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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

Sponsor
Philogen S.p.A. (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT02076646
Collaborator
(none)
96
Enrollment
2
Locations
3
Arms
106
Anticipated Duration (Months)
48
Patients Per Site
0.5
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

A prospective, open-label, multi-center, Phase I/II study of L19IL2 in combination with Dacarbazine in patients with metastatic melanoma.

Condition or Disease Intervention/Treatment Phase
  • Drug: L19IL2 - Ph I
  • Drug: L19IL2 at RD - Ph II
  • Drug: DTIC
 Phase 1/Phase 2

Detailed Description

A prospective, open-label, multi-center, Phase I/II dose escalation study in which cohorts of 3-6 patients with metastatic melanoma will be assigned to receive escalating doses of L19-IL2 in combination with a fixed dose of Dacarbazine.

After definition of MTD and RD during the phase II part of this study, 60 patients with Stage IV M1a and M1b melanoma will be randomized in a 1:1 ratio to receive open label the combination treatment at the RD (Arm 1) or DTIC monotherapy (Arm 2).

Study Design

Study Type:
Interventional
Anticipated Enrollment :
96 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
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
Actual Study Start Date :
Jul 31, 2013
Actual Primary Completion Date :
May 17, 2016
Anticipated Study Completion Date :
Jun 1, 2022

Arms and Interventions

Arm Intervention/Treatment
Experimental: Ph I: L19IL2 + DTIC

Cohorts of 3-6 patients will receive escalating doses of L19-IL2 until MTD is reached. L19-IL2 will be administered on days 1, 8 & 15 of each 21-day-cycle. Dacarbazine will be given at a fixed dose on day 1 of each 21-day cycle, 30 minutes after the end of the L19-IL2 infusion.

Drug: L19IL2 - Ph I
During phase I part of the study, increasing dose of L19IL2 from one cohort to the next will be performed in steps of 160,000 IU/kg starting at 480,000 IU/kg (i.e., 0.48; 0.64; 0.80 MioIU/kg until MTD is reached).

Drug: DTIC
Dacarbazine: 1 hour intravenous infusion on day 1 of each 21-cycle at a dosage of 1000 mg/m2 (fixed dose).
Other Names:
  • DETICENE®

    		•
    Experimental: Ph II - ARM 1: L19IL2 at RD + DTIC

    During the phase II part of this study, 60 patients with Stage IV M1a and M1b melanoma will be randomized in a 1:1 ratio: 30 patients assigned to Arm 1 will receive L19IL2 at the RD + DTIC at a fixed dose.

    Drug: L19IL2 at RD - Ph II
    L19IL2 at RD will be administered to Arm 1 patients during phase II part of the study.

    Drug: DTIC
    Dacarbazine: 1 hour intravenous infusion on day 1 of each 21-cycle at a dosage of 1000 mg/m2 (fixed dose).
    Other Names:
  • DETICENE®

    		•
    Active Comparator: Ph II - ARM 2: DTIC monotherapy

    During the phase II part of this study, 60 patients with Stage IV M1a and M1b melanoma will be randomized in a 1:1 ratio: 30 patients assigned to Arm 2 will receive DTIC at a fixed dose as monotherapy.

    Drug: DTIC
    Dacarbazine: 1 hour intravenous infusion on day 1 of each 21-cycle at a dosage of 1000 mg/m2 (fixed dose).
    Other Names:
  • DETICENE®

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Phase I: maximum tolerated dose (MTD) and recommended dose (RD) of L19IL2 [From day 1 to day 21 of Cycle 1 (each cycle is 21-days)]

      Establish the MTD and the RD of L19IL2 (in combination with dacarbazine) to be used for phase II study

    2. Phase II: best objective response rate (BORR) [Up to 1 year]

      Evaluation of antitumor activity

    Secondary Outcome Measures

    1. Phase I: best objective response rate (BORR) [Up to 1 year]

      Evaluation of antitumor activity

    2. Phase I: duration of objective response [From week 6 up to 1 year]

      Evaluation of the antitumor activity

    3. Phase I: disease control rate [At 6 months]

      Evaluation of the antitumor activity

    4. Phase I: median progression free survival (mPFS) [Up to 1 year]

      Evaluation of the antitumor activity

    5. Phase I: median overall survival and overall survival rate [Up to 1 year]

      Evaluation of the antitumor activity

    6. Phase II: safety and tolerability of L19-IL2 in combination with DTIC vs DTIC alone. [Up to 1 year]

      Safety evaluation including AEs, SAE and standard laboratory assessment

    7. Phase II: duration of objective response [Up to 1 year]

    8. Phase II: disease control rate [At 6 months]

    9. Phase II: median progression free survival (mPFS) [Up to 1 year]

    10. Phase II: median overall survival and overall survival rate [Up to 1 year]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 70 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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 109/L, platelet count ≥ 100 x 109/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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 University Hospital Tuebingen Germany
    2 Azienda Ospedaliera Universitaria Senese Siena Italy

    Sponsors and Collaborators

    • Philogen S.p.A.

    Investigators

    • Principal Investigator: Claus Garbe, Prof. M.D., University Hospital Tuebingen (Germany)
    • Principal Investigator: Michele Maio, Dr.med., Azienda Ospedaliera Universitaria Senese, Siena (Italy)

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Philogen S.p.A.
    ClinicalTrials.gov Identifier:
    NCT02076646
    Other Study ID Numbers:
    • PH-L19IL2DTIC-04-12
    First Posted:
    Mar 3, 2014
    Last Update Posted:
    Apr 14, 2022
    Last Verified:
    Apr 1, 2022
    Keywords provided by Philogen S.p.A.
    Interleukin
    IL2
    monoclonal
    antibody
    cytokine
    Dacarbazine
    metastatic
    melanoma
    tumor targeting
    Dose definition
    L19
    Additional relevant MeSH terms:
    Melanoma
    Interleukin-2

    Study Results

    No Results Posted as of Apr 14, 2022