Daratumumab Thalidomide and Dexamethasone in Relapse and/or Refractory Myeloma

  • STATUS
    Recruiting
  • End date
    Jul 1, 2022
  • participants needed
    100
  • sponsor
    National University Hospital, Singapore
Updated on 22 January 2021

Summary

Myeloma patients who relapse after prior treatment with bortezomib and lenalidomide have survival of less than 1 year. A number of new drugs have been approved for the treatment of relapse myeloma in the last couple of years, including, Elotuzumab, Panobinostat, Ixazomib, carfilzomib and Pomalidomide. However, most of these drugs either do not have good single agent activity or still belongs to the category of immunomodulatory drugs or proteasome inhibitors. Daratumumab is a monoclonal antibody against CD38 that is highly expressed on myeloma plasma cells. In phase studies, it has impressive single agent activity in relapse and refractory myeloma with a very acceptable toxicity profile. This set the stage for combinations with daratumumab to increase efficacy and improve outcome of patients with myeloma. The use of immunomodulatory drugs, such as thalidomide and lenalidomide, has been shown to augment NK cell activity. NK cells are important mediator of antibody dependent cellular cytotoxicity. We therefore hypothesize that the combination of Daratumumab with thalidomide may therefore improve the efficacy of the treatment.

In this study, we will plan to perform a phase II trial using the Daratumumab, Thalidomide, Dexamethasone combination in 100 myeloma patients with relapse myeloma in Asia.

Description

Daratumumab is a humanized antibody against CD38 which is expressed on myeloma cells. Daratumumab exhibited single agent activity in myeloma and is a promising new treatment. Recently, 2 phase 1 / 2 studies establishes the dosing regimen for Daratumumab and impressive single agent activity of about 30% response rates in patients who relapse after prior lenalidomide and bortezomib. Daratumumab also appear to be well tolerated. The most common toxicity is infusion-related and almost all confined to the first cycle. On the whole these are manageable with early intervention, concurrent corticosteroids and anti-histamines as well as slowing infusion rate. More recently, early results from 2 randomise study comparing Daratumumab plus lenalidomide and dexamethasone compared to lenalidomide and dexamethasone, and Daratumumab plus bortezomib and dexamethasone compared to bortezomib and dexamethasone, showed that the addition of Daratumumab significantly improved response and progression free survival, including a high minimal residual disease (MRD) negative rate of more than 20% in the relapse myeloma populations.

In addition, the use of immunomodulatory drugs, such as thalidomide and lenalidomide, has been shown to augment NK cell activity. NK cells are important mediator of antibody dependent cellular cytotoxicity, which is an important mechanism of action for Daratumumab. Furthermore, in the studies using another antibody target SLAMF7, Elotuzumab, the addition of dexamethasone greatly improve efficacy. Furthermore, thalidomide plus dexamethasone combination have a long history in myeloma and is relatively well tolerated and cost-effective. We therefore propose to add Daratumumab to thalidomide and dexamethasone, as this combination will be relatively easy to deliver in the Asian population because of availability and there is good rationale that such a combination will be synergistic and well-tolerated

Patients will be assessed every 28 days (+/-10 days). Patients shall receive the treatment until disease progression, unacceptable toxicity as determined by treating physician, withdrawal of consent or mortality (whichever occurs first). After disease progression, the treating physician should provide long-term follow-up data on disease status and survival. For patients who discontinued treatment before disease progression occurred, disease assessment measurements shall be performed once every 28 days (+/- 10 days) until disease progression. After patients have documented progression of disease, they will be followed for survival every 3 months (+/-10 days) until study closure or until patients withdraws consent, is lost to follow-up or until death, whichever comes first. For any patient who is lost to follow-up, the study site shall attempt to ascertain survival information via public database search.

Details
Condition Relapse and / or Refractory Myeloma, Relapse and / or Refractory Myeloma
Treatment Daratumumab, thalidomide and dexamethasone
Clinical Study IdentifierNCT03143036
SponsorNational University Hospital, Singapore
Last Modified on22 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Multiple myeloma, diagnosed according to standard criteria, with relapsing and refractory disease at study entry
Patients must have evaluable multiple myeloma with at least one of the following (within 21 days of starting treatment)
Serum M-protein 0.5g/dL, or
In subjects without detectable serum M-protein, Urine M-protein 200mg/24 hour, or serum free light chai (sFLC) > 100mg/L (involved light chain) and an abnormal kappa/Lambda ratio
Must receive at least 1 line of prior treatment. (Induction therapy followed by stem cell transplantation and consolidation/maintenance therapy will be considered as one line of treatment)
Must have relapsed disease and/or be refractory to prior treatment except for thalidomide or lenalidomide. Refractoriness is defined as disease progression on treatment or progression within 6 months after the last dose of a given therapy. Relapse is defined according to the criteria of IMWG
Males and females 18 years of age or > country's legal age for adult consent
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2
Patients must meet the following clinical laboratory criteria with 21 days of starting
treatment
Absolute neutrophil count (ANC) 1,000/mm3 and platelet 50,000/mm3 ( 30,000/mm3 if myeloma involvement in the bone marrow is >50%)
Total bilirubin 1.5 x the upper limit of the normal range (ULN). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 3 x ULN
Calculated creatinine clearance 30mL/min
Written informed consent in accordance with federal, local and institutional guidelines

Exclusion Criteria

Female patients who are lactating or pregnant
Multiple Myeloma of IgM subtype
Glucocorticoid therapy (prednisolone > 30mg/day or equivalent) within 14 days prior to informed consent obtained
POEMS syndrome
Plasma cell leukemia or circulating plasma cells 2 x 109/L
Waldenstrom's Macroglobulinaemia
Existing peripheral neuropathy of grade 2 or higher or presence of neuropathic pain
Patients with known amyloidosis
Chemotherapy with approved or investigation anticancer therapeutics within 21 days prior to starting Dara-TD treatment
Focal radiation therapy within 7 days prior to start of Dara-TD. Radiation therapy to an extended field involving a significant volume of bone marrow within 21 days prior to start of pomalidomide
Immunotherapy (excluding steroids) 21 days prior to start of Dara-TD
Major surgery (excluding kyphoplasty) within 28 days prior to start of Dara-TD
Active congestive heart failure (New York Heart Association [NYHA] Class III or IV), symptomatic ischaemia, or conduction abnormalities uncontrolled by conventional intervention. Myocardial infarction within 4 months prior to informed consent obtained
Known HIV seropositive, hepatitis C infection, and/or hepatitis B (except for patients with hepatitis B surface antigen or core antibody receiving and responding to antiviral therapy directed at hepatitis B: these patients are allowed)
Patients with known cirrhosis
Patients with creatinine clearance <30m/min
Second malignancy within the past 3 years except
Adequately treated basal cell or squamous cell skin cancer
Carcinoma in situ of the cervix
Breast carcinoma in situ with full surgical resection
Patients with myelodysplastic syndrome
Patients with steroid or thalidomide hypersensitivity
Patients previously treated with daratumumab or other anti-CD38 antibodies
Ongoing graft-versus-host disease
Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to starting Dara-TD treatment
Disease refractory to thalidomide or lenalidomide
Contraindication to any of the required concomitant drugs or supportive treatments
Any clinically significant medical disease or psychiatric condition that, in the investigator's opinion, may interfere with protocol adherence or a patient's ability to give informed consent
Clear my responses

How to participate?

Step 1 Connect with a study center
What happens next?
  • You can expect the study team to contact you via email or phone in the next few days.
  • Sign up as volunteer to help accelerate the development of new treatments and to get notified about similar trials.

You are contacting

Investigator Avatar

Primary Contact

site

0/250

Additional screening procedures may be conducted by the study team before you can be confirmed eligible to participate.

Learn more

If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.

Learn more

Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.

Learn more

Similar trials to consider

Loading...

Not finding what you're looking for?

Every year hundreds of thousands of volunteers step forward to participate in research. Sign up as a volunteer and receive email notifications when clinical trials are posted in the medical category of interest to you.

Sign up as volunteer

user name

Added by • 

 • 

Private

Reply by • Private
Loading...

Lorem ipsum dolor sit amet consectetur, adipisicing elit. Ipsa vel nobis alias. Quae eveniet velit voluptate quo doloribus maxime et dicta in sequi, corporis quod. Ea, dolor eius? Dolore, vel!

  The passcode will expire in None.
Loading...

No annotations made yet

Add a private note
  • abc Select a piece of text from the left.
  • Add notes visible only to you.
  • Send it to people through a passcode protected link.
Add a private note