Clinical trial NCT03649048: Low-Dose Weekly vs High-Dose Cisplatin
Official title: Randomized Trial Comparing Low-Dose Weekly to High-Dose Cisplatin Concurrent With Radiation for Locally Advanced Head and Neck Cancer.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Locally Advanced Head and Neck Squamous Cell Carcinoma
Lead sponsor: London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's
Sponsor class: OTHER
First posted: 2018-08-28
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

Brief summary: This study is a prospective open-label randomized clinical trial. Following informed consent eligible LASCCHN patients (n=100) planned for CRT will be stratified by tumor p16 status and then randomized in a 1:1 fashion to either concurrent HD cisplatin or concurrent weekly LD cisplatin.

Detailed description: Human papilloma virus-related oropharynx cancer is increasing in incidence and is now the most common indication for LASCCHN CRT. It more commonly affects younger patients without other comorbidities and is associated with high rates of cure. This creates a survivorship dilemma, as these patients suffer a greater and more prolonged impact from chronic treatment effects such as hearing loss on their HRQOL. Furthermore, this cohort of patients is more likely to be engaged in contributing to societal and economic productivity for a more prolonged period of time. Minimizing long term side effects through strategies to better individualize treatment has been recognized as a priority by the US NIH.

Efforts to identify risk factors for cisplatin toxicity have been previously reported in pediatric cancer patients. Pussegoda and colleagues identified greater risk of hearing loss with cisplatin in children who carried single nucleotide polymorphisms (SNPs) in thiopurine S-methyltransferase (TPMT) and catechol-O-methyltransferase (COMT) genes. However, the role of these genes in predicting ototoxicity risk has remained controversial with both confirmatory and conflicting reports. Two independent studies identified SNPs in the gene acylphosphatase 2 (ACYP2) as being predictive of ototoxicity in pediatric populations. Additional studies have implicated drug transporters involved in cisplatin disposition including the multidrug and toxin extrusion protein 1 (MATE1) to be associated with platinum response and toxicities. In vitro experiments and know-out studies identified cisplatin as a substrate of MATE1. To date, there remains a paucity of data investigating the association between genetic factors and hearing loss in adult LASCCHN patients. A prospective cohort study conducted at LHSC in collaboration with Dr. Richard Kim studied 206 adult LASCCHN patients receiving CRT with cisplatin and identified four independent risk factors for cisplatin-related hearing loss. Risk of hearing loss was increased with the presence of COMT SNPs (HR = 1.75; 95% CI, 1.17 - 2.52) while MATE1 reduced the risk (HR = 0.46; 95% CI, 0.26 - 0.84). The risk of hearing loss was reduced with cisplatin administered on a weekly low dose (LD) compared to a HD schedule. PFS and OS were similar between SNP cohorts and patients treated with weekly LD cisplatin and HD cisplatin regimens. To validate these results and confirm benefits on the pragmatic endpoint of hearing-related QOL, the investigators propose a prospective randomized clinical trial comparing HD and weekly LD cisplatin.

Opinion leaders such as the National Comprehensive Cancer Network guidelines endorse the use of weekly LD cisplatin as a reasonable alternative to HD cisplatin when administered concurrently with radiation. While the study conducted at LHSC observed weekly LD patients had reduced ototoxicity with similar efficacy compared to HD patients, there is no randomized control trial data in LASCCHN to support this practice. Current American Society of Clinical Oncology (ASCO) guidelines support HD cisplatin in this setting based strength of evidence. Therefore, the optimal schedule and dosing of cisplatin when administered as part of CRT in the curative intent treatment of patients with LASCCHN remains unresolved supporting clinical equipoise as to which constitutes the "best" approach.

The investigators primary hypothesis is that LD weekly cisplatin 40 mg/m² is associated with reduced frequency of severe hearing loss and improved hearing-related QOL when compared to conventional HD cisplatin 100 mg/m² days 1, 22 \& 43 (control arm) in LASCCHN patients treated with CRT. Furthermore, the investigators hypothesize that a significant proportion of the risk of cisplatin-related hearing loss is attributable to individual differences in pharmacogenomics factors affecting cisplatin disposition that could be identified prior to treatment.

Eligibility criteria: Inclusion Criteria:

* Age 18 or older
* Willing and able to provide written informed consent
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* Histologically or cytologically confirmed squamous cell carcinoma
* Primary tumor site includes oral cavity, oropharynx, nasal cavity, salivary glands (excluding parotid), hypopharynx, or larynx and primary unknown
* Patients must be deemed suitable for HD cisplatin therapy based on tumor characteristics, clinical condition and comorbidities in the judgement of the treating medical oncologist.
* Patients must be planned to receive radical intent radiation treatment based on clinical condition, comorbidities and tumor characteristics in the judgment of the treating radiation oncologist
* Adequate organ and marrow function independent of transfusion for at least 7 days prior to randomization defined as:

  * Hemoglobin \> 80 g/L; Absolute neutrophil count \>1.5x10⁹ /L, platelets \>100x10⁹/L; Bilirubin \< 35 umol/L; AST or ALT \< 3 x the upper limit of normal; Calculated creatinine clearance (as determined by Cockcroft- Gault) \> 50 ml/min

Males:

Creatinine Clearance = Weight (kg) x (140 - Age) (mL/min) 72 x serum creatinine (mg/dL)

Females:

Creatinine Clearance = Weight (kg) x (140 - Age) x 0.85 (mL/min) 72 x serum creatinine (mg/dL)

* Patient must be assessed at head and neck cancer multidisciplinary clinic (with assessment by radiation oncologist and surgeon) and presented at multidisciplinary tumor board prior to randomization.

Exclusion Criteria:

* Serious medical comorbidities or other contraindications to radiotherapy and/or chemotherapy.
* Prior history of head and neck cancer within 5 years.
* Nasopharyngeal primary confirmed or suspected.
* Severe hearing loss as determined clinically Pre-existing use of hearing aids.
* Peripheral neuropathy .grade 2 (CTCAE v4.02).
* Prior or planned neoadjuvant chemotherapy prior to CRT.
* Prior head and neck radiation at any time.
* Distant metastatic disease.
* Inability to attend full course of radiotherapy or follow-up visits.
* Prior invasive malignant disease unless disease-free for at least 5 years or more, with the exception of non-melanoma skin cancer or in-situ carcinoma.
* Unable or unwilling to complete QOL questionnaires.
* Pregnant or lactating women.
* Unable to use dual method of contraception.

Primary outcomes:
measure: Hearing related quality of life (QOL)
timeFrame: 1-year post start of treatment
measure: Hearing related quality of life (QOL)
timeFrame: 1-year post start of treatment
measure: Compare Incidence of > Grade 2 hearing loss
timeFrame: At 1 year post start of treatment
measure: Compare Incidence of > Grade 1 hearing loss
timeFrame: At 1 year post start of treatment
Secondary outcomes:
measure: Proportion of patients recommended for hearing amplification
timeFrame: at year 1 post start of treatment
measure: Compare incidence of > grade 2 hearing loss
timeFrame: At 6 months and at 1 year post start of treatment
measure: Change in Health related Quality of Life (HRQOL)
timeFrame: At 1 year post start of treatment
measure: Incidence of > Grade 3 treatment-related neuropathy
timeFrame: At baseline, day 21 and day 42
measure: Change in neuropathy-associated QOL
timeFrame: At year 1 post start of treatment
measure: Incidence of any treatment related nephropathy
timeFrame: A baseline, day 21 and day 42
measure: Prevalence of persistent > Grade 3 nephropathy
timeFrame: At 1 year post start of treatment
measure: Evaluate the validity of MATE1 SNPs as a predictor of ototoxicity
timeFrame: At baseline
measure: Evaluate the validity of COMT SNPs as a predictor of ototoxicity
timeFrame: At baseline
measure: Change in Health related Quality of Life (HRQOL)
timeFrame: At 1 year post start of treatment
Other outcomes:
measure: Overall Survival
timeFrame: Captured annually starting at a year post start of treatment and continued for up to 5 years following date of randomization.
measure: Progression-free Survival
timeFrame: Captured annually starting at a year post start of treatment and continued for up to 5 years following date of randomization.
measure: Locoregional control
timeFrame: Captured annually starting at a year post start of treatment and continued for up to 5 years following start of treatment.
measure: Cost-effectiveness analysis
timeFrame: At 1 year post start of treatment
measure: Radiation doses to the cochlea
timeFrame: At 1 year post-start of treatment.
Locations:
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre
state: Ontario
city: London
country: Canada
facility: London Regional Cancer Program
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
Study officials:
affiliation: London Health Sciences Centre, London Regional Cancer Program
name: Sara Kuruvilla, MD
role: PRINCIPAL_INVESTIGATOR
References: