Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Nivolumab

Ipilimumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Ipilumumab:1mg/kg q6weeks (1 dose per cycle, 4 planned treatments over 6 months total) Nivolumab:3mg/kg q2weeks (3 doses per cycle, 12 planned treatments over 6 months total)

Ipilumumab

Howard Safran, MD

Effective adjuvant treatment can increase cure in patients with high-risk resected melanoma. High dose interferon is a standard of care in the adjuvant setting but is highly toxic and marginally effective. The combination of ipilimumab and nivolumab is the most active regimen in patients with advanced melanoma so there is clear rationale to test this regimen in the adjuvant setting. Investigators are testing if nivolumab 3mg/kg every 2 weeks with 1mg/kg ipilimumab every 6 weeks in the high risk adjuvant setting. The duration of therapy will be six months.

Adjuvant Nivolumab & Low Dose Ipilimumab for Stage III & Resected Stage IV Melanoma

Adjuvant Nivolumab and Low Dose Ipilimumab for Stage III and Resected Stage IV Melanoma: A Phase II Brown University Oncology Research Group Trial

Rhode Island Hospital

The Miriam Hospital

Brown University

Adjuvant Treatment

Age, Categorical

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

Maria Constantinou, MD

Number of Participants With Treatment Related Toxicities

2-year progression free survival

2-year overall survall

Number of Participants With Progression-free and Survival Overall

Overall Study

Symptoms and General Pathology

Death

Melanoma, Cutaneous Malignant

Pembrolizumab

Immunomodulating Agents

Subjects will receive 2 cycles of BCD-217 neoadjuvant therapy, followed by index lymph node removal.

Subjects with pathological complete (pCR) and near complete response (pnCR) (Group 1A): excision of the primary lesion (if not previously performed) without regional lymphadenectomy, followed by up to 12 months of anti-PD1 agent in the adjuvant setting.

Subjects will receive 2 cycles of BCD-217 neoadjuvant therapy, followed by index lymph node removal.

Subjects with a pathological partial response (pPR) or non-responders (pNR) to neoadjuvant therapy (Group 1B): excision of the primary lesion (if not performed earlier), regional lymphadenectomy, then up to 12 months of adjuvant therapy with anti-PD1 agent.

Subjects start treatment with excision of the primary lesion (if not previously performed), regional lymphadenectomy followed by adjuvant therapy with anti-PD1 agent (up to 12 months). This approach is considered the standard therapy for patients in the target population.

BCD-217 (anti-CTLA4 agent nurulimab + anti-PD1) once every 3 weeks in the neoadjuvant setting

BCD-217

anti-PD1

Excision of the primary lesion will be performed per standard of care.

Excision of the primary lesion

Regional lymphadenectomy will be performed per standard of care.

Regional lymphadenectomy

Fedor B Kriukov, MD PhD

Anna A Siliutina, MD PhD

Nikolaii B Ermakov

Svetlana A Demidova

Natalia I Ivanova

Aleksei L Obukhov

Julia M Makarova, MD

Dmitry V Kirtbaya, MD

Nikolay V Kislov, MD, PhD

Natalya V Fadeeva, PhD in Medicine

Mariia V Smagina

Sufia Z Safina, MD

Artur Z Azanov

Vera A Vaschenko

Igor O Belogortsev

Leo Demidov

Igor A Utiashev

Elena V Poddubskaya

Elena F Satirova

Anastasiia S Mochalova

Daniil L Stroyakovsky, MD, PhD

Marina A Lyadova

Irina S Shumskaya

Artem A Zeidlits

Vadim V Kozlov

Natalia A Falaleeva

Anastasiia V Zimina

Svetlana V Odintsova, MD

Vladimir M Moiseenko, MD, PhD

Julia V Semiletova

Andrei V Kutkovich

Timur T Andabecov

Ivan S Sardaryan

Artem N Poltoratski

Konstantin D Pen'kov

Pavel Skopin, PhD

Dmitrii V Gladishev

Nadezhda V Kovalenko, MD

This study is an open-label, randomized, comparative phase III study, which will include subjects with resectable stage III skin melanoma (up to 3 resectable transient metastases are acceptable).

In both study groups, adjuvant therapy is possible until melanoma progresses to unresectable stage III-IV, unacceptable toxicity, withdrawal of ICF or the end of the therapy period (12 months).

In case of postoperative relapse of the disease, at the decision of the investigator and if the lesion is resectable, radical surgical treatment can be carried out (R0 - resection) in accordance with current clinical guidelines without withdrawing the patient from the study.

A Study of Neoadjuvant Therapy With BCD-217 (Nurulimab + Prolgolimab) in Patients With Resectable Stage III Skin Melanoma

A Randomized Study of the Efficacy and Safety of Neoadjuvant Therapy With BCD-217 (Nurulimab + Prolgolimab) Versus Standard Adjuvant Therapy With Pembrolizumab in Patients With Resectable Stage III Skin Melanoma.

Biocad

Trametinib

Dabrafenib

Protein Kinase Inhibitors

Enzyme Inhibitors

Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.

Subjects received matching placebos orally for 12 months

Each capsule contained 50 mg or 75 mg of free base (present as the mesylate salt)

Each tablet contained 0.5 mg or 2.0 mg of trametinib parent (present as the DMSO solvate)

The placebo capsules and tablets contained the same inactive ingredients and film coatings as the dabrafenib and trametinib study treatment

Placebos

Novartis Pharmaceuticals

This was a two-arm, randomized, double-blind Phase III study of dabrafenib in combination with trametinib versus two placebos in the adjuvant treatment of melanoma after surgical resection. Patients with completely resected, histologically confirmed, BRAF V600E/K mutation-positive, high-risk \[Stage IIIa (lymph node metastasis \>1 mm), IIIb or IIIc\] cutaneous melanoma were screened for eligibility. Subjects were randomized to receive either dabrafenib (150 milligram (mg) twice daily \[BID\]) and trametinib (2 mg once daily \[QD\]) combination therapy or two placebos for 12 months.

This was a two-arm, randomized, double-blind, multi-center, international phase III study of dabrafenib in combination with trametinib versus two matching placebos in the adjuvant treatment of melanoma after surgical resection. Patients with completely resected, histologically confirmed, BRAF V600E/K mutation-positive, high-risk \[Stage IIIa (lymph node metastasis \>1 mm), IIIb or IIIc\] cutaneous melanoma were screened for eligibility. Subjects were randomized to receive either dabrafenib (150 milligram (mg) twice daily \[BID\]) and trametinib (2 mg once daily \[QD\]). None of the patients had undergone previous systemic anticancer treatment or radiotherapy for melanoma. All the patients had undergone completion lymphadenectomy with no clinical or radiographic evidence of residual regional node disease within 12 weeks before randomization, had recovered from definitive surgery, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. BRAF V600 mutation status was confirmed in primary-tumor or lymph-node tissue by a central reference laboratory. All the patients provided written informed consent.

The primary end point was recurrence-free survival, Overall survival, as the key secondary end point, was to be tested in a hierarchical manner only if the primary end point met the criteria for significance. The overall survival analysis used a preplanned three-look Lan-DeMets group sequential design with an O'Brien-Fleming-type boundary, which was used to determine the significance threshold for the first interim overall survival analysis (two-sided P=0.000019).

Disease assessments included clinical examination and imaging by means of computed tomography, magnetic resonance imaging, or both.) Imaging was performed every 3 months during the first 24 months, then every 6 months until disease recurrence or the completion of the trial. Follow-up for survival began after recurrence and continued through the end of the trial. Adverse events and laboratory values were assessed at screening, on the date of randomization, at least once per month through month 12, and at every visit for disease-recurrence assessment after month 12. Adverse events and laboratory values were graded according to the Common Terminology Criteria for Adverse Events, version 4.0.

Dabrafenib With Trametinib in the Adjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma (COMBI-AD).

COMBI-AD: A Phase III Randomized Double Blind Study of Dabrafenib (GSK2118436) in COMBInation With Trametinib (GSK1120212) Versus Two Placebos in the ADjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma After Surgical Resection

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Recurrence-free survival was defined as the time from randomization to disease recurrence (local recurrence, distant recurrence, second primary melanoma), or death from any cause.

Overall survival (OS) of dabrafenib and trametinib as a combination therapy versus placebo

Distant metastasis-free survival (DMFS) of dabrafenib and trametinib as a combination therapy versus placebo. In the DMFS analysis, the first occurrence of distant metastasis or death (if it occurred before documented recurrence) was counted as an event.

Freedom from relapse (FFR) of dabrafenib and trametinib as a combination therapy versus placebo. In the FFR analysis, local or distant recurrence or a new primary melanoma were counted as events, and patients who died of causes other than melanoma or treatment-related toxicity were censored.

All cause mortality provided for the treatment period only.

Dabrafenib + Trametinib Combination Therapy

Dabrafenib and Trametinib Placebos

Dabrafenib and Trametinib Combination Therapy

Total

White

Asian

Race/Ethnicity, Customized

The Intent-to-Treat Population (ITT) consisted of all randomized patients whether or not randomized treatment was administered.

Study Director

The null hypothesis, H0: λ = 1 or reject it in favor of the alternative hypothesis, HA: λ ≠ 1, where λ is the hazard ratio (HR) of combination therapy relative to placebo.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Adjuvant Nivolumab & Low Dose Ipilimumab for Stage III & Resected Stage IV Melanoma	NCT02656706	Melanoma	Ipilumumab Nivolumab	18 Years -	Brown University
A Study of Neoadjuvant Therapy With BCD-217 (Nurulimab + Prolgolimab) in Patients With Resectable Stage III Skin Melanoma	NCT05751928	Melanoma Stage ... Melanoma (Skin)	BCD-217 anti-PD1 Excision of the... Regional lympha...	18 Years -	Biocad
Adjuvant Nivolumab & Low Dose Ipilimumab for Stage III & Resected Stage IV Melanoma	NCT02656706	Melanoma	Ipilumumab Nivolumab	18 Years -	Brown University
A Study of Neoadjuvant Therapy With BCD-217 (Nurulimab + Prolgolimab) in Patients With Resectable Stage III Skin Melanoma	NCT05751928	Melanoma Stage ... Melanoma (Skin)	BCD-217 anti-PD1 Excision of the... Regional lympha...	18 Years -	Biocad
Dabrafenib With Trametinib in the Adjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma (COMBI-AD).	NCT01682083	Melanoma	Dabrafenib Trametinib Placebos	18 Years -	Novartis
Dabrafenib With Trametinib in the Adjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma (COMBI-AD).	NCT01682083	Melanoma	Dabrafenib Trametinib Placebos	18 Years -	Novartis

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