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Trial registered on ANZCTR


Registration number
ACTRN12622000369729
Ethics application status
Approved
Date submitted
2/12/2021
Date registered
2/03/2022
Date last updated
15/10/2023
Date data sharing statement initially provided
2/03/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Window of opportunity trial of Tarloxotinib combined with stereotactic body radiotherapy (SBRT) in advanced human papilloma virus (HPV) negative head & neck cancer.
Scientific title
Evaluating the safety and logistics of Tarloxotinib combined with Stereotactic Body Radiation
Therapy (SBRT) in a window of opportunity trial of advanced Human Papilloma Virus (HPV) negative head & neck cancer.
Secondary ID [1] 305957 0
none
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
head and neck cancer 324555 0
Condition category
Condition code
Cancer 322023 322023 0 0
Head and neck

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
open label non randomised phase I combination of Tarloxotinib and stereotactic
body radiation in a window of opportunity setting prior to surgery for
advanced HPV negative head and neck cancer.
Cohort A: Four pts will undergo baseline and day 14 oxygen-enhanced magnetic resonance imaging (OE-MRI)
to test logistics of OE-MRI acquisition and University of Manchester analysis (CAMRI).
Cohort B: Four patients will undergo Tarloxotinib monotherapy 150 mg/m2 IV days 1,11 with baseline and day 14 OE-MRI to evaluate safety.
Cohort C: Four patients will undergo the combination of Tarloxotinib 150 mg/m2 IV days 1,11 and SBRT 6 Gy x 3 days 4,6 and 8, with baseline and day 14 OE-MRI.
After surgical resection (day 25 or later), pts from all cohorts will continue with standard care including post-operative radiation therapy (PORT) if appropriate.
Each cohort will recruit sequentially.
Tarloxotinib will be administered at a dose of 150 mg/m2 IV as a 1-hour infusion on Day 1 and Day 11 in Cohort B and Cohort C. Tarloxotinib infusions must be at least 1 hour (60 minutes) in duration.
SBRT will be administered by the Department of Radiation Oncology Auckland City Hospital.
Intervention code [1] 322347 0
Treatment: Drugs
Intervention code [2] 322540 0
Treatment: Devices
Comparator / control treatment
The 3 cohorts are recruiting sequentially for safety reasons and will not be compared.
Control group
Active

Outcomes
Primary outcome [1] 330231 0
The incidence of treatment related serious adverse events associated with Tarloxotinib and SBRT study protocol resulting in delay to surgery beyond day 39. Adverse events will be assessed using Common Toxicity Criteria for Adverse Events (CTCAE v5). Examples od adverse events which could be relevant include diarrhoea and macula-papular rash.
Timepoint [1] 330231 0
day 39 of study protocol.
Secondary outcome [1] 403738 0
A second objective of the study is to test if there is a significant change in the hypoxic fraction following treatment with Tarloxotinib on it's own or in combination with stereotactic body radiotherapy for human papilloma virus negative head and neck cancer prior to surgery. This will be evaluated using a specialised type of MRI scan, called Oxygen-enhanced MRI which calculates hypoxic fraction. The secondary outcome is change in hypoxic fraction between baseline and day 11 of study protocol.
Timepoint [1] 403738 0
baseline and day 11 of study protocol
Secondary outcome [2] 406144 0
To estimate the proportion of patients with a major pathological response (mPR; less than 10% viable tumour cells at surgery). The pathologists will be reporting the percentage of viable tumour cells in the resected specimen, banded in increments of 10%.
Timepoint [2] 406144 0
date of surgery
Secondary outcome [3] 406146 0
To describe the occurrence of treatment-related adverse events (unplanned delay to surgical resection due to toxicity, post-surgical complications grade 3 or higher using Clavien Dindo scale, and life-threatening arrhythmia). CTCAE v5 will be used to document treatment-related adverse event resulting in unplanned delay to surgery. The medical records will used to document post surgical complications using the Clavien Dindo scale. Patients will be on telemetry during Tarloxotinib infusions until 4 hours post infusion to document life-threatening threatening arrhythmias.
Timepoint [3] 406146 0
up to week 20 of study protocol

Eligibility
Key inclusion criteria
Stage III or stage IV advanced p16-ve HNSCC oral cavity, oropharynx, larynx or hypopharynx planned for definitive surgical resection.
1. Aged 18 years or older
2. Histologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, larynx or hypopharynx planned for definitive surgical resection.
3. Stage III or stage IV.
4. Primary able to be visualised on CT.
5. No prior treatment for head and neck cancer
6. Adequate haematological, renal, and hepatic function as defined by,
a.Absolute neutrophil count (ANC, segs + bands) greater than or equal to 1.5 x 109/L
b.Platelet count greater than or equal to 100 x 109/L
c.Haemoglobin greater than or equal to 90 g/L
d.Total bilirubin greater than or equal to 1.5 x upper normal limit
e.ALT greater than or equal to 2.5 x upper normal limit
f.Calculated creatinine clearance (Cockcroft-Gault formula) or isotopic GFR less than 55ml/min
1. ECOG performance status score of 0-1
2. Patients with inactive/asymptomatic carrier, chronic, or active hepatitis B virus (HBV) must have HBV DNA less than 500 IU/mL (or 2500 copies/mL) at Screening
3. Adequate cardiac function meeting all of the following ECG criteria:
a. No evidence of second or third degree atrioventricular block
b. No clinically significant arrhythmia (i.e., pauses of more than 4 seconds, ventricular tachycardia of any duration, supraventricular tachycardia more than 4 beats/minute)
c. QRS interval less than or equal to 110 msec
d. QTc interval of less than 450 msec as calculated according to Fridericia’s formula (QTcF = QT/[R to R interval]0.33)
e. PR interval less than or equal to 200 msec (does not apply to people with chronic stable atrial fibrillation or atrial flutter as determined by the Investigator)
4. Participants capable of childbearing are using adequate contraception and intend to continue use of contraception for at least 6 months following completion of treatment
5. Negative pregnancy test within 72 hours prior to randomisation of women who are of childbearing potential
6. Suitable for follow-up for at least 24 months as per trial protocol.
7. Sufficient proficiency in English, cognitive capacity and willingness to complete questionnaires
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
History of unknown primary of the head and neck.
2. Women who are pregnant or lactating.
3. Previous radiotherapy to the area to be treated (excluding superficial radiotherapy for a cutaneous malignancy)
4. Prior EGFR targeted therapy of any kind
5. History of myocardial infarction within 12 months prior to study entry, uncontrolled congestive heart failure, unstable angina, active cardiomyopathy, unstable arrhythmia, clinically significant thrombotic or embolic events within 3 months prior to enrollment (diagnosis of deep vein thrombosis allowed), uncontrolled psychotic disorders, active serious infections, active peptic ulcer disease, immunosuppression due to post-organ transplantation or use of immunosuppressants for autoimmune disorders.
6.Clinically active or symptomatic interstitial lung disease (ILD) or interstitial pneumonitis.
7.Any active malignancy less than or equal to 2 years before the first dose of study drug(s) except for the specific cancer under investigation in this study and any locally recurring cancer that has been treated with curative intent (e.g., resected basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast)
8. A known history hepatitis C virus (HCV) infection, except for patients with cured HCV.
9. Known human HIV infection
10.Uncontrolled diabetes or > Grade 1 laboratory test abnormalities in potassium, sodium, or corrected calcium despite standard medical management, or greater than or equal to Grade 3 hypoalbuminemia occurring less than or equal to 14 days before first dose of study drug
11. Administered a live vaccine less than or equal to 4 weeks before first dose of study drug Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines, and are not allowed
12. Underlying medical conditions (including laboratory abnormalities) or alcohol or drug abuse or dependence that will be unfavorable for the administration of study drug or that will affect the explanation of drug toxicity or AEs or result in insufficient or might impair compliance with study conduct.
13. Receiving medications that carry a risk of QTc prolongation and Torsade de Pointes (see concomitant medications section). Enrollment is allowed if discontinuation of such medications occurs at least 5 half-lives before Cycle 1 Day 1 Tarloxotinib.
14.Personal or familial history of Long QT Syndrome, sudden death, or Torsade de Pointes

15.History of severe allergic or anaphylactic reactions or hypersensitivity to compounds of similar chemical or biologic composition as tarloxotinib

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
The study is divided into 3 cohorts which will be described separately.
The primary hypothesis in the Phase I is that tarloxotinib and SBRT will not adversely impact on the ability to proceed with surgery, with no treatment related adverse events (AE) resulting in delay to surgery beyond day 39. Four pts will undergo baseline and day 14 OE-MRI to test logistics of OE-MRI acquisition and analysis (Cohort A). Four pts will undergo Tarloxotinib monotherapy 150 mg/m2 IV days 1,11 with baseline and day 14 OE-MRI (Cohort B). Four pts will undergo the combination of Tarloxotinib 150 mg/m2 IV days 1,11 and SBRT 6 Gy x 3 days 4,6 and 8, with baseline and day 14 OE-MRI (Cohort C). After surgical resection (day 25 or later), pts from all cohorts will continue with standard care including post operative radiotherapy if appropriate.
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis
The primary objective is that tarloxotinib and SBRT will not adversely impact on the ability to proceed with surgery with no treatment related adverse events (AE) resulting in delay to surgery beyond day 39. A descriptive report will be prepared.
Secondary objectives are
1. to estimate the proportion of patients who experience a reduction in tumour hypoxic fraction (measured using OE-MRI) of at least 50%.
2. To estimate the proportion of patients with a major pathological response (mPR; less than 10% viable tumour cells at surgery).
3. To describe the occurrence of treatment-related adverse events (unplanned delay to surgical resection due to toxicity, post-surgical complications grade 3 or higher using Clavien Dindo scale, and life-threatening arrhythmia).

Recruitment
Recruitment status
Stopped early
Data analysis
No data analysis planned
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
study has now closed
Rain Oncology Inc has withdrawn support for further clinical development of tarloxotinib.
Southern Health Disability Ethics Committee informed that study closed
Date of first participant enrolment
Anticipated
1/10/2022
Actual
12/10/2023
Date of last participant enrolment
Anticipated
Actual
12/10/2023
Date of last data collection
Anticipated
12/10/2023
Actual
12/10/2023
Sample size
Target
12
Accrual to date
Final
1
Recruitment outside Australia
Country [1] 24363 0
New Zealand
State/province [1] 24363 0

Funding & Sponsors
Funding source category [1] 310298 0
University
Name [1] 310298 0
University of Auckland Li Family Cancer Research Endowment
Country [1] 310298 0
New Zealand
Primary sponsor type
Hospital
Name
Te Puriri O Te Ora Directorate of Cancer & Blood at Auckland City Hospital
Address
Auckland City Hospital
2 Park Rd
Auckland 1023
New Zealand
Country
New Zealand
Secondary sponsor category [1] 311416 0
None
Name [1] 311416 0
Address [1] 311416 0
Country [1] 311416 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309961 0
Southern Health Disability Ethics Committee
Ethics committee address [1] 309961 0
Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140
Ethics committee country [1] 309961 0
New Zealand
Date submitted for ethics approval [1] 309961 0
19/08/2021
Approval date [1] 309961 0
19/10/2021
Ethics approval number [1] 309961 0
21/STH/158

Summary
Brief summary
This study is exploring the safety of Tarloxotinib combined with SBRT in head and neck cancer.
Advanced HPV negative head and squamous cell carcinoma is usually managed with surgery as the primary modality with adjuvant post-operative radiation therapy with or without Cisplatin based chemotherapy. Hypoxia is a marker of poor prognosis in this setting, and a predictor of recurrence post radiotherapy including in the postoperative setting. The level of EGFR over-expression correlates with hypoxia gene signatures and both EGFR and HIF-1 activity inversely correlate with the density of T cell infiltration in Head and neck squamous cell carcinoma (HNSCC). This provides a strong rationale for Tarloxitinib - a hypoxia activated prodrug that releases an irreversible HER1-4 inhibitor under conditions of severe hypoxia, resulting in shutdown of EGFR signalling for >7 days after a single dose of Tarloxtinib at human equivalent exposure. Tarloxotinib was found to be highly active in multiple HNSCC preclinical models. Tarloxotinib has also previously been evaluated as monotherapy in treatment-resistant (relapsed) HNSCC (NCT02449681). Six HNSCC patients had disease control, maintained for 95 to 175 days (RECIST 1.1 50% stable disease). No hypoxia biomarkers were included in the study.
Radiation is a potent modifier of the tumour microenvironment. Employing the early-passage UT-SCC-42B HNSCC tumour model there was striking synergy when combining radiotherapy with tarloxotinib . The antitumour activity of each treatment, individually, was modest (stable disease, SD) but when combined a complete response (CR) was achieved in 100% of tumours (maintained beyond day 40), illustrating a key concept that underpins the rational of this application.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 116002 0
Dr Andrew Macann
Address 116002 0
Department of Radiation Oncology
Te Puriri o Te Ora
Auckland City Hospital
Private Bag 92024
2 Park Road
Auckland 1023
Country 116002 0
New Zealand
Phone 116002 0
+6493797440
Fax 116002 0
Email 116002 0
[email protected]
Contact person for public queries
Name 116003 0
Andrew Macann
Address 116003 0
Department of Radiation Oncology
Te Puriri o Te Ora
Auckland District Health Board
Auckland City Hospital
Private Bag 92024
2 Park Road
Auckland 1023
Country 116003 0
New Zealand
Phone 116003 0
+6493797440
Fax 116003 0
Email 116003 0
[email protected]
Contact person for scientific queries
Name 116004 0
Andrew Macann
Address 116004 0
Department of Radiation Oncology
Te Puriri o Te Ora
Auckland District Health Board
Auckland City Hospital
Private Bag 92024
2 Park Road
Auckland 1023
Country 116004 0
New Zealand
Phone 116004 0
+6493797440
Fax 116004 0
Email 116004 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.