MUK Nine b: OPTIMUM Treatment Protocol (MUKnineb)

• ClinicalTrials.gov Identifier: NCT03188172
• Recruitment Status: Unknown
• First Posted: June 15, 2017
• Last Update Posted: May 25, 2022
• Sponsor: University of Leeds
• Collaborators: Myeloma UK; Celgene; Janssen, LP
• Information provided by (Responsible Party): University of Leeds

Tracking Information

• First Submitted Date: May 2, 2017
• First Posted Date: June 15, 2017
• Last Update Posted Date: May 25, 2022
• Actual Study Start Date: September 28, 2017
• Estimated Primary Completion Date: December 31, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 14, 2017)

Progression free survival [ Time Frame: At 18 months post registration ]

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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 14, 2017)

• Occurrence of Serious Adverse Events(SAE) and Suspected, Unexpected Serious Adverse Reactions (SUSAR) [ Time Frame: At 120 days post autologous stem cell transplant (ASCT) ]
  Will be reported based on occurrence of SAE & SUSARs with details of causality and expectedness.
• Progression free survival at 100 days post autologous stem cell transplant [ Time Frame: At 100 days post ASCT ]
  Determine whether the treatment schedule should be dropped for futility
• Minimal residual disease (MRD) negative disease [ Time Frame: At 100 days post ASCT ]
  Defined as absence of aberrant phenotype plasma cells
• Overall survival [ Time Frame: At 12 months, 24 months & 36 months post registration ]
  Median overall survival estimates
• Maximum response [ Time Frame: From registration to end of induction therapy, 100 days post ASCT, post consolidation part 2 ]
  Proportion of participants achieving each response category. Time from registration until the participant achieves a maximum response.
• Overall response [ Time Frame: At end of induction therapy, 100 days post ASCT, post consolidation part 2 ]
  Proportion of participants receiving at least a partial response
• Second progression free survival [ Time Frame: From registration until second disease progression, 3 years ]
  Time from registration to second disease progression or death.
• Overall treatment benefit [ Time Frame: At the end of induction therapy and 100 days post autologous stem cell transplant ]
  Clinician assessment of treatment benefit will be obtained
• Quality of Life [ Time Frame: From registration until second disease progression, 3 years ]
  Based on EQ-5D outcome measure combined with EORTC QLQ-C30 and MY20 responses

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: June 14, 2017)

• Progression free survival (comparison with Myeloma XI/XI+ data) [ Time Frame: From registration until second disease progression, 3 years ]
  Matched comparison of progression free survival
• Impact of minimal residual disease on progression free survival [ Time Frame: From registration until second disease progression, 3 years ]
  Analysis will include any participant with a MRD assessment
• Genomic instability [ Time Frame: From registration until second disease progression, 3 years ]
  To be investigated in an exploratory manner and will include analysis of new genetic abnormalities

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: MUK Nine b: OPTIMUM Treatment Protocol
• Official Title: MUK Nine b: OPTIMUM. A Phase II Study Evaluating Optimised Combination of Biological Therapy in Newly Diagnosed High Risk Multiple Myeloma and Plasma Cell Leukaemia.
• 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.

Detailed Description

Multiple myeloma (MM) is a plasma cell tumour with an annual incidence in the UK of approximately 40 -50 per million i.e. 4500 new cases per annum. Approximately 20% of the patients diagnosed with multiple myeloma have a significantly worse prognosis at 3 years than other multiple myeloma patients and these are characterised as having high risk (HR) disease defined by genetic lesions and gene expression profiles (GEP). There have been no significant improvements in outcome over the last decade for patients with HR disease. Therefore, it is important to identify more effective treatment options for this group of patients especially given that the number of novel agents are potentially available and which can be given as part of intensive therapy regimen.

Intensive treatment in HR patients has been used outside the UK with promising results but access to drugs in the UK has been challenging with constraints in the NHS treatment pathway. This is the first time in the UK that newly diagnosed multiple myeloma patients may be entered into a clinical trial prospectively according to their genetic risk profile. It provides a unique opportunity to improve outcomes and provide evidence for high cost novel treatment strategies in this restricted population of poor prognosis patients.

The MUKnine trial is designed to evaluate the novel treatment strategies for multiple myeloma patients with HR disease and incorporate a genetic screening component. Patients identified as having HR disease are then invited to take part in the phase II single arm, multi centre trial that investigates the intensive treatment schedule comprising four novel agents bortezomib (Velcade), lenalidomide (Revlimid), daratumumab (Daralex), dexamethasone with cyclophosphamide. The trial will determine if this treatment strategy is sufficiently active to take forward in to further testing in this population. Patients identified as not having HR disease will receive standard local treatment and will be followed up in a cohort study to assess response, progression free survival and overall survival.

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

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

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Multiple Myeloma

Intervention

• Drug: Cyclophosphamide
  Chemotherapy
• Drug: Bortezomib
  Chemotherapy
  Other Name: Velcade
• Drug: Lenalidomide
  Chemotherapy
  Other Name: Revlamid
• Drug: Daratumumab
  Chemotherapy
  Other Name: Daralex
• Drug: Dexamethasone
  Chemotherapy
• Drug: Melphalan
  Chemotherapy
• Drug: Filgrastim
  Haematopoietic agent for the stem cell harvest

Study Arms

Experimental: Trial Treatment

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

Interventions:

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

Publications *

• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: June 14, 2017): 95
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: June 30, 2023
• Estimated Primary Completion Date: December 31, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Confirmation of High Risk status from Institute of Cancer Research (ICR) following bone marrow and blood sample processed through the MUKnine a screening protocol.
2. 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).

3. 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.

4. Non measurable participants providing they accept a 3 monthly bone marrow during induction and a 6 monthly bone marrow assessment during consolidation and maintenance.
5. Aged 18 years or over.
6. Fit for intensive chemotherapy and autologous stem cell transplant (at clinician's discretion).
7. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2.

8. 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.
9. Calculated creatinine clearance ≥ 30mL/min (using Cockcroft-Gault formula).
10. Alanine transaminase (ALT) and/or Aspartate transaminase (AST) ≤ 2.5 times upper limit of normal (ULN).
11. Bilirubin ≤ 2.0 x ULN, except in participants with congenital bilirubinemia, such as Gilbert syndrome (direct bilirubin ≤2.0 times ULN
12. Platelet count ≥ 75 x 109/L. (≥ 50 x 109/L if myeloma involvement in the bone marrow is >50%). Platelet support is permitted.
13. Absolute neutrophil count (ANC) ≥ 1.0 x 109/L. Growth factor support is permitted.
14. Haemoglobin ≥ 80 g/L. (Participants may be receiving red blood cell (RBC) transfusions in accordance with institutional guidelines.
15. Corrected serum calcium ≤ 3.5 mmol/L.

Exclusion Criteria:

1. Solitary bone/solitary extramedullary plasmacytoma.
2. Primary diagnosis of amyloidosis, monoclonal gammopathy of undetermined significance or smoldering multiple myeloma or Waldenstrom's Disease.

3. 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.
4. 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).

5. 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.

6. Known to be seropositive for history of human immunodeficiency virus (HIV) or known to have active hepatitis B or hepatitis C.
7. 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.
8. Clinically significant allergies or intolerance to cyclophosphamide, lenalidomide, velcade, daratumumab or dexamethasone. · Previous treatment with daratumumab or any other anti-CD38 therapies.
9. Participants with contraindication to thromboprophylaxis.
10. Grade 2 or greater peripheral neuropathy (per NCI-CTCAEv4.0).
11. Participants with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).
12. Any concurrent medical or psychiatric condition or disease (e.g., active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study.
13. Known or suspected of not being able to comply with the study protocol (e.g., because of alcoholism, drug dependency, or psychological disorder). Participant has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
14. Participant is a woman who is pregnant, or breast-feeding, or planning to become pregnant while enrolled in this trial or within at least 6 months after the last dose of trial treatment. Or, participant is a man who plans to father a child while taking part in this trial or within at least 6 months after the last dose of trial treatment.
15. Major surgery within 2 weeks before treatment protocol registration or has not fully recovered from surgery, or has surgery planned during the time the participant is expected to participate in the study. Kyphoplasty or vertebroplasty is not considered major surgery.
16. Received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before treatment protocol registration or is currently enrolled in an interventional investigational study.

Inclusion Criteria for ASCT

1. Minimum stem cell harvest of 2 x 106 CD34+ cells/kg body weight.
2. Received a minimum of 4, unless a complete response (CR) has been achieved with a lesser number, or a maximum of 6 Induction (CVRDd) cycles.
3. Achieved a response of stable disease (SD) or better.

Exclusion Criteria for ASCT 1. Participants that have progressive disease.

Inclusion Criteria for Consolidation Part 1 (VRDd)

1. Undergone autologous transplant with high dose melphalan-velcade (HDM-V) conditioning (Participants must have received a minimum of 100 mg/m2 Melphalan in order to proceed with consolidation).
2. Neutrophils ≥ 1.0 x 109/L. Growth factor support is permitted.
3. Platelet count ≥ 75 x 109/L. Platelet support is permitted.

Exclusion Criteria for Consolidation Part 1 (VRDd)

1. Participants that have progressive disease.

Inclusion Criteria for Consolidation Part 2 (VRD)

1. Received 6 cycles of Consolidation Part 1 (VRDd) or 1 cycle of VRd pre-harvest plus 5 cycles of Consolidation Part 1 (VRDd).
2. Neutrophils ≥ 1.0 x 109/L. Growth factor support is permitted.
3. Platelet count ≥ 75 x 109/L. Platelet support is permitted.

Exclusion Criteria for Consolidation Part 2 (VRD)

1. Participants that have progressive disease.

Inclusion Criteria for Maintenance (RD)

1. Received 12 cycles of Consolidation Part 2 (VRD).
2. Neutrophils ≥ 1.0 x 109/L. Growth factor support is permitted.
3. Platelet count ≥ 75 x 109/L. Platelet support is permitted.

Exclusion Criteria for Maintenance (RD)

1. Participants that have progressive disease.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 100 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United Kingdom

Administrative Information

• NCT Number: NCT03188172
• Other Study ID Numbers: HM16/235
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: University of Leeds
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Leeds
• Original Study Sponsor: Same as current

Collaborators

• Myeloma UK
• Celgene
• Janssen, LP

Investigators

• Principal Investigator: Martin Kaiser; University of Leeds

• PRS Account: University of Leeds
• Verification Date: May 2022