A Phase I/II Dose Escalation Study of the Tumor-targeting Human L19-IL2 Monoclonal Antibody-cytokine Fusion Protein in Combination With Dacarbazine for Patients With Metastatic Melanoma
This trial is active, not recruiting.
|Condition||metastatic melanoma stage iv|
|Treatments||arm 1: l19il2 + dacarbazine, arm 2: dacarbazine|
|Phase||phase 1/phase 2|
|Start date||October 2013|
|End date||October 2016|
|Trial size||96 participants|
|Trial identifier||NCT02076646, PH-L19IL2DTIC-04-12|
This Phase II clinical study is an open-label, multicenter study of L19IL2 in combination with Dacarbazine in patients with metastatic melanoma.
The study is divided in two parts: a phase IIa part, designed to establish the recommended dose (RD) of L19IL2 when administered in combination with a fixed dose of Dacarbazine, as well as to determine the preliminary tolerability profile; the second phase IIb part evaluates the objective response rate (ORR) including a randomized study with a fixed dose of Dacarbazine with or without L19IL2, dosed at the RD determined in phase IIa.
|United States||No locations recruiting|
|Other Countries||No locations recruiting|
|Endpoint classification||safety/efficacy study|
|Intervention model||parallel assignment|
Phase I: Establish the maximum tolerated dose (MTD) and recommended dose (RD) of L19IL2
time frame: 21 days
Phase II: evaluation of the antitumor activity
time frame: 36 months
Phase I: evaluation of the antitumor activity
time frame: 36 months
Phase II: Safety and Tolerability of L19-IL2 in combination with DTIC vs DTIC alone.
time frame: 36 months
Phase II: Treatment efficacy
time frame: 36 months
Male or female participants from 18 years up to 70 years old.
Inclusion Criteria: 1. 18-70 years of age, inclusive 2. Must have histologically or cytologically confirmed cutaneous metastatic melanoma (Stage IV). For the Phase II part only patients with Stage IV M1a or M1b will be enrolled. 3. Must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as identified by CT or MRI scan within 28 days before the first study drug administration. 4. Baseline LDH within normal range 5. Maximal 1 line of previous systemic treatment for metastatic disease (prior adjuvant melanoma therapy, e.g., IFN, is permitted. 6. For women of childbearing potential, a negative pregnancy test within 72 hours prior to the first dose of study treatment. 7. Women with reproductive potential must be willing to practice acceptable methods of birth control during the study and for up to 12 weeks after the last dose of study medication. 8. Men with reproductive potential must be willing to practice acceptable methods of birth control during the study and for up to 12 weeks after the last dose of study medication. 9. Must have Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 10. Life expectancy of at least three months 11. Adequate organ function: serum creatinine ≤ 1.5 x ULN, total bilirubin ≤ 30 mM/L (or mg/dL, ≤ 2.0 mg/dL), hepatic transaminases ≤ 2.5 x ULN, alkaline phosphatase ≤ 2.5 x ULN. 12. ANC count ≥ 1.5 x 10^9/L, platelet count ≥ 100 x 10^9/L, hemoglobin > 9 g/dL 13. Normal 12-lead ECG and normal bidimensional echocardiogram or MUGA 14. All toxic effects of prior therapy must have resolved to grade ≤1 unless otherwise specified above 15. Willing and able to give written informed consent. Exclusion Criteria: 1. Pregnant or breastfeeding female 2. Primary ocular melanoma 3. Primary mucosal melanoma 4. Use of any investigational or other anti-cancer drug within 28 days or 5 half-lives, whichever is longer, preceding the first dose of DTIC and L19-IL2 5. Prior radiation to a target lesion, unless there has been clear progression of the lesion since radiotherapy 6. A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection 7. History or clinical evidence of brain metastases or leptomeningeal disease 8. Any other malignancy from which the patient has been disease-free for less than 5 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix 9. Treatment with DTIC within 6 months before start of study 10. Treatment with Ipilimumab within 6 months before start of study 11. Hypersensitivity to DTIC 12. Concomitant use of drugs known to alter cardiac conduction 13. Chronic use of corticosteroids used in the management of cancer or non-cancer-related illness 14. Unstable or serious concurrent uncontrolled medical conditions 15. Inadequately controlled cardiac arrhythmias including atrial fibrillation 16. History of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris 17. Heart insufficiency > grade II NYHA criteria 18. Uncontrolled hypertension 19. Ischemic peripheral vascular disease 20. Active infection or incomplete wound healing. 21. History or evidence of active autoimmune disease. 22. Known history of allergy to intravenously administered proteins/peptides/antibodies 23. History of organ allograft.or allogeneic peripheral blood progenitor cell or bone marrow transplantation 24. Major trauma including surgery within 4 weeks prior to entering the study. 25. Any underlying medical or psychiatric condition which in the opinion of the investigator will make administration of study drug hazardous or hinder the interpretation of study results (e.g. AE). 26. Melanoma patients with BRAF 600 E mutation who are amenable to receive approved treatments able to extend overall survival.
|Official title||A Phase I/II Dose Escalation Study of the Tumor-targeting Human L19-IL2 Monoclonal Antibody-cytokine Fusion Protein in Combination With Dacarbazine for Patients With Metastatic Melanoma|
|Principal investigator||Claus Garbe, Prof. M.D.|
|Description||Dose limiting toxicity will be assessed during the dose-escalation part of Phase IIa from day 1 through day 21 of the first cycle. Response will be measured using RECIST criteria every 6 weeks (after every 2 cycles of treatment). Patients with stable or responding disease at each assessment may receive additional treatment for a maximum of 6 cycles of induction. Patients with stable or responding disease after induction may receive L19IL2 (without dacarbazine) every 2 weeks as maintenance therapy. Tumor expression of ED-B FN and tumor uptake of L19IL2 and of Dacarbazine will be assessed via immunohistochemistry and/or other methods deemed appropriate on tumor tissue biopsies. Tumor biopsy will be performed on superficial accessible cutaneous and/or subcutaneous lesions only. Tumor biopsy will be considered optional and will not preclude patient entry on to study should the patient refuse. Pharmacokinetics of L19IL2, Dacarbazine and AIC will be assessed from serial blood samples using standard methods. Overall response rate, PFS, survival rate at 6 and 12 months, and overall survival time for all patients and separately for the patients in the Phase IIb part will be assessed using standard methods.|
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