Nivolumab Combined With Daratumumab With or Without Low-dose Cyclophosphamide

NCT03184194 | Completed Phase 2 DMC

• 1 other identifier: CA209-755
• Study Type: interventional
• Target: 62
• Locations: 1 country
• Sites: 9

Brief Summary

Evaluation of the effect of nivolumab and daratumumab with or without low-dose cyclophosphamide in patients with relapsed/refractory multiple myeloma.

Conditions

Myeloma

Keywords

daratumumab; nivolumab; cyclophosphamide

Outcome Measures

Primary Outcomes (1)

• overall response rate

  the best response obtained during treatment

  active treatment period up to 5 years

Secondary Outcomes (4)

• incidence of treatment emergent adverse events

  active treatment period up to 5 years

• progression-free survival

  up to 5 years

• overall survival

  up to 5 years

• tumor expression profile as prognostic factor for response/survival

  up to 5 years

Study Arms (2)

Nivolumab-daratumumab

EXPERIMENTAL

daratumumab 16 mg/kg: 8 times once weekly, then 8 times every 2 weeks; then every 4 weeks; nivolumab: 240 mg every 2 weeks during first 6 cycles, followed by 480 mg every 4 weeks

Drug: nivolumab-daratumumab

Nivolumab-daratumumab with cylclophosphamide

EXPERIMENTAL

daratumumab 16 mg/kg: weekly for 8 weeks, then Q2W for 16 weeks, ten Q4W thereafter; nivolumab: 240 mg every 2 weeks during first 6 cycles, followed by 480 mg every 4 weeks; low-dose cyclophosphamide 50mg daily on days 1-28 of each 28-day cycle;

Drug: nivolumab-daratumumab with low-dose cyclophosphamide

Interventions

nivolumab-daratumumab DRUG

nivolumab-daratumumab will be given without low-dose cyclophosphamide until progression

Also known as: Opdivo-darzalex

Nivolumab-daratumumab

nivolumab-daratumumab with low-dose cyclophosphamide DRUG

nivolumab-daratumumab with low-dose cyclophosphamide will be given until progression

Also known as: Opdivo-darzalex with endoxan

Nivolumab-daratumumab with cylclophosphamide

Eligibility Criteria

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

You may qualify if:

• Age \>=18 years
• Subject must have documented multiple myeloma as defined by the criteria below:
• Monoclonal plasma cells in the bone marrow ≥10% at some point in their disease history or presence of a biopsy proven plasmacytoma.
• Measurable disease as defined by any of the following:
• Serum monoclonal paraprotein (M-protein) level ≥5 g/L (0.5 g/dL); or urine M-protein level ≥200 mg/24 hours; or serum immunoglobulin free light chain ≥100 mg/L (10 mg/dL) and abnormal serum immunoglobulin kappa lambda free light chain ratio (See Appendix A)
• Relapsed or refractory disease. Relapse is defined as progression of disease after an initial response to previous treatment, more than 60 days after cessation of treatment. Refractory disease is defined as \<25% reduction in M-protein or progression of disease during treatment or within 60 days after cessation of treatment.
• Subject had at least 2 prior anti-myeloma regimens. (Note: Induction, bone marrow transplant with or without maintenance therapy is considered one regimen.)
• Subject has developed lenalidomide-refractory disease during prior treatment with a lenalidomide-containing regimen. Refractory disease is defined as \<25% reduction in M-protein or progression of disease during treatment or within 60 days after cessation of treatment.
• Subject received prior treatment with a proteasome inhibitor-containing regimen for at least 2 consecutive cycles.
• world health organization (WHO) performance 0, 1, or 2
• Life expectancy at least 3 months
• Written informed consent

You may not qualify if:

• Prior therapy with daratumumab or other anti-CD38 therapies
• Non-secretory myeloma
• Systemic amyloid light-chain (AL) amyloidosis or plasma cell leukemia (\>2.0x109/L circulating plasma cells by standard differential) or Waldenstrom's macroglobulinemia
• Subject has known meningeal involvement of multiple myeloma
• Subject has received anti-myeloma treatment within 2 weeks or 5 pharmacokinetic half-lives of the treatment, whichever is longer, before start of treatment. This included subjects who have received a cumulative dose of corticosteroid greater than or equal to the equivalence of 140 mg prednisone or a single dose of corticosteroid greater than or equal to the equivalence of 40 mg/day dexamethasone within the 2-week period before start of treatment.
• Prior treatment with an anti-PD1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
• Subject has previously received an allogeneic stem cell transplantation (at any time)
• Inadequate marrow reserve as defined by a platelet count \<75 x 109/L (\<50 x 109/L if ≥50% of bone marrow mononucleated cells are plasma cells) or an absolute neutrophil count \<1.0 x 109/L
• a) Subject has known chronic obstructive pulmonary disease (COPD) with an Forced Expiratory Volume in 1 second (FEV1) \< 50% of predicted normal. Note that FEV1 testing is required for patients suspected of having COPD and subjects must be excluded if FEV1 \<50% of predicted normal.
• b) Subject has known moderate or severe persistent asthma within the past 2 years, or currently has uncontrolled asthma of any classification. (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study).
• Subject has clinically significant cardiac disease, including:
• Myocardial infarction within 6 months before Cycle 1, Day 1, or unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV)
• Cardiac arrhythmia (Common Terminology Criteria for Adverse Events \[CTCAE\] Version 4 Grade 2 or higher) or clinically significant ECG abnormalities.
• Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF) \>470 msec.
• Significant hepatic dysfunction (total bilirubin \>1.5 times normal value (except subjects with Gilbert syndrome, who can have total bilirubin \<3.0 mg/dL) or transaminases \> 3 times normal value), unless related to myeloma

Sponsors & Collaborators

• Amsterdam UMC, location VUmc: lead
• Erasmus Medical Center: collaborator
• UMC Utrecht: collaborator
• Maastricht University Medical Center: collaborator
• Meander Medical Center: collaborator
• St. Antonius Hospital: collaborator
• Isala: collaborator
• Albert Schweitzer Hospital: collaborator
• Radboud University Medical Center: collaborator
• University Medical Center Groningen: collaborator
• Rijnstate Hospital: collaborator

Study Sites (9)

Rijnstate ziekenhuis

Arnhem, Ge, Netherlands

Location

Radboud MC

Nijmegen, Ge, Netherlands

Location

MUMC

Maastricht, Li, Netherlands

Location

VU University Medical Center

Amsterdam, North Holland, 1081HV, Netherlands

Location

UMC Groningen

Groningen, Provincie Groningen, Netherlands

Location

Albert Schweitzer Ziekenhuis

Dordrecht, South Holland, Netherlands

Location

Meander MC

Amersfoort, Utrecht, Netherlands

Location

St. Antonius Ziekenhuis

Nieuwegein, Utrecht, Netherlands

Location

UMC Utrecht

Utrecht, Utrecht, Netherlands

Location

Related Publications (1)

• Noori S, Verkleij CPM, Zajec M, Langerhorst P, Bosman PWC, de Rijke YB, Zweegman S, VanDuijn M, Luider T, van de Donk NWCJ, Jacobs JFM. Monitoring the M-protein of multiple myeloma patients treated with a combination of monoclonal antibodies: the laboratory solution to eliminate interference. Clin Chem Lab Med. 2021 Aug 16;59(12):1963-1971. doi: 10.1515/cclm-2021-0399. Print 2021 Nov 25.

  PMID: 34392637 DERIVED

MeSH Terms

Conditions

Neoplasms, Plasma Cell

Interventions

Cyclophosphamide

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• Niels van de Donk, MD PhD

  VUmc

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: June 2, 2017
• First Posted: June 12, 2017
• Study Start: February 21, 2018
• Primary Completion: January 25, 2023
• Study Completion: January 25, 2024
• Last Updated: May 22, 2024

Record last verified: 2024-05

Locations

NL (9)