Pomalidomide in Relapsed and Refractory Multiple Myeloma (RRMM) (MUKseven)

• Sponsor: University of Leeds
• Collaborators: Myeloma UK; Celgene
• Information provided by (Responsible Party): University of Leeds

Study Description

Brief Summary:

This study is determining whether the addition of cyclophosphamide to pomalidomide and dexamethasone improves progression free survival in patients with relapsed refractory myeloma (RRMM) compare to pomalidomide and dexamethasone alone. Patients will be randomised on a 1:1 basis to receive CPD or Pd. Treatment will be continued until disease progression or unacceptable toxicity.

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

Detailed Description:

Multiple myeloma is the second most common hematologic malignancy in the European Union (EU), responsible for an estimated 21,000 deaths in the EU in 2008. For patients that relapse or are refractory to current standard treatment (combination of bortezomib/lenalidomide, dexamethasone and an alkylating agent) there are few options available and therefore the prognosis within this group is often poor with response to treatment decreasing with successive relapses until resistant disease develops. . Current standard treatment at first relapse in the UK is the use of bortezomib in combination with dexamethasone and cyclophosphamide. Another common treatment is lenalidomide given with dexamethasone and cyclophosphamide. The addition of cyclophosphamide has demonstrated to improve treatment outcomes whilst being tolerated well. A recent clinical study has shown the addition of cyclophosphamide to the combination of pomalidomide and dexamethasone has shown to be safe and tolerable and beneficial in terms of treatment outcomes. The primary aim of this study is to investigate whether the addition of cyclophosphamide to pomalidomide and dexamethasone leads to an improved progression free survival. A secondary aim is to identify markers from clinical material that will predict response to pomalidomide in a group of relapsed and refractory multiple myeloma (RRMM) patients to provide important information for use in discussions with NICE on how best to improve the value and use of pomalidomide in the UK in the RRMM setting.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 250 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pomalidomide in Relapsed and Refractory Multiple Myeloma (RRMM)
• Study Start Date: March 2016
• Estimated Primary Completion Date: March 2019
• Estimated Study Completion Date: March 2023

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Pomalidomide and Dexamethasone; Pomalidomide and Dexamethasone will be administered as part of a 28 day cycle. Patients will continue with their treatment until disease progression, intolerance, toxicity or withdrawal. Dosing schedule: Pomalidomide 4mg orally on days 1-21; Dexamethasone 40mg orally on days 1, 8, 15 and 22	Drug: Pomalidomide; Chemotherapy; Drug: Dexamethasone; Chemotherapy
Experimental: Pomalidomide Dexamethasone Cylcophosphamide; Pomalidomide, Dexamethasone and Cyclophosphamide will be administered as part of a 28 day cycle. Patients will continue with their treatment until disease progression, intolerance, toxicity or withdrawal. Dosing schedule: Pomalidomide 4mg orally on days 1-21; Dexamethasone 40mg orally on days 1, 8, 15 and 22; Cyclophosphamide 500mg orally on days 1, 8 and 15	Drug: Pomalidomide; Chemotherapy; Drug: Dexamethasone; Chemotherapy; Drug: Cyclophosphamide; Chemotherapy

Outcome Measures

Primary Outcome Measures :

1. Progression free survival [ Time Frame: From randomisation up to 72 months ]
   To determine whether the addition of cyclophosphamide to pomalidomide and dexamethasone (CPD) improves progression-free survival in patients with relapsed refractory myeloma (RRMM) in the UK, compared to pomalidomide and dexamethasone (Pd) alone

Secondary Outcome Measures :

1. Maximum response overall [ Time Frame: From the start of treatment up to 72 months ]
   To determine the maximum response achieved from treatment
2. Response to treatment [ Time Frame: From the start of treatment up to 72 months ]
   Determine the response to treatment
3. Clinical benefit rate overall [ Time Frame: From the start of treatment up to 72 months ]
   Determine any clinical benefit that is derived from treatment
4. Time to maximum response [ Time Frame: From the start of treatment up to 72 months ]
   Determine the time to maximum response to treatment
5. Duration of response [ Time Frame: From the start of treatment up to 72 months ]
   Determine the duration that the response to treatment lasts for
6. Overall survival [ Time Frame: Date of randomisation to death, up to 72 months ]
   Determine overall survival for all patients that receive treatment
7. Treatment compliance [ Time Frame: From the start of treatment up to end of treatment ]
   Measured by treatment delays and missed treatment doses
8. Safety and Toxicity [ Time Frame: Time of registration to 28 days post treatment discontinuation ]
   Measured by adverse reactions and serious adverse event reporting

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Diagnosed with symptomatic multiple myeloma (according to International Myeloma Working Group (IMWG) 2009 criteria) and have measurable disease
• Participants must require therapy for relapsed and/or refractory disease
• Participants must have received ≥ 2 treatment lines of anti-myeloma therapy (induction therapy followed by autologous stem-cell transplantation (ASCT) and consolidation/maintenance will be considered as one line).
• Participants must have received prior treatment with both lenalidomide and proteasome inhibitor, either as single agents or in combination regimens

• All participants must have failed treatment with either lenalidomide and proteasome inhibitor in one of the following ways:

  1. Documented progressive disease on or within 60 days of completing treatment with lenalidomide and/or proteasome inhibitor ; or
  2. In case of prior response [≥ partial response (PR)] to lenalidomide or proteasome inhibitor, participants must have relapsed within 6 months after stopping treatment with lenalidomide and/or proteasome inhibitor containing regimens; or
  3. Participants who have not had a ≥ minimal response (MR) despite receiving at least 4 cycles of treatment or who have developed intolerance/toxicity after a minimum of two cycles of lenalidomide and/or proteasome inhibitor containing regimen

• Patients must have received adequate prior alkylator therapy in one of the following ways

  1. As part of a stem cell transplant; or
  2. A minimum of 4 consecutive cycles of an alkylator based therapy; or
  3. Progression on treatment with an alkylator; provided that the participant received at least 2 cycles of an alkylator containing therapy.
• Life expectancy of at least 3 months
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2

• Required laboratory values within 14 days of treatment:

  • Absolute neutrophil count ≥ 1.0 x109 /L (growth factor support is permitted)
  • Platelet count ≥ 30 x 109/L (platelet transfusion is permitted)
  • Creatinine clearance > 30 mL/min
  • Corrected serum calcium ≤ 3.5 mmol/L
  • Haemoglobin ≥ 8 g/dL (blood transfusion support is permitted)
  • Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) < 3 times Upper Limit of Normal (ULN)
  • Serum total bilirubin < 17 µmol/l
• Participants must consent to provide the bone marrow samples specified at screening and throughout the trial, in order to enter the trial. Confirmation of receipt of the sample from the lab must be received before treatment commences..
• Able to give informed consent and willing to follow trial protocol
• Aged over 18 or over
• Females of childbearing potential (FCBP) must agree to utilise one reliable form of contraception for 28 days prior to starting trial treatment, during the trial, and for 28 days after trial treatment discontinuation and even in the case of dose interruption and must agree to regular pregnancy testing during this timeframe
• Females must agree to abstain from breastfeeding during trial participation and 28 days after trial drug discontinuation
• Males must agree to use a latex condom during any sexual contact with FCBP during the trial, including during any dose interruptions and for 28 days following discontinuation from this trial even if he has undergone a successful vasectomy
• Males must also agree to refrain from donating semen or sperm while on pomalidomide, including during any dose interruptions and for 28 days after discontinuation from this trial
• All participants must agree to refrain from donation blood while on trial drug, including during dose interruptions and for 28 days after discontinuation from this trial

Exclusion Criteria:

• Previous therapy with pomalidomide
• Hypersensitivity to thalidomide, lenalidomide, cyclophosphamide or dexamethasone
• Participants with non-secretory multiple myeloma
• Peripheral neuropathy ≥ Grade 3
• Participants who have received an allogeneic bone marrow or allogeneic peripheral blood stem cell transplant
• Participants who are planned for a stem cell transplant post MUK Seven trial treatment
• Antitumour therapies including investigational medicinal products at any dose within 28 days before the start of protocol treatment (or 5 half-lives, whichever is longer). Bisphosphonates for bone disease and radiotherapy for palliative intent are permitted.

• Participants with any of the following

  1. Uncontrolled congestive heart failure
  2. Myocardial infarction within 12 months prior to starting trial treatment
  3. Unstable or poorly controlled angina pectoris, including Prinzmetal variant angina pectoris.
• Participants with gastrointestinal disease that may significantly alter absorption of pomalidomide
• Participants with a history of other malignancies within 5 years before the date of study entry (exceptions are squamous and basal cell carcinomas of the skin, carcinoma in situ of the cervix or breast, or other non-invasive lesion that is considered cured with minimal risk of recurrence within 5 years).
• Participants unable or unwilling to undergo antithrombotic prophylactic treatment
• Pregnant or breastfeeding females
• Participants known to be seropositive for HIV, or active infectious hepatitis A, B or C
• Any condition including the presence of laboratory abnormalities, which places the participant at unacceptable risk if he/she were to participate in the trial

Contacts and Locations

Contacts

Contact: Martin Kaiser; 01133431477; ctru_mukseven@leeds.ac.uk

Locations

United Kingdom

Belfast Health & Social Care Trust; Recruiting

Belfast, United Kingdom, BT9 7AB

University of Birmingham NHS Foundation Trust; Recruiting

Birmingham, United Kingdom, B15 2TH

Birmingham Heartlands Hospital; Recruiting

Birmingham, United Kingdom, B9 5SS

Royal Sussex County Hospital; Recruiting

Brighton, United Kingdom, BN2 5BE

Queens Hospital; Recruiting

Burton on Trent, United Kingdom, DE13 0RB

University Hospital of Wales NHS Trust; Recruiting

Cardiff, United Kingdom, CF14 4XW

Ninewells Hospital; Recruiting

Dundee, United Kingdom, DD1 9SY

Beatson Oncology Centre; Not yet recruiting

Glasgow, United Kingdom

St James's Hopsital; Recruiting

Leeds, United Kingdom, LS9 7TF

University Hospital of Leicester NHS Trust; Recruiting

Leicester, United Kingdom, LE1 5WW

St Bartholomew Hospital; Not yet recruiting

London, United Kingdom, EC1M 6BQ

University College London Hospital; Recruiting

London, United Kingdom, NW1 2BU

Guy's and St Thomas' NHS Foundation Trust; Recruiting

London, United Kingdom, SE1 9RT

The Royal Marsden NHS Foundation Trust; Recruiting

London, United Kingdom, SW3 6JJ

Imperial College Hospital; Recruiting

London, United Kingdom, W2 1NY

Central Manchester Univeristy Hospital NHS Trust; Recruiting

Manchester, United Kingdom, M13 9WL

The Christie Hospital; Recruiting

Manchester, United Kingdom, M20 4BX

Churchill Hospital; Recruiting

Oxford, United Kingdom, OX3 7LE

Sheffield Teaching Hospitals NHS FoundationTrust; Recruiting

Sheffield, United Kingdom, S10 2RB

University Hospital of North Tees; Recruiting

Stockton-on-Tees, United Kingdom, TS19 8PE

New Cross Hospital; Recruiting

Wolverhampton, United Kingdom, WV10 0QP

Sponsors and Collaborators

University of Leeds

Myeloma UK

Celgene

Investigators

• Principal Investigator: Martin Kaiser, Dr; Royal Marsden NHS Foundation Trust

More Information

• Responsible Party: University of Leeds
• ClinicalTrials.gov Identifier: NCT02406222 History of Changes
• Other Study ID Numbers: HM13/10758
• First Posted: April 2, 2015
• Last Update Posted: June 16, 2017
• Last Verified: June 2017

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Keywords provided by University of Leeds:

Relapsed; Refractory; Pomalidomide; Dexamethasone; Cyclophosphamide

Additional relevant MeSH terms:

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; Thalidomide; Dexamethasone; Dexamethasone acetate; Cyclophosphamide; Pomalidomide; BB 1101; 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