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Ixazomib Citrate, Lenalidomide, Dexamethasone, and Zoledronic Acid or Zoledronic Acid Alone After Radiation Therapy in Treating Patients With Solitary Plasmacytoma of Bone

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ClinicalTrials.gov Identifier: NCT02516423
Recruitment Status : Active, not recruiting
First Posted : August 5, 2015
Last Update Posted : December 5, 2018
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Millennium Pharmaceuticals, Inc.
Biologics, Inc.
Information provided by (Responsible Party):
Alliance for Clinical Trials in Oncology

Brief Summary:
This randomized phase III trial compares ixazomib citrate, lenalidomide, dexamethasone and zoledronic acid with zoledronic acid alone to see how well they work when given after radiation therapy in treating patients with solitary plasmacytoma of bone. Ixazomib citrate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Lenalidomide may help the immune system kill abnormal blood cells or cancer cells. Dexamethasone is a drug used in chemotherapy that may cause tumor cells to die. Zoledronic acid may prevent bone fractures and reduce bone pain, and may also improve survival. Standard treatment for this cancer is radiation therapy alone. It is not yet known whether ixazomib citrate, lenalidomide, dexamethasone and zoledronic acid or zoledronic acid alone is more effective, and whether adding these treatments after radiation therapy is more effective than radiation therapy alone in treating patients with solitary plasmacytoma of bone.

Condition or disease Intervention/treatment Phase
Solitary Osseous Plasmacytoma Drug: ixazomib Drug: lenalidomide Drug: dexamethasone Drug: zoledronic acid Phase 3

Detailed Description:

This phase III randomized clinical trial was designed to assess the impact of the addition of ixazomib, lenalidomide, and dexamethasone to zoledronic acid the multiple myeloma progression rate at 5 years. A dynamic allocation procedure will be used to allocate an equal number of patients to each of the treatment arms. This procedure will balance the number of patients which falls into each of the following categories between the two treatment arms:

  1. % of abnormal plasma cells in the bone marrow: 5-9%
  2. age < 60; % of abnormal plasma cells in the bone marrow < 5%; and monoclonal protein/clonal light chains present in the blood or urine
  3. age < 60; % of abnormal plasma cells in the bone marrow < 5% and no monoclonal protein/clonal light chains present in the blood or urine, (MRD+) minimal residual disease
  4. age ≥ 60; % of abnormal plasma cells in the bone marrow < 5%; and monoclonal protein/clonal light chains present in the blood or urine
  5. age ≥ 60; % of abnormal plasma cells in the bone marrow < 5% and no monoclonal protein/clonal light chains present in the blood or urine, (MRD+) minimal residual disease

The primary and secondary objectives are described below.

Primary objective

To assess whether ixazomib, lenalidomide, dexamethasone with zoledronic acid is more promising than zoledronic acid alone in increasing the time before progression to multiple myeloma.

Secondary objectives

  1. To assess changes in minimal residual disease [MRD] by flow cytometry from study entry, at the completion of treatment, and at 1 year post registration.
  2. To assess whether ixazomib, lenalidomide, dexamethasone with zoledronic acid is more promising than zoledronic acid alone in extending overall survival.
  3. To examine the pharmacodynamics effects of treatment on biochemical markers of bone formation (osteocalcin bone-specific alkaline phosphatase), resorption (serum CTX), and metabolism (OPG).

Follow-up requirements after documentation of progression to multiple myeloma includes a maximum of five years following registration.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 11 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Solitary Plasmacytoma of Bone: Randomized Phase III Trial to Evaluate Treatment With Adjuvant Systemic Treatment and Zoledronic Acid Versus Zoledronic Acid After Definite Radiation Therapy
Study Start Date : December 2015
Estimated Primary Completion Date : September 2024


Arm Intervention/treatment
Experimental: ixazomib + lenalidomide + dexamethasone + zoledronic acid
Patients receive 4 mg ixazomib by mouth on days 1, 8 and 15. Patients also receive 15 mg lenalidomide by mouth on days 1-21, 12 mg dexamethasone by mouth on days 1, 8, 15, and 22 and zoledronic acid (dose based on creatinine clearance on day 1) IV infusion on day 1. Patients receive treatment every 28 days for a maximum of 6 cycles.
Drug: ixazomib
oral

Drug: lenalidomide
oral

Drug: dexamethasone
oral

Drug: zoledronic acid
IV

Active Comparator: zoledronic acid
Patients receive zoledronic acid (dose based on creatinine clearance on day 1) IV on day 1. Patients receive treatment every 28 days for a maximum of 6 cycles.
Drug: zoledronic acid
IV




Primary Outcome Measures :
  1. Progression-free survival rate [ Time Frame: at 5 years ]

Secondary Outcome Measures :
  1. Changes in minimal residual disease from study entry to the completion of adjuvant treatment (approximately six months post-registration) and at 1 year post-registration [ Time Frame: at 6 and 12 months post-registration ]
  2. Clinical response rate at 12 months post-registration using whole body PET/CT [ Time Frame: at 12 months post-registration ]


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

Pre-registration eligibility criteria (Step 0)

  1. Documentation of Disease: Histologic Documentation of Solitary Bone Plasmacytoma

    1. For patients pre-registering after the completion of radiation therapy, documentation of a bone marrow aspirate and biopsy containing <10% clonal plasma cells done at most 28 days prior to start of radiation therapy
    2. For patients pre-registering before the start of radiation therapy, radiation therapy scheduled to begin at most 28 days after a bone marrow aspirate and biopsy were performed containing <10% clonal plasma cells
    3. Participants must have disease that is measurable by either serum or urine evaluation of the monoclonal component or by assay of serum free light chains or by minimal residual detection. Measurable disease is defined as one or more of the following:

      • serum M protein > 0.5 G/DL, or
      • urine M protein >200 MG/24H, and/or
      • serum FLC assay: involved FLC level > 10 MG/DL with abnormal serum FLC ratio
      • ≥ 50 Plasma cells detectable by multicolor flow cytometry, at a sensitive level of 10^-4
  2. Age ≥ 18 years
  3. ECOG Performance Status 0-2

Registration Eligibility Criteria (Step 1)

  1. Documentation of Disease:

    1. No lytic lesions on skeletal survey and whole body PET/CT other than a single lesion associated with solitary bone plasmacytoma within 28 days prior to registration.
    2. Participants must have disease that is measurable by either serum or urine evaluation of the monoclonal component or by assay of serum free light chains or by minimal residual detection. Measurable disease is defined as one or more of the following:

      • serum M protein > 0.5 G/DL, or
      • urine M protein >200 MG/24H, and/or
      • serum FLC assay: involved FLC level > 10 MG/DL with abnormal serum FLC ratio
      • ≥ 50 Plasma cells detectable by multicolor flow cytometry, at a sensitive level of 10^-4
  2. Prior Treatment

    1. No major surgery within 21 days of registration with stabilization or resolution of surgical adverse events.
    2. No investigational agent within 21 days prior to registration
    3. No ongoing therapy with corticosteroids greater than 10 mg of prednisone or its equivalent per day. Please note: Inhaled and topical steroids are permitted.
    4. No prior proteasome inhibitor or IMiD use.
    5. Prior bisphosphonate use is permitted.
    6. For all patients:

      • Radiation dose should range from 4500 cGy to 6000 cGy
      • No treatment for this disease following radiation therapy
      • Registration must be completed within 90 days of completion of radiation therapy.
  3. Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown and an agent that has known genotoxic, mutagenic and teratogenic effects.

    1. Females of childbearing potential (FCBP), defined as a sexually mature female who 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal for at least 24 consecutive months that is, has not had menses at any time in the preceding 24 consecutive months:

      • must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to and again within 24 hours of starting lenalidomide.
      • must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide.
      • must agree to ongoing pregnancy testing.
    2. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a vasectomy.
  4. ECOG Performance Status 0-2
  5. Required Initial Laboratory Values within 14 days of registration:

    1. Absolute Neutrophil Count (ANC) ≥ 1,500/mm^3
    2. Platelet Count ≥ 75,000/mm^3
    3. Hemoglobin ≥ 10 g/dL
    4. Serum Creatinine < 2.0 mg/dL [176.8 µmol/liter]
    5. Serum calcium ≤ 11.5 mg/dL
    6. Calc. Creatinine Clearance > 50 mL/min
    7. Bilirubin ≤ 1.5 x upper limits of normal (ULN)
    8. AST ≤ 2.5 x upper limits of normal (ULN)
  6. Intercurrent or Recent Illness

    1. If history of prior malignancy, subject should be in complete remission for ≥ 5 years at the time of registration (with the exception of basal cell or squamous cell carcinoma of the skin treated with local resection).
    2. HIV + patients are eligible provided they meet the other eligibility criteria and:

      • CD4+ cells are ≥ 250/mm^3
      • There is no history of AIDS defining conditions other than historically low CD4+ cell count.
      • The following antiretroviral agents are not allowed: zidovudine, stavudine, protease inhibitors, combination pills with pharmacologic boosters.
      • Recommended antiretroviral regimens to avoid PK interactions include strand integrase inhibitors with nucleoside and non-nucleoside reverse transcriptase inhibitors (for example, dolutegravir given with tenofovir and emtricitabine).
    3. Patients with HBV infection are eligible provided they meet the other eligibility criteria and:

      • There is no evidence of hepatic damage related to HBV infection.
      • They have had consistently suppressed HBV viral load to undetectable levels by PCR for a minimum of 12 months.
    4. Patients with HCV infection are eligible provided they meet the other eligibility criteria and:

      • They have previously undergone curative therapy and have no evidence of active HCV infection.
      • They have no evidence of liver damage owing to prior HCV infection.

      Patients with active HCV infection should be referred for HCV treatment and standard radiotherapy for the plasmacytoma.

    5. Patients cannot have:

      • Known allergy to boron or excipients in the formulation.
      • Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of study drugs including difficulty swallowing.
      • Infection requiring systemic antibiotic therapy or other serious infection within 14 days before registration.
      • Diarrhea ≥ Grade 1, based on the NCI CTCAE categorization within 14 days of registration
      • Life-threatening illness unrelated to cancer
      • The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide, pomalidomide, or similar drugs.
  7. Peripheral Neuropathy: ≤ Grade 2 Peripheral Neuropathy
  8. Adequate cardiac function, defined as:

    1. No cardiac arrhythmias within 182 days of registration.
    2. No congestive heart failure (CHF) within 182 days of registration.
    3. No angina or myocardial infarction within 182 days of registration. In view of potential cardiac risk with lenalidomide, patients with stable angina will be excluded.
  9. Concomitant Treatment: Patients cannot be on systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital) within 14 days of registration.
  10. QT c< 470 milliseconds (msec) on a 12-lead ECG ≤ 28 days before registration
  11. Dental evaluation within 35 days of registration: Complete dental exam; complete elimination of dental and periodontal pathology including crowns on teeth susceptible to fracture, extraction of non-restorable or periodontally uncorrectable teeth; creation of an oral environment that the patient can efficiently maintain in a high state of health; and oral hygiene instruction to maintain excellent oral health.

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): NCT02516423


  Show 388 Study Locations
Sponsors and Collaborators
Alliance for Clinical Trials in Oncology
National Cancer Institute (NCI)
Millennium Pharmaceuticals, Inc.
Biologics, Inc.
Investigators
Study Chair: Anuj Mahindra, MD Scripps Health

Responsible Party: Alliance for Clinical Trials in Oncology
ClinicalTrials.gov Identifier: NCT02516423     History of Changes
Other Study ID Numbers: A061402
NCI-2015-00323 ( Registry Identifier: NCI Clinical Trials Reporting Program )
U10CA180821 ( U.S. NIH Grant/Contract )
First Posted: August 5, 2015    Key Record Dates
Last Update Posted: December 5, 2018
Last Verified: December 2018

Additional relevant MeSH terms:
Plasmacytoma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone acetate
Dexamethasone
Lenalidomide
Ixazomib
Thalidomide
BB 1101
Zoledronic acid
Diphosphonates
Glycine
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action