Clinical Trials /

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

Description:

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.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: 19-00008
  • NCT ID: NCT03999749

Conditions

  • Melanoma

Interventions

DrugSynonymsArms
IpilimumabInduction Phase, Maintenance Phase
NivolumabInduction Phase, Maintenance Phase
TocilizumabInduction Phase, Maintenance Phase

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Induction Phase, Maintenance PhaseExperimentalInduction Phase: 2 induction treatment cycles of 42 days (6 weeks) each, of which the first cycle of 6 weeks is the DLT period. Maintenance Phase: Consists of treatment cycles of 84 days (12 weeks) each, and may extend up to 1 year.
  • Ipilimumab
  • Nivolumab
  • Tocilizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have signed and dated an Institutional Review Board (IRB)/Independent
             Ethics Committee (IEC)-approved written 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).

          -  Exceptions: Surgery for melanoma and/or post-resection brain radiotherapy (RT) if CNS
             metastases and adjuvant RT for locoregional disease after resection and/or prior
             treatment with adjuvant IFN-alpha, ipilimumab or nivolumab (as described in Exclusion
             Criterion 2).

          -  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.

          -  Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
             test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin
             [hCG] hormone) within 24 hours prior to the start of study drug.

          -  Women of childbearing potential must agree to follow instructions for method(s) of
             contraception for the duration of treatment with study drug(s) plus 5 half-lives of
             study drug plus 30 days (duration of ovulatory cycle). The half-life of nivolumab and
             ipilimumab is up to 25 days and 18 days, respectively. WOCBP should therefore use an
             adequate method to avoid pregnancy for a total of 23 weeks post treatment completion
             (Section 4.5).

          -  Males who are sexually active with WOCBP must agree to follow instructions for
             method(s) of contraception for the duration of treatment with study drug(s) plus 5
             half lives of the study drug (s) plus 90 days (duration of sperm turnover). The half
             lives of nivolumab and ipilimumab are up to 25 days and 18 days, respectively. Men
             should therefore use an adequate method of contraception for a total of 31 weeks post
             treatment completion (Section 4.5).

          -  Azoospermic males and WOCBP who are continuously not heterosexually active are exempt
             from contraceptive requirements. However, they must still undergo pregnancy testing as
             described in this section.

        Exclusion Criteria:

          -  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 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 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Antitumor activity of tocilizumab administered in combination with ipilimumab and nivolumab
Time Frame:24 Months
Safety Issue:
Description:Determine the preliminary antitumor activity of tocilizumab administered in combination with ipilimumab and nivolumab to patients with unresectable stage III or stage IV melanoma defined as best overall response rate (BORR) by 6 months by RECIST 1.1

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:NYU Langone Health

Last Updated