Atovaquone With Radical ChemorADIotherapy in Locally Advanced NSCLC

  • STATUS
    Recruiting
  • End date
    Mar 21, 2023
  • participants needed
    20
  • sponsor
    University of Oxford
Updated on 21 July 2021

Summary

This is a phase I, single arm, open-label trial that will utilise a Time To Event Continual Reassessment Method (TiTE-CRM) to determine the maximum tolerated dose (MTD) of atovaquone in combination with concurrent CRT in NSCLC. Twenty evaluable participants will be recruited at two centres.

Description

Twice daily oral atovaquone will be added to standard concurrent chemoradiotherapy (CRT): 66 Gy in 33 fractions, once daily, 5 days a week (Monday-Friday), with cisplatin (80 mg/m2 IV on days 1 and 22 of CRT) and vinorelbine (15 mg/m2 IV on days 1, 8, 22 and 29 of CRT). Whilst awaiting CRT to start, patients will receive two weeks (+/- 7 days) of oral atovaquone to ensure steady state is reached (after seven days). Patients will be allocated one of four dose levels: 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD). Atovaquone dose will be assigned as per the TiTE-CRM statistical model. The first two trial participants will receive 450 mg BD. In the absence of unacceptable toxicity, subsequent patients will be assigned doses up to and including 750 mg BD.

Hypoxia biomarker data will be collected at baseline (start of atovaquone run-in) and following two weeks (+/- 7 days) of atovaquone treatment. Atovaquone will then be continued without break for the duration of CRT, with the CRT schedule remaining constant for all patients at both centres. Assessment for Dose Limiting Toxicities (DLTs) will be from the first scheduled dose of atovaquone until three months after completion of CRT. The CT scan performed at the three-month follow up visit will be reviewed to collect tumour response data.

Details
Condition Locally Advanced Non Small Cell Lung Cancer
Treatment Standard of care chemotherapy, Standard of Care Radiotherapy, Atovaquone Oral Suspension
Clinical Study IdentifierNCT04648033
SponsorUniversity of Oxford
Last Modified on21 July 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

A patient will be eligible for inclusion in this study if all of the following
criteria
apply
Histologically or cytologically confirmed diagnosis of locally advanced NSCLC and selected for treatment with full dose radical concurrent CRT
At least one measurable lesion greater than 2 cm maximal length in any direction on routine imaging (CT or PET-CT scan performed in the 60 days prior to consent)
Male or female, age at least 18 years
ECOG performance status 0 or 1
Adequate pulmonary function tests for thoracic radiotherapy (FEV1 and TLCO, greater than 40 percent predicted)
Haematological and biochemical indices within the ranges shown below
Bilirubin 1.5 x upper limit of normal (ULN); ALT and/or AST 2.5 x ULN
Creatinine clearance 60 mL/min; Absolute Neutrophil Count 1.5 x 10 _9/L
Platelets 100 x 10_ 9/L; Haemoglobin 90 g/L; INR 1.5
\. The patient is willing and able to comply with the protocol scheduled
follow-up visits and examinations for the duration of the study
\. Written (signed and dated) informed consent and be capable of co-operating
with protocol

Exclusion Criteria

Pregnant or breast-feeding women, or women of childbearing potential unless effective methods of contraception are used
Previous systemic chemotherapy or biological therapy within 21 days of commencing atovaquone treatment
Treatment with any other investigational agent as part of a clinical trial within 28 days of study enrolment
Previous thoracic radiotherapy
Known previous adverse reaction to atovaquone or its excipients
Active hepatitis, gallbladder disease or pancreatitis
Impaired gastrointestinal function that may significantly alter absorption of atovaquone
Concurrent administration of warfarin in the 14 days prior to starting atovaquone
Concurrent administration of known electron transport chain inhibitors (e.g. metformin). A wash-out period prior to administration of atovaquone is required (e.g. 4 days for metformin)
An additional cancer diagnosis that the treating clinician feels may significantly impact planned CRT treatment tolerability or treatment outcome
Established diagnosis of pulmonary fibrosis
Established diagnosis of connective tissue disorder (e.g. scleroderma or systemic lupus erythematosus)
Cardiac morbidity such as angina, myocardial infarction in the previous six months, unstable angina or uncontrolled hypertension, left ventricular failure or severe valvular disease
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