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
Condition: Cancer
MeSH terms: Diarrhea
Intervention: Lapatinib; Capecitabine; Octreotide
Intervention description: 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; 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.; 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
Intervention MeSH terms: Capecitabine; Lapatinib; Octreotide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 62.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Randomised; Octreotide; Diarrhoea; Phase II; Capecitabine; Quality of life; Metastatic breast cancer; HER2; Lapatinib; Diarrhoea diary

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.
    

Eligibility criteria:

        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