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Neoadjuvant L19IL2/L19TNF- Pivotal Study (Pivotal)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02938299
Recruitment Status : Unknown
Verified May 2017 by Philogen S.p.A..
Recruitment status was:  Recruiting
First Posted : October 19, 2016
Last Update Posted : May 31, 2017
Sponsor:
Information provided by (Responsible Party):
Philogen S.p.A.

Tracking Information
First Submitted Date  ICMJE October 11, 2016
First Posted Date  ICMJE October 19, 2016
Last Update Posted Date May 31, 2017
Study Start Date  ICMJE July 2016
Estimated Primary Completion Date December 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 17, 2016)
Recurrence-free survival (RFS) rate [ Time Frame: 1 year after randomization. ]
Recurrence-free survival (RFS) rate in the L19IL2/L19TNF plus surgery treatment group (Arm 1) versus surgery alone (Arm 2), assessed at 1 year after randomization.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 17, 2016)
  • Local recurrence-free survival (LRFS) rate [ Time Frame: 1year, 2years, 3years after randomization and 1year after surgery ]
  • Distant metastasis-free survival (DMFS) rate [ Time Frame: 1year, 2years, 3years after randomization and 1year after surgery ]
  • Recurrence-free survival (RFS) rate [ Time Frame: 2years, 3years after randomization ]
  • Overall survival (OS) [ Time Frame: 1year, 2years, 3years after randomization ]
  • Percentage of Participants With On-Study Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: up to 3 years ]
  • Percentage of Participants With Worst On-Study Hematological and Chemistry Abnormalities [ Time Frame: up to 36 months ]
  • Clinically Meaningful Changes in Vital Signs and Physical Examinations [ Time Frame: up to 36 months ]
  • Changes in absolute counts and relative percentages of lymphocytic subpopulations over time [ Time Frame: (1) At screening, (2) At Day of surgery: from Day 1 to Day 54, (3) After 3 months from surgery: Day 91 to Day 144 ]
    Immunophenotypic characterization of PBMCs for changes in absolute counts and relative percentages of lymphocytic subpopulations (e.g., Tregs, MDSCs etc.) over time (only for patients recruited in German centers).
  • HAFA [ Time Frame: (1) At Day 1, (2) At Day 29, (3) After 3 months from surgery: Day 119 to Day 144 ]
    Assessment of the formation of human anti-fusion protein antibodies (HAFA) against L19IL2 and L19TNF.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Neoadjuvant L19IL2/L19TNF- Pivotal Study
Official Title  ICMJE A Pivotal Phase III, Open-label, Randomized, Controlled Multi-center Study of the Efficacy of L19IL2/L19TNF Neoadjuvant Intratumoral Treatment Followed by Surgery Versus Surgery Alone in Clinical Stage III B/C Melanoma Patients
Brief Summary Phase III, open-label, randomized, controlled multi-center study. In the study, 214 patients will be enrolled and parallel assigned (via randomization system) in a 1:1 fashion to one of two different arms.
Detailed Description

Phase III, open-label, randomized, controlled multi-center study. In the study, 214 patients will be enrolled and parallel assigned (via randomization system) in a 1:1 fashion to one of two different arms:

ARM 1:

Patients in Arm 1 will receive multiple intratumoral administrations into all injectable cutaneous, subcutaneous, and nodal tumors of a mixture of L19IL2 and L19TNF once weekly for up to 4 weeks (or until all injectable tumors have disappeared, or intolerance to study treatment or in the opinion of the investigator immediate surgical resection or any other treatment for melanoma is warranted, whichever occurs first). The whole volume of L19IL2/L19TNF will be equally distributed among all injectable lesions.

Newly occurring injectable melanoma lesions within the 4 weeks treatment period will also be treated as described. For the new lesions the treatment period will not be extended beyond the pre-defined 4 week- treatment period with a clock start at the time of the first intralesional L19IL2/L19TNF injection. Surgical resection of all existing metastases will follow within 4 weeks after end of treatment. Surgery will be performed after the safety evaluation carried out at week 5 and, if indicated, may be carried out on the same day of the safety evaluation.

ARM 2:

Patients in Arm 2 will receive directly surgical resection of melanoma tumor lesions within 4 weeks after randomization.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Malignant Melanoma
Intervention  ICMJE
  • Drug: L19IL2 + L19TNF
    Mixture of L19IL2 and L19TNF once weekly
  • Procedure: Surgery
    Surgical resection of melanoma tumor lesions
Study Arms  ICMJE
  • Experimental: Arm 1: neoadjuvant + surgery

    Patients in Arm 1 will receive multiple intratumoral administrations into all injectable cutaneous, subcutaneous, and nodal tumors of a mixture of L19IL2 and L19TNF once weekly for up to 4 weeks (or until all injectable tumors have disappeared, or intolerance to study treatment or in the opinion of the investigator immediate surgical resection or any other treatment for melanoma is warranted, whichever occurs first).

    Newly occurring injectable melanoma lesions within the 4 weeks treatment period will also be treated as described. Surgical resection of all existing metastases will follow within 4 weeks after end of treatment. Surgery will be performed after the safety evaluation carried out at week 5 and, if indicated, may be carried out on the same day of the safety evaluation.

    Interventions:
    • Drug: L19IL2 + L19TNF
    • Procedure: Surgery
  • Active Comparator: Arm 2: surgery alone
    Patients in Arm 2 will receive directly surgical resection of melanoma tumor lesions within 4 weeks after randomization.
    Intervention: Procedure: Surgery
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: October 17, 2016)
214
Original Estimated Enrollment  ICMJE Same as current
Study Completion Date  ICMJE Not Provided
Estimated Primary Completion Date December 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Diagnosis of malignant melanoma of the skin in clinical stage III B and III C, eligible for complete surgical resection.
  2. Eligible subjects must have measurable disease and must be candidate for intralesional therapy with at least one injectable cutaneous, subcutaneous, or nodal melanoma lesion (≥ 10 mm in longest diameter) or with multiple injectable lesions that in aggregate have a longest diameter of ≥ 10 mm.
  3. Males or females, age ≥ 18 years
  4. ECOG Performance Status/WHO Performance Status ≤ 1
  5. Life expectancy of at least 24 months (see paragraph 6.3.1)
  6. Absolute neutrophil count > 1.5 x 109/L
  7. Hemoglobin > 9.0 g/dL
  8. Platelets > 100 x 109/L
  9. Total bilirubin ≤ 30 µmol/L (or ≤ 2.0 mg/dl)
  10. ALT and AST ≤ 2.5 x the upper limit of normal (ULN)
  11. Serum creatinine < 1.5 x ULN
  12. LDH serum level ≤ 1.0 x ULN
  13. Documented negative test for HIV, HBV and HCV. For HBV serology, the determination of HBsAg, anti-HBsAg Ab and anti-HBcAg Ab is required. In patients with serology documenting previous exposure to HBV (e.g. anti-HBs Ab with no history of vaccination and/or anti-HBc Ab) negative serum HBV-DNA is also required.
  14. All acute toxic effects (excluding alopecia) of any prior therapy must have resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (v4.03) Grade ≤ 1 unless otherwise specified above
  15. All female subjects must have negative pregnancy test results at the screening. Women of childbearing potential (WOCBP) must be using, from the screening to three months following the last study drug administration, highly effective contraception methods, as defined by the "Recommendations for contraception and pregnancy testing in clinical trials" issued by the Head of Medicine Agencies' Clinical Trial Facilitation Group and which include, for instance, progesterone-only or combined (estrogen- and progesterone-containing) hormonal contraception associated with inhibition of ovulation, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal occlusion, vasectomized partner or sexual abstinence. Pregnancy test will be repeated at the end of treatment visit.
  16. Male patients with WOCBP partners must agree to use simultaneously two acceptable methods of contraception (i.e. spermicidal gel plus condom) from the screening to three months following the last study drug administration.
  17. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
  18. Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.

Exclusion Criteria:

  1. Uveal melanoma and mucosal melanoma
  2. Evidence of distant metastases at screening
  3. Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis & T1), second primary melanoma in situ or any cancer curatively treated ≥ 5 years prior to study entry
  4. Presence of active infections (e.g. requiring antimicrobial therapy) or other severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or interfere with the study.
  5. History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
  6. Inadequately controlled cardiac arrhythmias including atrial fibrillation
  7. Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria)
  8. LVEF ≤ 50% and/or abnormalities observed during baseline ECG and Echocardiogram investigations that are considered as clinically significant by the investigator.
  9. Uncontrolled hypertension
  10. Ischemic peripheral vascular disease (Grade IIb-IV)
  11. Severe diabetic retinopathy
  12. Active autoimmune disease
  13. History of organ allograft or stem cell transplantation
  14. Recovery from major trauma including surgery within 4 weeks prior to enrollment.
  15. Known history of allergy to IL2, TNF, or other human proteins/peptides/antibodies or any other constituent of the product.
  16. Breast feeding female
  17. Anti-tumor therapy (except small surgery) within 4 weeks before enrollment
  18. Previous in vivo exposure to monoclonal antibodies for biological therapy in the 6 weeks before enrollment
  19. Planned administration of growth factors or immunomodulatory agents within 7 days before enrollment
  20. Patient requires or is taking corticosteroids or other immunosuppressant drugs on a long-term basis. Limited use of corticosteroids to treat or prevent acute hypersensitivity reactions is not considered an exclusion criterion.
  21. Any conditions that in the opinion of the investigator could hamper compliance with the study protocol.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany,   Italy,   Poland
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02938299
Other Study ID Numbers  ICMJE PH-L19IL2TNF-02/15
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Philogen S.p.A.
Study Sponsor  ICMJE Philogen S.p.A.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Benjamin Weide, MD Tuebingen Clinical Hospital
Principal Investigator: Mario Santinami, MD Istituto Nazionale Tumori Milano
PRS Account Philogen S.p.A.
Verification Date May 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP