Neoplasms

All Conditions

Carcinoma

Carcinoma, Squamous Cell

Head and Neck Neoplasms

Squamous Cell Carcinoma of Head and Neck

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Squamous Cell

Antineoplastic Agents

All Drugs and Chemicals

Cisplatin

BYL719, orally, at a starting dose of 200-350 mg, once daily, for 7 weeks. Cisplatin, intravenously, at 100 mg/m2 over 1 hour, every 3 weeks for 3 doses. Radiation therapy, Monday to Friday, for 7 weeks.

BYL719

Intensity modulated radiation therapy (IMRT)

Aaron Hansen, M.D.

This is a phase 1 study (the first step in testing a new drug or combination, to see how safe the drug and/or combination are) of investigational agent BYL719 in patients with locally advanced head and neck cancer (LA-SCCHN) in combination with standard radiation and chemotherapy (cisplatin).

BYL719 is a new drug that is able to bind (attach to) and block a protein called PI3K-alpha. PI3K-alpha is part of an important pathway called EGFR/PI3K/Akt. A pathway is a series of chemical reactions among proteins in the cells that are involved in the support of normal cellular function. If the pathway is too active, due to changes in those proteins, the pathway can lead to tumor cell growth, survival and invasion. BYL719 has been shown to stop cancers in laboratory and animal studies.

This study is the first time BYL719 will be combined with radiation and chemotherapy.

Participants will be screened for eligibility within 30 days of the intended start of the study treatment. Procedures for research purposes done during screening include archival tumor tissue collection for pharmacodynamic and predictive biomarker research and optional HPV status (if not already known).

Eligible participants will take BYL719, by mouth, once a day, starting one week prior to start of radiation and chemotherapy, for 8 weeks. The starting dose of BYL719 is 200 mg. Participants will be asked to record their doses on a study drug diary. Participants will also receive radiation therapy every day from Monday to Friday for 7 weeks.

Chemotherapy (cisplatin) will be given intravenously on Monday of weeks 1, 4, and 7 (48 hour window during weeks 4 and 7).

While receiving the study treatment, participants will have tests and procedures done once every week for safety purposes.

After the end of the study treatment, participants will be asked to visit the centre every 2 weeks up to week 8 for additional tests and procedures for safety purposes. Between week 8-12 after completing the study treatment, participants will have tumor measurements done to assess efficacy.

Participants will continued to be followed every 3 months up to 1 year, then every 6 months for 2 years (total of 3 years).

Phase I Study of BYL719 in Combination With Cisplatin and Radiotherapy in Patients With Squamous Cell Head and Neck Cancer

Phase I Trial of BYL719 in Combination With Concurrent Cisplatin-based Chemoradiotherapy in Patients With Locoregionally Advanced Squamous Cell Carcinoma of Head and Neck (LA-SCCHN)

Novartis Pharmaceuticals

University Health Network, Toronto

Mouth and Tooth Diseases

Ear, Nose, and Throat Diseases

Rare Diseases

Nasopharyngeal Carcinoma

Nasopharyngeal Neoplasms

Pharyngeal Neoplasms

Otorhinolaryngologic Neoplasms

Nasopharyngeal Diseases

Pharyngeal Diseases

Stomatognathic Diseases

Otorhinolaryngologic Diseases

Gemcitabine

Immune Checkpoint Inhibitors

Durvalumab

Antimetabolites

Antineoplastic Agents, Immunological

Induction phase: Durvalumab 1500mg via intravenous infusion every 4 weeks, with chemotherapy gemcitabine 1000mg/m2 on day 1 and day 8 and cisplatin 100mg/m2 on day 1 via intravenous infusion every 3 weeks for 3 cycles.

Concurrent phase: Durvalumab 1500mg via intravenous infusion every 4 weeks for 2 cycles, with cisplatin 100mg/m2 via intravenous infusion every 3 weeks for 3 cycles.

Maintenance phase: Durvalumab 1500mg daily via intravenous infusion every 4 weeks for 8 cycles.

Induction phase: Chemotherapy with gemcitabine 1000mg/m2 on day 1 and day 8 and cisplatin 100mg/m2 on day 1 via intravenous infusion every 3 weeks for 3 cycles.

Concurrent phase: Cisplatin 100mg/m2 on day 1 of radiation therapy via intravenous infusion every 3 weeks for 3 cycles.

Intravenous infusion of durvalumab 1500mg every 4 weeks for 13 cycles (1 year), starting 1 week before start of induction chemotherapy

Induction phase: cisplatin 100mg/m2 on day 1 via intravenous infusion every 3 weeks for 3 cycles Concurrent phase: cisplatin 100mg/m2 starting on day 1 of radiation therapy via intravenous infusion every 3 weeks for 3 cycles

Induction phase: gemcitabine 1000mg/m2 on day 1 and day 8 via intravenous infusion every 3 weeks for 3 cycles

Victor Lee, MD

Sandy Cheung, MSc

Ka-On Lam, FRCR

Ka On Lam, FRCR

The investigators propose a phase II randomized-controlled study on using durvalumab in combination with induction chemotherapy followed by concurrent chemoradiation and adjuvant durvalumab, compared to induction chemotherapy followed by concurrent chemoradiation for previously untreated locoregionally advanced stage III to IVA NPC. In parallel, the investigators will also perform collateral tumor and serum biomarker studies which will be correlated with the treatment response. The investigators will collect fresh tumour biopsies at pretreatment, then serially after induction chemotherapy and after concurrent chemoradiation to investigate the change in microenvironment of the tumour and the surrounding inflammatory cells before and after durvalumab. In addition, the investigators will also measure the change in number and intensity of PD-L1-positive circulating tumour cells (CTC) before and after durvalumab and evaluate their correlation with treatment response.

Nasopharyngeal carcinoma (NPC) of the undifferentiated histology is endemic in southern China and southeast Asia including Hong Kong, Taiwan, Singapore and Malaysia, with a peak annual incidence of up to 30 per 100,000 persons. According to global cancer registry, NPC ranked 11th most common among all malignancies in China in 2008 with an incidence of 2.8/100,000 person-years in men and 1.9/100,000 person-years in females. It is highly associated with prior infection with Epstein-Barr virus and thus it is a highly immune-related malignancy. Treatment strategy is mainly based on the disease stage according to the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging system. In general, stage I-II diseases are treated with radiation therapy alone while stage III-IV diseases are treated with concurrent chemoradiation with or without adjunct chemotherapy (induction or adjuvant). Intensive pretreatment workup including blood hematology and biochemistry, dedicated head and neck imaging with computed tomography and magnetic resonance imaging and positron-emission tomography with integrated computed tomography (PET-CT) and plasma Epstein-Barr virus (EBV) deoxyribonucleic acid (DNA) are essential in high-risk locoregionally advanced diseases to confirm non-metastatic diseases, since the treatment protocol and overall prognosis between locoregionally advanced (stage III-IVA) disease differ significantly from metastatic disease.

Despite intensive radical treatment in the contemporary radiotherapy era with concurrent chemoradiation with or without adjunct chemotherapy, between 15% and 30% of these patients with stage III-IVA disease develop metastatic diseases at distant sites. Further systemic chemotherapy following radical concurrent chemoradiation may not bring survival benefits, attributed by the compromised physique following intensive radical concurrent chemoradiation and the prolonged treatment-related toxicities brought by adjuvant chemotherapy. The recent Hong Kong NPC Study Group NPC-0502 study failed to show survival benefit in patients with post-treatment detectable plasma EBV DNA after a further 6 cycles of adjuvant chemotherapy compared to those who just observed after radical concurrent chemoradiation. On the other hand, induction chemotherapy followed by concurrent chemoradiation may be the more preferred regimen due to the perceived efficacy of eradication of tumor micro-metastasis and early shrinkage of primary tumor and bulky neck nodes, which allow a more radical radiotherapy dose and better coverage of both the primary tumor and neck nodes. Very recently, a China multi-centre phase III randomised-controlled trial demonstrated an improvement in recurrence-free survival and overall survival (OS) with induction chemotherapy gemcitabine plus cisplatin followed by concurrent chemoradiation versus concurrent chemoradiation alone. Nevertheless, new treatment strategies must be developed to improve treatment outcomes of these high-risk patients with stage III-IVA disease, which has become the major research focus in the past decade. A recent meta-analysis demonstrated that induction chemotherapy followed by concurrent chemoradiation improved overall survival compared to concurrent chemoradiation in the era of modern radiotherapy with intensity-modulated radiation therapy (IMRT).

Immune checkpoint inhibitors are now comprehensively and extensively tested in combination with radiotherapy (RT) as well (NCT01935921, NCT01860430). It has been recently known that RT increases the expression of the major histocompatibility complex (MHC). In turn, the MHC class-I restricted tumor antigen-specific cells elicited by RT will upregulate interferons in the tumors. This radiation-induced local inflammation and tumor-specific effector T cells will provide an additional mechanism for tumor control by modification of the tumor vasculature. In addition, RT will increase dendritic cell surface antigen presentation to T cells and production of cytokines leading to recruitment and activation of leucocytes from peripheral blood and extravasation to tumor parenchyma. These are part of the mechanisms of abscopal effect, a phenomenon where the tumors at the sites far away from the irradiated sites also regress after localized radiotherapy. Having learnt from the pivotal PACIFIC trial on the use of consolidation therapy with durvalumab (anti-PD-L1 monoclonal antibody) which confirmed the efficacy and safety of combination of chemoradiation and immunotherapy for stage III non-small-cell lung cancer, it is prime time to consider incorporation of immune checkpoint inhibitors into concurrent chemoradiation for other solid tumors like head and neck squamous cell carcinoma and NPC. In concurrent +/- adjuvant setting for locoregionally advanced NPC, there are at least two clinical trials on immune checkpoint inhibitors for locoregionally advanced disease. The first one is a phase II single-arm study using nivolumab in combination with concurrent chemoradiation with or without by adjuvant nivolumab for up to 3 months at different dose schedules (NCT03267498). A phase III multi-center randomized-controlled trial (RCT) in China on the use of a locally-manufactured PD-1 monoclonal antibody (SHR-1210) every 4 weeks for 12 cycles starting at 4-6 weeks after concurrent chemoradiation for stage III-IVA NPC versus no adjuvant therapy is currently under way (NCT03427827). It is highly expected and eagerly awaited that immunotherapy with immune checkpoint inhibitors will bring a new insight on the adjuvant treatment for NPC.

In view of the above with promising synergy between radiation therapy and immune checkpoint inhibitors, the investigators propose a phase II RCT on adding durvalumab in combination with induction chemotherapy followed by concurrent chemoradiation and adjuvant durvalumab for previously untreated locoregionally advanced NPC. In parallel, the investigators will also perform collateral tumor and serum biomarker studies which will be correlated with the treatment response. The investigators will collect fresh tumour biopsies at pretreatment, then serially after induction chemotherapy and after concurrent chemoradiation to investigate the change in microenvironment of the tumour and the surrounding inflammatory cells before and after durvalumab. In addition, the investigators will also measure the change in number and intensity of PD-L1-positive circulating tumour cells before and after durvalumab and evaluate their correlation with treatment response.

Concurrent Chemoradiation and Durvalumab for Locoregionally Advanced Nasopharyngeal Carcinoma

A Multi-centre Phase II Randomized-controlled Study on Addition of Durvalumab (MEDI4736) to Induction Chemotherapy and Concurrent Chemoradiation and Followed by Maintenance Durvalumab for Locoregionally Advanced Nasopharyngeal Carcinoma

There is no plan to make individual participant data (IPD) available to other researchers.

Toxicity profile as assessed by Common Terminology Criteria for Adverse Events version 5.0

Changes in the number of PD-L1 positive circulating tumor cells before and after induction chemotherapy and concurrent chemoradiation

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Phase I Study of BYL719 in Combination With Cisplatin and Radiotherapy in Patients With Squamous Cell Head and Neck Cancer	NCT02537223	Squamous Cell C... Locoregionally ...	BYL719 Cisplatin Intensity modul...	18 Years -	University Health Network, Toronto
Concurrent Chemoradiation and Durvalumab for Locoregionally Advanced Nasopharyngeal Carcinoma	NCT04447612	Nasopharyngeal ...	Durvalumab Cisplatin Gemcitabine	18 Years - 75 Years	The University of Hong Kong

Spots Global Cancer Trial Database for locoregionally advanced