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Phase II Randomised Trial of Cyclophosphamide and Dexamethasone in Combination With Ixazomib in Relapsed or Refractory Multiple Myeloma. (MUKEight)

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ClinicalTrials.gov Identifier: NCT02461888
Recruitment Status : Recruiting
First Posted : June 3, 2015
Last Update Posted : November 17, 2016
Sponsor:
Collaborators:
Myeloma UK
Millennium Pharmaceuticals, Inc.
Information provided by (Responsible Party):
Gordon Cook, University of Leeds

Brief Summary:
This study evaluates a new treatment combination of ixazomib with cyclophosphamide and dexamethasone in relapsed or refractory multiple myeloma. Participants will either receive ixazomib with cyclophosphamide and dexamethasone or cyclophosphamide and dexamethasone alone.

Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: Ixazomib Drug: Cyclophosphamide Drug: Dexamethasone Phase 2

Detailed Description:

Cyclophosphamide and dexamethasone are very commonly used in the treatment of multiple myeloma and are often given with a third drug (e.g. thalidomide, lenalidomide or bortezomib). The combination of conventional and new drugs has provided benefits in both overall survival and progression free survival, however there are few treatments available for patients who have not responded well (refractory) to their previous treatment or who need further treatment because their myeloma has come back (relapsed). Thus there is a need for new agents for these patients.

The development of ixazomib provides the opportunity to increase anti-tumour activity against a wider range of tumour types. Early clinical trials data suggests it has anti-tumour activity in heavily pre-treated multiple myeloma patients with durable responses/disease control and is generally well tolerated.

Cyclophosphamide and dexamethasone are both predominantly used in treatment of multiple myeloma and for patients with relapsed or refractory multiple myelomas (RRMM), who have relapsed after bortezomib and lenalidomide. Therefore the evaluation of ixazomib in combination with cyclophosphamide and dexamethasone is the most valuable and practical option for patients.

The primary end point of this study is progression-free survival (PFS). Secondary end points include toxicity and safety.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 250 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomised Phase II Trial of Cyclophosphamide and Dexamethasone in Combination With Ixazomib in Relapsed or Refractory Multiple Myeloma (RRMM) Patients Who Have Relapsed After Treatment With Thalidomide, Lenalidomide and Bortezomib.
Study Start Date : December 2015
Estimated Primary Completion Date : May 2018
Estimated Study Completion Date : May 2019


Arm Intervention/treatment
Experimental: Ixazomib, CD

Ixazomib, cyclophosphamide and dexamethasone (ICD) will be administered as part of a 28 days cycle until disease progression, intolerance, toxicity or withdrawal.

Dosing schedule:

  • Ixazomib 4mg orally on days 1, 8 and 15
  • Cyclophosphamide 500mg orally on days 1, 8 and 15
  • Dexamethasone 40mg orally on days 1-4 and 12-15
Drug: Ixazomib
Chemotherapy

Drug: Cyclophosphamide
Chemotherapy

Drug: Dexamethasone
Chemotherapy

Active Comparator: CD

Cyclophosphamide and dexamethasone (CD) will be administered as part of a 28 days cycle until disease progression, intolerance, toxicity or withdrawal.

Dosing schedule:

  • Cyclophosphamide 500mg orally on days 1, 8 and 15
  • Dexamethasone 40mg orally on days 1-4 and 12-15
Drug: Cyclophosphamide
Chemotherapy

Drug: Dexamethasone
Chemotherapy




Primary Outcome Measures :
  1. Progression free survival [ Time Frame: From randomisation to first documented evidence of disease progression or death, up to 36 months. ]

Secondary Outcome Measures :
  1. Response to treatment [ Time Frame: From initial trial treatment until at least partial response is achieved, up to 36 months.. ]
  2. Maximum response [ Time Frame: From initial trial treatment each of the response categories are achieved stringent complete response, complete response, very good partial response, partial response, minimal response or stable disease, up to 36 months. ]
  3. Time to progression [ Time Frame: From randomisation to first documented evidence of disease progression, up to 36 months.. ]
  4. Time to maximum response [ Time Frame: From randomisation until the participant achieves any of the categories stringent complete response, complete response, very good partial response, partial response, minimal response or stable disease, up to 36 months. ]
  5. Response duration [ Time Frame: From the first observation of at least partial response until disease progression, up to 36 months. ]
  6. Overall survival [ Time Frame: From randomisation to death, up to 36 months. ]
  7. Evaluate the safety and toxicity as measured by adverse reactions and serious adverse event reporting. [ Time Frame: From consent until 28 days after the last dose of trial treatment, up to 36 months. ]
  8. Treatment compliance measured by treatment delays and missed treatment doses. [ Time Frame: From initial treatment received as per protocol until withdrawal from treatment, up to 36 months. ]
  9. Quality of life measured by the completion of EQ-5D and EORTC QLQ-C30 questionnaires [ Time Frame: Completed every 3 months from consent until disease progression, up to 36 months. ]
  10. Cost effectiveness of treatment assessed by health economic evaluations. [ Time Frame: From consent up to 36 months. ]


Information from the National Library of Medicine

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

Inclusion Criteria:

  • Able to give informed consent and willing to follow study protocol assessments
  • Aged 18 years or over
  • Participants with confirmed multiple myeloma based on International Myeloma Working Group (IMWG) criteria, 2009
  • Measurable disease
  • Participants with relapsed or relapsed refractory myeloma and now require further treatment following exposure to thalidomide, lenalidomide and bortezomib regardless of response to these
  • Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2
  • Required laboratory values within 14 days prior to Randomisation:
  • Platelet count ≥50x109/L. Platelet support is permitted within 14 days prior to Randomisation
  • Absolute neutrophil count ≥1.0 x 109/L
  • Haemoglobin > 9 g/dL. Blood support is permitted
  • Alanine aminotransferase (ALT) and / or Aspartate aminotransferase (AST) ≤3 x upper limit of normal
  • Creatinine clearance ≥ 30 ml/min (using Cockcroft Gault formula)
  • Bilirubin ≤1.5 x upper limit of normal
  • Both non-sterilised and sterilised females and males of reproductive age should use effective methods of contraception during the entire trial treatment (including treatment breaks) and up to 90 days after the last dose of trial treatment
  • Post allograft patients may be included

Exclusion Criteria:

  • Those with non-measurable disease
  • Those with a solitary bone or solitary extramedullary plasmacytoma
  • Plasma cell leukaemia
  • Prior malignancy other than those treated with curative surgery.
  • Participants with a known or underlying uncontrolled concurrent illness that, in the investigators opinion, would make the administration of the study drug hazardous or circumstances that could limit compliance with the study
  • Patients who have previously received MLN9708/Ixazomib in a trial. Previous experimental agents or approved anti-tumour treatment within 30 days before the date of randomisation.
  • A maximum of 160mg of dexamethasone (in 40mg blocks) may be given between screening and the beginning of treatment if medically required but should be stopped before trial treatment starts. Bisphosphonates for bone disease and radiotherapy for palliative intent are also permitted
  • Participants with a history of a refractory nausea, diarrhoea, vomiting, malabsorption, gastrointestinal surgery or other procedures that might, in the opinion of the Investigator, interfere with the absorption or swallowing of the study drug(s)
  • Peripheral neuropathy of ≥ grade 2 severity
  • Gastrointestinal disorders that may interfere with absorption of the study drug
  • Active symptomatic fungal, bacterial, and/or viral infection including known active HIV or known viral (A, B or C) hepatitis
  • Female patients who are lactating or have a positive serum pregnancy test during the screening period
  • Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent
  • Systemic treatment, within 14 days before the first dose of MLN9708, with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort
  • Major surgery within 14 days prior to the date of randomisation
  • Radiotherapy within 14 days prior to randomisation
  • Disease involving the Central Nervous System

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): NCT02461888


Contacts
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Contact: Debbie Sherratt 0113 343 1477 ext 39141 medmuk08@leeds.ac.uk

Locations
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United Kingdom
Queen Elizabeth Medical Centre Recruiting
Birmingham, United Kingdom, B15 2TH
Heart of England NHS Foundation Trust Recruiting
Birmingham, United Kingdom, B9 5ST
Royal Bournemouth General Hospital Recruiting
Bournemouth, United Kingdom, BH7 7DW
University Hospital Bristol NHS Foundation Trust Recruiting
Bristol, United Kingdom, BS1 3NU
North Tees and Hartlepool NHS Foundation Trust Recruiting
Hartlepool, United Kingdom, TS24 9AH
Leeds Teaching Hospitals NHS Trust Recruiting
Leeds, United Kingdom, LS9 7TF
Royal Liverpool and Broadgreen University Hospital NHS Trust Recruiting
Liverpool, United Kingdom, L7 8XP
Barts and the London NHS Trust Recruiting
London, United Kingdom, E1 1BB
University College London Hospitals NHS Foundation Trust Recruiting
London, United Kingdom, NW1 2PG
Guy's and St Thomas's NHS Foundation Trust Recruiting
London, United Kingdom, SE1 9RT
Royal Marsden Hospital Recruiting
London, United Kingdom, SW3 6JJ
Imperial College Healthcare NHS Trust Recruiting
London, United Kingdom, W2 1NY
The Christie NHS Foundation Trust Recruiting
Manchester, United Kingdom, M20 4BX
Nottingham University Hospital NHS Trust Recruiting
Nottingham, United Kingdom, NG7 2UH
Churchill Hospital Recruiting
Oxford, United Kingdom, OX3 7LE
Sheffield Teaching Hospitals NHS Foundation Trust Recruiting
Sheffield, United Kingdom, S5 7AU
Southampton University Hospital NHS Trust Recruiting
Southampton, United Kingdom, SO16 6YD
The Royal Wolverhampton Hospital NHS Trust Recruiting
Wolverhampton, United Kingdom, WV10 0QP
Sponsors and Collaborators
University of Leeds
Myeloma UK
Millennium Pharmaceuticals, Inc.
Investigators
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Principal Investigator: Gordon Cook Leeds Teaching Hospitals NHS Trust

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Responsible Party: Gordon Cook, Chief Investigator, University of Leeds
ClinicalTrials.gov Identifier: NCT02461888     History of Changes
Other Study ID Numbers: HM13/10993
First Posted: June 3, 2015    Key Record Dates
Last Update Posted: November 17, 2016
Last Verified: May 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Gordon Cook, University of Leeds:
Relapsed
Refractory
Cyclophosphamide
Dexamethasone

Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone
Dexamethasone acetate
Cyclophosphamide
Ixazomib
BB 1101
Glycine
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal