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

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

Study Overview

• Status: Active, not recruiting
• Conditions: Metastatic Melanoma Stage IV
• Intervention / Treatment: Drug: L19IL2 - Ph I; Drug: DTIC; Drug: L19IL2 at RD - Ph II

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 Type: Interventional
• Enrollment (Anticipated): 96
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Germany
  • Tuebingen, Germany
    • University Hospital
• Italy
  • Siena, Italy
    • Azienda Ospedaliera Universitaria Senese

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I: maximum tolerated dose (MTD) and recommended dose (RD) of L19IL2	Establish the MTD and the RD of L19IL2 (in combination with dacarbazine) to be used for phase II study	From day 1 to day 21 of Cycle 1 (each cycle is 21-days)
Phase II: best objective response rate (BORR)	Evaluation of antitumor activity	Up to 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I: best objective response rate (BORR)	Evaluation of antitumor activity	Up to 1 year
Phase I: duration of objective response	Evaluation of the antitumor activity	From week 6 up to 1 year
Phase I: disease control rate	Evaluation of the antitumor activity	At 6 months
Phase I: median progression free survival (mPFS)	Evaluation of the antitumor activity	Up to 1 year
Phase I: median overall survival and overall survival rate	Evaluation of the antitumor activity	Up to 1 year
Phase II: safety and tolerability of L19-IL2 in combination with DTIC vs DTIC alone.	Safety evaluation including AEs, SAE and standard laboratory assessment	Up to 1 year
Phase II: duration of objective response		Up to 1 year
Phase II: disease control rate		At 6 months
Phase II: median progression free survival (mPFS)		Up to 1 year
Phase II: median overall survival and overall survival rate		Up to 1 year

Collaborators and Investigators

• Sponsor: Philogen S.p.A.
• Investigators: Principal Investigator: Michele Maio, Dr.med., Azienda Ospedaliera Universitaria Senese, Siena (Italy)

Study record dates

Study Major Dates

• Study Start (Actual): July 31, 2013
• Primary Completion (Actual): May 17, 2016
• Study Completion (Anticipated): June 1, 2022

Study Registration Dates

• First Submitted: February 24, 2014
• First Submitted That Met QC Criteria: February 26, 2014
• First Posted (Estimate): March 3, 2014

Study Record Updates

• Last Update Posted (Actual): April 14, 2022
• Last Update Submitted That Met QC Criteria: April 13, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: antibody; metastatic; melanoma; Dacarbazine; cytokine; Interleukin; monoclonal; tumor targeting; L19; IL2; Dose definition
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antineoplastic Agents; Interleukin-2
• Other Study ID Numbers: PH-L19IL2DTIC-04-12