This is an open-label, multi-cohort, 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).
Patients will be divided into two cohorts based on prior response to PD-1 monoclonal antibody
(mAb) therapy:
- Cohort 1 is for participants who are receiving a PD-1 mAb and have achieved either
stable disease or a partial response after approximately 6 months of PD-1 mAb therapy.
- Cohort 2 is for participants who previously had progressive disease when receiving a
PD-1 mAb.
Participants in cohort 1 will receive 4 cycles of nivolumab and ipilimumab followed by 15
cycles of nivolumab maintenance therapy (up to ~18 months of total treatment)
Participants in cohort 2 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. Participants in cohort 2 will receive up to ~
24 months of study treatment.
After completion of therapy (in either cohort), 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 32 people will participate in this research study, including
approximately 20 people in cohort 1 and 10-15 people in cohort 2.
Bristol Myers Squibb (BMS) is supporting this research study by providing the study drugs and
funding for the study.
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.
- Patients must have received a prior PD-1 monoclonal antibody, with the following
specific requirements for each cohort.
- Cohort 1
- Received 18-30 weeks of single-agent PD-1 mAb (with last dose within 12
weeks)
- Underwent a restaging PET scan 18-30 weeks after initiation of PD-1
monotherapy which demonstrated:
- Partial response or stable disease (based on Lugano criteria)
- Note: Patients achieving an indeterminate response based on LYRIC
criteria(23) on an initial staging PET scan are eligible if they
achieve stable disease (<10% increase in tumor burden and <50% decrease
in tumor burden) or a partial response on a subsequent staging PET
scan.
- Cohort 2
- Progression of disease or relapse following treatment with nivolumab or
pembrolizumab. Intervening treatments 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.
