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Trial registered on ANZCTR


Registration number
ACTRN12619001407189
Ethics application status
Approved
Date submitted
25/09/2019
Date registered
14/10/2019
Date last updated
12/04/2022
Date data sharing statement initially provided
14/10/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Exploratory Phase Ib/IIa Study of Intratumourally Administered Tigilanol Tiglate to Assess Safety, Tolerability and Tumour Response in Patients with Head and Neck Squamous Cell Carcinoma
Scientific title
Exploratory Phase Ib/IIa Study of Intratumourally Administered Tigilanol Tiglate to Assess Safety, Tolerability and Tumour Response in Patients with Head and Neck Squamous Cell Carcinoma
Secondary ID [1] 299148 0
QB46C-H03
Secondary ID [2] 300024 0
CTRI/2019/11/022032
Universal Trial Number (UTN)
U1111-1232-3725
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Head and neck squamous cell carcinoma. 314211 0
Condition category
Condition code
Cancer 312574 312574 0 0
Head and neck

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a multi-centre, single-agent, open-label, Phase Ib/IIa study to evaluate the safety, tolerability and signs of efficacy of tigilanol tiglate when administered as a single or multiple (two or three) intratumoural treatment(s) to patients with head and neck squamous cell carcinoma.
The study consists of 2 stages.
In Stage 1, patient will be enrolled into one of two cohorts at a starting dose level of up to 1.2 mg/m2 body surface area (BSA). A single treatment will be administered to 1 – 4 target tumours via intratumoural injection, followed by monitoring for 21 days. The first cohort, containing patients with a larger combined target tumour volume (~4.0 - 150.0 cm3) which cannot be entirely treated at 50% v/v (0.5 mL dose volume / 1.0 cm3 tumour) at the current dose level (mg/m2 BSA), will be of a standard 3+3 escalation design with dose-escalation being based on the incidence and severity of adverse events and determined by an independent Data Safety Monitoring Board (DSMB). The second cohort, containing patients with a smaller combined target tumour volume (0.1 - ~4.0 cm3) that can be entirely treated at 50% v/v (0.5 mL dose volume / 1.0 cm3 tumour) without reaching the current dose level (mg/m2 BSA), will escalate in dose level based on the first cohort's DSMB results. Following completion of Stage 1, and at the principal investigator's discretion, patients may progress on to Stage 2.
In Stage 2 patients that have completed Stage 1 may receive up to two additional treatments, one week apart, to the same target tumour(s) and at the same dose level as in Stage 1.
The study will conclude when either a Maximum Tolerated Dose is identified, or the Sponsor and DSMB decide that the study should be terminated.
Intervention code [1] 315422 0
Treatment: Drugs
Comparator / control treatment
Nil
Control group
Uncontrolled

Outcomes
Primary outcome [1] 321225 0
To assess the safety and tolerability of tigilanol tiglate when administered as a single intratumoural dose (at escalating cohorts of dose levels) to patients with head and neck squamous cell carcinoma. This will be determined by evaluation of the safety parameters collected during the trial including: clinical laboratory tests (haematology, biochemistry, coagulation, and urinalysis); 12-lead electrocardiogram; adverse events/serious adverse events (toxicities will be assessed using the Common Terminology for Adverse Events [CTCAE] V5.0); Injection site assessments (including wound healing and necrosis assessment); and vital signs.
Timepoint [1] 321225 0
Between Day 0 (first treatment day) and Day 14 to allow for dose-escalation, however safety will be evaluated throughout Stage 1 up to Day 21.
Secondary outcome [1] 374391 0
To assess the safety and tolerability of tigilanol tiglate, when administered as repeat dose (a maximum of two or three treatments) intratumoural injections to patients with head and neck squamous cell carcinoma. This will be determined by the same means as the primary outcome (discussed above).
Timepoint [1] 374391 0
For patients who continue to Stage 2, between Day 0 (first treatment day) the completion of Stage 2.
Secondary outcome [2] 374392 0
To determine the MTD level and recommended dose (RD) level of tigilanol tiglate. This will be determined through the review of dose-escalation patient safety information at DSMB meetings.
Timepoint [2] 374392 0
Between Day 0 (first treatment day) and Day 14 of all dose-escalation patients.
Secondary outcome [3] 374393 0
To evaluate the effects of tigilanol tiglate on head and neck squamous cell carcinoma tumours. Evaluations will use modified Response Evaluation Criteria In Solid Tumours (RECIST) criteria which will be applied to evaluate response and change in the treated (1-4 target) and non-treated (up to 5 non-target) tumour sizes, as well as the size of the largest cervical lymph node. Volumetric analysis will also be conducted for target and non-target tumours. Computed tomography (CT) scans and calliper measurements will be used to estimate tumour volume and to estimate tumour response based on tumour volume relative to baseline measurements. Area, volume (if possible) and degree of necrosis will also be evaluated using clinical photography and CT.
Timepoint [3] 374393 0
Calliper measurements will be performed at every study visit, clinical photography will be performed at every study visit from Day 0 (first treatment day), and CT scans will be performed at screening, Day 14, and 7 days following Treatment 3 (if administered). Modified RECIST criteria will be assessed at Day 14 and 7 days following Treatment 3 (if administered).
Secondary outcome [4] 374395 0
To characterise the plasma pharmacokinetic (PK) profile of intratumourally administered tigilanol tiglate in head and neck squamous cell carcinoma. Analysis will be completed using a validated LC-MS/MS method and may include the following PK parameters: Cmax, Tmax, AUC0-last, AUC0-inf, T1/2, and systemic clearance.
Timepoint [4] 374395 0
PK time points on Day 0 (first treatment day) and Treatment 3 (if administered) at pre-dose and 5-, 15-, 30-minutes, 1-, 2-, 4-, 6-, 8- and 24-hours post-dose.
Secondary outcome [5] 374396 0
An additional exploratory objective is to explore pharmacodynamic measures of biological activity including biopsy tumour biomarker responses. Analysis related to the mechanism of action of tigilanol tiglate and prediction of efficacy and tumour architecture will be undertaken on tumour biopsies.
Timepoint [5] 374396 0
Target tumour biopsy samples will be collected prior to (between Day -14 and Day -7) and after (1-hour, 8-hours or 24-hours) dosing. For patients continuing on to scheduled surgery after Day 14, a sample of the excised treated target tumour(s) will be collected during surgery and analysed as for the above-mentioned biopsies.

Eligibility
Key inclusion criteria
A patient will be eligible for study participation (Stage 1 and Stage 2, if applicable) if they meet all of
the following criteria:
1. An adult (>= 18 years old);
2. Willing and able to provide written informed consent prior to any protocol-required procedures and comply with all local and study requirements;
3. Resectable or unresectable, histologically or cytologically confirmed HNSCC, accessible and amenable for IT injection, that meets at least one of the following:
• refractory to at least one round of conventional therapy; or
• no available standard therapy; or
• patient declined standard therapy after appropriate counselling (with the decision documented); or
• patient awaiting surgery or therapy or is explicitly being monitored with the aim of delaying therapy.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2;
5. Life expectancy more than 12 weeks;
6. Disease that is measurable (i.e., each target tumour >= 2 mm in diameter that can be accurately measured in at least two dimensions) by calliper. Up to 4 measurable target tumours with a maximum combined volume of 150 cm3 and up to 5 non-target tumours to be selected at the discretion of the PI;
7. Selected target tumours that are suitable for biopsy (multiple 2 mm punch sampling) and patient willingness to provide tumour biopsies;
8. Haemoglobin >= 9.0 g/dL, neutrophils >= 1.5 x 10^9/L, and platelets >= 100 x 10^9/L;
9. Total bilirubin =< 1.5 x upper limit of normal (ULN);
10. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN;
11. Plasma creatinine =< 2.0 x ULN;
12. International Normalised Ratio (INR) and APTT =< 1.5 x ULN;
13. Women of child-bearing potential (i.e., not pre-menarchal, surgically permanently sterile [hysterectomy, bilateral salpingectomy and bilateral oophorectomy], or >= 12 months postmenopausal without an alternative medical cause) must not be pregnant (as demonstrated by negative serum beta-human chorionic gonadotropin [hCG] pregnancy test) and all men must agree to use adequate contraception (i.e., sexual abstinence [only if preferred method of birth control]; oral, intravaginal, or transdermal combined estrogen and progesterone hormonal contraception associated with inhibition of ovulation; oral, injectable, or implantable progesterone-only hormonal contraception associated with inhibition of ovulation; intrauterine device [IUD]; intrauterine hormone-releasing system [IUS]; bilateral tubal occlusion; or only vasectomized sexual partner[s]) prior to study entry, for the duration of study participation, and for 90 days following the last treatment day. Additionally, men must agree to not donate sperm for the duration of study participation or for 90 days following the last treatment day.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
A patient will be excluded from the study if they meet any of the following criteria:
1. Target tumours intended for treatment immediately adjacent to, or with infiltration into, major arteries or veins;
2. Target tumours intended for treatment located in an area where post-injection swelling could compromise the airway;
3. Target tumours intended for treatment requiring urgent resection;
4. Participated in any investigational intervention study within 30 days prior to study treatment;
5. Treatment with any anti-cancer treatment (e.g., immunotherapy [e.g., anti-PD-1/L1 inhibitor], biological therapy, chemotherapy, anti-cancer vaccine therapy, oncolytic viral or microbial therapy [e.g., T-VEC/Imlygic(TM), toll-like receptor [TLR] agonists, STING or RIG-1], etc.) other than prior tigilanol tiglate injection as part of this study, within 4 weeks prior to study treatment;
6. Oncology related surgery within 4 weeks prior to study treatment;
7. Any previous surgery in the area of the intended target tumour in proximity of the airway (such that tracking of the injected fluid may be unpredictable and could lead to airway swelling);
8. Any radiation therapy to a visceral organ or tumours within 3 weeks prior to study treatment;
9. Any previous radiation of the intended target tumour in proximity of the airway (such that tracking of the injected fluid may be unpredictable and could lead to airway swelling);
10. Unrecovered to CTCAE version 5 Grade 1 or better from the toxic effects of any previous therapy prior to study enrolment, except for fatigue (Grade =< 2) due to radiation treatment and alopecia (Grade =< 2). Other Grade 2 AEs that are deemed as Grade 2 due to replacement hormonal or steroid therapies may qualify for exception to this criterion with approval of the Medical Monitor;
11. Known, uncontrolled CNS metastasis;
12. History of significant tumour bleeding in the target tumour intended for treatment;
13. Therapeutic anticoagulation or antiplatelet agents (e.g., clopidogrel) (Prophylactic doses of low molecular weight heparins or low dose aspirin [=< 150 mg daily] are allowed) (low molecular weight heparin must be stopped at least 24 hours prior to study treatment);
14. A bleeding diathesis or coagulopathy that would make IT injection or biopsy unsafe;
15. Myocardial infarction, unstable angina pectoris, cerebrovascular accident, pulmonary embolism, uncontrolled congestive heart failure, cardiac arrhythmia (except for controlled atrial fibrillation), arterial thrombosis, or transient ischaemic attack within 6 months prior to study treatment;
16. Significant cardiac comorbidity or uncontrolled hypertension (> 150/100 mmHg), despite optimal medical therapy, that may confound the assessment of safety and tolerability;
17. History of allergic reactions attributed to compounds of similar chemical or biologic composition to tigilanol tiglate or other agents used in this study;
18. Uncontrolled bacterial, viral, or fungal infections requiring systemic therapy, known infection with human immunodeficiency virus (HIV), or active infection with Hepatitis B or Hepatitis C;
19. Pregnant or nursing (the effects of tigilanol tiglate on congenital development and nursing infants are unknown);
20. In the opinion of the PI, the patient is an inappropriate candidate for the study;
21. For consideration when entering Stage 2 - Repeat-Dosing only: Any anti-cancer treatment (e.g., immunotherapy, biological therapy, chemotherapy, anti-cancer vaccine therapy, surgery, etc.) to the target tumour since the previous treatment with tigilanol tiglate;
22. For consideration when entering Stage 2 - Repeat-Dosing only: No unacceptable toxicity to a previous tigilanol tiglate injection.

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)
Allocation is not concealed.
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
In Stage 1, patient will be enrolled into one of two cohorts at a starting dose level of up to 1.2 mg/m2. The first cohort will contain patients with a larger combined target tumour volume (~4.0 - 150.0 cm3) that cannot be entirely treated at 50% v/v (0.5 mL dose volume / 1.0 cm3 tumour) at the current dose level (mg/m2 BSA). The second cohort will contain patients with a smaller combined target tumour volume (0.1 - ~4.0 cm3) that can be entirely treated at 50% v/v (0.5 mL dose volume / 1.0 cm3 tumour) without reaching the current dose level (mg/m2 BSA).
In Stage 2 patients that have completed Stage 1 may receive up to two additional treatments, one week apart, to the same target tumour(s) and at the same dose level as received in Stage 1.
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety
Statistical methods / analysis
Descriptive statistics.

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Participant recruitment difficulties
Other reasons/comments
Other reasons
A difference in the demographics and tumour type was noted in the two jurisdictions where the trial was conducted, along with a difference in the treatment paradigm. Therefore contributing to ambiguity in assessment of the data generated and creating difficulty achieving the secondary objectives. As a result, the sponsor decided to close the study. No dose-limiting toxicities or safety concerns were noted.
Date of first participant enrolment
Anticipated
31/10/2019
Actual
29/11/2019
Date of last participant enrolment
Anticipated
31/12/2021
Actual
13/09/2021
Date of last data collection
Anticipated
28/02/2022
Actual
28/09/2021
Sample size
Target
40
Accrual to date
Final
19
Recruitment in Australia
Recruitment state(s)
NSW,QLD
Recruitment hospital [1] 14869 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [2] 16031 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment postcode(s) [1] 28136 0
4102 - Woolloongabba
Recruitment postcode(s) [2] 29542 0
2010 - Darlinghurst
Recruitment outside Australia
Country [1] 21819 0
India
State/province [1] 21819 0
Mumbai, Maharashtra, 400012
Country [2] 21820 0
India
State/province [2] 21820 0
Kolkata, West Bengal, 700160

Funding & Sponsors
Funding source category [1] 303687 0
Commercial sector/Industry
Name [1] 303687 0
QBiotics Group Limited
Country [1] 303687 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
QBiotics Group Limited
Address
3A/165 Moggill Road, Taringa, QLD, 4068
Country
Australia
Secondary sponsor category [1] 303793 0
Commercial sector/Industry
Name [1] 303793 0
Southern Star Research Pty Ltd
Address [1] 303793 0
Level 1, 1 Merriwa Street, Gordon, NSW, 2072
Country [1] 303793 0
Australia
Secondary sponsor category [2] 303794 0
Commercial sector/Industry
Name [2] 303794 0
Excel Life Sciences Pvt Itd
Address [2] 303794 0
Assotech Business, Cresterra-Tower 2 9th Floor, Units 910-913 Plot No 22 Sector 135, Noida, Uttar Pradesh 201301
Country [2] 303794 0
India

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304212 0
Metro South Human Research Ethics Committee
Ethics committee address [1] 304212 0
Ethics committee country [1] 304212 0
Australia
Date submitted for ethics approval [1] 304212 0
04/06/2019
Approval date [1] 304212 0
11/07/2019
Ethics approval number [1] 304212 0
HREC/2019/QMS/54004
Ethics committee name [2] 304909 0
Bellberry Limited
Ethics committee address [2] 304909 0
Ethics committee country [2] 304909 0
Australia
Date submitted for ethics approval [2] 304909 0
02/10/2019
Approval date [2] 304909 0
28/11/2019
Ethics approval number [2] 304909 0
2019-10-846 (REGIS 2019/ETH13063)
Ethics committee name [3] 304910 0
Tata Memorial Hospital - Institutional Review Board
Ethics committee address [3] 304910 0
Ethics committee country [3] 304910 0
India
Date submitted for ethics approval [3] 304910 0
23/08/2019
Approval date [3] 304910 0
02/12/2019
Ethics approval number [3] 304910 0
IEC/1219/3370/001
Ethics committee name [4] 304911 0
Tata Medical Center - Institutional Review Board
Ethics committee address [4] 304911 0
Ethics committee country [4] 304911 0
India
Date submitted for ethics approval [4] 304911 0
06/06/2019
Approval date [4] 304911 0
29/08/2019
Ethics approval number [4] 304911 0
2019/PHARMA/57/IRB39

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 96158 0
Prof Benedict Panizza
Address 96158 0
Princess Alexandra Hospital, Ward 1D Outpatients, Head and Neck, Plastics, Maxillo-facial Surgery, 199 Ipswich Road, Woolloongabba, QLD, 4102
Country 96158 0
Australia
Phone 96158 0
+61731765837
Fax 96158 0
Email 96158 0
ben@panizza.com.au
Contact person for public queries
Name 96159 0
Daniel Swart
Address 96159 0
QBiotics Group Limited, Suite 3A/165 Moggill Road, Taringa, QLD, 4068
Country 96159 0
Australia
Phone 96159 0
+61 738708933
Fax 96159 0
Email 96159 0
enquiries@qbiotics.com
Contact person for scientific queries
Name 96160 0
Victoria Gordon
Address 96160 0
QBiotics Group Limited, Suite 3A/165 Moggill Road, Taringa, QLD, 4068
Country 96160 0
Australia
Phone 96160 0
+61 738708933
Fax 96160 0
Email 96160 0
enquiries@qbiotics.com

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
SourceTitleYear of PublicationDOI
Dimensions AIExploratory phase Ib/IIa study of intratumorally administered tigilanol tiglate to assess safety, tolerability and tumour response in patients with head and neck squamous cell carcinoma2020https://doi.org/10.1016/j.annonc.2020.08.1089
Dimensions AILEAP-010: Phase III study of first-line pembrolizumab with or without lenvatinib in patients (pts) with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC)2020https://doi.org/10.1016/j.annonc.2020.08.1088
N.B. These documents automatically identified may not have been verified by the study sponsor.