"Curcumin" in Combination With Chemotherapy in Advanced Breast Cancer
Condition: Advanced Breast Cancer; Metastatic Breast Cancer
MeSH terms: Breast Neoplasms
Study type: Interventional
Phase: Phase 2

Summary: 
      The aim of this study is to assess benefits of treatment with intravenous Curcumin® (CUC-01)
      vs placebo, in combination with paclitaxel chemotherapy, and to estimate the risk of adverse
      events in patients with locally advanced and metastatic breast cancer.

      This is a randomized, double-blind, placebo-controlled, two arms parallel group phase 2
      clinical trial:

      Group A, 75 patients, treatment with Curcumin (CUC-01, yellow solution), 300mg i.v. plus i.v.
      Paclitaxel (colorless solution) 80 mg /m2 BS i.e., once weekly for 12 weeks.

      Group B, 75 patients, treatment with Paclitaxel (colorless solution) 80 mg /m2 BS, i.v. plus
      placebo i.v. solution (250 ml, yellow solution for masking/blinding), once weekly for 12
      weeks.

      Primary objective of the study:

      To assess:

        -  Efficacy of combined therapy with Curcumin ®, (CUC-01) and Paclitaxel vs Paclitaxel in
           patients with advanced and metastatic breast cancer in terms of Objective Response Rate
           (ORR) assessed with the Modified Response Evaluation Criteria In Solid Tumours (RECIST).

      Secondary objectives of the study:

      To assess:

        -  The safety of Curcumin+Paclitaxel combination compared to Paclitaxel+placebo treatment
           by assessment of adverse effects.

        -  Quality of life (QOL) in patient treated with Curcumin+Paclitaxel combination compared
           to Paclitaxel+Placebo

        -  Response duration in terms of Progression free survival (PFS), Time to Disease
           Progression (TTP) and Time to treatment failure (TTTF)
    

Detailed description: 
      RATIONALE

      Various preclinical, clinical, and animal studies suggest that curcumin has potential as an
      antiproliferative, anti-invasive, and antiangiogenic, as a mediator of chemoresistance,
      chemopreventive, and as a therapeutic agent. However, the main problem associated with the
      use of curcumin in humans is its low absorption from the gastrointestinal tract, poor
      solubility in body fluids and low bioavailability. To overcome the pharmacokinetic and
      bioavailability limitations of oral administration, water soluble curcumin, Curcumin®
      (CUC-01) injection, a clear, yellow viscous solution intended for dilution with a suitable
      parenteral fluid prior to intravenous infusion was elaborated. Curcumin® (CUC-01) injection
      is patented pharmacy product and sold per individual prescription in Germany and other
      countries for Cancer Centers. However, clinical efficacy and safety of these formulation have
      to be confirmed in this study.

      Development of multidrug resistance (MDR) against a variety of conventional and novel
      chemotherapeutic agents is a significant challenge in effective cancer therapy. Paclitaxel,
      one of the most prescribed conventional chemotherapeutic agents, acts as microtubule
      stabilizer and blocks cancer cells in the G2/M phase, thus preventing them from mitosis. It
      is also an apoptosis inducer in cancer cells. However, one of the main drawbacks of its use
      is that it is also a substrate of P-gp and treatment with PCL induces the overexpression of
      the efflux pump in the cancer cells. NF-κB is a transcription factor that controls the
      expression of genes involved in a number of physiological responses including
      differentiation, inflammation, apoptosis and upregulation of the P-gp. The PI3K/Akt pathway
      is also another over-activated pathway in a wide range of tumor types and therefore its
      over-activation leads to increased cancer-cell survival, proliferation, and growth and it
      also promotes NF-κB activity, all affects the success of the chemotherapy with Paclitaxel.
      Curcumin is known to downregulate both the PI3K/Akt and NF-κB pathways independent of each
      other, and thus it can act as a mediator of chemoresistance by sensitizing cancer cells to a
      conventional chemotherapeutic agents.

      It has been suggested that co-administration of Paclitaxel and curcumin will help to overcome
      multidrug resistance in cancer. Synergistic interaction of curcumin and paclitaxel was
      demonstrated in paclitaxel (Taxol)-resistant breast cancer cells, human breast cancer
      xenograft model, in MDA-MB-231 and MCF-7 human breast cancer cells and many other cancer cell
      lines. In vivo, this combination treatment produced a three-fold tumor inhibition with each
      of these cell lines. Furthermore, the combination of paclitaxel and curcumin exerted
      increased anti-tumor efficacy on mouse models These results clearly indicate combination of
      Curcumin with paclitaxel could have significant clinical advantages for the treatment of
      breast cancer.

      Curcumin exerted in vitro anti-breast cancer activities through regulation of matrix
      metalloproteinase (MMP)-2, B-cell lymphoma 2 (Bcl-2), Bax, flap endonuclease 1 (Fen1),
      NF-E2-related factor 2 (Nrf-2) factors, and phosphoinositide 3-kinase (PI3K)/protein kinase B
      (Akt) signaling.

      Therefore, and based on this evaluation, we intend examining the effect of Curcumin ®,
      (CUC-01) in advanced and metastatic breast cancer in this randomized, double-blind,
      placebo-controlled study.

      STUDY DESIGN

      This is a randomized, double-blind, placebo-controlled, two arms parallel group phase 2
      study:

      Group A, 75 patients, treatment with Curcumin (CUC-01, yellow solution), 300mg i.v. plus i.v.
      Paclitaxel (colorless solution) 80 mg /m2 BS i.e., once weekly for 12 weeks.

      Group B, 75 patients, treatment with Paclitaxel (colorless solution) 80 mg /m2 BS, i.v. plus
      placebo i.v. solution (250 ml, yellow solution for masking/blinding), once weekly for 12
      weeks.

      Therapy schedule weekly:

        -  Preload-infusion containing Dexamethasone 8 mg in 100ml NaCl

        -  Paclitaxel 80mg/m2 body surface in 250 ml 0.9% NaCl

        -  Curcumin 300 mg or placebo in 250ml 0.9% NaCl

      PRIMARY OBJECTIVE

      To assess:

        -  Efficacy of combined therapy with Curcumin ®, (CUC-01) and Paclitaxel vs Paclitaxel in
           patients with advanced and metastatic breast cancer in terms of Objective Response Rate
           (ORR)

      SECONDARY OBJECTIVES

      To assess:

        -  The safety of Curcumin+Paclitaxel combination compared to Paclitaxel+placebo treatment
           by assessment of adverse effects.

        -  Quality of life (QOL) in patient treated with Curcumin+Paclitaxel combination compared
           to Paclitaxel+Placebo

        -  Response duration in terms of Progression free survival (PFS), and Time to Disease
           Progression (TTP) and Time to treatment failure (TTTF)

      NUMBER OF SUBJECTS

      150

      TEST PRODUCT, DOSE, AND ROUTE OF ADMINISTRATION

      Curcumin® (CUC-01) injection, BRIU GmbH at dose 300 mg. Each vial contains 20 ml of the
      concentrate (concentration of Curcumin - 15 mg/ml) containing in total of 300 mg of Curcumin,
      which has to be diluted in 250 ml of physiological solution (0.9% NaCl) before use, total
      volume - 270 ml of infusion solution.

      Investigational Active Ingredients: Curcuminoids (syn: Curcumin, isolated from turmeric
      rhizome Curcuma longa, Zingiberaceae.

      CUC-01 will be administered intravenously (IV) once in every 7 days for 12 weeks.

      Therapy schedule weekly:

        -  Preload-infusion containing Dexamethasone 8 mg in 100ml NaCl

        -  Curcumin 300 mg in 250ml 0.9% NaCl

        -  Paclitaxel 80mg/m2 body surface in 250 ml o.9% NaCl

      CONTROL PRODUCT, DOSE AND ROUTE OF ADMINISTRATION

      Placebo: Riboflavin solution which has strong yellow-orange color and visually is not
      distinguishable from Curcumin.

      Placebo will be administered intravenously (IV) once in every 7 days for 12 weeks

      Therapy schedule weekly:

        -  Preload-infusion containing Dexamethasone 8 mg in 100ml NaCl

        -  Placebo(Riboflavin solution) in 250ml 0,9% NaCl

        -  Paclitaxel 80mg/m2 body surface in 250 ml 0.9% NaCl

      EFFICACY EVALUATIONS.

      Primary endpoint

      Primary outcome measures:

      Clinically, radiologically measurable disease, tumour markers:

        -  Objective response rate, assessed with the Modified Response Evaluation Criteria In
           Solid Tumours (RECIST) using plain radiographs, ultrasound imaging, computed tomography
           scans and magnetic resonance imaging. Other studies may be acceptable with the approval
           of the principal investigator.

        -  Carcinoembryonic antigen (CEA) assay and Cancer antigen15-3 (CA 15-3) assay

      Secondary endpoints.

      Secondary outcome measures:

        -  Adverse events and defined by National Cancer Institute (NCI) Common Toxicity Criteria
           Version 4.0 (CTCAE, v4.0≤)

        -  Quality of Life measures (EORTC QLQ-C30, Global Health Status/QoL scales)Response
           Duration measures:

        -  Progression free survival (PFS) assessed from study enrolment to tumour progression as
           per the Modified RECIST criteria or disease related

        -  Time to Treatment Failure (TTTF), assessed from study enrolment to cessation of study
           treatment for any reason

        -  Time to Tumour Progression (TTP), assessed from study enrolment to tumour progression as
           per the Modified RECIST criteria.

      Safety Evaluations

      Tolerability will be assessed by the nature and incidence of adverse events. Change in
      clinical safety labs from baseline to end of the study Incidence of adverse events, (CTCAE,
      v4.0≤).

      STATISTICS

      Statistical analysis will be performed on an intent-to-treat basis. Survival Analysis for
      time-to event endpoints.

      Assessment of baseline characteristics - between groups comparison will be made by:

        -  Kruskal-Wallis (KW) non-parametric one way ANOVA rank order test, with post hoc Dunn's
           Multiple Comparison Test or

        -  parametric One-way independent measures ANOVA with Dunnett's Multiple Comparison Test,

      Analysis of changes within treatment groups in the course of the study (before versus after)
      was performed by:

        -  paired t-test (parametric data - variables with normal distribution) or/and

        -  Wilcoxon signed rink test (nonparametric data), or

        -  Friedman test for repeated several measures (nonparametric data),

      Assessment of efficacy of study medications was achieved by between groups comparison of mean
      changes from the baseline (differences before and after treatment of every single patient)
      using:

        -  Kruskal-Wallis (KW) non-parametric one way ANOVA rank order test, with post hoc Dunn's
           Multiple Comparison Test, and/or

        -  parametric One-way independent measures ANOVA with Tukkey's Multiple Comparison Test
           (variables with normal distribution).

      Survival Analysis Statistical tools (Kaplan-Mayer analysis with log-rank test, Cox regression
      etc.) will be used for assessment of the TTP, PFS and TTTF.
    

Intervention name(s): Curcumin; Paclitaxel; Placebo
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Curcumin (CUC-01), 300mg i.v. , once weekly for 12 weeks.; Paclitaxel (colorless solution) 80 mg /m2 BS, i.v., once weekly for 12 weeks.; Placebo i.v. solution, once weekly for 12 weeks
Other intervention name(s): CUC-01
Intervention MeSH terms: Curcumin; Paclitaxel
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment