1219

EORTC

83 Avenue Emmanuel Mounier, Brussels, Belgium, 1200

Project, Budget and Regulatory Dep , European Organisation for Research and Treatment of Cancer, +32 27741542, regulatory@eortc.be

Project, Budget and Regulatory Dep , European Organisation for Research and Treatment of Cancer, +32 27741542, regulatory@eortc.be

No

No

No

Final

06 Sep 2019

Yes

28 May 2018

Yes

06 Sep 2019

Yes

There are two primary objectives in this study: - to evaluate in a blinded randomized trial, whether the hypoxic cell radiosensitizer nimorazole can improve the effect of primary curative accelerated fractionated concomitant chemo-radiotherapy with cisplatin given to patients with locally advanced (HNSCC) larynx, hypopharynx and HPV/p16 negative oropharynx. - To investigate if patients who may have such benefit can be predicted by the use of a hypoxic gene profile, i.e. if the treatment benefit is larger and essentially restricted to the subset of patients who are hypoxic cell signature positive.

The responsible investigator ensures that this study is conducted in agreement with either the Declaration of Helsinki (available on the World Medical Association web site (http://www.wma.net)) and/or the laws and regulations of the country, whichever provides the greatest protection of the patient. The protocol has been written, and the study conducted according to the ICH Harmonized Tripartite Guideline on Good Clinical Practice (ICH-GCP, available online at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002874.pdf). The protocol was approved by the competent ethics committee(s) as required by the applicable national legislation.

25 Jul 2014

No

Yes

Netherlands: 43

Poland: 1

Belgium: 42

France: 69

Germany: 10

Australia: 12

Switzerland: 12

Canada: 5

194

165

0

0

0

0

0

0

137

57

0

Randomization (overall period)

Randomised - controlled

Yes

Nimorazole

Tablet

Oral use

Nimorazole/placebo is to be administered in doses of approximately 1.2 g/m2 body surface area prior to daily irradiation treatments (first daily irradiation treatment if there are 2 given on that day). Total dose over the entire irradiation period should be approximately 36 g/m2 and must not exceed 40 g/m2 or a total of 75 g. This dose level provides maximum radiotherapy enhancement ratio and is the maximum tolerated dose level. Table 1: Nimorazole dose prescription Body surface1 # tablets/intake Dose of nimorazole/intake Total dose < 1.6 m2 3 1.5 g 45 g 1.6–1.9 m2 4 2.0 g 60 g > 1.9 m2 5 2.5 g 75 g

Cisplatin

Infusion

Intravenous use

Cisplatin 40 mg/m² i.v. on day 1, 8, 15, 22, 29 of radiotherapy.

Cisplatin

Infusion

Intravenous use

Cisplatin 40 mg/m² i.v. on day 1, 8, 15, 22, 29 of radiotherapy.

Placebo

Tablet

Oral use

Nimorazole/placebo is to be administered in doses of approximately 1.2 g/m2 body surface area prior to daily irradiation treatments (first daily irradiation treatment if there are 2 given on that day). Total dose over the entire irradiation period should be approximately 36 g/m2 and must not exceed 40 g/m2 or a total of 75 g. This dose level provides maximum radiotherapy enhancement ratio and is the maximum tolerated dose level. Table 1: Nimorazole dose prescription Body surface1 # tablets/intake Dose of nimorazole/intake Total dose < 1.6 m2 3 1.5 g 45 g 1.6–1.9 m2 4 2.0 g 60 g > 1.9 m2 5 2.5 g 75 g

Nimorazole

Tablet

Oral use

Nimorazole/placebo is to be administered in doses of approximately 1.2 g/m2 body surface area prior to daily irradiation treatments (first daily irradiation treatment if there are 2 given on that day). Total dose over the entire irradiation period should be approximately 36 g/m2 and must not exceed 40 g/m2 or a total of 75 g. This dose level provides maximum radiotherapy enhancement ratio and is the maximum tolerated dose level. Table 1: Nimorazole dose prescription Body surface1 # tablets/intake Dose of nimorazole/intake Total dose < 1.6 m2 3 1.5 g 45 g 1.6–1.9 m2 4 2.0 g 60 g > 1.9 m2 5 2.5 g 75 g

Cisplatin 100mg

Infusion

Intravenous use

Cisplatin 100 mg/m² i.v. on day 1 and 22 of radiotherapy

Placebo

Tablet

Oral use

Nimorazole/placebo is to be administered in doses of approximately 1.2 g/m2 body surface area prior to daily irradiation treatments (first daily irradiation treatment if there are 2 given on that day). Total dose over the entire irradiation period should be approximately 36 g/m2 and must not exceed 40 g/m2 or a total of 75 g. This dose level provides maximum radiotherapy enhancement ratio and is the maximum tolerated dose level. Table 1: Nimorazole dose prescription Body surface1 # tablets/intake Dose of nimorazole/intake Total dose < 1.6 m2 3 1.5 g 45 g 1.6–1.9 m2 4 2.0 g 60 g > 1.9 m2 5 2.5 g 75 g

Cisplatin 100mg

Infusion

Intravenous use

Cisplatin 100 mg/m² i.v. on day 1 and 22 of radiotherapy

Nimorazole - Cisplatin 40mg

Placebo - Cisplatin 40mg

Nimorazole - Cisplatin 100mg

Placebo - Cisplatin 100mg

ITT

All randomized patients will be analyzed in the arm they were allocated by randomization.

Nimorazole - Cisplatin 40mg

Placebo - Cisplatin 40mg

Nimorazole - Cisplatin 100mg

Placebo - Cisplatin 100mg

ITT

All randomized patients will be analyzed in the arm they were allocated by randomization.

Estimated using cumulative incidence rates. Time to locoregional recurrence is counted from the day of randomization to the day of the first record of appearance of local or regional progression. Patients without any of the listed events (i.e. events of interest or competing risks events) are censored at the date of the most recent follow-up examination. Distant recurrence/progression and second cancers diagnosed before locoregional recurrence and death in absence of locoregional recurrence are considered as competing risk events in the analysis of this endpoint. - Patients with no assessment performed at 3 months were considered to be not assessable and were censored at the date of randomization. - Residual mass at 3 months was considered an event for this endpoint. Date of residual mass was, by convention, defined as the date of randomization.

Primary

Disease status assessed at three months after the end of treatment and yearly basis up to 5 years after end of treatment, or in case of clinical suspicion of relapse or residual disease.

The effect of treatment on the time to locoregional recurrence is estimated with a Fine&Gray model adjusted for the stratification factors (except institution). As the protocol treatment changed after IDMC recommendations made on the 23/05/2016, the analysis is also adjusted according to the date of the urgent safety amendment (ie patient randomized before vs after 02/06/2016).

Nimorazole - Cisplatin 40mg v Placebo - Cisplatin 40mg

122

Pre-specified

1.92

2-sided

The effect of treatment on the time to locoregional recurrence is estimated with a Fine&Gray model adjusted for the stratification factors (except institution). As the protocol treatment changed after IDMC recommendations made on the 23/05/2016, the analysis is also adjusted according to the date of the urgent safety amendment (ie patient randomized before vs after 02/06/2016).

Nimorazole - Cisplatin 100mg v Placebo - Cisplatin 100mg

72

Pre-specified

1.18

2-sided

Estimated using Kaplan-Meier method.

Secondary

Overall survival will be measured from the date of randomization to the date of death whatever the cause of death. Patients who are alive are censored at the date of the most recent follow-up examination.

A Cox proportional hazard regression model adjusted for the stratification factors was fitted to estimate the effect size using hazard ratios (HR) and the associated 95% confidence interval

Nimorazole - Cisplatin 40mg v Placebo - Cisplatin 40mg

122

Pre-specified

1.08

2-sided

A Cox proportional hazard regression model adjusted for the stratification factors was fitted to estimate the effect size using hazard ratios (HR) and the associated 95% confidence interval

Nimorazole - Cisplatin 100mg v Placebo - Cisplatin 100mg

72

Pre-specified

1.62

2-sided

Estimated using cumulative incidence rates. Time to distant-metastases is counted from the day of randomization to the day of the first record of appearance of distant recurrence/progression. "Locoregional-only" progression or second cancers diagnosed before the distant metastases and death in absence of distant metastases are not considered events of interest for this endpoint. Patients without any of the events of interest are censored at the date of the most recent follow-up examination. Death in absence of distant-metastases is considered as a competing risk event in the analysis of this endpoint.” In addition, it was agreed with the study team that deaths due to progressive disease would be considered as competing risks, because the CRF did not allow to distinguish between death due to locoregional progression or due to distant metastasis.

Secondary

Disease status assessed at three months after the end of treatment and yearly basis up to 5 years after end of treatment, or in case of clinical suspicion of relapse or residual disease.

The effect of treatment is estimated with a Fine&Gray model adjusted for the stratification factors (except institution). As the protocol treatment changed after IDMC recommendations made on the 23/05/2016, the analysis is also adjusted according to the date of the urgent safety amendment (ie patient randomized before vs after 02/06/2016).

Placebo - Cisplatin 40mg v Nimorazole - Cisplatin 40mg

122

Pre-specified

3.12

2-sided

The effect of treatment is estimated with a Fine&Gray model adjusted for the stratification factors (except institution). As the protocol treatment changed after IDMC recommendations made on the 23/05/2016, the analysis is also adjusted according to the date of the urgent safety amendment (ie patient randomized before vs after 02/06/2016).

Nimorazole - Cisplatin 100mg v Placebo - Cisplatin 100mg

72

Pre-specified

0.62

2-sided

Estimated using cumulative incidence rates. Time to recurrence or death is measured from the date of randomization to the date of first occurrence of any of the following events: - any locoregional recurrence (i.e. local recurrence in the tumor bed or any positive node in the contralateral or ipsilateral neck). - distant recurrence/progression. - death due to any cause. Patients alive and free of disease recurrence/progression (as defined above) are censored at the date of the most recent follow-up examination.” In addition, second cancer in absence of locoregional or distant recurrence is considered as a competing risk event for the analysis of this endpoint.

Secondary

Disease status assessed at three months after the end of treatment and yearly basis up to 5 years after end of treatment, or in case of clinical suspicion of relapse or residual disease.

The effect of treatment is estimated with a Fine&Gray model adjusted for the stratification factors (except the institution). As the protocol treatment changed after IDMC recommendations made on the 23/05/2016, the analysis is also adjusted according to the date of the urgent safety amendment (ie patient randomized before vs after 02/06/2016).

Nimorazole - Cisplatin 100mg v Placebo - Cisplatin 100mg

72

Pre-specified

1.08

2-sided

The effect of treatment is estimated with a Fine&Gray model adjusted for the stratification factors (except the institution). As the protocol treatment changed after IDMC recommendations made on the 23/05/2016, the analysis is also adjusted according to the date of the urgent safety amendment (ie patient randomized before vs after 02/06/2016).

Nimorazole - Cisplatin 40mg v Placebo - Cisplatin 40mg

122

Pre-specified

1.67

2-sided

Disease-specific survival is measured from the date of randomization to the date of death due to primary HNSCC. Patients alive are censored at the date of the most recent follow-up examination. Death from causes other than primary HNSCC is considered as a competing risk event in the analysis of this endpoint.

Secondary

Disease-specific survival is measured from the date of randomization to the date of death due to primary HNSCC. Patients alive are censored at the date of the most recent follow-up examination. Death from causes other than primary HNSCC is considered

The effect of treatment is estimated with a Fine&Gray model adjusted for the stratification factors (except the institution). As the protocol treatment changed after IDMC recommendations made on the 23/05/2016, the analysis is also adjusted according to the date of the urgent safety amendment (ie patient randomized before vs after 02/06/2016).

Nimorazole - Cisplatin 100mg v Placebo - Cisplatin 100mg

72

Pre-specified

1.95

2-sided

The effect of treatment is estimated with a Fine&Gray model adjusted for the stratification factors (except the institution). As the protocol treatment changed after IDMC recommendations made on the 23/05/2016, the analysis is also adjusted according to the date of the urgent safety amendment (ie patient randomized before vs after 02/06/2016).

Nimorazole - Cisplatin 40mg v Placebo - Cisplatin 40mg

122

Pre-specified

1.56

2-sided

Secondary

Disease status assessed at three months after the end of treatment and yearly basis up to 5 years after end of treatment, or in case of clinical suspicion of relapse or residual disease.

The effect of treatment is estimated with a Fine&Gray model adjusted for the stratification factors (except the institution). As the protocol treatment changed after IDMC recommendations made on the 23/05/2016, the analysis is also adjusted according to the date of the urgent safety amendment (ie patient randomized before vs after 02/06/2016).

Nimorazole - Cisplatin 100mg v Placebo - Cisplatin 100mg

72

Pre-specified

4.41

2-sided

The effect of treatment is estimated with a Fine&Gray model adjusted for the stratification factors (except the institution). As the protocol treatment changed after IDMC recommendations made on the 23/05/2016, the analysis is also adjusted according to the date of the urgent safety amendment (ie patient randomized before vs after 02/06/2016).

Nimorazole - Cisplatin 40mg v Placebo - Cisplatin 40mg

122

Pre-specified

1.19

2-sided

Adverse events, laboratory and physical abnormalities were collected till three months after the end of treatment. Afterwards, only treatment related AE are collected. For SAEs: all SAEs till 30 days after end of treatment; afterwards, only related SAEs.

AEs are evaluated using CTC grading, SAEs using MedDRA. Non-SAEs have not been collected specifically, all AEs including laboratory and physical abnormalities will be reported in non-SAE section. AEs are tabulated for each arm (Nimorazole versus Placebo), with both cisplatin regimens pooled together, for consistency with SAE reporting.

23.1

Nimorazole

Placebo