Patient case: 56-year-old female with melanoma; genetic feature: KIT (L576P), KIT amplification

Clinical trial: Neoadjuvant L19IL2/L19TNF- Pivotal Study

Summary: Phase III, open-label, randomized, controlled multi-center study. In the study, 214 patients will be enrolled and parallel assigned (via randomization system) in a 1:1 fashion to one of two different arms.

Detailed description: Phase III, open-label, randomized, controlled multi-center study. In the study, 214 patients will be enrolled and parallel assigned (via randomization system) in a 1:1 fashion to one of two different arms:
  ARM 1:
  Patients in Arm 1 will receive multiple intratumoral administrations into all injectable cutaneous, subcutaneous, and nodal tumors of a mixture of L19IL2 and L19TNF once weekly for up to 4 weeks (or until all injectable tumors have disappeared, or intolerance to study treatment or in the opinion of the investigator immediate surgical resection or any other treatment for melanoma is warranted, whichever occurs first). The whole volume of L19IL2/L19TNF will be equally distributed among all injectable lesions.
  Newly occurring injectable melanoma lesions within the 4 weeks treatment period will also be treated as described. For the new lesions the treatment period will not be extended beyond the pre-defined 4 week- treatment period with a clock start at the time of the first intralesional L19IL2/L19TNF injection. Surgical resection of all existing metastases will follow within 4 weeks after end of treatment. Surgery will be performed after the safety evaluation carried out at week 5 and, if indicated, may be carried out on the same day of the safety evaluation.
  ARM 2:
  Patients in Arm 2 will receive directly surgical resection of melanoma tumor lesions within 4 weeks after randomization.

Eligibility: Inclusion Criteria:
  1. Diagnosis of malignant melanoma of the skin in clinical stage III B and III C, eligible for complete surgical resection.
  2. Eligible subjects must have measurable disease and must be candidate for intralesional therapy with at least one injectable cutaneous, subcutaneous, or nodal melanoma lesion (≥ 10 mm in longest diameter) or with multiple injectable lesions that in aggregate have a longest diameter of ≥ 10 mm.
  3. Males or females, age ≥ 18 years
  4. ECOG Performance Status/WHO Performance Status ≤ 1
  5. Life expectancy of at least 24 months (see paragraph 6.3.1)
  6. Absolute neutrophil count > 1.5 x 109/L
  7. Hemoglobin > 9.0 g/dL
  8. Platelets > 100 x 109/L
  9. Total bilirubin ≤ 30 µmol/L (or ≤ 2.0 mg/dl)
  10. ALT and AST ≤ 2.5 x the upper limit of normal (ULN)
  11. Serum creatinine < 1.5 x ULN
  12. LDH serum level ≤ 1.0 x ULN
  13. Documented negative test for HIV, HBV and HCV. For HBV serology, the determination of HBsAg, anti-HBsAg Ab and anti-HBcAg Ab is required. In patients with serology documenting previous exposure to HBV (e.g. anti-HBs Ab with no history of vaccination and/or anti-HBc Ab) negative serum HBV-DNA is also required.
  14. All acute toxic effects (excluding alopecia) of any prior therapy must have resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (v4.03) Grade ≤ 1 unless otherwise specified above
  15. All female subjects must have negative pregnancy test results at the screening. Women of childbearing potential (WOCBP) must be using, from the screening to three months following the last study drug administration, highly effective contraception methods, as defined by the "Recommendations for contraception and pregnancy testing in clinical trials" issued by the Head of Medicine Agencies' Clinical Trial Facilitation Group and which include, for instance, progesterone-only or combined (estrogen- and progesterone-containing) hormonal contraception associated with inhibition of ovulation, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal occlusion, vasectomized partner or sexual abstinence. Pregnancy test will be repeated at the end of treatment visit.
  16. Male patients with WOCBP partners must agree to use simultaneously two acceptable methods of contraception (i.e. spermicidal gel plus condom) from the screening to three months following the last study drug administration.
  17. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
  18. Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.
  Exclusion Criteria:
  1. Uveal melanoma and mucosal melanoma
  2. Evidence of distant metastases at screening
  3. Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis & T1), second primary melanoma in situ or any cancer curatively treated ≥ 5 years prior to study entry
  4. Presence of active infections (e.g. requiring antimicrobial therapy) or other severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or interfere with the study.
  5. History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
  6. Inadequately controlled cardiac arrhythmias including atrial fibrillation
  7. Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria)
  8. LVEF ≤ 50% and/or abnormalities observed during baseline ECG and Echocardiogram investigations that are considered as clinically significant by the investigator.
  9. Uncontrolled hypertension
  10. Ischemic peripheral vascular disease (Grade IIb-IV)
  11. Severe diabetic retinopathy
  12. Active autoimmune disease
  13. History of organ allograft or stem cell transplantation
  14. Recovery from major trauma including surgery within 4 weeks prior to enrollment.
  15. Known history of allergy to IL2, TNF, or other human proteins/peptides/antibodies or any other constituent of the product.
  16. Breast feeding female
  17. Anti-tumor therapy (except small surgery) within 4 weeks before enrollment
  18. Previous in vivo exposure to monoclonal antibodies for biological therapy in the 6 weeks before enrollment
  19. Planned administration of growth factors or immunomodulatory agents within 7 days before enrollment
  20. Patient requires or is taking corticosteroids or other immunosuppressant drugs on a long-term basis. Limited use of corticosteroids to treat or prevent acute hypersensitivity reactions is not considered an exclusion criterion.
  21. Any conditions that in the opinion of the investigator could hamper compliance with the study protocol.

Relevance to patient case: not relevant