Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu
Help guide our efforts to modernize ClinicalTrials.gov.
Send us your comments by March 14, 2020.

Nivolumab Combined With Daratumumab With or Without Low-dose Cyclophosphamide

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03184194
Recruitment Status : Recruiting
First Posted : June 12, 2017
Last Update Posted : October 2, 2019
Sponsor:
Collaborators:
Erasmus Medical Center
UMC Utrecht
Maastricht University Medical Center
Meander Medical Center
St. Antonius Hospital
Isala
Albert Schweitzer Hospital
Radboud University
University Medical Center Groningen
Rijnstate Hospital
Information provided by (Responsible Party):
WCJ van de Donk, VU University Medical Center

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

Condition or disease Intervention/treatment Phase
Myeloma Drug: nivolumab-daratumumab Drug: nivolumab-daratumumab with low-dose cyclophosphamide Phase 2

Detailed Description:

Myeloma patients who develop bortezomib and lenalidomide-resistant disease have a very poor survival of only a median of 9 months, indicating that new agents are urgently needed. Recent studies have shown that daratumumab as a single agent is effective and well tolerated in these heavily pretreated MM patients. However, approximately 60% of patients do not achieve a partial response, and ultimately all patients will develop progressive disease during daratumumab therapy. In less pretreated patients daratumumab-based combinations (daratumumab plus lenalidomide-dexamethasone or daratumumab plus bortezomib-dexamethasone) were very effective and well tolerated. Therefore, in this study, the investigators will combine daratumumab with other agents to improve survival of heavily pretreated MM patients.

The PD-1 blocker nivolumab, as single agent, does not induce objective responses but induces stable disease in approximately 67% of relapsed/refractory MM patients. We have recently shown that daratumumab treatment results in increased T cell frequencies by eliminating CD38-positive immune suppressor cells, which probably contributes to the durable responses observed with daratumumab.

Cyclophosphamide, at a dose substantially lower than the maximum tolerated dose, has next to its direct anti-tumor activity serveral other effects including anti-angiogenic effects, induction of changes in the micro-environment, and also improvement of the anti-tumor immune response.

In this study, the investigators will combine two or three immune modulating agents with different mechanisms of action in order to improve the outcome of relapsed/refractory MM patients.

The investigators will evaluate in Part A, nivolumab combined with daratumumab with or without low-dose cyclophosphamide (total 40 patients). Based on efficacy and tolerability, the investigators will treat in Part B 20 additional patients with nivolumab combined with daratumumab either with or without low-dose cyclophosphamide based on tolerability and efficacy data obtained in Part A.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Study of Nivolumab Combined With Daratumumab With or Without Low-dose Cyclophosphamide in Relapsed/Refractory Multiple Myeloma
Actual Study Start Date : February 21, 2018
Estimated Primary Completion Date : March 1, 2020
Estimated Study Completion Date : March 1, 2021


Arm Intervention/treatment
Experimental: Nivolumab-daratumumab
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 will be given without low-dose cyclophosphamide until progression
Other Name: Opdivo-darzalex

Experimental: Nivolumab-daratumumab with cylclophosphamide
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
nivolumab-daratumumab with low-dose cyclophosphamide will be given until progression
Other Name: Opdivo-darzalex with endoxan




Primary Outcome Measures :
  1. overall response rate [ Time Frame: active treatment period up to 5 years ]
    the best response obtained during treatment


Secondary Outcome Measures :
  1. incidence of treatment emergent adverse events [ Time Frame: active treatment period up to 5 years ]
    type, frequency and severity of adverse events

  2. progression-free survival [ Time Frame: up to 5 years ]
    time from registration to progression or death from any cause, whichever comes first)

  3. overall survival [ Time Frame: up to 5 years ]
    measured until death from any cause. Patients still alive or lost to follow up are censored at the date they were last known to be alive

  4. tumor expression profile as prognostic factor for response/survival [ Time Frame: up to 5 years ]
    tumor expresssion profile by flow-cytometric detection



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age >=18 years
  2. 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)
  3. 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.
  4. Subject had at least 2 prior anti-myeloma regimens. (Note: Induction, bone marrow transplant with or without maintenance therapy is considered one regimen.)
  5. 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.
  6. Subject received prior treatment with a proteasome inhibitor-containing regimen for at least 2 consecutive cycles.
  7. world health organization (WHO) performance 0, 1, or 2
  8. Life expectancy at least 3 months
  9. Written informed consent

Exclusion Criteria:

  1. Prior therapy with daratumumab or other anti-CD38 therapies
  2. Non-secretory myeloma
  3. Systemic amyloid light-chain (AL) amyloidosis or plasma cell leukemia (>2.0x109/L circulating plasma cells by standard differential) or Waldenstrom's macroglobulinemia
  4. Subject has known meningeal involvement of multiple myeloma
  5. 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.
  6. 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).
  7. Subject has previously received an allogeneic stem cell transplantation (at any time)
  8. 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
  9. 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).

  10. 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.
  11. 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
  12. Creatinine clearance <30 ml/min.
  13. Known hypersensitivity to components of the investigational products or severe allergic or anaphylactic reactions to humanized products.
  14. Subject has any concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, etc.) that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study.
  15. Subject is known to be seropositive for human immunodeficiency virus (HIV) or known to have acquired immunodeficiency syndrome (AIDS), or any positive test for hepatitis B or hepatitis C indicating acute or chronic infection.
  16. History of active malignancy during the past 3 years, except squamous cell and basal cell carcinomas of the skin and carcinoma in situ of the cervix or breast and incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor, nodes, metastasis] clinical staging system) or prostate cancer that is curative, or malignancy that in the opinion of the local investigator, with concurrence with the principal investigator, is considered cured with minimal risk of recurrence within 3 years.
  17. Subjects with active interstitial pneumonitis
  18. Subjects with active, known or suspected autoimmune disease or inflammatory disorder (including inflammatory bowel disease [eg, colitis, Crohn's disease], systemic lupus erythematosus, Wegener's syndrome, myasthenia gravis, Grave's disease, rheumatoid arthritis, hypophysitis, uveitis, etc.). Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
  19. Subjects with a condition (other than MM) requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
  20. Subject is known or suspected of not being able to comply with the study protocol (eg, because of alcoholism, drug dependency, or psychological disorder) or the subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise their well-being) or that could prevent, limit, or confound the protocol-specified assessments.
  21. Pregnant or lactating females
  22. Women of childbearing potential not willing to use adequate contraception, defined as hormonal birth control or intrauterine device, during the trial and for 1 year after the last dose of daratumumab or nivolumab or lenalidomide. Men who are sexually active with women of childbearing potential who are not willing to use adequate contraception for the duration of treatment with the study drugs and for 1 year after the last dose of daratumumab or nivolumab or lenalidomide.
  23. Peripheral neuropathy of ≥grade 2.
  24. History of allergy to study drug components

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03184194


Contacts
Layout table for location contacts
Contact: Niels van de Donk, MD PhD 0204444444 ext +31 n.vandedonk@vumc.nl
Contact: Christie Verkleij, MD 0204444444 ext +31 c.verkleij@vumc.nl

Locations
Layout table for location information
Netherlands
Rijnstate ziekenhuis Not yet recruiting
Arnhem, Ge, Netherlands
Contact: Ellen van der Spek, MD PhD         
Radboud MC Not yet recruiting
Nijmegen, Ge, Netherlands
Contact: Sandra Croockewit, MD PhD         
UMC Groningen Not yet recruiting
Groningen, Gr, Netherlands
Contact: Goda Choi, MD PhD         
MUMC Recruiting
Maastricht, Li, Netherlands
Contact: Gerard Bos, MD PhD         
VU University Medical Center Recruiting
Amsterdam, NH, Netherlands, 1081HV
Contact: Niels van de Donk, MD PhD       n.vandedonk@vumc.nl   
Contact: Christie Verkleij, MD       c.verkleij@vumc.nl   
Isala Klinieken Not yet recruiting
Zwolle, Ov, Netherlands
Contact: Juleon Coenen, MD PhD         
Meander MC Recruiting
Amersfoort, Ut, Netherlands
Contact: Saskia Klein, MD PhD         
St. Antonius Ziekenhuis Recruiting
Nieuwegein, Ut, Netherlands
Contact: Okke de Weerdt, MD PhD         
UMC Utrecht Recruiting
Utrecht, Ut, Netherlands
Contact: Monique Minnema, MD PhD         
Albert Schweitzer Ziekenhuis Recruiting
Dordrecht, ZH, Netherlands
Contact: MD Levin, MD PhD         
Erasmus MC Not yet recruiting
Rotterdam, ZH, Netherlands
Contact: Pieter Sonneveld, MD PhD         
Contact: Annemiek Broyl, MD PhD         
Sponsors and Collaborators
VU University Medical Center
Erasmus Medical Center
UMC Utrecht
Maastricht University Medical Center
Meander Medical Center
St. Antonius Hospital
Isala
Albert Schweitzer Hospital
Radboud University
University Medical Center Groningen
Rijnstate Hospital
Investigators
Layout table for investigator information
Principal Investigator: Niels van de Donk, MD PhD VUmc

Layout table for additonal information
Responsible Party: WCJ van de Donk, Principal Investigator, VU University Medical Center
ClinicalTrials.gov Identifier: NCT03184194    
Other Study ID Numbers: CA209-755
First Posted: June 12, 2017    Key Record Dates
Last Update Posted: October 2, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by WCJ van de Donk, VU University Medical Center:
daratumumab
nivolumab
cyclophosphamide
Additional relevant MeSH terms:
Layout table for MeSH terms
Multiple Myeloma
Daratumumab
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Nivolumab
Antibodies, Monoclonal
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Immunological