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

• ClinicalTrials.gov Identifier: NCT02731729
• Recruitment Status: Completed
• First Posted: April 7, 2016
• Results First Posted: February 21, 2021
• Last Update Posted: December 23, 2022
• Sponsor: Parker Institute for Cancer Immunotherapy
• Collaborator: Bristol-Myers Squibb
• Information provided by (Responsible Party): Parker Institute for Cancer Immunotherapy

Tracking Information

• First Submitted Date: April 4, 2016
• First Posted Date: April 7, 2016
• Results First Submitted Date: January 12, 2021
• Results First Posted Date: February 21, 2021
• Last Update Posted Date: December 23, 2022
• Actual Study Start Date: June 21, 2016
• Actual Primary Completion Date: August 27, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 2, 2021)

Overall Response Rate (ORR) as Defined by RECIST v1.1 at Week 18 [ Time Frame: 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.

Original Primary Outcome Measures (submitted: April 6, 2016)

objective response as defined by RECIST v1.1 criteria [ Time Frame: week 18 ]

as defined by RECIST v1.1 criteria by week 18.

Current Secondary Outcome Measures (submitted: February 2, 2021)

• Disease Control Rate (DCR) Status at Week 18 [ Time Frame: 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.
• Time to Treatment Failure (TTF) [ Time Frame: The time from treatment initiation until a subsequent therapy is started or death. ]
  Time to Treatment Failure is defined as the time from treatment initiation until the participant starts a subsequent therapy or death, whichever comes first.
• Overall Survival (OS) [ Time Frame: Death ]
  Overall Survival is defined as the time of treatment initiation to death by any cause
• Number of Participants With Grade 3 or 4 Adverse Events [ Time Frame: AE were monitored during each treatment cycle and could be reported until 30 days after the last dose of study treatment had been administered. ]
  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.
• Disease Control Rate (DCR) Status at Week 12 [ Time Frame: 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.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Ipilimumab vs Ipilimumab Plus Nivolumab in Patients With Stage III-IV Melanoma Who Have Progressed or Relapsed on PD-1 Inhibitor Therapy
• Official Title: 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
• Brief Summary: 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®).
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Melanoma

Intervention

• Drug: ipilimumab
  Other Name: Yervoy
• Drug: nivolumab
  Other Name: Opdivo

Study Arms

• 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.
  Interventions:

  • Drug: ipilimumab
  • Drug: nivolumab
• 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.
  Intervention: Drug: ipilimumab

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 2, 2021): 20
• Original Estimated Enrollment (submitted: April 6, 2016): 70
• Actual Study Completion Date: February 13, 2019
• Actual Primary Completion Date: August 27, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02731729
• Other Study ID Numbers: PICI0001; 16-043 ( Other Identifier: Memorial Sloan Kettering Cancer Center )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Parker Institute for Cancer Immunotherapy
• Original Responsible Party: Memorial Sloan Kettering Cancer Center
• Current Study Sponsor: Parker Institute for Cancer Immunotherapy
• Original Study Sponsor: Memorial Sloan Kettering Cancer Center
• Collaborators: Bristol-Myers Squibb

Investigators

• Study Director: Ramy Ibrahim, MD; Parker Institute for Cancer Immunotherapy

• PRS Account: Parker Institute for Cancer Immunotherapy
• Verification Date: December 2022