Immunotherapy, radiation and an immune modulatory combination in cervical and uterine cancer | Anticancerfund

Immunotherapy, radiation and an immune modulatory combination in cervical and uterine cancer

A phase II trial of pembrolizumab (Keytruda) in combination with radiation and immune modulation in patients with cervical and uterine cancer (PRIMMO).

Status
Recruiting
 
Cancer types
  • Gynaecological cancer
Trial phase
2

Funding

€858,143
ACF donation
€1,553,643
Estimated trial cost

Why this trial?

Cervical cancer is the third-most common cancer type in women. The 5-year survival rate for women with cervical cancer that has spread, is only 17%. For women with recurrent disease, prognosis is even worse. Treatment options that can improve survival while maintaining quality of life are urgently needed.

Endometrial cancer is the most frequent gynaecological cancer. When endometrial cancer is diagnosed in late stages or is very aggressive, the chance of recurrence is very high. The prognosis for patients with recurrent disease is dismal because few treatment options are available. Currently available treatment options for these patients are scarce and often accompanied with considerable side effects. Therefore, effective and less toxic treatments are urgently needed for patients with refractory or recurrent endometrial cancer.

Uterine sarcomas are very rare but have a high mortality rate. Even after radical hysterectomy, most patients relapse or present with distant metastases. The very limited benefit of adjuvant chemotherapy is reflected by high mortality rates, emphasising the need for new treatment strategies.

Over the last decades, treatments that revolve around inhibitory immune checkpoints (e.g. anti-PD-1) have entered the forefront of immune-oncology. These immune checkpoints make sure the organism doesn’t target itself with its own immune system. Tumours can use these immune checkpoints to avoid being attacked. Antibodies preventing the activation of these immune checkpoints can overrule the inhibition of the immune system that was highjacked by the tumour.

Unfortunately, less than 20% of cervical and endometrial cancer patients respond to anti-PD-1 treatment. The reason for this may be that these types of tumours and their microenvironments suppress the immune system in other ways, which might hamper effectiveness of the treatment. Because a tumour is a complex composition of different cells, a combination of therapies is more likely to destroy it efficiently.

The PRIMMO trial aims to improve the treatment for cervical and endometrial cancer and uterine sarcoma patients through a combination of 7 therapies that collectively enable the immune system to kill the tumour.

Why this drug?

Vitamin D3 is essential for an effective immune response, and vitamin D3 has been shown to increase immune response to tumours in the laboratory.

Lansoprazole counteracts the acidic microenvironment in tumours. It has been shown that tumour acidosis restrains the immune system.

Aspirin prevents the formation of prostaglandins. Prostaglandins are increased in cancer and are often associated with aggressive tumour behaviour. Tumour-derived prostaglandins have potent immune-inhibitory effects. Furthermore, aspirin has also been shown to benefit overall anti-angiogenic balance. Finally, aspirin also has an anti-metastatic effect.

Cyclophosphamide is a familiar chemotherapy. At low “metronomic” doses, it can stimulate the immune system and prevent the formation of new blood vessels that feed the tumour.

Curcumin has both a direct effect on cancer cells as well as anti-inflammatory effects. Regarding its direct effect on cancer cells, curcumin has been shown to sensitise tumour cells to the cytocidal effects of radiation. The anti-inflammatory mechanisms of curcumin are: (1) inhibition of NF-B and COX-2, levels of which are often increased in cancer; (2) inhibition of arachidonic acid metabolism; (3) decreased expression of inflammatory cytokines, resulting in growth inhibition of cancer cell lines; (4) downregulation of enzymes that mediate inflammation and tumour cell proliferation.

Trial design

This is a phase II study in 65 patients with advanced/refractory cervical cancer, endometrial carcinoma or uterine sarcoma, performed in 4 Belgian centres.

Patients will be treated with an immunomodulatory combination (daily intake of 2000 IU vitamin D, 325 mg aspirin, 50 mg cyclophosphamide and 180 or 30 mg lansoprazole), together with pembrolizumab administered intravenously at 200 mg in 21-day treatment cycles and with radiation (3x 8Gy in 48h-intervals). In addition, patients will take curcumin on a daily basis.

The goal is to assess efficacy, safety and effect on the quality of life for these patients.

Partners

Principal Investigator:

  • Hannelore Denys, University Hospital of Ghent, Ghent, Belgium

Sponsor:

  • University Hospital of Ghent, Ghent, Belgium

ACF funding partner:

  • Nationale Loterij

Other funding partner:

  • Kom Op Tegen Kanker

Our role

financial support + consortium building + protocol development and documentation
Why we support this trial
Intervention has little or no commercial value
No major hurdle for clinical implementation
Use in a population with high unmet needs

Funding

€1,553,643
Estimated trial cost
€858,143
ACF donation
€37,550
ACF internal support (2017)
Questions about participation?
Questions about this trial?
The Anticancer Fund
studies [at] anticancerfund.org

References

More info on clinicaltrials.gov: NCT03192059

Borch, T.H., et al., Reorienting the immune system in the treatment of cancer by using anti-PD-1 and anti-PD-L1 antibodies. Drug Discov Today, 2015.

Brahmer, J.R., et al., Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med, 2012. 366(26): p. 2455-65.

Cuppens, T., S. Tuyaerts, and F. Amant, Potential Therapeutic Targets in Uterine Sarcomas. Sarcoma, 2015. 2015: p. 243298.

Garg, G. and D.G. Mutch, Treatment Strategies and Prognosis of Endometrial Cancer, in Cancer of the Uterine Endometrium - Advances and Controversies, J.S. Saldivar, Editor. 2012, InTech.

Hirte, H., et al., Systemic therapy for recurrent, persistent, or metastatic cervical cancer: a clinical practice guideline. Curr Oncol, 2015. 22(3): p. 211-9.

Last updated: june 2018.