Study of Combination of Ipilimumab and Nivolumab in Patients With Melanoma

• Sponsor: NYU Langone Health (Other)
• Overall Status: Completed
• CT.gov ID: NCT02970981
• Collaborator: Bristol-Myers Squibb (Industry)
• Enrollment: 19
• Location: 1
• Arm: 1
• Actual Duration (Months): 65.1
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the safety and tolerability of treatment with Nivolumab in combination with Ipilimumab in subjects with resected Stages IIIB/IIIC/ IV melanoma.

Condition or Disease	Intervention/Treatment	Phase
Melanoma	Biological: Nivolumab; Biological: Ipilimumab	Phase 2

Detailed Description

The investigators hypothesize that PD-1 blockade combined with CTLA-4 blockade using ipilimumab would have a favorable effect on the expansion and activity of human CD8+ T cytotoxic lymphocytes (CTLs) specific for tumor-associated antigens (ie, self antigens), which would translate into improved anti-cancer therapy.

Study Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Trial of Ipilimumab With Nivolumab for Participants With Resected Stages IIIB/IIIC/ IV Melanoma
• Actual Study Start Date: Nov 29, 2016
• Actual Primary Completion Date: Nov 1, 2018
• Actual Study Completion Date: May 2, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Nivolumab and Ipilimumab Dosing during cycle 1 will consist of: 3 mg/kg of Nivolumab+ Ipilimumab at 1 mg/kg. Each induction treatment cycle is comprised of 4 doses of Nivolumab and 4 doses of Ipilimumab given every three weeks for a total of 12 weeks (cycle 1) Dosing during cycles 2-5 will consist of flat dose Nivolumab at 480 mg every 4 weeks (Q4W) for 48 weeks.	Biological: Nivolumab; Other Names: Opdivo NSC 748726 ; Biological: Ipilimumab; Other Names: Yervoy NSC 732442

Outcome Measures

Primary Outcome Measures

1. Number of Cases of Adverse Events Occurring During Study [12 weeks post-treatment start]

   The adverse events are evaluated per Common Terminology Criteria for Adverse Events (CTCAE) V4.

Secondary Outcome Measures

1. Time to Relapse [Up to 4 years]

   Time to relapse will be reported (in months post-treatment) to assess the preliminary efficacy of the study drugs.

2. Immune Response Assessment [12 Weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Be at least 16 years of age;

• Histologic diagnosis of resected Stages IIIB/IIIC/ IV melanoma, with no evidence of disease clinically and radiologically, and negative surgical margins. All melanomas regardless of primary site of disease will be allowed;

• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.

• Prior chemotherapy or immunotherapy (tumor vaccine, cytokine, or growth factor given to control the cancer) must have been completed at least 4 weeks before study drug administration, and all adverse events have either returned to baseline or stabilized;

• Prior treated brain or meningeal metastases must be without magnetic resonance imaging (MRI) evidence of progression for at least 8 weeks and off immunosuppressive doses of systemic steroids (> 10 mg/day prednisone or equivalent) for at least 2 weeks before study drug administration;

• Prior systemic radiation therapy must have been completed at least 4 weeks before study drug administration. Prior focal radiotherapy completed at least 2 weeks before study drug administration. No radiopharmaceuticals (strontium, samarium) within 8 weeks before study drug administration;

• Immunosuppressive doses of systemic medications, such as steroids or absorbed topical steroids (doses > 10 mg/day prednisone or equivalent) must be discontinued at least 2 weeks before study drug administration;

• Completed nitrosourea treatment at least 6 weeks before administration of any study drug;

• 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 and subjects should be recovered;

• Screening laboratory values must meet the following criteria:

white blood cells (WBCs) ≥ 2000 cells/μL

• neutrophils ≥ 1500 cells/μL

• platelets ≥ 100 x 103/μL

• hemoglobin ≥ 9.0 g/dL

• serum creatinine ≤ 2 mg/dL

• AST ≤ 2.5 x upper limit of normal (ULN) without, and ≤ 5 x ULN with hepatic metastasis

• ALT ≤ 2.5 x ULN without, and ≤ 5 x ULN with hepatic metastasis

• bilirubin ≤ 2 x ULN (except subjects with Gilbert's syndrome, who must have total bilirubin < 3.0 mg/dL)

• Females of childbearing potential must:

• use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug.

• Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of nivolumab.

• For female subjects to be considered as not having childbearing potential, they must meet 1 or more of the following criteria:

• postmenopausal for at least 24 consecutive months;

• surgically sterile (ie, have had a hysterectomy or bilateral oophorectomy);

• females with irregular menstrual periods and/or on hormone replacement therapy must have a documented serum follicle stimulating hormone level > 35 mIU/mL;

• Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception.

• Subject must have read, understood, and provided written informed consent and HIPAA authorization after the nature of the study has been fully explained; and

• Willing to adhere to the study visit schedule and the prohibitions and restrictions specified in this protocol.

Exclusion Criteria:

• Subjects who fulfill any of the following conditions at Screening will not be eligible for admission into the study:

• History of severe hypersensitivity reactions to other mAbs;

• Prior non-melanoma malignancy active within the previous 2 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix or breast;

• Subjects with any active autoimmune disease (Appendix 3) or a documented history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications, except for subjects with vitiligo or resolved childhood asthma/atopy;

• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS);

• Positive tests for hepatitis B virus surface antigen (HBV SAg) or hepatitis C virus ribonucleic acid (HCV RNA) indicating active or chronic infection;

• Prior therapy with an anti-PD-1, anti-PD-L1, anti-PDL-2, or anti-CTLA-4 antibody (or any other antibody targeting T cell co-stimulation pathways);

• Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids;

• Underlying medical condition (eg, a condition associated with diarrhea) that, in the Investigator's opinion, would make the administration of either study drug or both study drugs hazardous to the subject or obscure the interpretation of toxicity determination or adverse events;

• Pregnant or nursing; or

• Current participation in another clinical study involving treatment with medications, radiation or surgery, or prior participation in this study.

• Patients are excluded if they have active brain metastases or leptomeningeal metastases. Subjects with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for [lowest minimum is 4 weeks or more] after treatment is complete and within 28 days prior to the first dose of nivolumab administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration.

As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab combinations, drugs with a predisposition to hepatoxicity should be used with caution in patients treated with nivolumab-containing regimen.

• Allergies and Adverse Drug Reaction

1. History of allergy to study drug components

2. History of severe hypersensitivity reaction to any monoclonal antibody

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Laura and Isaac Perlmutter Cancer Center	New York	New York	United States	10016

Sponsors and Collaborators

• NYU Langone Health
• Bristol-Myers Squibb

Investigators

• Principal Investigator: Jeffrey S Weber, MD, PhD, NYU Perlmutter Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 10, 2017

More Information

Publications

None provided.

• Responsible Party: NYU Langone Health
• ClinicalTrials.gov Identifier: NCT02970981
• Other Study ID Numbers: 16-00098
• First Posted: Nov 22, 2016
• Last Update Posted: Aug 15, 2022
• Last Verified: Aug 1, 2022

• 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
• Keywords provided by NYU Langone Health: Monoclonal antibody; Programmed Death-1 (PD-1); Programmed Death-Ligand 1 (PD-L1); Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4); Antigen
• Additional relevant MeSH terms: Melanoma; Nivolumab; Ipilimumab

Study Results

Participant Flow

Arm/Group Title	Nivolumab and Ipilimumab
Arm/Group Description	Dosing during cycle 1 will consist of: 3 mg/kg of Nivolumab+ Ipilimumab at 1 mg/kg. Each induction treatment cycle is comprised of 4 doses of Nivolumab and 4 doses of Ipilimumab given every three weeks for a total of 12 weeks (cycle 1) Dosing during cycles 2-5 will consist of flat dose Nivolumab at 480 mg every 4 weeks (Q4W) for 48 weeks. Nivolumab Ipilimumab
Period Title: Overall Study
STARTED	16
COMPLETED	16
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Nivolumab and Ipilimumab
Arm/Group Description	Dosing during cycle 1 will consist of: 3 mg/kg of Nivolumab+ Ipilimumab at 1 mg/kg. Each induction treatment cycle is comprised of 4 doses of Nivolumab and 4 doses of Ipilimumab given every three weeks for a total of 12 weeks (cycle 1) Dosing during cycles 2-5 will consist of flat dose Nivolumab at 480 mg every 4 weeks (Q4W) for 48 weeks. Nivolumab Ipilimumab
Overall Participants	16
Age, Customized (Count of Participants)
>= 16 years	16 100%
Sex: Female, Male (Count of Participants)
Female	2 12.5%
Male	14 87.5%
Race and Ethnicity Not Collected (Count of Participants)
Disease Stage at Entry (Count of Participants)
IIIB	6 37.5%
IIIC	5 31.3%
IV	4 25%
IIB	1 6.3%

Outcome Measures

1. Primary Outcome

Title	Number of Cases of Adverse Events Occurring During Study
Description	The adverse events are evaluated per Common Terminology Criteria for Adverse Events (CTCAE) V4.
Time Frame	12 weeks post-treatment start

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nivolumab and Ipilimumab
Arm/Group Description	Dosing during cycle 1 will consist of: 3 mg/kg of Nivolumab+ Ipilimumab at 1 mg/kg. Each induction treatment cycle is comprised of 4 doses of Nivolumab and 4 doses of Ipilimumab given every three weeks for a total of 12 weeks (cycle 1) Dosing during cycles 2-5 will consist of flat dose Nivolumab at 480 mg every 4 weeks (Q4W) for 48 weeks. Nivolumab Ipilimumab
Measure Participants	16
Number [cases of adverse events]	238

2. Secondary Outcome

Title	Time to Relapse
Description	Time to relapse will be reported (in months post-treatment) to assess the preliminary efficacy of the study drugs.
Time Frame	Up to 4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Immune Response Assessment
Time Frame	12 Weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	12 weeks post-treatment
Arm/Group Title	Nivolumab and Ipilimumab
Arm/Group Description	Dosing during cycle 1 will consist of: 3 mg/kg of Nivolumab+ Ipilimumab at 1 mg/kg. Each induction treatment cycle is comprised of 4 doses of Nivolumab and 4 doses of Ipilimumab given every three weeks for a total of 12 weeks (cycle 1) Dosing during cycles 2-5 will consist of flat dose Nivolumab at 480 mg every 4 weeks (Q4W) for 48 weeks. Nivolumab Ipilimumab
All Cause Mortality
	Nivolumab and Ipilimumab
	Affected / at Risk (%)	# Events
Total	0/16 (0%)
Serious Adverse Events
	Nivolumab and Ipilimumab
	Affected / at Risk (%)	# Events
Total	4/16 (25%)
Blood and lymphatic system disorders
Hyponatremia	1/16 (6.3%)	1
Gastrointestinal disorders
Enterocolitis	1/16 (6.3%)	1
Diarrhea	1/16 (6.3%)	1
General disorders
Fever	1/16 (6.3%)	1
Fatigue	1/16 (6.3%)	1
Musculoskeletal and connective tissue disorders
Generalized Muscle Weakness	1/16 (6.3%)	1
Other (Not Including Serious) Adverse Events
	Nivolumab and Ipilimumab
	Affected / at Risk (%)	# Events
Total	16/16 (100%)
Blood and lymphatic system disorders
Anemia	4/16 (25%)
Edema	2/16 (12.5%)
Decrease in platelet count	1/16 (6.3%)
Eye disorders
Conjunctivitis	1/16 (6.3%)
Green floater in eye	1/16 (6.3%)
Gastrointestinal disorders
Abdominal Pain	3/16 (18.8%)
Bloating	2/16 (12.5%)
Constipation	2/16 (12.5%)
Diarrhea	6/16 (37.5%)
Enterocolitis	2/16 (12.5%)
GERD	2/16 (12.5%)
Loose stool	7/16 (43.8%)
Mucositis oral	1/16 (6.3%)
Vomiting	4/16 (25%)
General disorders
Increase in Alkalina Phosphatase	1/16 (6.3%)
Allergic rhinitis	2/16 (12.5%)
Blurred vision	2/16 (12.5%)
Chills	3/16 (18.8%)
Dehydration	1/16 (6.3%)
Dry mouth	2/16 (12.5%)
Fever	2/16 (12.5%)
Alopecia	1/16 (6.3%)
Malaise	1/16 (6.3%)
Nasal congestion	5/16 (31.3%)
Non productive cough	1/16 (6.3%)
Nausea	6/16 (37.5%)
General pain	9/16 (56.3%)
Productive cough	2/16 (12.5%)
Hepatobiliary disorders
Increase in alanine aminotransferase	3/16 (18.8%)
Infections and infestations
Sore throat	3/16 (18.8%)
Metabolism and nutrition disorders
Increase in Creatinine	1/16 (6.3%)
Musculoskeletal and connective tissue disorders
Cramping	2/16 (12.5%)
Hernia	1/16 (6.3%)
Myalgia	5/16 (31.3%)
Psychiatric disorders
Anorexia	1/16 (6.3%)
Renal and urinary disorders
Urinary urgency	1/16 (6.3%)
Respiratory, thoracic and mediastinal disorders
Chest wall discomfort	1/16 (6.3%)
Skin and subcutaneous tissue disorders
Papulopostular rash	3/16 (18.8%)
Pruritis	16/16 (100%)	17
Rash maculopapular	16/16 (100%)	30

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.