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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

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03999749
Recruitment Status : Recruiting
First Posted : June 27, 2019
Last Update Posted : August 19, 2020
Sponsor:
Information provided by (Responsible Party):
NYU Langone Health

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.

Condition or disease Intervention/treatment Phase
Melanoma Drug: Ipilimumab Drug: Nivolumab Drug: Tocilizumab Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 67 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : June 11, 2019
Estimated Primary Completion Date : June 2022
Estimated Study Completion Date : June 2024


Arm Intervention/treatment
Experimental: Induction Phase, Maintenance Phase

Induction 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.

Drug: Ipilimumab
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

Drug: Nivolumab
administered first at a dose of 3 mg/kg;

Drug: Tocilizumab
Administered intravenously for each 42-day induction treatment cycle.




Primary Outcome Measures :
  1. Antitumor activity of tocilizumab administered in combination with ipilimumab and nivolumab [ Time Frame: 24 Months ]
    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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03999749


Contacts
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Contact: Sandra John-Henry 212-263-4432 Sandra.John-Henry@nyulangone.org

Locations
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United States, California
The Angeles Clinic Recruiting
Los Angeles, California, United States, 90025
Contact: Omid Hamid, MD         
Contact: MaDonna Johnson    310-231-2128      
United States, Massachusetts
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Cindy Ngo    617-632-4503      
Principal Investigator: Stephen Hodi, MD         
United States, New York
NYU Langone Health Recruiting
New York, New York, United States, 10016
Contact: sandra John-Henry    212-263-4432    Sandra.John-Henry@nyulangone.org   
Principal Investigator: Jeffrey Weber, MD         
Sponsors and Collaborators
NYU Langone Health
Investigators
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Principal Investigator: Jeffrey Weber, MD New York Langone Health
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Responsible Party: NYU Langone Health
ClinicalTrials.gov Identifier: NCT03999749    
Other Study ID Numbers: 19-00008
First Posted: June 27, 2019    Key Record Dates
Last Update Posted: August 19, 2020
Last Verified: August 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Nivolumab
Ipilimumab
Antineoplastic Agents, Immunological
Antineoplastic Agents