NCT03728179: RACIN

RACIN in Patients With Advanced TIL-negative Solid Tumors

Completed Phase 1 Last updated 20 February 2024

What this trial tests

Phase 1 trial testing Low dose irradiation + Nivolumab + Ipilimumab or Cyclophosphamide + Aspirin/Celecoxib in Solid Tumor, Adult in 40 participants. Completed in 27 October 2023.

Timeline

16 January 2019

Primary endpoint
27 October 2023

27 October 2023

Quick facts

Lead sponsor	Centre Hospitalier Universitaire Vaudois
Phase	Phase 1
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	sequential
Masking	none
Primary purpose	treatment
Enrollment	40
Start date	16 January 2019
Primary completion	27 October 2023
Estimated completion	27 October 2023
Sites	1 location across Switzerland

Drugs / interventions tested

• Low dose irradiation + Nivolumab + Ipilimumab or Cyclophosphamide + Aspirin/Celecoxib

Conditions studied

• Solid Tumor, Adult — all drugs for Solid Tumor, Adult →

Sponsor

Centre Hospitalier Universitaire Vaudois

Who can join

18 and older, any sex, with Solid Tumor, Adult. Patients with the condition only — healthy volunteers not accepted.

Sponsor's own description

Subjects with locally advanced or metastatic incurable Tumor Infiltrating Lymphocytes (TIL)-negative solid tumors who are not eligible for, declined or failed standard therapy will be treated with a combination nivolumab, low-dose ionizing radiation (RT) (0.5-2 Gy), aspirin (ASA)(cohorts 1 and 2)/celecoxib (cohorts 3, 4 and Phase Ib), and either ipilimumab or low-dose cyclophosphamide. The study comprises 2 phases: The aim of Phase Ia, is to determine safety and tolerability of a given combination therapy, as well as the maximum tolerated dose (MTD) or recommended phase Ib dose (RP1bD) of radiotherapy. Phase Ib aims to further explore safety and tolerability of this treatment in an expansion cohort.

In Phase Ia, 4 distinct cohorts will receive the following combination therapy:

Cohort1: combination therapy for 5 cycles (C0-C4) which includes: RT 0.5 Gy every 2 weeks (Q2W), Cy (200 mg/m2) Q2W (cycles C0 to C4); ASA (300 mg) daily, with nivolumab 240 mg flat dose Q2W and ipilimumab 1 mg/kg every 6 weeks (Q6W) will be administered (cycles C1 to C4).

Cohort2: combination therapy for 5 cycles (C0-C4) which includes: RT 1 Gy every 2 weeks (Q2W), Cy (200 mg/m2) Q2W (cycles C0 to C4); ASA (300 mg) daily, with nivolumab 240 mg flat dose Q2W and ipilimumab 1 mg/kg (Q6W) will be administered (cycles C1 to C4).

Cohorts 3a and 4a: Patients will receive Cy (200 mg/m2) Q2W, celecoxib (2x200mg daily), nivolumab (240 mg flat dose) Q2W, and low-dose radiation. Cohort 3a will receive 1 Gy of low-radiation dose and cohort 4a will receive 2 Gy.

Cohorts 3b and 4b: Patients will receive nivolumab (240 mg flat dose) Q2W, ipilimumab 1 mg/kg (Q6W), celecoxib (2x200mg daily) and low-dose radiation. Cohort 3b will receive 1 Gy of low-radiation dose and cohort 4b will receive 2 Gy.

In Phase Ia, the safety of combination (nivolumab, celecoxib, low-dose irradiation and cyclophosphamide) or (nivolumab, celecoxib, low-dose irradiation and ipilimumab) will be evaluated , and MTD or RP1bD will be defined. RP1bD will be the MTD or, in the absence of dose limiting toxicities (DLTs), the biologically best RT dose based on pharmacodynamics parameters.

In Phase Ib, patients will be treated with the MTD or RP1bD dose of RT and will follow the selected schema of treatment used in the Phase Ia cohort 3 or 4. At the end of the 5th cycle, patients eligible for nivolumab maintenance, will be treated with nivolumab at 240 mg Q2W until progression or excessive toxicity; celecoxib will be maintained according to tolerability.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. The updated landscape of tumor microenvironment and drug repurposing.
   Jin MZ, Jin WL. · · 2020 · cited 900× · PMID 32843638 · DOI 10.1038/s41392-020-00280-x
2. Low-Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy.
   Herrera FG, Ronet C, Ochoa de Olza M, Barras D, et al · · 2022 · cited 343× · PMID 34479871 · DOI 10.1158/2159-8290.cd-21-0003
3. The Evasion Mechanisms of Cancer Immunity and Drug Intervention in the Tumor Microenvironment.
   Kim SK, Cho SW. · · 2022 · cited 300× · PMID 35685630 · DOI 10.3389/fphar.2022.868695
4. Trial watch: chemotherapy-induced immunogenic cell death in immuno-oncology.
   Vanmeerbeek I, Sprooten J, De Ruysscher D, Tejpar S, et al · · 2020 · cited 179× · PMID 32002302 · DOI 10.1080/2162402x.2019.1703449
5. Neutrophils in the era of immune checkpoint blockade.
   Faget J, Peters S, Quantin X, Meylan E, et al · · 2021 · cited 94× · PMID 34301813 · DOI 10.1136/jitc-2020-002242
6. Landscape of Myeloid-derived Suppressor Cell in Tumor Immunotherapy.
   Hao Z, Li R, Wang Y, Li S, et al · · 2021 · cited 72× · PMID 34689842 · DOI 10.1186/s40364-021-00333-5
7. Cyclooxygenase-2 Inhibitor: A Potential Combination Strategy With Immunotherapy in Cancer.
   Pu D, Yin L, Huang L, Qin C, et al · · 2021 · cited 69× · PMID 33718229 · DOI 10.3389/fonc.2021.637504
8. Neutrophils and polymorphonuclear myeloid-derived suppressor cells: an emerging battleground in cancer therapy.
   Raskov H, Orhan A, Gaggar S, Gögenur I. · · 2022 · cited 64× · PMID 35504900 · DOI 10.1038/s41389-022-00398-3