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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

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ClinicalTrials.gov Identifier: NCT02076646
Recruitment Status : Unknown
Verified October 2016 by Philogen S.p.A..
Recruitment status was:  Active, not recruiting
First Posted : March 3, 2014
Last Update Posted : October 31, 2016
Sponsor:
Information provided by (Responsible Party):
Philogen S.p.A.

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
Metastatic Melanoma Stage IV 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).

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Study Type : Interventional  (Clinical Trial)
Estimated 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
Study Start Date : October 2013
Estimated Primary Completion Date : April 2017
Estimated Study Completion Date : June 2017

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma
MedlinePlus related topics: Melanoma
Drug Information available for: Dacarbazine

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 Name: 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 Name: 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 Name: DETICENE®




Primary Outcome Measures :
  1. Phase I: maximum tolerated dose (MTD) and recommended dose (RD) of L19IL2 [ Time Frame: 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) [ Time Frame: Up to 1 year ]
    Evaluation of antitumor activity


Secondary Outcome Measures :
  1. Phase I: best objective response rate (BORR) [ Time Frame: Up to 1 year ]
    Evaluation of antitumor activity

  2. Phase I: duration of objective response [ Time Frame: From week 6 up to 1 year ]
    Evaluation of the antitumor activity

  3. Phase I: disease control rate [ Time Frame: At 6 months ]
    Evaluation of the antitumor activity

  4. Phase I: median progression free survival (mPFS) [ Time Frame: Up to 1 year ]
    Evaluation of the antitumor activity

  5. Phase I: median overall survival and overall survival rate [ Time Frame: 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. [ Time Frame: Up to 1 year ]
    Safety evaluation including AEs, SAE and standard laboratory assessment

  7. Phase II: duration of objective response [ Time Frame: Up to 1 year ]
  8. Phase II: disease control rate [ Time Frame: At 6 months ]
  9. Phase II: median progression free survival (mPFS) [ Time Frame: Up to 1 year ]
  10. Phase II: median overall survival and overall survival rate [ Time Frame: Up to 1 year ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02076646


Locations
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Germany
University Hospital
Tuebingen, Germany
Italy
Azienda Ospedaliera Universitaria Senese
Siena, Italy
Sponsors and Collaborators
Philogen S.p.A.
Investigators
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Principal Investigator: Claus Garbe, Prof. M.D. University Hospital Tuebingen (Germany)
Principal Investigator: Michele Maio, Dr.med. Azienda Ospedaliera Universitaria Senese, Siena (Italy)
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Responsible Party: Philogen S.p.A.
ClinicalTrials.gov Identifier: NCT02076646    
Other Study ID Numbers: PH-L19IL2DTIC-04-12
First Posted: March 3, 2014    Key Record Dates
Last Update Posted: October 31, 2016
Last Verified: October 2016
Keywords provided by Philogen S.p.A.:
Interleukin
IL2
monoclonal
antibody
cytokine
Dacarbazine
metastatic
melanoma
tumor targeting
Dose definition
L19
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Interleukin-2
Antineoplastic Agents
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs