GLPG5101 for Non-Hodgkin's Lymphoma

(Atalanta-1 Trial)

Recruiting at 9 trial locations

Overseen By Galapagos Medical Information

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Galapagos NV

Disqualifiers: Richter's transformation, Other malignancy, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

250 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is evaluating whether an experimental treatment called GLPG5101 helps to treat non-Hodgkin lymphoma (NHL) and if it is safe to use. This study will be carried out in 2 phases: * The first phase is to see which doses of GLPG5101 work best with the least number of side effects. * In the second phase, participants will receive the selected dose(s) based on the results in the first phase.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment GLPG5101 for Non-Hodgkin's Lymphoma?

Chimeric antigen receptor (CAR) T-cell therapy, similar to GLPG5101, has shown significant success in treating B-cell non-Hodgkin lymphoma, with durable remissions in nearly half of the patients who previously had poor outcomes with standard treatments. This success has led to regulatory approval for CAR T-cell therapies in various types of lymphoma, indicating their potential effectiveness. ^{1 2 3 4 5}

What safety data exists for GLPG5101 (CAR T-cell therapy) in humans?

CAR T-cell therapies, including those targeting CD19, have shown potential in treating certain blood cancers but can cause serious side effects like cytokine release syndrome (a severe immune reaction) and neurological issues. These therapies have been tested in clinical trials, and while they can be effective, managing these toxicities is crucial for their safe use. ^{3 6 7 8 9}

How is the treatment GLPG5101 unique for Non-Hodgkin's Lymphoma?

GLPG5101 is a CAR T-cell therapy that is unique because it uses genetically modified T-cells to specifically target and destroy cancerous B cells in Non-Hodgkin's Lymphoma. This approach is different from traditional chemotherapy or radiation, as it harnesses the body's immune system to fight the cancer. ^{10 11 12 13 14}

Research Team

Galapagos Study Director

Principal Investigator

Galapagos NV

Eligibility Criteria

This clinical trial is for individuals with various types of non-Hodgkin lymphoma, specifically B-cell lymphomas. Participants should meet certain health criteria to be eligible, but specific inclusion and exclusion details are not provided.

Inclusion Criteria

Measurable disease according to the Lugano classification or IPCG criteria for PCNSL

My diagnosis is a specific type of non-Hodgkin lymphoma.

My kidney, liver, and lung functions are all within normal ranges.

Exclusion Criteria

Selected prior treatments as defined in the protocol

I do not have active HIV, hepatitis B, or hepatitis C.

My cancer has spread to my brain and is affecting my nervous system.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive escalating doses of GLPG5101 to determine the optimal dose based on efficacy and safety outcomes

8-12 weeks

Multiple visits for dose administration and monitoring

Dose Expansion

Participants receive the recommended phase 2 dose (RP2D) of GLPG5101 based on their NHL subtype

8-12 weeks

Single dose administration with follow-up visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Regular follow-up visits

Treatment Details

Interventions

• GLPG5101

Trial Overview The study tests GLPG5101's effectiveness and safety in treating non-Hodgkin lymphoma. It has two phases: the first determines the optimal dose with minimal side effects; the second gives all participants this best dose.

Participant Groups

Group I: Phase 2 (Dose expansion phase): Cohort 7: DLBCL-RT 2L+ Experimental Treatment 1 Intervention

Participants in this cohort will receive a single dose of GLPG5101 IV cell suspension for infusion at the selected RP2D level for this disease subtype on Day 0

Group II: Phase 2 (Dose expansion phase): Cohort 6b: PCNSL first-line consolidation Experimental Treatment 1 Intervention

Participants in this cohort will receive a single dose of GLPG5101 IV cell suspension for infusion at the selected RP2D level for this disease subtype on Day 0

Group III: Phase 2 (Dose expansion phase): Cohort 6a: PCNSL 2L+ Experimental Treatment 1 Intervention

Participants in this cohort will receive a single dose of GLPG5101 IV cell suspension for infusion at the selected RP2D level for this disease subtype on Day 0

Group IV: Phase 2 (Dose expansion phase): Cohort 5: BL 2L+ Experimental Treatment 1 Intervention

Participants in this cohort will receive a single dose of GLPG5101 IV cell suspension for infusion at the selected RP2D level for this disease subtype on Day 0

Group V: Phase 2 (Dose expansion phase): Cohort 4: MCL 2L+ Experimental Treatment 1 Intervention

Participants in this cohort will receive a single dose of GLPG5101 IV cell suspension for infusion at the selected RP2D level for this disease subtype on Day 0

Group VI: Phase 2 (Dose expansion phase): Cohort 3: Indolent B-cell NHL (FL and MZL 3L+) Experimental Treatment 1 Intervention

Participants in this cohort will receive a single dose of GLPG5101 IV cell suspension for infusion at the selected RP2D level for this disease subtype on Day 0

Group VII: Phase 2 (Dose expansion phase): Cohort 2: High-risk first-line DLBCL Experimental Treatment 1 Intervention

Participants in this cohort will receive a single dose of GLPG5101 IV cell suspension for infusion at the selected RP2D level for this disease subtype on Day 0

Group VIII: Phase 2 (Dose expansion phase): Cohort 1b: DLBCL 2L+ SCNSL Experimental Treatment 1 Intervention

Participants in this cohort will receive a single dose of GLPG5101 IV cell suspension for infusion at the selected RP2D level for this disease subtype on Day 0

Group IX: Phase 2 (Dose expansion phase): Cohort 1a: DLBCL 2L+ Experimental Treatment 1 Intervention

Participants in this cohort will receive a single dose of GLPG5101 IV cell suspension for infusion at the selected RP2D level for this disease subtype on Day 0

Group X: Phase 1 (Dose escalation phase): Dose level 3 Experimental Treatment 1 Intervention

Participants will receive a single dose of GLPG5101 IV cell suspension for infusion at dose level 3 on Day 0.

Group XI: Phase 1 (Dose escalation phase): Dose level 2 Experimental Treatment 1 Intervention

Participants will receive a single dose of GLPG5101 IV cell suspension for infusion at dose level 2 on Day 0.

Group XII: Phase 1 (Dose escalation phase): Dose level 1 Experimental Treatment 1 Intervention

Participants will receive a single dose of GLPG5101 intravenous (IV) cell suspension for infusion at dose level 1 on Day 0.

Who Is Running the Clinical Trial?

Galapagos NV

Lead Sponsor

Trials

140

Recruited

23,500+

Dr. Walid Abi-Saab

Galapagos NV

Chief Medical Officer since 2017

MD from the American University of Beirut, specialization in Internal Medicine and Rheumatology

Dr. Paul Stoffels

Galapagos NV

Chief Executive Officer since 2022

MD from the University of Antwerp, specialization in Infectious Diseases and Tropical Medicine at the Institute of Tropical Medicine in Antwerp

Findings from Research

Adoptive cellular therapy using CAR-modified T cells targeting CD19 has shown significant clinical efficacy in treating relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) in both children and adults, with some patients also benefiting from treatment for chronic lymphocytic leukemia (CLL) and B-cell non-Hodgkin lymphoma (B-NHL).

Current research is expanding the use of CAR T-cell therapies to other cancers, including multiple myeloma and solid tumors, while also addressing challenges such as severe cytokine release syndrome and neurologic toxicities associated with the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review: Current clinical applications of chimeric antigen receptor (CAR) modified T cells. Geyer, MB., Brentjens, RJ.[2022]

In a study involving six B-cell lymphoma patients, second-generation chimeric antigen receptor (CAR)-T cells showed superior expansion and persistence compared to first-generation CAR-T cells, indicating improved potential for effective cancer treatment.

This research highlights the importance of CAR-T cell design, as the enhanced ability of second-generation CAR-T cells to home in on tumor sites may lead to better clinical outcomes for patients with lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing tumor-targeting chimeric antigen receptor T cells in B-cell lymphoma patients. Gandhi, M., Jones, K.[2011]

Second-generation CAR T cells targeting CD19 can effectively eliminate B cell lymphoma in mice, but they also induce dose-dependent acute toxicity and chronic granulomatous reactions due to elevated Th2 cytokines.

In contrast, first-generation CAR T cells did not exhibit such toxic effects, suggesting that the design of CAR constructs significantly impacts both their therapeutic efficacy and safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential role of Th1 and Th2 cytokines in autotoxicity driven by CD19-specific second-generation chimeric antigen receptor T cells in a mouse model. Cheadle, EJ., Sheard, V., Rothwell, DG., et al.[2022]

CD19-directed CAR-T therapy has shown promising long-term results, achieving durable remissions in nearly 50% of patients with relapsed/refractory large B-cell lymphoma, significantly improving their prognosis compared to the previous median survival of about 6 months with standard treatments.

The success of CAR-T therapy in large B-cell lymphoma has led to its expansion into other types of lymphomas, such as mantle cell and follicular lymphoma, and ongoing development of new CAR-T platforms aimed at enhancing efficacy and reducing toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Indications and platforms for CAR-T therapy in lymphomas beyond DLBCL. Iqbal, M., Savani, BN., Hamadani, M.[2023]

Approximately 20% of lymphoma patients develop resistance to conventional therapies, leading to a poor prognosis with a median survival of only 6.3 months, highlighting the need for effective new treatments.

T-cell immunotherapy, particularly CAR T-cell therapy targeting the CD19 antigen, has shown remarkable efficacy in inducing complete and durable responses in patients with chemotherapy-refractory B-cell non-Hodgkin lymphoma, and has been approved by the FDA for this use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use of chimeric antigen receptor T cells in patients with non-Hodgkin lymphoma. Lulla, PD., Hill, LC., Ramos, CA., et al.[2021]

CAR T-cell therapy, particularly anti-CD19 CAR T cells, shows strong efficacy in treating resistant forms of B-cell lymphomas, achieving durable complete remissions lasting over 2 years in some patients with refractory diffuse large-B-cell lymphoma (DLBCL).

Despite their effectiveness, CAR T-cell therapies can lead to severe toxicities, such as cytokine-release syndrome and neurological issues, highlighting the need for careful management and ongoing research into safer CAR designs and treatment combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor T-cell therapies for lymphoma. Brudno, JN., Kochenderfer, JN.[2022]

CAR T cells have shown significant clinical effectiveness in treating blood cancers, but their success in solid tumors has been less impressive, highlighting the need for further research in this area.

While CAR T cell therapy can lead to serious side effects like cytokine release syndrome and neurological toxicity, some theoretical risks have not yet been observed in clinical settings, emphasizing the importance of managing known toxicities for safe treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity and management in CAR T-cell therapy. Bonifant, CL., Jackson, HJ., Brentjens, RJ., et al.[2023]

Chimeric antigen receptor (CAR) T cell therapy targeting CD19 and CD20 has shown a promising overall response rate of 61% in treating B-cell hematologic malignancies, with a complete response rate of 42% and partial response rate of 19% across 16 studies involving 195 patients.

However, the therapy is associated with significant adverse events, including cytokine release syndrome and neurotoxicity (both at 33%), and B-cell aplasia in 54% of patients, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-CD 19 and anti-CD 20 CAR-modified T cells for B-cell malignancies: a systematic review and meta-analysis. Riaz, IB., Zahid, U., Kamal, MU., et al.[2023]

Gene-modified T cells expressing a CD19-specific chimeric antigen receptor (CAR) effectively targeted and eliminated B cell lymphoma cells in mice, demonstrating strong antitumor activity even in the presence of normal CD19-positive B cells.

Despite the initial success in eradicating tumors, the CAR T cells showed a significant decrease in numbers over time, but importantly, there were no signs of harmful effects on normal tissues, indicating a favorable safety profile for this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Natural expression of the CD19 antigen impacts the long-term engraftment but not antitumor activity of CD19-specific engineered T cells. Cheadle, EJ., Hawkins, RE., Batha, H., et al.[2023]

Anti-CXCR5 CAR-T cell therapy effectively targets both B cell Non-Hodgkin's lymphoma (B-NHLs) and follicular T helper (Tfh) cells, showing greater potency in eradicating these cells compared to traditional CD19 CAR-T cells in laboratory studies.

In murine models, anti-CXCR5 CAR-T cells specifically deplete both malignant B cells and Tfh cells without causing harmful effects on normal tissues, suggesting a safe and effective treatment strategy for nodal B-NHLs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CXCR5 CAR-T cells simultaneously target B cell non-Hodgkin's lymphoma and tumor-supportive follicular T helper cells. Bunse, M., Pfeilschifter, J., Bluhm, J., et al.[2021]

Adoptive T cell therapy using anti-CD19-CAR5-T cells, which secrete anti-PD-L1, showed improved effectiveness in killing aggressive B cell lymphomas compared to traditional anti-CD19-CAR-T cells, especially at low effector-to-target ratios.

The study demonstrated that anti-CD19-CAR5-T cells not only proliferated better but also enhanced cytotoxicity against CD19+/PD-L1high tumor cells, suggesting a promising new approach for treating difficult-to-treat B cell malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-CD19 chimeric antigen receptor T cells secreting anti-PD-L1 single-chain variable fragment attenuate PD-L1 mediated T cell inhibition. Yuti, P., Wutti-In, Y., Sawasdee, N., et al.[2022]

The study reports on three patients with relapsed B-cell lymphomas who were treated with autologous T cells modified to express a CD20-targeted chimeric antigen receptor (CAR), showing promising clinical efficacy.

The treatment demonstrated a favorable safety profile, indicating that genetically modified T cells can be a viable option for patients with relapsed B-cell lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CARs and cancers: questions and answers. Brentjens, RJ.[2021]

In a study involving 16 healthy donors, researchers found that using specific activation conditions (soluble anti-CD3/CD28 mAbs with IL15 and IL21) improved the quality and function of gene-modified T cells, which is crucial for effective cancer treatment.

These optimized T cells showed better binding to target molecules and a more favorable phenotype, suggesting that these methods could enhance the efficacy of CAR and TCR therapies in future clinical trials for patients with certain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T cell receptor-engineered T cells to treat solid tumors: T cell processing toward optimal T cell fitness. Lamers, CH., van Steenbergen-Langeveld, S., van Brakel, M., et al.[2018]

The study developed a murine CAR-T cell therapy targeting CD105, showing that while higher doses were toxic, lower doses were safe and modestly effective against melanoma in mice.

A human version of the CD105 CAR-T cell was also created, demonstrating efficacy in treating human melanoma and acute myeloid leukemia, suggesting CD105 as a promising target for CAR-T therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fully murine CD105-targeted CAR-T cells provide an immunocompetent model for CAR-T cell biology. Lontos, K., Wang, Y., Colbert, M., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Review: Current clinical applications of chimeric antigen receptor (CAR) modified T cells. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Optimizing tumor-targeting chimeric antigen receptor T cells in B-cell lymphoma patients. [2011]

3. United States pubmed.ncbi.nlm.nih.gov

Differential role of Th1 and Th2 cytokines in autotoxicity driven by CD19-specific second-generation chimeric antigen receptor T cells in a mouse model. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

New Indications and platforms for CAR-T therapy in lymphomas beyond DLBCL. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

The use of chimeric antigen receptor T cells in patients with non-Hodgkin lymphoma. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor T-cell therapies for lymphoma. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Toxicity and management in CAR T-cell therapy. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Anti-CD 19 and anti-CD 20 CAR-modified T cells for B-cell malignancies: a systematic review and meta-analysis. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Natural expression of the CD19 antigen impacts the long-term engraftment but not antitumor activity of CD19-specific engineered T cells. [2023]

10. England pubmed.ncbi.nlm.nih.gov

CXCR5 CAR-T cells simultaneously target B cell non-Hodgkin's lymphoma and tumor-supportive follicular T helper cells. [2021]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Anti-CD19 chimeric antigen receptor T cells secreting anti-PD-L1 single-chain variable fragment attenuate PD-L1 mediated T cell inhibition. [2022]

12. United States pubmed.ncbi.nlm.nih.gov

CARs and cancers: questions and answers. [2021]

13. United States pubmed.ncbi.nlm.nih.gov

T cell receptor-engineered T cells to treat solid tumors: T cell processing toward optimal T cell fitness. [2018]

14. United States pubmed.ncbi.nlm.nih.gov

Fully murine CD105-targeted CAR-T cells provide an immunocompetent model for CAR-T cell biology. [2022]