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

Sponsor

University of Leeds (Other)

Overall Status

Unknown status

CT.gov ID

NCT02461888

Collaborator

Myeloma UK (Other), Millennium Pharmaceuticals, Inc. (Industry)

112

Enrollment

Locations

Arms

Duration (Months)

6.2

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

112 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 :

Dec 1, 2015

Anticipated Primary Completion Date :

Dec 1, 2020

Anticipated Study Completion Date :

Jan 1, 2021

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Progression free survival [From randomisation to first documented evidence of disease progression or death, up to 36 months.]

Secondary Outcome Measures

Response to treatment [From initial trial treatment until at least partial response is achieved, up to 36 months..]
Maximum response [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.]
Time to progression [From randomisation to first documented evidence of disease progression, up to 36 months..]
Time to maximum response [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.]
Response duration [From the first observation of at least partial response until disease progression, up to 36 months.]
Overall survival [From randomisation to death, up to 36 months.]
Evaluate the safety and toxicity as measured by adverse reactions and serious adverse event reporting. [From consent until 28 days after the last dose of trial treatment, up to 36 months.]
Treatment compliance measured by treatment delays and missed treatment doses. [From initial treatment received as per protocol until withdrawal from treatment, up to 36 months.]
Quality of life measured by the completion of EQ-5D and EORTC QLQ-C30 questionnaires [Completed every 3 months from consent until disease progression, up to 36 months.]
Cost effectiveness of treatment assessed by health economic evaluations. [From consent up to 36 months.]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Queen Elizabeth Medical Centre	Birmingham	United Kingdom	B15 2TH
2	Heart of England NHS Foundation Trust	Birmingham	United Kingdom	B9 5ST
3	Royal Bournemouth General Hospital	Bournemouth	United Kingdom	BH7 7DW
4	University Hospital Bristol NHS Foundation Trust	Bristol	United Kingdom	BS1 3NU
5	North Tees and Hartlepool NHS Foundation Trust	Hartlepool	United Kingdom	TS24 9AH
6	Leeds Teaching Hospitals NHS Trust	Leeds	United Kingdom	LS9 7TF
7	Royal Liverpool and Broadgreen University Hospital NHS Trust	Liverpool	United Kingdom	L7 8XP
8	Barts and the London NHS Trust	London	United Kingdom	E1 1BB
9	University College London Hospitals NHS Foundation Trust	London	United Kingdom	NW1 2PG
10	Guy's and St Thomas's NHS Foundation Trust	London	United Kingdom	SE1 9RT
11	Royal Marsden Hospital	London	United Kingdom	SW3 6JJ
12	Imperial College Healthcare NHS Trust	London	United Kingdom	W2 1NY
13	The Christie NHS Foundation Trust	Manchester	United Kingdom	M20 4BX
14	Nottingham University Hospital NHS Trust	Nottingham	United Kingdom	NG7 2UH
15	Churchill Hospital	Oxford	United Kingdom	OX3 7LE
16	Sheffield Teaching Hospitals NHS Foundation Trust	Sheffield	United Kingdom	S5 7AU
17	Southampton University Hospital NHS Trust	Southampton	United Kingdom	SO16 6YD
18	The Royal Wolverhampton Hospital NHS Trust	Wolverhampton	United Kingdom	WV10 0QP