High-Dose Aldesleukin and Ipilimumab in Treating Patients With Stage III-IV Melanoma That Cannot Be Removed By Surgery

• ClinicalTrials.gov Identifier: NCT02203604
• Recruitment Status: Completed
• First Posted: July 30, 2014
• Last Update Posted: June 19, 2020
• Sponsor: Rutgers, The State University of New Jersey
• Collaborators: National Cancer Institute (NCI); Rutgers Cancer Institute of New Jersey
• Information provided by (Responsible Party): Janice Mehnert, MD, Rutgers Cancer Institute of New Jersey

Study Description

Brief Summary:

This phase II trial studies how well high-dose aldesleukin and ipilimumab works in treating patients with stage III-IV melanoma that cannot be removed by surgery. Biological therapies, such as aldesleukin, may stimulate or suppress the immune system in different ways and stop tumor cells from growing. Monoclonal antibodies, such as ipilimumab, interfere with the ability of tumor cells to grow and spread. Giving high-dose aldesleukin together with ipilimumab may work better in treating patients with melanoma.

Condition or disease	Intervention/treatment	Phase
Recurrent Melanoma; Stage IIIA Melanoma; Stage IIIB Melanoma; Stage IIIC Melanoma; Stage IV Melanoma	Biological: aldesleukin; Biological: ipilimumab; Other: laboratory biomarker analysis	Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. The best overall response rate within the first 24 weeks of combination interleukin (IL)-2 (aldesleukin) and ipilimumab using the immune-related response criteria.

SECONDARY OBJECTIVES:

I. Best overall response (BOR). II. Progression-free survival (PFS). III. Disease control rate (DCR). IV. Overall survival. V. To collect data on the safety and feasibility of combined high-dose IL-2 and ipilimumab.

VI. To evaluate the cluster of differentiation (CD)4+ and CD8+ T cell response in the tumor microenvironment and peripheral blood of patients treated on this study.

OUTLINE:

INDUCTION: Patients receive ipilimumab intravenously (IV) over 90 minutes on days 1, 22, 43, and 64 and high-dose aldesleukin IV on days 22-26 and 43-47.

MAINTENANCE: Beginning on weeks 24, patients without disease progression or unacceptable toxicity receive ipilimumab IV over 90 minutes once every 12 weeks for up to 24 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 36 months.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 9 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Single Arm Study of High-Dose IL-2 and Ipilimumab in Patients With Unresectable Stage III and Stage IV Melanoma
• Actual Study Start Date: November 26, 2014
• Actual Primary Completion Date: January 27, 2020
• Actual Study Completion Date: January 27, 2020

Arms and Interventions

Arm

Intervention/treatment

Experimental: Treatment (aldesleukin, ipilimumab); INDUCTION: Patients receive ipilimumab IV over 90 minutes on days 1, 22, 43, and 64 and high-dose aldesleukin IV on days 22-26 and 43-47. MAINTENANCE: Beginning on weeks 24, patients without disease progression or unacceptable toxicity receive ipilimumab IV over 90 minutes once every 12 weeks for up to 24 weeks in the absence of disease progression or unacceptable toxicity.

Biological: aldesleukin; Given IV; Other Names: IL-2; Proleukin; recombinant human interleukin-2; recombinant interleukin-2; Biological: ipilimumab; Given IV; Other Names: anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody; MDX-010; MDX-CTLA-4; monoclonal antibody CTLA-4; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures :

1. Objective response rate as determined by mWHO criteria [ Time Frame: Up to 24 weeks ]
   Defined as the ratio of the number of patients whose best response is a complete response or partial response divided by the total number of patients enrolled who have baseline and post-treatment assessments. Performed using exact one-sample binomial tests where the objective response rate of Ipilimumab and high-dose aldesleukin combination will be compared with published response rate of Ipilimumab alone and high-dose aldesleukin alone.

Secondary Outcome Measures :

1. Incidence of adverse events, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 60 weeks ]
   The number of events in each classification of severity and relationship to treatment will be tabulated for each patient and summarized by treatment arm.
2. Overall survival [ Time Frame: Time from the date of registration to the date of death from any cause, assessed up to 3 years ]
   Will be estimated using Kaplan-Meier method and their 90% confidence intervals will also be reported.
3. PFS based on the mWHO criteria [ Time Frame: Time from the date of registration until the date of documented disease progression or death, assessed up to 36 months ]
   Will be estimated using Kaplan-Meier method and the median PFS and its 90% confidence interval will be reported.
4. BOR, defined as the best response across all time points [ Time Frame: After the first 24 weeks ]
   The best overall response will be tabulated for all patients and the rate reported.
5. Frequency of effector CD8+ T cells [ Time Frame: Up to 104 weeks ]
   Treatment effect for each patient will be measured as paired differences between pre and post measurements of these parameters at various times. Transformation of the data will be performed if appropriate, e.g. log transformation, and hence treatment effect will be expressed on a log scale. Data relating to immune response will be presented as descriptive summary statistics (such as mean, standard error and 90% confidence intervals [CI]).
6. Frequency of CD4+FoxP3+ regulatory T cells [ Time Frame: Up to 104 weeks ]
   Treatment effect for each patient will be measured as paired differences between pre and post measurements of these parameters at various times. Transformation of the data will be performed if appropriate, e.g. log transformation, and hence treatment effect will be expressed on a log scale. Data relating to immune response will be presented as descriptive summary statistics (such as mean, standard error and 90% CI).

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Willing and able to give written informed consent
• Histologic or cytologic diagnosis of cutaneous melanoma that is considered unresectable (stage III) or metastatic (stage IV); ocular and mucosal melanoma is excluded
• White blood cell (WBC) >= 2000/uL
• Absolute neutrophil count (ANC) >= 1000/uL
• Platelets >= 75 x 10^3/uL
• Hemoglobin >= 9 g/dL (>= 80 g/L; may be transfused)
• Creatinine =< 2.0 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN for patients without liver metastasis, =< 5 times for patients with liver metastases
• Bilirubin =< 2.0 x ULN, (except patients with Gilbert's syndrome, who must have a total bilirubin less than 3.0 mg/dL)
• No known active or chronic infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C; testing is not required unless clinically suspected
• Performance status (Eastern Cooperative Oncology Group [ECOG] 0-1)
• Patients must have a life expectancy of greater than three months at the start of the trial
• Patients must have a brain magnetic resonance imaging (MRI) that is free of active metastases; metastases that have been treated with radiation or surgical resection, are stable for at least 4 weeks and do not require steroids are eligible
• Patients may have received treatment of completely resected early stage melanoma, comprising interferon, radiation treatment, or experimental vaccine therapy, and in the metastatic setting patient can have had treatment such as chemotherapy, immunotherapy (except prior treatment with ipilimumab and IL-2), and other experimental agent which was completed 4 weeks prior to enrollment
• Normal cardiac stress test for patients over 50 years of age
• Forced expiratory volume in 1 second (FEV1) > 65% of prediction for those patients with extensive pulmonary metastases or chronic pulmonary disease history
• Forced vital capacity (FVC) > 65% of prediction for those patients with extensive pulmonary metastases or chronic pulmonary disease history

• Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 26 weeks after the last dose of investigational product, in such a manner that the risk of pregnancy is minimized; in general, the decision for appropriate methods to prevent pregnancy should be determined by discussions between the investigator and the study subject; WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not post-menopausal; post-menopause is defined as:

  • Amenorrhea >= 12 consecutive months without another cause, or
  • For women with irregular menstrual periods and taking hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level >= 35 mIU/mL
  • Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (eg, vasectomy) should be considered to be 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]) within 72 hours before the start of ipilimumab
  • Men of fathering potential must be using an adequate method of contraception to avoid conception throughout the study (and for up to 26 weeks after the last dose of investigational product) in such a manner that the risk of pregnancy is minimized

Exclusion Criteria:

• Any other malignancy form which the patient has been disease-free for less than 5 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix
• Patients with primary ocular or mucosal melanoma are excluded
• Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's disease, are excluded from this study, as are patients with a history of symptomatic disease (eg, rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [eg, Wegener's granulomatosis]); motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre syndrome and Myasthenia Gravis)
• Any underlying medical or psychiatric condition, which in the opinion of the investigator will make the administration of ipilimumab hazardous or obscure the interpretation of adverse events (AEs), such as a condition associated with frequent diarrhea
• Patients with underlying heart conditions who are deemed ineligible for surgery by cardiology consult; patients with reversible ischemic changes on cardiac stress test
• Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 1 month before or after any dose of ipilimumab)
• A history of prior treatment with IL-2, ipilimumab or prior cytotoxic T-lymphocyte antigen 4 (CTLA4) inhibitor or agonist
• Concomitant therapy with any of the following: interferon, or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids

• Women of childbearing potential (WOCBP), who:

  • Are unwilling or unable to use an acceptable method of contraception to avoid pregnancy for their entire study period and for at least 8 weeks after cessation of study drug, or
  • Have a positive pregnancy test at baseline, or
  • Are pregnant or breastfeeding
• Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (eg, infectious) illness

Contacts and Locations

Locations

United States, Illinois

Loyola University Medical Center

Maywood, Illinois, United States, 60153

United States, Massachusetts

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States, 02215

United States, New Jersey

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, United States, 08903

United States, Oregon

Providence Portland Medical Center

Portland, Oregon, United States, 97213

United States, Tennessee

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37240

Sponsors and Collaborators

Rutgers, The State University of New Jersey

National Cancer Institute (NCI)

Rutgers Cancer Institute of New Jersey

Investigators

• Principal Investigator: Howard Kaufman; Rutgers Cancer Institute of New Jersey

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Silk AW, Kaufman HL, Curti B, Mehnert JM, Margolin K, McDermott D, Clark J, Newman J, Bommareddy PK, Denzin L, Najmi S, Haider A, Shih W, Kane MP, Zloza A. High-Dose Ipilimumab and High-Dose Interleukin-2 for Patients With Advanced Melanoma. Front Oncol. 2020 Jan 10;9:1483. doi: 10.3389/fonc.2019.01483. eCollection 2019.

• Responsible Party: Janice Mehnert, MD, Associate Professor of Medicine; Director, Phase 1/Investigational Therapeutics, Rutgers Cancer Institute of New Jersey
• ClinicalTrials.gov Identifier: NCT02203604
• Other Study ID Numbers: 091309; NCI-2014-01306 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); CA184-084; 091309 ( Other Identifier: Rutgers Cancer Institute of New Jersey ); P30CA072720 ( U.S. NIH Grant/Contract ); Pro20140000135 ( Other Identifier: IRB number )
• First Posted: July 30, 2014
• Last Update Posted: June 19, 2020
• Last Verified: June 2020

Additional relevant MeSH terms:

Melanoma; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Aldesleukin; Antineoplastic Agents, Immunological; Ipilimumab; Interleukin-2; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Immunologic Factors; Physiological Effects of Drugs; Antineoplastic Agents; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents