lymphocytes and reduces SHIV RNA in lymph nodes. PLoS Pathog. 2018 Feb 23;14(2):e1006902. doi: 10.1371/journal.ppat.1006902. eCollection 2018 Feb. Erratum In: PLoS Pathog. 2018 Oct 11;14(10):e1007345.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02452268
• Other Study ID Numbers: CNIZ985X2102J; NIZ985X2102J ( Other Identifier: Novartis )
• First Posted: May 22, 2015
• Last Update Posted: March 23, 2022
• Last Verified: March 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Neoplasm Metastasis; Neoplastic Processes; Neoplasms; Pathologic Processes; Spartalizumab; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents