RACIN in Patients With Advanced TIL-negative Solid Tumors

NCT03728179 | Completed Phase 1 DMC

• 1 other identifier: CHUV-DO-0003-RACIN_2017
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Solid Tumor, Adult

Outcome Measures

Primary Outcomes (2)

• Phases Ia and Ib: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]

  Phase Ia and IB: Toxicity and tolerability will be assessed through measure and evaluation of adverse events occuring during the study, using the National Cancer Institute (NCI) CommonTerminology Criteria for Adverse Events (CTCAE v.4.03)

  3.5 years

• Maximum Tolerated dose (MTD) or recommended phase Ib dose of low-dose irradiation for radio-immunotherapy combination (RP1bD).

  MTD is defined as the dose level below the dose that causes a dose limiting toxicity (DLT) in more than 17% of participants. The MTD analysis population will consist of all evaluable participants registered in the phase Ia , who completed the DLT/ backbone limiting toxicity (BLT) period (cycle C0 and C1), unless discontinued due to toxicity. RP1bD will be the MTD or, in the absence of DLTs, the biologically best radiotherapy dose based on pharmacodynamics parameters.

  3.5 years

Secondary Outcomes (5)

• Objective response rate (ORR)

  3.5 years

• Disease Control Rate (DCR)

  6,12 and 24 months

• Progression free survival (PFS) rate

  6,12 and 24 months

• Time to Progression (TTP):

  3.5 years

• Overall survival (OS)

  12 and 24 months

Other Outcomes (3)

• Exploratory outcomes: Assessment of treatment response

  5 years

• Exploratory outcomes: Immune monitoring of the tumor

  5 years

• Exploratory outcomes: Immune monitoring of the tumor microenvironment

  5 years

Study Arms (7)

Cohort 1

EXPERIMENTAL

0,5 Gy of RT + Cyclophosphamide + Nivolumab + Ipilimumab + Aspirin

Combination Product: Low dose irradiation + Nivolumab + Ipilimumab or Cyclophosphamide + Aspirin/Celecoxib

Cohort 2

EXPERIMENTAL

1 Gy of RT + Cyclophosphamide + Nivolumab + Ipilimumab + Aspirin

Combination Product: Low dose irradiation + Nivolumab + Ipilimumab or Cyclophosphamide + Aspirin/Celecoxib

Cohort 3a

EXPERIMENTAL

1 Gy of RT + Cyclophosphamide + Nivolumab + Celecoxib

Combination Product: Low dose irradiation + Nivolumab + Ipilimumab or Cyclophosphamide + Aspirin/Celecoxib

Cohort 4a

EXPERIMENTAL

2 Gy of RT + Cyclophosphamide + Nivolumab + Celecoxib

Combination Product: Low dose irradiation + Nivolumab + Ipilimumab or Cyclophosphamide + Aspirin/Celecoxib

Phase I b

EXPERIMENTAL

Recommended Phase Ib RT dose (RP1bD) + Nivolumab + Ipilimumab or Cyclophosphamide + Celecoxib

Combination Product: Low dose irradiation + Nivolumab + Ipilimumab or Cyclophosphamide + Aspirin/Celecoxib

Cohort 3b

EXPERIMENTAL

1 Gy of RT + Ipilimumab + Nivolumab + Celecoxib

Combination Product: Low dose irradiation + Nivolumab + Ipilimumab or Cyclophosphamide + Aspirin/Celecoxib

Cohort 4b

EXPERIMENTAL

2 Gy of RT + Ipilimumab + Nivolumab + Celecoxib

Combination Product: Low dose irradiation + Nivolumab + Ipilimumab or Cyclophosphamide + Aspirin/Celecoxib

Interventions

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

Low Dose Radiation (RT): RT will be administered as single fractions every 2 weeks (Q2W) from cycle C0 to cycle C4. RT will be delivered to a number of metastatic deposits visible by PET/CT, at the PI's discretion. Cyclophosphamide: 200mg/m2 will be administered as intravenous infusion (IV) Q2W from cycle C0 to C4. Nivolumab: 240 mg will be administered as IV Q2W from cycle C1 to C4. Ipilimumab: 1mg/kg will be administered as IV every 6 weeks (Q6W) from cycle C1 to C4 Aspirin: 300mg will be administered orally daily from cycle C1 to C4. All subjects will receive mandatory gastric prophylaxis with an oral H2 antagonist. Celecoxib: 200mg will be administered orally twice a day from cycle C1 to C4. At the end of cycle C4, patients eligible for maintenance will be treated with nivolumab at 240mg Q2W until progression or excessive toxicity; celecoxib will be maintained if the drug is well tolerated

Cohort 1; Cohort 2; Cohort 3a; Cohort 3b; Cohort 4a; Cohort 4b; Phase I b

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed pre-screening Informed Consent Form
• Patients with recurrent or metastatic solid tumor (any histology), who progress after at least one standard therapy for advanced disease
• Patient willingness and acceptance to participate in the immunology research is mandatory
• At least one lesion accessible to biopsy without putting patient at risk
• Biopsies obtained previously (within a maximum of 12 weeks before pre-screening visit), outside this protocol, for TIL assessment can be also considered for patient selection. Fresh tumor biopsies for subsequent translational studies will be used as baseline and collected at pre-screening (when biopsy will be performed for TIL status) or at screening (when archival biopsy will be used for TIL status). Biopsy from metastatic lymph nodes is accepted.
• Eastern Cooperative Oncology Group (ECOG) clinical performance status: 0-1 for all patients, independently of the number of previous lines of therapy.
• Life expectancy of ≥ 12 weeks
• Patients with Glycose-6-Phosphate Dehydrogenase (G6PD) deficiency or any other hereditary coagulation disorder are excluded, as well as patients with clinical history of Reye syndrome
• Adequate serology defined by the following laboratory results obtained during pre-screening period (day-28 to day-14).
• Seronegative for HIV infection (anti-HIV-1/-2)
• Seronegative for hepatitis B infection (HBs Ag, total anti-hemoglobin C (HBc), anti-HBs). Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen HBsAg test and a positive anti-HBc antibody test) are eligible, if hepatitis B virus (HBV) DNA test is negative.
• Seronegative for hepatitis C infection (anti-HCV): if a patient has positive anti-HCV antibody, a negative hepatitis C virus (HCV) RNA need to be obtain to register the patient.
• Study registration
• Signed main study Informed Consent Form
• Absence of tumor-infiltrating intraepithelial Cluster of differentiation-8 positive T cells (CD8+ T cells) by immunohistochemistry (IHC) on baseline biopsy defined as \<5 CD8+ cells per high power field of tumor

You may not qualify if:

• Patients with soft tissue sarcoma, glioblastoma, or lymphoma are excluded.
• Pregnant or breast-feeding women.
• Symptomatic brain or leptomeningeal disease; any brain metastases must be stable for at least 6 months
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
• Uncontrolled hypercalcemia (\> 1.5 mmol/L ionized calcium or Ca \> 12 mg/dL or corrected serum calcium \> ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab
• a) Patients who are receiving bisphosphonate therapy or denosumab specifically to prevent skeletal events and who do not have a history of clinically significant hypercalcemia are eligible.
• Life expectancy of \< 12 weeks
• Current, recent (within 4 weeks prior to registration), or planned participation in an experimental drug study
• New York Heart Association Class II or greater congestive heart failure
• History of myocardial infarction or unstable angina within 6 months prior registration
• History of stroke or transient ischemic attack within 6 months prior registration
• Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior registration)
• Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
• Patients with active peptic or duodenal ulceration (within 4 weeks prior to registration)
• Current or recent (within 14 days prior registration) treatment use of dipyramidole, ticlopidine, clopidogrel, cilostazol, prasugrel, or ticagrelor

Sponsors & Collaborators

• Centre Hospitalier Universitaire Vaudois: lead

Study Sites (1)

Centre Hospitalier Universitaire Vaudois

Lausanne, 1011, Switzerland

Location

MeSH Terms

Interventions

Radiation; Nivolumab; Ipilimumab; Cyclophosphamide; Aspirin; Celecoxib

Intervention Hierarchy (Ancestors)

Physical Phenomena; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Salicylates; Hydroxybenzoates; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Benzenesulfonamides; Sulfonamides; Amides; Sulfones; Sulfur Compounds; Pyrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: October 15, 2018
• First Posted: November 1, 2018
• Study Start: January 16, 2019
• Primary Completion: October 27, 2023
• Study Completion: October 27, 2023
• Last Updated: February 20, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

CH (1)