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

NCT ID: NCT02076646

Last Updated: 2022-04-14

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 96 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-07-31
• Study Completion Date: 2022-06-30

Brief Summary

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

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).

Conditions

Metastatic Melanoma Stage IV

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

L19IL2 - Ph I

Intervention Type: DRUG

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).

DTIC

Intervention Type: DRUG

Dacarbazine: 1 hour intravenous infusion on day 1 of each 21-cycle at a dosage of 1000 mg/m2 (fixed dose).

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.

Group Type: EXPERIMENTAL

L19IL2 at RD - Ph II

Intervention Type: DRUG

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

DTIC

Intervention Type: DRUG

Dacarbazine: 1 hour intravenous infusion on day 1 of each 21-cycle at a dosage of 1000 mg/m2 (fixed dose).

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.

Group Type: ACTIVE_COMPARATOR

DTIC

Intervention Type: DRUG

Dacarbazine: 1 hour intravenous infusion on day 1 of each 21-cycle at a dosage of 1000 mg/m2 (fixed dose).

Interventions

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).

Intervention Type: DRUG

L19IL2 at RD - Ph II

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

Intervention Type: DRUG

DTIC

Dacarbazine: 1 hour intravenous infusion on day 1 of each 21-cycle at a dosage of 1000 mg/m2 (fixed dose).

Intervention Type: DRUG

Other Intervention Names

DETICENE®

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Philogen S.p.A.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Claus Garbe, Prof. M.D.

Role: PRINCIPAL_INVESTIGATOR

University Hospital Tuebingen (Germany)

Michele Maio, Dr.med.

Role: PRINCIPAL_INVESTIGATOR

Azienda Ospedaliera Universitaria Senese, Siena (Italy)

Locations

University Hospital

Tübingen, , Germany

Azienda Ospedaliera Universitaria Senese

Siena, , Italy

Countries

Germany; Italy

Other Identifiers

PH-L19IL2DTIC-04-12

Identifier Type: -

Identifier Source: org_study_id