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

NCT ID: NCT02452268

Last Updated: 2023-03-03

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 83 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-05-08
• Study Completion Date: 2022-03-07

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

Conditions

Metastatic and Advanced Solid Tumors

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

NIZ985

Intervention Type: DRUG

Subcutaneous administration of hetIL-15 three times a week for two consecutive weeks

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.

Group Type: EXPERIMENTAL

PDR001

Intervention Type: DRUG

• PDR001 is a human monoclonal antibody (MAb) administered day 1 of each cycle

Interventions

NIZ985

Subcutaneous administration of hetIL-15 three times a week for two consecutive weeks

Intervention Type: DRUG

PDR001

• PDR001 is a human monoclonal antibody (MAb) administered day 1 of each cycle

Intervention Type: DRUG

Other Intervention Names

IL-15/sIL-15Ra, heterodimeric IL-15

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

National Cancer Institute National Cancer Institute

Bethesda, Maryland, United States

Washington University School of Medicine SC

St Louis, Missouri, United States

The Ohio State University Comprehensive Cancer Center

Columbus, Ohio, United States

Providence Portland Medical Center SC

Portland, Oregon, United States

Huntsman Cancer Institute

Salt Lake City, Utah, United States

Seattle Cancer Care Alliance

Seattle, Washington, United States

University of Wisconsin

Madison, Wisconsin, United States

Countries

United States

References

Leidner R, Conlon K, McNeel DG, Wang-Gillam A, Gupta S, Wesolowski R, Chaudhari M, Hassounah N, Lee JB, Ho Lee L, O'Keeffe JA, Lewis N, Pavlakis GN, Thompson JA. First-in-human phase I/Ib study of NIZ985, a recombinant heterodimer of IL-15 and IL-15Ralpha, as a single agent and in combination with spartalizumab in patients with advanced and metastatic solid tumors. J Immunother Cancer. 2023 Oct;11(10):e007725. doi: 10.1136/jitc-2023-007725.

Reference Type: DERIVED

PMID: 37907221 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34799399 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 29474450 (View on PubMed)

Related Links

https://www.novctrd.com/ctrdweb/trialresult/trialresults/pdf?trialResultId=18021

Study Results

Other Identifiers

NIZ985X2102J

Identifier Type: OTHER

Identifier Source: secondary_id

CNIZ985X2102J

Identifier Type: -

Identifier Source: org_study_id