Daratumumab, Thalidomide and Dexamethasone in Relapse and/or Refractory Myeloma

NCT03143036 | Unknown Phase 2

• 1 other identifier: AMN004
• Study Type: interventional
• Target: 100
• Locations: 4 countries
• Sites: 5

Brief 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 ½ 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.

Conditions

Relapse and / or Refractory Myeloma

Keywords

daratumumab

Outcome Measures

Primary Outcomes (1)

• Progression free survival (PFS)

  To assess the progression free survival (PFS) for daratumumab in combination with thalidomide and dexamethasone in Asian patients with relapsed myeloma.

  Time from commencement of treatment to disease progression or death, whichever occurs first, assessed up to 100 months

Secondary Outcomes (4)

• Overall Response Rate (ORR)

  anytime from commencement of treatment with daratumumab, thalidomide and dexamethasone to the end of studyaseline until disease progression, unmanageable adverse event or death, whichever occurs first, approximately up to 3 years

• Overall survival (OS)

  Up to approximately 5 years (anticipated) after the last participant is enrolled

• Duration of response (DOR)

  the time from first evidence of PR or VGPR, or CR, or sCR to confirmation of disease progression or death due to any cause, assessed up to 100 months

• Number of Participants affected by Adverse Events

  from the time of enrolment into study till 3 years from the date of the last patient randomized

Study Arms (1)

Daratumumab, thalidomide and dexamethasone

EXPERIMENTAL

Drug: Daratumumab, thalidomide and dexamethasone

Interventions

Daratumumab, thalidomide and dexamethasone DRUG

Patients will be treated with with the following schedule. IV daratumumab 16mg/kg body weight weekly for weeks 1-8 followed by daratumumab 16mg/kg body weight once every 2 weeks from weeks 9 to 24 and then daratumumab 16mg/kg once every 4 weeks from weeks 25 onwards until disease progression; PO thalidomide 100mg daily for 1 year and PO Dexamethasone 40mg (starting dose of dexamethasone is 20mg once weekly for patients \>75 years old) once weekly for 1 year (13 cycles, each cycle is 4 weeks). After 1 year, patient only continue on daratumumab until progression Patients will be assessed every 28 days (+/-10 days).

Daratumumab, thalidomide and dexamethasone

Eligibility Criteria

• Age: 21 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National University Hospital, Singapore: lead
• Janssen, LP: collaborator
• International Myeloma Foundation: collaborator

Study Sites (5)

Queen Mary Hospital

Hong Kong, Hong Kong

NOT YET RECRUITING

National University Hospital

Singapore, Singapore

RECRUITING

Singapore General Hospital

Singapore, Singapore

RECRUITING

Samsung Medical Center

South Korea, South Korea

NOT YET RECRUITING

National Taiwan University

Taipei, Taiwan

NOT YET RECRUITING

Related Publications (4)

• Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, Belch A, Krishnan A, Vescio RA, Mateos MV, Mazumder A, Orlowski RZ, Sutherland HJ, Blade J, Scott EC, Oriol A, Berdeja J, Gharibo M, Stevens DA, LeBlanc R, Sebag M, Callander N, Jakubowiak A, White D, de la Rubia J, Richardson PG, Lisby S, Feng H, Uhlar CM, Khan I, Ahmadi T, Voorhees PM. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016 Apr 9;387(10027):1551-1560. doi: 10.1016/S0140-6736(15)01120-4. Epub 2016 Jan 7.

  PMID: 26778538 BACKGROUND

• Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, Minnema MC, Lassen U, Krejcik J, Palumbo A, van de Donk NW, Ahmadi T, Khan I, Uhlar CM, Wang J, Sasser AK, Losic N, Lisby S, Basse L, Brun N, Richardson PG. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N Engl J Med. 2015 Sep 24;373(13):1207-19. doi: 10.1056/NEJMoa1506348. Epub 2015 Aug 26.

  PMID: 26308596 BACKGROUND

• 3. Palumbo A, Chanan-Khan A, Weisel K, et al. Phase III randomized controlled study of daratumumab, bortezomib and dexamethasone (DVd) versus bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma (RRMM): CASTOR study. J Clin Oncol 2016; 34 (Suppl abstr LBA4)

  BACKGROUND

• 4. Dimopoulos MA, Oriol A, Nahi H, et al. An open-label, randomised phase 3 study of daratumumab, lenalidomide, dexamethasone (DRD) versus lenalidomide and dexamethasone (RD) in relapsed or refractory multiple myeloma (RRMM): POLLUX. EHA 2016 Abstract LB2238

  BACKGROUND

MeSH Terms

Conditions

Recurrence; Neoplasms, Plasma Cell

Interventions

daratumumab; Thalidomide; Dexamethasone

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Study Officials

• Wee Joo Chng

  National University Hospital, Singapore

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Wee Joo Chng

CONTACT

6779 5555; mdccwj@nus.edu.sg

Adeline Lin

CONTACT

6779 5555; adeline_hf_lin@nuhs.edu.sg

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: This is a phase 2 study of the combination of Daratumumab, thalidomide and dexamethasone in 100 Asian patients with relapse or refractory multiple myeloma.

Study Record Dates

• First Submitted: April 13, 2017
• First Posted: May 8, 2017
• Study Start: May 1, 2018
• Primary Completion: July 1, 2019
• Study Completion: July 1, 2022
• Last Updated: June 7, 2018

Record last verified: 2018-05

Locations

HK (1); TW (1); KR (1); SG (2)