Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000182998
Ethics application status
Approved
Date submitted
3/12/2019
Date registered
18/02/2020
Date last updated
18/02/2020
Date data sharing statement initially provided
18/02/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Phase 1b trial to investigate the prevention of hearing loss in cancer patients receiving cisplatin chemotherapy
Scientific title
Phase 1b Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Repeated Doses of DB-020 in Patients Receiving Cisplatin
Secondary ID [1] 299838 0
Sponsor Name: Decibel Therapeutics
Protocol Number: DB-020-002
Universal Trial Number (UTN)
U1111-1243-8337
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hearing loss (ototoxicity from cisplatin medication) 315234 0
Condition category
Condition code
Ear 313541 313541 0 0
Deafness
Cancer 313542 313542 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Brief name of intervention: Repeated intratympanic (IT) injections of sodium thiosulfate (STS) pentahydrate in patients receiving cisplatin.
STS pentahydrate to be hereafter designated as DB-020.

Repeated doses: IT injections will be administered once every 3 weeks or once every 4 weeks, according to the cisplatin dosing schedule, as close to cisplatin administration as possible, ideally after intravenous(IV) fluids for hydration have been started but within 3 hours prior to the patient receiving his/her cisplatin treatment. Eligible patients are those planned to receive a minimum cumulative dose of cisplatin of greater than or equal to 280 mg per m^2 over at least three cycles (21-day or 28-day cycles) for treatment of cancer of any type.

Study Drug Administration: Patients will be randomized to receive blinded, bilateral, IT treatment where patients will receive DB-020 in one ear with placebo in the other. In Part B, patients may receive DB-020 in both ears. The administration of these injections, to be performed by a qualified otolaryngologist and is expected to take 1-2 min per injection.
DB-020 for Injection, at either 12% or 25%, is provided as a single use vial containing a sterile viscous solution of DB-020 and sodium hyaluronate in sterile water. The placebo is provided as a single use vial containing a sterile viscous solution of sodium hyaluronate in 0.9% sodium chloride.

The study will comprise 2 parts. Separate patients will participate in Parts A and B
Part A: Eligible patients will be randomized to 12% or 25% dose levels of DB-020. Patients will be randomized to receive blinded, bilateral, IT treatment. Patients will receive DB-020 in one ear with placebo in the other. The ear to be injected with DB-020 throughout the treatment period will be randomly assigned and the contralateral ear will be injected with placebo.
Part B: Patients will be randomized to a single dose level of DB-020, as selected from data collected in Part A. The output of the interim analysis of Part A will provide the information necessary to select the concentration for Part B. This analysis will incorporate key safety and efficacy data to ensure patient safety and opportunity for efficacy and will be used to select the most appropriate dose for Part B.
If the prevention of ototoxicity as defined by American Speech-Language-Hearing Association (ASHA) criteria is observed in DB-020 treated ears in Part A, the Sponsor has the option of dosing at one of these concentrations either unilaterally (ie, with placebo administered in the contralateral ear) or bilaterally (ie, open-label DB-020 administered to both ears) in Part B.
This protocol uses a 1:1:1:1 central randomization without stratification variables. Each patient will be randomized to receive one of two dose strengths (12% or 25%) in Part A, and the ear to receive active IP vs. placebo is also randomly assigned.
Intervention code [1] 316094 0
Prevention
Intervention code [2] 316095 0
Treatment: Drugs
Comparator / control treatment
Patients will be randomized to receive blinded, bilateral, IT treatment where patients will receive study drug in one ear with placebo in the other.
Control group
Placebo

Outcomes
Primary outcome [1] 321992 0
Safety and tolerability of intratympanic DB-020 administered to cancer patients receiving cisplatin, which include the incidence of AEs, observed and change from baseline values for vital signs, electrocardiogram (ECG), and clinical laboratory assessments
Timepoint [1] 321992 0
1. Complete physical examination during Screening and prior to dosing at Cycle 2 through End of Treatment. Symptom-directed physical examinations will be performed at other times at discretion of the Investigator, if necessary, to evaluate AEs or other abnormalities.
2. Vital signs measured at Screening and Day 1 of each Cycle (including oral temperature, respiratory rate, sitting blood pressure, and pulse) will be obtained prior to dosing study drug) and at End of Treatment (28 days after last study drug injection). Height and weight will be measured at the Screening visit only. Predose vital signs may be performed up to 60 minutes prior to study treatment dosing.
3. 12-lead ECG measurements at Screening, Baseline and End of Treatment (28 days after last study drug injection)
4. Laboratory samples will be drawn at Screening and at Day 1 of each Cycle prior to dosing with paracetamol and study drug. These will consist of complete blood count, clinical chemistry, coagulation parameters (international normalized ratio, activated partial thromboplastin time, prothrombin time), and urinalysis (macroscopic examination with microscopic examination in the event of abnormal findings)
Secondary outcome [1] 379909 0
To evaluate changes in hearing after repeated intratympanic injections of DB-020 compared to repeated injections of placebo in patients with cancer receiving cisplatin. This is a composite outcome, with the following endpoints:
1. Incidence of ototoxicity/ changes in hearing (as defined by American Speech-Language-Hearing Association [ASHA] criteria) through to end of treatment visit (196 days)
2. Changes from baseline in Pure Tone Thresholds at end of treatment through to end of treatment visit (196 days)
3. Changes from baseline in Tinnitus Functional Index (TFI) scores through to end of treatment visit (196 days)
4. Changes from baseline in Distortion Product Otoacoustic Emissions (DPOAE) measures through to end of treatment visit (196 days)
5. Changes from baseline in Words- In-Noise, and Hearing Handicap Inventory for Adults (HHIAA) scores through to end of treatment visit (196 days)
Timepoint [1] 379909 0
Pure-tone thresholds: Screening, baseline, Day 1 of each cisplatin cycle prior to dosing (unless already measured 14 days or less prior to dosing), and End of Treatment (28 days after last study drug injection)
TFI scores: Baseline, Day 1 of each cisplatin cycle prior to dosing (unless already measured 14 days or less prior to dosing), and End of Treatment (28 days after last study drug injection)
DPOAE: Baseline, Day 1 of Cycle 1 prior to dosing (unless already measured 14 days or less prior to dosing), and End of Treatment (28 days after last study drug injection)
Words-in-noise: Baseline, Day 1 of Cycle 1 prior to dosing (unless already measured 14 days or less prior to dosing), and End of Treatment (28 days after last study drug injection).
HHIAA scores: Baseline, Day 1 of Cycle 1 prior to dosing (unless already measured 14 days or less prior to dosing), and End of Treatment (28 days after last study drug injection)
Secondary outcome [2] 379910 0
To determine the plasma pharmacokinetics of free (unbound) cisplatin administered to patients with cancer receiving cisplatin. The specific parameters being assessed are
1. AUC0-inf - The area under the plasma concentration-time curve from time 0 extrapolated to infinity. AUC0-inf is calculated as the sum of AUC0-t plus the ratio of the last measurable plasma concentration to the elimination rate constant.
2. Cmax - Maximum observed concentration.
3. tmax - Time to reach Cmax. If the maximum value occurs at more than 1 timepoint, tmax is defined as the first timepoint with this value.
4. T0.5 - Apparent first-order terminal elimination half-life will be calculated as 0.693 divided by the elimination rate constant.
Timepoint [2] 379910 0
Plasma samples for measurement of unbound cisplatin will be collected at 0.25 hours prior to cisplatin dose on Day 1 of each Cycle, mid-infusion, end-infusion and 0.25, 0.5,1 and 2 hours post end of IV cisplatin infusion
Secondary outcome [3] 379912 0
To determine the plasma pharmacokinetics of DB-020 administered to patients with cancer receiving cisplatin. The specific parameters being assessed are
1. AUC0-inf - The area under the plasma concentration-time curve from time 0 extrapolated to infinity. AUC0-inf is calculated as the sum of AUC0-t plus the ratio of the last measurable plasma concentration to the elimination rate constant.
2. Cmax - Maximum observed concentration.
3. tmax - Time to reach Cmax. If the maximum value occurs at more than 1 timepoint, tmax is defined as the first timepoint with this value.
4. T0.5 - Apparent first-order terminal elimination half-life will be calculated as 0.693 divided by the elimination rate constant.
Timepoint [3] 379912 0
Plasma samples for measurement of DB-020 levels will be collected at 0 hour (predose) on Day 1 and at 0.25 hours prior to cisplatin dose on Cycle 1 Day 1 only.

Eligibility
Key inclusion criteria
1. Ability to communicate with medical team and staff, willingness to participate in the study, willingness to give written informed consent, and willingness to comply with the study restrictions.
2. Adults aged 18 to 75 years, inclusive, at the time of signing the informed consent form.
3. Patients with cancer for whom treatment with IV cisplatin once every 21 or 28 days is indicated must meet all of the following criteria.
a. Plan to receive a minimum cumulative dose of cisplatin of greater than or equal to 280 mg/m2 over at least three cycles (21-day or 28-day cycles) for treatment of cancer of any type.
b. Concomitant use of other chemotherapy and radiation is permitted except investigational agents and/or radiation > 35 Gy involving the cochlear area
4. Male patients, their female partner(s), and female patients of childbearing potential must agree to use 2 forms of contraception, 1 of which must be a barrier method, during the study and for 90 days after the last study drug administration. Acceptable barrier forms of contraception are condom and diaphragm. Acceptable forms of contraception for this study for female partner(s) of childbearing potential and premenopausal female patients are nonhormonal and hormonal intrauterine device (IUD), hormonal birth control pills, hormonal birth control patches, hormonal birth control injections (eg, Depo-Provera®), hormonal birth control implants, NuvaRing®, and/or spermicide. Male and female patients who consider themselves abstinent, and who agree to remain abstinent during the study and for 90 days after the last study drug administration, will be eligible to participate in the study.
Women of nonchildbearing potential are eligible for the study and are defined as 12 months with no menses prior to screening and a serum FSH >40 IU/L at Screening (ie, postmenopausal female patients), or surgically sterile female patients, eg, those having undergone total abdominal hysterectomy, bilateral oophorectomy, or bilateral tubal ligation at least 6 months prior to screening for study participation. Surgically sterile female patients may participate if they agree to use condoms with spermicide during the study and for
90 days after the last study drug administration.
Men who have undergone a vasectomy at least 6 months prior to Screening and who have a documented negative sperm count (eg, medical records or single semen specimen) after the procedure are not required to use contraception.
Male patients must agree to refrain from sperm donation within 90 days after the last study drug administration.
5. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
6. Anticipated survival > 1 year.
7. Normal or not clinically significant otoscopic findings in both ears.
8. Patient has read, understood, and voluntarily signed the informed consent form.
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Female or male patients with female partners who are pregnant, lactating, or planning to attempt to become pregnant during this study or within 90 days after last dose of study drug.
2. Prior treatment with a cisplatin regimen.
3. Signs of disturbed integrity of the tympanic membrane on otoscopy or tympanometry.
4. History of congenital hearing loss, ontological surgery (excluding myringotomy tubes or simple tympanoplasty), sudden hearing loss, conductive hearing loss > 10 dB at 2 frequencies in either ear, Meniere’s disease, or autoimmune middle ear disease.
5. Hearing loss greater than (not including) 35 dB HL averaged at 6 and 8 kHz in either ear.
6. Asymmetry in hearing thresholds between left and right ear equal to or exceeding 20 dB at any single frequency or 10 dB at any 3 consecutive frequencies, up to and including 8 kHz.
7. Previous radiation exposure > 35 Gy to all or part of the cochlea.
8. Consumption of > 6 g of salicylate or > 5 g of acetaminophen (paracetamol) per day for the past month, or aminoglycoside use in the past month
9. Use of any investigational drug or device within 30 days prior to the first dose of study medication (6 months for biologic therapies) or 5 half-lives of the investigational drug, if known, whichever time is longer.
10. History of any significant drug allergy (such as anaphylaxis or hepatotoxicity) and/or allergy
to the excipients of the study medications.
11. Presence of hepatitis C antibody with reflex hepatitis C virus (HCV) RNA testing (if anti-HCV is positive), hepatitis B surface antigen, or HIV antibodies 1 and 2.
12. History or presence of malignancy within the past 5 years other than a history of localized or surgical removal of focal basal cell skin cancer; cervical cancer in situ treated successfully in the past by local treatment (including but not limited to cryotherapy or laser therapy) or by hysterectomy, or malignancy for which the patient is receiving cisplatin therapy.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomization will be performed using an online Randomisation and Trial Supply Management system, supplied by an external vendor.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Patients will be randomized to receive blinded, bilateral, IT treatment with both DB-020 and placebo. In Part A, patients will be randomized in a 1:1:1:1 ratio to DB-020 dose 12% right ear and placebo left ear, DB-020 dose 12% left ear and placebo right ear, DB-020 dose 25% right ear and placebo left ear, or DB-020 dose 25% left ear and placebo right ear. In Part B, patient will be randomized in a 1:1 ratio to either DB-020 right ear and placebo left ear or DB-020 left ear and placebo right ear. The dose used for Part B will be decided using the data from Part A. If bilateral dosing of DB-020 is used in Part B, there will be no randomization as all patients will receive the selected DB-020 dose in both ears.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Other
Other design features
This is a randomized, double-blind, placebo-controlled, multiple dose study where in Part A patients will be randomized in a 1:1:1:1 ratio to one of two DB- doses with the active and placebo ears randomly assigned, allowing each patient to be their own control. The dose used for Part B will be decided using the data from Part A. If bilateral dosing of DB-020 is used in Part B, there will be no randomization as all patients will receive the selected DB-020 dose in both ears.
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Up to fifty (50) patients will be randomized into Part A of the study to yield approximately 28 evaluable patients (i.e., those that complete at least 3 cycles of cisplatin treatment and have a cumulative cisplatin exposure of =280 mg/m2); this sample size allows for up to 45% of randomized patients to be non-evaluable. An interim analysis of Part A data will inform which DB-020 dose level will be used in Part B of the study. In Part B, approximately 20 patients are planned to be randomized to yield approximately 11 evaluable patients.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
28/02/2020
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
70
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC
Recruitment hospital [1] 15170 0
Westmead Hospital - Westmead
Recruitment hospital [2] 15171 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [3] 15172 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [4] 15173 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment postcode(s) [1] 28472 0
2145 - Westmead
Recruitment postcode(s) [2] 28473 0
4102 - Woolloongabba
Recruitment postcode(s) [3] 28474 0
3065 - Fitzroy
Recruitment postcode(s) [4] 28475 0
3000 - Melbourne
Recruitment outside Australia
Country [1] 22121 0
United States of America
State/province [1] 22121 0
MO, WV, KS, IL, CO, NY

Funding & Sponsors
Funding source category [1] 304298 0
Commercial sector/Industry
Name [1] 304298 0
Decibel Therapeutics Australia Pty Ltd
Country [1] 304298 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Decibel Therapeutics Australia Pty Ltd
Address
Care of: Prime Accounting & Business Advisory Pty Ltd
Floor 19, HWT Tower
40 City Road
Southbank, Victoria, 3006
Country
Australia
Secondary sponsor category [1] 304542 0
Commercial sector/Industry
Name [1] 304542 0
Syneos Health
Address [1] 304542 0
159 Port Road
Hindmarsh, Australia SA 5007
Country [1] 304542 0
Australia
Secondary sponsor category [2] 304543 0
Commercial sector/Industry
Name [2] 304543 0
Syneos Health
Address [2] 304543 0
1030 Sync Street
Morrisville, NC 27560
Country [2] 304543 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304752 0
Metro South Health Human Ethics Research Committee
Ethics committee address [1] 304752 0
Ethics committee country [1] 304752 0
Australia
Date submitted for ethics approval [1] 304752 0
Approval date [1] 304752 0
11/07/2019
Ethics approval number [1] 304752 0
HREC/2019/QMS/53837

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

Contacts
Principal investigator
Name 98086 0
Prof Ben Panizza
Address 98086 0
Queensland Head and Neck Cancer Centre
Building 1 (Main Building)
Princess Alexandra Hospital
199 Ipswich Road,
Woolloongabba QLD 4102
Country 98086 0
Australia
Phone 98086 0
+61731764238
Fax 98086 0
Email 98086 0
[email protected]
Contact person for public queries
Name 98087 0
Heather Wolff
Address 98087 0
Decibel Therapeutics, Inc.
1325 Boylston Street Suite 500
Boston, MA 02215 USA
Country 98087 0
United States of America
Phone 98087 0
+1 617 370 8701
Fax 98087 0
Email 98087 0
[email protected]
Contact person for scientific queries
Name 98088 0
John Keilty
Address 98088 0
Decibel Therapeutics, Inc.
1325 Boylston Street Suite 500
Boston, MA 02215 USA
Country 98088 0
United States of America
Phone 98088 0
+1 617 370 8701
Fax 98088 0
Email 98088 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
Listings will not be shared.


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.