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RACIN in Patients With Advanced TIL-negative Solid Tumors (RACIN)

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ClinicalTrials.gov Identifier: NCT03728179
Recruitment Status : Not yet recruiting
First Posted : November 1, 2018
Last Update Posted : November 1, 2018
Sponsor:
Information provided by (Responsible Party):
Dr Fernanda Herrera, Centre Hospitalier Universitaire Vaudois

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 of checkpoint inhibitors (nivolumab and ipilimumab), low dose cyclophosphamide (Cy), low-dose ionizing radiation (RT) (0.5-3 Gy) and aspirin (ASA). The study comprises 2 phases: The aim of Phase Ia, is to determine safety and tolerability of this 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 combination therapy for 5 cycles (C0-C4) which includes: RT (0.5-3 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). RT will be given at an escalation design (0.5, 1, 2, 3 Gy) for 5 cycles (cycle C0 without Ipi/Nivo and ASA, and then C1-C4). In Phase Ia, 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 same schema of treatment used in the Phase Ia cohort (5 cycles). 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; ASA will be maintained according to tolerability.


Condition or disease Intervention/treatment Phase
Solid Tumor, Adult Combination Product: Low dose irradiation + Nivolumab + Ipilimumab + Aspirin Phase 1

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: RACIN, A Phase I Study of the Combination of Nivolumab Plus Ipilimumab Associated With Low-dose Radiation, Aspirin, and Low-dose Cyclophosphamide, Followed by Nivolumab Maintenance, in Patients With Advanced, TIL-negative Solid Tumors
Estimated Study Start Date : November 15, 2018
Estimated Primary Completion Date : March 15, 2023
Estimated Study Completion Date : March 15, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Cohort 1
0,5 Gy of RT + Cyclophosphamide + Nivolumab + Ipilimumab + Aspirin
Combination Product: Low dose irradiation + Nivolumab + Ipilimumab + Aspirin

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 maximum of 10 metastatic deposits visible by PET/CT.

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.

At the end of cycle C4, patients eligible for maintenance will be treated with nivolumab at 240mg Q2W until progression or excessive toxicity; aspirin with prophylactic H2 antagonist will be maintained according to tolerability.


Experimental: Cohort 2
1 Gy of RT + Cyclophosphamide + Nivolumab + Ipilimumab + Aspirin
Combination Product: Low dose irradiation + Nivolumab + Ipilimumab + Aspirin

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 maximum of 10 metastatic deposits visible by PET/CT.

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.

At the end of cycle C4, patients eligible for maintenance will be treated with nivolumab at 240mg Q2W until progression or excessive toxicity; aspirin with prophylactic H2 antagonist will be maintained according to tolerability.


Experimental: Cohort 3
2 Gy of RT + Cyclophosphamide + Nivolumab + Ipilimumab + Aspirin
Combination Product: Low dose irradiation + Nivolumab + Ipilimumab + Aspirin

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 maximum of 10 metastatic deposits visible by PET/CT.

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.

At the end of cycle C4, patients eligible for maintenance will be treated with nivolumab at 240mg Q2W until progression or excessive toxicity; aspirin with prophylactic H2 antagonist will be maintained according to tolerability.


Experimental: Cohort 4
3 Gy of RT + Cyclophosphamide + Nivolumab + Ipilimumab + Aspirin
Combination Product: Low dose irradiation + Nivolumab + Ipilimumab + Aspirin

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 maximum of 10 metastatic deposits visible by PET/CT.

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.

At the end of cycle C4, patients eligible for maintenance will be treated with nivolumab at 240mg Q2W until progression or excessive toxicity; aspirin with prophylactic H2 antagonist will be maintained according to tolerability.


Experimental: Phase I b
Recommended Phase Ib RT dose (RP1bD) + Cyclophosphamide + Nivolumab + Ipilimumab + Aspirin
Combination Product: Low dose irradiation + Nivolumab + Ipilimumab + Aspirin

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 maximum of 10 metastatic deposits visible by PET/CT.

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.

At the end of cycle C4, patients eligible for maintenance will be treated with nivolumab at 240mg Q2W until progression or excessive toxicity; aspirin with prophylactic H2 antagonist will be maintained according to tolerability.





Primary Outcome Measures :
  1. Phases Ia and Ib: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: 3.5 years ]
    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)

  2. Maximum Tolerated dose (MTD) or recommended phase Ib dose of low-dose irradiation for radio-immunotherapy combination (RP1bD). [ Time Frame: 3.5 years ]
    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.


Secondary Outcome Measures :
  1. Objective response rate (ORR) [ Time Frame: 3.5 years ]
    Best objective response rate (Complete Response or Partial Response) during the period from enrolment to termination of trial treatment, will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1.

  2. Disease Control Rate (DCR) [ Time Frame: 6,12 and 24 months ]
    Percentage of patients achieving Complete Response, Partial Response or Stable Disease at the end of four cycles of combination therapy (i.e. at 6 months) as well as at 12 and 24 months, will be measured by RECIST v.1.1

  3. Progression free survival (PFS) rate [ Time Frame: 6,12 and 24 months ]
    The time from enrolment until objective tumor progression or death, whichever occurs first, will be evaluated at 6,12 and 24 months by RECIST v.1.1.

  4. Time to Progression (TTP): [ Time Frame: 3.5 years ]
    The time from enrolment until objective tumor progression, will be evaluated by RECIST v.1.1

  5. Overall survival (OS) [ Time Frame: 12 and 24 months ]
    OS will be assessed at 12 and 24 months


Other Outcome Measures:
  1. Exploratory outcomes: Assessment of treatment response [ Time Frame: 5 years ]
    Assessment of treatment response will be performed through monitoring of tumor metabolism using 18Fludeoxyglucose (FDG) PET-CT.

  2. Exploratory outcomes: Immune monitoring of the tumor [ Time Frame: 5 years ]
    Tumor immune profile will be assessed by multiplexed immunohistochemistry, tumor immunophenotyping, RNA expression as well as flow cytometry, ELISA and ELISPOT (enzyme-linked immunospot) assays.

  3. Exploratory outcomes: Immune monitoring of the tumor microenvironment [ Time Frame: 5 years ]
    Tumor microenvironment immune profile will be assessed by multiplexed immunohistochemistry, tumor immunophenotyping, RNA expression as well as flow cytometry, ELISA and ELISPOT (enzyme-linked immunospot) assays.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Pre-screening registration

Inclusion Criteria:

  1. Signed pre-screening Informed Consent Form
  2. Patients with recurrent or metastatic solid tumor (any histology), who progress after at least one standard therapy for advanced disease
  3. Patient willingness and acceptance to participate in the immunology research is mandatory
  4. At least one lesion accessible to biopsy without putting patient at risk
  5. 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.
  6. Eastern Cooperative Oncology Group (ECOG) clinical performance status: 0-1 for all patients, independently of the number of previous lines of therapy.
  7. Life expectancy of ≥ 12 weeks
  8. 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
  9. Adequate serology defined by the following laboratory results obtained during pre-screening period (day-28 to day-14).

    1. Seronegative for HIV infection (anti-HIV-1/-2)
    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.
    3. 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

Inclusion Criteria

  1. Signed main study Informed Consent Form
  2. 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
  3. At least one lesion accessible to biopsy without putting patient at risk
  4. Number of metastatic lesions viewed on Positron emission tomography-computed tomography (PET/CT) scan: for both Phase Ia and Phase Ib, the patient may have any number of metastatic lesions. A maximum of 10 metastatic lesions visible by PET/CT scan will be irradiated at the investigator's discretion. It is at the discretion of the investigator to exclude a metastatic site from the radiation field that, due to the radiotherapy volume, dose or location too close to a healthy organ, may put the patient at risk of suffering from radiation induced toxicity. If this would be the only metastatic site to be irradiated, the concerned patient will be excluded from the study.
  5. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol
  6. Adequate hematologic and end-organ function, defined by the following laboratory results obtained within 14 days prior to the first study treatment:

    1. Absolute neutrophil count ≥ 1.5 g/L (without granulocyte colony-stimulating factor support within 2 weeks prior registration)
    2. White Blood Cell (WBC) counts > 2.5 g/L and < 15 g/L
    3. Lymphocyte count ≥ 0.5 g/L
    4. Platelet count ≥ 100 g/L (without transfusion within 1 week prior registration)
    5. Hemoglobin ≥ 90 g/L (Patients may be transfused to meet this criterion but it should not be done within 1 week prior registration)
    6. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase ≤ 2.5 x ULN (with the exception for patients with documented liver metastases: AST, ALT and alkaline phosphatase ≤ 5 x ULN)
    7. Serum bilirubin ≤ 1.5 x ULN (with the exception for: patients with known or suspicion of Gilbert disease who have serum bilirubin level ≤ 3 x ULN may be enrolled)
    8. Coagulation: International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or Partial Thromboplastin Time (PTT) is within therapeutic range of intended use of anticoagulants; Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
    9. Serum albumin > 25 g/L
    10. Serum creatinine ≤1.5 x ULN or creatinine clearance ≥ 40 ml/min on the basis of Cockcroft-Gault Formula
  7. No prior radiation therapy in areas of desired radiation
  8. Patients may have had prior therapy provided a washout period of 4 weeks prior to registration is allowed. Exception: hormone therapy for breast and prostate cancer is allowed to be continued during the study.
  9. Recovery from any toxic effects of prior registration to ≤ Grade 1 per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v4.03) except fatigue or alopecia.
  10. For women of childbearing potential (WOCBP: sexually mature women who have not undergone a hysterectomy, have not been naturally post-menopausal for at least 12 consecutive months or have a serum follicle-stimulating hormone (FSH) < 40 Millions International Units (mIU)/ml):

    1. Agreement to use 2 acceptable methods of contraception during participation in the trial and for 6 months after last study combined treatment and after 5 months of maintenance treatment
    2. Women must have a negative urine pregnancy test within 7 days before registration. A positive urine test must be confirmed by a serum pregnancy test, or menopausal as per National Comprehensive Cancer Network (NCCN) guidelines.
  11. For men: agreement to use 2 acceptable methods of effective contraception during participation in the trial and for 7 months after last study treatment (combined or maintenance treatment). Female partners of men who take part in this trial must also use at least one method of effective contraception during the trial and 7 months after last study treatment (combined or maintenance).

Exclusion Criteria:

  1. Patients with soft tissue sarcoma, glioblastoma, or lymphoma are excluded.
  2. Pregnant or breast-feeding women.
  3. Symptomatic brain or leptomeningeal disease; any brain metastases must be stable for at least 6 months
  4. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
  5. 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.

  6. Life expectancy of < 12 weeks
  7. Current, recent (within 4 weeks prior to registration), or planned participation in an experimental drug study
  8. New York Heart Association Class II or greater congestive heart failure
  9. History of myocardial infarction or unstable angina within 6 months prior registration
  10. History of stroke or transient ischemic attack within 6 months prior registration
  11. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior registration)
  12. Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
  13. Patients with active peptic or duodenal ulceration (within 4 weeks prior to registration)
  14. Current or recent (within 14 days prior registration) treatment use of dipyramidole, ticlopidine, clopidogrel, cilostazol, prasugrel, or ticagrelor
  15. Current or recent (within 14 days prior registration) use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to prophylactic) purpose

    1. Prophylactic anticoagulation for the patency of venous access devices is allowed, provided the activity of the agent results in an International Normalized Ratio (INR) < 1.5 x ULN and aPTT is within normal limits within 2 weeks prior registration.
    2. Prophylactic use of low molecular-weight heparin (e.g., enoxaparin) is allowed.
  16. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins or allergy to biopharmaceuticals produced in Chinese hamster ovary cells
  17. Known hypersensitivity to any component of the Investigational Medicinal Products (IMPs)
  18. History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. The following exceptions are considered:

    1. Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone are eligible for this study.
    2. Patients with controlled Type I diabetes mellitus on a stable insulin regimen are eligible
  19. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), druginduced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest Computerized Tomography (CT) scan. Exception: history of radiation pneumonitis in previous radiation field (fibrosis) is permitted provided that this area does not undergo current low dose irradiation as part of this protocol.
  20. Severe infections within 4 weeks prior registration including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
  21. Signs or symptoms of infection within 2 weeks prior registration
  22. Received therapeutic oral or IV antibiotics within 2 weeks prior registration. Exception: patients receiving routine antibiotic prophylaxis (e.g., to prevent chronic obstructive pulmonary disease exacerbation or for dental extraction) are eligible.
  23. Prior allogeneic stem cell or solid organ transplant
  24. Administration of a live, attenuated vaccine within 4 weeks before registration. Exception: influenza vaccination should be given during influenza season only (approximately October to March). Patients must not receive live, attenuated influenza vaccine within 4 weeks prior registration or at any time during the study.
  25. Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
  26. Patients who have received prior treatment with anti-Programmed Cell Death-1 (PD1), anti-Programmed Cell Death Ligand-1 (PD-L1) or anti-Cytotoxic T-lymphocyte Associated 4 (CTLA-4) may be enrolled, provided at least 5 half-lives (approximately 75 days) have elapsed from the last dose to the registration and there was no history of severe immune-mediated adverse effects from such therapy (NCI CTCAE Grade 3 and 4).
  27. Treatment with systemic immunostimulatory agents (including but not limited to interferon-alpha (IFN-a), interleukin-2 (IL-2)) for any reason within 6 weeks or five half-lives of the drug, whichever is shorter, prior registration
  28. Treatment with systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor (anti-TNF) agents) within 2 weeks prior registration

    1. Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) or physiologic replacement doses (i.e., prednisone 5-7.5 mg/day) for adrenal insufficiency may be enrolled in the study.
    2. The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) is allowed.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03728179


Contacts
Contact: George Coukos, Dr. +41 21 314 06 27 george.coukos@chuv.ch

Locations
Switzerland
Centre Hospitalier Universitaire Vaudois
Lausanne, Switzerland, 1011
Sponsors and Collaborators
Centre Hospitalier Universitaire Vaudois

Responsible Party: Dr Fernanda Herrera, Principal Investigator, Centre Hospitalier Universitaire Vaudois
ClinicalTrials.gov Identifier: NCT03728179     History of Changes
Other Study ID Numbers: CHUV-DO-0003-RACIN_2017
First Posted: November 1, 2018    Key Record Dates
Last Update Posted: November 1, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Cyclophosphamide
Aspirin
Nivolumab
Antibodies, Monoclonal
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Anti-Inflammatory Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Platelet Aggregation Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Antipyretics