Emactuzumab for Giant Cell Tumor

(TANGENT Trial)

Recruiting in Palo Alto (17 mi)

+40 other locations

Overseen by Jean Y Blay, Prof, MD

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: SynOx Therapeutics Limited

Must not be taking: Immunosuppressants, Antiretrovirals, Tyrosine kinase inhibitors

Disqualifiers: Pregnancy, Metastatic cancer, Liver disease, others

Pivotal Trial (Near Approval)

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial tests emactuzumab, a new treatment for patients with TGCT tumors that can't be removed by surgery. The drug aims to control or reduce tumor growth by targeting the tumor cells.

Will I have to stop taking my current medications?

The trial requires that you stop taking any systemic immunosuppressive medications (like glucocorticoids) at least 4 weeks before starting and during the study. If you are on systemic therapy for TGCT or certain other treatments, you must stop them 3 months before screening.

Is emactuzumab safe for humans?

Emactuzumab has been studied for safety in patients with a type of tumor called diffuse-type tenosynovial giant-cell tumor. The research shows that it has been generally safe and well-tolerated in humans over a follow-up period of up to 2 years. ^{1 2 3 4 5}

How is the drug Emactuzumab different from other treatments for giant cell tumor?

Emactuzumab is unique because it targets the CSF1R (colony-stimulating factor 1 receptor), which is different from other treatments like Denosumab that target RANKL (a protein involved in bone destruction). This makes Emactuzumab potentially effective in reducing the tumor's growth by a different mechanism. ^{4 6 7 8 9}

Research Team

Jean Y Blay, Prof, MD

Principal Investigator

Comprehensive Cancer Centre of Lyon

Eligibility Criteria

This trial is for individuals over 12 with TGCT where surgery could worsen joint function or has high recurrence risk, and who can't have improved outcomes from surgery. Participants need proper organ/bone marrow function, a negative pregnancy test for women of childbearing age, and must agree to use effective contraception.

Inclusion Criteria

My biopsy shows TGCT that could worsen my joint function or recur quickly.

I am older than 12 years.

If a woman of childbearing potential, must have a negative pregnancy test prior to starting treatment and agree to use a highly effective method of contraception

Exclusion Criteria

I have had heart or lung problems in the last 6 months.

I have a history of liver disease.

Pregnant or breastfeeding female

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive emactuzumab or placebo intravenously every 2 weeks for a total of 5 doses, followed by an observation period

24 weeks

5 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with options for open-label retreatment or crossover

up to 24 months

Treatment Details

Interventions

• Emactuzumab (Monoclonal Antibodies)

Trial Overview The study tests emactuzumab's effectiveness and safety in treating TGCT when surgery isn't an option. It's a double-blind trial comparing emactuzumab with placebo given as an IV every two weeks for five sessions, followed by observation and long-term follow-up phases.

Participant Groups

Group I: Group 1 in Part 1/Part 2: Emactuzumab Experimental Treatment 1 Intervention

Group 1: Subjects receiving emactuzumab administered intravenously (i.v) on Day(D)1 and repeated once every two weeks (Q2W) for a total of 5 times, followed by an observation period of 3 months leading to a total period of 24 weeks in Part 1 and continued with a follow-up phase in Part 2. Eligible Subjects assigned to active drug in Part 1 have the option to receive open-label retreatment in Part 2.

Group II: Group 2 in Part 1 and Part 2: Placebo Placebo Group 1 Intervention

Group 2: Subjects receiving placebo administered intravenously (i.v) on D1 and repeated once every two weeks (Q2W) for 5 times followed by an observation period of 3 months to a total period of 24 weeks in Part 1. In Part 2, Eligible Subjects will have the option to receive open-label emactuzumab, administered by i.v once every 2 weeks (Q2W) for a total of 5 times.

Who Is Running the Clinical Trial?

SynOx Therapeutics Limited

Lead Sponsor

Trials

1

Recruited

130+

Findings from Research

In a study of 63 patients with diffuse-type tenosynovial giant-cell tumour (dTGCT), treatment with emactuzumab showed a high overall response rate of 71%, indicating significant clinical activity over a follow-up period of up to 2 years.

The treatment was associated with a manageable safety profile, with common side effects including pruritus, asthenia, and edema, while also leading to improvements in quality of life as measured by standard questionnaires.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term clinical activity, safety and patient-reported quality of life for emactuzumab-treated patients with diffuse-type tenosynovial giant-cell tumour. Cassier, PA., Italiano, A., Gomez-Roca, C., et al.[2021]

Emactuzumab, a monoclonal antibody targeting CSF1R, was found to be safe and well-tolerated in a phase 1 study involving 25 patients with diffuse-type tenosynovial giant cell tumor (dt-GCT), with no dose-limiting toxicities reported during the dose-escalation phase.

The treatment showed promising efficacy, with 86% of patients achieving an objective response and 7% achieving a complete response, indicating that emactuzumab could be a viable therapeutic option for this rare disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CSF1R inhibition with emactuzumab in locally advanced diffuse-type tenosynovial giant cell tumours of the soft tissue: a dose-escalation and dose-expansion phase 1 study. Cassier, PA., Italiano, A., Gomez-Roca, CA., et al.[2022]

Denosumab, a medication used for treating giant cell tumor of bone, has been associated with a risk of clinically significant hypercalcemia after the treatment is stopped.

Healthcare providers should be aware of this risk and monitor patients for hypercalcemia following discontinuation of denosumab to ensure patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MHRA Drug Safety Update: denosumab (Xgeva) and rebound hypercalcaemia. [2019]

In a study of 37 patients with recurrent or unresectable giant-cell tumors (GCT), 86% of evaluable patients showed a significant tumor response after treatment with denosumab, a monoclonal antibody targeting RANKL, indicating its potential efficacy in managing GCT.

While adverse events were common, with 33 out of 37 patients reporting issues, only one serious event was possibly related to the treatment, suggesting that denosumab has a manageable safety profile in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study. Thomas, D., Henshaw, R., Skubitz, K., et al.[2022]

In a pilot study of 8 central giant cell lesion (CGCL) specimens, 37.5% were found to have clinically relevant genomic alterations (CRGAs), including oncogenic mutations in genes like BRAF, GNAS, and KRAS.

The presence of somatic mutations that may activate the mitogen-activated protein kinase signaling pathway in 25% of the samples suggests this pathway could be a key driver of the aggressive behavior of CGCLs, indicating potential targets for personalized therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comprehensive Genomic Profiling of Central Giant Cell Lesions Identifies Clinically Relevant Genomic Alterations. Bezak, B., Lehrke, H., Elvin, J., et al.[2017]

Denosumab treatment in 15 patients with giant cell tumor of bone (GCTB) led to a significant reduction in tumor proliferation and angiogenesis, indicating its efficacy in managing this type of tumor.

The treatment resulted in the disappearance of osteoclast-like giant cells and a partial maturation of neoplastic cells towards an osteoblastic phenotype, suggesting a mechanism of action that may involve RANKL pathways, although immunophenotypical changes were minimal.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Denosumab treated giant cell tumour of bone: a morphological, immunohistochemical and molecular analysis of a series. Girolami, I., Mancini, I., Simoni, A., et al.[2022]

Denosumab is effective in treating giant cell tumors (GCT) of the spine, providing pain relief and sometimes reducing tumor volume, making it a valuable option when traditional surgery is too risky or leads to significant functional loss.

In a cohort of 10 patients treated with Denosumab, there were no local recurrences after gross total excision followed by postoperative treatment, suggesting that Denosumab can enhance surgical outcomes and may be beneficial as a preoperative treatment as well.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Denosumab in the treatment of giant cell tumor of the spine. Preliminary report, review of the literature and protocol proposal. Boriani, S., Cecchinato, R., Cuzzocrea, F., et al.[2021]

References

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

Long-term clinical activity, safety and patient-reported quality of life for emactuzumab-treated patients with diffuse-type tenosynovial giant-cell tumour. [2021]

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

CSF1R inhibition with emactuzumab in locally advanced diffuse-type tenosynovial giant cell tumours of the soft tissue: a dose-escalation and dose-expansion phase 1 study. [2022]

3. England pubmed.ncbi.nlm.nih.gov

MHRA Drug Safety Update: denosumab (Xgeva) and rebound hypercalcaemia. [2019]

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

Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study. [2022]

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

Comprehensive Genomic Profiling of Central Giant Cell Lesions Identifies Clinically Relevant Genomic Alterations. [2017]

6. Cyprus pubmed.ncbi.nlm.nih.gov

Therapeutic benefits of neoadjuvant and post-operative denosumab on sacral giant cell tumor: a retrospective cohort study of 30 cases. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Denosumab treated giant cell tumour of bone: a morphological, immunohistochemical and molecular analysis of a series. [2022]

8. Germany pubmed.ncbi.nlm.nih.gov

Denosumab in the treatment of giant cell tumor of the spine. Preliminary report, review of the literature and protocol proposal. [2021]

9. Denmark pubmed.ncbi.nlm.nih.gov

[Denosumab may be a supplement to the surgical treatment of giant cell tumours of bone]. [2022]