Status and phase
Conditions
Treatments
About
This is a Phase II study of the combination of All-Trans Retinonic Acid (ATRA) and PD-1 inhibition (Retifanlimab) in patient with recurrent IDH-mutant glioma. The Sponsor-Investigator hypothesizes that the proposed regimen will be safe and stimulate a robust anti-tumor immune response.
Full description
The study has a Safety Run-In, a Phase 2 Portion, and a Surgical Portion. The Phase 2 portion and Surgical portion will open to enrollment simultaneously following successful completion of the Safety Run-In.
Safety Run-In subjects receive 28-day cycles of treatment, with ATRA 45mg/m2/day given orally in two equally divided doses on days 1-14 and retifanlimab 500mg IV on day 1. Once Safety Run-In is complete, the Phase 2 and Surgical cohorts will commence uninterrupted.
Phase 2: All Phase 2 patients will receive 28-day cycles of treatment, with ATRA 45mg/m2/day given orally in two equally divided doses on days 1 through 14 and retifanlimab 500mg IV on day 1.
Arm A includes alkylator-refractory patients at high risk for progression of disease, having failed temozolomide and another alkylating agent. At the first stage, 12 subjects will be enrolled onto the study. This arm of the trial will be stopped if no response was obtained among the first 12 subjects (0/12). Otherwise, this arm of the study will continue to stage Four additional subjects will be enrolled on the second stage of this arm of the trial.
Arm B includes patients who have failed only one prior alkylating chemotherapy regimen and have gone at least 12 months since the last treatment (chemotherapy or radiation therapy), i.e., favorable risk patients. At the first stage, 14 subjects will be enrolled onto the study. This arm of the trial will be stopped if 5 or fewer responses were obtained among the first 14 subjects greater than or equal to 5 out of 14 subjects. Otherwise, this arm of the study will continue to stage 2. Three additional subjects will be enrolled on the second stage of this arm of the trial.
Surgical Portion: This portion of the study will enroll patients who are eligible for re-resection at the time of recurrence. Prior to surgical resection, patients are randomized 1:1 to receive either 1) single-agent ATRA 45mg/m2/day orally in two equally divided doses for 14 days pre-surgery (Arm C), or 2) the combination of ATRA 45mg/m2/day orally in two equally divided doses for 14 days pre-surgery plus a 500mg IV dose of retifanlimab 14 (+/-3) days prior to the date of surgery (Arm D). At surgery fresh tumor tissue will be collected for correlative studies. Following surgery all patients will receive 28-day cycles of treatment, with ATRA 45mg/m2/day given orally in two equally divided doses on days 1-14 and retifanlimab 500mg IV on day 1.
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Prior histopathologically proven diagnosis of astrocytoma (grade 2-4) or oligodendroglioma (grade 2-3) according to the World Health Organization (WHO) 2021 Classification System that is progressive or recurrent following at least one prior alkylating chemotherapy regimen (i.e., temozolomide and/or lomustine), +/- radiation therapy
Patient's tumor must have a known mutation in IDH1 or IDH2. IDH1/2 mutation status must be confirmed by DNA sequencing and could have been performed in any CLIA/CAP-certified laboratory. IDH1/2 mutational testing could have been performed on patient's tumor either at initial diagnosis or on a subsequent recurrent tumor.
Safety Run-In and Phase 2 (Arm A and Arm B) patients:
Surgical patients (Arm C and Arm D):
Patient must have documented 1p/19q and O-6-methylguanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT) methylation testing. If either of these has not been performed previously, they can be done prior to enrollment.
Patients must be able to undergo MRI of the brain with gadolinium. Patients must be maintained on a stable or decreased dose of corticosteroid regimen (no increase for 5 days) prior to this baseline MRI.
Patients must have recovered from severe toxicity of prior therapy; the following intervals from previous treatments are required to be eligible:
If patient is on systemic corticosteroids to treat brain edema and/or brain edema-related symptoms, the dose must be 2mg of dexamethasone (or equivalent) daily or less for a minimum of 5 days prior to first dose of retifanlimab.
Patients must be able to swallow oral medications
Age 18 or older
Karnofsky performance status greater than or equal to 60
Life expectancy >3 months
Adequate organ and marrow function:
Reproductive Status
At a minimum, participants of childbearing potential who are sexually active and their partners must agree to the use of a highly effective form of contraception (as defined below) throughout their participation beginning with the time of consent, during the study treatment, and for 180 days after last dose of study treatment(s).
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION:
Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, injectables, implants and intrauterine devices (IUDs) by WOCBP subject or male subject's WOCBP partner. Female partners of male subjects participating in the study may use hormone-based contraceptives as one of the acceptable methods of contraception since they will not be receiving study drug
Nonhormonal IUDs
Bilateral Tubal ligation
Vasectomy
Sexual Abstinence
Participant must, in the opinion of the Investigator, be able to comply with study procedures
Patients must be able to understand the study procedures and agree to participate in the study by providing written informed consent (or have legally authorized representative sign on patient's behalf if patient physically unable to sign consent due to neurologic deficit)
Exclusion criteria
Any of the following would exclude the subject from participation in the study:
Contrast-enhancing tumor in brainstem or spinal cord (subjects do not need spinal MRI for screening, but known spinal cord tumor is exclusionary)
Diffuse leptomeningeal disease
Patients who have received bevacizumab within the last 3 months are ineligible
Patients with clinically significant mass effect or midline shift (e.g., 1-2 cm of midline shift)
Use of any immunosuppressive medication other than steroids, including but not limited to antimetabolites, calcineurin inhibitors, and/or anti-TNF agents within six months of start of study drug
Prior diagnosis of immunodeficiency
Prior solid organ or bone marrow transplantation
Active autoimmune disease requiring systemic immunosuppression in excess of physiologic maintenance doses of corticosteroids (> 10 mg/day of prednisone or equivalent).
EXCEPTIONS: Patients with the following autoimmune diseases may participate: type I diabetes mellitus, hypothyroidism only requiring hormone replacement, Grave's disease that is previously treated with thyroidectomy or radioiodine, celiac disease with symptoms controlled with a gluten-free diet.
Evidence of interstitial lung disease, history of interstitial lung disease, or active, noninfectious pneumonitis.
Immune related toxicity during prior checkpoint inhibitor therapy for which permanent discontinuation of therapy was recommended (per product label or consensus guidelines) or any immune-related toxicity requiring intensive or prolonged immunosuppression to manage (with the exception of endocrinopathy that is well controlled on replacement hormones).
Known active hepatitis B virus (HBsAg reactive) or active hepatitis C virus (HCV RNA detectable by PCR)
Human immunodeficiency virus (HIV)-positive patients on antiretroviral therapy
Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen are excluded from this trial. Otherwise, patients with prior or concurrent malignancy are eligible.
Any serious, uncontrolled medical disorder, nonmalignant systemic disease, or active, uncontrolled infection that, in the opinion of the investigator, would put the subject at undue risk from the study treatment.
Patients with uncontrolled or significant cardiovascular disease including, but not limited to, any of the following are ineligible:
Known hypersensitivity to another monoclonal antibody that cannot be controlled with standard measures (e.g., antihistamines and corticosteroids)
Known allergy or hypersensitivity to any component of retifanlimab or formulation components.
Known allergy or hypersensitivity to all-trans retinoic acid (tretinoin), any of its components, or other retinoids
Prisoners or subjects who are involuntarily incarcerated
Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
Pregnant women are excluded
Has received a live vaccine within 28 days before the planned start of study treatment
Note: Examples of live vaccines include but are not limited to measles, mumps, rubella, varicella-zoster (chickenpox), yellow fever, rabies, BCG, and typhoid vaccines. Seasonal influenza vaccines for injection are generally killed-virus vaccines and are allowed; however, intranasal influenza vaccines are live, attenuated vaccines and are not allowed.
Participant must not be simultaneously enrolled in any interventional clinical trial
Primary purpose
Allocation
Interventional model
Masking
55 participants in 4 patient groups
Loading...
Data sourced from clinicaltrials.gov
Clinical trials
Research sites
Resources
Legal