MC# 18-01 - MC# 18-01 - A Phase Ib Open Label, Dose Finding Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of Avelumab in Combination with M9241 (NHS-IL12) in Subjects with Locally Advanced, Unresectable, or Metastatic Solid Tumors

  • Agent(s): NHS-IL12
  • Disease Type(s): Bladder
  • Phase(s): I
  • Drug Classification(s): Targeted Therapy, Cytokines, Immunotherapy
  • Molecular Target(s): PD-L1 (CD274), CD38

Mechanism of Action

NHS-IL12 (M9241), is a novel fusion protein designed to deliver the human IL-12 to the tumor microenvironment, which targets exposed DNA such as that found in necrotic regions of tumors.


  • The safety and tolerability of NHS-IL12 and Avelumab
  • How much of NHS-IL12 and Avelumab is absorbed into the blood and how fast it is removed
  • If research tests can be used in the future to predict who will benefit from NHS-IL12
  • How proteins that indicate the status of your disease are affected with use of NHS-IL12 when given with Avelumab
  • If your body develops proteins that work against NHS-IL12 when given with Avelumab
Inclusion Criteria
  • Signed written informed consent
  • Male or female subjects age ≥ 18 years
  • Subjects must have one of the following tumor specific indications:
    • Urothelial carcinoma, second line or later: Histologically or cytologically documented locally advanced or metastatic transitional cell carcinoma of the urothelium (including renal pelvis, ureters, urinary bladder, and urethra). Subjects must have progressed after treatment with at least 1 platinum-containing regimen (eg, platinum plus another agent such as gemcitabine, methotrexate, vinblastine, doxorubicin, etc) for inoperable locally advanced or metastatic UC or disease recurrence
    • Non-small cell lung cancer, first-line metastatic: Histologically proven Stage IV (per seventh International Association for the Study of Lung Cancer classification) NSCLC. Subjects must not have received treatment for their metastatic disease. Subjects could have received adjuvant chemotherapy or loco-regional treatment that included chemotherapy for locally advanced disease, as long as disease recurrence occurred at least 6 months after the completion of the last administration of chemotherapy. Only epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) wild-type are allowed (ie, EGFR mutation and ALK translocation / re-arrangement excluded). Non-squamous cell histologies and never / former light smoker (< 15 pack years) squamous cell carcinoma subjects (per local standard of care) require testing if status is unknown. Subjects must have low tumor PD-L1 expression defined as < 50% tumor proportion score determined using PD-L1 IHC 22C3 pharmDx test or an equivalent FDA-approved PD-L1 test. This cohort will not be opened for enrollment in Belgium, Czech Republic, Germany, Hungary, Italy, Netherlands, Spain, and United Kingdom
    • Colorectal cancer, second line or later: Histologically or cytologically confirmed recurrent or refractory metastatic CRC (according to American Joint Committee on Cancer
      / International Union Against Cancer Tumor Node Metastasis [TNM] Staging System seventh edition) after failure of prior therapy containing oxaliplatin / fluoropyrimidine and / or irinotecan / fluoropyrimidine and, if eligible, cetuximab (Erbitux®) and bevacizumab (Avastin®). Only subjects with MSI-low or MSS metastatic CRC are eligible. Subjects without existing MSI test results will have MSI status performed locally by a CLIA-certified IHC or PCR-based test (PCR-based MSI test is preferred). Subjects must be willing to undergo an on-treatment biopsy procedure. For Belgium, Czech Republic, Germany, Hungary, Italy, Netherlands, Spain, and United Kingdom, subjects in the second‑line setting should have exhausted or be considered ineligible or intolerant (in the opinion of the Investigator) of available second‑line chemotherapy options
    • Renal cell carcinoma, primary immune checkpoint inhibitor failure: Histologically or cytologically documented metastatic RCC with a component of clear cell subtype, with metastasis. Subjects must have had PD within 6 months or SD for ≥ 6 months following therapy with any antibody / drug targeting T-cell co-regulatory proteins (immune checkpoints) such as anti-PD-1, anti-PD-L1, or CTLA-4 for advanced or metastatic disease (either as monotherapy or combination therapy, in any line). Fresh tumor biopsy is required for enrollment. Subjects must be willing to undergo an on-treatment biopsy procedure
  • Availability of fresh tumor biopsy is mandatory for eligibility in the RCC cohort. The biopsy or surgical specimen should be collected within 28 days prior to the first IMP administration. For other expansion cohorts, availability of either tumor archival material (< 6 months old) or fresh biopsies (obtained within 28 days) is acceptable with one of these being mandatory. For formalin-fixed paraffin-embedded (FFPE) samples, either block or sections (> 15) may be provided. Tumor biopsies and tumor archival material must be suitable for biomarker assessment (refer to the Laboratory Specific Document for details).
  • At least 1 unidimensional radiographically measurable lesion based on RECIST v1.1
  • ECOG PS of 0 to 1 at Screening
  • Estimated life expectancy of more than 12 weeks
  • Adequate hematological function as defined below:
    • WBC count ≥ 3.0 × 109/L
    • Absolute neutrophil count ≥ 1.5 × 109/L
    • Lymphocyte count ≥ 0.5 × 109/L
    • Platelet count ≥ 100 × 109/L
    • Hemoglobin ≥ 9 g/dL (may have been transfused)
  • Adequate hepatic function as defined below:
    • A total bilirubin level ≤ 1.5 × the ULN range
    • AST levels ≤ 2.5 × ULN
    • ALT levels ≤ 2.5 × ULN
    • Subjects with documented Gilbert disease are allowed if total bilirubin > 1.5 but less than 3 × ULN
    • For  subjects  with  liver  involvement  in  their   tumor,   AST   ≤   5.0   ×   ULN, ALT ≤ 5.0 × ULN, and bilirubin ≤ 3.0 is acceptable
  • Adequate renal function as defined by an estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula
  • Negative blood pregnancy test at Screening for women of childbearing potential. For the purposes of this study, women of childbearing potential are defined as all female subjects after puberty unless they are postmenopausal for at least 1 year, are surgically sterile or are sexually inactive.
  • Highly effective contraception (ie, methods with a failure rate of less than 1% per year) must be used before the start of treatment, for the duration of the study treatment, and for at least 50 days after stopping study treatment for both men and women if the risk of conception exists. The effects of avelumab and NHS-IL12 on the developing human fetus are unknown; thus, women of childbearing potential and men must agree to use highly effective contraception.
Exclusion Criteria
  • Concurrent treatment with a non-permitted drug/intervention (listed below)
    • Anticancer treatment (eg, cytoreductive therapy, radiotherapy, immune therapy, cytokine therapy, monoclonal antibody, targeted small molecule therapy) or any investigational drug within 4 weeks or 5 half-lives, whichever is shorter, prior to start of study treatment, or not recovered from AE related to such therapies, with the following exceptions:
      1. Palliative radiotherapy delivered in a normal organ-sparing technique is permitted (concurrently or within pretreatment period as described in the study protocol)
      2. Erythropoietin and darbepoetin-α are permitted
      3. Hormonal therapies acting on the hypothalamic-pituitary-gonadal axis are permitted (ie, luteinizing hormone-releasing hormone agonist/antagonists). No other hormonal anticancer therapy is permitted
    • Major surgery (as deemed by Investigator) for any reason (except diagnostic biopsy), within 4 weeks prior to start of study treatment, or not fully recovered from surgery within 4 weeks prior to start of study treatment
    • Subjects receiving immunosuppressive agents (such as steroids) for any reason should be tapered off these drugs before start of study treatment, with the following exceptions:
      1. Subjects with adrenal insufficiency, may continue corticosteroids at physiologic replacement dose, equivalent to ≤ 10 mg prednisone daily
      2. Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intra-ocular, or inhalation) is permitted
      3. Previous or ongoing administration of systemic steroids for the management of an acute allergic phenomenon is acceptable as long as it is anticipated that the administration of steroids will be completed in 14 days, or that the dose after 14 days will be equivalent to
        ≤ 10 mg prednisone daily
  • Any prior treatment with any form of IL-12
  • For the NSCLC, CRC, and UC expansion cohorts, prior therapy with any antibody / drug targeting T-cell co-regulatory proteins (immune checkpoints) such as anti-PD-1, anti-PD-L1, or anticytotoxic T lymphocyte antigen-4 (CTLA-4) antibody is prohibited
  • Intolerance to checkpoint inhibitor therapy, as defined by the occurrence of an AE requiring drug discontinuation
  • Active or history of primary or metastatic central nervous system tumors
  • Prior organ transplantation, including allogeneic stem-cell transplantation
  • Previous malignant disease (other than the indication for this study) within the last 5 years (except adequately treated non-melanoma skin cancers, carcinoma in situ of skin, bladder, cervix, colon/rectum, breast, or prostate) unless a complete remission without further recurrence was achieved at least 2 years prior to study entry and the subject was deemed to have been cured with no additional therapy required or anticipated to be required
  • Significant acute or chronic infections requiring systemic therapy including, among others:
    • History of testing positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome
    • Hepatitis B or C infection (hepatitis B virus [HBV] surface antigen positive and HBV core antibody positive with reflex to positive HBV DNA or HBV core antibody positive alone with reflex to positive HBV DNA or positive hepatitis C virus [HCV] antibody with reflex to positive HCV ribonucleic acid [RNA]). Subjects with history of infection must have PCR documentation that infection is cleared.
  • Active or history of autoimmune disease that might deteriorate when receiving an immune-stimulatory agent. Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible if they are stable on other medical treatment and do not fulfill exclusion criterion 15 .
  • Known severe hypersensitivity reactions to monoclonal antibodies  (Grade ≥ 3 NCI-CTCAE v4.03), or uncontrolled asthma (ie, 3 or more features of partially controlled asthma)
  • History of allergic reaction to methotrexate (trace methotrexate may be present in NHS-IL12 as a part of the manufacturing process) or history of severe hypersensitivity reaction to any other ingredient of the study drug(s) and / or their excipients. Since NHS‑IL12 contains sucrose as an excipient, subjects suffering from hereditary fructose intolerance are also excluded
  • Persisting toxicity related to prior therapy of Grade > 1 NCI-CTCAE v4.03 with the following exceptions:
    • Neuropathy Grade ≤ 2 is acceptable
    • All grades of alopecia are acceptable
    • Endocrine dysfunction on replacement therapy is acceptable
  • Pregnancy or lactation
  • Known alcohol or drug abuse as deemed by the Investigator
  • Uncontrolled intercurrent illness including, but not limited to:
    • Hypertension uncontrolled by standard therapies (not stabilized to 150/90 mm Hg or lower)
    • Uncontrolled active infection
    • Uncontrolled diabetes (eg, glycosylated hemoglobin ≥ 8%)
  • Clinically significant (or  active) cardiovascular disease: cerebral vascular accident /  stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure  (New  York  Heart  Association  Classification Class ≥ II), or serious cardiac arrhythmia requiring medication
  • All other significant diseases (eg, inflammatory bowel disease, current severe acute or chronic colitis) or chronic medical conditions (including laboratory abnormalities) that in the opinion of the Investigator might impair the subject’s tolerance of study treatment or interpretation of study results
  • Any psychiatric condition that would prohibit the understanding or rendering of informed consent or that would limit compliance with study requirements
  • Legal incapacity or limited legal capacity
  • Administration of a live vaccine within 30 days prior to study entry
  • Any subject with possible area of ongoing necrosis (non-disease related), such as active ulcer, non-healing wound, or intercurrent bone fracture that may be at risk of delayed healing due to protocol therapy
  • Oxygen saturation < 90% at rest, known pulmonary fibrosis, or active interstitial lung disease
  • History of congenital or active immunodeficiency, with the exception of acquired treatment-related hypogammaglobulinemia requiring periodic IV immunoglobulin infusion


  • Dallas, TX - Mary Crowley Cancer Research - Medical City
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Re: MC# 18-01