Bahig et al. BMC Cancer (2019) 19:68
`https://doi.org/10.1186/s12885-019-5266-4
`
`Open Access
`
`S T U D Y P R O T O C O L
`Phase I/II trial of Durvalumab plus
`Tremelimumab and stereotactic body
`radiotherapy for metastatic head and
`neck carcinoma
`Houda Bahig1,3, Francine Aubin2,3, John Stagg3, Olguta Gologan3,4, Olivier Ballivy1,3, Eric Bissada3,5,
`Felix-Phuc Nguyen-Tan1,3, Denis Soulières2,3, Louis Guertin3,5, Edith Filion1,3, Apostolos Christopoulos3,5,
`Louise Lambert1,3, Mustapha Tehfe2,3, Tareck Ayad3,5, Danielle Charpentier2,3, Rahima Jamal2,3 and
`Philip Wong1,3*
`
`Abstract
`
`Background: The efficacy of immunotherapy targeting the PD-1/PD-L1 pathway has previously been demonstrated
`in metastatic head and neck squamous cell carcinoma (HNSCC). Stereotactic Body Radiotherapy (SBRT) aims at
`ablating metastatic lesions and may play a synergistic role with immunotherapy. The purpose of this study is to
`assess the safety and efficacy of triple treatment combination (TTC) consisting of the administration of durvalumab
`and tremelimumab in combination with SBRT in metastatic HNSCC.
`Method: This is a phase I/II single arm study that will include 35 patients with 2–10 extracranial metastatic lesions.
`Patients will receive durvalumab (1500 mg IV every 4 weeks (Q4W)) and tremelimumab (75 mg IV Q4W for a total of
`4 doses) until progression, unacceptable toxicity or patient withdrawal. SBRT to 2–5 metastases will be administered
`between cycles 2 and 3 of immunotherapy. The safety of the treatment combination will be evaluated through
`assessment of TTC-related toxicities, defined as grade 3–5 toxicities based on Common Terminology Criteria for
`Adverse Events (v 4.03), occurring within 6 weeks from SBRT start, and that are definitely, probably or possibly
`related to the combination of all treatments. We hypothesize that dual targeting of PD-L1 and CTLA-4 pathways
`combined with SBRT will lead to < 35% grade 3–5 acute toxicities related to TTC. Progression free survival (PFS) will
`be the primary endpoint of the phase II portion of this study and will be assessed with radiological exams every 8
`weeks using the RECIST version 1.1 criteria.
`Discussion: The combination of synergistic dual checkpoints inhibition along with ablative radiation may
`significantly potentiate the local and systemic disease control. This study constitutes the first clinical trial combining
`effects of SBRT with dual checkpoint blockade with durvalumab and tremelimumab in the treatment of metastatic
`HNSCC. If positive, this study would lead to a phase III trial testing this treatment combination against standard of
`care in metastatic HNSCC.
`Trial registration: NCT03283605. Registration date: September 14, 2017; version 1.
`Keywords: Head and neck cancer, Metastatic, Immunotherapy, SBRT, Durvalumab, Tremelimumab
`
`* Correspondence: philip.wong.chum@ssss.gouv.qc.ca
`1Department of Radiation Oncology, Centre Hospitalier de l’Université de
`Montréal, 1051 Sanguinet Street, Montreal, QC H2X 3E4, Canada
`3Centre de Recherche du Centre Hospitalier de l’Université de Montréal,
`Montréal, QC, Canada
`Full list of author information is available at the end of the article
`
`© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
`International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
`reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
`the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
`(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
`
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`Page 2 of 15
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`Background
`Metastatic head and neck cancer
`Each year, up to 60,000 new cases of head and neck
`squamous cell cancer (HNSCC) are diagnosed in the
`United States [1]. The prevalence of distant metastasis at
`diagnosis varies between 4 and 26% [2–5]. Among pa-
`tients without metastasis at diagnosis, up to 30% will de-
`velop distant failure [6, 7]. The prognosis of patients
`with distant metastasis is poor, and standard of care re-
`mains palliative chemotherapy. Palliative chemotherapy
`includes combinations of cetuximab, platinum and
`fluorouracil-based combinations associated with a me-
`dian overall survival of 10 months and a response rate of
`30% [8]. Alternatively, doublet platinum chemotherapy
`is associated with a median overall survival (OS) of 6–8
`months [9]. Patients that are refractory or progress on
`first-line chemotherapy have limited treatment options
`as response rates to second-line therapies are between 3
`and 13% [10].
`
`Local ablative therapy for oligometastatic HNSCC
`Local ablation (by surgical resection or radiotherapy) of
`oligometastasis (defined broadly as metastatic cancer
`with limited burden of disease) [11], aims at achieving
`prolonged progression free survival (PFS), and sometimes
`cure [12, 13]. This model is supported by results of the
`phase II randomized trial by Gomez et al. [14] showing
`that local ablation of non-small cell lung cancer oligome-
`tastasis was associated with 3 folds increase in median
`PFS compared to systemic maintenance treatment (12 vs.
`4 months). A meta-analysis of 13 studies including 403 pa-
`tients with HNSCC that underwent surgical resection of
`metachronous lung metastases showed 5-year OS of 29%
`[15]. SBRT is a highly conformal imaged-guided radiother-
`apy technique allowing for delivery of an ablative dose of
`radiotherapy in a small number of fractions [16]. The use
`of SBRT as a radical approach in oligometastatic disease is
`attractive given its non-invasive nature, its excellent local
`control (above 80%) [17, 18], and its safety with < 5–10%
`risk of grade ≥ 3 toxicities [19–22].
`
`Immunotherapy in HNSCC
`HNSCC tumors are highly immunogenic, with PD-L1 ex-
`pression found in up to 60% of HNSCC along with ele-
`vated levels of intra-tumoral regulatory T cells infiltration
`[23, 24], thus making immunotherapy particularly attract-
`ive in HNSCC. Pembrolizumab and nivolumab are human
`IgG4 anti-PD-1 monoclonal antibodies approved as sec-
`ond line therapy for metastatic HNSCC by the US FDA,
`which respectively showed 3 months OS benefit over
`standard chemotherapy in platinum-refractory recurrent
`and metastatic HNSCC [25], and 18% response rate in re-
`current or metastatic HNSCC [26, 27]. Results from Key-
`note 048, a randomized phase 3 study of pembrolizumab
`
`vs. cetuximab combined with platinum chemotherapy plus
`fluorouracil as first-line systemic therapy recurrent/meta-
`static HNSCC, were presented at the European Society for
`Medical Oncology 2018 meeting and showed that pem-
`brolizumab was associated with significantly improved OS
`compared to the standard arm. Similarly, Keynote 040, a
`phase 3 randomized trial of pembrolizumab vs. investiga-
`tor’s choice of methotrexate, docetaxel, or cetuximab,
`showed improved OS with pembrolizumab (8.4 vs. 6.9
`months) and reduced grade 3 or worse toxicities in the
`treatment of recurrent or metastatic HNSCC [28].
`human
`Durvalumab
`(MEDI4736)
`is
`a
`selective
`anti-PD-L1 IgG1 monoclonal antibody that blocks the
`interaction of PD-L1 with PD-1 and CD80. Durvalumab in-
`duced overall response rates of 11% in metastatic or recur-
`rent HNSCC and 18% in patients with high PD-L1
`expression [29]. Tremelimumab is a selective human
`anti-CTLA-4 IgG2 monoclonal antibody [30]. The mecha-
`nisms of action of CTLA-4 and PD-L1 pathways are
`non-redundant as preclinical data indicate that inhibiting
`both pathways have synergistic antitumor activity [31].
`While anti-PD-1/PD-L1 monotherapy seems associated
`with a greater clinical benefit in tumors expressing PD-L1,
`combination with anti-CTLA-4 therapy has the potential to
`enhance antitumor activity of anti-PD-1/PD-L1 agents in
`both PD-L1 positive and PD-L1 negative tumors [32]. The
`combination of anti-PD-1 and anti-CTLA-4 was shown to
`improve PFS vs. anti-PD-1 alone in melanoma (12 months
`vs. 7 months) [33]. This benefit came however at the price
`of increased grade 3–4 toxicities (55% vs. 27%, respectively.)
`A multicenter phase IB study assessing the combination of
`durvalumab and tremelimumab in non-small cell lung can-
`cer reported 23% objective responses, irrespective of PD-L1
`status; treatment related grade 3–4 toxicities were observed
`in 22% of patients [34]. In HNSCC, several trials are
`on-going to assess the safety and efficacy durvalumab and
`tremelimumab vs. monotherapy in recurrent or metastatic
`HNSCC [35] or as first line approach in advanced HNSCC
`(KESTREL (NCT02551159) and EAGLE [36]).
`
`Combining immunotherapy and radiotherapy in head and
`neck cancers
`Radiotherapy has been shown to induce anti-tumor im-
`mune effect in addition to cytotoxic effect [37, 38]. In
`fact, radiotherapy plays a role in the recruitment of T
`cells in the tumor microenvironment [39], secretion of
`cytokines, enhanced tumor antigen presentation [40, 41],
`and increased expression of PD-L1 in irradiated tumors
`[42]. In addition,
`induction of abscopal effect, which
`consists in anti-tumor response outside the radiotherapy
`field [42–45], has been suggested in both pre-clinical
`and clinical data. In mice, concomitant radiotherapy and
`anti-CTLA-4 antibodies induced abscopal effect [46, 47];
`in addition, PD-1 blockade
`after
`completion of
`
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`

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`Page 3 of 15
`
`radiotherapy was shown to induce elimination of persist-
`ent
`tumors [42]. Dual checkpoint blockade (anti-C-
`TLA-4 and anti-PD-L1) in combination with radiation
`has been shown to activate non-redundant
`immune
`mechanisms [38]. Single fraction radiation doses be-
`tween 15 Gy and 25 Gy were shown to promote
`T-cell-mediated anti-tumor response at both the primary
`and distant metastases sites in mice model [48]. Simi-
`larly, hypofractionated regimen of 15 Gy in 1 fraction
`were associated with a greater tumor infiltration by im-
`mune cells compared to 15 Gy in 5 fractions regimen
`[49]. SBRT fractionation may therefore be advantageous
`for immune-stimulation and may work synergistically
`with immunotherapy [50]. Abscopal effect is reported in
`an increasing number of clinical reports, in particular in
`the context of the combination of immune checkpoint
`inhibitors and radiation [51–53].
`Dual checkpoint blockade in combination with SBRT
`has not yet been reported in human clinical trials. Al-
`though the addition of SBRT to immunotherapy may
`generate higher response rates, it may increase the fre-
`quency and/or severity of toxicities. In this study, we will
`assess the safety and efficacy of a triple treatment com-
`bination (TTC) consisting of durvalumab, tremelilumab
`and SBRT in the treatment of patients with 2–10 metas-
`tasis from HNSCC.
`
`Methods and design
`Study design
`This is a phase I/II single arm study evaluating the safety
`and efficacy of durvalumab, tremelimumab and SBRT com-
`bination in metastatic HNSCC. The study will include 35
`patients with ≥2 extracranial measurable metastatic lesions
`and a maximum of 10 metastatic lesions in total, at the time
`of enrolment. Patients will be treated with durvalumab
`(1500 mg IV every 4 weeks (Q4W)) and tremelimumab (75
`mg IV Q4W for a total of 4 doses) until progression, un-
`acceptable toxicity or patient withdrawal. SBRT to 2–5 me-
`tastases will be administered between cycles 2 and 3 of
`immunotherapy (Fig. 1). This study is approved by the
`Centre de Recherche du Centre Hospitalier de l’Université
`de Montréal Institutional Review Board and is registered on
`clinicaltrials.gov (NCT03283605). Other participating aca-
`demic institutions can be found on clinicaltrials.gov.
`
`Primary objectives
`Phase I
`To determine the safety of durvalumab and tremelimu-
`mab in combination with SBRT to 2–5 metastatic lesions
`by assessing rates of TTC-related serious adverse events
`(SAE) within 6 weeks from the start of SBRT treatments.
`
`Primary endpoint TTC-related SAE, defined as grade 3–5
`toxicities based on Common Terminology Criteria for
`
`Adverse Events (CTCAE), are defined as definitely, probably,
`or possibly related to the combination of all 3 treatments,
`beyond what is expected by either treatment alone.
`
`Phase II
`To provide an estimate of PFS at 6-months in patients
`treated with durvalumab and tremelimumab in combin-
`ation and SBRT.
`
`Primary endpoint PFS will be measured from the start
`of treatment with durvalumab and tremelimumab until
`the documentation of regional or distant disease progres-
`sion or death due to any cause, whichever occurs first.
`
`Secondary objectives
`
`1. To assess the rate and proportion of SAE at each time
`point (at 3, 6, 12 and 28 weeks post-radiotherapy).
`2. To estimate local control (LC) of the treatment
`combination.
`3. To estimate median OS of the treatment combination.
`4. To estimate the rate of abscopal events from the
`combination therapy.
`5. To measure patient quality of life.
`6. To correlate LC and PFS with biopsy and serum
`biomarkers (exploratory).
`7. To correlate OS and treatment toxicity with activity
`tracker metrics (exploratory).
`
`Secondary endpoints LC of treated lesions will be mea-
`sured from the end of SBRT treatment to date of local
`failure. OS will be measured from the start of treatment
`with durvalumab and tremelimumab to time of death. In
`subset of patients where at least 1 measurable lesion will
`not have been addressed by SBRT, abscopal effect will be
`estimated by comparing response rate of untreated le-
`sion to historical response rate expected from durvalu-
`mab and tremelimumab combination alone. Quality of
`life will be measured in evaluable patients using the Euro-
`pean Organization for Research and Treatment of Cancer
`(EORTC) Quality of Life Questionnaire Core-30 (QLQ-C30;
`version 3.0) and the head and neck cancer specific module
`EORTC QLQ-H&N35.
`
`Conditions for patient eligibility
`
`1. Patient willing and able to give written informed
`consent
`2. Patient willing and able to comply with the protocol
`for the duration of the study
`3. ≥ 18 years of age at time of study entry
`4. Body weight > 30 kg
`5. Life expectancy > 24 weeks, as estimated by the
`treating team
`
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`

`Bahig et al. BMC Cancer (2019) 19:68
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`Page 4 of 15
`
`Fig. 1 Study schema. HNSCC = head and neck squamous cell carcinoma; SBRT = stereotactic body radiotherapy; PFS = Progression free survival;
`LC = local control; OS = overall survival
`
`6. All standard tumor-staging procedures necessary to
`define the baseline disease burden must be com-
`pleted within 28 days to registration
`7. Pathologically (histologically or cytologically)
`confirmed diagnosis HNSCC at a metastatic site
`8. ≥ 2 extracranial measurable metastatic lesions (no
`brain metastases) as per RECIST v1.1, or lesions <
`1 cm showing at least a 1 mm increase in size 2
`consecutive imaging that amenable to SBRT.
`
`9. ≤ 10 metastatic lesions
`10. Eastern Cooperative Oncology Group/World
`Health Organisation (ECOG/WHO) performance
`status score of ≤1
`11. Adequate normal organ and marrow function as
`defined below:
` Haemoglobin ≥9.0 g/dL
` Absolute neutrophil count (ANC ≥ 1.5 x (> 1500
`per mm3)
`
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` Platelet count ≥100 × 109/L (> 75,000 per mm3)
` Serum bilirubin ≤1.5 x institutional upper limit
`of normal (ULN).
` AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional
`upper limit of normal unless liver metastases are
`present, in which case it must be ≤5x ULN
` Serum creatinine CL > 40 mL/min by the
`Cockcroft-Gault formula
`12. The following imaging workup to document
`metastases within 45 days prior to study registration:
`a. Computed tomography of the chest, abdomen
`and pelvis OR whole body Positron Emission
`Tomography/Computed Tomography
` Patients with locoregional recurrence(s) are
`included only if they have evidence of distant
`metastasis; patients with locoregional
`recurrences which are symptomatic and/or
`potentially affect quality of life may undergo
`palliative radiation therapy to this region
`prior to enrolment on the protocol at the
`discretion of the treating physician. The dose
`and technique (conventional vs. SBRT) is at
`the discretion of the treating physician, with a
`dosimetric planning prioritization on organs at
`risk over tumor target coverage when in
`conflict. However, a minimum of 28 days must
`elapse before receiving protocol treatment.
`13. Serum pregnancy test for female pre-menopausal
`patients
`14. Patients who have received prior anti-PD-1, anti
`PD-L1 or anti CTLA-4, including durvalumab and
`tremelimumab if the following are fulfilled:
` Must not have experienced a toxicity that led to
`permanent discontinuation of prior
`immunotherapy.
` All adverse events (AE) of prior immunotherapy
`must have completely resolved or returned to
`baseline prior to screening for this study.
` Must not have experienced a ≥ Grade 3 immune
`related AE or an immune-related neurologic or
`ocular AE of any grade while receiving prior
`immunotherapy.
` Must not have required the use of additional
`immunosuppression other than corticosteroids for
`the management of an AE and not have
`experienced recurrence of an AE if re-challenged.
`
`Conditions for patient ineligibility
`
`1. Nasopharyngeal carcinoma
`2. Concurrent enrolment in another clinical study,
`unless it is an observational clinical study or during
`the follow-up period of an interventional study
`
`3. > 4 prior treatment lines with systemic therapy
`4. Receipt of the last dose of anti-cancer therapy
`(chemotherapy, immunotherapy, endocrine therapy,
`targeted therapy, biologic therapy, tumour
`embolization, monoclonal antibodies) ≤ 30 days
`prior to the first dose of study drug
`5. Any unresolved toxicity CTCAE Grade ≥ 2 from
`previous anticancer therapy with the exception of
`alopecia, vitiligo, and the laboratory values defined
`in the inclusion criteria
`○ Patients with Grade ≥ 2 neuropathy will be
`evaluated on a case-by-case basis after consult-
`ation with the Study Physician
`○ Patients with irreversible toxicity not
`reasonably expected to be exacerbated by
`treatment with durvalumab or tremelimumab
`may be included only after consultation with
`the Study Physician
`6. Any concurrent chemotherapy, investigational product
`(IP), biologic, or hormonal therapy for cancer
`treatment. Concurrent use of hormonal therapy for
`non-cancer-related conditions is acceptable
`7. Radiotherapy treatment to more than 30% of the
`bone marrow or with a wide field of radiation
`within 4 weeks of the first dose of study drug
`8. Major surgical procedure (as defined by the
`Investigator) within 28 days prior to the first dose of
`IP. Note: Local surgery of isolated lesions for
`palliative intent is acceptable
`9. History of allogenic organ transplantation
`10. Active or prior documented autoimmune or
`inflammatory disorders including diverticulitis,
`systemic lupus erythematosus, Sarcoidosis
`syndrome, or Wegener syndrome are excluded.
`However, patients without active disease in the last
`5 years may enter the trial after consultation with
`the study physician.
`11. Uncontrolled undercurrent illness that would limit
`compliance with study requirement, substantially
`increase risk of incurring AEs or compromise the
`ability of the patient to give written informed consent
`12. History of another primary malignancy except for
`○ Malignancy treated with curative intent and with
`no known active disease ≥5 years and of low
`potential risk for recurrence
`○ Adequately treated non-melanoma skin cancer
`or lentigo maligna without evidence of disease
`○ Adequately treated carcinoma in situ without
`evidence of disease
`13. Presence of brain metastases or spinal cord
`compression. Patients with suspected brain
`metastases at screening should have an MRI
`(preferred) or CT each preferably with IV contrast
`of the brain prior to study entry
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`14. History of active primary immunodeficiency
`15. Current or prior use of immunosuppressive
`medication within 14 days before the first dose of
`durvalumab or tremelimumab. The following are
`exceptions to this criterion:
`○ Intranasal, inhaled, topical steroids, or local
`steroid injections (eg, intra articular injection).
`○ Systemic corticosteroids at physiologic doses not to
`exceed 10 mg/day of prednisone or its equivalent
`○ Steroids as premedication for hypersensitivity
`reactions (eg. CT scan premedication)
`16. Receipt of live attenuated vaccine within 30 days prior
`to the first dose of durvalumab or tremelimumab
`17. Known allergy or hypersensitivity to any of the
`study drugs or any of the study drug excipients
`18. Past medical history of interstitial lung disease
`(ILD), drug-induced ILD, radiation pneumonitis
`which required steroid treatment, or any evidence
`of clinically active interstitial lung disease
`19. Judgment by the investigator that the patient is
`unsuitable to participate in the study and the
`patient is unlikely to comply with study procedures,
`restrictions and requirements
`20. Female patients who are pregnant or breastfeeding
`or male or female patients of reproductive potential
`who are not willing to employ effective birth
`control from screening to 180 days after the last
`dose of durvalumab + tremelimumab combination
`therapy or 90 days after the last dose of durvalumab
`monotherapy, whichever is the longer time period.
`
`cycle 3 of durvalumab and tremelimumab combination
`treatment. SBRT for all metastases should be completed
`within 3 weeks of the first dose of SBRT. Metastases will
`be treated on an every other day schedule. However, a
`patient may receive radiation for different metastases on
`consecutive days.
`
`Planning
`Patients positioning and immobilization device will be at
`the discretion of
`the treating physician. Positioning
`should be stable to avoid uncontrolled movement during
`treatments and maintain treatment accuracy. Patient
`immobilization must be reliable enough to ensure that
`the gross tumor volume does not deviate beyond the
`confines of the planning treatment volume (PTV).
`All patients will undergo planning CT of the region con-
`taining the treated metastasis. CT scan range will be as per
`standard limits used in our department for each anatomical
`site. Use of intravenous contrast will be required for liver
`metastases, but will be as per treating physician for all other
`sites. In addition, a 4D planning CT scan will be obtained
`for all metastases with potential for respiratory motion.
`Motion management strategies, including internal target
`volume technique, tracking, as well as abdominal compres-
`sion, active breathing control, gating, breath hold, should
`be used as required. Image guided radiotherapy technique
`will therefore include orthogonal in-room 2D kV X-rays in
`cases of near-rela time robotic tracking, or volumetric im-
`aging (kV cone beam computed tomography; MV com-
`puted tomography).
`
`Intervention
`Durvalumab + tremelimumab
`Durvalumab 1500 mg plus tremelimumab 75 mg via IV
`infusion Q4W, starting on Week 0, for up to a max-
`imum of 4 doses/cycles followed by durvalumab mono-
`therapy 1500 mg via IV infusion Q4W, starting 4 weeks
`after the last infusion of the combination, until con-
`firmed disease progression, death, unacceptable toxicity,
`withdrawal of consent, or other discontinuation criteria
`met (Fig. 2). Tremelimumab will be administered first;
`the durvalumab infusion will start at a maximum of 2 h
`after the end of the tremelimumab infusion.
`
`SBRT
`The targeting of lesions will be determined at the discre-
`tion of the treating physician. The maximum dimension
`receiving the prescribed SBRT dose is 4 cm. Treating
`physician may choose to treat a part of the target lesion’s
`gross tumor volume (GTV) in order to avoid exceeding
`the 4 cm maximum dimension limit or to reduce the
`chance of incurring radiation related toxicities. SBRT
`will be delivered during cycle 2 and completed prior to
`
`Dose & prescription
`SBRT doses will vary based on tumor location (Table 1).
`Patients will receive 3 or 5 SBRT fractions. The following
`table details suggested dose per tumor site, as per
`NRG-BR001 protocol (NCT02206334):
`The prescription isodose line covering 95% the PTV will
`generally be 80–90% but may range from 60 to 90% where
`the maximum dose is 100%. All dose calculations will be
`performed using corrections for tissue heterogeneities.
`
`Target volume determination
`GTV definition will be based on planning CT as well as
`any other standard multi-modality imaging used in the
`clinic. Clinical target volume and PTV definition will de-
`pend on tumor site and will be as per institutional
`protocols.
`
`1. Central lung tumor will be defined as tumors within
`or touching the zone of the proximal bronchial tree,
`defined as a volume 2 cm in all directions around the
`proximal bronchial tree (carina, right and left main
`bronchi, right and left upper lobe bronchi, intermedius
`
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`Fig. 2 Durvalumab (MEDI4736) and tremelimumab administration schedule
`
`bronchus, right middle lobe bronchus, lingular
`bronchus right and left lower lobe bronchi) as well as
`tumors that are immediately adjacent to mediastinal
`or pericardial pleura (PTV touching the pleura), as per
`RTOG 0813.
`2. Peripheral lung tumors will be defined as
`metastases within the lungs outside of the central
`tumor definition above. Rib/scapular metastases
`within the thorax adjacent to lung parenchyma will
`be classified into the lung metastasis location given
`the similar normal tissues at risk.
`3. Mediastinal/Cervical lymph nodes (LN):
`Mediastinal LN will include tumors arising within
`the anatomic space between the lungs, above the
`diaphragm, and below the thoracic inlet at the level
`of the top of the sternal notch. Cervical LN will
`include tumors occurring within cervical lymph
`node Levels I-VI and/or retropharyngeal spaces.
`Sternal metastases will be assigned to the medias-
`tinal/cervical lymph node location given the similar
`normal tissues at risk.
`4. Liver will include metastasis arising within the liver,
`however, as per NRG-BR001, rib metastases imme-
`diately adjacent to the liver will be assigned to the
`liver metastasis location.
`5. Abdominal-pelvic tumors will include metastasis
`arising within the anatomic space defined by the
`diaphragm superiorly, the genitourinary diaphragm
`inferiorly including the peritoneal and
`retroperitoneal spaces, not including liver, osseous,
`or spinal metastases. Rib metastases adjacent to the
`stomach/abdominal wall will be classified into the
`
`Table 1 Suggested dose and number of fractions per tumor site
`Site
`Dose (Gy)
`Fractions
`Lung-peripheral
`45
`3
`
`Lung-central
`
`Mediastinal/cervical lymph node
`
`Liver
`
`Spinal/paraspinal
`
`Osseous
`
`Abdominal-pelvic metastasis
`(lymph node/adrenal gland)
`
`50
`
`50
`
`45
`
`30
`
`30
`
`45
`
`5
`
`5
`
`3
`
`3
`
`3
`
`3
`
`intra-abdominal location given the similar normal
`tissues at risk.
`6. Spinal metastases could involve any portion(s) of
`the vertebral spine. Rib metastases that are within
`1 cm of the vertebral bodies will be classified into
`the spinal metastasis location given the similar
`normal tissues at risk.
`7. Osseous lesions will be defined as any bone
`metastasis not included in all other site definition.
`
`Critical structures
`Dose limits used for organs at risk will be as per
`NRG-BR001 protocol, with prioritization of normal tis-
`sues over tumor coverage.
`
`Study assessments
`Table 2 summarizes schedule of assessments during the
`participation to this study.
`
`Data collection
`The current study will be coordinated by a clinical re-
`search organization, Ozmosis Research Inc. Data will be
`collected centrally using electronic Case Report Forms
`designed and built in Medidata Rave. Data are stored
`within the University Health Network server in Canada.
`All data points will be reviewed by Ozmosis Research
`Data Managers. To ensure the quality of the data, site
`initiation will be conducted, where all components re-
`quired for the conduct of the study will be evaluated
`prior to study opening. A risk-based monitoring visit
`plan was designed and at least 4 visits per year will occur
`to ascertain the quality of the data. One close out visit
`per accrual site is also planned. The monitor and trial
`audit is independent of the investigators and sponsor.
`Follow up for survival status and subsequent anti-cancer
`therapy will occur every 3 months from the time of
`treatment discontinuation. As the trial will be conducted
`across Canadian institutions, patient death, a public rec-
`ord captured for all Canadian citizens, can be collected
`from provincial health care databases if necessary to en-
`sure the availability of overall survival data.
`
`

`

`Bahig et al. BMC Cancer (2019) 19:68
`
`Page 8 of 15
`
`Table 2 Schedule of study assessments
`Required investigations
`Screening
`
`Day 1 of
`each Cycle1
`
`Treatment with
`SBRT (Cycle 2)
`
`End of Cycle 2, 4,
`6, 8, 10, and 12
`
`Window
`
`History and
`physical examination
`
`Vital signs
`
`FFPE tumor tissue
`sample collection
`for PD-L1 assay
`
`Urine hCG/serum
`βhCGa
`Durvalumab
`
`Tremelimumab
`
`SBRT
`
`ECG
`
`ECOG Status
`
`Hematology
`
`Serum chemistry: complete
`clinical chemistry panel,
`creatinine clearance,
`liver enzyme panel.
`
`Urinalysis
`
`Thyroid function test:
`TSH, fT3 and fT4
`
`Correlative samples
`collection: plasma,
`serum, whole blood
`
`Coagulation parameters:
`PPT, APTT and INR
`
`Tumor assessments: CT
`head/neck, CT chest,
`CT abdomen/pelvis,
`FDG-PET, biopsy
`
`Patient questionnaires
`
`Within 28 days
`prior to registration
`
`±3 days
`
`±7 days
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`Safety Visit
`(28 days after end
`of treatment)
`±7 days
`
`Follow up15
`(Every 3 months
`from EOT)
`±7 days
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`As per SOC
`
`Adverse events & concomitant
`medications review
`
`Continuous
`
`Continuous
`Activity Tracker
`FFPE Formalin-Fixed Paraffin-Embedded, EOT End of treatment, SOC standard of care
`
`Biological sampling procedures
`All patients entered into the study must provide blood
`samples, consent
`to the use of previously obtained
`paraffin-embedded tissues, and their clinical data for col-
`lection and translational studies. Paraffin-embedded tis-
`sues from any prior biopsies or resections will also be
`collected for correlative sciences.
`
`Assessment of safety
`This study will utilize the CTCAE Version 4.03 for ad-
`verse event reporting. TTC-related toxicities are defined
`as toxicities that occur after SBRT treatment start and that
`are judged, by the sponsor or investigators, to be definitely,
`probably or possibly related to the combination of dual
`
`immunotherapy and SBRT based on the location of the
`metastases treated as well as exposure of surrounding nor-
`mal tissues. Toxicity that is clearly and directly related to
`the primary disease or to another etiology is excluded
`from this definition. The following toxicities related to
`TTC are expected:
` Any Grade 4 immune-related AE (irAE)
` Any ≥ Grade 3 colitis
` Any Grade 3 or 4 non-infectious pneumonitis irre-
`spective of duration
` Any Grade 2 pneumonitis that does not resolve
`to ≤ Grade 1 within 3 days of the initiation of
`maximal supportive care
`
`

`

`Bahig et al. BMC Cancer (2019) 19:68
`
`Page 9 of 15
`
` Any Grade 3 irAE, excluding colitis or pneumonitis,
`that does not downgrade to Grade 2 within 3 days after
`onset of the event despite optimal medical
`management including systemic corticosteroids or does
`not downgrade to ≤ Grade 1 or baseline within 14 days
` Liver transaminase elevation > 8 × ULN or total
`bilirubin > 5 × ULN
` Grade 3 or 4 Pericarditis
` Grade 3 or 4 Esophagitis
` Grade 3 or 4 Central Airway/Bronchial Injury
` Grade 3 or 4 Radiation pneumonitis
` Grade 3 or 4 Radiation-induced liver disease
` Radiation Myelitis
` Grade 3 or 4 radiation Laryngitis or Pharyngitis
` Any other ≥ Grade 3 non-irAE, except for the exclu-
`sions listed below
`
`The expected TTC-related toxicity definition defined
`above excludes the following conditions:
` Grade 3 fatigue lasting ≤7 days
` Grade 3 endocrine disorder (thyroid, pituitary, and/
`or adrenal insufficiency) that is managed with or
`without systemic corticosteroid therapy and/or
`hormone replacement therapy and the subject is
`asymptomatic
` Grade 3 inflammatory reaction attributed to a local
`antitumor response (eg. inflammatory reaction at
`sites of metastatic disease, lymph nodes, etc.)
` Concurrent vitiligo or alopecia of any AE grade
` Grade 3 infusion-related reaction (first occurrence and
`in the absence of steroid prophylaxis) that resolves
`within 6 h with appropriate clinical management
` Grade 3 or 4 neutropenia that is not associated
`with fever or systemic infection that improves by
`at least 1 grade within 3 days. Grade 3 or Grade
`4 febrile neutropenia will be a SAE regardless of
`duration or reversibility
` Grade 3 or 4 lym