ClinicalTrials.gov
ClinicalTrials.gov Menu

Dual mTorc Inhibition in advanCed/Recurrent Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer (of Clear Cell, Endometrioid and High Grade Serous Type, and Carcinosarcoma) (DICE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03648489
Recruitment Status : Not yet recruiting
First Posted : August 27, 2018
Last Update Posted : August 27, 2018
Sponsor:
Collaborators:
Takeda Pharmaceuticals International, Inc.
North Eastern Germany Society of Gynaecologic Oncology
Information provided by (Responsible Party):
Imperial College London

Brief Summary:

This study is for women with ovarian cancer that has come back following treatment, and is resistant to platinum chemotherapy. Weekly paclitaxel chemotherapy is standard for these women, but there is a need to provide more effective treatments. TAK228 is an unlicensed oral drug that blocks the PI3K/AKT/mTOR pathway, which is important to the survival and spread of cancer cells. When TAK228 is combined with paclitaxel in the laboratory, the anti-cancer effect of both is increased. The DICE trial will show whether using TAK228 in combination with weekly paclitaxel is more effective at treating the patient population than weekly paclitaxel alone. DICE will also look for 'biomarkers' that measure the activity of the cancer and the effects of treatment. This may help us understand which women might benefit from receiving TAK228 and weekly paclitaxel in future.

DICE is a randomised study recruiting 126 women over 3 years from hospitals in the UK and Germany. Eligible patients will have tissue based diagnosis of advanced/recurrent ovarian cancer (clear cell, endometrioid or high grade serous or carcinosarcoma), have had chemotherapy before, and be platinum-resistant (the cancer has returned/grown significantly during or within 6 months of platinum-containing chemotherapy).

Randomisation will be to one of 2 groups (63 women in each). Treatment is divided into 4 week 'cycles':

Group 1: weekly paclitaxel for 3 weeks followed by 1 week rest each cycle

Group 2: weekly paclitaxel (see Group 1) plus TAK228 for 12 days each cycle

Women will stop treatment when the cancer grows significantly, there are unacceptable side effects, or the investigator and/or patient decides to stop. Women will be followed up until 6 months after the last patient receiving study treatment stops that treatment.


Condition or disease Intervention/treatment Phase
Ovarian Cancer Ovarian Neoplasms Ovarian Carcinosarcoma Ovarian Serous Adenocarcinoma Ovarian Endometrioid Adenocarcinoma Ovarian Clear Cell Adenocarcinoma Fallopian Tube Cancer Fallopian Tube Neoplasms Primary Peritoneal Carcinoma Primary Peritoneal Serous Adenocarcinoma Drug: Paclitaxel Drug: TAK228 Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 126 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An International Multi-centre Randomised Phase II Study to Assess the Efficacy of TAK228 in Combination With Intravenous Weekly Paclitaxel Compared With Weekly Paclitaxel Alone in Women With Advanced/Recurrent Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer (of Clear Cell, Endometrioid and High Grade Serous Type, and Carcinosarcoma)
Estimated Study Start Date : September 2018
Estimated Primary Completion Date : March 2022
Estimated Study Completion Date : March 2022


Arm Intervention/treatment
Active Comparator: Arm 1: Weekly paclitaxel alone
Paclitaxel, concentrate for solution for infusion 80mg per metre squared on day 1, 8 and 15 of a 28 day cycle. Cycles continue until disease progression and/or death, unacceptable adverse event/s, patient and/or investigator decision, other protocol stopping criteria
Drug: Paclitaxel
Please refer to arm/group description

Experimental: Arm 2: Weekly paclitaxel plus TAK228

Paclitaxel, concentrate for solution for infusion 80mg per metre squared on day 1, 8 and 15 of a 28 day cycle. Cycles continue until disease progression and/or death, unacceptable adverse event/s, patient and/or investigator decision, other protocol stopping criteria

TAK228, oral capsule 4mg on days 2-4, 9-11, 16-18 and 23-25 of a 28 day cycle i.e. in concurrence with paclitaxel. Cycles continue until disease progression and/or death, unacceptable adverse event/s, patient and/or investigator decision, other protocol stopping criteria

Drug: Paclitaxel
Please refer to arm/group description

Drug: TAK228
Please refer to arm/group description




Primary Outcome Measures :
  1. Progression Free Survival (PFS) [ Time Frame: 12 months ]
    PFS (as assessed by RECIST v1.1), defined as time from study entry to first evidence of disease progression or death due to any cause


Secondary Outcome Measures :
  1. Progression Free Survival (PFS) at 24 weeks [ Time Frame: 6 months ]
    PFS (as assessed by RECIST v1.1) at 24 weeks, defined as time from study entry to first evidence of disease progression or death due to any cause

  2. Overall Response Rate (ORR) [ Time Frame: 12 months ]
    ORR (as assessed by RECIST v1.1) defined by complete response (CR) or partial response (PR)

  3. Duration of Response (DOR) [ Time Frame: 12 months ]
    DOR defined as time from study entry to change in response from CR or PR to stable disease (SD) or progressive disease (SD) (as assessed by RECIST v1.1)

  4. Time to Progression (TTP) [ Time Frame: 12 months ]
    TTP defined as time from study entry to first evidence of disease progression or death due to any cause

  5. Clinical Benefit Rate (CBR) at 4 months [ Time Frame: 4 months ]
    TTP defined as time from study entry to first evidence of disease progression or death due to any cause

  6. Response according to Gynecologic Cancer Intergroup (GCIG) CA125 criteria [ Time Frame: 12 months ]
    A response according to CA125 has occurred if there is at least a 50% reduction in CA125 levels from a pretreatment sample. The response must be confirmed and maintained for at least 28 days. Patients can be evaluated according to CA125 only if they have a pretreatment sample that is at least twice the upper limit of normal and within 2 weeks prior to starting treatment

  7. Overall Survival (OS) [ Time Frame: 12 months ]
    OS defined as time from study entry to death due to any cause or to study termination

  8. Number of participants with treatment-related adverse events as assessed by CTCAE v4.03 [ Time Frame: 12 months ]
    The number of patients experiencing 1 or more AEs will be summarised by the event name, relationship to study treatment and severity

  9. Change from baseline quality of life (QOL) as assessed by EORTC QLQ-C30 questionnaire Global Health Status Domain [ Time Frame: 12 months ]
    EORTC QLQ-C30 is used to assess the overall quality of life in cancer patients. It consists of 30 questions and 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Global Health Status/QOL scale is scored between 0 and 100, with a high score indicating better Global Health Status/QOL. Negative change from Baseline values indicate deterioration in QOL or functioning and positive values indicate improvement

  10. Change from baseline QOL as assessed by EORTC QLQ-OV28 questionnaire [ Time Frame: 12 months ]
    EORTC QLQ-OV28 is used to assess the overall health-related quality of life in patients with local or advanced ovarian cancer. EORTC QLQ-OV28 consists of 28 questions evaluated across eight multi-item and 4 single item scales: abdominal/GI symptoms, peripheral neuropathy, hormonal symptoms, body image, attitude to disease/treatment, chemotherapy side effects, and sexuality, and single items scales for indigestion/heartburn, hair loss, upset due to hair loss, and taste. Questions use a 4-point scale (from 1 'Not at All' to 4 'Very Much'). Scores are averaged, and transformed to a 0-100 scale; a higher score represents a more severe overall side effect of treatment



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Able to understand and willing to sign informed consent form prior to initiation of any study procedures
  • Females ≥ 18 years of age
  • Pathological diagnosis of ovarian, fallopian tube or primary peritoneal cancer, of clear cell, endometrioid or high grade serous subtype or carcinosarcoma. Local tumour board/MDT histological review is required and in mixed tumours more than 50% endometrioid, clear cell or high grade serous elements are required to define the predominant histology
  • Platinum-resistant disease (recurrence within 6 months of last platinum treatment), patients having received at least one prior line of chemotherapy. Carboplatin and weekly paclitaxel are permitted as first line therapy
  • Measurable disease as per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 by CT or MRI
  • Fresh tumour biopsy during screening is compulsory, if judged technically feasible by radiologist
  • Patients with a history of brain metastasis are eligible as long as all the following criteria are met: brain metastases must have been treated, have no evidence of progression or haemorrhage after treatment, have been off dexamethasone for 4 weeks prior to first study treatment, and no ongoing requirement for dexamethasone or anti‐epileptic drugs
  • Available blocks for immunohistochemistry (IHC) and tissue microarray (TMA) or, if no block is available, 20 ordinary unstained slides (5µm sections) will be acceptable
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0‐2
  • Adequate organ and bone marrow function
  • Female patients who are postmenopausal for ≥ 1 year before the screening visit OR are surgically sterile OR if of childbearing potential, patient agrees to practice 1 highly effective and 1 additional effective method of contraception or true abstinence from informed consent to 90 days after the last dose of study treatment
  • For women of child‐bearing potential, negative blood serum pregnancy test within 14 days prior to the first study treatment
  • Able to swallow oral medication

Exclusion Criteria:

  • Previous treatment with PI3K, AKT, dual PI3K/mTOR inhibitors, mTORC1/2 inhibitors or mTORC1 inhibitors
  • Prior weekly single agent paclitaxel
  • Known allergy to paclitaxel and/or any excipients of investigational medicinal products that, in the investigator's opinion, precludes study treatment on clinical and/or safety grounds
  • Treatment with strong inhibitor/s and/or inducer/s of cytochrome P450 (CYP) 3A4 or CYP2C8 within 7 days of study treatment
  • Central nervous system (CNS) metastasis, for patients who have brain metastases, they will be eligible if their brain metastases must have been treated, have no evidence of progression or haemorrhage after treatment, have been off dexamethasone for 4 weeks prior to first study drug administration, and no ongoing requirement for dexamethasone or anti‐epileptic drugs
  • Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active central nervous system disease, active infection, or any other condition that could compromise the patient's participation in the study
  • Known human immunodeficiency virus infection
  • Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection
  • Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol
  • German sites only: Unable to be regularly followed up for any reason (geographic, familiar, social, psychological, housed in an institution e.g. prison because of a court agreement or administrative order)
  • German sites only: Subjects that are dependent on the sponsor (and/or contracted body e.g. CRO) or investigational site as well as on the investigator
  • Diagnosed or treated for another malignancy within 2 years before administration of the first dose of study treatment, or previously diagnosed with another malignancy and evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection
  • Breast feeding or pregnant
  • Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of TAK228. In addition, patients with enteric stomata are also excluded
  • Treatment with any investigational products, chemotherapy or radiotherapy within 28 days, or major surgery within 21 days of study treatment
  • History of any of the following within the last 6 months before administration of the first dose of study treatment:

    1. Ischemic myocardial event, including angina requiring therapy and artery revascularisation procedures
    2. Ischemic cerebrovascular event, including transient ischemic attack and artery revascularisation procedures
    3. Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation or ventricular tachycardia)
    4. Placement of a pacemaker for control of rhythm
    5. New York Heart Association (NYHA) Class III or IV heart failure
    6. Pulmonary embolism
  • Significant active cardiovascular or pulmonary disease including:

    1. Uncontrolled hypertension (i.e., systolic blood pressure > 180 mm Hg, diastolic blood pressure > 95 mm Hg). Use of anti-hypertensive agents to control hypertension before first dose of study treatment is allowed.
    2. Pulmonary hypertension
    3. Uncontrolled asthma or O2 saturation < 90% by arterial blood gas analysis or pulse oximetry on room air
    4. Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with medical intervention, or history of valve replacement
    5. Medically significant (symptomatic) bradycardia
    6. History of arrhythmia requiring an implantable cardiac defibrillator
    7. Baseline prolongation of the rate-corrected QT interval (QTc) (e.g., repeated demonstration of QTc interval > 480 milliseconds, or history of congenital long QT syndrome, or torsades de pointes)
  • Patients receiving systemic corticosteroids (either IV or oral steroids, excluding inhalers or low-dose hormone replacement therapy) within 1 week before administration of the first dose of study treatment
  • Daily or chronic use of a proton pump inhibitor (PPI) and/or having taken a PPI within 7 days before receiving the first dose of study treatment
  • Poorly controlled diabetes mellitus defined as glycosylated haemoglobin (HbA1c) > 7%; patients with a history of transient glucose intolerance due to corticosteroid administration may be enrolled in this study if all other inclusion/exclusion criteria are met

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03648489


Contacts
Contact: Lee Webber +44 20 7594 2165 dice-trial@imperial.ac.uk

Locations
United Kingdom
Imperial College Healthcare NHS Trust Not yet recruiting
London, Greater London, United Kingdom, W12 0HS
Contact: Senior Research Trials Coordinator         
Principal Investigator: Jonathan Krell         
Sponsors and Collaborators
Imperial College London
Takeda Pharmaceuticals International, Inc.
North Eastern Germany Society of Gynaecologic Oncology
Investigators
Principal Investigator: Jonathan Krell Imperial College London

Responsible Party: Imperial College London
ClinicalTrials.gov Identifier: NCT03648489     History of Changes
Other Study ID Numbers: C/30/2011
First Posted: August 27, 2018    Key Record Dates
Last Update Posted: August 27, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Imperial College London:
TAK228
TAK-228
Paclitaxel
Ovarian cancer
Platinum resistant

Additional relevant MeSH terms:
Sarcoma
Neoplasms
Adenocarcinoma
Ovarian Neoplasms
Fallopian Tube Neoplasms
Carcinoma, Endometrioid
Cystadenocarcinoma, Serous
Carcinosarcoma
Mixed Tumor, Mullerian
Adenocarcinoma, Clear Cell
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Endocrine Gland Neoplasms
Neoplasms by Site
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Fallopian Tube Diseases
Endometrial Neoplasms
Uterine Neoplasms
Cystadenocarcinoma
Neoplasms, Cystic, Mucinous, and Serous
Neoplasms, Complex and Mixed
Neoplasms, Connective and Soft Tissue
Paclitaxel