STP938 for Lymphoma

Recruiting at 15 trial locations

Overseen By Maureen Higgins

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Step Pharma, SAS

Must not be taking: Monoclonal antibodies, others

Disqualifiers: Pregnancy, CNS involvement, Active malignancy, others

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

Compensation: Varies

Number of Visits: Unknown

180 Participants Needed

Trial Summary

What is the purpose of this trial?

The Phase 1 part of the study is a dose escalation of STP938 as monotherapy. The Phase 2 part of the study is cohort expansion of STP938 as a monotherapy in 5 different B and T cell lymphomas.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have had systemic cancer treatments or certain other therapies within 4 weeks before enrolling.

What data supports the effectiveness of the drug STP938 (Dencatistat) for treating lymphoma?

Research on similar drugs like pevonedistat, which targets the same NEDD8-activating enzyme, shows promising results in reducing lymphoma cell viability and inducing tumor regression in preclinical models. This suggests that STP938 may also be effective in treating lymphoma by targeting similar pathways. ^{1 2 3 4 5}

How does the drug STP938 differ from other treatments for lymphoma?

STP938 is unique because it targets the CD38 molecule, which is present on many lymphoma cells, making it a promising option for antibody therapy. This approach is different from traditional treatments as it specifically aims to inhibit CD38 activity, potentially offering a more targeted and effective treatment for lymphoma. ^{6 7 8 9 10}

Research Team

Maureen Higgins

Principal Investigator

Step Pharma

Eligibility Criteria

Adults over 18 with B-cell or T-cell lymphoma that's come back or hasn't responded to treatment can join this trial. They must have tried at least two other treatments and have no other options left. Participants need good organ function, measurable disease, a decent performance status, and a life expectancy of more than three months.

Inclusion Criteria

My lymphoma has returned or didn't respond to treatment.

Life expectancy > 3 months as assessed by the Investigator

Signed and dated informed consent, and able to comply with the study procedures and any locally required authorization

Exclusion Criteria

I am not pregnant, breastfeeding, and if capable of childbearing or fathering a child, I agree to use contraception.

My cancer has spread to my brain or spinal cord.

I have had cancer within the last 2 years.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1: Dose Escalation

Participants receive STP938 as oral monotherapy to determine safety and optimal dosing

16 days

Multiple visits for dose escalation and monitoring

Phase 2: Cohort Expansion

Participants receive STP938 at defined dose levels to evaluate efficacy in different lymphoma types

9 months

Regular visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• STP938

Trial Overview STP938 is being tested in adults with certain types of lymphoma. The first phase will find the right dose of STP938 when used alone. The second phase will see how well it works on its own in different groups of patients with B and T cell lymphomas.

Participant Groups

Group I: Phase 2 (Part 2; expansion) Experimental Treatment 1 Intervention

At defined dose level(s) with STP938 administered as oral monotherapy

Group II: Phase 1 (Part 1, Dose Escalation) Experimental Treatment 1 Intervention

Up to 5 dose levels with STP938 administered as oral monotherapy

Who Is Running the Clinical Trial?

Step Pharma, SAS

Lead Sponsor

Trials

3

Recruited

270+

Findings from Research

Pevonedistat, a selective NEDD8-activating enzyme inhibitor, effectively reduces the viability of canine diffuse large B-cell lymphoma (DLBCL) cells by inducing G1 cell cycle arrest and apoptosis, targeting the deregulated NF-κB pathway.

In vivo studies demonstrated that pevonedistat administration led to significant tumor regression in mice with canine DLBCL xenograft tumors, supporting its potential as a novel anti-cancer therapy for both dogs and humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting NEDD8-activating enzyme is a new approach to treat canine diffuse large B-cell lymphoma. Assumpção, ALFV., Lu, Z., Marlowe, KW., et al.[2023]

LP-284, a new-generation acylfulvene compound, shows strong potential in treating non-Hodgkin's lymphoma (NHL) by inducing repair of double-strand DNA breaks and demonstrating nanomolar potency across fifteen NHL cell lines.

In vivo studies revealed that LP-284 significantly prolongs survival in mice with mantle cell lymphoma, outperforming existing treatments like bortezomib and ibrutinib, and effectively inhibits tumor growth in cases resistant to these therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

LP-284, a small molecule acylfulvene, exerts potent antitumor activity in preclinical non-Hodgkin's lymphoma models and in cells deficient in DNA damage repair. Zhou, J., Sturtevant, D., Love, C., et al.[2023]

Pevonedistat, a NEDD8-activating enzyme inhibitor, effectively induced cell death in activated B-cell diffuse large B-cell lymphoma (DLBCL) cell lines and inhibited NFκB activity, suggesting a promising mechanism of action against this type of cancer.

In pre-clinical models, pevonedistat enhanced the effectiveness of several chemotherapy agents and targeted therapies, leading to prolonged survival in mice when combined with ibrutinib or cytarabine, indicating its potential as a valuable treatment option in DLBCL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pevonedistat, a NEDD8-Activating Enzyme Inhibitor, Induces Apoptosis and Augments Efficacy of Chemotherapy and Small Molecule Inhibitors in Pre-clinical Models of Diffuse Large B-cell Lymphoma. Torka, P., Mavis, C., Kothari, S., et al.[2022]

Recent advances in understanding B-cell lymphomas have led to the development of new therapeutic agents that target specific tumor cell signaling pathways and microenvironments, enhancing treatment options.

The review highlights various innovative therapies, including B-cell receptor pathway inhibitors, Bcl-2 inhibitors, monoclonal antibodies, and CAR T-cell therapies, which show promise based on recent clinical data.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Breakthrough therapies in B-cell non-Hodgkin lymphoma. Cheah, CY., Fowler, NH., Wang, ML.[2020]

Advances in genomic and proteomic technologies have identified new biomarkers and drug targets for aggressive B- and T-cell non-Hodgkin's lymphomas (NHLs), but the development of effective therapies has been slow due to the absence of a therapeutic signature for these subtypes.

Promising new therapies are being developed that target key oncogenic pathways involved in NHL, including immune kinases and apoptosis, with a focus on creating a therapeutic signature based on the 10 hallmarks of cancer to guide future drug development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel therapeutics for aggressive non-Hodgkin's lymphoma. Mahadevan, D., Fisher, RI.[2021]

CD38, an enzyme on lymphocytes, can stimulate strong cell growth when combined with other factors, but B cells from xid mice do not respond to this stimulation, indicating a signaling defect.

The unresponsiveness of xid B cells to CD38 stimulation suggests that Bruton's tyrosine kinase (btk) plays a crucial role in the signaling pathway necessary for this response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD38 unresponsiveness of xid B cells implicates Bruton's tyrosine kinase (btk) as a regular of CD38 induced signal transduction. Santos-Argumedo, L., Lund, FE., Heath, AW., et al.[2019]

In a study using SCID mice injected with the aggressive Burkitt's lymphoma cell line Ramos, treatment with anti-CD19 and anti-CD38 immunotoxins significantly prolonged survival compared to controls, with the anti-CD38 immunotoxin showing the greatest effect.

Combining both immunotoxins resulted in a remarkable therapeutic outcome, with 20% of treated mice surviving disease-free for up to 300 days, suggesting that targeting both CD19 and CD38 could be an effective strategy for treating B-cell lymphomas and acute lymphoblastic leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapy of human B-cell lymphoma bearing SCID mice is more effective with anti-CD19- and anti-CD38-saporin immunotoxins used in combination than with either immunotoxin used alone. Flavell, DJ., Boehm, DA., Emery, L., et al.[2019]

The compound ST2825 effectively inhibits the growth of various lymphoma and leukaemia cell lines by inducing apoptosis and down-regulating key components of the NF-κB signaling pathway, including MYD88 and BTK.

ST2825 shows potential as a novel treatment for both B-lymphoid malignancies with MYD88 mutations and those with wild-type MYD88, indicating its broad applicability in targeting these cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MYD88 Inhibitor ST2825 Suppresses the Growth of Lymphoma and Leukaemia Cells. Shiratori, E., Itoh, M., Tohda, S.[2017]

CD38 is a promising target for antibody therapy in various lymphoid tumors, including multiple myeloma, due to its strong presence on tumor cell surfaces.

Recent advancements in anti-CD38 antibodies have shown potent cytolytic effects against myeloma cells, with some antibodies also inhibiting CD38's cyclase activity, enhancing their therapeutic potential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD38 as a therapeutic target. Stevenson, GT.[2018]

P38α/β plays a crucial role in the proliferation and survival of acute lymphoblastic leukemia (ALL), with its activation linked to the growth of leukemia cells and associated with relapses in patients with TEL-AML1-positive leukemia.

Inhibition of p38α/β using small molecules has been shown to suppress leukemic growth and improve survival in experimental models, suggesting that targeting this pathway could enhance the effectiveness of existing leukemia treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of p38α/β inhibition on acute lymphoblastic leukemia proliferation and survival in vivo. Alsadeq, A., Strube, S., Krause, S., et al.[2018]

References

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

Targeting NEDD8-activating enzyme is a new approach to treat canine diffuse large B-cell lymphoma. [2023]

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

LP-284, a small molecule acylfulvene, exerts potent antitumor activity in preclinical non-Hodgkin's lymphoma models and in cells deficient in DNA damage repair. [2023]

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

Pevonedistat, a NEDD8-Activating Enzyme Inhibitor, Induces Apoptosis and Augments Efficacy of Chemotherapy and Small Molecule Inhibitors in Pre-clinical Models of Diffuse Large B-cell Lymphoma. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Breakthrough therapies in B-cell non-Hodgkin lymphoma. [2020]

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

Novel therapeutics for aggressive non-Hodgkin's lymphoma. [2021]

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

CD38 unresponsiveness of xid B cells implicates Bruton's tyrosine kinase (btk) as a regular of CD38 induced signal transduction. [2019]

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

Therapy of human B-cell lymphoma bearing SCID mice is more effective with anti-CD19- and anti-CD38-saporin immunotoxins used in combination than with either immunotoxin used alone. [2019]

8. Greece pubmed.ncbi.nlm.nih.gov

MYD88 Inhibitor ST2825 Suppresses the Growth of Lymphoma and Leukaemia Cells. [2017]

9. England pubmed.ncbi.nlm.nih.gov

CD38 as a therapeutic target. [2018]

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

Effects of p38α/β inhibition on acute lymphoblastic leukemia proliferation and survival in vivo. [2018]