Golcadomide With Pemetrexed, Rituximab, and Dexamethasone for Relapsed and Refractory CNS Lymphomas

Official title

Phase I Pilot Trial of Golcadomide With Pemetrexed, Rituximab, and Dexamethasone for Relapsed and Refractory CNS Lymphomas

Overview

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.

Detailed description

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.

Interventions

• Drug Golcadomide
  To be taken orally daily on days 1-7 of the cycle Maximum 3 cycles but participants may received up to 3 additional cycles (for a total of up to 6 cycles) Cycle Length : 21 days Dose Levels: * Level -1 : 0.2milligrams/day * Level 1 : 0.2milligrams/day * Level 2 : 0.4milligrams/day
• Drug Pemetrexed
  To be given intravenously (IV) on day 1 of each cycle Maximum 3 cycles but participants may receive up to 3 additional cycles (for a total of up to 6 cycles) Cycle Length: 21 days Dose Level * Level -1 : 675 milligrams/square meter * Level 1 : 900 milligrams/square meter * Level 2 : 900 milligram/square meter
• Drug Rituximab
  To be given intravenously on day 1 of each cycle Maximum 3 cycles but participants may receive up to 3 additional cycles (for a total of up to 6 cycles) Cycle Length: 21 days Dose Level * Level -1 : 500 milligram/ square meter * Level 1 : 500 milligram/ square meter * Level 2 : 500 milligram/ square meter
• Drug Dexamethasone
  To be given orally on days 1-4 of each cycle Day 1 dose should be given at least 30 minutes before rituximab infusion Maximum 3 cycles but participants may receive up to 3 additional cycles (for a total of up to 6 cycles) Cycle Length: 21 days Dose Level * Level -1 : 10 milligrams * Level 1 : 10 milligrams * Level 2 : 10 milligrams

Primary outcome measures

• Safety of Golcadomide + Pemetrexed, Rituximab and Dexamethasone [Time frame: up to 6 cycles (up to 6 months)]
• Identify the maximum tolerated dose of Golcadomide + Pemetrexed, Rituximab and Dexamethasone [Time frame: up to 6 cycles (up to 6 months)]

Secondary outcome measures (6)

• Overall response rate (ORR) by International Primary CNS Lymphoma Collaborative Group (IPCG) of Golca + PRD [Time frame: up to 18 months]
• Disease control rate (DCR) by IPCG [Time frame: 18 months]
• Overall survival rate [Time frame: 18 months]
• Progression free survival rate [Time frame: 18 months]
• Proportion of participants designated for cellular therapy who receive cellular therapy [Time frame: 18 months]
• Proportion of participants who have a successful mobilization of autologous stem cell transplant [Time frame: 18 months]

Eligibility criteria

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:

• Large B-cell lymphoma NOS
• Diffuse large B-cell lymphoma (including GCB and ABC types)
• High-grade B-cell lymphoma with MYC and BCL2 rearrangements (double hit lymphomas)
• High-grade B-cell lymphoma NOS
• T-cell/histiocyte/rich large B-cell lymphoma (THRLBCL)
• EBV + DLBCL
• PMBCL
• Follicular Large B-Cell (previously referred to as Follicular Lymphoma, Grade 3B)
• 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:

• CNS disease on MRI (brain or spine including parenchymal and leptomeningeal)
• Detectable in the CSF
• Detectable on ophthalmologic exam
• 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.

• Participants who have received methotrexate as their first line of therapy but are no longer eligible for ongoing methotrexate and have persistent disease are eligible
• 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:

• Absolute neutrophil ≥ 1.5 x 109/L
• Platelet count ≥ 100 x 109/L

• Hemoglobin ≥ 8 g/dL
• Adequate organ function, defined by the following laboratory parameters:

• Adequate hepatic function, with transaminases (alanine aminotransferase \[ALT\], aspartate aminotransferase \[AST\], and gamma glutamyl transferase \[GGT\]) ≤ 2.5 times the upper limit of normal
• 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:

• If the intent of therapy is a bridge to cellular therapy or to complete all six cycles of therapy. If bridge to cellular therapy is planned, the type of cellular therapy should also be specified at this time.
• If the r/r CNS lymphoma is primary or secondary
• 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).

• Examples of contraceptive methods include highly effective methods such as oral, injectable, or implantable hormonal contraceptive; tubal ligation; intrauterine device; vasectomized partner and barrier methods with spermicide.
• 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.
• Must agree to pregnancy testing per protocol. This applies even if the participant practices true abstinence from heterosexual contact.
• Agree to abstain from breastfeeding or providing breast milk while on golcadomide and 28 days after discontinuation of golcadomide and according to the approved
• 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. Particpants 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:

• Uncontrolled and/or active systemic infection (viral, bacterial or fungal)
• Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: participants with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen negative-, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate.
• Other uncontrolled conditions including uncontrolled cardiovascular disease or arrhythmia, decompensated diabetes or COPD.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Cleveland Clinic, Case Comprehensive Cancer Center — Cleveland

Identifiers

NCT: NCT07608731 · CASE3425

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗