ANZCTR - Registration

Registration number

ACTRN12620000540910

Ethics application status

Approved

Date submitted

2/04/2020

Date registered

4/05/2020

Date last updated

4/05/2020

Date data sharing statement initially provided

4/05/2020

Type of registration

Prospectively registered

Titles & IDs

Public title

A Phase 2, Multicenter, Randomized Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of ST-617 for the Attenuation of Oral Mucositis in Patients Receiving Chemoradiation for Head and Neck Cancer

Scientific title

A Phase 2, Multicenter, Randomized Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of ST-617 for the Attenuation of Oral Mucositis in Patients Receiving Chemoradiation for Head and Neck Cancer

Secondary ID [1]

None

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Oral Mucositis

Head and Neck Cancer

Condition category

Condition code

Cancer

Head and neck

Oral and Gastrointestinal

Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

This Phase 2 part of the study will be a double-blind, randomised, placebo-controlled study to:

• Evaluate and compare the efficacy of a daily dose of ST-617 on reducing the duration and severity of severe oral mucositis (OM) in patients receiving concomitant chemoradiation for the treatment of cancers of the oral cavity, oropharynx, hypopharynx, and nasopharynx.

• Assess the acute and long-term safety of ST-617.

Participants will receive an oral suspension, either ST-617 or a placebo treatment equivalent to the volume of the study drug. The placebo will look and taste very similar to the study drug and will be supplied in identical bottles/caps. ST-Placebo has an added sub-pharmacologic level of quinine as the bitter flavouring to mimic the active ingredient in ST-617.

ST-617 at its recommended Phase 2 dose (RP2D), which will be determined from the Phase 1b study, will be administered daily for 3 days prior to the start of radiation, and then daily during radiation treatment. On days of radiation treatment, ST-617 or placebo will be administered and completely consumed 60 minutes to 120 minutes prior to each day’s radiation treatment. On days that patients will not have radiation treatment, ST-617 will be administered at the same time of day as it had been on days of radiation. Every patient, regardless of placebo or study drug administration, will receive best supportive care (BSC) for the prevention of oral mucositis.

BSC is defined as a specific oral hygiene regimen based on current guidelines, and practices to minimise the risk of mucosal injury and reduce the risk of secondary oral infection. To assure compliance each patient will be provided with a kit containing supplies necessary for BSC and instructions regarding its use. During the study, patients will be given a kit that has been specifically designed for patients at risk of radiation induced dental disease. This kit contains a toothbrush, toothpaste, dental floss, fluoride gel, oral rinse, and chewing gum. Patients will also receive instructions on how best to use these items to lower the amounts of bacteria on teeth and gums and make teeth more resistant to tooth decay.
Radiation treatment duration will last for up to approximately 6 to 8 weeks, however this duration will vary among participants and will depend on clinician's discretion.

Accountability for the study drug at the study site is the responsibility of the Investigator. The Investigator will ensure that the study drug is used only in accordance with the study protocol. The Investigator may assign the drug accountability responsibilities to a pharmacist or other appropriately trained individual; however, the Investigator remains ultimately responsible for drug accountability.

Drug accountability records indicating the drug’s delivery date to the site, inventory at the site and use/dispensing will be maintained. These records will adequately document that study drugs were used and dispensed as specified in the study protocol.
Accountability records will include dates, quantities, batch/lot numbers, number of vials, and patient numbers. The Sponsor (or its designee) will review drug accountability records at the site on an ongoing basis during the study. All unused supplies must be inventoried, accounted for, and returned to Sponsor (or its designee), or if authorised, disposed of at the study site. Records of disposal must be maintained with the study records.
To ensure compliance each patient will be provided with a kit containing supplies necessary for BSC and instructions regarding their use.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

ST-617, an oral suspension, will be compared to a placebo treatment, also an oral suspension, in equivalent volume to the active drug. The placebo will look and taste very similar to the active ingredient and is supplied in identical bottles/caps. ST-Placebo has an added sub-pharmacologic level of quinine as the bitter flavoring to mimic the active ingredient. The placebo dosage should be prepared exactly as that described for the active drug.

Control group

Placebo

Outcomes

Primary outcome [1]

Duration of, equal to or greater than, Grade 3 oral mucositis as determined by the World Health Organisation (WHO) oral mucositis assessment scale.

Incidence of oral mucositis will be assessed by trained assessors using a structured template developed by Primary Endpoint Solutions (PES). Data collection will be standardised, and oral mucositis scores will be centrally assigned by PES to the WHO, National Cancer Institute (NCI)and Radiation Therapy Oncology Group (RTOG) scales based on the information provided.

Timepoint [1]

OM assessments will be done at Screening, before each weekly treatment on Day 1, and then twice weekly with at least 48 hours between assessments, and then once weekly (if necessary) after cessation of radiation therapy until OM resolves to less than or equal to Grade 1 or until start of new treatment. OM will also be assessed at the End of Treatment Visit and the 30-Day Safety Follow-Up Visit.

The End of Treatment visit will be assessed on the last day of the last week that participants receive radiation therapy. Participants will be asked to come to the clinic for approximately 1-2 hours to complete the required tests (e.g. heart rate, blood pressure, breathing rate and body temperature) and answer straight forward questions (e.g. whether any adverse events were experienced).

Secondary outcome [1]

Incidence of severe oral mucositis.

Incidence of OM will be assessed by trained assessors using a structured template developed by PES. Data collection will be standardised, and oral mucositis scores will be centrally assigned by PES to the WHO, NCI and RTOG scales based on the information provided.

Timepoint [1]

Oral mucositis assessments will be done at Screening, before each weekly treatment on Day 1, and then twice weekly with at least 48 hours between assessments, and then once weekly (if necessary) after cessation of radiation therapy until oral mucositis resolves to less than or equal to Grade 1 or until start of new treatment. Oral mucositis will also be assessed at the End of Treatment Visit and the 30-Day Safety Follow-Up Visit.

The End of Treatment visit will be assessed on the last day of the last week that participants receive radiation therapy. Participants will be asked to come to the clinic for approximately 1-2 hours to complete the required tests (e.g. heart rate, blood pressure, breathing rate and body temperature) and answer straight forward questions (e.g. whether any adverse events were experienced).

Secondary outcome [2]

Incidence of ulcerative mucositis.

The incidence of ulcerative mucositis will be assessed by clinicians that employ assessment scales developed by the World Health Organisation, National Cancer Institute and Radiation Therapy Oncology Group.

Timepoint [2]

OM assessments will be done at Screening, before each weekly treatment on Day 1, and then twice weekly with at least 48 hours between assessments, and then once weekly (if necessary) after cessation of radiation therapy until oral mucositis resolves to less than or equal to Grade 1 or until start of new treatment. OM will also be assessed at the End of Treatment Visit and the 30-Day Safety Follow-Up Visit.

The End of Treatment visit will be assessed on the last day of the last week that participants receive radiation therapy. Participants will be asked to come to the clinic for approximately 1-2 hours to complete the required tests (e.g. heart rate, blood pressure, breathing rate and body temperature) and answer straight forward questions (e.g. whether any adverse events were experienced).

Secondary outcome [3]

Time in onset of greater than, or equal to, Grade 3 oral mucositis as determined by WHO oral mucositis assessment scale.

Time to onset of greater than, or equal to, Grade 3 oral mucositis will be assessed by clinicians that employ assessment scales developed by the WHO, NCI and RTOG.

Timepoint [3]

OM assessments will be done at Screening, before each weekly treatment on Day 1, and then twice weekly with at least 48 hours between assessments, and then once weekly (if necessary) after cessation of radiation therapy until OM resolves to less than or equal to Grade 1 or until start of new treatment. OM will also be assessed at the End of Treatment Visit and the 30-Day Safety Follow-Up Visit.

The End of Treatment visit will be assessed on the last day of the last week that participants receive radiation therapy. Participants will be asked to come to the clinic for approximately 1-2 hours to complete the required tests (e.g. heart rate, blood pressure, breathing rate and body temperature) and answer straight forward questions (e.g. whether any adverse events were experienced).

Secondary outcome [4]

Time to onset of ulcerative mucositis.

Time to onset of ulcerative mucositis will be assessed by clinicians that employ assessment scales developed by the WHO, NCI and RTOG.

Timepoint [4]

OM assessments will be done at Screening, before each weekly treatment on Day 1, and then twice weekly with at least 48 hours between assessments, and then once weekly (if necessary) after cessation of radiation therapy until OM resolves to less than or equal to Grade 1 or until start of new treatment. OM will also be assessed at the End of Treatment Visit and the 30-Day Safety Follow-Up Visit.

The End of Treatment visit will be assessed on the last day of the last week that participants receive radiation therapy. Participants will be asked to come to the clinic for approximately 1-2 hours to complete the required tests (e.g. heart rate, blood pressure, breathing rate and body temperature) and answer straight forward questions (e.g. whether any adverse events were experienced).

Secondary outcome [5]

Time to onset of opioid use due to mouth pain.

Time to onset of opioid use due to mouth pain will be assessed as per normal protocols and standard care regimens using patient medical records, regardless of patients having entered this study as patients can unfortunately be exposed to pain during chemotherapy and as such our aim is to minimise this pain and provide them with adequate treatment.

Timepoint [5]

OM assessments will be done at Screening, before each weekly treatment on Day 1, and then twice weekly with at least 48 hours between assessments, and then once weekly (if necessary) after cessation of radiation therapy until oral mucositis resolves to less than or equal to Grade 1 or until start of new treatment. OM will also be assessed at the End of Treatment Visit and the 30-Day Safety Follow-Up Visit.

The End of Treatment visit will be assessed on the last day of the last week that participants receive radiation therapy. Participants will be asked to come to the clinic for approximately 1-2 hours to complete the required tests (e.g. heart rate, blood pressure, breathing rate and body temperature) and answer straight forward questions (e.g. whether any adverse events were experienced).

Secondary outcome [6]

Change in patient-reported mouth pain.

The Oral Mucositis Daily Questionnaire (OMQD) , developed by PES, will be used to assess patient-reported mouth pain.

Timepoint [6]

Participants will be asked to complete the OMQD at the start of the first dose of the study drug (3 days prior to the initiation of radiation), and then daily through to the 30-Day Safety Follow-Up Visit.

This questionnaire will be used by participants to assess a change in patient-reported mouth pain.

Secondary outcome [7]

Change in analgesic use.

The OMQD, developed by PES, will be used to assess a change in analgesic use.

Timepoint [7]

Participants will be asked to complete the OMQD at the start of the first dose of the study drug (3 days prior to the initiation of radiation), and then daily through to the 30-Day Safety Follow-Up Visit.

This questionnaire will be used by participants to assess a change in analgesic use.

Secondary outcome [8]

Duration of ulcerative mucositis.

The duration of ulcerative mucositis will also be assessed by clinicians that employ assessment scales developed by the WHO, NCI and RTOG.

Timepoint [8]

OM assessments will be done at Screening, before each weekly treatment on Day 1, and then twice weekly with at least 48 hours between assessments, and then once weekly (if necessary) after cessation of radiation therapy until OM resolves to less than or equal to Grade 1 or until start of new treatment. Oral mucositis will also be assessed at the End of Treatment Visit and the 30-Day Safety Follow-Up Visit.

The End of Treatment visit will be assessed on the last day of the last week that participants receive radiation therapy. Participants will be asked to come to the clinic for approximately 1-2 hours to complete the required tests (e.g. heart rate, blood pressure, breathing rate and body temperature) and answer straight forward questions (e.g. whether any adverse events were experienced).

Eligibility

Key inclusion criteria

Patient Inclusion Criteria
Each patient must meet all the following criteria to participate in the study:

1. Histopathologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or nasopharynx.

2. Unknown Human Papillomavirus (HPV) positive primaries thought to be of oropharyngeal origin may be included if other inclusion criteria are met.

3. Documentation of HPV status for tumors of the oropharynx, tonsils or base of tongue. HPV status is determined by testing of the tumor (not an oral swab).

4. Planned therapy to include a continuous course of external beam radiation to include intensity-modulated radiotherapy (IMRT) with concurrent cisplatin monotherapy administered every week (30-40 mg/m2 for 6-7 doses) or every 3-weeks (60-100 mg/m2 for 3 doses).

5. Planned total radiation dose of between 60-72 Gy administered in single daily fractions of 2.0-2.2 Gy.

6. Radiation field must include at least 2 mucosal sites within the oral cavity (buccal mucosa, floor of mouth, lateral or ventral tongue, anterior tonsillar pillars, or soft palate) in which both sites receive a minimum cumulative radiation dose of 55 Gy.

7. Patient able to voluntarily provide written informed consent to participate in the study.

8. Capable of understanding and complying with the protocol requirements.

9. Adult patients aged between 18 to 75 years old.

10. Eastern Cooperative Oncology Group (ECOG) Performance Status of less than or equal to 2.

11. Adequate organ and bone marrow function as defined by:
a. Absolute neutrophil count (ANC) greater than or equal to 1.0 × 10^9/L (1,000/mm^3).
b. Haemoglobin (Hgb) greater than or equal to 9.0 g/dL.
c. Platelets greater than or equal to 75 × 10^9/L (75,000/mm^3).
d. Bilirubin less than or equal to 1.5 x the upper limit of normal (ULN).
e. Serum creatinine less than or equal to 1.5 x ULN or calculated creatinine clearance greater than or equal to 60 mL/min.
f. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 2.5 x ULN if no liver involvement, or less than or equal to 5 x ULN with liver involvement.
g. Albumin less than or equal to 3.5 g/dL or within normal range.

12. No evidence of any active oral mucositis (must be Grade 0 on WHO scale).

13. Ability to swish and swallow fluids in mouth without difficulty.

14. Able to minimise time in direct sunlight while on protocol.

15. Sexually active patients must agree to use medically-accepted barrier methods of contraception (e.g., male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 3 months after the last dose of study drug.

16. Women of childbearing potential (WCBP) must have a negative serum or urine pregnancy test at screening. WCBP includes any woman who has experienced menarche and who has not undergone successful surgical sterilisation (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal.

17. Patient’s written informed consent to test for the human immunodeficiency virus (HIV).

Minimum age

18 Years

Maximum age

75 Years

Sex

Both males and females

Can healthy volunteers participate?

No

Key exclusion criteria

Patient Exclusion Criteria
Patients who meet any of the following criteria will be excluded from the study:

1. Planned continuation of cisplatin or other chemotherapy following radiotherapy.

2. Patients with known infection of Human Immunodeficiency Virus (HIV) or have clinical signs and symptoms consistent with current HIV infection.

3. Known presence in serum of Hepatitis B surface antigen.

4. Evidence of any current active oral mucositis (must be Grade 0 on WHO scale).

5. Prior treatment including:
a. Radiotherapy or brachytherapy to the head and neck;
b. Cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) within 3 weeks, or nitrosoureas / mitomycin C within 6 weeks before the first dose of study treatment;
c. Treatment with therapeutic antibody less than 4 weeks before the first dose of study treatment;
d. Small molecule kinase inhibitor or other small molecule investigational agent within 14 days or 5 half-lives of the compound or active metabolites, whichever is greater, before the first dose of study treatment.

6. The patient has not recovered from toxicity due to all prior therapies (i.e., return to pre-therapy baseline or to Grade 0). Persistent > Grade 0 toxicity from prior therapy will be considered by the Sponsor for inclusion if there is no evidence of an overlapping ST-617 toxicity.

7. Major surgery within 21 days prior to first dose of study drug.

8. Current untreated or unresolved oral candidiasis or oral herpes simplex virus (HSV) infection.

9. History of thromboembolic or peripheral vascular disease (including Raynaud’s and systemic lupus erythematosus (SLE)).

10. Grade 2 or greater baseline neuropathy.

11. History of malabsorption or other gastrointestinal disease that may significantly alter the absorption of ST-617 (e.g., greater than or equal to Grade 2 nausea, vomiting or diarrhea).

12. History of poorly controlled Type 1 or Type 2 diabetes mellitus, with a haemoglobin A1c greater than or equal to 8%.

13. Uncontrolled significant intercurrent illness including, but not limited to, ongoing or active infection, history of congestive heart failure within 6 months, hypertension, unstable angina pectoris within 6 months, stroke within 6 months, myocardial infarction within 6 months, or cardiac arrhythmias. (Controlled chronic atrial fibrillation will not be excluded).

14. QTc interval corrected by Fridericia’s method greater than 450 msec for male patients or greater than 470 msec for female patients or history or risk factors for or use of medications known to prolong QTc interval or that may be associated with Torsades de Pointes (TdP) within 7 days of treatment start. CredibleMeds list of drugs known to cause TdP may be used as a reference for this study to determine which drugs are prohibited using the following link: https://crediblemeds.org/new-drug-list or a crediblemeds mobile application.

15. History of other medical or psychiatric illness or organ dysfunction which, in the opinion of the Investigator, would either compromise the patient’s safety or interfere with the evaluation of the safety of the study agent.

16. Concurrent administration of strong inhibitors of CYP3A4.

17. Concurrent administration of drugs that enhance photosensitivity.

18. The patient has a previously identified allergy or hypersensitivity to components of the study treatment formulation, dithiolethiones or platinum compounds.

19. Pregnant or breast-feeding women.

20. Unable to eat a solid diet due to sequelae of surgery or tumor, or gastrostomy-feeding dependence at baseline.

Study design

Statistical methods / analysis

Recruitment

Recruitment status

Not yet recruiting

Date of first participant enrolment

Anticipated

1/05/2021

Actual

Date of last participant enrolment

Anticipated

Actual

Date of last data collection

Anticipated

Actual

Sample size

Target

110

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW,SA,VIC

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Supportive Therapeutics LLC

Country [1]

United States of America

Primary sponsor type

Commercial sector/Industry

Name

PSI CRO Australia Pty. Ltd.

Country

Australia

Secondary sponsor category [1]

Commercial sector/Industry

Name [1]

Supportive Therapeutics LLC

Country [1]

United States of America

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Central Adelaide Local Health Network Human Research Ethics Committee

Ethics committee address [1]

Level 3, Roma Mitchell House, 136 North Terrace, Adelaide, South Australia, 5000

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

10/04/2019

Ethics approval number [1]

Ethics committee name [2]

Southern Adelaide Clinical Human Research Ethics Committee

Ethics committee address [2]

Flinders Medical Centre
Ward 6C
Room 6A219
Flinders Drive
Bedford Park SA 5042

Ethics committee country [2]

Australia

Date submitted for ethics approval [2]

23/11/2018

Approval date [2]

07/05/2019

Ethics approval number [2]

HREC/18/SAC/413

Summary

Brief summary

As you are going to be treated with chemoradiation therapy for your head and neck cancer, you will most likely develop oral mucositis. As such this study is testing an experimental treatment for oral mucositis. This experimental treatment is called ST-617. 

Oral mucositis involves painful ulcers or lesions developing in the lining of your mouth.  There are currently no approved medicines to successfully prevent and/or treat oral mucositis for head and neck cancer patients. Most patients are treated with best supportive care (BSC) which includes such things as making sure you are taking care of your mouth properly, providing ice chips or lozenges to suck on, or swishing with a mouthwash.

This study aims to test the safety and tolerability of ST-617 on patients and their oral cavities while they are being treated with chemoradiation for head and neck cancer. There are two arms to this study, Phase 1b and Phase 2. It is hoped that the Phase 1 arm will help determine the recommended dose of ST-617 that will be used in head and neck cancer patients in the Phase 2 part of the study.

ST-617 is a medication that has been widely studied in multiple human clinical trials and belongs to a group of medications that have been shown to help protect cells from damage.

Who is it for?

You may be eligible for this study if you are an adult who has been diagnosed with head and neck cancer who is planning to undergo chemoradiation.

Study details

In the Phase 2 part of the study, participants randomised to the Treatment Arm will receive ST-617 at the RP2D doses as determined in Phase 1b. Patients in the Control Arm will receive a placebo in equivalent volume to the active drug.

Participants will attend hospital visits for approximately 4 months. After the last visit, their study doctor will check on the status of their cancer every 3 months for up to 1 year after they started radiation.

Most of the exams, tests, and procedures that will be done during this study are part of regular medical care, but will be done multiple times so more information can be gathered. 
Participation in this study will be divided into different visits: Screening Period, Treatment Period, End of Treatment, 30-Day Safety Follow-Up and Response Follow-Up Visits.
Blood will be taken from a vein in the participants’ arm for testing of their general health and to check their medical condition.

Trial website

Public notes

Contacts

Principal investigator

Name

Dr Hien Le

Address

Department of Radiation Oncology, Royal Adelaide Hospital, Port Road, Adelaide, South Australia, 5000

Country

Australia

Phone

+61 8 8222 4391

Email

hien.le@sa.gov.au

Contact person for public queries

Name

Justine Lee

Address

PSI CRO Australia Pty. Ltd.
Suite 2.01, 16 Giffnock Avenue, Macquarie Park, New South Wales, 2113.

Country

Australia

Phone

+61 2 8582 1672

Email

justine.lee@psi-cro.com

Contact person for scientific queries

Name

Justine Lee

Address

PSI CRO Australia Pty. Ltd.
Suite 2.01, 16 Giffnock Avenue, Macquarie Park, New South Wales, 2113.

Country

Australia

Phone

+61 2 8582 1672

Email

justine.lee@psi-cro.com

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