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A Phase I/Ib Study of NIZ985 Alone and in Combination With Spartalizumab

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04261439
Recruitment Status : Recruiting
First Posted : February 7, 2020
Last Update Posted : October 8, 2021
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
The purpose of this phase I/Ib study is to determine the safety profile of NIZ985 (new formulation), and if it can be safely combined with Spartalizumab and to determine the appropriate dose and schedule for further study. Moreover, the study will characterize the pharmacokinetic profiles of NIZ985 as a single agent and in combination with Spartalizumab and identify preliminary anti-tumor activity.

Condition or disease Intervention/treatment Phase
In Escalation: All Patients With Solid Tumors and Lymphoma In Expansion: Melanoma Drug: NIZ985 and Spartalizumab Phase 1

Detailed Description:

This is a phase I/Ib, open-label, global, multi-center study of subcutaneously administered NIZ985 alone and in combination with Spartalizumab in subjects with advanced solid tumors and lymphoma who have progressed after obtaining a previous response to anti-PD-1/ Check Point Inhibitor (CPI) therapy.

The study consists of two parts, dose escalation and dose expansion. Two separate arms will be examined during the escalation portion: 1) evaluation of NIZ985 as a single agent. Spartalizumab may be added at the time of the first disease re-evaluation and 2) administration of NIZ985 and Spartalizumab as a combination starting from Cycle 1Day 1.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 68 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/Ib Study of Subcutaneous Recombinant Human NIZ985 ((hetIL-15) (IL-15/sIL-15Rα)) in Combination With Spartalizumab in Patients With Check Point Inhibitor (CPI) Relapsed Advanced Solid Tumors and Lymphoma
Actual Study Start Date : February 27, 2020
Estimated Primary Completion Date : October 24, 2022
Estimated Study Completion Date : October 24, 2022

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma

Arm Intervention/treatment
Experimental: Arm 1
Single agent arm. NIZ985 is administered as a single agent (subjects may be treated with the NIZ985-Spartalizumab combination after their first disease re-evaluation)
Drug: NIZ985 and Spartalizumab
NIZ985 injection Spartalizumab infusion

Experimental: Arm 2
Combination arm. NIZ985 and Spartalizumab combination is administered starting at Cycle 1 Day 1
Drug: NIZ985 and Spartalizumab
NIZ985 injection Spartalizumab infusion

Primary Outcome Measures :
  1. To characterize safety and tolerability of NIZ985 as a single agent and in combination with Spartalizumab: Dose Limiting Toxcities (DLTs) [ Time Frame: 24 months ]
    Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 (28 days) for NIZ985 as a single agent and in combination with Spartalizumab

  2. Incidence and severity of adverse events (AEs) [ Time Frame: 24 months ]

  3. Incidence and severity of serious adverse events (SAEs) [ Time Frame: 24 months ]

Secondary Outcome Measures :
  1. To assess preliminary anti-tumor activity of the NIZ985 and Spartalizumab combination: Overall response Rate (ORR) [ Time Frame: 24 months ]
    as per RECIST 1.1 or Cheson (2014)

  2. Best Overall Response (BOR) [ Time Frame: 24 months ]
    as per RECIST1.1 or Cheson (2014)

  3. Disease control Rate (DCR) [ Time Frame: 24 months ]
    as per RECIST 1.1 or Cheson (2014)

  4. Progression Free Survival (PFS) (expansion group only) [ Time Frame: 24 months ]
    as per RECIST 1.1 or Cheson (2014)

  5. Duration of Response (DOR) (expansion group only) [ Time Frame: 24 months ]
    as per RECIST 1.1 or Cheson (2014)

  6. To characterize the pharmacokinetics (PK) of NIZ985 as a single agent and NIZ985 and Spartalizumab in combination [ Time Frame: 24 months ]
    measurement of serum concentrations of NIZ985 and Spartalizumab

Information from the National Library of Medicine

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

Inclusion Criteria:

  • 1. Signed informed consent must be obtained prior to participation in the study.

For Japan only: written consent is necessary both from the patient and his/her legal representative if he/she is under the age of 20 years.

2. Male or female patients ≥ 18 years of age 3. Histologically confirmed and documented advanced solid tumors and lymphoma (includes locally advanced malignancies that are not curable by surgery or radiotherapy, and those with metastatic disease) with documented progression following standard therapy, and for whom, in the opinion of the Investigator, no standard therapy is available, tolerated or appropriate. Disease must be measurable as determined by RECIST 1.1 (refer to Appendix 1) or Cheson et al (2014).

  • Escalation: Patients previously treated with CPI (anti PD-1/PD-L1 and/or anti CTLA-4) who have previously responded and progressed. Previous response is an initial radiographic CR/PR (a confirmatory scan is not required) or SD lasting ≥ 6 months if the most recent regimen included CPI.
  • Expansion: Patients with cutaneous melanoma previously treated with CPI (anti PD 1/ PD-L1 and/or anti CTLA-4) who have previously responded and progressed. Previous response is radiographic CR/PR (a confirmatory scan is not required) or SD lasting ≥ 6 months if the most recent regimen included CPI.

    4. Patients must be willing and able to comply with the protocol for the duration of the study including undergoing treatment, scheduled visits, and examinations including follow up.

    5. Patients must have a site of disease amenable to biopsy and be a candidate for tumor biopsy according to the treating institution's guidelines. Patient must be willing to undergo a new tumor biopsy at screening and during therapy on the study. At screening, submission of a recent archival biopsy sample is permitted if the following 3 conditions are met:

  • Biopsy was collected ≤ 3 months before screening
  • No immunotherapy was given to the patient since collection of the biopsy.
  • Biopsy sample is present at site prior to the first dose of study treatment. 6. ECOG performance status ≤1 and in the opinion of the investigator, likely to complete at least 28 days of treatment.

Exclusion Criteria:

  1. Patients that have received any prior IL-15 treatment.
  2. History of severe hypersensitivity reactions to any ingredient of study drug(s) and other mAbs and/or their excipients.
  3. Patients with primary CNS tumors are excluded. Presence of symptomatic CNS metastases, or CNS metastases that require local CNS-directed therapy (such as radiotherapy or surgery), or increasing doses of corticosteroids 2 weeks prior to study entry. Patients with treated symptomatic brain metastases should be neurologically stable (for 4 weeks post-treatment and prior to study entry) and at a dose of ≤ 10 mg per day prednisone or equivalent for at least 2 weeks before administration of any study treatment.
  4. Systemic chronic steroid therapy (> 10mg/day prednisone or equivalent) or any immunosuppressive therapy, other than replacement-dose steroids in the setting of adrenal insufficiency, within 7 days of the first dose of study treatment. Topical, inhaled, nasal and ophthalmic steroids are allowed.
  5. Malignant disease, other than that being treated in this study, that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer or other tumors that will not affect life expectancy.
  6. Patients having out of range lab values during screening and before the first dose of study treatment. Out of range lab values are defined as:

    • Absolute neutrophil count (ANC) <1.0 x 109/L
    • Platelets <75 x 109/L
    • Hemoglobin (Hgb) < 9 g/dL
    • Serum creatinine > 1.5 x ULN or creatinine clearance < 40mL/min using Cockcroft-Gault formula
    • Total bilirubin > 1.5 x ULN, (except for patients with Gilbert's syndrome > 3.0 x ULN or direct bilirubin > 1.5 x ULN)
    • Aspartate transaminase (AST) > 3 x ULN
    • Alanine transaminase (ALT) > 3x ULN
    • Serum electrolytes ≥ grade 2 despite adequate supplementation.
  7. Impaired cardiovascular function or clinically significant cardiovascular disease, including any of the following:

    • Clinically significant and/or uncontrolled heart disease such as congestive heart failure requiring treatment (NYHA Grade ≥ 2), uncontrolled hypertension or clinically significant arrhythmia
    • QTcF >470 msec on screening ECG or congenital long QT syndrome
    • Acute myocardial infarction or unstable angina < 3 months prior to study entry
  8. Infection(s):

    • HIV infection
    • Active HBV or HCV infection (per institutional guidelines). Patients with chronic HBV or HCV disease that is controlled under antiviral therapy are allowed in expansion but not in escalation.
    • Infection requiring systemic antibiotic therapy. Patients requiring systemic antibiotics for infection must have completed treatment before screening is initiated.
  9. Active, known or suspected autoimmune disease. Patients with vitiligo, type I diabetes, residual hypothyroidism only requiring hormone replacement, psoriasis not requiring systemic treatment or conditions not expected to recur may be considered. Patients previously exposed to CPI treatment who were adequately treated for skin rash or with replacement therapy for endocrinopathies should not be excluded.
  10. History of or current interstitial lung disease or pneumonitis grade ≥ 2.
  11. Radiotherapy within 2 weeks of the first dose of study drug, except for palliative radiotherapy to a limited field. To allow evaluation for response to treatment, patients enrolled in the expansion must have remaining measurable disease that has not been irradiated.
  12. Treatment with cytotoxic or targeted antineoplastics within 3 weeks of initiation of study treatment. For cytotoxic agents that have major delayed toxicities, a washout period of one cycle is indicated (examples are nitrosoureas and mitomycin C which typically require a 6 week washout). Prior antibodies or immunotherapies require a 4 week washout. Ongoing bisphosphonate therapy and growth hormone-releasing hormone (GHRH) agonist therapy is allowed. Supportive therapy with denosumab is allowed. For patients with lymphoma, the following washout criteria may be used:

    • Systemic antineoplastic therapy (including cytotoxic chemotherapy, alfa-interferon, kinase inhibitors or other targeted small molecules, and toxin immunoconjugates) or any experimental therapy within 14 days or 5 half-lives, whichever is shorter, before the first dose of study treatment

  13. Presence of Grade ≥ 2 toxicity according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v5.0), from prior cancer therapy with the exception of neuropathy (inclusion of patients with neuropathy of Grade 2 or less is permitted), ototoxicity, and alopecia.
  14. Two weeks since major surgery treatment (mediastinoscopy, insertion of a central venous access device and insertion of a feeding tube are not considered major surgery)
  15. Use of any live vaccines against infectious diseases within 4 weeks of initiation of study treatment.
  16. Use of hematopoietic growth factors or transfusion support ≤ 2 weeks prior to start of study treatment. If growth factors were initiated more than 2 weeks prior to the first dose of study treatment and the patient is on a stable dose, they can be maintained.
  17. Any medical condition that would, in the investigator's judgement, prevent the patient's participation in the clinical study due to safety concerns, compliance with clinical study procedures, or interpretation of study results.
  18. Pregnant or nursing (lactating) women.
  19. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study medication and for 150 days after stopping medication. Highly effective methods of contraception methods include:

    • Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
    • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking investigational drug(s). In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
    • Male sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject
    • Use of oral (estrogen and progesterone), injected, or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example, hormone vaginal ring or transdermal hormone contraception.
    • In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.

    NOTE: Women are considered post-menopausal and not of child bearing potential if they have had over 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate [generally age from 40 to 59 years], history of vasomotor symptoms [e.g. hot flush]) in the absence of other medical justification or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.

  20. A condom is required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner. Sexually active males receiving NIZ985 as a single agent or in combination with Spartalizumab must use a condom during intercourse for 30 days after their last dose of NIZ985. In addition, male participants must not donate sperm for 30 days after the last dose of NIZ985. Patients should not father a child during this post treatment period. A condom is required to be used also by vasectomized men as well as during intercourse with a male partner in order to prevent delivery of the drug via semen.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04261439

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Contact: Novartis Pharmaceuticals 1-888-669-6682
Contact: Novartis Pharmaceuticals +41613241111

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United States, California
City of Hope National Medical Center Recruiting
Duarte, California, United States, 91010
Contact: Shamili Thiagarajan    +1 626 256 4673 Ext 85013   
Principal Investigator: Yan Xing         
Moores UCSD Cancer Center Recruiting
La Jolla, California, United States, 92093
Contact: Kaelah Wilson    858-822-6267   
Principal Investigator: Sandip Patel         
United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Diana Jasso    713-792-2921   
Principal Investigator: Vivek Subbiah         
Novartis Investigative Site Recruiting
Leuven, Belgium, 3000
Novartis Investigative Site Recruiting
Essen, Germany, 45147
Novartis Investigative Site Recruiting
Napoli, Italy, 80131
Novartis Investigative Site Recruiting
Chuo ku, Tokyo, Japan, 104 0045
Novartis Investigative Site Recruiting
Barcelona, Catalunya, Spain, 08035
Novartis Investigative Site Recruiting
Taipei, Taiwan, 10048
Sponsors and Collaborators
Novartis Pharmaceuticals
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Responsible Party: Novartis Pharmaceuticals Identifier: NCT04261439    
Other Study ID Numbers: CNIZ985B12101
First Posted: February 7, 2020    Key Record Dates
Last Update Posted: October 8, 2021
Last Verified: October 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
NIZ985, Spartalizumab, immunotherapy, checkpoint Inhibitor, checkpoint inhibitor resistance, melanoma
Additional relevant MeSH terms:
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Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Nevi and Melanomas
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents