Clinical trial NCT03567889: Efficacy of Daromun Neoadjuvant Intratumoral Treatment in Clinical Stage IIIB/C Melanoma Patients
Official title: An Open-Label, Randomized, Controlled Multi-Center Study of The Efficacy of Daromun (L19IL2 + L19TNF) Neoadjuvant Intratumoral Treatment Followed by Surgery and Adjuvant Therapy Versus Surgery and Adjuvant Therapy in Clinical Stage IIIB/C Melanoma Patients
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Melanoma Stage IIIB/C
Lead sponsor: Philogen S.p.A.
Sponsor class: INDUSTRY
First posted: 2018-06-26
Enrollment: 186
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Total patients: approximately 186. Daromun plus surgery and adjuvant therapy treatment group (Arm 1): 93 evaluable patients. Surgery and adjuvant therapy (Arm 2): 93 evaluable patients. Patients enrolled will be randomized to the two different arms of the study.
Primary purpose: TREATMENT

Brief summary: The trial aims to evaluate the efficacy of Daromun neoadjuvant treatment followed by surgery and adjuvant therapy to improve in a statistically significant manner the recurrence-free survival (RFS) of Stage IIIB/C melanoma patients with respect to the standard of care (surgery and adjuvant therapy).

Detailed description: The present study is an open-label, randomized, controlled, two-arm multi-center study of the efficacy of Daromun neoadjuvant intratumoral treatment followed by surgery and adjuvant therapy versus surgery and adjuvant therapy in clinical stage III B/C melanoma patients. 186 patients will be randomized in a 1:1 ratio to receive Daromun treatment followed by surgery and adjuvant therapy (Arm 1) or surgery and adjuvant therapy (Arm 2).

In both arms, follow-up for assessing recurrence-free survival will be performed up to five years after randomization. Survival information will also be collected in the following year (up to six years in total after randomization).

This is an open-label study, so there is no blinding.

Patients who successfully complete the screening evaluations and are eligible for participation in the study will be enrolled and randomly assigned (1:1) to two parallel treatment arms: Daromun plus surgery and adjuvant therapy (Arm 1) or surgery and adjuvant therapy (Arm 2).

To ensure a balance across treatment groups, stratified randomization with permuted block will be used and separate randomization list for each subgroup (stratum) will be produced. Patients will be stratified on the basis of the following prognostic factors:

* Stage of disease (2 levels): Stage IIIB vs. Stage IIIC
* Planned post-surgical adjuvant therapy (2 levels): anti-PD-1 and other adjuvant therapies.

The primary objective of the study is to demonstrate that a neoadjuvant Daromun treatment followed by surgery and adjuvant therapy improves in a statistically significant manner the recurrence-free survival (RFS) of Stage IIIB/C melanoma patients with respect to the standard of care (surgery and adjuvant therapy).

Primary endpoint of the study is RFS in a time-to-event analysis in the Daromun plus surgery and adjuvant therapy treatment group (Arm 1) versus the surgery plus adjuvant therapy control group (Arm 2). Analysis will be based on the "Intention To Treat" population.

The key secondary objective of the study is to demonstrate that a neoadjuvant Daromun treatment followed by surgery and adjuvant therapy improves in a statistically significant manner the overall survival (OS) of patients with resectable Stage IIIB/ or C melanoma patients with respect to the standard of care (surgery and adjuvant therapy).

For patients enrolled in both arms, local approved post-surgery adjuvant therapies (as part of the standard of care) are allowed and decided at the investigator's discretion. These include high-dose interferon- α2b, anti-CTLA-4 antibodies (e.g. Ipilimumab), anti-PD1 antibodies (e.g. Nivolumab, Pembrolizumab), targeted therapies (e.g. Dabrafenib + Trametinib), or other new local approved treatments.

Eligibility criteria: Inclusion Criteria:

1. Diagnosis of clinical stage IIIB and IIIC (AJCC v7) metastatic melanoma, eligible for complete surgical resection of all metastases (surgically resectable).
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 \> 24 months.
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 ≤ 1.5 x ULN.
13. Documented negative test for HIV, HBV and HCV. For HBV serology, the determination of HBsAg, and anti-HBcAg Ab is required. In patients with serology documenting previous exposure to HBV 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 women of childbearing potential (WOCBP) must have negative pregnancy test results at the screening. WOCBP must be using, from the screening to three months following the last study drug administration, highly effective contraception methods. WOCBP and effective contraception methods are 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 safety visit (only WOCBP and only for patients in Arm 1).
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 or 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 requiring or 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.
22. Previous enrolment and randomization in the same study.

Primary outcomes:
measure: Recurrence Free Survival (RFS)
timeFrame: From date of randomization until the date of the first recurrence or date of death from any cause, whichever occurs first assessed up to 60 months.
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: From date of randomization until the date of the first recurrence or date of death from any cause, whichever occurs first, assessed up to 72 months.
measure: Recurrence free survival (RFS) as determined by the local investigator
timeFrame: From date of randomization until the date of the first recurrence or date of death from any cause, whichever occurs first assessed up to 60 months.
measure: Pathological response (only for patients in Arm 1)
timeFrame: Time Frame: Assessed at the time of surgical resection of the tumor lesions
measure: Adverse Events (AE)
timeFrame: From the inclusion in the study (signature of the informed consent form - ICF) until the first follow-up visit (up to approximately 5 months).
measure: Serious Adverse Event (SAEs)
timeFrame: From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 60 months).
measure: Drug-Induced Liver Injury (DILI)
timeFrame: From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 60 months).
measure: Adverse Events of Special Interest (AESI)
timeFrame: From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 60 months).
measure: Percentage of Subjects with Haematological/chemical Laboratory Abnormalities
timeFrame: From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 60 months).
measure: Percentage of participants with Electrocardiogram (ECG) and echocardiogram (ECHO) abnormality findings.
timeFrame: 1) day 0-14 (screening) for both arm; 2) at week 5 (Safety assessment) only for arm 1.
measure: Number of subjects with a clinically significant change from baseline in physical examination
timeFrame: From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 60 months)
measure: Concomitant medication
timeFrame: From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 60 months)
measure: Human anti-fusion protein antibodies (HAFA)
timeFrame: 1) day 0-14 (screening) for arm 1; 2) at week 5 (Safety assessment) for Arm 1; 3) at week 12 (only first follow-up) for Arm 1.
measure: Vital signs (blood pressure)
timeFrame: From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 60 months).
measure: Number of subjects with a clinically significant change from baseline in vital signs (heart rate) by visit
timeFrame: From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 60 months)
measure: Number of subjects with a clinically significant change from baseline in vital signs (body temperature) by visit
timeFrame: From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 60 months)
Other outcomes:
measure: Local recurrence-free survival (LRFS)
timeFrame: From date of randomization until the date of the first recurrence or date of death from any cause, whichever occurs first assessed up to 60 months
measure: Distant metastasis-free survival (DMFS)
timeFrame: From date of randomization until the date of the first recurrence or date of death from any cause, whichever occurs first assessed up to 60 months
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic Hospital
state: Arizona
city: La Jolla
country: United States
facility: UC San Diego Moores Cancer Center
state: California
city: Orange
country: United States
facility: UC Irvine Health-Chao Family Comprehensive Cancer Center
state: California
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Winship Cancer Institute
state: Georgia
city: Chicago
country: United States
facility: Rush University Cancer Center - - 1750 W. Harrison Street, Jelke 601
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute, 195 Little Albany Street
state: New Jersey
city: Durham
country: United States
facility: Duke University Medical Center - Duke Cancer Center
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University Wexner Medical Center
state: Ohio
city: Easton
country: United States
facility: St. Luke's Cancer Center, Clinical Trial, 3rd floor, 1600 St. Luke's Blvd.
state: Pennsylvania
city: Hershey
country: United States
facility: Penn State Cancer Institute
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center 333 Cottman Avenue
state: Pennsylvania
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute, University of Utah 2000 Circle of Hope
state: Utah
city: Barcelona
country: Spain
facility: Hospital Clinic Barcelona
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Coruña
country: Spain
facility: Hospital Teresa Herrera
city: Donostia
country: Spain
facility: Hospital Universitario Donostia
city: Las Palmas De Gran Canaria
country: Spain
facility: HU Gran Canaria Doctor Negrin
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: MD Anderson Madrid
city: Murcia
country: Spain
facility: Hospital Clínico Universitario Virgen de la Arrixaca
city: Málaga
country: Spain
facility: Hospital Universitario Regional de Málaga
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena
city: Valencia
country: Spain
facility: Hospital General Universitario de Valencia
city: Basel
country: Switzerland
facility: Universitätsspital Basel
city: Bellinzona
country: Switzerland
facility: Istituto Oncologico della Svizzera Italiana
city: Bern
country: Switzerland
facility: Universitätsspital Inselspital Bern
city: Genève
country: Switzerland
facility: Hôpitaux Universitaires de Genève
city: Saint Gallen
country: Switzerland
facility: Kantonsspital St.Gallen
city: Zürich
country: Switzerland
facility: Universitätsspital Zürich (USZ)
Study officials:
affiliation: Moffitt Cancer Center
name: Jonathan S Zager, MD FACS
role: PRINCIPAL_INVESTIGATOR
References:
citation: Miura JT, Zager JS. Neo-DREAM study investigating Daromun for the treatment of clinical stage IIIB/C melanoma. Future Oncol. 2019 Nov;15(32):3665-3674. doi: 10.2217/fon-2019-0433. Epub 2019 Sep 20.