Clinical Study for the Treatment of Breast Cancer: the Patient Will Receive Afatinib Plus Letrozole or Letrozole Alone

• Sponsor: Translational Research in Oncology (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02115048
• Collaborator: Boehringer Ingelheim (Industry)
• Enrollment: 44
• Locations: 26
• Arms: 2
• Duration (Months): 52
• Patients Per Site: 1.7
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of the study is to compare the efficacy of treatment with afatinib plus letrozole to treatment with letrozole alone in women diagnosed with a specific type of breast cancer.

Condition or Disease	Intervention/Treatment	Phase
Breast Neoplasms	Drug: Letrozole; Drug: Afatinib	Phase 2

Detailed Description

This is an open-label, multicenter, international, randomized, Phase II clinical trial that will assess the efficacy and safety of letrozole in combination with afatinib(oral epidermal growth factor receptor (EGFR ) inhibitor) versus letrozole monotherapy for the first-line treatment of postmenopausal women with ER+, Human Epidermal Growth Factor Receptor 2 (HER2) negative advanced breast cancer with low ER expression.

In order to assess the level of estrogen receptor (ER) expression we will use a semi-quantitative scoring system (McClelland, 1990) defined as :

H-score = (% of cells stained at intensity category 1x1) + (% of cells stained at intensity category 2x2) + (% of cells stained at intensity category 3x3).

This formula results in an H-score in the range of 0-300 where 300 equals 100% of tumor cells stained strongly (i.e., 3+). Low ER expression will be defined as tumor sample with H-score below 160 (Finn, 2009).

All subjects who consented for the study must submit a tumor sample to the designated central laboratory for central confirmation of ER / Progesterone receptor (PR) and HER2 statuses and determination of the H-score. This will be assessed prior to randomization.

Subjects with HER2 negative, ER+ advanced breast cancer with low ER expression defined as H-score between 1 and 159 will enter screening phase and perform the required screening assessments.

Eligible subjects will be randomly assigned in a 1:1 ratio and stratified according to sites of disease (bone only disease vs. other) and prior administration of hormonal therapy in neo/adjuvant setting (Yes vs. No) to either:

Arm A : Continuous regimen of oral letrozole 2.5 mg until progression of disease or any other study treatment discontinuation criteria.

or Arm B : Continuous regimen of oral letrozole 2.5 mg daily plus oral afatinib 30 mg daily until progression of disease or any other study treatment discontinuation criteria.

IN ADDITION the following applies whichever comes first:

• If the patients treated with the combination of afatinib and letrozole (arm B) discontinue the trial treatment (whatever the reason) before 30 November 2018, the patients from the other arm (arm A, letrozole alone) still on treatment will also be discontinued from the trial at the same time. They may continue receiving letrozole using commercial drug as standard of care according to their treating physician discretion.

• If the patients treated with afatinib and letrozole (arm B) have not discontinued the trial treatment by 30 November 2018, all patients currently on treatment in the trial (including the ones only treated by letrozole alone (arm A)) will be discontinued from the trial at that time. They may continue receiving their treatment if in alignment with their treating physician judgment as follows:

• Patients in arm A: may continue receiving letrozole using commercial drug as standard of care according to their treating physician discretion.

• Patients in arm B: may continue receiving afatinib in the context of alternative drug supply outside the clinical trial as appropriate according to local legislation. Additionally, they may continue receiving letrozole using commercial drug as standard of care according to their treating physician discretion.

Once the patient is discontinued from trial treatment and has undergone the End of Treatment Visit, she will be permanently discontinued from the trial and treated as per local clinical practice.

Study Design

• Study Type: Interventional
• Actual Enrollment: 44 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Open-label Phase II Study of Letrozole Plus Afatinib Versus Letrozole Alone in First-line Treatment of Advanced ER+, HER2- Postmenopausal Breast Cancer With Low ER Expression
• Study Start Date: Jul 1, 2014
• Actual Primary Completion Date: Nov 1, 2018
• Actual Study Completion Date: Nov 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm A Continuous regimen of oral Letrozole 2.5 mg daily	Drug: Letrozole
Experimental: Arm B Continuous regimen of oral Letrozole 2.5 mg daily plus oral Afatinib 30 mg daily	Drug: Letrozole; Drug: Afatinib

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) [Tumor assessments were every 12 weeks up to 9 months (average) for subjects in Arm A or up to 14 months (average) for subjects in Arm B.]

   Progression Free Survival (PFS) is defined as the time from randomization until date of progression (assessed by Response Evaluation Criteria in Solid Tumors - RECIST) or death due to any cause, whichever occurs first. For evaluation of PFS, the randomization date for each patient was the "start date". If the status at the last assessment date was "Non-complete response/ Non-progressive disease" or "Complete response", then the patient was considered "censored". If the status at the last assessment for any tumor was "Progressive disease", then the patient was considered as having an event. Progressive disease is defined using RECIST v1 .1 as a ≥ 20% increase in the sum of the longest diameter of target lesions compared with the smallest-sum longest diameter recorded or the appearance of one or more target or non-target new lesions and/or unequivocal progression of existing non-target lesions.

Secondary Outcome Measures

1. Overall Survival (OS) [Under treatment: every 4 wks up to 9 months (average) for subject in the Arm A or up to 14 months (average) for subjects in Arm B. After documentation of disease progression up to the end of the study: every 6 months up to 42 months]

   Overall Survival is defined as the time from randomization until death to any cause. For subjects in which treatment is discontinued for reasons different than Progression Disease: after treatment and up to documentation of disease progression: Overall Survival is assessed every 12 weeks

2. Objective Response Rate (ORR) [Tumor assessment: every 12 weeks up to 9 months (average) for subjects in Arm A or up to 14 months (average) for subjects in Arm B.]

   Objective response rate (ORR) is defined as the proportion of randomized subjects achieving a best overall response of complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST). As per RECIST (version 1.1): CR is defined as disappearance of all target and non target lesions - lymph node (LN) <10mm. PR is defined as at least a 30% decrease in the Sum of Diameters, taking as reference the Baseline Sum of Diameters

3. Time to Tumor Progression (TTP) [Tumor assessments: every 12 weeks up to 9 months (average) for subjects in Arm A or up to 14 months (average) for subjects in Arm B.]

   As per Response Evaluation Criteria In Solid Tumors (RECIST). Time to progression (TTP) is defined as the time interval from date of randomization to date of the first documented objective tumor progression.

4. Number of Participants With Adverse Events [Under treatment: every 4 wks up to 9 months (average) for subjects in Arm A or up to 14 months (average) for subjects in Arm B. After documentation of disease progression up to the end of the study: every 6 months up to 42 months]

   Participants who experienced at least one Treatment Emergent Adverse Event (TEAE) are presented. Participants with at least one serious TEAE, those who had at least one TEAE related to letrozole or afatinib (serious/non-serious), including participants who experienced a grade 3/4 TEAE, or who discontinued/died as a result of their TEAE are listed by treatment arm. Adverse events were tabulated by system organ class, preferred term and toxicity grade by treatment arm. For subjects in which treatment was discontinued for reasons different than progression of disease, the assessment was conducted every 12 weeks following treatment, and up to documentation of disease progression. ** Enrollment was closed prematurely due to low recruitment (only 44 participants enrolled) compared to what was initially planned (150 participants), therefore no statistical evaluations were completed. Adverse event data collected are described per arm but no statistical comparison was made.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Signed and dated informed consent.

• Postmenopausal females, 18 years of age or older.

• Histologically or cytologically proven diagnosis of adenocarcinoma of the breast with evidence of locally recurrent disease not amenable to resection or radiation therapy with curative intent, or metastatic disease.

• HER2 negative breast cancer. Central testing (required for all subjects) must demonstrate that the tumor is HER2 negative by FISH or Immunohistochemistry (IHC).

• ER positive breast cancer. Central testing (required for all subjects) must demonstrate that the tumor is ER+ with low expression (H-score [1-159]).

• Paraffin-embedded tumor block(s) or 15 to 20 unstained slides available for centralized assessment of ER, PR, and HER2.

• Measurable disease according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 or bone-only non measurable disease.

• Eastern Cooperative Oncology Group (ECOG) Performance status 0 or 1.

• Adequate hematological, hepatic and renal functions.

• Baseline left ventricular ejection fraction (LVEF) 50%.

• Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.

Exclusion Criteria:

• Brain metastases, spinal cord compression, carcinomatous meningitis, or leptomeningeal disease.

• Prior treatment with any type of systemic therapy for advanced disease.

• Prior treatment with letrozole in (neo)adjuvant setting with disease-free interval ≤ 12 months from completion of treatment until randomization.

• Prior treatment with any anti HER-family targeted therapy in (neo)adjuvant setting.

• Any concurrent or previous malignancy within 5 years prior to randomization, except for adequately and radically treated basal or squamous skin cancer, or carcinoma in situ of the cervix, or other non-invasive/in-situ neoplasm.

• Non-measurable disease according to RECIST 1.1, with the exception of bone-only non-measurable disease.

• Known pre-existing interstitial lung disease.

• Significant or recent acute gastrointestinal disorders with diarrhea as a major symptom.

• History or presence of clinically relevant cardiovascular abnormalities as per investigator assessment.

• Any other concomitant serious illness or organ system dysfunction as per investigator assessment

• Any contraindication to oral agents.

• Active hepatitis B infection, active hepatitis C infection or known HIV carrier.

• Known or suspected active drug or alcohol abuse.

• Known hypersensitivity to afatinib or letrozole or the excipients of any of the trial drugs.

• Concomitant treatment with strong inhibitor of P-gp.

• Any ongoing acute clinically significant toxic effect of prior anticancer therapy or any persisting complication of prior surgery.

• Subjects with known history of keratitis, ulcerative keratitis or severe dry eye.

• Participation in the active phase of other clinical trials of investigational agents in which last study treatment was administered within 2 weeks prior to randomization

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	St. Jude Heritage Healthcare	Fullerton	California	United States	92835
2	University of California Los Angeles Hematology Oncology	Los Angeles	California	United States	90095
3	West Valley Hematology Oncology Medical Group	Northridge	California	United States	91328
4	DBA Torrance Memorial Physician Network/Cancer Care Associates	Redondo Beach	California	United States	90277
5	Coastal Integrative Cancer Care	San Luis Obispo	California	United States	93401
6	Central Coast Medical Oncology Corporation	Santa Maria	California	United States	93454
7	Orlando Health, Inc.	Orlando	Florida	United States	32806
8	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada	United States	89169
9	Hope Women's Cancer Centers	Asheville	North Carolina	United States	28806
10	University Hospital Clinical Center Banja Luka, Oncology Clinic	Banja Luka		Bosnia and Herzegovina	78000
11	Clinical Center of University in Sarajevo, Clinic for Oncology	Sarajevo		Bosnia and Herzegovina	71000
12	University Clinical Center Tuzla Clinic for Oncology, Hematology and Radiotherapy	Tuzla		Bosnia and Herzegovina	75000
13	Filantropia Clinical Hospital	Bucuresti		Romania
14	County Emergency Clinical Hospital Cluj-Napoca Oncology Department	Cluj Napoca		Romania	400006
15	SC Medisprof SRL	Cluj Napoca		Romania	400058
16	County Hospital Ploiesti	Ploiesti		Romania	100337
17	County Emergency Hospital "Sf Ioan cel Nou"	Suceava		Romania	720237
18	Oncomed SRL Timisoara	Timisoara		Romania
19	Complejo Hospitalario Universitario de Albacete	Albacete		Spain	02006
20	Hospital General Universitario de Alicante	Alicante		Spain	03010
21	Complexo Hospitalario Universitario A Coruña	Coruña		Spain	15006
22	Hospital de Especialidades de Jerez de La Frontera	Jerez de la Frontera		Spain	11408
23	Hospital Clínico Universitario Virgen de La Arrixaca	Murcia		Spain	30120
24	Hospital Son Llatzer	Palma de Mallorca		Spain	07198
25	Hospital Universitari de Sant Joan de Reus	Reus		Spain	43204
26	Hospital Universitario Miguel Servet	Zaragoza		Spain	50009

Sponsors and Collaborators

• Translational Research in Oncology
• Boehringer Ingelheim

Investigators

• Study Chair: Richard Finn, MD, University of California, Los Angeles

Study Documents (Full-Text)

• Study Protocol - Jul 31, 2018
• Statistical Analysis Plan - Dec 4, 2014

More Information

Publications

None provided.

• Responsible Party: Translational Research in Oncology
• ClinicalTrials.gov Identifier: NCT02115048
• Other Study ID Numbers: TRIO 020
• First Posted: Apr 15, 2014
• Last Update Posted: Dec 26, 2019
• Last Verified: Dec 1, 2019

• Additional relevant MeSH terms: Breast Neoplasms; Letrozole; Afatinib

Study Results

Participant Flow

Pre-assignment Detail	For all patients consented on the trial, a tumor sample was sent to the central lab for testing of ER/PR and HER2 and determination of the H-score. This was assessed prior to randomization. Patients with HER2 negative, ER+ advanced breast cancer with low ER expression defined as H-score between 1 and 159 entered screening phase.

Arm/Group Title	Arm A	Arm B
Arm/Group Description	Letrozole 2.5 mg	Letrozole 2.5 mg + Afatinib 30 mg
Period Title: Overall Study
STARTED	23	21
COMPLETED	23	21
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Arm A	Arm B	Total
Arm/Group Description	Letrozole 2.5 mg	Letrozole 2.5 mg + Afatinib 30 mg	Total of all reporting groups
Overall Participants	23	21	44
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	14 60.9%	10 47.6%	24 54.5%
>=65 years	9 39.1%	11 52.4%	20 45.5%
Sex: Female, Male (Count of Participants)
Female	23 100%	21 100%	44 100%
Male	0 0%	0 0%	0 0%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
Romania	3 13%	5 23.8%	8 18.2%
United States	9 39.1%	6 28.6%	15 34.1%
Bosnia and Herzegovina	4 17.4%	3 14.3%	7 15.9%
Spain	7 30.4%	7 33.3%	14 31.8%
Menopausal Status (Count of Participants)
Pre-Menopausal	0 0%	0 0%	0 0%
Post-Menopausal	23 100%	21 100%	44 100%
ECOG Performance Status (Count of Participants)
0	12 52.2%	14 66.7%	26 59.1%
1	11 47.8%	7 33.3%	18 40.9%
Weight (kg) (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	77.39 (16.25)	69.59 (11.14)	73.67 (14.44)

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS)
Description	Progression Free Survival (PFS) is defined as the time from randomization until date of progression (assessed by Response Evaluation Criteria in Solid Tumors - RECIST) or death due to any cause, whichever occurs first. For evaluation of PFS, the randomization date for each patient was the "start date". If the status at the last assessment date was "Non-complete response/ Non-progressive disease" or "Complete response", then the patient was considered "censored". If the status at the last assessment for any tumor was "Progressive disease", then the patient was considered as having an event. Progressive disease is defined using RECIST v1 .1 as a ≥ 20% increase in the sum of the longest diameter of target lesions compared with the smallest-sum longest diameter recorded or the appearance of one or more target or non-target new lesions and/or unequivocal progression of existing non-target lesions.
Time Frame	Tumor assessments were every 12 weeks up to 9 months (average) for subjects in Arm A or up to 14 months (average) for subjects in Arm B.

Outcome Measure Data

Analysis Population Description

The timeframe specifies when tumor assessments were performed. Enrollment was closed prematurely due to low recruitment (only 44 participants enrolled) compared to what was initially planned (150 participants), therefore no statistical evaluations were completed (including PFS).

Arm/Group Title	Arm A	Arm B
Arm/Group Description	Letrozole 2.5 mg	Letrozole 2.5 mg + Afatinib 30 mg
Measure Participants	18	18
Failed (Progressed or Died)	4 17.4%	2 9.5%
Censored	14 60.9%	16 76.2%

2. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall Survival is defined as the time from randomization until death to any cause. For subjects in which treatment is discontinued for reasons different than Progression Disease: after treatment and up to documentation of disease progression: Overall Survival is assessed every 12 weeks
Time Frame	Under treatment: every 4 wks up to 9 months (average) for subject in the Arm A or up to 14 months (average) for subjects in Arm B. After documentation of disease progression up to the end of the study: every 6 months up to 42 months

Outcome Measure Data

Analysis Population Description

The timeframe specifies when tumor assessments were performed. Enrollment was closed prematurely due to low recruitment (only 44 participants enrolled) compared to what was initially planned (150 participants), therefore no statistical evaluations were completed (including OS).

Arm/Group Title	Arm A	Arm B
Arm/Group Description	Letrozole 2.5 mg	Letrozole 2.5 mg + Afatinib 30 mg
Measure Participants	18	18
Died	2 8.7%	0 0%
Censored	16 69.6%	18 85.7%

3. Secondary Outcome

Title	Objective Response Rate (ORR)
Description	Objective response rate (ORR) is defined as the proportion of randomized subjects achieving a best overall response of complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST). As per RECIST (version 1.1): CR is defined as disappearance of all target and non target lesions - lymph node (LN) <10mm. PR is defined as at least a 30% decrease in the Sum of Diameters, taking as reference the Baseline Sum of Diameters
Time Frame	Tumor assessment: every 12 weeks up to 9 months (average) for subjects in Arm A or up to 14 months (average) for subjects in Arm B.

Outcome Measure Data

Analysis Population Description

The timeframe specifies when tumor assessments were performed. Enrollment was closed prematurely due to low recruitment (only 44 participants enrolled) compared to what was initially planned (150 participants), therefore no statistical evaluations were completed (including ORR).

Arm/Group Title	Arm A	Arm B
Arm/Group Description	Letrozole 2.5 mg	Letrozole 2.5 mg + Afatinib 30 mg
Measure Participants	18	18
Complete Response (CR)	2 8.7%	1 4.8%
Death	2 8.7%	0 0%
Progessive Disease (PD)	2 8.7%	2 9.5%
Non-CR / Non-PD	12 52.2%	15 71.4%

4. Secondary Outcome

Title	Time to Tumor Progression (TTP)
Description	As per Response Evaluation Criteria In Solid Tumors (RECIST). Time to progression (TTP) is defined as the time interval from date of randomization to date of the first documented objective tumor progression.
Time Frame	Tumor assessments: every 12 weeks up to 9 months (average) for subjects in Arm A or up to 14 months (average) for subjects in Arm B.

Outcome Measure Data

Analysis Population Description

The timeframe specifies when tumor assessments were performed. Enrollment was closed prematurely due to low recruitment (only 44 participants enrolled) compared to what was initially planned (150 participants), therefore data for TTP was not produced due to the small number of patients (evaluation would not produce meaningful data).

Arm/Group Title	Arm A	Arm B
Arm/Group Description	Letrozole 2.5 mg	Letrozole 2.5 mg + Afatinib 30 mg
Measure Participants	0	0

5. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	Participants who experienced at least one Treatment Emergent Adverse Event (TEAE) are presented. Participants with at least one serious TEAE, those who had at least one TEAE related to letrozole or afatinib (serious/non-serious), including participants who experienced a grade 3/4 TEAE, or who discontinued/died as a result of their TEAE are listed by treatment arm. Adverse events were tabulated by system organ class, preferred term and toxicity grade by treatment arm. For subjects in which treatment was discontinued for reasons different than progression of disease, the assessment was conducted every 12 weeks following treatment, and up to documentation of disease progression. ** Enrollment was closed prematurely due to low recruitment (only 44 participants enrolled) compared to what was initially planned (150 participants), therefore no statistical evaluations were completed. Adverse event data collected are described per arm but no statistical comparison was made.
Time Frame	Under treatment: every 4 wks up to 9 months (average) for subjects in Arm A or up to 14 months (average) for subjects in Arm B. After documentation of disease progression up to the end of the study: every 6 months up to 42 months

Outcome Measure Data

Analysis Population Description

Participants who experienced at least one Treatment Emergent Adverse Event (TEAE) are listed. Participants with at least one serious TEAE, those who had at least one TEAE related to letrozole or afatinib (serious/non-serious), including participants who experienced a grade 3/4 TEAE, or who discontinued/died as a result of their TEAE are presented.

Arm/Group Title	Arm A	Arm B
Arm/Group Description	Letrozole 2.5 mg	Letrozole 2.5 mg + Afatinib 30 mg
Measure Participants	23	21
Patient having at least one TEAE	16 69.6%	20 95.2%
Patient having at least one serious TEAE	5 21.7%	2 9.5%
At least one TEAE related to letrozole	6 26.1%	11 52.4%
At least one TEAE related to afatinib	0 0%	18 85.7%
At least one serious TEAE related to letrozole	0 0%	0 0%
At least one serious TEAE related to afatinib	0 0%	1 4.8%
Patient having at least one grade 3/4 TEAE	7 30.4%	3 14.3%
TEAE leading to discontinuation - letrozole	1 4.3%	1 4.8%
TEAE leading to discontinuation - afatinib	0 0%	1 4.8%
Fatal TEAE	0 0%	0 0%

Adverse Events

Time Frame	4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.
Arm/Group Title	Arm A		Arm B
Arm/Group Description	Letrozole 2.5 mg		Letrozole 2.5 mg + Afatinib 30 mg
All Cause Mortality
	Arm A		Arm B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/23 (8.7%)		0/21 (0%)
Serious Adverse Events
	Arm A		Arm B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/23 (21.7%)		2/21 (9.5%)
Gastrointestinal disorders
Enteritis	0/23 (0%)	0	1/21 (4.8%)	1
Haematemesis	1/23 (4.3%)	1	0/21 (0%)	0
Nausea	1/23 (4.3%)	1	0/21 (0%)	0
General disorders
Pyrexia	0/23 (0%)	0	1/21 (4.8%)	1
Hepatobiliary disorders
Cholecystitis acute	0/23 (0%)	0	1/21 (4.8%)	1
Infections and infestations
Cellulitis	1/23 (4.3%)	1	0/21 (0%)	0
Sepsis	1/23 (4.3%)	1	0/21 (0%)	0
Injury, poisoning and procedural complications
Multiple Fractures	1/23 (4.3%)	1	0/21 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal Cell Carcinoma	1/23 (4.3%)	1	0/21 (0%)	0
Malignant Melanoma in Situ	1/23 (4.3%)	1	0/21 (0%)	0
Nervous system disorders
Subarachnoid Haemorrhage	1/23 (4.3%)	1	0/21 (0%)	0
Other (Not Including Serious) Adverse Events
	Arm A		Arm B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/23 (69.6%)		20/21 (95.2%)
Gastrointestinal disorders
Diarrhoea	2/23 (8.7%)		15/21 (71.4%)
Nausea	3/23 (13%)		3/21 (14.3%)
Stomatitis	0/23 (0%)		6/21 (28.6%)
Abdominal Distension	1/23 (4.3%)		2/21 (9.5%)
General disorders
Fatigue	1/23 (4.3%)		6/21 (28.6%)
Infections and infestations
Paronychia	0/23 (0%)		6/21 (28.6%)
Urinary Tract Infection	0/23 (0%)		5/21 (23.8%)
Upper Respiratory Tract Infection	3/23 (13%)		1/21 (4.8%)
Investigations
Weight Increased	2/23 (8.7%)		4/21 (19%)
Weight Decreased	2/23 (8.7%)		2/21 (9.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	4/23 (17.4%)		2/21 (9.5%)
Back Pain	4/23 (17.4%)		2/21 (9.5%)
Bone Pain	0/23 (0%)		4/21 (19%)
Musculoskeletal Pain	1/23 (4.3%)		2/21 (9.5%)
Myalgia	2/23 (8.7%)		1/21 (4.8%)
Skin and subcutaneous tissue disorders
Rash	1/23 (4.3%)		6/21 (28.6%)
Dry Skin	1/23 (4.3%)		5/21 (23.8%)
Dermatitis Acneiform	0/23 (0%)		4/21 (19%)
Pruritus	1/23 (4.3%)		3/21 (14.3%)
Alopecia	2/23 (8.7%)		1/21 (4.8%)

Limitations/Caveats

Enrolment was closed prematurely with only 44 participants enrolled compared to what was initially planned (150 participants). Thus, preventing appropriate statistical evaluation (primary/secondary objectives no longer applicable as per protocol).

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

No publication, abstract or presentation of the Study will be made without the approval of the Study Steering Committee (SCC). The SSC will be solely responsible for the analysis, interpretation and public disclosure of the results of the trial in accordance with the statistical plan.