CompARE: study protocol for a phase III randomised controlled platform trial comparing alternative regimens for escalating treatment of intermediate and high-risk oropharyngeal cancer

Abstract

Background: Patients with intermediate and high-risk oropharyngeal cancer (OPC) have poorer response to standard treatment and poorer overall survival compared to low-risk OPC. CompARE is designed to test alternative approaches to intensified treatment for these patients to improve survival.

Methods: CompARE is a pragmatic phase III, open-label, multicenter randomised controlled trial with an adaptive multi-arm, multi-stage design and an integrated QuinteT Recruitment Intervention. Eligible OPC patients include those with human papillomavirus (HPV) negative, T1-T4, N1-N3 or T3-4, N0, or HPV positive N3, T4, or current smokers (or ≥ 10 pack years previous smoking history) with T1-T4, N2b-N3. CompARE was originally designed with four arms (one control [arm 1] and three experimental: arm 2-induction chemotherapy followed by arm 1; arm 3-dose-escalated radiotherapy plus concomitant cisplatin; and arm 4-resection of primary followed by arm 1). The three original experimental arms have been closed to recruitment and a further experimental arm opened (arm 5-induction durvalumab followed by arm 1 and then adjuvant durvalumab). Currently recruiting are arm 1 (control): standard treatment of 3-weekly cisplatin 100 mg/m² or weekly 40 mg/m² with intensity-modulated radiotherapy using 70 Gy in 35 fractions ± neck dissection determined by clinical and radiological assessment 3 months post-treatment, and arm 5 (intervention): one cycle of induction durvalumab 1500 mg followed by standard treatment then durvalumab 1500 mg every 4 weeks for a total of 6 months. The definitive and interim primary outcome measures are overall survival time and event-free survival (EFS) time, respectively. Secondary outcome measures include quality of life, toxicity, swallowing outcomes, feeding tube incidence, surgical complication rates, and cost-effectiveness. The design anticipates that after approximately 7 years, 84 required events will have occurred to enable analysis of the definitive primary outcome measure for this comparison. Planned interim futility analyses using EFS will also be performed.

Discussion: CompARE is designed to be efficient and cost-effective in response to new data, emerging new treatments or difficulties, with the aim of bringing new treatment options for these patients.

Trial registration: ISRCTN ISRCTN41478539 . Registered on 29 April 2015.

Keywords: Adaptive multi-arm multi-stage design; Clinical trial; Oropharyngeal cancer; QuinteT recruitment intervention.

Fig. 1

CompARE trial design. CompARE is a pragmatic phase III open-label multicenter randomised controlled trial with an adaptive multi-arm multi-stage design. Recruitment remains open for arms 1 and 5. Recruitment was suspended to arm 2 on 9 January 2017, recruitment suspended to arm 3 on 12 September 2019, and recruitment suspended to arm 4 on 7 February 2019. ¹Samples collected for translational research (CompARE Collect) if the patient has consented. ²Additional baseline tests (clinical chemistry) are required for patients randomised to arm 5. *Neck dissection is required if a persistent disease is identified in the neck on clinical and radiological imaging at 3 months post-treatment. °Screening assessment: confirmation of HPV/p16 status should be provided by central laboratory services. For randomisation purposes, local p16 test results can be used; however, the diagnostic biopsy sample must still be sent to central laboratory services for confirmation. 5-FU, 5-fluorouracil; ECOG, Eastern Cooperative Oncology Group; HPV, human papillomavirus; IMRT, intensity-modulated radiotherapy; MDT, multidisciplinary team; OPC, oropharyngeal cancer

Fig. 2

Schedule of events for arm 1 of the CompARE trial. Schedule of events for treatment arm 1, concomitant cisplatin chemotherapy plus radiotherapy. *Assessment which is part of standard practice. ****Patient followed up annually for survival data for up to 5 years. ^#Biochemistry screen: alkaline phosphatase, alanine transferase, biocarbonate, calcium, creatinine, glomerular filtration rate, liver function tests, glucose, magnesium, potassium, sodium, total bilirubin, total protein, urea, or blood urea nitrogen. Serum or plasma analysis will include albumin, glucose, and gamma-glutamyl transferase. ^oCisplatin 100 mg/m² 3-weekly: full blood count and biochemistry screen to be performed 3-weekly. Cisplatin 40 mg/m² weekly: full blood count and biochemistry screen to be performed weekly. ⁺Toxicity and adverse events assessed during chemoradiotherapy. ¹Samples collected if the patient has consented for CompARE Collect. ²Blood and oral fluid samples should also be collected at recurrence or progression (formalin-fixed paraffin-embedded tissue block or needle aspirate sample should also be collected if recurrence is confirmed by histology/cytology). ³Questionnaires to be completed by the patient in the clinic at defined visits. ⁴Toxicity will be reviewed using CTCAE version 4.0 and version 3.0 for scoring mucositis. The RTOG Radiation Morbidity Scoring Criteria will be used to grade late side effects due to radiotherapy. ⁵Neck dissection is required if persistent disease is identified in the neck on imaging (PET-CT or contrast CT or contrast MRI) at 3 months post-chemoradiotherapy treatment. The same modality PET CT or CT or MRI should be used for all arms

Fig. 3

Schedule of events for arm 5 of the CompARE trial. Schedule of events for treatment arm 5, induction durvalumab plus arm 1 followed by adjuvant durvalumab. *Assessment part of standard practice. ****Patient followed up annually for survival data for up to 5 years. ^#Biochemistry screen: alkaline phosphatase (ALP), alanine transferase (ALT), biocarbonate, calcium, creatinine, glomerular filtration rate, liver function tests (LFTs), glucose, magnesium, potassium, sodium, total bilirubin, total protein, urea, or blood urea nitrogen. Serum or plasma analysis will include albumin, glucose, and gamma-glutamyl transferase. Biochemistry screen must take place within 120 h prior to durvalumab infusion. ^##Clinical chemistry screen: amylase, lactose dehydrogenase, and aspartate aminotransferase (AST). It is preferable that both amylase and lipase parameters are assessed. For sites where only one of these parameters is routinely measured then either lipase or amylase is acceptable. Clinical chemistry screen must take place within 120 h prior to durvalumab infusion. ^$Results for LFTs, electrolytes, full blood count, and creatinine must be available before commencing an infusion (within 120 h) and reviewed by the treating physician or investigator prior to dosing. ^~Tests for ALT, AST, ALP, and total bilirubin must be conducted and assessed concurrently. If total bilirubin is ≥ 2× upper limit of normal (and no evidence of Gilbert’s syndrome) then fractionate into direct and indirect bilirubin. ^aFor women of childbearing potential only. A urine or serum pregnancy test is acceptable. Women of childbearing potential are required to have a pregnancy test within 7 days prior to the first dose of study drug. ^bIf thyroid-stimulating hormone (TSH) is measured within 14 days prior to day 1 (first durvalumab infusion day), it does not need to be repeated at day 1. ^cFree T3 or free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system. ^dAny clinically significant abnormalities detected require triplicate ECG results. ^oCisplatin 100 mg/m² 3-weekly: full blood count, biochemistry screen, and clinical chemistry screen to be performed 3-weekly. Cisplatin 40 mg/m² weekly: full blood count, biochemistry screen, and clinical chemistry screen to be performed weekly. ⁺Toxicity and adverse events assessed during chemoradiotherapy. ^TAssessments to be performed 4-weekly during adjuvant durvalumab treatment. ^Toxicity and adverse events assessed 2-weekly. ¹Samples collected if the patient has consented for CompARE Collect. ²Blood and oral fluid samples should be collected at recurrence or progression (formalin-fixed paraffin-embedded tissue block or needle aspirate sample should also be collected if recurrence is confirmed by histology/cytology). ³Questionnaires to be completed by the patient in the clinic at defined visits. ⁴Toxicity will be reviewed using CTCAE version 4.0 and version 3.0 for scoring mucositis. The RTOG Radiation Morbidity Scoring Criteria will be used to grade late side effects due to radiotherapy. ⁵Neck dissection is required if persistent disease is identified in the neck on imaging (PET-CT or contrast CT or contrast MRI) at 3 months post-chemoradiotherapy treatment. The same modality PET CT or CT or MRI should be used for all arms. ^~Questionnaires to be completed at the end of chemoradiotherapy and end of durvalumab treatment