IL2 With Ipilimumab Followed by Nivolumab in Stage 3 or 4 Melanoma Patients

A Phase II Study of High Dose Bolus IL2 in Combination With Low Dose Ipilimumab Followed Sequentially by Nivolumab in Patients With Inoperable Stage III or Stage IV Melanoma Who Have Failed Prior Anti-PD1 Immunotherapy

The purpose of this study is to find out if the administration of Interleukin-2 concurrently with ipilimumab followed by Nivolumab will result in improved anti-cancer activity and if it is effective for advanced melanoma.

Study Overview

• Status: Recruiting
• Conditions: Melanoma Stage IV; Melanoma Stage III; Inoperable Disease
• Intervention / Treatment: Drug: Interleukin-2; Drug: Ipilimumab; Drug: Nivolumab

Detailed Description

This is a Phase II study of high dose bolus interleukin-2 (HD IL2) in combination with low dose ipilimumab followed sequentially by nivolumab in patients with advanced inoperable stage III or stage IV melanoma who have failed prior anti-PD1 immunotherapy.

The planned treatment consists of up to 3 courses (One cycle is 21 days and one course is 4 cycles). HD IL2 will be given during week 1 of the 2 initial cycles or each course. Ipilimumab will be given concurrently at the low dose of 1 mg/kg on Day 1 of the 2 initial cycles of each course for up to 2 doses, total. Nivolumab will be given on Day 1 of the 3rd cycle of each course. No systemic treatment will be administered during the 4th cycle. Response assessment will occur at the end of the 4th cycle. Patients without evidence of disease progression (RECIST v.1.1) or limiting toxicities will be offered additional courses of treatment for up to a maximum of 3 courses, total

• Study Type: Interventional
• Enrollment (Estimated): 29
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Leticia Tetth; Phone Number: 813-745-4617; Email: Leticia.Tetteh@moffitt.org

Study Locations

• United States
  • Florida
    • Tampa, Florida, United States, 33612
      • Recruiting
      • Moffitt Cancer Center
      • Sub-Investigator: Nikhil Khushalani, MD
      • Sub-Investigator: Zeynep Eroglu, MD
      • Principal Investigator: Ahmad Tarhini, MD, PhD
      • Contact: Leticia Tetteh; Phone Number: 813-745-4617; Email: Leticia.Tetteh@moffitt.org
      • Sub-Investigator: Andrew Brohl, MD
      • Sub-Investigator: Joseph Markowitz, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically or cytologically confirmed metastatic melanoma. This includes American Joint Committee on Cancer (AJCC) stage IV or advanced/inoperable stage III. This also includes patients with a history of lower stage melanoma and subsequent recurrent metastatic disease that is either locally/regionally advanced/inoperable disease or distant metastases
• Measurable disease, according to RECIST version 1.1
• Must be free of active brain metastasis by contrast-enhanced CT/MRI scans within 4 weeks prior to enrollment. If known to have prior brain metastases, these must have been adequately managed with standard of care radiation therapy, stereotactic radiosurgery or surgery prior to registration on the study.
• Must have previously received anti-PD1 immunotherapy (nivolumab or pembrolizumab) and later experienced disease progression.
• Must not have received systemic therapy or radiotherapy (including SRS) within the preceding 3 weeks. Patients must have recovered from adverse events from previous therapy by the time registration.
• Must be at least 4 weeks from major surgery and have fully recovered from any effects of surgery, and must be free of significant detectable infection prior to registration.
• Patients who have received prior anti-CTLA4 monoclonal antibody therapy (ipilimumab or tremelimumab) are eligible.
• Patients who have previously experienced prior high-grade (grade 3 or 4 by CTCAE criteria) immune related adverse events with immune checkpoint inhibitors must be discussed with the study PI and cleared prior to enrollment on this study in order to ensure patient safety.
• Patients with BRAF V600 mutant melanoma must have previously received BRAF targeted therapy for metastatic melanoma and later experienced disease progression. Patients who refuse or decline to receive BRAF targeted therapy or were intolerant of BRAF targeted therapy are eligible.
• Life expectancy of greater than 3 months in the opinion of the investigator
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Must have normal organ and marrow function as specified per protocol.
• Patients on full-dose anticoagulants with Prothrombin Time Test International Normalized Ratio (PT INR) >1.5 are eligible provided that both of the following criteria are met: (a) The patient has an in-range INR (usually between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin. (b) The patient has no active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices).
• Pulmonary: Forced Expiratory Volume at 1 second (FEV1) > 2.0 liters or > 75% of predicted for height and age. Pulmonary function tests (PFTs) are required for patients over 50 years old or with significant pulmonary or smoking history
• No evidence of congestive heart failure, symptoms of coronary artery disease, myocardial infarction less than 6 months prior to entry, serious cardiac arrhythmias, or unstable angina.
• Patients who are over 40 years old or have had previous myocardial infarction greater than 6 months prior to study entry or have significant cardiac family history (CAD or serious arrhythmias) will be required to have a negative or low probability cardiac stress test (for example, thallium stress test, stress multigated acquisition scan (MUGA), stress echo or exercise stress test) for cardiac ischemia within 8 weeks prior to registration.
• No history of cerebrovascular accident or transient ischemic attacks within the past 6 months from registration.
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for at least 6 months after completion of study therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
• Women should not be lactating and, if of childbearing age, should have a negative pregnancy test (b-HCG test; serum or urine, minimum sensitivity 25 IU/L or equivalent units of b-HCG) within two weeks of registration in the study.

Exclusion Criteria:

• Patients who have had systemic therapy for melanoma or radiotherapy within 3 weeks prior to registering on the study or those who have not recovered from adverse events due to agents administered more than 3 weeks earlier. Patients with a history of endocrinopathies (e.g. hypothyroidism) are eligible if they are stable on hormone replacement therapy. Patients with a history of adrenal insufficiency are not eligible.
• Patients may not be receiving any other investigational agents.
• Patients with active brain metastasis are excluded
• Patients with clinically significant cardiovascular or cerebrovascular disease
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements.
• Patients who have other current malignancies are not eligible. Patients with other malignancies are eligible if they have been continuously disease free for > 2 years prior to the time of registration. Patients with prior history at any time of any in situ cancer, lobular carcinoma of the breast in situ, cervical cancer in situ, atypical melanocytic hyperplasia or melanoma in situ are eligible. Patients with prior history of basal or squamous skin cancer are eligible. Patients who have had multiple primary melanomas are eligible.
• Patients must not have autoimmune disorders or conditions of immunosuppression that require current ongoing treatment with systemic corticosteroids (or other systemic immunosuppressants), including oral steroids (i.e., prednisone, dexamethasone) or continuous use of topical steroid creams or ointments or ophthalmologic steroids or steroid inhalers. If a patient had been taking steroids, at least 2 weeks must have passed since the last dose.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment; HD IL2 (600,000 units/kg/dose IV) will be given during week 1 of the 2 initial cycles or each course. Ipilimumab will be given concurrently at the low dose of 1 mg/kg during week one of the 2 initial cycles of each course for up to 2 doses, total. Nivolumab will be given on during week one of the 3rd cycle of each course. No systemic treatment will be administered during the 4th cycle. Patients without evidence of disease progression (RECIST v.1.1) or limiting toxicities will be offered additional courses of treatment for up to a maximum of 3 courses, total.

Drug: Interleukin-2; High dose interleukin-2 (HD IL2) administered week 1 and 4 of each course (approximately 12 weeks); Other Names: Aldesleukin; Drug: Ipilimumab; Low dose Ipilimumab given at time of HD IL2 administration on day 1 of the first 2 cycles of each course.; Drug: Nivolumab; Nivolumab will be given at a dose of 480 mg IV week 7 of each course.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response Rate	Response rate (Complete Response + Partial Response) of HD IL2 plus low dose ipilimumab followed sequentially by nivolumab in patients with inoperable stage III or stage IV melanoma who have either failed prior treatment with anti-PD1 immunotherapy (nivolumab or pembrolizumab) or have demonstrated tumor progression following such therapy.	Up to 9 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival	Progression Free Survival (PFS) is defined as the duration of time from start of treatment to time of progression (or death if there is no progression date). Patients with neither a progression date nor date of death will be censored as of last contact.	Up to 5 years
Overall Survival	Overall Survival (OS) will be measured from the initial date of treatment to the recorded date of death.	Up to 5 years

Collaborators and Investigators

• Sponsor: H. Lee Moffitt Cancer Center and Research Institute
• Collaborators: Clinigen, Inc.
• Investigators: Principal Investigator: Ahmad Tarhini, MD, PhD, Moffitt Cancer Center

Publications and helpful links

Helpful Links

• Moffitt Clinical Trials Website

Study record dates

Study Major Dates

• Study Start (Actual): September 24, 2020
• Primary Completion (Estimated): September 1, 2024
• Study Completion (Estimated): September 1, 2029

Study Registration Dates

• First Submitted: September 18, 2020
• First Submitted That Met QC Criteria: September 18, 2020
• First Posted (Actual): September 24, 2020

Study Record Updates

• Last Update Posted (Estimated): January 25, 2024
• Last Update Submitted That Met QC Criteria: January 24, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: skin cancer
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Aldesleukin; Nivolumab; Ipilimumab; Interleukin-2
• Other Study ID Numbers: MCC-20494; CIIT19PLK13 (Other Identifier: Clinigen)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• 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.: Yes