CompARE: Escalating Treatment of Intermediate and High-risk Oropharyngeal Cancer (OPC)

University of Birmingham

Status and phase: Active, not recruiting; Phase 3

Conditions: Oropharyngeal Cancer

Treatments: Procedure: Radiotherapy; Drug: Durvalumab; Drug: Cisplatin

Study type: Interventional

Funder types: Other; NETWORK; Industry

Identifiers

NCT04116047

ISRCTN41478539 (Registry Identifier)

RG 14-093

2014-003389-26 (EudraCT Number)

Details and patient eligibility

About

CompARE is a multicentre, phase III open-label randomised controlled trial using an adaptive, Multi-Arm, Multi-Stage (MAMS) design.

Full description

The CompARE Trial examines alternative regimens for escalating treatment of intermediate and high-risk oropharyngeal cancer in an adult patient population. The aim is to assess whether escalated radiotherapy, adding surgery or immunotherapy will improve overall survival and quality of life in these patients.

Enrollment: 785 estimated patients

Sex: All

Ages: 18 to 70 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Oropharyngeal squamous cell carcinoma (OPSCC) in base of tongue and tonsil with a Multidisciplinary Team (MDT) recommendation for treatment with definitive concurrent chemoradiotherapy
2. All OPC T4 or N3 (HPV+ and HPV-) OR all HPV -ve (negative) OPC T1-T4, N1-N3 or T3-4, N0 OR HPV +ve (positive) OPC T1-T4 with N2b-N3 nodes AND who are smokers ≥ 10 pack years current or previous smoking history
3. Minimum life expectancy of 3 months
4. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
5. Adequate renal function, glomerular filtration rate (GFR) >50ml/min calculated using Cockcroft-Gault formula
6. Adequate bone marrow function (absolute neutrophil count (ANC) ≥1.5 x 109/L, haemoglobin ≥9.0g/dL and platelets ≥100 x 109/L)
7. Adequate liver function i.e. plasma bilirubin ≤1.5 times the upper limit of normal (ULN), and alanine aminotransferase (ALT) and alkaline phosphatase (ALP) ≤2.5 x ULN
8. Prothrombin time (PT) ≤1.5 x ULN or International Normalised Ratio (INR) ≤1. 5
9. Magnesium ≥ lower limit of normal
10. No cancers in previous 5 years, except basal cell carcinoma of skin and cervical intra-epithelial neoplasia (CIN)
11. Aged 18-70
12. Written informed consent given for the trial
13. Surgically resectable disease if being randomised to all four arms
14. Females must either be of non-reproductive potential (i.e. post-menopausal by history: ≥55 years old and no menses for ≥1 year without an alternative medical cause; or history of hysterectomy, or history of bilateral tubal ligation or history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry
15. Willingness to comply with the protocol for the duration of the study, including undergoing treatment and scheduled visits and examinations including follow up

Exclusion criteria

1. All T1-T2,N0 OPC (HPV +ve or HPV-ve)

2. HPV positive patients who are:

   T1-T3, N0-N2c non-smokers T1-T3, N0-N2c smokers with ≤10 pack years or T1-T2, N0-N2a smokers with ≥10 pack years

3. Unfit for chemoradiotherapy regimens

4. Creatinine Clearance <50ml/min

5. Treatment with any of the following, prior to randomisation:

   1. Any Investigational Medicinal Products (IMP) within 30 days
   2. Any other chemotherapy, immunotherapy or anticancer agents within 3 weeks
   3. Major surgery within 4 weeks

6. History of allergic reactions to any of the IMPs and excipients used in this trial

7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C, Human Immunodeficiency Virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent

8. Women who are pregnant or breast-feeding. Women of child- bearing potential must have a negative pregnancy test performed within 7 days prior to randomisation

9. Men or women who are not prepared to practise methods of contraception of proven efficacy during treatment and for 6 months following the end of treatment

10. Any condition that, in the opinion of the Investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results

    Additional Exclusion Criteria for Arm 5 only:

11. Any previous treatment with PD-L or PD-L1 inhibitor, including durvalumab

12. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid dose

13. Active or prior documented autoimmune or inflammatory disorders including inflammatory bowel disease e.g. colitis or Crohn's disease, diverticulitis (with the exception of diverticulosis), celiac disease, systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis). The following are exceptions to this criterion:

    • Patients with vitiligo or alopecia
    • Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement
    • Any chronic skin condition that does not require systemic therapy
    • Patients without active disease in the last 5 years may be included but only after consultation with the study physician

14. Patients with an active non-infectious pneumonitis

15. History of primary immunodeficiency

16. History of allogeneic organ transplant

17. Known history of previous clinical diagnosis of tuberculosis

18. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab. Inactivated viruses, such as those in the influenza vaccine, are permitted

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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785 participants in 2 patient groups

Arm 1 (control): chemoradiotherapy

Active Comparator group

Description:

Concomitant chemoradiotherapy, 3-weekly cisplatin 100mg/m2 or weekly 40mg/m2 with Intensity Modulated Radiotherapy (IMRT) using 70 gray (Gy) in 35F(fractions) +/- neck dissection as indicated by clinical and radiological assessment 3-months post treatment. This is the international gold standard.

Treatment:

Drug: Cisplatin

Procedure: Radiotherapy

Arm 5: Durvalumab + Arm 1

Experimental group

Description:

One dose of induction durvalumab 1500mg by intravenous (IV) infusion followed by arm 1 within four weeks. Within one-two weeks after the completion of arm 1, durvalumab 1500mg every four weeks will be initiated for a total of 6 months

Treatment:

Drug: Cisplatin

Procedure: Radiotherapy

Drug: Durvalumab