Open-label, Phase II, Study of Everolimus Plus Letrozole in Postmenopausal Women With ER+, HER2- Metastatic or Locally Advanced Breast Cancer

Hormone Receptor Positive Breast Cancer Clinical Trial

— BOLERO-4  

Official title:

An Open-label, Phase II, Single-arm Study of Everolimus in Combination With Letrozole in the Treatment of Postmenopausal Women With Estrogen Receptor Positive HER2 Negative Metastatic or Locally Advanced Breast Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01698918
• Other study ID #: CRAD001Y24135
• Secondary ID: 2012-003065-17
• Status: Completed
• Phase: Phase 2
• Start date: March 7, 2013
• Est. completion date: January 13, 2021

Study information

• Verified date: April 2023
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study was to assess the efficacy and safety of first-line treatment with everolimus plus letrozole in postmenopausal women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) locally advanced or metastatic breast cancer.

Moreover, the study also aimed to investigate the efficacy and safety of second line treatment with everolumus plus examestane in participants whose disease progressed during everolimus plus letrozole therapy.

Description:

This was an open-label, phase II, multicenter, international, single-arm study for postmenopausal women with ER+/HER2- metastatic or locally advanced breast cancer.

This study was comprised of 2 phases:

• Core Phase: from first participant first visit to 24 months after enrollment of the last participant (and upon approval of amendment 5 dated 14-Feb-2017), up to approximately 4 years. The main purpose of the amendment 5 was to implement an Extension Phase up to 3 years.

During the core phase, all enrolled participants received everolimus in combination with letrozole in the first line setting until disease progression or any other reason for which the participant might be discontinued. Only those participants who had disease progression in the first line setting were offered second line treatment (everolimus in combination with exemestane). Participants who discontinued first line treatment due to reasons other than disease progression were not eligible for second line treatment. The participants who were treated in the second line setting continued treatment until disease progression, unacceptable toxicity or withdrawal of consent.

• Extension Phase: Participants that were still benefiting from everolimus at the end of the Core Phase (and upon approval of amendment 5 dated 14-Feb-2017) were transitioned to the Extension phase of the study. Participants were continued on their existing line of treatment (everolimus plus letrozole or everolimus plus exemestane) in the extension, up to 3 years or until progression or any other reason for which the participant might be discontinued. Participants entering the Extension Phase on first line treatment and deemed to no longer be clinically benefiting were not offered second line treatment in the context of the study

This study included a randomized, open-label sub-study for participants in countries where the alcohol-free 0.5mg/5ml dexamethasone oral solution was commercially available who experienced a stomatitis event: at the first onset of symptoms suggestive of stomatitis, participants were to contact the study site and based on preliminary confirmation of diagnosis, participants were asked to visit the study site within 24 hours. Upon confirmation of stomatitis, participants in countries where the alcohol-free 0.5 mg/5 mL dexamethasone oral solution was commercially available (US sites only) were randomly assigned in a 1:1 ratio to take either 0.5 mg/5 mL dexamethasone mouth rinse or the standard of care used to treat stomatitis at the participant's center.

All participants who experienced stomatitis (regardless of inclusion in the sub-study) were instructed to fill out the Oral Stomatitis Daily Questionnaire (OSDQ) at home every day until the participant recovered. For subsequent episodes of stomatitis, participants were instructed to contact the physician. If part of the randomized set upon telephone confirmation, they were instructed to utilize the same treatment they were assigned to after the first episode and complete the OSDQ booklet.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 202
• Est. completion date: January 13, 2021
• Est. primary completion date: December 17, 2015
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients with metastatic or locally advanced, unresectable breast cancer not amenable to curative treatment by surgery or radiotherapy

• Histological or cytological confirmation of ER+/ HER2- breast cancer

• Postmenopausal women

• No prior treatment for metastatic breast cancer

Exclusion Criteria:

• Patients with only non-measurable lesions other than bone metastases (e.g., pleural effusion, ascites, etc)

• Patients who had received prior hormonal or any other systemic therapy for metastatic breast cancer. Patients might have received prior neoadjuvant or adjuvant endocrine therapy. In the case of neoadjuvant or adjuvant NSAI (letrozole/anastrozole) therapy patients must have completed therapy at least 1 year prior to study enrollment.

• Previous treatment with mTOR inhibitors.

• Known hypersensitivity to mTOR inhibitors, e.g., sirolimus (rapamycin).

Other protocol-defined inclusion/exclusion criteria might apply

Related Conditions & MeSH terms

• Breast Neoplasms
• Hormone Receptor Positive Breast Cancer

Intervention

Drug:
• Everolimus
Everolimus was self-administered as a daily dose of 10mg (two 5mg tablets) taken orally continuously until progression of disease, unacceptable toxicity or withdrawal of consent.
• Letrozole
1st line study treatment: Letrozole was self administered as a daily dose of 2.5mg continuously until disease progression or any other reason for which the patient might be discontinued
• Exemestane
2nd Line Study Treatment: Exemestane was self administered as a daily dose of 25mg taken orally continuously until disease progression or any other reason for which the patient might be discontinued
• Alcohol-free dexamethasone mouth rinse (Stomatitis sub-study)
Alcohol-free 0.5mg/5ml dexamethasone oral solution was self-administered at a daily dose of 10ml 3 times per day (participants with confirmed stomatitis who entered the stomatitis sub-study).
• Standard of care to treat stomatitis (Stomatitis sub-study)
Standard of care used to treat stomatitis at the patient's center (participants with confirmed stomatitis who entered the stomatitis sub-study).

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Rosario	Santa Fe
Argentina	Novartis Investigative Site	Santa Rosa	La Pampa
Brazil	Novartis Investigative Site	Porto Alegre	RS
Brazil	Novartis Investigative Site	Sao Paulo	SP
Brazil	Novartis Investigative Site	Sao Paulo	SP
France	Novartis Investigative Site	Besancon cedex
France	Novartis Investigative Site	Bordeaux
France	Novartis Investigative Site	Hyères
France	Novartis Investigative Site	Le Chesnay
France	Novartis Investigative Site	Lyon
France	Novartis Investigative Site	Nancy
France	Novartis Investigative Site	Nantes Cedex
Hungary	Novartis Investigative Site	Gyula
Hungary	Novartis Investigative Site	Kecskemet	Bacs Kiskun
Hungary	Novartis Investigative Site	Szekszard
Japan	Novartis Investigative Site	Kawasaki-city	Kanagawa
Japan	Novartis Investigative Site	Kumamoto City	Kumamoto
Japan	Novartis Investigative Site	Nagoya-city	Aichi
Japan	Novartis Investigative Site	Sapporo-city	Hokkaido
Japan	Novartis Investigative Site	Shiwa-gun	Iwate
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Netherlands	Novartis Investigative Site	Maastricht	AZ
Portugal	Novartis Investigative Site	Lisboa
Portugal	Novartis Investigative Site	Lisboa
Portugal	Novartis Investigative Site	Porto
Spain	Novartis Investigative Site	La Coruna	Galicia
Spain	Novartis Investigative Site	Salamanca	Castilla Y Leon
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Bangkok
Turkey	Novartis Investigative Site	Antalya
Turkey	Novartis Investigative Site	Istanbul
Turkey	Novartis Investigative Site	Izmir
United Kingdom	Novartis Investigative Site	Bath
United States	University of New Mexico Hospital SC	Albuquerque	New Mexico
United States	University of Alabama Comprehensive Cancer Center SC-2	Birmingham	Alabama
United States	Banner MD Anderson Cancer Center	Gilbert	Arizona
United States	Cone Health Cancer Center	Greensboro	North Carolina
United States	Broome Oncology SC	Johnson City	New York
United States	Saint Barnabas Medical Center CancerCenter of Saint Barnabas	Livingston	New Jersey
United States	Loma Linda University Loma Linda	Loma Linda	California
United States	Breastlink Medical Group Dept. of BreastlinkResearchGrp	Long Beach	California
United States	Norton Healthcare Inc SC	Louisville	Kentucky
United States	East Texas Hematology Clinic SC	Lufkin	Texas
United States	Columbia University Medical Center- New York Presbyterian Columbia	New York	New York
United States	Oncology Specialists, SC Advocate Medical Group-Niles	Park Ridge	Illinois
United States	Utah Cancer Specialists Dept.of Utah Cancer Spec. (3)	Salt Lake City	Utah
United States	Baystate Medical Center SC-2	Springfield	Massachusetts
United States	St. Francis Health Comprehensive Cancer Center	Topeka	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Brazil,  France,  Hungary,  Japan,  Korea, Republic of,  Netherlands,  Portugal,  Spain,  Thailand,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	First-line Treatment: Progression-free Survival (PFS)	PFS in the first line setting is defined as the time from the date of enrollment to the date of first documented progression based on local radiology review or death due to any cause. If a participant did not progress or was not known to have died at the date of the analysis cut-off or start of another antineoplastic therapy, the PFS date was censored to the date of last adequate tumor assessment prior to cut-off date or start of antineoplastic therapy. The median PFS was estimated and presented along with 95% confidence intervals. The primary analysis of PFS for first line was performed 12 months after the last patient's recruitment.	From the date of enrollment to the date of first documented progression or deaths, assessed up to approximately 2.8 years
Secondary	First-line Treatment: Overall Response Rate (ORR)	ORR in first line setting is defined as the percentage of participants while on first-line treatment with best overall response of complete response (CR) or partial response (PR) according to RECIST version 1.0 based on local review. Confidence intervals were calculated based on the Exact Clopper-Pearson method.; ORR while on first-line treatment was assessed up to 24 months after the last patient's recruitment.; CR: disappearance of all target lesions PR: at least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters.	From the date of enrollment until discontinuation of first-line treatment, assessed up to approximately 3.8 years
Secondary	First-line Treatment: Clinical Benefit Rate (CBR)	CBR in first line is defined as the percentage of participants while on first-line treatment with best overall response of CR, PR or stable disease (SD) with a duration of 24 weeks or longer, according to RECIST version 1.0 based on local review. Confidence intervals (CI) were calculated based on the Exact Clopper-Pearson method.; CBR while on first-line treatment was assessed up to 24 months after the last patient's recruitment.; CR: disappearance of all target lesions PR: at least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters.; SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease	From the date of enrollment until first-line treatment discontinuation, assessed up to approximately 3.8 years
Secondary	Second-line Treatment: Progression-free Survival (PFS)	PFS in the second line setting is defined as the time interval between the start of the second-line treatment and documented disease progression based on local radiology review or death due to any cause reported during or after second-line treatment period. If a participant did not progress or was not known to have died at the date of the analysis cut-off or start of another antineoplastic therapy, the PFS date was censored to the date of last adequate tumor assessment prior to cut-off date or start of antineoplastic therapy. The median PFS was estimated and presented along with 95% confidence intervals.; PFS while on second-line treatment was assessed up to 24 months after the last patient's recruitment.	From the start of the second-line treatment until the date of first documented progression or death, assessed up to approximately 2.4 years
Secondary	Second-line Treatment: Overall Response Rate (ORR)	ORR in second line is defined as the percentage of participants receiving second-line study treatment with best overall response of complete response (CR) or partial response (PR) according to RECIST version 1.0 based on local review. Confidence intervals (CI) were calculated based on the Exact Clopper-Pearson method.; ORR while on second-line treatment was assessed up to 24 months after the last patient's recruitment.; CR: disappearance of all target lesions PR: at least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters	From the start of the second-line treatment up to approximately 2.4 years
Secondary	Second-line Treatment: Clinical Benefit Rate (CBR)	CBR in second line is defined as the percentage of participants receiving second-line study treatment with best overall response of CR, PR or stable disease (SD) with a duration of 24 weeks or longer, according to RECIST version 1.0 based on local review. Confidence intervals (CI) were calculated based on the Exact Clopper-Pearson method.; CBR while on second-line treatment was assessed up to 24 months after the last patient's recruitment.; CR: disappearance of all target lesions PR: at least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters.; SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease	From the start of the second-line treatment up to approximately 2.4 years
Secondary	Overall Survival (OS)	OS following first-line treatment with everolimus + letrozole is defined as the time from the date of receiving first line study treatment to date of death due to any cause (including first-line and second-line treatment periods). If a participant was not known to have died, survival was censored at the date of last contact.; OS following first-line treatment was assessed up to 24 months after last patient's recruitment.	From the date of enrollment to date of death, assessed up to approximately 3.8 years
Secondary	First-line Treatment: Time to First Stomatitis Episode as Assessed by the Oral Stomatitis Daily Questionnaire (OSDQ)	The time to first occurrence of stomatitis based on OSDQ is defined as time from first-line treatment administration to start date of the stomatitis episode recorded in the OSDQ in the first line. The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The first item asked the participants when they experienced the first symptoms of stomatitis. Start date of the first occurrence of stomatitis is defined as the first date ever recorded for this item in the questionnaire. Patient reported outcomes (PROs) were assessed up to 24 months after last patient's recruitment.	From first-line treatment administration until first stomatitis episode in the first line, assessed up to approximately 3.8 years
Secondary	First-line Treatment: Duration of First Stomatitis Based on OSDQ	The duration of the first stomatitis episode was calculated using the start and end date recorded in the OSDQ. The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis. The first item of the questionnaire asked the participants the date when they experienced the first symptoms of stomatitis. Start date of the first occurrence of stomatitis is defined as the first date ever recorded for this item in the questionnaire. Stop date of the first stomatitis episode is defined as the last date the OSDQ was completed for this episode. Participants were censored if they died before resolution of stomatitis, received a new anticancer therapy, discontinued the study treatment with no resolution of the stomatitis or the stomatitis event was still on-going at the cut-off. PROs were assessed up to 24 months after last patient's recruitment.	From start date of first stomatitis episode in first line until its resolution, assessed up to 3.8 years
Secondary	First-line Treatment: Number of Participants With Shift of Response in OSDQ Score on Overall Health at the End of the First Stomatitis Episode	The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily up to the resolution of the stomatitis episode. The second item asked the participant to rate their overall health from 0 (worst possible) to 10 (perfect health). The overall health OSDQ scores are presented as the shift from Day 1 of first stomatitis episode value to the value at the end of the first episode of stomatitis. Day 1 is defined as the first OSDQ questionnaire recorded. End of first stomatitis value is defined as the last OSDQ questionnaire of the first episode of stomatitis. PROs were assessed up to 24 months after last patient's recruitment.	From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
Secondary	First-line Treatment: Number of Participants With Shift of Response in OSDQ Score on Mouth and Throat Soreness at the End of the First Stomatitis Episode	The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The third item asked the participant to rate their mouth and throat soreness from 0 (no soreness) to 4 (extreme soreness). The mouth and throat soreness OSDQ scores are presented as the shift from Day 1 of first stomatitis episode value to the value at the end of the first episode of stomatitis. Day 1 is defined as the first OSDQ questionnaire recorded. End of first stomatitis value is defined as the last OSDQ questionnaire of the first episode of stomatitis. PROs were assessed up to 24 months after last patient's recruitment.	From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
Secondary	First-line Treatment: Number of Participants With Shift of Response in OSDQ Score on Mouth and Throat Soreness Limiting Swallowing, Drinking, Eating, Talking and Sleeping at the End of the First Stomatitis Episode	The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The fourth item asked the participant to rate how much their mouth and throat soreness limited them in 1) swallowing, 2) drinking, 3) eating, 4) talking and 5) sleeping. For each activity, mouth and throat soreness scores ranged from 0 (not limited) to 4 (unable to do). Scores are presented as the shift from Day 1 of first stomatitis episode value to the value at the end of the first episode of stomatitis. Day 1 is defined as the first OSDQ questionnaire recorded. End of first stomatitis value is defined as the last OSDQ questionnaire of the first episode of stomatitis. PROs were assessed up to 24 months after last patient's recruitment.	From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
Secondary	First-line Treatment: Number of Participants With Shift of Response in OSDQ Score on Mouth Pain Severity at the End of the First Stomatitis Episode	The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The fifth item asked the participant to rate their mouth pain severity from 0 (no pain) to 10 (unbearable pain). The mouth pain severity OSDQ scores are presented as the shift from Day 1 of first stomatitis episode value to the value at the end of the first episode of stomatitis. Day 1 is defined as the first OSDQ questionnaire recorded. End of first stomatitis value is defined as the last OSDQ questionnaire of the first episode of stomatitis. PROs were assessed up to 24 months after last patient's recruitment.	From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
Secondary	First-line Treatment: Number of Participants With Shift of Response in OSDQ Score on Mouth Pain Severity Affecting Daily Activities at the End of the First Stomatitis Episode	The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The sixth item asked the participant to rate their mouth pain severity affecting daily activities score from 0 (no effect on daily activities) to 10 (completely prevented from doing daily activities). The mouth pain severity affecting daily activities OSDQ scores are presented as the shift from Day 1 of first stomatitis episode value to the value at the end of the first episode of stomatitis. Day 1 is defined as the first OSDQ questionnaire recorded. End of first stomatitis value is defined as the last OSDQ questionnaire of the first episode of stomatitis. PROs were assessed up to 24 months after last patient's recruitment.	From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
Secondary	First-line Treatment (Stomatitis Sub-study): Time to First Stomatitis Episode as Assessed by the OSDQ	The time to first occurrence of stomatitis based on OSDQ is defined as time from first study treatment administration in the first line to start date of the first stomatitis episode recorded in the OSDQ. The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The first item asked the participants when they experienced the first symptoms of stomatitis. Start date of the first occurrence of stomatitis is defined as the first date ever recorded for this item in the questionnaire. PROs were assessed up to 24 months after last patient's recruitment.; Only participants who were randomized in the stomatitis sub-study were included in this analysis.	From first study treatment administration in the first line until first stomatitis episode, assessed up to approximately 3.8 years
Secondary	First-line Treatment (Stomatitis Sub-study): Duration of First Stomatitis Based on OSDQ	The duration of the first stomatitis was calculated using the start and end date reported in the OSDQ. The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis. The first item asked the participants the date when they experienced the first symptoms of stomatitis. Start date of the first stomatitis is defined as the first date ever recorded for this item in the questionnaire. Stop date of the first stomatitis is defined as the last date the OSDQ was completed for this episode. Participants were censored if they died before resolution of stomatitis, received a new anticancer therapy, discontinued the study treatment with no resolution of the stomatitis or the stomatitis was still on-going at the cut-off. PROs were assessed up to 24 months after last patient's recruitment. Only participants who were randomized in the stomatitis sub-study were included in this analysis.	From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
Secondary	First-line Treatment (Stomatitis Sub-study): Number of Participants With Shift of Response in OSDQ Score on Overall Health at the End of the First Stomatitis Episode	The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The second item asked the participant to rate their overall health from 0 (worst possible) to 10 (perfect health). The overall health OSDQ score are presented as the shift from Day 1 of first stomatitis episode value to the value at the end of the first episode of stomatitis. Day 1 is defined as the first OSDQ questionnaire recorded. End of first stomatitis value is defined as the last OSDQ questionnaire of the first episode of stomatitis. PROs were assessed up to 24 months after last patient's recruitment.; Only participants who were randomized in the stomatitis sub-study were included in this analysis.	From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
Secondary	First-line Treatment (Stomatitis Sub-study): Number of Participants With Shift of Response in OSDQ Score on Mouth and Throat Soreness at the End of the First Stomatitis Episode	The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The third item asked the participant to rate their mouth and throat soreness from 0 (no soreness) to 4 (extreme soreness). The mouth and throat soreness OSDQ scores are presented as the shift from Day 1 of first stomatitis episode value to the value at the end of the first episode of stomatitis. Day 1 is defined as the first OSDQ questionnaire recorded. End of first stomatitis value is defined as the last OSDQ questionnaire of the first episode of stomatitis. PROs were assessed up to 24 months after last patient's recruitment.; Only participants who were randomized in the stomatitis sub-study were included in this analysis.	From start date of stomatitis episode until its resolution, assessed up to 3.8 years
Secondary	First-line Treatment (Stomatitis Sub-study): Number of Participants With Shift of Response in OSDQ Score on Mouth and Throat Soreness Limiting Swallowing, Drinking, Eating, Talking and Sleeping at the End of the First Stomatitis Episode	The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The fourth item asked the participant to rate how much their mouth and throat soreness limited them in 1) swallowing, 2) drinking, 3) eating, 4) talking and 5) sleeping. For each activity, mouth and throat soreness scores ranged from 0 (not limited) to 4 (unable to do). Scores are presented as the shift from Day 1 of first stomatitis stomatitis value to the value at the end of the first episode of stomatitis. Day 1 is defined as the first OSDQ questionnaire recorded. End of first episode value is defined as the last OSDQ questionnaire of the first episode of stomatitis. PROs were assessed up to 24 months after last patient's recruitment.; Only participants who were randomized in the stomatitis sub-study were included in this analysis.	From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
Secondary	First-line Treatment (Stomatitis Sub-study): Number of Participants With Shift of Response in OSDQ Score on Mouth Pain Severity at the End of the First Stomatitis Episode	The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The fifth item asked the participant to rate their mouth pain severity from 0 (no pain) to 10 (unbearable pain). The mouth pain severity OSDQ scores are presented as the shift from Day 1 of first stomatitis episode value to the value at the end of the first episode of stomatitis. Day 1 is defined as the first OSDQ questionnaire recorded. End of first stomatitis value is defined as the last OSDQ questionnaire of the first episode of stomatitis. PROs were assessed up to 24 months after last patient's recruitment.; Only participants who were randomized in the stomatitis sub-study were included in this analysis.	From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
Secondary	First-line Treatment (Stomatitis Sub-study): Number of Participants With Shift of Response in OSDQ Score on Mouth Pain Severity Affecting Daily Activities at the End of the First Stomatitis Episode	The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The sixth item asked the participant to rate their mouth pain severity affecting daily activities score from 0 (no effect on daily activities) to 10 (completely prevented from doing daily activities). The mouth pain severity affecting daily activities OSDQ scores are presented as the shift from Day 1 of first stomatitis episode value to the value at the end of the first episode of stomatitis. Day 1 is defined as the first OSDQ questionnaire recorded. End of first stomatitis value is defined as the last OSDQ questionnaire of the first episode of stomatitis. PROs were assessed up to 24 months after last patient's recruitment.; Only participants who were randomized in the stomatitis sub-study were included in this analysis.	From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
Secondary	Number of Participants With Clinical Benfit During Extension Phase	Number of participants with clinical benefit as judged by the investigator during the extension phase. The extension phase for up to 3 years for participants who were continuing to benefit from study treatment following the end of the core study phase (24 months after last patient's recruitment) was added in the amendment 5 (dated 14-Feb-2017). Results are presented by line of treatment	From the end of core phase (upon approval of amendment 5) up to approximately 3 years