A phase II Investigation of pembrolizumab (Keytruda) in combination with radiation and an immune modulatory cocktail in patients with cervical and uterine cancer (PRIMMO trial)

Info

Location: Universitair Ziekenhuis Gent, Gent, België
Collaboration: Prof. Dr. H. Denys,

Over the last decades, interacting with inhibitory immune checkpoints (e.g. anti-CTLA-4 and anti-PD-1) have entered the forefront of immune-oncology. These inhibitory immune checkpoints are inhibitory pathways of the immune system that function in physiological conditions to maintain tolerance of the organism towards self and to limit tissue damage when the immune system responds to an infection. However, tumors can co-opt certain immune checkpoints pathways in order to resist anti-tumor immunity. Antibodies avoiding the activation of these inhibitory immune checkpoints have revolutionized oncological practise for several tumor types since it abrogates the inhibition of the immune system which was highjacked by the tumor. As such they ‘release the brakes’ of the immune system. However, except for a small subset of patients with mismatch repair deficiency (MRR-D) or POLE mutation, less than 20% of cervical and endometrial cancer patients respond to anti-PD-1 treatment.

Gynaecological tumors and their microenvironment also exerts other immunosuppressive effects, which might hamper effectiveness. Because a tumour is a complex composition of different cells, it is generally assumed that a combination of therapies is necessary to destroy it efficiently. The PRIMMO trial aims to improve the treatment for cervical and endometrial cancer patients and uterine sarcoma patients by a combination of 7 therapies which try collectively to support the immune system enabling it to kill the tumour.
Treatment consists of anti-PD-1 (pembrolizumab) every 3 weeks for six cycles in which the first administration is combined with hypofractionated radiotherapy (3x 8Gy). To modulate the tumor microenvironment patients take vitamin D, lansoprazole, aspirin, (low dose) cyclophosphamide along with the food supplement curcumin two weeks ahead as well as concomitant with the anti-PD-1 cycles.

The PRIMMO trial will open in 4 Belgian hospitals and both endometrium cancer, cervix cancer and uterine sarcoma patients can participate. To assess efficacy the difference in tumor load after 26 weeks of treatment will be compared with the tumor load before this treatment started. Besides this also safety, best overall response, progression-free survival, overall survival and quality of life will be measured. Exploratory immune biomarker changes in blood and tumor biopsies will be evaluated, extracellular vesicles characterized, cell death biomarkers in blood analysed and the impact on the gut microbiome assessed.

A total of 18 evaluable cervix cancer patients and 25 evaluable endometrium cancer patients will be enrolled. Uterine sarcoma patients are allowed for as long as the trial is open, but no sample size calculation was performed due to the rarity of the disease. Recruitment started in July 2017. An interim analysis for efficacy and futility is planned when half of the required number of evaluable patients in each group have reached their primary endpoint, estimated around Q3 2019. Final data analysis is expected Q2 2022.

More details about this study (NCT03192059) at www.clinicaltrials.gov or via info@anticancerfund [dot] org

Professional info

Location: Universitair Ziekenhuis Gent, Gent, België
Collaboration: Prof. Dr. H. Denys,

Over the last decades, interacting with inhibitory immune checkpoints (e.g. anti-CTLA-4 and anti-PD-1) have entered the forefront of immune-oncology. These inhibitory immune checkpoints are inhibitory pathways of the immune system that function in physiological conditions to maintain tolerance of the organism towards self and to limit tissue damage when the immune system responds to an infection. However, tumors can co-opt certain immune checkpoints pathways in order to resist anti-tumor immunity. Antibodies avoiding the activation of these inhibitory immune checkpoints have revolutionized oncological practise for several tumor types since it abrogates the inhibition of the immune system which was highjacked by the tumor. As such they ‘release the brakes’ of the immune system. However, except for a small subset of patients with mismatch repair deficiency (MRR-D) or POLE mutation, less than 20% of cervical and endometrial cancer patients respond to anti-PD-1 treatment.

Gynaecological tumors and their microenvironment also exerts other immunosuppressive effects, which might hamper effectiveness. Because a tumour is a complex composition of different cells, it is generally assumed that a combination of therapies is necessary to destroy it efficiently. The PRIMMO trial aims to improve the treatment for cervical and endometrial cancer patients and uterine sarcoma patients by a combination of 7 therapies which try collectively to support the immune system enabling it to kill the tumour.
Treatment consists of anti-PD-1 (pembrolizumab) every 3 weeks for six cycles in which the first administration is combined with hypofractionated radiotherapy (3x 8Gy). To modulate the tumor microenvironment patients take vitamin D, lansoprazole, aspirin, (low dose) cyclophosphamide along with the food supplement curcumin two weeks ahead as well as concomitant with the anti-PD-1 cycles.

The PRIMMO trial will open in 4 Belgian hospitals and both endometrium cancer, cervix cancer and uterine sarcoma patients can participate. To assess efficacy the difference in tumor load after 26 weeks of treatment will be compared with the tumor load before this treatment started. Besides this also safety, best overall response, progression-free survival, overall survival and quality of life will be measured. Exploratory immune biomarker changes in blood and tumor biopsies will be evaluated, extracellular vesicles characterized, cell death biomarkers in blood analysed and the impact on the gut microbiome assessed.

A total of 18 evaluable cervix cancer patients and 25 evaluable endometrium cancer patients will be enrolled. Uterine sarcoma patients are allowed for as long as the trial is open, but no sample size calculation was performed due to the rarity of the disease. Recruitment started in July 2017. An interim analysis for efficacy and futility is planned when half of the required number of evaluable patients in each group have reached their primary endpoint, estimated around Q3 2019. Final data analysis is expected Q2 2022.

More details about this study (NCT03192059) at www.clinicaltrials.gov or via info@anticancerfund [dot] org