Atovaquone With Radical ChemorADIotherapy in Locally Advanced NSCLC

NCT04648033 | Completed Phase 1 Results DMC

• 1 other identifier: OCTO_088
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 3

Brief Summary

This is a phase I, 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 three centres.

Conditions

Locally Advanced Non-Small Cell Lung Cancer

Outcome Measures

Primary Outcomes (1)

• Number of Dose Limiting Toxicities in Patients Taking Atovaquone in Combination With Radical Concurrent Chemoradiotherapy for Non-small Cell Lung Cancer.

  To determine the maximum tolerated dose level (and therefore recommended phase II dose) of atovaquone when administered concomitantly with radical concurrent chemoradiotherapy (CRT) in patients with non-small cell lung cancer (NSCLC). This is the dose of atovaquone associated with no more than 48% dose limiting toxicity (DLT) rate (target toxicity level).

  From first dose of atovaquone to 3-month follow up visit (up to 25 weeks)

Secondary Outcomes (7)

• Severity of Worst Adverse Events Per Dose Level of Atovaquone Administered in Combination With Radical Concurrent Chemotherapy for NSCLC According to CTCAE V4.03

  From first dose of atovaquone until last follow up visit at 6 months post completion of CRT (up to 38 weeks)

• Number of Patients for Whom it Was Possible to Derive a Hypoxia Metagene Signature Score From 3'RNA-Seq of Genetic Material From Archival Tumour Samples

  At baseline (diagnosis)

• Mean Baseline Tumour Hypoxia Level (TBRvol) Assessed by F18-FMISO PET-CT

  At baseline (prior to atovaquone treatment)

• Mean Baseline Plasma miR-210 Level Assessed Via TaqMan Quantitative PCR

  At baseline (prior to atovaquone treatment)

• Mean Percentage Change in Tumour Hypoxia Level Between Baseline and After Two Weeks (+/- 7 Days) of Atovaquone Treatment

  Between baseline (prior to atovaquone treatment) and following two weeks (+/- 7 days) of atovaquone treatment (up to 21 days)

Study Arms (4)

Dose level 1 - 450 mg BD atovaquone + concurrent CRT

EXPERIMENTAL

Atovaquone: * Taken during an initial run in period (2 weeks +/- 7 days), then continued during standard of care chemoradiotherapy. * One of 4 dose levels is allocated to each patient by a TiTE-CRM statistical model which takes into account all toxicity data to date. * Dose levels - 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD). * Last dose atovaquone taken on the last day of radiotherapy. * Total duration of atovaquone treatment is 59 days (+/- 7 days), unless stopped earlier for toxicity or any other reason. Chemotherapy: * 2 x 21-day cycles. * 80 mg/m2 cisplatin on day 1 and 22 of chemoradiotherapy. * 15 mg/m2 vinorelbine on days 1,8, 22 and 29 of chemoradiotherapy. Radiotherapy: * 66 Gy in 33 fractions. * Delivered once daily, 5 days a week (Monday-Friday) for 6.5 weeks.

Drug: Atovaquone Oral Suspension; Drug: Standard of care chemotherapy; Radiation: Standard of care radiotherapy

Dose level 2 - 600 mg BD atovaquone + concurrent CRT

EXPERIMENTAL

Atovaquone: * Taken during an initial run in period (2 weeks +/- 7 days), then continued during standard of care chemoradiotherapy. * One of 4 dose levels is allocated to each patient by a TiTE-CRM statistical model which takes into account all toxicity data to date. * Dose levels - 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD). * Last dose atovaquone taken on the last day of radiotherapy. * Total duration of atovaquone treatment is 59 days (+/- 7 days), unless stopped earlier for toxicity or any other reason. Chemotherapy: * 2 x 21-day cycles. * 80 mg/m2 cisplatin on day 1 and 22 of chemoradiotherapy. * 15 mg/m2 vinorelbine on days 1,8, 22 and 29 of chemoradiotherapy. Radiotherapy: * 66 Gy in 33 fractions. * Delivered once daily, 5 days a week (Monday-Friday) for 6.5 weeks.

Drug: Atovaquone Oral Suspension; Drug: Standard of care chemotherapy; Radiation: Standard of care radiotherapy

Dose level 3 - 675 mg BD atovaquone + concurrent CRT

EXPERIMENTAL

Atovaquone: * Taken during an initial run in period (2 weeks +/- 7 days), then continued during standard of care chemoradiotherapy. * One of 4 dose levels is allocated to each patient by a TiTE-CRM statistical model which takes into account all toxicity data to date. * Dose levels - 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD). * Last dose atovaquone taken on the last day of radiotherapy. * Total duration of atovaquone treatment is 59 days (+/- 7 days), unless stopped earlier for toxicity or any other reason. Chemotherapy: * 2 x 21-day cycles. * 80 mg/m2 cisplatin on day 1 and 22 of chemoradiotherapy. * 15 mg/m2 vinorelbine on days 1,8, 22 and 29 of chemoradiotherapy. Radiotherapy: * 66 Gy in 33 fractions. * Delivered once daily, 5 days a week (Monday-Friday) for 6.5 weeks.

Drug: Atovaquone Oral Suspension; Drug: Standard of care chemotherapy; Radiation: Standard of care radiotherapy

Dose level 4 - 750 mg BD atovaquone + concurrent CRT

EXPERIMENTAL

Atovaquone: * Taken during an initial run in period (2 weeks +/- 7 days), then continued during standard of care chemoradiotherapy. * One of 4 dose levels is allocated to each patient by a TiTE-CRM statistical model which takes into account all toxicity data to date. * Dose levels - 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD). * Last dose atovaquone taken on the last day of radiotherapy. * Total duration of atovaquone treatment is 59 days (+/- 7 days), unless stopped earlier for toxicity or any other reason. Chemotherapy: * 2 x 21-day cycles. * 80 mg/m2 cisplatin on day 1 and 22 of chemoradiotherapy. * 15 mg/m2 vinorelbine on days 1,8, 22 and 29 of chemoradiotherapy. Radiotherapy: * 66 Gy in 33 fractions. * Delivered once daily, 5 days a week (Monday-Friday) for 6.5 weeks.

Drug: Atovaquone Oral Suspension; Drug: Standard of care chemotherapy; Radiation: Standard of care radiotherapy

Interventions

Atovaquone Oral Suspension DRUG

Atovaquone, cisplatin and vinorelbine are all considered Investigational Medicinal Products (IMPs) in this trial due to the investigation of these drugs in a novel combination. Patients will be allocated one of four doses of atovaquone: 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD).

Also known as: Wellvone

Dose level 1 - 450 mg BD atovaquone + concurrent CRT; Dose level 2 - 600 mg BD atovaquone + concurrent CRT; Dose level 3 - 675 mg BD atovaquone + concurrent CRT; Dose level 4 - 750 mg BD atovaquone + concurrent CRT

Standard of care chemotherapy DRUG

Atovaquone, cisplatin and vinorelbine are all considered Investigational Medicinal Products (IMPs) in this trial due to the investigation of these drugs in a novel combination. Patients will receive two 21-day cycles of cisplatin and vinorelbine chemotherapy, comprising 80 mg/m2 cisplatin on days 1 \& 22 of their CRT treatment and 15 mg/m2 vinorelbine on days 1, 8, 22 \& 29.

Also known as: Cisplatin, Vinorelbine

Dose level 1 - 450 mg BD atovaquone + concurrent CRT; Dose level 2 - 600 mg BD atovaquone + concurrent CRT; Dose level 3 - 675 mg BD atovaquone + concurrent CRT; Dose level 4 - 750 mg BD atovaquone + concurrent CRT

Standard of care radiotherapy RADIATION

Thoracic radiotherapy will commence on day one of chemotherapy and be delivered in 66 Gy in 33 fractions, once daily, 5 days a week (Monday-Friday) for 6.5 weeks.

Dose level 1 - 450 mg BD atovaquone + concurrent CRT; Dose level 2 - 600 mg BD atovaquone + concurrent CRT; Dose level 3 - 675 mg BD atovaquone + concurrent CRT; Dose level 4 - 750 mg BD atovaquone + concurrent CRT

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Oxford: lead
• Cancer Research UK: collaborator
• National Institute for Health Research, United Kingdom: collaborator
• NHS Lothian: collaborator
• Oxford University Hospitals NHS Trust: collaborator
• NHS Research Scotland: collaborator
• Guy's and St Thomas' NHS Foundation Trust: collaborator

Study Sites (3)

Western General Hospital, NHS Lothian

Edinburgh, EH4 2XU, United Kingdom

Location

Guy's and St Thomas'

London, SE1 9RT, United Kingdom

Location

Churchill Hospital, Oxford University Hospitals

Oxford, OX3 7LE, United Kingdom

Location

MeSH Terms

Interventions

Atovaquone; Cisplatin; Vinorelbine

Intervention Hierarchy (Ancestors)

Naphthoquinones; Quinones; Organic Chemicals; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines

Results Point of Contact

• Title: Professor Geoff Higgins
• Organization: University of Oxford

geoffrey.higgins@oncology.ox.ac.uk

01865 617311

Study Officials

• Geoffrey Higgins

  University of Oxford

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Time-to-Event Continual Reassessment Method to determine the maximum tolerated dose (MTD) of atovaquone in combination with concurrent CRT in NSCLC

Study Record Dates

• First Submitted: October 8, 2020
• First Posted: December 1, 2020
• Study Start: December 7, 2020
• Primary Completion: October 2, 2023
• Study Completion: October 2, 2023
• Last Updated: January 29, 2026
• Results First Posted: November 25, 2024

Record last verified: 2023-05

Locations

GB (3)