CCS1477 for Blood Cancers

Recruiting at 20 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment called CCS1477 (also known as Inobrodib) for its safety and effectiveness in treating certain blood cancers, including Non-Hodgkin Lymphoma, Multiple Myeloma, Acute Myeloid Leukemia, and high-risk Myelodysplastic Syndrome. The study examines how CCS1477 works alone and with other medications to determine its potential for patients who haven't responded to standard treatments. It seeks participants diagnosed with these conditions who have not found success with other treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that CCS1477, also known as inobrodib, is undergoing safety testing for various blood cancers. Earlier studies found that CCS1477 slowed the growth of cancer cells in conditions like acute myeloid leukemia (AML) and multiple myeloma (MM).

Before human testing, studies indicated that CCS1477 effectively stopped cancer cells from multiplying, suggesting it could be a promising treatment.

In terms of safety, CCS1477 remains in the early stages of human trials, with researchers closely monitoring any side effects. These trials focus on treatment tolerance and potential negative effects. While detailed safety information is still being gathered, the ongoing trials aim to ensure the treatment's safety for patients. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about CCS1477 because it offers a novel approach by targeting the p300/CBP proteins, which are crucial for the growth and survival of certain blood cancers, like AML, multiple myeloma, and non-Hodgkin lymphoma. Unlike existing treatments that often target DNA or the cell cycle, CCS1477 intervenes at a different point in the cancer growth pathway, potentially offering benefits even when patients have already tried other treatments. Additionally, CCS1477 is being tested both as a standalone therapy and in combination with other drugs like azacitidine and venetoclax, which may enhance its effectiveness and provide more treatment options for patients with these challenging conditions.

What evidence suggests that CCS1477 could be an effective treatment for blood cancers?

Research has shown that CCS1477, also known as inobrodib, may be effective against several blood cancers, including multiple myeloma and acute myeloid leukemia. In this trial, participants may receive CCS1477 as monotherapy or in combination with other drugs. An early study on multiple myeloma found that 67% of patients responded positively when CCS1477 was combined with other drugs. For acute myeloid leukemia, it targets specific proteins in cancer cells, potentially stopping their growth. Studies also suggest it could help with non-Hodgkin lymphoma, where some positive responses have been observed. The drug blocks certain proteins that aid cancer cell growth, which might halt their growth and cause them to die. Early results are promising, indicating that CCS1477 could be effective for these cancers, but more research is needed to confirm these findings. ^{1 2 6 7 8}

Who Is on the Research Team?

Tim Somervaille

Principal Investigator

The Christie NHS Foundation Trust

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

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 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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04068597

NCT04068597 | Study to Evaluate CCS1477 (Inobrodib) in ... 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 ...

2. aacrjournals.org aacrjournals.org/cancerres/article/83/8_Supplement/CT136/725394/Abstract-CT136-An-open-label-phase-I-IIa-study-to

Abstract CT136: An open-label phase I/IIa study to evaluate ... An open-label phase I/IIa study to evaluate the safety and efficacy of CCS1477 as monotherapy and in combination in patients with advanced ...

3. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/5795/505153/Preclinical-and-Early-Clinical-Results-Indicate-a

Preclinical and Early Clinical Results Indicate a Role for the ... Inobrodib (CCS1477) is a potent, selective, and orally bioavailable inhibitor of the bromodomains of CBP and EP300, two homologous histone acetyltransferases.

4. sciencedirect.com sciencedirect.com/science/article/pii/S1535610823003665

Therapeutic targeting of EP300/CBP by bromodomain ... CCS1477 (inobrodib) is a potent, selective EP300/CBP bromodomain inhibitor which induces cell-cycle arrest and differentiation in hematologic malignancy model ...

5. cellcentric.com cellcentric.com/press-release/cellcentric-discloses-significant-new-clinical-data-demonstrating-inobrodibs-efficacy-in-ongoing-phase-i-iia-clinical-trials/

CellCentric discloses significant new clinical data ... Results show promising early efficacy of 67% patients (ORR) treated at 35mg doses of inobrodib in combination with pomalidomide (pom) and dexamethasone ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S0006497118591837

An Open-Label Phase I/IIa Study to Evaluate the Safety ... In pre-clinical studies, CCS1477 was found to be a potent inhibitor of cell proliferation in acute myeloid leukaemia (AML) multiple myeloma (MM) and non-Hodgkin ...

7. myeloma.org myeloma.org/sparkcures/trial/1718/NCT04068597

Inobrodib - Clinical Trial A Phase 1/2a study to assess the safety, tolerability, PK and biological activity of CCS1477 in patients with Non-Hodgkin Lymphoma, Multiple Myeloma, ...

8. mayo.edu mayo.edu/research/clinical-trials/cls-20533340

Study to Evaluate CCS1477 in Haematological Malignancies The compound causes G1 cell cycle arrest and is anti-proliferative across a broad range of haematological cell models, representative of AML, MM and lymphomas.