None listed
Conditions
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.
Interventions
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-
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.
Sponsors
Te Puriri O Te Ora Directorate of Cancer & Blood at Auckland City Hospital
Study design
Allocation
Non-randomised trial
Intervention model
Other
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
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
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
Outcome results
None listed