Study of Prophylactic Octreotide to Prevent or Reduce the Frequency and Severity of Diarrhoea in Subjects Receiving Lapatinib With Capecitabine for the Treatment of Metastatic Breast Cancer

Study Overview
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Brief Summary
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Diarrhoea is the most commonly reported adverse event (AE) associated with Lapatinib treatment, and is also commonly associated with Capecitabine treatment. Although these events are generally mild to moderate in severity, diarrhoea adversely affects the tolerability of cancer treatment, and in severe cases diarrhoea has the potential to affect the efficacy of treatment due to poor compliance, or treatment interruption or withdrawal. The efficacy of Octreotide in the management of cancer treatment-associated diarrhoea has not been extensively evaluated in large, well-controlled studies. This is a randomised, multi-centre, open-label Phase II study in subjects with Human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer which has progressed following prior therapy, which must have included anthracyclines and taxanes and therapy with Trastuzumab in the metastatic setting. This study is not placebo controlled, and there is no active comparator. The study evaluates whether the prophylactic use of Octreotide Long Acting Release (LAR) offers a clinically meaningful benefit by reducing the frequency and severity of diarrhoea associated with treatment with Lapatinib and Capecitabine. Study completion for a subject is defined as the completion of 24 weeks of treatment with Lapatinib and Capecitabine, or progression of cancer or the death of the subject during treatment, whichever occurs first. Approximately 140 subjects were planned to be randomized out of which 70 were planned to receive octreotide and 70 were planned to receive no Octreotide.

Official Title
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A Randomised, Multicentre, Open Label, Phase II Study of Prophylactic Octreotide to Prevent or Reduce the Frequency and Severity of Diarrhoea in Subjects Receiving Lapatinib With Capecitabine for the Treatment of Metastatic Breast Cancer

Conditions
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Cancer

Intervention / Treatment
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* Drug: Lapatinib
* Drug: Capecitabine
* Drug: Octreotide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent Histologically or cytologically confirmed HER2-positive advanced or metastatic breast cancer which has progressed following prior therapy, which must have included anthracyclines and taxanes and therapy with trastuzumab in the metastatic setting Females age >=18 years old Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Life expectancy of at least 12 weeks Able to swallow and retain oral medications Incapable of becoming pregnant, or not pregnant and using an adequate form of contraception, i.e. a female who is of: non-childbearing potential (physiologically incapable of becoming pregnant), including any female who has had hysterectomy, bilateral oophorectomy, bilateral tubular ligation or is post-menopausal (total cessation of menses for at least 1 year); childbearing potential must have a negative serum pregnancy test within 7 days prior to treatment with Octreotide if randomised to receive Octreotide or the first dose of Lapatinib with Capecitabine if randomised to receive no Octreotide, preferably as close to the first dose as possible, and must agree to use adequate contraception (intrauterine device, birth control pills unless clinically contraindicated, or barrier device) and other acceptable contraceptive methods during the study and continuing for at least 4 weeks after the final dose of treatment with Lapatinib and Capecitabine Subjects must complete all screening assessments as outlined in the protocol Subjects must complete the Functional Assessment of Chronic Illness Therapy-Diarrhoea (FACIT-D) and diarrhoea diary before receiving the first dose of Octreotide if randomised to receive Octreotide. All subjects must complete the FACIT-D and diarrhoea diary before receiving the first dose of Lapatinib with Capecitabine Prior treatment with other chemotherapeutic agents or endocrine therapy is permitted. All prior treatment related toxicities, except diarrhoea and alopecia, must be National Cancer Institute common terminology criteria for adverse events (NCI CTCAE) (version 4.03)<= Grade 1 at the time of randomization.Subjects with diarrhoea with any grade of severity within 14 days prior to randomisation are excluded from LAP117314 Prior treatment with radiation therapy is permitted provided that at least 2 weeks have elapsed since the last fraction of radiation therapy prior to treatment with Octreotide if randomised to receive Octreotide or the first dose of Lapatinib with Capecitabine if randomised to receive no Octreotide, and all radiation therapy related AEs are <= Grade 1 at the time of randomization French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category Exclusion Criteria: Concurrent treatment with an investigational agent or concurrent participation in another clinical study Administration of an investigational drug within 30 days or 5 half-lives, whichever is longer, prior to treatment with Octreotide for subjects randomised to receive Octreotide or the first dose of Lapatinib and Capecitabine for subjects randomised to receive no Octreotide Treatment with Octreotide within the 3 months prior to randomization Concurrent chemotherapy, radiation therapy, immunotherapy, biologic therapy (including an Epidermal growth factor receptor (EGFR) and/or HER2 inhibitor), or hormonal therapy for treatment of cancer Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent, unless a legally acceptable representative could provide informed consent (if in accordance with the policies of the local Ethics Committee) Concurrent disease or condition that would make the subject inappropriate for study participation or any serious medical or psychiatric disorder that would interfere with the subject's safety or compliance with study procedures Diarrhoea with any grade of severity within 14 days prior to treatment with Octreotide for subjects randomised to receive Octreotide or within 14 days prior to the first dose of Lapatinib and Capecitabine for subjects randomised to receive no Octreotide Malabsorption syndrome, inflammatory bowel disease (ulcerative colitis, Chrohn's disease), irritable bowel syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel Pregnant or lactating subjects Prior treatment with Lapatinib French subjects: the French subject has participated in any study using an investigational drug during the previous 30 days or 5 half-lives, whichever is longer, preceding the first dose of protocol treatment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Octreotide treatment<br>Subjects randomised to receive Octreotide were administered with Octreotide (Sandostatin LAR™) 40mg 7 days before the start of treatment with Lapatinib and Capecitabine and again 28 days later. All subjects received treatment with Lapatinib 1250milligram (mg) once daily and Capecitabine 1000 milligram/square meter (mg/m^2) twice daily until disease progression. Lapatinib was given every day; Capecitabine was given in 3 week cycles of two weeks treatment followed by one week off treatment. SANDOSTATIN™ is a trademark of Novartis. | Drug: Lapatinib<br>* Lapatinib was supplied as 250mg tablets that are oval, biconvex, and orange film-coated with one side plain and the opposite side debossed, or as 250mg tablets that are oval, biconvex, and yellow film-coated with one side plain and the opposite side debossed. Each tablet contained 405mg of Lapatinib ditosylate monohydrate, equivalent to 250mg Lapatinib free base<br>Drug: Capecitabine<br>* Capecitabine (Xeloda™) was supplied as a biconvex, oblong, light peach or peach colored film-coated tablet for oral administration. Each light peach colored tablet contained 150mg Capecitabine and each peach colored tablet contained 500mg Capecitabine. Generic versions of capecitabine may have been used within the study if Xeloda cannot be provided. XELODA™ is a trademark of Hoffmann-La Roche AG.<br>Drug: Octreotide<br>* Octreotide (Sandostatin LAR™) was supplied as sterile 5milliliter (mL) vials delivering 20mg Octreotide as the free peptide. When mixed with diluent (approximately 2mL or 2.5 mL) it becomes a suspension that is given as an intramuscular injection. Two 20mg intramuscular injections were given to deliver a total dose of 40mg. The Octreotide is uniformly distributed within the microspheres which are made of a biodegradable glucose star polymer, D,L-lactic and glycolic acids copolymer. Sterile mannitol was added to the microspheres to improve suspendability<br>|
| Experimental: No Octreotide treatment<br>Subjects randomised to receive no octreotide, treatment with Lapatinib and Capecitabine was initiated immediately following enrolment. All subjects received treatment with Lapatinib 1250mg once daily and Capecitabine 1000mg/m^2 twice daily until disease progression. Lapatinib was given every day; Capecitabine was given in 3 week cycles of two weeks treatment followed by one week off treatment | Drug: Lapatinib<br>* Lapatinib was supplied as 250mg tablets that are oval, biconvex, and orange film-coated with one side plain and the opposite side debossed, or as 250mg tablets that are oval, biconvex, and yellow film-coated with one side plain and the opposite side debossed. Each tablet contained 405mg of Lapatinib ditosylate monohydrate, equivalent to 250mg Lapatinib free base<br>Drug: Capecitabine<br>* Capecitabine (Xeloda™) was supplied as a biconvex, oblong, light peach or peach colored film-coated tablet for oral administration. Each light peach colored tablet contained 150mg Capecitabine and each peach colored tablet contained 500mg Capecitabine. Generic versions of capecitabine may have been used within the study if Xeloda cannot be provided. XELODA™ is a trademark of Hoffmann-La Roche AG.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Subjects Experiencing Diarrhoea of Grade 2 and Above (up to 24 Weeks) | Proportion of subjects experiencing at least one episode of diarrhoea with a severity of Grade 2 and above, as defined by the National Cancer Institute common terminology criteria for adverse events (NCI CTCAE) version 4.03, recorded as AEs in the Electronic case report form (eCRF) | Up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Subjects Experiencing Diarrhoea of Grade 3 and Above (up to 24 Weeks) | Proportion of subjects experiencing diarrhoea with a severity of Grade 3 and above, as defined by the NCI CTCAE, version 4.03 and recorded as AEs in the eCRF | Up to 24 weeks | 
| Proportion of Subjects Experiencing Diarrhoea of Any Grade of Severity (up to 24 Weeks) | Proportion of subjects experiencing diarrhoea of any grade of severity as defined by the NCI CTCAE, version 4.03 and recorded as AEs in the eCRF | Up to 24 weeks | 
| Duration of Diarrhoea of Any Grade of Severity | Duration of diarrhoea of any grade of severity, recorded as AEs in the eCRF | Up to 24 weeks | 
| Time to Onset of the First Episode of Diarrhoea of Any Grade of Severity | Time to onset of the first episode of diarrhoea of any grade of severity, recorded as an AE in the eCRF. Subject are censored if there was no event. Median time and 95% confidence intervals were calculated using Kaplan-Meier estimates. | Up to 24 weeks | 
| Proportion of Subjects Taking Anti-diarrhoeal Medication | Proportion of subjects taking anti-diarrhoeal medication as recorded in the eCRF | Up to 24 weeks | 
| Proportion of Subjects Who Had Unscheduled Visits to Healthcare Professionals Due to Diarrhoea | Proportion of subjects making diarrhoea related unscheduled visits to healthcare professionals as recorded in the eCRF | Up to 24 weeks | 
| Proportion of Subjects Requiring Dose Reduction in Lapatinib and Capecitabine | Proportion of subjects requiring diarrhoea related Lapatinib and Capecitabine dose reduction as recorded in the eCRF | Up to 24 weeks | 
| Proportion of Subjects Requiring Dose Delay in Lapatinib and Capecitabine | Proportion of subjects requiring diarrhoea related Lapatinib and Capecitabine dose delay as recorded in the eCRF | Up to 24 weeks | 
| Proportion of Subjects Requiring Treatment Withdrawal in Lapatinib and Capecitabine | Proportion of subjects requiring diarrhoea related Lapatinib and Capecitabine treatment withdrawal as recorded in the eCRF | Up to 24 weeks | 
| Proportion of Subjects Requiring Use of Diarrhoea-related Intravenous Fluids | Proportion of subjects requiring use of diarrhoea-related intravenous fluids for rehydration as recorded in the eCRF | Up to 24 weeks | 
| Number of Lapatinib and Capecitabine Tablets Dispensed and Returned | Number of Lapatinib and Capecitabine tablets dispensed and returned as recorded in the eCRF | Up to 24 weeks | 
| Overall Response Rate (up to 24 Weeks) | Overall response rate as measured in accordance with the Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) >=20% and >= 5mm increase in the sum of diameters of target lesions; Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. | Up to 24 weeks | 
| Clinical Benefit Response (up to 24 Weeks) | Clinical benefit response as measured in accordance with the Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1. Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Clinical Benefit Response rate (CBR) is defined as the percentage of subjects with a CR, PR or SD at week 24. | Up to 24 weeks | 
| Proportion of Subjects Reporting Changes in Bowel Movements From Baseline (Frequency and/or Consistency) as Recorded in the Diarrhoea Management Diary (DMD) | All subjects completed the baseline DMD during the 3 days prior to randomisation, before any study-related treatment is administered. Subjects randomised to receive Octreotide completed a second baseline DMD before starting the first cycle of treatment with Lapatinib and Capecitabine. The baseline DMD comprised of 3 questions to record stool form and consistency. The DMD to be completed throughout the rest of the study comprised of 3 questions in the baseline DMD and a further 5 questions and 6 sub-questions to evaluate the consequences and management of diarrhoea. | Up to 24 weeks | 
| Time to the First Subject Reported Change in Frequency and/or Consistency of Bowel Movements From Baseline as Recorded in the DMD | Event is defined as Subjects reporting change in frequency and/or consistency of bowel movements from baseline at least once in DMD. Subject are censored if there is no change in bowel movement frequency/consistency as compared to baseline. Median time and 95% confidence intervals were calculated using Kaplan-Meier estimates. | Up to 24 weeks | 
| Proportion of Subjects Taking Anti-diarrhoeal Medication as Recorded in the DMD | The proportion of subjects taking medication at least once as a result of diarrhoea are summarised | Up to 24 weeks | 
| Proportion of Subjects Making Dietary Changes Due to Diarrhoea as Recorded in the DMD | The proportion of subjects making dietary changes to help with the diarrhoea are summarised | Up to 24 weeks | 
| Proportion of Subjects Contacting Other Non-hospital Healthcare Professionals to Discuss Diarrhoea as Recorded in the DMD | The proportion of subjects contacting a health care professional other than the hospital doctors/nurses to discuss diarrhoea are summarised | Up to 24 weeks | 
| Proportion of Subjects Reporting Stopping Completely or Missing Doses of Anti-cancer Tablets Due to Diarrhoea as Recorded in the DMD | The proportion of subjects reducing or completely stopping the number of anti-cancer tablets to help with diarrhoea are summarised | Up to 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Randomised, Octreotide, Diarrhoea, Phase II, Capecitabine, Quality of life, Metastatic breast cancer, HER2, Lapatinib, Diarrhoea diary