Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Symptoms and General Pathology

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Hypoxia

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Vinorelbine

Cisplatin

Atovaquone

Tubulin Modulators

Antimitotic Agents

Antimalarials

Antiprotozoal Agents

Antiparasitic Agents

Enzyme Inhibitors

Atovaquone is taken during an initial run in period (2 weeks +/- 7 days), then continued during standard of care CRT. Atovaquone dose level is allocated to each patient by a TiTE-CRM statistical model which takes into account all toxicity data to date: 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD).

Two 21-day cycles of cisplatin and vinorelbine chemotherapy will be given concurrently during radiotherapy treatment. Patients will receive 80 mg/m2 cisplatin on days 1 \& 22 of their CRT treatment and 15 mg/m2 vinorelbine on days 1, 8, 22 \& 29. Thoracic radiotherapy will be delivered in 66 Gy in 33 fractions, once daily, 5 days a week (Monday-Friday).

The last dose of atovaquone will be on the morning of the last fraction of radiotherapy. Total duration of atovaquone treatment will be 59 days (+/- 7 days), unless stopped earlier for toxicity or any other reason.

Patients will be followed up at 1, 3 and 6 months post-CRT.

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).

Atovaquone Oral Suspension

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.

Standard of care chemotherapy

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.

Standard of care radiotherapy

Geoffrey Higgins

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 three centres.

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.

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

Atovaquone With Radical ChemorADIotherapy in Locally Advanced NSCLC

A Phase I Trial of the Hypoxia Modifier Atovaquone in Combination With Radical Concurrent Chemoradiotherapy in Locally Advanced Non-Small Cell Lung Cancer

Assessment of the correlation between plasma atovaquone levels and hypoxia response, as measured by FMISO PET-CT

Assessment of the correlation between plasma atovaquone levels and hypoxia response, as measured by plasma miR-210 level

Determination of the maximum tolerated dose (MTD), and therefore recommended phase II dose (RPTD), of atovaquone when combined with radical concurrent chemoradiotherapy in patients with non-small cell lung cancer (NSCLC)

Assessment of the safety and toxicity profile of atovaquone in combination with radical concurrent chemotherapy for NSCLC

Confirmation of feasibility of measuring hypoxia metagene signature using 3'RNA-Seq in diagnostic NSCLC samples

To assess agreement of hypoxic volume determined by FMISO PET-CT with plasma miR-210 level pre-treatment with atovaquone

To assess agreement of hypoxic volume determined by FMISO PET-CT with hypoxia metagene signature from diagnostic tissue pre-treatment with atovaquone

To assess agreement of hypoxic volume determined by FMISO PET-CT with plasma miR-210 level following two weeks (+/- 7 days) of atovaquone

Assessment of the tumour response rate at three months following treatment

Cancer Research UK

National Institute for Health Research, United Kingdom

NHS Lothian

Oxford University Hospitals NHS Trust

NHS Research Scotland

Guy's and St Thomas' NHS Foundation Trust

University of Oxford

Mouth and Tooth Diseases

Rare Diseases

Salivary Gland Neoplasms

Mouth Neoplasms

Head and Neck Neoplasms

Mouth Diseases

Stomatognathic Diseases

Salivary Gland Diseases

Myotonic Dystrophy Type 1

Oral Cancer

Anti-Arrhythmia Agents

Vasodilator Agents

Analgesics

Carboplatin

Trastuzumab

Ado-Trastuzumab Emtansine

Adenosine

Maytansine

Antineoplastic Agents, Immunological

Participants will undergo standard of care surgery followed by standard of care radiation and chemotherapy with the addition of T-DM1.

Study cycles are 21 days (3 weeks):

* Participants will be given the study treatment T-DM1 at a predetermined dose (3.6 mg/kg) intravenously once (1x) every 3 weeks for up to 52 weeks (or about 1 year).
* Participants will be given standard of care radiation and chemotherapy

  * Radiation will be given on Cycle 1 Day 8, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 8, Cycle 2 Day 15, and Cycle 3 Day 1
  * Chemotherapy (cisplatin 40 mg/m2 intravenously or carboplatin AUC 2 intravenously) will be given on Cycle 1 Day 8, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 8, Cycle 2 Day 15, and Cycle 3 Day 1

Participants will be followed for 3 years.

Intravenous infusion ever 21 days (3weeks) for 1 year (52 weeks)

Ado-trastuzumab (T) emtansine (T-DM1)

Standard of Care Radiotherapy

Standard of Care Chemotherapy

Glenn J Hanna, MD

Alexander T Pearson, MD, PhD

Cancer Clinical Trials Office

Glenn J. Hanna, MD

Alan L Ho, MD, PhD

Jay Liao, MD

This research is being done to see how safe and effective the use of the study drug Ado-trastuzumab (T) emtansine (DM1), T-DM1, and standard of care chemoradiation are when used together in treating HER2-positive salivary gland cancer. It will also examine the effectiveness of study drug Ado-trastuzumab (T) emtansine (DM1) on cancer recurrence.

This is a phase II, open-label, non-randomized, multi-institutional study investigating postoperative or adjuvant human epidermal growth factor receptor (HER2)-directed therapy with adjuvant ado-trastuzumab emtansine (T-DM1) in HER2-positive salivary gland carcinomas (SGC).

This research study is:

* Studying the use of T-DM1 in combination with radiation and chemotherapy; and the use of maintenance T-DM1 alone for up to a year after surgery
* Evaluating the effectiveness, safety, and toxicity of T-DM1

T-DM1 is a specialized antibody targeting HER-2 (a protein that is expressed in some breast and salivary gland cancers). The drug is a HER-2 antibody that is bound to a chemotherapy agent (DM1) and delivered intravenously. T-DM1 then binds cancer cells that express HER-2 and is taken up into the cell to allow DM1 to kill cancer cells in a more targeted way. This allows the use of a targeted treatment along with chemoradiation to treat HER-2 expressing salivary cancers.

The U.S. Food and Drug Administration (FDA) has not approved T-DM1 for HER2-positive salivary gland cancer but it has been approved for other uses (for breast cancers that express HER2 protein).

The research study procedures include: screening for eligibility and study treatment including evaluations and follow up visits.

This research study involves radiation, chemotherapy, and targeted therapy given after surgery for up to 1-year, and participants will be followed for 3 years.

It is expected that about 55 people will take part in this research study.

Genentech is supporting this research study by providing the research study drug, T-DM1.

Post-op T-DM1 in HER-2+ Salivary Gland Carcinomas

A Phase II Study of Adjuvant Ado-trastuzumab Emtansine (T-DM1) in HER2-positive Salivary Gland Carcinomas

The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: \[contact information for Sponsor Investigator or designee\]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.

Kaplan-Meier method will be used to estimate 2 Year Disease-free survival (DFS) Rate

Evaluate adverse events for patient receiving T-DM1, defined as adverse events of all grades utilizing CTCAE v5

Overall Survival (OS) estimated using a Kaplan-Meier or competing risk methodology (whichever is appropriate).

Distant metastatic-free survival (DMFS) Rate estimated using a Kaplan-Meier or competing risk methodology (whichever is appropriate).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Atovaquone With Radical ChemorADIotherapy in Locally Advanced NSCLC	NCT04648033	Locally Advance...	Atovaquone Oral... Standard of car... Standard of car...	18 Years -	University of Oxford
Atovaquone With Radical ChemorADIotherapy in Locally Advanced NSCLC	NCT04648033	Locally Advance...	Atovaquone Oral... Standard of car... Standard of car...	18 Years -	University of Oxford
Post-op T-DM1 in HER-2+ Salivary Gland Carcinomas	NCT04620187	Salivary Gland ... HER2 Gene Mutat...	Ado-trastuzumab... Standard of Car... Standard of Car...	18 Years -	Dana-Farber Cancer Institute
Post-op T-DM1 in HER-2+ Salivary Gland Carcinomas	NCT04620187	Salivary Gland ... HER2 Gene Mutat...	Ado-trastuzumab... Standard of Car... Standard of Car...	18 Years -	Dana-Farber Cancer Institute

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