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

Phase 2

Terminated

Conditions: Cancer

Interventions: Drug: Lapatinib
Drug: Capecitabine
Drug: Octreotide

Registration Number: NCT02294786

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: Female

Target Recruitment: 62

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:
1. 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);
2. 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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
No Octreotide treatment	Lapatinib	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
Octreotide treatment	Capecitabine	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.
Octreotide treatment	Lapatinib	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.
Octreotide treatment	Octreotide	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.
No Octreotide treatment	Capecitabine	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

Primary Outcome Measures

Name	Time	Method
Proportion of Subjects Experiencing Diarrhoea of Grade 2 and Above (up to 24 Weeks)	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)

Secondary Outcome Measures

Name	Time	Method
Proportion of Subjects Experiencing Diarrhoea of Grade 3 and Above (up to 24 Weeks)	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
Proportion of Subjects Experiencing Diarrhoea of Any Grade of Severity (up to 24 Weeks)	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
Time to Onset of the First Episode of Diarrhoea of Any Grade of Severity	Up to 24 weeks	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.
Duration of Diarrhoea of Any Grade of Severity	Up to 24 weeks	Duration of diarrhoea of any grade of severity, recorded as AEs in the eCRF
Proportion of Subjects Taking Anti-diarrhoeal Medication	Up to 24 weeks	Proportion of subjects taking anti-diarrhoeal medication as recorded in the eCRF
Proportion of Subjects Requiring Treatment Withdrawal in Lapatinib and Capecitabine	Up to 24 weeks	Proportion of subjects requiring diarrhoea related Lapatinib and Capecitabine treatment withdrawal as recorded in the eCRF
Proportion of Subjects Who Had Unscheduled Visits to Healthcare Professionals Due to Diarrhoea	Up to 24 weeks	Proportion of subjects making diarrhoea related unscheduled visits to healthcare professionals as recorded in the eCRF
Proportion of Subjects Requiring Dose Reduction in Lapatinib and Capecitabine	Up to 24 weeks	Proportion of subjects requiring diarrhoea related Lapatinib and Capecitabine dose reduction as recorded in the eCRF
Proportion of Subjects Requiring Dose Delay in Lapatinib and Capecitabine	Up to 24 weeks	Proportion of subjects requiring diarrhoea related Lapatinib and Capecitabine dose delay as recorded in the eCRF
Proportion of Subjects Requiring Use of Diarrhoea-related Intravenous Fluids	Up to 24 weeks	Proportion of subjects requiring use of diarrhoea-related intravenous fluids for rehydration as recorded in the eCRF
Number of Lapatinib and Capecitabine Tablets Dispensed and Returned	Up to 24 weeks	Number of Lapatinib and Capecitabine tablets dispensed and returned as recorded in the eCRF
Overall Response Rate (up to 24 Weeks)	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.
Clinical Benefit Response (up to 24 Weeks)	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.
Proportion of Subjects Reporting Changes in Bowel Movements From Baseline (Frequency and/or Consistency) as Recorded in the Diarrhoea Management Diary (DMD)	Up to 24 weeks	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.
Time to the First Subject Reported Change in Frequency and/or Consistency of Bowel Movements From Baseline as Recorded in the DMD	Up to 24 weeks	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.
Proportion of Subjects Reporting Stopping Completely or Missing Doses of Anti-cancer Tablets Due to Diarrhoea as Recorded in the DMD	Up to 24 weeks	The proportion of subjects reducing or completely stopping the number of anti-cancer tablets to help with diarrhoea are summarised
Proportion of Subjects Taking Anti-diarrhoeal Medication as Recorded in the DMD	Up to 24 weeks	The proportion of subjects taking medication at least once as a result of diarrhoea are summarised
Proportion of Subjects Making Dietary Changes Due to Diarrhoea as Recorded in the DMD	Up to 24 weeks	The proportion of subjects making dietary changes to help with the diarrhoea are summarised
Proportion of Subjects Contacting Other Non-hospital Healthcare Professionals to Discuss Diarrhoea as Recorded in the DMD	Up to 24 weeks	The proportion of subjects contacting a health care professional other than the hospital doctors/nurses to discuss diarrhoea are summarised