CCS1477 for Blood Cancers

Recruiting at 19 trial locations

Overseen By Karen Clegg, MD, MFPM

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: CellCentric Ltd.

Must not be taking: Chemotherapy, Statins, CYP3A4 inhibitors, others

Disqualifiers: Severe diseases, Uncontrolled illness, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 35 days

250 Participants Needed

Trial Summary

What is the purpose of this trial?

A Phase 1/2a study to assess the safety, tolerability, PK and biological activity of CCS1477 (inobrodib) in patients with Non-Hodgkin Lymphoma, Multiple Myeloma, Acute Myeloid Leukaemia or High Risk Myelodysplastic syndrome.

Do I have to stop taking my current medications for the trial?

Yes, you may need to stop some medications. You must stop taking any chemotherapy, investigational agents, or other anti-cancer drugs at least 14 days before the trial. You also need to stop strong inhibitors or inducers of CYP3A4, statins, and CYP2C8 substrates within 2-4 weeks before starting the trial.

What data supports the idea that CCS1477 for Blood Cancers is an effective treatment?

The available research does not provide specific data on the effectiveness of CCS1477 for Blood Cancers. Instead, it focuses on other treatments for chronic myeloid leukemia, such as tyrosine kinase inhibitors (TKIs) like imatinib, dasatinib, bosutinib, and nilotinib. These studies highlight the challenges of resistance and side effects associated with these drugs, but do not mention CCS1477. Therefore, there is no direct evidence from the provided information to support the effectiveness of CCS1477 for Blood Cancers. ^{1 2 3 4 5}

What safety data exists for CCS1477 (Inobrodib) in blood cancers?

The provided research does not contain specific safety data for CCS1477 (Inobrodib) in blood cancers. The articles focus on immune checkpoint inhibitors and their associated hematological toxicities, but do not mention CCS1477 or Inobrodib. Further research specific to CCS1477 is needed to determine its safety profile in blood cancer clinical trials. ^{6 7 8 9 10}

Is the drug CCS1477 a promising treatment for blood cancers?

The information provided does not directly mention CCS1477 or its effects on blood cancers, so we cannot determine if it is a promising treatment based on this data. ^{11 12 13 14 15}

Research Team

Tim Somervaille

Principal Investigator

The Christie NHS Foundation Trust

Eligibility Criteria

This trial is for adults with certain blood cancers like Non-Hodgkin Lymphoma, Multiple Myeloma, Acute Myeloid Leukemia or High Risk Myelodysplastic Syndrome who have relapsed after standard treatments. They must be relatively active (ECOG 0-2), have good organ function and not have taken other cancer drugs recently. People with severe diseases, recent major surgeries or those on specific drugs that affect the body's drug processing enzymes are excluded.

Inclusion Criteria

I can take care of myself and perform daily activities.

I have undergone standard treatment for my condition.

Provision of consent

Exclusion Criteria

I will stop taking statins before starting the study treatment.

I haven't taken any sensitive CYP2C8 drugs in the last 2 weeks.

I haven't taken any cancer drugs or experimental treatments in the last 14 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive CCS1477 as monotherapy or in combination with other drugs for dose escalation and expansion

35 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 12 months

Treatment Details

Interventions

• CCS1477

Trial Overview The study is testing CCS1477 alone or in combination with other drugs like Pomalidomide, Azacitidine, Dexamethasone, and Venetoclax to see how safe they are and how well they work against different blood cancers. It's an early-stage trial (Phase 1/2a) which means it's partly about finding the right dose as well as checking for any signs of effectiveness.

Participant Groups

Group I: CCS1477 monotherapy expansion and combination dose finding and expansion - MM Experimental Treatment 3 Interventions

CCS1477 monotherapy, CCS1477 combination with pomalidomide-dexamethasone

Group II: CCS1477 monotherapy expansion and combination dose finding and expansion - Higher risk MDS Experimental Treatment 3 Interventions

CCS1477 monotherapy, CCS1477 combination with azacitidine, CCS1477 combination with azacitidine and venetoclax

Group III: CCS1477 monotherapy expansion and combination dose finding and expansion - AML Experimental Treatment 3 Interventions

CCS1477 monotherapy, CCS1477 combination with azacitidine, CCS1477 combination with azacitidine and venetoclax

Group IV: CCS1477 expansion phase NHL/Peripheral T-cell lymphoma Experimental Treatment 1 Intervention

CCS1477 monotherapy

Group V: CCS1477 dose escalation NHL/MM Experimental Treatment 1 Intervention

CCS1477 monotherapy

Group VI: CCS1477 dose escalation AML/Higher risk MDS Experimental Treatment 1 Intervention

CCS1477 monotherapy

Who Is Running the Clinical Trial?

CellCentric Ltd.

Lead Sponsor

Trials

3

Recruited

620+

Findings from Research

In a study of 79 patients with chronic myeloid leukaemia, early increases in ABCB1 mRNA expression during imatinib therapy were found to predict poor treatment responses, indicating a potential for resistance to therapy.

Patients with a significant rise in ABCB1 mRNA (≥2.2 fold) were less likely to achieve early and major molecular responses, and this trend continued even when switched to nilotinib, suggesting that monitoring ABCB1 levels could help identify those needing alternative treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The clinical significance of ABCB1 overexpression in predicting outcome of CML patients undergoing first-line imatinib treatment. Eadie, LN., Dang, P., Saunders, VA., et al.[2022]

A meta-analysis of 70 studies found that dasatinib is associated with the highest prevalence of hematological adverse events (AEs) in chronic myeloid leukemia (CML) patients, particularly anemia (54.5%), neutropenia (51.2%), and thrombocytopenia (62.2%).

Compared to imatinib, dasatinib significantly increases the odds of developing anemia (OR = 1.65), neutropenia (OR = 1.72), and thrombocytopenia (OR = 2.04), while nilotinib shows a lower risk for these AEs, indicating varying safety profiles among different TKIs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematological Adverse Events with Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia: A Systematic Review with Meta-Analysis. Kronick, O., Chen, X., Mehra, N., et al.[2023]

Dendritic cells (DC) can be effectively generated from the blood of chronic myeloid leukemia (CML) patients, especially those treated with tyrosine kinase inhibitors (TKI), indicating a potential for DC immunotherapy in patients who do not achieve complete remission.

Patients treated with TKI showed a higher yield of mature DC and differences in immune cell populations, such as increased T regulatory and Th17 cells, suggesting these cells may play a role in the immune response against CML and warrant further investigation for enhancing immunotherapy outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of monocyte-derived dendritic cells, T regulatory and Th17 cells in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. Hus, I., Tabarkiewicz, J., Lewandowska, M., et al.[2019]

Chronic myeloid leukemia (CML) patients with high levels of the T-cell inhibitory receptor CD86 on plasmacytoid dendritic cells (pDC) are at a greater risk of relapse after stopping tyrosine kinase inhibitor (TKI) therapy, with a one-year relapse-free survival rate of only 30.1% for those with high CD86+pDC counts compared to 70.0% for those with lower counts.

The study suggests that low CD86+pDC levels may be a predictive marker for treatment-free remission (TFR) in CML patients, indicating that longer TKI exposure before discontinuation benefits those with lower CD86+pDC counts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expression of the CTLA-4 ligand CD86 on plasmacytoid dendritic cells (pDC) predicts risk of disease recurrence after treatment discontinuation in CML. Schütz, C., Inselmann, S., Saussele, S., et al.[2020]

In a study of 31 patients with chronic myeloid leukemia treated with dasatinib, those with the NKG2D HNK1 haplotype achieved a deeper remission (MR4.5) more quickly, indicating a potential genetic marker for treatment response.

The presence of the NKG2D HNK1 allele was linked to enhanced NK cell activity, as shown by increased phosphorylation of VAV1, suggesting that genetic variations in NK cell receptors could help predict successful treatment-free remission after dasatinib therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NKG2D gene polymorphisms are associated with disease control of chronic myeloid leukemia by dasatinib. Hara, R., Onizuka, M., Matsusita, E., et al.[2018]

In a study of 333 patients in early phase clinical trials, four cases of immune checkpoint inhibitor anemias (ICI-A) were identified, highlighting the need for awareness of these potentially life-threatening conditions during treatment.

Glucocorticoids were found to be an effective first-line treatment for ICI-A, with most patients achieving complete recovery and continuing with non-immunotherapy treatments, indicating a positive outcome when these anemias are promptly recognized and managed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spectrum of Immune Checkpoint Inhibitor Anemias: Results From a Single Center, Early-Phase Clinical Trials Case Series Experience. Nelson, BE., Ejezie, CL., Stephen, BA., et al.[2022]

Immune checkpoint inhibitors (ICIs) can lead to serious hematologic immune-related adverse events (heme-irAEs) such as agranulocytosis, aplastic anemia, and thrombocytopenia, with a notable fatality rate of 12%.

The most common heme-irAEs are immune thrombocytopenia and hemolytic anemia, particularly associated with nivolumab, and these adverse events tend to occur earlier with CTLA-4 inhibitors compared to anti-PD-L1/PD-1 agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current challenges of hematologic complications due to immune checkpoint blockade: a comprehensive review. Ghanem, P., Marrone, K., Shanbhag, S., et al.[2022]

In a meta-analysis of five studies involving 2399 patients, nivolumab was found to significantly lower the risk of hematological toxicities such as anemia, neutropenia, and leukopenia compared to other treatments.

The relative risks for these conditions were notably low, indicating that nivolumab may be a safer option regarding hematological side effects, which is important for clinicians when considering treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The risks of hematological toxicities of nivolumab in cancer patients: A PRISMA-compliant meta-analysis. Shi, Z., Liu, X., Chen, M., et al.[2023]

Monoclonal antibodies targeting CTLA-4 and PD-1 have been approved for treating metastatic melanoma and advanced non-small-cell lung cancers, making them widely available in cancer centers globally.

While these immune checkpoint inhibitors are effective, they can cause immune-related adverse events (irAEs) in about 10% of patients, which can be severe and life-threatening if not properly managed, highlighting the need for oncologists to be aware of and prepared for these potential toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Champiat, S., Lambotte, O., Barreau, E., et al.[2022]

Immune checkpoint inhibitors (ICIs), particularly nivolumab and pembrolizumab, are effective treatments for relapsed and refractory classical Hodgkin lymphoma and primary mediastinal large B cell lymphoma, highlighting their role in hematological malignancies.

While ICIs work by enhancing the immune system's ability to fight cancer, they can also cause immune-related adverse events (irAEs) that may affect any organ and can be severe, necessitating careful management in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity of Immune-Checkpoint Inhibitors in Hematological Malignancies. Hradska, K., Hajek, R., Jelinek, T.[2021]

The Bcr-Abl fusion protein's abnormal tyrosine kinase activity is a key factor in chronic myelogenous leukemia (CML), making it a prime target for treatment.

ST1571, a specific inhibitor of the Bcr-Abl tyrosine kinase, has shown effectiveness in preclinical studies by selectively killing Bcr-Abl-positive cells, indicating its potential as a new therapy for CML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ST1571, a tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia: validating the promise of molecularly targeted therapy. Mauro, MJ., O'Dwyer, ME., Druker, BJ.[2019]

A study of over 100 hematological cell line models revealed that certain mantle cell lymphoma (MCL) cell lines are highly sensitive to B cell receptor (BCR) signaling inhibitors like ibrutinib and sotrastaurin, linked to chronic activation of the classical NF-κB pathway.

In contrast, MCL cell lines that are insensitive to these inhibitors often have genetic mutations affecting the alternative NF-κB pathway, suggesting that targeting the protein kinase NIK could be a promising new treatment strategy for patients with refractory MCL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological and genomic profiling identifies NF-κB-targeted treatment strategies for mantle cell lymphoma. Rahal, R., Frick, M., Romero, R., et al.[2023]

The BCR-ABL oncoprotein, responsible for chronic myeloid leukaemia (CML), is a key target for treatment, and the compound ST1571 has shown promising efficacy in early trials, particularly in patients resistant to interferon-alpha.

Phase I trials indicated that ST1571 is well-tolerated and effective in achieving hematological control and cytogenetic responses, although there is a risk of drug resistance that may necessitate combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tyrosine kinase inhibitors in the treatment of chronic myeloid leukaemia: so far so good? Drummond, MW., Holyoake, TL.[2015]

Olverembatinib (HQP1351) is a third-generation tyrosine kinase inhibitor specifically designed to target BCR-ABL1 mutations, including the T315I mutation that causes resistance to earlier treatments, making it a promising option for patients with chronic myeloid leukaemia (CML).

In November 2021, olverembatinib was approved in China for adult patients with TKI-resistant chronic-phase or accelerated-phase CML harboring the T315I mutation, indicating its efficacy in overcoming resistance that limits other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olverembatinib: First Approval. Dhillon, S.[2022]

The bcr-abl fusion protein, which is crucial for the development of chronic myelogenous leukemia, is effectively targeted by the tyrosine kinase inhibitor ST1571, showing selective toxicity to bcr-abl-expressing cells in both laboratory and animal studies.

Early clinical trials of ST1571 have yielded promising results, indicating that it may soon be integrated into treatment plans for patients with chronic myelogenous leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Status of bcr-abl tyrosine kinase inhibitors in chronic myelogenous leukemia. O'Dwyer, ME., Druker, BJ.[2019]

References

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

The clinical significance of ABCB1 overexpression in predicting outcome of CML patients undergoing first-line imatinib treatment. [2022]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Hematological Adverse Events with Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia: A Systematic Review with Meta-Analysis. [2023]

3. Poland pubmed.ncbi.nlm.nih.gov

Evaluation of monocyte-derived dendritic cells, T regulatory and Th17 cells in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. [2019]

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

Expression of the CTLA-4 ligand CD86 on plasmacytoid dendritic cells (pDC) predicts risk of disease recurrence after treatment discontinuation in CML. [2020]

5. Japan pubmed.ncbi.nlm.nih.gov

NKG2D gene polymorphisms are associated with disease control of chronic myeloid leukemia by dasatinib. [2018]

6. Canada pubmed.ncbi.nlm.nih.gov

Spectrum of Immune Checkpoint Inhibitor Anemias: Results From a Single Center, Early-Phase Clinical Trials Case Series Experience. [2022]

7. Germany pubmed.ncbi.nlm.nih.gov

Current challenges of hematologic complications due to immune checkpoint blockade: a comprehensive review. [2022]

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

The risks of hematological toxicities of nivolumab in cancer patients: A PRISMA-compliant meta-analysis. [2023]

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

Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. [2022]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Toxicity of Immune-Checkpoint Inhibitors in Hematological Malignancies. [2021]

11. Germany pubmed.ncbi.nlm.nih.gov

ST1571, a tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia: validating the promise of molecularly targeted therapy. [2019]

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

Pharmacological and genomic profiling identifies NF-κB-targeted treatment strategies for mantle cell lymphoma. [2023]

13. England pubmed.ncbi.nlm.nih.gov

Tyrosine kinase inhibitors in the treatment of chronic myeloid leukaemia: so far so good? [2015]

14. New Zealand pubmed.ncbi.nlm.nih.gov

Olverembatinib: First Approval. [2022]

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

Status of bcr-abl tyrosine kinase inhibitors in chronic myelogenous leukemia. [2019]