Cyclophosphamide-Bortezomib-Dexamethasone (CyBorD) With Daratumumab (DARA)

NCT02955810 | Unknown Phase 1 DMC

• 1 other identifier: 16-BCNI-001
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

This study is a Phase Ib open label, single arm, adaptive multicentre trial. Patients with newly diagnosed Multiple Myeloma (MM) will be treated with Cyclophosphamide-Bortezomib-Dexamethasone (CyBorD) in combination with Daratumumab (DARA). The safety profile of daratumumab to date, which does not appear to overlap with those known for approved agents, combined with its distinct MoA, suggest that the therapeutic profile of daratumumab combined with various backbone regimens may improve the treatment effect of these regimens. Additionally, daratumumab as a single agent may prolong the progression free interval for these patients. Based on the potential for cyclophosphamide to enhance ADCP, there is a strong rationale to combine DARA with a cyclophosphamide, bortezomib containing regimen. This will be the first clinical trial to explore the feasibility of combining daratumumab with a cyclophosphamide containing backbone induction regimen and if successful will provide the rationale for larger studies exploring the efficacy of this combination in greater detail.

Conditions

Multiple Myeloma

Keywords

Newly Diagnosed; Treatment Naiive

Outcome Measures

Primary Outcomes (2)

• MTD

  To determine the Maximum Tolerated Dose (MTD) for cyclophosphamide and bortezomib that can be safely administered with DARA.

  15 months

• The rate of Complete Response (CR) post Autologous Stem Cell Transplantation (ASCT)

  Efficacy assessed by the rate of Complete Response (CR) post Autologous Stem Cell Transplantation (ASCT)

  42 months

Secondary Outcomes (7)

• Safety and Tolerability as assessed by adverse events

  42 months

• Complete Response Rate at the end of induction, ASCT, consolidation and maintenance

  42 months

• Best Overall Response

  42 months

• Minimal Residual Disease (MRD) negative rate at the end of induction, ASCT, consolidation and maintenance

  42 months

• Progression Free Survival (PFS) at the end of maintenance phase

  42 months

Study Arms (1)

CyBorD-DARA

EXPERIMENTAL

Drug: Daratumumab; Drug: Cyclophosphamide; Drug: Bortezomib; Drug: Dexamethasone

Interventions

Daratumumab DRUG

Also known as: Darzalex

CyBorD-DARA

Cyclophosphamide DRUG

Also known as: Cytoxan

CyBorD-DARA

Bortezomib DRUG

Also known as: Velcade

CyBorD-DARA

Dexamethasone DRUG

CyBorD-DARA

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Each patient must sign an Informed Consent Form (ICF) indicating that he or she understands the purpose of and procedures required for the study and is willing to participate in the study.
• Patient must be between 18 and \<70 years of age.
• Patient must have documented diagnosis of multiple myeloma requiring treatment as per IMWG updated criteria for the diagnosis of multiple myeloma and measurable disease as defined by:
• Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy proven plasmacytoma
• Measurable disease as defined by any of the following:
• IgG multiple myeloma: serum monoclonal paraprotein (M-protein) level
• ≥1.0g/dl or urine M-protein level ≥200mg/24 hours; or
• IgA, IgE, IgD or IgM multiple myeloma: serum M-protein level ≥0.5g/dl or urine M-protein level ≥200mg/24 hours; or
• Light chain multiple myeloma without measurable disease in the serum or the urine: serum immunoglobulin free light chain ≥10mg/dl and abnormal serum immunoglobulin kappa lambda free light chain ratio.
• Newly diagnosed patient eligible for high dose therapy and autologous stem cell transplantation.
• Patient must have an ECOG performance status score of 0-2.
• Patient must have pre-treatment clinical laboratory values meeting the following criteria during the Screening Phase:
• Haemoglobin ≥7.5g/dl (≥5mmol/l); prior red blood cell \[RBC\] transfusion or recombinant human erythropoietin use is permitted);
• absolute neutrophil count (ANC) ≥1.0x109/l (GCSF is permitted);
• AST ≤ 2.5 x upper limit of normal (ULN);

You may not qualify if:

• Patient has received daratumumab or other anti-CD38 therapies previously.
• Patient has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, or smoldering multiple myeloma. Monoclonal gammopathy of undetermined significance is defined by presence of serum M-protein \< 3g/dl; absence of criteria consistent with active/symptomatic multiple myeloma as per IMWG criteria. Smoldering multiple myeloma is defined as asymptomatic multiple myeloma with absence of related organ or tissue impairment (ROTI) end organ damage.
• Patient has a diagnosis of Waldenstrom's macroglobulinemia or other conditions in which IgM M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions.
• Patient has prior or current systemic therapy or stem cell transplantation for any plasma cell dyscrasia, with the exception of an emergency use of a short course (equivalent of dexamethasone 40mg/day for a maximum 4 days) of corticosteroids before treatment.
• Patient has peripheral neuropathy or neuropathy grade 2 or higher, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.
• Patient has had any prior or concurrent invasive malignancy (other than multiple myeloma) within 5 years of screening period except adequately treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, localized prostate adenocarcinoma diagnosed ≥3 years and without evidence of biochemical failure, or other cancer for which the patient has undergone potentially curative therapy and has no evidence of that disease for ≥10 years.
• Patient has had radiation therapy within 14 days prior to start of study treatment.
• Patient has had plasmapheresis within 28 days of registration.
• Patient is exhibiting clinical signs of meningeal involvement of multiple myeloma.
• \. a) Patient has known chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) \< 50% of predicted normal. Note that FEV1 testing is required for patients suspected of having COPD and patients must be excluded if FEV1 \< 50% of predicted normal.
• b) Patient has known moderate or severe persistent asthma within the past 2 years, or currently has uncontrolled asthma of any classification. (Note that patients who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study).
• Patient is known to be seropositive for or active human immunodeficiency virus (HIV) or known to have active hepatitis B or hepatitis C.
• Patient has 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.
• Patient has clinically significant cardiac disease, including:
• myocardial infarction within 1 year before registration, 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 IIIIV), OR

Sponsors & Collaborators

• National University of Ireland, Galway, Ireland: lead
• Janssen Pharmaceuticals: collaborator
• Cancer Trials Ireland: collaborator

Study Sites (1)

Galway University Hospital

Galway, Ireland

Location

Related Publications (1)

• O'Dwyer M, Henderson R, Naicker SD, Cahill MR, Murphy P, Mykytiv V, Quinn J, McEllistrim C, Krawczyk J, Walsh J, Lenihan E, Kenny T, Hernando A, Hirakata G, Parker I, Kinsella E, Gannon G, Natoni A, Lynch K, Ryan AE. CyBorD-DARA is potent initial induction for MM and enhances ADCP: initial results of the 16-BCNI-001/CTRIAL-IE 16-02 study. Blood Adv. 2019 Jun 25;3(12):1815-1825. doi: 10.1182/bloodadvances.2019000010.

  PMID: 31201169 DERIVED

MeSH Terms

Conditions

Multiple Myeloma

Interventions

daratumumab; Cyclophosphamide; Bortezomib; Dexamethasone

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; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: October 18, 2016
• First Posted: November 4, 2016
• Study Start: November 1, 2016
• Primary Completion: September 1, 2018
• Study Completion: November 1, 2020
• Last Updated: March 29, 2018

Record last verified: 2018-03

Locations

IE (1)