ALERT: A Phase II Study of Alternating Eribulin and Hormonal Therapy in Pre-treated ER+ve Breast Cancer.

• Sponsor: Imperial College London (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02681523
• Collaborator: (none)
• Enrollment: 8
• Location: 1
• Arm: 1
• Actual Duration (Months): 32.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

A single centre, single arm phase II study of alternating eribulin and hormonal therapy in 12 patients with locally advanced or metastatic breast cancer who have received at least one hormonal therapy and at least one chemotherapy in the metastatic setting.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Eribulin	Phase 2

Detailed Description

12 patients with locally advanced or metastatic breast cancer who have received at least one hormonal therapy and at least one chemotherapy in the metastatic setting will be enrolled to receive treatment. Once patients are consented and have completed on study screening, eribulin and Aromatase Inhibitor (AI) treatment will be alternated for up to 9 months, until disease progression or unacceptable toxicities, whichever is sooner. Patients will then attend a safety follow-up visit 4 weeks after completing treatment.

Eribulin (Halaven®) is a non-taxane microtubule dynamics inhibitor. Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and sequesters tubulin into non-productive aggregates. Eribulin exerts its effects via a tubulin-based antimitotic mechanism leading to G2/M cell-cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death after prolonged mitotic blockage.

Eribulin is licenced for the treatment of patients with locally advanced or metastatic breast cancer who have previously received at least one chemotherapeutic regimen for the treatment of advanced disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting unless patients were not suitable for these treatments.

The aim of this study is to alternate eribulin and aromatase inhibitors, examining whether there may be breakthrough relapse during the AI therapy or on the other hand we can extend the duration that eribulin may be used for. Importantly, blood based biomarkers, the tumour derived fraction of circulating free DNA (cfDNA) termed circulating tumor DNA (ctDNA), and circulating tumour cells will be measured. A major aim of this study is to test whether biomarkers fluctuate between chemotherapy and AI treatment in the setting of advanced breast cancer.

Study Design

• Study Type: Interventional
• Actual Enrollment: 8 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: ALERT: A Phase II Study of Alternating Eribulin and Hormonal Therapy in Pre-treated ER+ve Breast Cancer.
• Actual Study Start Date: Oct 28, 2015
• Actual Primary Completion Date: Jul 24, 2018
• Actual Study Completion Date: Jul 24, 2018

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Single arm study 3 x 3 weekly cycles at the recommended dose of eribulin as the ready to use solution, 1.23 mg/m2, administered intravenously over 2-5 minutes on days 1 and 8 of every 21 day cycle. This will then be followed by 9 weeks of AI treatment, to be followed again by 3 x 3 weekly cycles of eribulin and 9 weeks AI treatment. Patients will remain on treatment for up to 9 months, or until disease progression or unacceptable toxicities, whichever is sooner.

Drug: Eribulin; Other Names: Halaven

Outcome Measures

Primary Outcome Measures

1. Estimated Kaplan-Meier Progression Free Survival as Assessed by RECIST v1.1 [Fixed timepoints - 3, 6 and 9 months]

   Estimated Kaplan-Meier Progression free survival (PFS) to be defined as time from study entry to first evidence of disease progression or death due to any cause, as assessed by RECIST v1.0.

Secondary Outcome Measures

1. Clinical Benefit Rate as Assessed by RECIST v1.1 [To be assessed at 3, 6 and 9 months.]

   Clinical benefit rate (CBR), defined as the proportion of patients whose best overall response according to Response Evaluation Criteria in Solid Tumours (RECIST), v1.0 is either a complete response, partial response or stable disease for a least 6 months.

2. Safety and Tolerability [Collected form consent to follow-up]

   Safety and Tolerability were assessed by adverse events (AEs) and serious adverse events (SAEs) according the Common Terminology Criteria for Adverse Event (NCI-CTCAE) v4.03.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• 1. Written informed consent prior to admission to this study
• 1. Aged 18≥over
• 1. Histologically confirmed ER+ve metastatic breast cancer according to local criteria
• 1. Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2
• 1. Have progressed after at least one hormonal therapy regime and at least one chemotherapy regime for advanced disease
• 1. Patients must have had prior treatment with an anthracycline and a taxane (either sequential or in combination) unless patients were not suitable for these treatments. This treatment can be in the adjuvant setting
• 1. Measurable sites of locally advanced and/or metastatic disease that can be accurately assessed by CT/MRI scan at baseline (RECIST v1.1)¹
• 1. Life expectancy of ≥6 months
• 1. Adequate organ function, as defined by:

• Haemoglobin (Hb) ≥ 9 g/dL

• Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L

• Platelet count (Plts) ≥ 100 x 109/L

• White Blood Cell (WBC) ≥ 3.0 x 109/L

• Serum albumin ≤ 1.5 Upper Limit of Normal (ULN)

• Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 3 x ULN if no demonstrable liver metastases or ≤ 5 x ULN in the presence of liver metastases.

• Alkaline Phosphatase Level (ALP) ≤ 5 x ULN

• Total bilirubin ≤ 1.5 x ULN if no demonstrable liver metastases or ≤ 3 x ULN in the presence of liver metastases

• Creatinine ≤ 1.5 x ULN or creatinine clearance >50ml/min

• 1. Postmenopausal as defined by age >50, no menstruation for >2 years, previous oophorectomy or lab results confirming this status
• 1. Premenopausal if has been subject to ovarian ablation/ suppression at least 3 weeks prior to commencing AI therapy

• RECIST v1.1 updated and now considers bone metastasis with an identifiable soft tissue mass to be measurable disease. Therefore, patients with bone metastasis are eligible, provided they have evaluable disease.

Exclusion Criteria:

• 1.Triple negative or Human Epidermal Growth Factor Receptor 2 (HER2) positive cancer

• 1. Hypersensitivity to the active substance or to any of its excipients
• 1. History of another primary malignancy within 5 years prior to starting study treatment, except adequately treated basal or squamous cell carcinoma of the skin, carcinoma in site and the disease under study
• 1. Evidence of uncontrolled active infection
• 1. Severe hepatic impairment (Child-Pugh C)
• 1. Evidence of significant medical condition or laboratory finding which, in the opinion of the Investigator, makes it undesirable for the patient to participate in the trial
• 1. Concurrent therapy with any other investigational agent or everolimus
• 1. Concomitant use within 14 days prior to commencement of study treatment of any investigational agent
• 1. Uncontrolled abnormalities of serum potassium, sodium, calcium (corrected) phosphate or magnesium levels
• 1. Pregnant or lactating women. Effective non-hormonal contraception is mandatory for all patients of reproductive potential
• 1. Evidence of ovarian activity
• 1. Prior eribulin therapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Charing Cross Hopsital	London		United Kingdom	W6 8RF

Sponsors and Collaborators

• Imperial College London

Investigators

• Principal Investigator: Laura Kenny, Consultant Medical Oncologist

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 21, 2017

More Information

Publications

None provided.

• Responsible Party: Imperial College London
• ClinicalTrials.gov Identifier: NCT02681523
• Other Study ID Numbers: C/31/2014; 2014-004112-11
• First Posted: Feb 12, 2016
• Last Update Posted: Feb 5, 2021
• Last Verified: Jan 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Imperial College London: Breast Cancer
• Additional relevant MeSH terms: Breast Neoplasms

Study Results

Participant Flow

Recruitment Details	This was a pilot of proof study recruiting 8 breast cancer patients over a 2 year period from the Charing Cross Hospital, London. The last patient completed in July 2018.
Pre-assignment Detail	Of the 58 patients screened, during the period between February 2016 and July 2018, 13 patients were consented to the study; and upon screening, 8 were recruited to receive study treatment, eribulin1.23mg/m2 on day 1 and day 8 of 21 day cycles, alternated with an aromatase inhibitor (AI), orally once daily for 9 weeks.

Arm/Group Title	Single Arm Study
Arm/Group Description	3 x 3 weekly cycles at the recommended dose of eribulin as the ready to use solution, 1.23 mg/m2, administered intravenously over 2-5 minutes on days 1 and 8 of every 21 day cycle. This was then followed by 9 weeks of an Aromatase Inhibitor (AI) treatment (either letrozole, exemestane or anastrozole), followed again by 3 x 3 weekly cycles of eribulin and 9 weeks AI treatment. Patients remained on treatment for up to 9 months, or until disease progression or unacceptable toxicities, whichever was sooner.
Period Title: Overall Study
STARTED	8
COMPLETED	6
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Single Arm Study
Arm/Group Description	3 x 3 weekly cycles at the recommended dose of eribulin as the ready to use solution, 1.23 mg/m2, administered intravenously over 2-5 minutes on days 1 and 8 of every 21 day cycle. This will then be followed by 9 weeks of AI treatment, to be followed again by 3 x 3 weekly cycles of eribulin and 9 weeks AI treatment. Patients will remain on treatment for up to 9 months, or until disease progression or unacceptable toxicities, whichever is sooner.
Overall Participants	8
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	8 100%
>=65 years	0 0%
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	50
Sex: Female, Male (Count of Participants)
Female	8 100%
Male	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	6 75%
Middle Eastern	1 12.5%
Turkish	1 12.5%
Mixed	0 0%
Asian	0 0%
Black	0 0%
Region of Enrollment (participants) [Number]
United Kingdom	8 100%
Eastern Cooperative Oncology Group (ECOG) Performance Status (Count of Participants)
ECOG Performamce Status 0	4 50%
ECOG Performamce Status 1	4 50%
ECOG Performamce Status 2	0 0%
ECOG Performamce Status 3	0 0%
ECOG Performamce Status 4	0 0%
ECOG Performamce Status 5	0 0%
Smoking Status (Count of Participants)
Never	3 37.5%
Former	3 37.5%
Current	1 12.5%
No Information	1 12.5%
Tumour Type (Count of Participants)
Invasive Ducal Carcinoma	8 100%
Other Tumour type	0 0%
Oestrogen Receptor (ER) Status Assessment Method (Count of Participants)
Allred	3 37.5%
Other	5 62.5%
Progesterone Receptors (PgR) Status (Count of Participants)
Positive	7 87.5%
Negative	0 0%
Unknown	1 12.5%
Human Epidermal Growth Factor Receptor 2 (HER2) Status (Count of Participants)
Zero	5 62.5%
1+	1 12.5%
2+	0 0%
3+	0 0%
Not measured	2 25%
Primary Tumour Stage (Count of Participants)
Stage I	1 12.5%
Stage IIA	1 12.5%
Stage IIIA	1 12.5%
Stage IIIC	1 12.5%
No information	4 50%
Primary Tumour Grade (Count of Participants)
Grade 1	1 12.5%
Grade 2	5 62.5%
Grade 3	2 25%
Prior Chemotherapy (Count of Participants)
Yes	8 100%
No	0 0%
Prior Radiotherapy (Count of Participants)
Yes	8 100%
No	0 0%
Prior Surgery (Count of Participants)
Yes	8 100%
No	0 0%
Prior Endocrine Therapy (participants) [Number]
Tamoxifen	8 100%
Exemestane	5 62.5%
Letrozole	3 37.5%
Anastrozole	5 62.5%
Body Mass Index (kg/m^2) [Median (Full Range) ]
Median (Full Range) [kg/m^2]	26.5
Primary Tumour Size (millimeteres (mm)) [Median (Full Range) ]
Median (Full Range) [millimeteres (mm)]	28

Outcome Measures

1. Primary Outcome

Title	Estimated Kaplan-Meier Progression Free Survival as Assessed by RECIST v1.1
Description	Estimated Kaplan-Meier Progression free survival (PFS) to be defined as time from study entry to first evidence of disease progression or death due to any cause, as assessed by RECIST v1.0.
Time Frame	Fixed timepoints - 3, 6 and 9 months

Outcome Measure Data

Analysis Population Description

PFS was measured at fixed time points of 3, 6 and 9 months, as estimated by the Kaplan-Meier curve. The median PFS at the end of the study was 235 days. PFS could not be calculated at 3 months, as no patient experienced disease progression at follow-up.

Arm/Group Title	Single Arm Study
Arm/Group Description	3 x 3 weekly cycles at the recommended dose of eribulin as the ready to use solution, 1.23 mg/m2, administered intravenously over 2-5 minutes on days 1 and 8 of every 21 day cycle. This will then be followed by 9 weeks of AI treatment, to be followed again by 3 x 3 weekly cycles of eribulin and 9 weeks AI treatment. Patients will remain on treatment for up to 9 months, or until disease progression or unacceptable toxicities, whichever is sooner.
Measure Participants	8
3 months	NA
6 months	202
9 months	235

2. Secondary Outcome

Title	Clinical Benefit Rate as Assessed by RECIST v1.1
Description	Clinical benefit rate (CBR), defined as the proportion of patients whose best overall response according to Response Evaluation Criteria in Solid Tumours (RECIST), v1.0 is either a complete response, partial response or stable disease for a least 6 months.
Time Frame	To be assessed at 3, 6 and 9 months.

Outcome Measure Data

Analysis Population Description

Only 6 patients had at least one tumour assessment during the study period.

Arm/Group Title	Single Arm Study
Arm/Group Description	3 x 3 weekly cycles at the recommended dose of eribulin as the ready to use solution, 1.23 mg/m2, administered intravenously over 2-5 minutes on days 1 and 8 of every 21 day cycle. This will then be followed by 9 weeks of AI treatment, to be followed again by 3 x 3 weekly cycles of eribulin and 9 weeks AI treatment. Patients will remain on treatment for up to 9 months, or until disease progression or unacceptable toxicities, whichever is sooner.
Measure Participants	6
Complete Response	0 0%
Partial response	3 37.5%
Stable Disease	3 37.5%

3. Secondary Outcome

Title	Safety and Tolerability
Description	Safety and Tolerability were assessed by adverse events (AEs) and serious adverse events (SAEs) according the Common Terminology Criteria for Adverse Event (NCI-CTCAE) v4.03.
Time Frame	Collected form consent to follow-up

Outcome Measure Data

Analysis Population Description

AEs and SAEs were collected for all 8 subjects who received at least one dose of study treatment

Arm/Group Title	Single Arm Study
Arm/Group Description	3 x 3 weekly cycles at the recommended dose of eribulin as the ready to use solution, 1.23 mg/m2, administered intravenously over 2-5 minutes on days 1 and 8 of every 21 day cycle. This will then be followed by 9 weeks of AI treatment, to be followed again by 3 x 3 weekly cycles of eribulin and 9 weeks AI treatment. Patients will remain on treatment for up to 9 months, or until disease progression or unacceptable toxicities, whichever is sooner.
Measure Participants	8
Measure Events	129
Mild	71
Moderate	39
Severe	17
Life Threatening or disabling	2
Death	0

Adverse Events

Time Frame	Collected from consent to follow-up for all subjects who receive at least one dose of study treatment, 9 months.
Arm/Group Title	Single Arm Study
Arm/Group Description	3 x 3 weekly cycles at the recommended dose of eribulin as the ready to use solution, 1.23 mg/m2, administered intravenously over 2-5 minutes on days 1 and 8 of every 21 day cycle. This will then be followed by 9 weeks of AI treatment, to be followed again by 3 x 3 weekly cycles of eribulin and 9 weeks AI treatment. Patients will remain on treatment for up to 9 months, or until disease progression or unacceptable toxicities, whichever is sooner.
All Cause Mortality
	Single Arm Study
	Affected / at Risk (%)	# Events
Total	0/8 (0%)
Serious Adverse Events
	Single Arm Study
	Affected / at Risk (%)	# Events
Total	5/8 (62.5%)
Gastrointestinal disorders
Vomiting	1/8 (12.5%)	1
General disorders
Mucositis	1/8 (12.5%)	1
Infections and infestations
Neutopenic Sepsis	2/8 (25%)	2
Metabolism and nutrition disorders
Hypercalcemia	1/8 (12.5%)	1
Nervous system disorders
Ischaemia cerebrovascular	1/8 (12.5%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/8 (12.5%)	1
Respiratory distress syndrome	1/8 (12.5%)	1
Other (Not Including Serious) Adverse Events
	Single Arm Study
	Affected / at Risk (%)	# Events
Total	8/8 (100%)
Blood and lymphatic system disorders
Lymphadenopathy	2/8 (25%)	2
Neutropenia	1/8 (12.5%)	2
Cardiac disorders
Palpitations	1/8 (12.5%)	1
Ear and labyrinth disorders
Ear pain	2/8 (25%)	2
Gastrointestinal disorders
Abdominal distension	3/8 (37.5%)	3
Abdominal pain upper	1/8 (12.5%)	1
Abdominal pain	2/8 (25%)	2
Ascites	1/8 (12.5%)	1
Constipation	4/8 (50%)	4
Diarrhoea	1/8 (12.5%)	1
Dry mouth	1/8 (12.5%)	1
Dyspepsia	1/8 (12.5%)	1
Heartburn/burping	1/8 (12.5%)	1
Melaena	1/8 (12.5%)	1
Mouth ulceration	2/8 (25%)	2
Nausea	4/8 (50%)	4
Oral pain	1/8 (12.5%)	1
Rectal haemorrhage	1/8 (12.5%)	1
Teeth and gum darkening	1/8 (12.5%)	1
Teeth and gum thinning	1/8 (12.5%)	1
Vomiting	1/8 (12.5%)	1
General disorders
Fatigue	5/8 (62.5%)	6
Influenza like illness	1/8 (12.5%)	1
Mucosal inflammation gg	1/8 (12.5%)	1
Oedema peripheral	1/8 (12.5%)	1
Pain	3/8 (37.5%)	4
Peripheral swelling	3/8 (37.5%)	3
Pyrexia	2/8 (25%)	2
Hepatobiliary disorders
Hepatic pain	1/8 (12.5%)	1
Hepatomegaly	2/8 (25%)	2
Infections and infestations
Ear infection	2/8 (25%)	2
Neutropenic sepsis	2/8 (25%)	2
Oral herpes	1/8 (12.5%)	1
Vaginal infection	1/8 (12.5%)	1
Investigations
Alanine aminotransferase increased	2/8 (25%)	2
Aspartate aminotransferase	2/8 (25%)	2
Blood alkaline phosphatase	1/8 (12.5%)	1
Blood cholesterol increased	1/8 (12.5%)	1
Grip strength decreased	1/8 (12.5%)	1
Neutrophil count decreased	1/8 (12.5%)	1
Platelet count decreased	1/8 (12.5%)	1
Weight decreased	1/8 (12.5%)	1
White blood cell count decreased	1/8 (12.5%)	1
Metabolism and nutrition disorders
Decreased appetite	1/8 (12.5%)	1
Diabetes mellitus	1/8 (12.5%)	1
Hypercalcaemia	1/8 (12.5%)	1
Hypoalbuminaemia	1/8 (12.5%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	3/8 (37.5%)	3
Back pain	2/8 (25%)	2
Muscle spasms	1/8 (12.5%)	1
Musculoskeletal pain	1/8 (12.5%)	2
Pain in jaw	1/8 (12.5%)	1
Nervous system disorders
Ageusia	2/8 (25%)	2
Diziness	2/8 (25%)	2
Headache	1/8 (12.5%)	1
Neuropathy peripheral	4/8 (50%)	4
Paraesthesia	1/8 (12.5%)	1
Sciatica	1/8 (12.5%)	1
Cognitive disorder	1/8 (12.5%)	1
Respiratory, thoracic and mediastinal disorders
Cough	3/8 (37.5%)	3
Dyspnoe	4/8 (50%)	6
Nasopharyngitis	1/8 (12.5%)	1
Oropharyngeal pain	1/8 (12.5%)	1
Pleural effusion	2/8 (25%)	2
Tonsillar erythema	1/8 (12.5%)	1
Skin and subcutaneous tissue disorders
Alopecia	6/8 (75%)	6
Hyperhidrosis	1/8 (12.5%)	1
Pruritus	1/8 (12.5%)	1
Skin striae	1/8 (12.5%)	1
Vascular disorders
Flushing	2/8 (25%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.