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