Ipilimumab With or Without Nivolumab in Relapsed/Refractory cHL

• ClinicalTrials.gov Identifier: NCT04938232
• Recruitment Status: Active, not recruiting
• First Posted: June 24, 2021
• Last Update Posted: March 20, 2024
• Sponsor: Dana-Farber Cancer Institute
• Collaborator: Bristol-Myers Squibb
• Information provided by (Responsible Party): Reid Merryman, MD, Dana-Farber Cancer Institute

Tracking Information

• First Submitted Date: June 8, 2021
• First Posted Date: June 24, 2021
• Last Update Posted Date: March 20, 2024
• Actual Study Start Date: June 4, 2021
• Actual Primary Completion Date: March 1, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 6, 2023)

Overall response rate (ORR) after 4 cycles of ipilimumab monotherapy [ Time Frame: From enrollment to completion of 4 cycles (each cycle is 21 days) of treatment ]

Assessed by PET/CT (using Lugano criteria and LYRIC criteria)

Original Primary Outcome Measures (submitted: June 22, 2021)

• 6-month Progression Free Survival (PFS)-Cohort 1 [ Time Frame: 6 months ]
  6-month PFS (from initiation of combination therapy) assessed using Lugano criteria
• Overall response rate (ORR) after 4 cycles of ipilimumab monotherapy -Cohort 2 [ Time Frame: From enrollment to completion of 4 cycles (each cycle is 21 days) of treatment ]
  Assessed by PET/CT (using Lugano criteria and LYRIC criteria)

Current Secondary Outcome Measures (submitted: February 6, 2023)

• Overall response rate (ORR) Ipilimumab monotherapy [ Time Frame: 12 weeks ]
  Assessed by PET/CT (using Lugano criteria and LYRIC criteria) after ipilimumab monotherapy
• Partial Response rate (PRR) Ipilimumab monotherapy [ Time Frame: 12 weeks ]
  Assessed by PET/CT (using Lugano criteria and LYRIC criteria) after 4 ipilimumab monotherapy
• Complete Response rate (CRR) Ipilimumab monotherapy [ Time Frame: 12 weeks ]
  Assessed by PET/CT (using Lugano criteria and LYRIC criteria) after ipilimumab monotherapy
• Overall response rate (ORR) ipilimumab and nivolumab combination therapy [ Time Frame: 24 weeks ]
  Assessed by PET/CT (using Lugano criteria and LYRIC criteria) after ipilimumab and nivolumab combination therapy
• Partial Response rate (PRR) ipilimumab and nivolumab combination therapy [ Time Frame: 24 weeks ]
  Assessed by PET/CT (using Lugano criteria and LYRIC criteria) after ipilimumab and nivolumab combination therapy
• Complete Response rate (CRR) ipilimumab and nivolumab combination therapy [ Time Frame: 24 weeks ]
  Assessed by PET/CT (using Lugano criteria and LYRIC criteria) after ipilimumab and nivolumab combination therapy
• Duration of Response ipilimumab maintenance [ Time Frame: 2 years ]
  Using Lugano criteria and LYRIC criteria
• Duration of Response ipilimumab and nivolumab combination therapy [ Time Frame: 2 years ]
  Using Lugano criteria and LYRIC criteria
• Progression-free survival [ Time Frame: 2 years ]
  Lugano criteria and LYRIC criteria
• Overall Survival [ Time Frame: 2 years ]
  Lugano criteria and LYRIC criteria
• Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE Version 5.0 [ Time Frame: 2 years ]
  Descriptions and grading scales per NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0

Original Secondary Outcome Measures (submitted: June 22, 2021)

• Best Overall response rate (ORR)-Cohort 1 [ Time Frame: 2 years ]
  Assessed by PET/CT (using Lugano criteria and LYRIC criteria)
• Best Partial Response rate (PRR)-Cohort 1 [ Time Frame: 2 years ]
  Assessed by PET/CT (using Lugano criteria and LYRIC criteria)
• Best Complete Response rate (CRR)-Cohort 1 [ Time Frame: 2 years ]
  Assessed by PET/CT (using Lugano criteria and LYRIC criteria)
• 6-month progression-free survival Lyric Criteria-Cohort 1 [ Time Frame: 6 months ]
  6-month progression-free survival using Lyric Criteria
• Duration of response (DOR)-Cohort 1 [ Time Frame: 2 years ]
  Using Lugano criteria and LYRIC criteria
• Overall response rate (ORR) Ipilimumab monotherapy-Cohort 2 [ Time Frame: From enrollment to completion of 4 cycles (each cycle is 21 days) of treatment ]
  Assessed by PET/CT (using Lugano criteria and LYRIC criteria) after 4 cycles of ipilimumab monotherapy
• Partial Response rate (PRR) Ipilimumab monotherapy-Cohort 2 [ Time Frame: From enrollment to completion of 4 cycles (each cycle is 21 days) of treatment ]
  Assessed by PET/CT (using Lugano criteria and LYRIC criteria) after 4 cycles of ipilimumab monotherapy
• Complete Response rate (CRR) Ipilimumab monotherapy-Cohort 2 [ Time Frame: From enrollment to completion of 4 cycles (each cycle is 21 days) of treatment ]
  Assessed by PET/CT (using Lugano criteria and LYRIC criteria) after 4 cycles of ipilimumab monotherapy
• Overall response rate (ORR) ipilimumab and nivolumab combination therapy-Cohort 2 [ Time Frame: From enrollment to completion of 4 cycles (each cycle is 21 days) of monotherapy and 4 cycles (each cycle is 21 days) of combination therapy ]
  Assessed by PET/CT (using Lugano criteria and LYRIC criteria) after 4 cycles of ipilimumab and nivolumab combination therapy
• Partial Response rate (PRR) ipilimumab and nivolumab combination therapy-Cohort 2 [ Time Frame: From enrollment to completion of 4 cycles (each cycle is 21 days) of monotherapy and 4 cycles (each cycle is 21 days) of combination therapy ]
  Assessed by PET/CT (using Lugano criteria and LYRIC criteria) after 4 cycles of ipilimumab and nivolumab combination therapy
• Complete Response rate (CRR) ipilimumab and nivolumab combination therapy-Cohort 2 [ Time Frame: Approximately 24 weeks ]
  Assessed by PET/CT (using Lugano criteria and LYRIC criteria) after 4 cycles of ipilimumab and nivolumab combination therapy
• Duration of Response ipilimumab maintenance-cohort 2 [ Time Frame: 2 years ]
  Using Lugano criteria and LYRIC criteria
• Duration of Response ipilimumab and nivolumab combination therapy-cohort 2 [ Time Frame: 2 years ]
  Using Lugano criteria and LYRIC criteria
• Progression-free survival-Cohort 2 [ Time Frame: 2 years ]
  Lugano criteria and LYRIC criteria
• Overall Survival-Cohort 1 [ Time Frame: 2 years ]
  Lugano criteria and LYRIC criteria
• Overall Survival-Cohort 2 [ Time Frame: 2 years ]
  Lugano criteria and LYRIC criteria
• Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE Version 5.0-Cohort 2 [ Time Frame: 2 years ]
  Descriptions and grading scales per NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
• Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE Version 5.0-Cohort 1 [ Time Frame: 2 years ]
  Descriptions and grading scales per NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0

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

Descriptive Information

• Brief Title: Ipilimumab With or Without Nivolumab in Relapsed/Refractory cHL
• Official Title: A Phase II Trial of Ipilimumab With and Without Nivolumab in Patients With Relapsed/Refractory Classic Hodgkin Lymphoma

Brief Summary

This study is looking at the effects of Ipilimumab when it is given alone or in combination with Nivolumab to patients with relapsed or refractory classic Hodgkin's lymphoma (cHL).

The names of the study drugs involved in this study are:

• Ipilimumab
• Nivolumab

Detailed Description

This is an open-label, multi-center, phase II study of ipilimumab with or without nivolumab for patients with relapsed or refractory (R/R) classic Hodgkin lymphoma (cHL).

Nivolumab is a drug which is approved by the United States Food and Drug Administration (FDA) for the treatment of adult patients experiencing relapsed Hodgkin lymphoma (cHL) who have received at least two prior systemic therapies.

Ipilimumab has been approved by the FDA for the treatment of metastatic melanoma (a type of skin cancer), and specific types of previously treated advanced kidney cancers.

The study drugs have not been approved in combination for cHL by the Food and Drug Administration (FDA). This study is for participants who previously had progressive disease when receiving a PD-1 mAb.

Participants will receive 4 cycles of ipilimumab monotherapy and then undergo restaging imaging. Patients who achieved an objective response will continue treatment with ipilimumab maintenance. Other patients will receive 4 cycles of nivolumab and ipilimumab followed by ipilimumab maintenance treatment. Patients who have progressive disease after fewer than 4 cycles of ipilimumab are eligible to proceed to combination therapy with nivolumab and ipilimumab if they are clinically stable. Participants will receive up to ~ 24 months of study treatment.

After completion of therapy, participants will be followed every 3 months for 2 years and then every 6 months for the next 5 years.

It is expected that about 13 people will participate in this research study.

Bristol Myers Squibb (BMS) is supporting this research study by providing the study drugs and funding for the study.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Hodgkin Lymphoma
• Relapsed Hodgkin's Disease, Adult
• Refractory Hodgkin Lymphoma

Intervention

• Drug: Nivolumab
  Intravenous infusion
  Other Name: Opdivo
• Drug: Ipilimumab
  Intravenous infusion
  Other Name: Yervoy

Study Arms

Experimental: Disease Progression after previous therapy

Participants will receive Ipilimumab alone and depending on response will receive either a maintenance course of Ipilimumab or a course of Nivolumab and Ipilimumab in combination followed by a maintenance course of Ipilimumab. Patients who have progressive disease after fewer than 4 cycles of ipilimumab are also eligible to proceed to combination therapy with nivolumab and ipilimumab, if they are clinically stable.

• Ipilimumab Monotherapy: Every 3 weeks for 4 study cycles
• Complete Response/Partial Response: Maintenance Ipilimumab every 12 weeks for 8 cycles
• Stable or Progressive Disease Response: Nivolumab and Ipilimumab every 3 weeks for 4 study cycles, followed by Maintenance Ipilimumab every 12 weeks for 7 cycles

Interventions:

• Drug: Nivolumab
• Drug: Ipilimumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: February 6, 2023): 13
• Original Estimated Enrollment (submitted: June 22, 2021): 32
• Estimated Study Completion Date: August 1, 2026
• Actual Primary Completion Date: March 1, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Patients must have histologically determined classic Hodgkin lymphoma with pathologic review at the participating institution.
• Participants must have measurable disease, defined as a lymph node or tumor mass ≥1.5 cm in at least one dimension by CT, PET/CT, or MR. Imaging must have been completed no greater than 6 weeks prior to study enrollment. Measurable disease that has previously been irradiated is permissible only if there has been evidence of progression since the radiation.
• Patients must have progressed after two or more lines of systemic treatment, including autologous stem cell transplantation, if eligible.
• Progression of disease or relapse following treatment with nivolumab or pembrolizumab. Intervening treatments with between PD-1 mAb therapy and the trial are permitted.
• Patients may have had a prior autologous stem cell transplant and may have been treated with chimeric antigen receptor T-cells (CAR T-cells).
• Age ≥18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (see Appendix A)

• Adequate hematologic and organ function as defined below:

  • Absolute neutrophil count > 1.0x109/L unless due to marrow involvement by lymphoma in which case ANC must be >0.75x109/L. Growth factor support is allowed provided it is received at least 5 days prior to enrollment labs.
  • Platelets > 75 x109/L, unless due to marrow involvement by lymphoma, in which case platelets must be >50 x109/L
  • Estimated GFR (by Cockroft-Gault equation) > 40ml/min
  • Total bilirubin < 1.5 X ULN
  • AST/ALT < 2.5 X ULN
• Ability to understand and the willingness to sign a written informed consent document.
• Willingness to provide pre-treatment tumor sample by core needle or excisional surgical biopsy. An archival sample is acceptable in the following situations: the sample was acquired within 90 days of initiation of PD-1 therapy AND the following provisions are met: 1) availability of a tumor-containing formalin fixed, paraffin embedded (FFPE) tissue block, 2) if the tumor containing FFPE tissue block cannot be provided in total, sections from this block should be provided that are freshly cut and mounted on positively charged glass slides (SuperFrost Plus are recommended). Preferably, 25 slides should be provided; if not possible, a minimum of 15 slides is required. Exceptions to this criterion may be made with approval of the Study Chair.
• Willingness to use contraception during and after study treatment. Women of child-baring potential (WOCBP) will be instructed to adhere to contraception for a period of 5 months following last dose of nivolumab and 6 months following the last dose of ipilimumab. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 7 months after last dose of nivolumab and 6 months after the last dose of ipilimumab.

Exclusion Criteria:

• Patients currently receiving anticancer therapies or who have received anticancer therapies within 28 days of the start of study drug (including chemotherapy, radiation therapy, antibody-based therapy, etc.), or 56 days for radioimmunotherapy. Steroids for symptom palliation are allowed but must be either discontinued or on stable doses of < 10mg daily of prednisone (or the equivalent) at the time of initiation of protocol therapy.
• Patients may not be receiving any other investigational agents or have received investigational agents within 4 weeks (or 3 half-lives, whichever is longer) of beginning treatment.
• History of severe allergic or anaphylactic reactions to monoclonal antibody therapy unless in consultation with an allergy specialist they are deemed eligible for retreatment with desensitization.
• Patients who have undergone prior allogeneic stem cell transplantation
• Patients with a history of or active autoimmune disease (except controlled asthma, Hashimoto thyroiditis, atopic dermatitis, or vitiligo), or requiring systemic corticosteroids at a dose of 10mg prednisone equivalent daily. Patients with a history of autoimmune disease who never required corticosteroids and with no evidence of disease activity, and in whom the risk of reactivation is felt not to be serious, may be enrolled after discussion with the overall study chair. Exceptions to this are patients with a history of inflammatory bowel disease (ulcerative colitis and Crohn's disease). These patients are excluded regardless of whether their disease is active or inactive.
• Patients who experienced grade 4 immune-related adverse events (irAEs) during treatment with a PD-1 mAb.
• Patients with active pneumonitis or colitis, or patients with cirrhosis.
• Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia).
• Patients with known HIV infection or hepatitis B or C infection. Testing for HIV is optional. Testing for hepatitis B and C is mandatory. Patients with hepatitis B core Ab positivity but negative surface antigen and negative viral load may be enrolled if they can be treated with a prophylactic agent (eg, entecavir); patients with hepatitis C seropositivity who have a negative viral load can also be enrolled.
• Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).
• Prior history of another malignancy (except for non-melanoma skin cancer or in situ cervical or breast cancer) unless disease free for at least 2 years. Patients with prostate cancer are allowed if PSA is less than 1.
• Patients should not have received immunization with attenuated live vaccine within one week of study entry or during study period.
• History of noncompliance to medical regimens.
• Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study.
• Patients with any one of the following currently on or in the previous 6 months will be excluded: myocardial infarction, congenital long QT syndrome, torsade de pointes, left anterior hemiblock, unstable angina, coronary/peripheral artery bypass graft, or cerebrovascular accident.
• Other uncontrolled intercurrent illness that would limit adherence to study requirements.

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: NCT04938232
• Other Study ID Numbers: 21-204
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

• Current Responsible Party: Reid Merryman, MD, Dana-Farber Cancer Institute
• Original Responsible Party: Reid Merryman, Dana-Farber Cancer Institute, Principal Investigator
• Current Study Sponsor: Dana-Farber Cancer Institute
• Original Study Sponsor: Same as current
• Collaborators: Bristol-Myers Squibb

Investigators

• Principal Investigator: Reid W Merryman, MD; Dana-Farber Cancer Institute

• PRS Account: Dana-Farber Cancer Institute
• Verification Date: March 2024