MUK Nine b: OPTIMUM Treatment Protocol

NCT03188172 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: HM16/235
• Study Type: interventional
• Target: 95
• Locations: 1 country
• Sites: 21

Brief Summary

To determine whether a combination of four novel agents bortezomib(Velcade), lenalidomide (Revlimid), Daratumumab (Darzalex) \& dexamethasone in combination with low-dose cyclophosphamide is sufficiently active in a high risk population of myeloma patients, to take forward into a phase III trial compared to standard treatment.

Conditions

Multiple Myeloma

Outcome Measures

Primary Outcomes (1)

• Progression free survival

  Defined as the time from registration until first documented evidence of progressive disease or death. Participants not progressed at analysis will be censored at the last date known to be alive and progression free.

  At 18 months post registration

Secondary Outcomes (11)

• Occurrence of Serious Adverse Events(SAE) and Suspected, Unexpected Serious Adverse Reactions (SUSAR)

  At 120 days post autologous stem cell transplant (ASCT)

• Progression free survival at 100 days post autologous stem cell transplant

  At 100 days post ASCT

• Minimal residual disease (MRD) negative disease

  At 100 days post ASCT

• Overall survival

  At 12 months, 24 months & 36 months post registration

• Maximum response

  From registration to end of induction therapy, 100 days post ASCT, post consolidation part 2

Other Outcomes (3)

• Progression free survival (comparison with Myeloma XI/XI+ data)

  From registration until second disease progression, 3 years

• Impact of minimal residual disease on progression free survival

  From registration until second disease progression, 3 years

• Genomic instability

  From registration until second disease progression, 3 years

Study Arms (1)

Trial Treatment

EXPERIMENTAL

Induction: Cyclophosphamide 500mg, days 1, 8 Bortezomib 1.3mg/m2, days 1, 4, 8, 11 Lenalidomide 25mg, days 1-14 Daratumumab 16mg/kg, days 1, 8, 15 (cycles 1\& 2), day 1 only from cycle 3 Dexamethasone 20-40mg, days 1, 4, 8, 11 ASCT stem cell harvest: with Bortezomib 1.3mg/m2, (12 hours post melphalan) Bortezomib 1.3mg/m2, day +5, +14, weekly Consolidation part 1: Bortezomib 1.3mg/m2 days 1, 8, 15, 22 Lenalidomide 25mg days 1-21 Daratumumab 16mg/kg day 1 Dexamethasone 20-40mg days 1, 8, 15, 22 Consolidation part 2: Bortezomib 1.3mg/m2 days 1, 8, 15 Lenalidomide 25mg days 1-21 Daratumumab 16mg/kg day 1 Maintenance: Lenalidomide 10mg days 1-21 Daratumumab 16mg/kg day 1

Drug: Cyclophosphamide; Drug: Bortezomib; Drug: Lenalidomide; Drug: Daratumumab; Drug: Dexamethasone; Drug: Melphalan; Drug: Filgrastim

Interventions

Cyclophosphamide DRUG

Chemotherapy

Trial Treatment

Bortezomib DRUG

Chemotherapy

Also known as: Velcade

Trial Treatment

Lenalidomide DRUG

Chemotherapy

Also known as: Revlamid

Trial Treatment

Daratumumab DRUG

Chemotherapy

Also known as: Daralex

Trial Treatment

Dexamethasone DRUG

Chemotherapy

Trial Treatment

Melphalan DRUG

Chemotherapy

Trial Treatment

Filgrastim DRUG

Haematopoietic agent for the stem cell harvest

Trial Treatment

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Confirmation of High Risk status from Institute of Cancer Research (ICR) following bone marrow and blood sample processed through the MUKnine a screening protocol.
• Previously untreated participants, although participants may have received up to 2 cycles of cyclophosphamide, thalidomide, dexamethasone (CTD), cyclophosphamide, velcade, dexamethasone (CVD), cyclophosphamide, lenalidomide, dexamethasone (CRD) or velcade, thalidomide, dexamethasone (VTD) pre-trial induction chemotherapy while awaiting the results of the laboratory analysis from the MUKnine a Screening Protocol. (In addition, non-systemic therapy such as therapeutic plasma exchange, dexamethasone up to a maximum of 160mg or radiotherapy sufficient to alleviate or control pain or local invasion is permitted).
• Measurable disease with at least one of the following or willing to undergo further bone marrows for assessment:
• \- Paraprotein ≥ 5g/L or ≥ 0.5 g/L for IgD subtypes.
• \- Serum free kappa or lambda light chains ≥ 100 mg/L with abnormal ratio (for light chain only myeloma).
• \- Urinary Bence Jones protein ≥ 200 mg/L.
• Non measurable participants providing they accept a 3 monthly bone marrow during induction and a 6 monthly bone marrow assessment during consolidation and maintenance.
• Aged 18 years or over.
• Fit for intensive chemotherapy and autologous stem cell transplant (at clinician's discretion).
• Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2.
• The Celgene Pregnancy Prevention Plan must be followed and participants must agree to comply with this:
• Females of childbearing potential (FCBP) must agree to utilise two reliable forms of contraception simultaneously or practice complete abstinence for at least for 28 days prior to starting trial treatment, during the trial and for at least 28 days after trial treatment discontinuation, and even in case of dose interruption, and must agree to regular pregnancy testing during this timeframe.
• Males must agree to use a latex condom during any sexual contact with FCBP during the trial, including during dose interruptions and for 28 days following discontinuation from this trial even if he has undergone a successful vasectomy o Males must also agree to refrain from donating semen or sperm while on trial treatment including during any dose interruptions and for at least 6 months after discontinuation from this trial
• All participants must agree to refrain from donating blood while on trial drug including during dose interruptions and for 28 days after discontinuation from this trial.
• Calculated creatinine clearance ≥ 30mL/min (using Cockcroft-Gault formula).

You may not qualify if:

• Solitary bone/solitary extramedullary plasmacytoma.
• Primary diagnosis of amyloidosis, monoclonal gammopathy of undetermined significance or smoldering multiple myeloma or Waldenstrom's Disease.
• Prior or concurrent invasive malignancies except the following:
• Adequately treated basal cell or squamous cell skin cancer.
• Incidental finding of low grade (Gleason 3+3 or less) prostate cancer.
• Any cancer from which the subject has been disease free for at least 3 years.
• Known/underlying medical conditions that, in the investigator's opinion, would make the administration of the study drug hazardous (e.g. uncontrolled diabetes or uncontrolled coronary artery disease).
• Any clinically significant cardiac disease, including:
• \- myocardial infarction within 1 year before randomization, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV.
• \- Uncontrolled cardiac arrhythmia (National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE\] Version 4 Grade ≥2) or clinically significant ECG abnormalities.
• \- screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF) \>470 msec. · Known chronic obstructive pulmonary disease (COPD) (defined as a forced expiratory volume \[FEV\] in 1 second \<60% of predicted normal), persistent asthma, or a history of asthma within the last 2 years (intermittent asthma is allowed). Participants with known or suspected COPD or asthma must have a FEV1 test during screening.
• Known to be seropositive for history of human immunodeficiency virus (HIV) or known to have active hepatitis B or hepatitis C.
• Any known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to respective package inserts), or known sensitivity to mammalian-derived products.
• Clinically significant allergies or intolerance to cyclophosphamide, lenalidomide, velcade, daratumumab or dexamethasone. · Previous treatment with daratumumab or any other anti-CD38 therapies.
• Participants with contraindication to thromboprophylaxis.

Sponsors & Collaborators

• University of Leeds: lead
• Myeloma UK: collaborator
• Celgene: collaborator
• Janssen, LP: collaborator

Study Sites (21)

Queen Elizabeth Hospital

Birmingham, B15 2TH, United Kingdom

Location

Birmingham Heartlands Hospital

Birmingham, United Kingdom

Location

Blackpool Victoria Hospital

Blackpool, United Kingdom

Location

Royal Hampshire County Hospital

Bournemouth, BH7 7DW, United Kingdom

Location

Royal Bournemouth Hospital

Bournemouth, United Kingdom

Location

Bristol Haematology & Oncology Centre

Bristol, United Kingdom

Location

Ninewells Hospital

Dundee, DD1 9SY, United Kingdom

Location

Beatson Oncology Centre

Glasgow, United Kingdom

Location

Kettering General Hosptial

Kettering, NN16 8UZ, United Kingdom

Location

Leicester Royal Infirmary

Leicester, LE1 5WW, United Kingdom

Location

Kings College Hosptial

London, United Kingdom

Location

Manchester Royal Infirmary

Manchester, United Kingdom

Location

The Christie Hospital

Manchester, United Kingdom

Location

Norfolk and Norwich University Hospital

Norwich, United Kingdom

Location

Nottingham University Hosptial

Nottingham, United Kingdom

Location

Churchill Hospital

Oxford, United Kingdom

Location

Derriford Hospital

Plymouth, United Kingdom

Location

Southampton General Hospital

Southampton, SO16 6YD, United Kingdom

Location

Royal Stoke Hospital

Stoke-on-Trent, United Kingdom

Location

Royal Marsden Hospital

Sutton, SM2 5PT, United Kingdom

Location

Worcester Royal Hospital

Worcester, WR5 1DD, United Kingdom

Location

Related Publications (5)

• Keaveney S, Dragan A, Rata M, Blackledge M, Scurr E, Winfield JM, Shur J, Koh DM, Porta N, Candito A, King A, Rennie W, Gaba S, Suresh P, Malcolm P, Davis A, Nilak A, Shah A, Gandhi S, Albrizio M, Drury A, Pratt G, Cook G, Roberts S, Jenner M, Brown S, Kaiser M, Messiou C. Image quality in whole-body MRI using the MY-RADS protocol in a prospective multi-centre multiple myeloma study. Insights Imaging. 2023 Oct 15;14(1):170. doi: 10.1186/s13244-023-01498-3.

  PMID: 37840055 DERIVED

• Kaiser MF, Hall A, Walker K, Sherborne A, De Tute RM, Newnham N, Roberts S, Ingleson E, Bowles K, Garg M, Lokare A, Messiou C, Houlston RS, Jackson G, Cook G, Pratt G, Owen RG, Drayson MT, Brown SR, Jenner MW. Daratumumab, Cyclophosphamide, Bortezomib, Lenalidomide, and Dexamethasone as Induction and Extended Consolidation Improves Outcome in Ultra-High-Risk Multiple Myeloma. J Clin Oncol. 2023 Aug 10;41(23):3945-3955. doi: 10.1200/JCO.22.02567. Epub 2023 Jun 14.

  PMID: 37315268 DERIVED

• Rata M, Blackledge M, Scurr E, Winfield J, Koh DM, Dragan A, Candito A, King A, Rennie W, Gaba S, Suresh P, Malcolm P, Davis A, Nilak A, Shah A, Gandhi S, Albrizio M, Drury A, Roberts S, Jenner M, Brown S, Kaiser M, Messiou C. Implementation of Whole-Body MRI (MY-RADS) within the OPTIMUM/MUKnine multi-centre clinical trial for patients with myeloma. Insights Imaging. 2022 Jul 28;13(1):123. doi: 10.1186/s13244-022-01253-0.

  PMID: 35900614 DERIVED

• Oliva S, Kaiser MF. Is it time to tailor treatment on the basis of minimal residual disease in multiple myeloma? Lancet Haematol. 2021 Dec;8(12):e876-e877. doi: 10.1016/S2352-3026(21)00341-0. No abstract available.

  PMID: 34826409 DERIVED

• Pawlyn C. High-risk myeloma: a challenge to define and to determine the optimal treatment. Lancet Haematol. 2021 Jan;8(1):e4-e6. doi: 10.1016/S2352-3026(20)30361-6. Epub 2020 Dec 22. No abstract available.

  PMID: 33357481 DERIVED

MeSH Terms

Conditions

Multiple Myeloma

Interventions

Cyclophosphamide; Bortezomib; Lenalidomide; daratumumab; Dexamethasone; Melphalan; Filgrastim

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Piperidones; Piperidines; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Granulocyte Colony-Stimulating Factor; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Proteins; Biological Factors

Study Officials

• Martin Kaiser

  University of Leeds

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The trial is designed as a single arm phase II trial with interim assessments for futility, using a Bayesian strategy for monitoring multiple outcomes.

Study Record Dates

• First Submitted: May 2, 2017
• First Posted: June 15, 2017
• Study Start: September 28, 2017
• Primary Completion: October 1, 2025
• Study Completion (Estimated): May 31, 2026
• Last Updated: May 14, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

GB (21)