A Phase II Study of the Interleukin-6 Receptor Inhibitor Tocilizumab in Combination With Ipilimumab and Nivolumab in Patients With Unresectable Stage III or Stage IV Melanoma

NCT03999749 | Active Not Recruiting Phase 2 Results DMC FDA Drug

• 1 other identifier: 19-00008
• Study Type: interventional
• Target: 71
• Locations: 1 country
• Sites: 4

Brief Summary

This is a Phase II, open-label, single arm study. The study will consist of an assessment of the safety and tolerability of tocilizumab administered concurrently at 4 mg/kg every 6 weeks for 5 doses in combination with ipilimumab and nivolumab for four induction doses to week 12, then maintenance nivolumab alone up to one year to patients with advanced melanoma. Treatment will be divided into induction and maintenance phases. It is anticipated that this clinical study will inform the use of this 3-drug combination for further phase II and/or phase III clinical testing. The trial will include an assessment of the pharmacodynamic activity of tocilizumab administered in combination with ipilimumab and nivolumab.

Conditions

Melanoma

Outcome Measures

Primary Outcomes (2)

• Percentage of Participants With Grades 3-5 Treatment Related Immune Related Adverse Events (irAEs)

  Adverse events are graded according to the NCI CTCAE version 5.0. Immune-related adverse events (irAEs) are specific events occurring within 100 days of the last dose (which includes pneumonitis, diarrhea/colitis, hepatitis, nephritis/renal dysfunction, rash, and endocrine abnormalities \[adrenal insufficiency, hypothyroidism/thyroiditis, hyperthyroidism, diabetes mellitus, and hypophysitis\]), regardless of causality, for which patients received immunosuppressive medication for treatment of the event. The exception to the immunosuppressive medication criteria for irAEs is endocrine events (e.g., hypothyroidism/thyroiditis, hyperthyroidism, hypophysitis, diabetes mellitus, adrenal insufficiency), which are included regardless of treatment since these events are often managed without immunosuppression.

  From start of treatment up to 100 days post treatment, *up to 18 months*

• Objective Response Rate (ORR)

  Objective Response Rate (ORR) is defined as the total number of patients whose best response outcome is a CR or PR by week 24 divided by the total number of evaluable patients. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

  Week 24

Secondary Outcomes (10)

• Disease Control Rate (DCR)

  From beginning of treatment until the first observation of disease progression (up to 5 years)

• Progression-Free Survival (PFS)

  From start of treatment until the first observation of disease progression or death due to any cause, whichever came first (up to 5 years)

• Duration of Overall Response

  From date of best overall response until the first observation of disease progression or death due to any cause, whichever came first (up to 5 years)

• Duration of Disease Control

  From start of treatment until the first observation of disease progression (up to 5 years)

• Immune-related Response Rate (irRR)

  From beginning of treatment until the first observation of disease progression (up to 5 years)

Study Arms (1)

Induction Phase, Maintenance Phase

EXPERIMENTAL

Induction Phase: 2 induction treatment cycles of 42 days (6 weeks) each, of which the first cycle of 6 weeks is the dose-limiting toxicity (DLT) period. Maintenance Phase: Consists of treatment cycles of 84 days (12 weeks) each, and may extend up to 1 year.

Drug: Ipilimumab; Drug: Nivolumab; Drug: Tocilizumab

Interventions

Ipilimumab DRUG

4 induction doses (during the 2 treatment cycles) at a dose of 1 mg/kg intravenously (IV) every 3 weeks, 4 times during the 12-week induction period, concurrent with nivolumab at 3 mg/kg administered at the same interval

Induction Phase, Maintenance Phase

Nivolumab DRUG

Nivolumab (3 mg/kg) will be administered IV on Days 1 and 22 of each 42-day induction treatment cycle. Nivolumab will continue to be administered IV at 240 mg flat dose every 2 weeks; i.e., at Days 1, 15, 29, 43, 57, and 71 of the 84-day treatment cycle for the first maintenance cycle until week 24, then nivolumab will be administered at 480 mg flat dose every 4 weeks to a maximum of 2 years

Induction Phase, Maintenance Phase

Tocilizumab DRUG

Administered intravenously for each 42-day induction treatment cycle. After 12 weeks of therapy, starting at Week 13, subjects enter the maintenance phase. Tocilizumab will be administered intravenously every 6 weeks during the first 84 day maintenance treatment cycle only at 4 mg/kg

Induction Phase, Maintenance Phase

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have signed and dated an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved written informed consent form (ICF) in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal patient care.
• Patients must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, tumor biopsies, and other requirements of the study.
• All patients must be either Stage IIIb/c/d or Stage IV melanoma according to the American Joint Committee on Cancer (AJCC) (8th edition) and have histologically-confirmed melanoma that is felt to be surgically unresectable in order to be eligible. Please refer to the AJCC 8th edition Cancer Staging Manual for a description of tumor, lymph node, metastasis, and staging.
• All melanomas, except ocular/uveal melanoma, regardless of primary site of disease will be allowed; mucosal melanomas are eligible.
• Patients must not have received prior anticancer treatment for metastatic disease (for example, but not limited to, systemic, local, radiation, radiopharmaceutical).
• All patients must have their disease status documented by a complete physical examination and imaging studies within 4 weeks prior to the first dose of study drug. Imaging studies must include computerized tomography (CT) scan of chest, abdomen, pelvis, and all known sites of resected disease in the setting of Stage IIIb/c/d or Stage IV disease, and brain magnetic resonance imaging (\[MRI\]; brain CT is allowable if MRI is contraindicated).
• The complete set of baseline radiographic images must be available before treatment initiation.
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
• Tumor tissue from the resected site of disease must be provided for biomarker analyses
• Prior treated CNS metastases must be without MRI evidence of recurrence for at least 4 weeks after treatment. Patients must be off immunosuppressive doses of systemic steroids (10 mg/day prednisone or equivalent) for at least 14 days prior to study drug administration, and must have returned to neurologic baseline status postoperatively.
• The 4-week period of stability is measured after the completion of the neurologic interventions (i.e., surgery and/or radiation).
• In addition to neurosurgery to treat CNS metastases, adjuvant radiation after the resection of CNS metastasis is allowed. Immunosuppressive doses of systemic steroids (doses \> 10 mg/day prednisone or equivalent) must be discontinued at least 14 days before study drug administration.
• Prior surgery that required general anesthesia must be completed at least 4 weeks before study drug administration. Surgery requiring local/epidural anesthesia must be completed at least 72 hours before study drug administration.
• Normal labs
• Patient Re-enrollment: This study permits the re-enrollment of a patient that has discontinued the study as a screen failure (i.e., patient has not been dosed/has not been treated). If re-enrolled, the patient must be re-consented and satisfy all eligibility criteria.

You may not qualify if:

• Patients with carcinomatosis meningitis or a history of current ocular/uveal melanoma are excluded.
• Patients with previous nonmelanoma malignancies are excluded unless a complete resection or remission was achieved at least 2 years prior to study entry and no additional therapy is required or anticipated to be required during the study period (exceptions include, but are not limited to, nonmelanoma skin cancers, in situ bladder cancer, in situ gastric cancer or gastrointestinal stromal tumor, in situ colon cancers, in situ cervical cancers/dysplasia, or breast carcinoma in situ).
• Patients with active, known, or suspected autoimmune disease. Patients with type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, or skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are permitted to enroll. For any cases of uncertainty, it is recommended that the Principal Investigator be consulted prior to signing informed consent.
• Patients with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids are permitted in the absence of active autoimmune disease.
• Prior therapy for melanoma with the following exceptions which are allowed: 1) surgery for the melanoma lesion(s), 2) adjuvant RT after neurosurgical resection for CNS lesions or for resected locoregional disease, and 3) prior adjuvant interferon (IFN)-alpha, ipilimumab and nivolumab (see qualifier below).
• Prior treatment with adjuvant IFN-alpha, adjuvant ipilimumab and/or nivolumab are allowed if completed 6 months prior to treatment.
• Treatment directed against the melanoma (eg, chemotherapy, targeted agents, biotherapy, limb perfusion) that is administered after a prior complete resection other than adjuvant radiation after neurosurgical resection or resection of locoregional disease and IFN-alpha, ipilimumab and nivolumab for resected melanoma.
• abnormalities labs
• Corrected QT interval using Fridericia's formula value \> 480 msec at screening; family or personal history of long corrected QT interval (QTc) syndrome or ventricular arrhythmias including ventricular bigeminy at screening; previous history of drug induced QTc prolongation or the need for treatment with medications known or suspected of producing prolonged QTc intervals on electrocardiogram (ECG).
• Congestive heart failure (New York Heart Association Class III or IV), myocardial infarction
• Any serious or uncontrolled medical disorder or active infection

Sponsors & Collaborators

• NYU Langone Health: lead

Study Sites (4)

The Angeles Clinic

Los Angeles, California, 90025, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

NYU Langone Health

New York, New York, 10016, United States

Location

Related Publications (1)

• Fa'ak F, Buni M, Falohun A, Lu H, Song J, Johnson DH, Zobniw CM, Trinh VA, Awiwi MO, Tahon NH, Elsayes KM, Ludford K, Montazari EJ, Chernis J, Dimitrova M, Sandigursky S, Sparks JA, Abu-Shawer O, Rahma O, Thanarajasingam U, Zeman AM, Talukder R, Singh N, Chung SH, Grivas P, Daher M, Abudayyeh A, Osman I, Weber J, Tayar JH, Suarez-Almazor ME, Abdel-Wahab N, Diab A. Selective immune suppression using interleukin-6 receptor inhibitors for management of immune-related adverse events. J Immunother Cancer. 2023 Jun;11(6):e006814. doi: 10.1136/jitc-2023-006814.

  PMID: 37328287 DERIVED

MeSH Terms

Conditions

Melanoma

Interventions

Ipilimumab; Nivolumab; tocilizumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Janice Mehnert, M.D.
• Organization: NYU Langone Health

janice.mehnert@nyulangone.org

212-731-5431

Study Officials

• Janice Mehnert, MD

  New York Langone Health

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 25, 2019
• First Posted: June 27, 2019
• Study Start: June 11, 2019
• Primary Completion: July 1, 2023
• Study Completion (Estimated): April 7, 2030
• Last Updated: March 9, 2026
• Results First Posted: October 9, 2024

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research.
• Access Criteria: The investigator who proposed to use the data will be provided access upon reasonable request. Requests should be directed to janice.mehnert@nyulangone.org. To gain access, data requestors will need to sign a data access agreement.

Locations

US (4)