Ipilimumab vs Ipilimumab Plus Nivolumab in Patients With Stage III-IV Melanoma Who Have Progressed or Relapsed on PD-1 Inhibitor Therapy

A Randomized, Phase 2 Study of Ipilimumab vs Ipilimumab Plus Nivolumab in Patients With Stage III-IV Melanoma Who Have Progressed or Relapsed on PD-1 Inhibitor Therapy

The purpose of this research study is to learn whether patients whose disease grows after being treated with nivolumab or pembrolizumab respond to ipilimumab (Yervoy®) alone or in combination with nivolumab (Opdivo®).

Study Overview

• Status: Completed
• Conditions: Melanoma
• Intervention / Treatment: Drug: ipilimumab; Drug: nivolumab

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California, Los Angeles
    • San Francisco, California, United States, 94134
      • University of California, San Francisco
  • New Jersey
    • Basking Ridge, New Jersey, United States, 07920
      • Memorial Sloan Kettering Basking Ridge
  • New York
    • Harrison, New York, United States, 10604
      • Memorial Sloan Kettering Westchester
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18103
      • Lehigh Valley Health Network
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Main Inclusion Criteria:

1. American Joint Committee on Cancer (AJCC) (2009) Stage IV cutaneous melanoma or Stage III cutaneous, acral or mucosal melanoma that is judged inoperable. Patients with a history of uveal melanoma are not eligible.
2. Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >20 mm with conventional techniques or as >10 mm with computerized tomography (CT) scan. Patients must have at least one measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST) and a separate lesion amenable to biopsy.
3. Histologic proof of melanoma reviewed and confirmed by the enrolling site.
4. Previous treatment with a programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor with documented progression of disease on most recent CT scan. Progression of disease is defined as 1) the appearance of a new measureable lesion (>10 mm) on cross-sectional imaging or physical examination OR 2) enlargement of previously detected lesions on two consecutive imaging studies OR 3) enlargement of a previously detected lesion with correlative symptomatology on one cross-sectional imaging study. Patients remain eligible if they had a previous response to a PD-1 inhibitor, including patients who had a complete response, partial response or stable disease (SD). Primary progressing patients are defined as those who received anti-PD-1 therapy within 2 months of study enrollment. Patients with relapsed disease are defined as those who received their last dose of PD-1 blocking antibody ≥2 months prior to enrollment.
5. Patients who received adjuvant PD-1 therapy who then develop measurable disease are eligible. However, they must have received their last dose of PD-1/PD-L1 blockade within two months of enrollment in this study. They will be stratified with patients who have primary progressive disease.
6. Life expectancy of greater than 3 months.
7. Age ≥ 18 years old.
8. Eastern Cooperative Oncology Group performance status = 0 or 1 or Karnofsky Performance Status equivalent.

9. Patients must have adequate organ and marrow function as defined below:

   1. White blood cells >2, 000/microliter (mcL)
   2. Absolute neutrophil count >1,500/mcL
   3. Platelets >100,000/mcL
   4. Hemoglobin > 9.0 g/dL
   5. Total bilirubin ≤ 1.5 X institution's upper limit of normal
   6. Aspartate aminotransferase (serum glutamic oxaloacetic transaminase)/alanine aminotransferase (serum glutamic pyruvic transaminase) ≤ 2.5 X institution's upper limit of normal for patients with no concurrent liver metastases, OR ≤ 5 X institution's upper limit of normal for patients with concurrent liver metastases
   7. Serum creatinine < 1.5x OR creatinine clearance of at least 40
10. Women of childbearing potential must have a negative serum pregnancy test within 24 hours prior to the start of study drug. A woman of childbearing potential is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over age 50 in the absence of other biologic or physiologic causes.
11. Women with child bearing potential and men with reproductive potential must be willing to practice acceptable methods of contraception.
12. Ability to understand and the willingness to sign a written informed consent document.
13. Willingness to undergo biopsy of metastatic site or site of unresectable disease prior to randomization.

Main Exclusion Criteria:

1. History of another malignancy except for those who have been disease-free for 3 years, or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent secondary malignancies not requiring active therapy, are eligible. Consult the study Medical Monitor if unsure whether second malignancies meet the requirements specified above.
2. Any major surgical procedures or external beam radiotherapy within 14 days prior to study drug administration.
3. Use of other investigational drugs within 28 days prior to study drug administration.
4. Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression. Treated brain metastases must have been stable for at least 1 month and require treatment with less than 10mg/day prednisone equivalent for at least 2 weeks prior to study drug administration.
5. Prior exposure to either ipilimumab or combined checkpoint blockade.
6. Any diagnosis of autoimmune disease. Patients with Type I diabetes mellitus, hypothyroidism only requiring hormone replacement, adrenal insufficiency on replacement dose steroids, skin disorders (such as vitiligo, psoriasis or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
7. Pregnant women and lactating women.
8. History of uveal melanoma.
9. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (with the exception of chronic or cleared HBV or HCV infection, which will be allowed). Once-documented negative result for HIV, HBV, and HCV is sufficient.
10. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection and psychiatric illness/social situations that would limit compliance with study requirements.
11. Patients with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalent are permitted.
12. Patients with history of any grade 4 toxicity during previous anti PD-1 treatment or history of Grade 3 or higher pneumonitis.
13. Patients with a history of Grade ≥2 neuropathy.
14. Prisoners or patients who are involuntarily incarcerated.
15. Children under the age of 18.
16. Patients who require hemodialysis.
17. Patients with a history of allergy to study drug components or history of a severe hypersensitivity reaction to any monoclonal antibody.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ipilimumab and nivolumab; For patients in the combination arm, nivolumab will first be administered intravenously at a dose of 1 mg/kg of body weight over a period of 60 minutes, once every 3 weeks for four doses. Thirty minutes after the completion of each nivolumab infusion, patients will receive 3 mg/kg of ipilimumab over a period of 30 minutes.	Drug: ipilimumab; Other Names: Yervoy; Drug: nivolumab; Other Names: Opdivo
Experimental: ipilimumab; In the ipilimumab monotherapy group, patients will receive 3 mg/kg of ipilimumab over a period of 30 minutes once every 3 weeks for four doses.	Drug: ipilimumab; Other Names: Yervoy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR) as Defined by RECIST v1.1 at Week 18	Overall Response Rate was defined as any participant who had a Complete Response (CR) or Partial Response (PR) as defined by RECIST v1.1 by week 18 of treatment.	Week 18

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease Control Rate (DCR) Status at Week 18	Disease Control Rate was defined as any participant who achieved a complete response (CR), partial response (PR), or who remained stable (SD) as defined in Recist v1.1 at week 18.	Week 18
Time to Treatment Failure (TTF)	Time to Treatment Failure is defined as the time from treatment initiation until the participant starts a subsequent therapy or death, whichever comes first.	The time from treatment initiation until a subsequent therapy is started or death.
Overall Survival (OS)	Overall Survival is defined as the time of treatment initiation to death by any cause	Death
Number of Participants With Grade 3 or 4 Adverse Events	The occurrence of Grade 3 and Grade 4 adverse events (AE) assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	AE were monitored during each treatment cycle and could be reported until 30 days after the last dose of study treatment had been administered.
Disease Control Rate (DCR) Status at Week 12	Disease Control Rate was defined as any participant who achieved a complete response (CR), partial response (PR), or who remained stable (SD) as defined in Recist v1.1 at week 12.	Week 12

Collaborators and Investigators

• Sponsor: Parker Institute for Cancer Immunotherapy
• Collaborators: Bristol-Myers Squibb
• Investigators: Study Director: Ramy Ibrahim, MD, Parker Institute for Cancer Immunotherapy

Publications and helpful links

General Publications

• Friedman CF, Spencer C, Cabanski CR, Panageas KS, Wells DK, Ribas A, Tawbi H, Tsai K, Postow M, Shoushtari A, Chapman P, Karakunnel J, Bucktrout S, Gherardini P, Hollmann TJ, Chen RO, Callahan M, LaVallee T, Ibrahim R, Wolchok J. Ipilimumab alone or in combination with nivolumab in patients with advanced melanoma who have progressed or relapsed on PD-1 blockade: clinical outcomes and translational biomarker analyses. J Immunother Cancer. 2022 Jan;10(1):e003853. doi: 10.1136/jitc-2021-003853.

Helpful Links

• Memorial Sloan Kettering Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): June 21, 2016
• Primary Completion (Actual): August 27, 2018
• Study Completion (Actual): February 13, 2019

Study Registration Dates

• First Submitted: April 4, 2016
• First Submitted That Met QC Criteria: April 6, 2016
• First Posted (Estimate): April 7, 2016

Study Record Updates

• Last Update Posted (Estimate): December 23, 2022
• Last Update Submitted That Met QC Criteria: December 21, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: Nivolumab; Ipilimumab; Stage III-IV Melanoma; Progressed or Relapsed on PD-1 Inhibitor Therapy; 16-043
• 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; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab; Ipilimumab
• Other Study ID Numbers: PICI0001; 16-043 (Memorial Sloan Kettering Cancer Center)