Trial Title:
Evaluating Combination of Nivolumab and Axatilimab in Patients With Relapsed/Refractory Classical Hodgkin Lymphoma
NCT ID:
NCT05723055
Condition:
Hodgkin Lymphoma
Conditions: Official terms:
Lymphoma
Hodgkin Disease
Nivolumab
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Suspended
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Axatilimab
Description:
Axatilimab (SNDX-6352) is a humanized IgG4 monoclonal antibody (mAb) with high affinity
against colony stimulating factor-1 receptor (CSF-1R).
Arm group label:
Treatment: All Patients
Other name:
SNDX6532
Intervention type:
Drug
Intervention name:
Nivolumab
Description:
Nivolumab is a programmed death receptor-1 (PD-1)-blocking antibody
Arm group label:
Treatment: All Patients
Other name:
OPDIVO
Summary:
The goal of this clinical trial is to study the combination of nivolumab and axatilimab
in patients with relapsed/refractory classical Hodgkin Lymphoma. This study will mainly
look at if the combination works as expected.
Detailed description:
This study is a phase II, proof-of concept, prospective, multi-center study of
combination of nivolumab and Axatilimab (SNDX-6352) in subjects with relapsed/refractory
classical Hodgkin lymphoma. Nine evaluable patients will be enrolled and receive
Axatilimab 3mg/kg Q4 weeks in combination with nivolumab 480mg Q4 weeks. If more than one
DLT is observed during the DLT period (first two cycles) in the first 6 patients, the
study drug dose will be reduced to 2mg/kg and additional patients (up to 6 at 2mg/kg
dose) may be included to the study. This could result in maximum 12 patients for the
entire study. The combination of Nivolumab and Axatilimab will be continued until
progression/toxicity or a maximum of 12 months of treatment. The investigators expect
that in patients who respond to this combination, the tumor microenvironment will shift
towards immunocompetent phenotype within a few months of combination treatment. Thus,
there may not be further benefit of continuing the combination for more than 12 months.
If patients have responded to the combination, patients are able to continue anti-PD(L)1
off-study after 12 months as their tumor microenvironment might have reset for it to work
better.
Safety Run-In A total of 6 to 9 subjects may be evaluated in Part 1 depending on the
frequency of DLTs and the need for dose reductions. A dose de-escalation design will be
used to determine the recommended phase 2 dose, while ensuring the safety and
tolerability of the treatment. In this trial, the dose determined to be the maximum
tolerated dose will be the recommended phase 2 dose for a potential future study. The
study may test two dose levels of Axatilimab (SNDX-6352) as described in the protocol.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Subject aged ≥ 18 years.
- Histologically confirmed relapsed or refractory Classical Hodgkin Lymphoma who have
progressed on or after at least one line of prior therapy and have had prior
exposure to anti-PD-1/anti-PDL-L1 therapy
- Partial response or stable disease after at least 4 cycles of anti-PD-1/ anti-PDL-1
therapy such as, but not limited to, nivolumab, pembrolizumab, atezolizumab,
tislelizumab, and durvalumab or progression on anti-PD-1/ anti-PDL-1 therapy such
as, but not limited to, nivolumab, pembrolizumab, atezolizumab, tislelizumab, and
durvalumab. (Notes: prior combination treatment with chemotherapy and an
anti-PD-1/anti-PDL-1 therapy is acceptable.)
- Subject must have at least one measurable area of disease (greater than 1.5 cm
longest transverse diameter (LDi) to allow for response assessment and biopsy) by
Lugano Criteria
- Subjects with prior history of allogeneic or autologous stem cell transplant must
have had at least 90 days since the transplant and must be off of immunosuppressive
agents for Graft vs Host disease for at least 2 months.
- Subjects with a prior autologous transplant are eligible
- Transplant ineligible subjects are permitted on this study if they have had
exposure to anti-PD(L)1 therapy as defined above.
- ECOG Performance Status ≤ 2.
- Adequate organ function, without the use of transfusions or growth factors within 7
days, as defined as:
- Hematologic:
---Platelet count ≥ 50,000/mm3 (unless bone marrow involved)
- Hemoglobin ≥ 8 g/dL (unless bone marrow involved)
- Absolute Neutrophil Count (ANC) ≥.5 × 10^9/L unless bone marrow
involvement from classical Hodgkin lymphoma
- Hepatic:
- Total Bilirubin ≤ 1.5x institutional upper limit of normal (ULN).
Exceptions include patients with underlying Gilbert Syndrome in whom ≤ 3x
institutional upper limit of normal (ULN) of Total Bilirubin will be
allowed.
- AST(SGOT)/ALT(SGPT) ≤ 3 × Institutional ULN
- Subjects with liver metastases will be allowed to enroll with AST and
ALT levels ≤ 5 x ULN.
- Renal:
- Estimated creatinine clearance ≥ 50 mL/min by Cockcroft-Gault formula
- For female subjects: Negative pregnancy test or evidence of post-menopausal status.
The post-menopausal status will be defined as having been amenorrheic for 12 months
without an alternative medical cause. The following age-specific requirements apply:
- Women < 50 years of age:
---Amenorrheic for ≥ 12 months following cessation of exogenous hormonal
treatments; and
- Luteinizing hormone and follicle-stimulating hormone levels in the
post-menopausal range for the institution; or
- Underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
- Women ≥ 50 years of age:
- Amenorrheic for 12 months or more following cessation of all exogenous
hormonal treatments; or
- Had radiation-induced menopause with last menses >1 year ago; or
- Had chemotherapy-induced menopause with last menses >1 year ago; or
- Underwent surgical sterilization (bilateral oophorectomy, bilateral
salpingectomy, or hysterectomy).
- Female subjects of childbearing potential and male subjects with a sexual partner of
childbearing potential must agree to use a highly effective method of contraception
as described in Section 5.4.1.
- Recovery to baseline or ≤ Grade 1 CTCAE v5.0 from toxicities related to any prior
cancer therapy, unless considered stable or clinically not significant by the
treating investigator.
- Able to provide informed consent and willing to sign an approved consent form that
conforms to federal and institutional guidelines.
Exclusion Criteria:
- Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other
form of immunosuppressive therapy within 14 days prior to the first dose of study
drug.
--Of note, the following are allowed:
- The use of physiologic doses of corticosteroids (i.e., ≤10 mg per day of
equivalent prednisone) is allowed.
- Steroids with no or minimal systemic effect (topical, inhalation) are allowed.
- Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency) is not considered a
form of systemic treatment.
- Steroids as premedication for hypersensitivity reactions (e.g., CT scan
premedication)
- Previously treated with a CSF-1, CSF-1R, and/or IL-34-blocking agents.
- Subjects with toxicity from prior treatment that has not resolved to Grade ≤1,
except grade 2 peripheral neuropathy, any grade alopecia/vitiligo, grade 3 rash,
endocrinopathy managed with replacement therapy.
- History of Grade ≥3 immune-mediated adverse event attributed to prior immune
checkpoint-inhibitor therapy; other than endocrinopathy managed with replacement
therapy.
--All immune-mediated adverse events related to prior cancer immunotherapy must have
resolved to baseline.
- History of autoimmune disease, including, but not limited to: myasthenia gravis,
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
inflammatory bowel disease, vascular thrombosis associated with antiphospholipid
syndrome, Wegener granulomatosis, Sjogren syndrome, Guillain-Barre syndrome,
multiple sclerosis, vasculitis, or glomerulonephritis, with the following
exceptions:
--Autoimmune hypothyroidism on stable dose of thyroid replacement, controlled Type 1
Diabetes Mellitus on insulin, history of disease-related ITP or AIHA, or remote
history of or well-controlled autoimmune disease with treatment-free interval from
immunosuppressive therapy for at least 12 months.
- History or current clinically significant pulmonary disease, such as obstructive
pulmonary disease, bronchospasm, or non-infectious pneumonitis (drug-induced or
autoimmune).
- Prior systemic anti-cancer therapy or any investigational therapy ≤ 14 days or
within five half-lives prior to starting study treatment, whichever is shorter.
Patients are allowed to be actively receiving anti-PD-1(anti-PD-L1) therapy at the
time of enrollment but must stop agents other than Nivolumab prior to dosing with
Nivolumab.
- Evidence of muscle disorders or muscle injury that are known to cause serum creatine
kinase (CK) elevation
- History of PML, HLH, CNS vasculitis, uncontrolled seizure disorder, or
neurodegenerative disease.
- Allogeneic stem cell transplant within 90 days prior to screening or on current
treatment for graft vs host disease
- Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of
radiation within 4 weeks or palliative radiation therapy within 2 weeks of the first
dose of study drug.
- Major surgery 4 weeks prior to starting study drug or who have not fully recovered
from major surgery.
- The diagnosis of another malignancy within ≤ 2 years before study enrollment, except
for those considered to be adequately treated with no evidence of disease or
symptoms and/or will not require therapy during the study duration (i.e., basal cell
or squamous cell skin cancer, carcinoma in situ of the breast, bladder or of the
cervix, or low-grade prostate cancer with Gleason Score ≤ 6).
- Known brain metastases or cranial epidural disease.
--Note: Brain metastases or cranial epidural disease adequately treated with
radiotherapy and/or surgery and stable for at least 4 weeks before the first dose of
study treatment will be allowed on trial. Subjects must be neurologically
asymptomatic and without corticosteroid treatment at the time of the first dose of
study treatment.
- Current evidence of uncontrolled, significant intercurrent illness including, but
not limited to, the following conditions:
- Cardiovascular disorders:
- Congestive heart failure New York Heart Association Class III or IV,
unstable angina pectoris, serious cardiac arrhythmias.
- Stroke, myocardial infarction (MI), or other ischemic events within 3
months before the first dose.
- QTc prolongation defined as a QTcF > 500 ms.
- Known congenital long QT.
- Any other condition that would, in the Investigator's judgment, contraindicate
the subject's participation in the clinical study due to safety concerns or
compliance with clinical study procedures (e.g., infection/inflammation,
intestinal obstruction, unable to swallow medication, [subjects may not receive
the drug through a feeding tube], social/ psychological issues, etc.)
- Known HIV infection with a detectable viral load within 6 months of the anticipated
start of treatment.
--Note: Subjects on effective antiretroviral therapy with an undetectable viral load
within 6 months of the anticipated start of treatment are eligible for this trial.
- Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination, radiographic findings, and TB testing in line with
local practice).
- Clinically significant liver disease, including viral or other hepatitis or
cirrhosis.
--Note: Subjects with a past or resolved HBV infection (defined as the presence of
hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Subjects
positive for hepatitis C (HCV) antibody are eligible only if polymerase chain
reaction is negative for HCV RNA.
- Medical, psychiatric, cognitive, or other conditions that may compromise the
subject's ability to understand the subject information, give informed consent,
comply with the study protocol or complete the study.
- Known prior severe hypersensitivity to nivolumab or SNDX-6352 or any component in
its formulations (NCI CTCAE v5.0 Grade ≥ 3).
- Subjects taking prohibited medications as described in Section 6. A washout period
of prohibited medications for a period of at least five half-lives or as clinically
indicated should occur before the start of treatment.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Karmanos Cancer Institute
Address:
City:
Detroit
Zip:
48201
Country:
United States
Facility:
Name:
Huntsman Cancer Institute at the University of Utah
Address:
City:
Salt Lake City
Zip:
84112
Country:
United States
Start date:
April 18, 2023
Completion date:
April 2028
Lead sponsor:
Agency:
University of Utah
Agency class:
Other
Collaborator:
Agency:
Incyte Corporation
Agency class:
Industry
Source:
University of Utah
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05723055
