Phase I Pilot Trial of Golcadomide With Pemetrexed, Rituximab, and Dexamethasone for Relapsed and Refractory CNS Lymphomas
Phase I Pilot Trial of Golcadomide With Pemetrexed, Rituximab, and Dexamethasone for Relapsed and Refractory CNS Lymphomas
This research study is for people who have been diagnosed with large B-cell lymphoma of the central nervous system (CNS), which has either returned or is not responding to current treatment. Goldcadomide is a new experimental drug that works by binding to a specific protein inside cancer cells and helps stimulate immune cells that help fight cancer cells. It also has the ability to enter the central nervous system. It has shown promising safety and effectiveness when combined with standard of care chemotherapy. Participants will be treated with this study drug combined with standard of care chemotherapy. Participation in the research will last about 2.5 years. The purpose of this study is to help researchers learn if the study drug, Golcadomide, in combination with the standard of care regimen is a safe and effective way to treat large B-cell lymphoma with CNS involvement.
People with systemic diffuse large B-cell lymphoma (DLCBL) can either have a a disease that involves the central nervous system or does not involve the central nervous system. The disease could also be only located in the central nervous system. The central nervous system lymphoma includes disease within the brain, meninges, cranial nerves, cerebrospinal fluid, spinal cord, and/or intraocular. For people with disease that involves the CNS it can be difficult to treat. This is because many effective lymphoma treatments do not cross the blood-brain barrier (BBB).
In general there is a large unmet need for effective and feasible therapies for CNS lymphomas. This study addresses these gaps by combining standard of care chemotherapy with Golcadomide.This approach aims to provide a feasible and potentially effective treatment option for a population with historically poor outcomes.
The purpose of this study is to find out the safety and efficacy of Golcadomide in combination with drugs in the standard care chemotherapy. Another goal is to find the recommended phase 2 dose of Golcadomide in combination with standard of care chemotherapy.
Inclusion Criteria:
Participants or their legally acceptable representative must have signed and dated an IRB approved written ICF in accordance with regulatory, local, and institutional guidelines.
Participants ≥ 18 years of age.
Confirmed histopathological diagnosis of aggressive malignant B-cell lymphoma based upon a representative histology specimen according to the WHO classification. For participants with secondary CNS lymphoma, this can be confirmed by prior systemic biopsy. If a CNS lesion was not amenable for biopsy, imaging (e.g. MRI Brain ± MRI Full Spine) with CSF analysis for cytology may be used to confirm diagnosis, in lieu of a biopsy. Required. Acceptable histologies include:
Participants must have active CNS lymphoma for which this trial is planned. Confirmation of the histology in relapsed setting is not required but participants must have measurable disease per the International PCSNL Collaboration Group Criteria (Section 11.1), as evidenced by at least one of the following:
Participants must have received ≥ 1 prior systemic therapy for treatment of their CNS lymphoma. Participants who had systemic lymphoma and then relapsed with secondary CNS lymphoma must have received at least one prior line of therapy to specifically treat the CNS lymphoma.
Participants must have received prior high dose methotrexate as a line of therapy OR have been ineligible for methotrexate therapy based on the investigator's discretion.
ECOG performance status ≤ 0-3. PS 3 is allowed if it is disease related and not due to comorbidities or frailty and PS 4 is allowed if it is from CNS causing motor weakness and not due to comorbidities or frailty. (see Appendix I)
Adequate bone marrow function, defined by the following laboratory parameters:
Platelet count ≥ 100 x 109/L
Adequate organ function, defined by the following laboratory parameters:
Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)
Calculated creatinine clearance > 45 mL/min by the Cockcroft-Gault equation.
Treating investigator must specify at screening:
For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use two methods of contraception simultaneously from signing the ICF, at least 28 days before starting golcadomide, throughout the study, for up to 28 days following the last dose of golcadomide, and for 12 months after the last dose of rituximab, whichever is longer.. Two methods of contraception must include one highly effective method and one additional effective (barrier method).
A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (< 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries, fallopian tubes, and/or uterus).
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for at least 28 days after the last dose of study intervention or 90 days for rituximab, whichever is longer. Men must refrain from donating sperm during this same period.
With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 28 days after the last dose of study intervention or 90 days for rituximab, whichever is longer.
The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
Exclusion Criteria:
Prior treatment toxicities not resolved to grade < 2 according to NCI CTCAE 6.0 (with the exception of alopecia or grade 2 sensory peripheral neuropathy).
Participants receiving any other investigational agents.
History of anaphylactic reactions or severe allergic reactions prohibiting further administration attributed to compounds of similar chemical or biologic composition to rituximab or other agents used in this study.
Autologous stem cell transplant within 30 days of start of study drug (C1D1).
CAR T-cell therapy within 90 days of start of study drug (C1D1).
Previous allogeneic stem cell transplant
Women who are pregnant or breastfeeding.
Clinically significant autoimmune disease.
Known seropositive and requiring anti-viral therapy for human immunodeficiency (HIV) virus.
Malabsorption syndrome or other conditions that precludes enteral route of administration.
Chemotherapy or radiation within 2 weeks of the first scheduled study treatment
Participant is currently receiving warfarin. Participants may begin screening if the plan is to change to an alternative anticoagulant such as a DOAC prior to enrollment.
Participant has current treatment with strong cytochrome P450 3A4/5 (CYP3A4/5) modulators. The washout period for strong CYP3A4/5 modulators is 7 days or 5 half-lives (whichever is longer) before initiation of golcadomide.
Evidence of other clinically significant uncontrolled condition(s) including, but not limited to:
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