Immunotherapy and Carbon Ion Radiotherapy In Solid Cancers With Stable Disease

NCT05229614 | Recruiting Phase 2

• 1 other identifier: CNAO 44 2021 C
• Study Type: interventional
• Target: 27
• Locations: 2 countries
• Sites: 4

Brief Summary

Immunotherapy has become the standard of care in different advanced malignancies. Its effectiveness in the palliative setting was demonstrated by several phase III trials. However, the response rate varies according to the cancer under study and to the line of treatment. A potential way to improve the activity of single agent immune checkpoint inhibitors (ICIs) is to enhance the clinical response through further antitumor agents, including radiotherapy. Studies showed that carbon ions may lead to a broader immunogenic response; for their dosimetric characteristics it is possible to reduce integral dose sparing immune cells to direct and sustain a tumor specific immune response. Considering the available preclinical and clinical evidence together, the goal of this study is to explore the feasibility and the clinical activity of adding carbon ion radiotherapy (CIRT), employed with a fractionation strategy comparable to stereotactic body radiation, to ICIs in advanced malignancies where immunotherapy is currently the standard of care.

Conditions

Non Small Cell Lung Cancer; Head and Neck Squamous Cell Carcinoma; Melanoma; Urothelial Carcinoma

Keywords

Hadrontherapy; CIRT; Immunotherapy; NSCLC; HNSCC; Melanoma; Urothelial

Outcome Measures

Primary Outcomes (1)

• Objective response rate assessed by RECIST V1.1

  To estimate the effect, in terms of clinical response, of immunotherapy associating carbon ion treatment (CIRT) in the palliative setting across different malignancies, for which immunotherapy is currently the standard of care. Objective response rate (ORR) will be evaluated after CIRT administrated during immunotherapy maintenance in patients with stable disease. ORR will be assessed in the whole population according to RECIST v1.1. The proportion of ORR will be estimated within each disease.

  At least 8 weeks

Secondary Outcomes (2)

• Treatment-related adverse events assessed by CTCAE V5.0

  At least 8 weeks

• Efficacy in terms of survival

  At least 8 weeks

Study Arms (1)

Solid cancers with stable disease

EXPERIMENTAL

Only cancer patients under treatment with pembrolizumab monotherapy, administered within clinical practice and according to the Italian Drug Regulatory Agency (Agenzia Italiana del Farmaco, AIFA), will be enrolled. Patients diagnosed with NSCLC, HNSCC, melanoma and urothelial carcinoma will be eligible for the study.

Radiation: Carbon Ion Therapy; Drug: Immunotherapy (Pembrolizumab)

Interventions

Carbon Ion Therapy RADIATION

After confirming the disease stability and upon patient inclusion in the study, hypofractionated carbon ion boost will be administered to one site of disease previously untreated. Patient will be irradiated to a single lesion with a total dose of 24 Gy\[RBE\], 8 Gy\[RBE\]/fraction, one fraction/day, for 3 days.

Solid cancers with stable disease

Immunotherapy (Pembrolizumab) DRUG

Only cancer patients under treatment with pembrolizumab monotherapy, administered within clinical practice and according to the Italian Drug Regulatory Agency (Agenzia Italiana del Farmaco, AIFA), will be enrolled.

Also known as: Pembrolizumab

Solid cancers with stable disease

Eligibility Criteria

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

You may qualify if:

• Signed written informed consent
• Having a disease stability as assessed by AIFA monitoring sheet
• Presence of at least 2 measurable target lesions, of which at least one to be followed up as per RECIST and one suitable for CIRT
• Willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study
• Females and males, 18 years of age or older (no upper limit for age)
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• Subjects must have measurable disease by CT or MRI per RECIST 1.1

You may not qualify if:

• Patients treated with chemo-immunotherapy associations
• Patients treated with immunotherapy combinations (e.g. subjects treated with anti-CTLA4 + anti-PD1/PDL1 are excluded)
• Patients receiving immunotherapy within clinical trials
• Patients receiving off-label immunotherapy or within expanded access programs or as compassionate use
• Patients with high tumor burden defined as \> 10 lesions and/or sum of diameters \> 19 cm
• Patients with distant metastases only located in the CNS are excluded
• Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results
• Patients with autoimmune diseases (ADs), including local and systemic collagen-vascular (CVD) and inflammatory bowel diseases (IBD)
• Previous RT, regardless of energy, on the metastatic site selected to be irradiated.
• Any immune-related CTCAE grade 4 adverse event, before study entry
• Any CTCAE grade ≥3 immune-related adverse event observed within 3 weeks prior to CIRT start
• Presence of metal prostheses or any other condition to prevent adequate imaging for identification of the target volume and calculation of the dose
• Loco-regional conditions not allowing hadron therapy (e.g. active infections in RT target region)
• Prisoners or subjects who are involuntarily incarcerated
• Subjects who are compulsorily detained for treatment of either a psychiatric or physical illness (e.g. infectious disease)

Sponsors & Collaborators

• CNAO National Center of Oncological Hadrontherapy: lead
• Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy: collaborator
• Fondazione IRCCS Policlinico San Matteo, Pavia, Italy: collaborator
• GSI Helmholtzzentrum für Schwerionenforschung GmbH, Darmstadt, Germany: collaborator

Study Sites (4)

GSI Helmholtzzentrum für Schwerionenforschung GmbH

Darmstadt, Germany

ACTIVE NOT RECRUITING

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, Italy

RECRUITING

National Center for Oncological Hadrontherapy (CNAO)

Pavia, 27100, Italy

NOT YET RECRUITING

Fondazione IRCCS Policlinico San Matteo

Pavia, Italy

RECRUITING

Related Publications (13)

• Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Kurata T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeno J, Faivre-Finn C, Reck M, Vansteenkiste J, Spigel DR, Wadsworth C, Melillo G, Taboada M, Dennis PA, Ozguroglu M; PACIFIC Investigators. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl J Med. 2018 Dec 13;379(24):2342-2350. doi: 10.1056/NEJMoa1809697. Epub 2018 Sep 25.

  PMID: 30280658 BACKGROUND

• Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC, Demaria S. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res. 2009 Sep 1;15(17):5379-88. doi: 10.1158/1078-0432.CCR-09-0265. Epub 2009 Aug 25.

  PMID: 19706802 BACKGROUND

• Durante M, Paganetti H. Nuclear physics in particle therapy: a review. Rep Prog Phys. 2016 Sep;79(9):096702. doi: 10.1088/0034-4885/79/9/096702. Epub 2016 Aug 19.

  PMID: 27540827 BACKGROUND

• Deng L, Liang H, Xu M, Yang X, Burnette B, Arina A, Li XD, Mauceri H, Beckett M, Darga T, Huang X, Gajewski TF, Chen ZJ, Fu YX, Weichselbaum RR. STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors. Immunity. 2014 Nov 20;41(5):843-52. doi: 10.1016/j.immuni.2014.10.019. Epub 2014 Nov 6.

  PMID: 25517616 BACKGROUND

• Vanpouille-Box C, Alard A, Aryankalayil MJ, Sarfraz Y, Diamond JM, Schneider RJ, Inghirami G, Coleman CN, Formenti SC, Demaria S. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat Commun. 2017 Jun 9;8:15618. doi: 10.1038/ncomms15618.

  PMID: 28598415 BACKGROUND

• Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, Fu YX. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014 Feb;124(2):687-95. doi: 10.1172/JCI67313. Epub 2014 Jan 2.

  PMID: 24382348 BACKGROUND

• Antonioli L, Blandizzi C, Pacher P, Hasko G. Immunity, inflammation and cancer: a leading role for adenosine. Nat Rev Cancer. 2013 Dec;13(12):842-57. doi: 10.1038/nrc3613. Epub 2013 Nov 14.

  PMID: 24226193 BACKGROUND

• Golden EB, Demaria S, Schiff PB, Chachoua A, Formenti SC. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res. 2013 Dec;1(6):365-72. doi: 10.1158/2326-6066.CIR-13-0115.

  PMID: 24563870 BACKGROUND

• Dovedi SJ, Adlard AL, Lipowska-Bhalla G, McKenna C, Jones S, Cheadle EJ, Stratford IJ, Poon E, Morrow M, Stewart R, Jones H, Wilkinson RW, Honeychurch J, Illidge TM. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res. 2014 Oct 1;74(19):5458-68. doi: 10.1158/0008-5472.CAN-14-1258.

  PMID: 25274032 BACKGROUND

• Tang C, Welsh JW, de Groot P, Massarelli E, Chang JY, Hess KR, Basu S, Curran MA, Cabanillas ME, Subbiah V, Fu S, Tsimberidou AM, Karp D, Gomez DR, Diab A, Komaki R, Heymach JV, Sharma P, Naing A, Hong DS. Ipilimumab with Stereotactic Ablative Radiation Therapy: Phase I Results and Immunologic Correlates from Peripheral T Cells. Clin Cancer Res. 2017 Mar 15;23(6):1388-1396. doi: 10.1158/1078-0432.CCR-16-1432. Epub 2016 Sep 20.

  PMID: 27649551 BACKGROUND

• Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.

  PMID: 19097774 BACKGROUND

• Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbe C, Maio M, Binder M, Bohnsack O, Nichol G, Humphrey R, Hodi FS. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009 Dec 1;15(23):7412-20. doi: 10.1158/1078-0432.CCR-09-1624. Epub 2009 Nov 24.

  PMID: 19934295 BACKGROUND

• Cavalieri S, Vitolo V, Barcellini A, Ronchi S, Facoetti A, Campo C, Klersy C, Molinelli S, Agustoni F, Ferretti VV, Silvestri A, Platania M, Del Vecchio M, Durante M, Helm A, Fournier C, Braud F, Pedrazzoli P, Orlandi E, Licitra L. Immune checkpoint inhibitors and Carbon iON radiotherapy In solid Cancers with stable disease (ICONIC). Future Oncol. 2023 Jan;19(3):193-203. doi: 10.2217/fon-2022-0503. Epub 2023 Mar 28.

  PMID: 36974574 DERIVED

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Squamous Cell Carcinoma of Head and Neck; Melanoma; Carcinoma, Transitional Cell

Interventions

Heavy Ion Radiotherapy; Immunotherapy; pembrolizumab

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Head and Neck Neoplasms; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Radiotherapy; Therapeutics; Immunomodulation; Biological Therapy

Study Officials

• Viviana Vitolo, MD

  Fondazione CNAO

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Chiara Campo, PhD

CONTACT

+39 0382078407; campo@cnao.it

Cristina Bono

CONTACT

+39 0382078613; bono@cnao.it

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Patient with solid cancer (NSCLC, HNSCC, melanoma, urothelial carcinoma) and a stable disease will be enrolled in the study.

Study Record Dates

• First Submitted: January 10, 2022
• First Posted: February 8, 2022
• Study Start: July 26, 2022
• Primary Completion: August 1, 2025
• Study Completion (Estimated): August 1, 2026
• Last Updated: August 21, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

IT (3); DE (1)