Golcadomide and Nivolumab in Patients With Non-Hodgkin Lymphoma With Refractory Disease After Chimeric Antigen T-cell Therapy

Phase I/II Study of Combination Golcadomide and Nivolumab in Patients With Non-Hodgkin Lymphoma With Refractory Disease After Chimeric Antigen T-cell Therapy

In this combined phase I/II, open label, single arm trial to study, the safety and efficacy of combination Golcadomide and nivolumab in patients with non-Hodgkin lymphoma (NHL) who have experienced refractory/residual disease, at or after 30 days of receiving chimeric antigen T-cell (CAR-T) therapy will be studied. A dose escalation phase will be followed by a dose expansion design.

Study Overview

• Status: Withdrawn
• Conditions: Non Hodgkin Lymphoma
• Intervention / Treatment: Drug: GOLCADOMIDE; Drug: Nivolumab

Detailed Description

Non-Hodgkin lymphoma (NHL) is a diverse group of lymphoid neoplasms affecting 80,470 new cases in the USA every year.1 Among the common types of NHL, diffuse large B-cell lymphoma (DLBCL) carries a five-year survival of 64.4% (SEER). Prognosis depends on disease specific factors such as stage and extent of spread, in addition to patient specific factors, such as age and performance status. Prior studies suggest that anti-PD-1 therapy may be effective in this population, especially if there is a way to further sensitize tumor cells to anti-PD-1 therapy to reduce T-cell exhaustion and increase inflammatory cytokines. Exposure to CELMoDs in addition to anti-PD1 therapy following CAR-T relapse may lead to deeper and more durable responses through re-expansion of CAR-T cells and modulation of tumor microenvironment (TME). This trial hypothesizes that combination Golcadomide at the selected dose and nivolumab at standard dosing will be safe and effective and that an overall response rate 45% or greater with a maximum dose-limiting toxicity (DLT) rate of 25% would be sufficient to warrant further interest in this combination in patients who have refractory NHL after 30 days of receiving therapy.

• Study Type: Interventional
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • UPMC Hillman Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Provision of signed informed consent and willingness to comply with all study requirements for the duration of the study.
2. Patients 18 years of age or older.
3. Patients must have histologically confirmed high-grade large B-cell lymphoma such as diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL grade 3B), primary mediastinal B-cell lymphoma (PMBCL). Patient with transformation from indolent to large cell lymphoma will be allowed to enroll in the study.
4. Presence of FDG avid, radiographically measurable disease (Deauville 4-5) per Lugano 2014 response criteria which will include patients with metabolic partial response (PR), stable disease (SD), and progressive disease (PD), as assessed by the investigator.
5. Patients who received FDA-approved CD19-directed CAR T-cell product(s) (exclusive of any investigational CAR T-cell products).
6. Evidence of measurable residual disease 30 days and up to 1 year after receiving CAR-T therapy. Screening visit should be performed no later than day 365 after CAR-T infusion.
7. Eastern Cooperative Oncology group ECOG performance status ≤ 2.
8. Patients must have adequate organ and marrow function as defined in the protocol at the time of consent. Abnormalities reasonably attributed to underlying lymphoma will be allowed (e.g. anemia due to marrow involvement or LFT elevation due to metastatic involvement)
9. Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load are eligible.
10. For patients with evidence of chronic hepatitis virus infection (HBV or HCV), the viral load must be undetectable on suppressive therapy, if indicated.
11. Patients with CNS relapse (as an extension of systemic disease) are eligible, as determined by the investigator.
12. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. The malignancy should not be progressing or requiring active systemic treatment within the past year.
13. Patients with known history or current symptoms of cardiac disease should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification and may require an echocardiogram at the discretion of the investigator. To be eligible for this trial, patients should be class II, stage B or better.
14. Females of childbearing potential (FCBP) must have a negative pregnancy test during screening.
15. All subjects of childbearing potential must agree to use contraceptive methods (hormonal or barrier method of birth control; abstinence) for the duration of the study and for at least 28 days after the last dose of golcadomide. Should a woman become pregnant while she or her partner is participating in this study, she should inform her treating physician and discontinue therapy immediately. Pregnancies (both those of female patients and female partners of male patients) are reported in the same manner as SAEs within 24 hours of the Investigator's knowledge.
16. Ability to take oral medication and be willing to adhere to the golcadomide and nivolumab regimen.

Exclusion Criteria:

1. Treatment with any intervening anti-cancer therapies (other than palliative radiation) following CAR-T therapy. This study is intended to be the first treatment of residual disease after CAR-T therapy.
2. Patients who have not recovered from AEs (other than hematologic) of prior anti-neoplastic therapy (i.e., have residual toxicities > Grade 1) for the exception of alopecia, that require active management.
3. Hypersensitivity reaction to any of the study drugs or their derivatives.
4. Medical or psychiatric co-morbidities that in the opinion of the treating physician may compromise either compliance with or tolerance of study drugs.
5. Patients with GI malabsorption that may compromise absorption of oral golcadomide.
6. Presence of active autoimmune disease.

7. Patients requiring strong CYP3A inducers or inhibitors will be excluded. Note:

   1. Avoid coadministration of moderate CYP3A inhibitors and
   2. Avoid coadministration of moderate CYP3A inducers until more information regarding the potential DDI risk is available.

   Patients previously taking strong CYP3A inhibitors/inducers will require a washout period of at least 14 days or 5 half-lives, whichever is shorter, prior to the initiation of study treatment.

8. Currently breastfeeding females.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: GOLCADOMIDE + Nivolumab 480 mg IV; GOLCADOMIDE PO QD (Day 1-14) Nivolumab 480 mg IV (Q4 wk) Continue up to 24 cycles or until intolerable toxicity or disease progression

Drug: GOLCADOMIDE; Golcadomide (GOLCA, CC-99282) is an oral cereblon E3 ligase modulator (CELMoD®) agent with immunomodulatory and tumor cell-autonomous activities. It is a modulator of the E3 ubiquitin ligase complex containing cereblon (CRL4-CRBN E3 ubiquitin ligase), with potential immunomodulating and antineoplastic activities.; Other Names: Golcadomide (GOLCA; CC-99282); Drug: Nivolumab; Nivolumab is an immune checkpoint inhibitor targeted therapy drug that blocks the PD-1 (programmed death receptor-1) pathway to help prevent cancer cells from hiding from the immune system, boosting the immune system's response.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose (MTD) / Recommended Phase 2 dose (RP2D)	The number and type of Dose Limiting Toxicities experienced during the first two cycles of treatment will be observed and assessed (per NCI-CTCAE v5.0) to determine the Maximum tolerated dose (MTD) / recommended phase 2 dose (RP2D) of golcadomide combined with standard dose nivolumab in participants with NHL who experienced disease progression or relapse after receiving CAR-T therapy as determined.	Up to 56 days from start of treatment
Lugano Response Evaluation	Occurrence of partial response or better (objective response) per the Lugano PET-CT treatment response criteria. The Lugano classification (2014) is a lymphoma staging system that includes response based on CT evaluation. Scoring: (1)=no uptake or no residual uptake (when used interim), (2)=slight uptake, but below blood pool (mediastinum), (3)=uptake above mediastinal, but below or equal to uptake in the liver, (4)=uptake slightly to moderately higher than liver, (5)=markedly increased uptake or any new lesion (on response evaluation). Complete metabolic response (CMR) (score of 1, 2 or 3 in nodal or extranodal sites with or without a residual mass. Partial metabolic response (PMR) (score of 4 or 5 with reduced uptake compared with baseline and residual mass(es) of any size), or stable disease or no metabolic response (score of 4 or 5 with no obvious change in FDG uptake)	Up to 36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events and Serious Adverse Events (Phase l - Dose Escalation)	Incidence of severity of adverse events and serious adverse events at least possibly related to trial treatment, per NCI-CTCAE v5.0.	Up to 56 days from start of treatment
Adverse Events and Serious Adverse Events (Phase ll - Dose Expansion)	Incidence of severity of adverse events and serious adverse events at least possibly related to trial treatment, per NCI-CTCAE v5.0.	Up to 36 months
Preliminary Efficacy per Lugano Response Evaluation	Occurrence of partial response or better (objective response) per the Lugano PET-CT treatment response criteria. The Lugano classification (2014) is a lymphoma staging system that includes response based on CT evaluation. Scoring: (1)=no uptake or no residual uptake (when used interim), (2)=slight uptake, but below blood pool (mediastinum), (3)=uptake above mediastinal, but below or equal to uptake in the liver, (4)=uptake slightly to moderately higher than liver, (5)=markedly increased uptake or any new lesion (on response evaluation). Complete metabolic response (CMR) (score of 1, 2 or 3 in nodal or extranodal sites with or without a residual mass. Partial metabolic response (PMR) (score of 4 or 5 with reduced uptake compared with baseline and residual mass(es) of any size), or stable disease or no metabolic response (score of 4 or 5 with no obvious change in FDG uptake)	Up to 26 months
Progression-free survival (PFS)	Median time patients do not experience disease progression per Lugano classification (2014). Lugano criteria is a staging system including CT response evaluation. Scoring: (1)=no uptake or no residual uptake (when used interim),(2)=slight uptake, but below blood pool (mediastinum),(3)=uptake above mediastinal, but below or equal to uptake in the liver,(4)=uptake slightly to moderately higher than liver,(5)=markedly increased uptake or any new lesion (on response evaluation). Disease progression score=4 or 5 in any lesion with an increase in intensity of FDG uptake from baseline (and/or new FDG-avid foci consistent with lymphoma). Complete metabolic response (CMR) (score=1, 2 or 3 in nodal or extranodal sites with or without a residual mass, partial metabolic response (PMR) (score= 4 or 5 with reduced uptake compared with baseline and residual mass(es) of any size), or stable disease or no metabolic response (score=4 or 5 with no obvious change in FDG uptake)	Up to 36 months

Collaborators and Investigators

• Sponsor: University of Pittsburgh
• Collaborators: Bristol-Myers Squibb
• Investigators: Principal Investigator: Natalie Galanina, MD, University of Pittsburgh

Study record dates

Study Major Dates

• Study Start (Estimated): June 30, 2025
• Primary Completion (Estimated): April 30, 2027
• Study Completion (Estimated): April 30, 2028

Study Registration Dates

• First Submitted: January 5, 2025
• First Submitted That Met QC Criteria: January 5, 2025
• First Posted (Actual): January 10, 2025

Study Record Updates

• Last Update Posted (Actual): April 13, 2026
• Last Update Submitted That Met QC Criteria: April 7, 2026
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: B cell lymphomas; tumor microenvironment (TME); refractory disease; chimeric antigen; Cereblon E3 Ligase Modulators (CELMoD); immunomodulatory drugs (IMiD)
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; Disease; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Nivolumab
• Other Study ID Numbers: HCC 23-161

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes