Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 4 of 6 for:    "Anemia, Autoimmune Hemolytic" | "Hormone Antagonists"

Efficacy and Safety of Ixazomib and Dexamethasone Refractory Autoimmune Cytopenia (Ixa-Cyto)

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03965624
Recruitment Status : Withdrawn (Decision of sponsor: impossibility of contract with Takeda)
First Posted : May 29, 2019
Last Update Posted : October 28, 2019
Sponsor:
Collaborator:
Takeda Pharmaceuticals International, Inc.
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief Summary:

Some patients with antibody-mediated autoimmune hematological diseases (warm autoimmune hemolytic anemia (wAIHA), cold agglutinin disease (cAIHA) and immune thrombocytopenia (ITP)) shows no or only minor and transient response to therapy despite several treatment-lines. Such patients are more likely to have a severe disease, with a higher morbidity and mortality.

Hypothesis Effective depletion of autoreactive plasma cells might be the key for a curative approach of these diseases. Therefore, there is a rationale for using proteasome inhibitors (PIs) in these refractory patients.

The rationale is that non-tumoral autoreactive plasma cells are rapidly targeted by proteasome inhibitors. It led us to propose a short course of dexamethasone and ixazomib (5 cycles), to evaluate the safety/efficacy of this innovative strategy of treatment.

Method Prospective interventional uncontrolled single arm open study evaluating the rate of patients achieving 5 cycles of ixazomib and dexamethasone without severe toxicity and response on therapy.


Condition or disease Intervention/treatment Phase
Immune Thrombocytopenia Warm Autoimmune Hemolytic Anemia Drug: Ninlaro Phase 2

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Intervention Model: Single Group Assignment
Intervention Model Description:

Prospective interventional uncontrolled single arm open study evaluating the rate of patients achieving 5 cycles without severe toxicity and response on therapy: Interventional clinical study phase IIb , Non-comparative, Not randomised, Not controlled, Unblinded.

Oral ixazomib will be given on days 1, 8, 15 of a 28-days cycle, in combination with dexamethasone 20 mg weekly. The investigator will start with first test dose levels of ixazomib of 3 mg and process with dose escalation, in case of non-response and no severe adverse events at cycle 1 or de-escalation in case of response and severe adverse events.

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Prospective Open-label Trial to Assess the Efficacy and Safety of Ixazomib and Dexamethasone in Patients With Refractory Autoimmune Cytopenia
Estimated Study Start Date : September 1, 2019
Estimated Primary Completion Date : March 1, 2023
Estimated Study Completion Date : September 1, 2023


Arm Intervention/treatment
Experimental: Ixazomib
Oral ixazomib will be given on days 1, 8, 15 of a 28-day cycle, in combination with dexamethasone 20 mg weekly. The investigator will start with first test dose levels of ixazomib of 3 mg and process with dose escalation, in case of non-response and no severe adverse events at cycle 1 (see below) or de-escalation in case of response and severe adverse events.
Drug: Ninlaro
Oral ixazomib will be given on days 1, 8, 15 of a 28-day cycle, the investigator will start with first test dose levels of ixazomib of 3 mg and process with dose escalation, in case of non-response and no severe adverse events at cycle 1 (see above) or de-escalation in case of response and severe adverse events.
Other Name: Ixazomib




Primary Outcome Measures :
  1. Rate of patients achieving a response (CR+R) with 5 cycles without severe toxicity (grade III/IV) [ Time Frame: 6 months ]

    Criteria of response:

    ITP: A complete response is defined by a platelet count > 100 x 109/L maintained in the absence of any other ITP directed therapies. A responder to treatment is defined by a patient with a maintained platelet count at > 30 x109/L (Rodeghiero et al Blood 2008) and a minimum twofold increase from initial platelet levels in the absence of bleeding and/or use of ITP directed therapies.

    AIHA: Complete response (CR) is defined as normalization in haemoglobin concentration (Hb≥12 g/dL) without any ongoing immunosuppressive treatment and without any biochemical signs of hemolytic activity. Response (R) is defined as a haemoglobin concentration ≥10 g/dL and requiring continued low-dose prednisolone (<20 mg/day prednisone) or at least 2 g/dL increase in Hb, and no transfusion requirement



Secondary Outcome Measures :
  1. Number of patients responding to treatment (CR+R) [ Time Frame: At Day 28, Day 56, Day 84, Day 112, 6 months, 9 months and 12 months. ]
    CR=complete response, R= Response

  2. Number of patients experiencing a A treatment-emergent adverse event (TEAE) along the course of the study. [ Time Frame: Up to 12 months ]

    A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug (AE start date ≥ first dose date) and within 30 days after receiving the last dose of study drug. TEAE will be scaled according to Common Terminology Criteria for Adverse Events (CTCAE) version 4. A severe toxicity severe toxicity is defined as ≥ grade III.

    For ITP patients, thrombocytopenia will not be included in TEAE if it is due to disease activity. But severe bleeding manifestations as unexpected severe hemorrhagic events defined as intracranial hemorrhage, gastrointestinal or visceral bleeding with a decrease of hemoglobin by more than 2 g/dl should be reported as SAE.

    For AIHA patients, anemia will not be included in TEAE if it is due to disease activity. But, severe, unexpected anemia (less thant 6 g/dl) in patients who have previously achieved a response should be reported as SAE.


  3. Gammablobulin level (and isotype) along the study [ Time Frame: Day 28, Day 56, Day 84, Day 112, 9 months and 12 months ]
  4. Number of infectious events along the study [ Time Frame: Up to 12 months ]
  5. Number of bleeding manifestations according to the French bleeding score for ITP patients [ Time Frame: At Day 28, Day 56, Day 84, Day 112, 6 months, 9 months and 12 months. ]
  6. Protective antibody titers (measles, mumps, tetanus) (Ancillary Study) [ Time Frame: Day 0, Day 84, 6 months, 9 months and 12 months ]
  7. Number of pathogenic circulating plasmablasts (Ancillary study) [ Time Frame: Day 0, 28, 56, 84, 112 months 6, 9, 12 months ]
  8. Number and program of bone marrow pathogenic plasma cells for patients with refractory disease (Ancillary study). [ Time Frame: Day 0, 6 months ]
  9. Anti-platelets/red blood cells antibodies (Ancillary study) [ Time Frame: Day 0, Day 84, 6 months ]
  10. Level of serum cytokines (Ancillary study) [ Time Frame: Day 0, Day 28, Day 56, Day 84, Day 112 and 6 months , 9 months , 12 months ]


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:

ITP patients:

  1. Age >= 18 years
  2. Diagnosis of ITP according to the international definition (Rodeghiero et al Blood 2009)
  3. Platelets count < 30 x 109/L or <50 x 109/L if presence of hemorrhagic events or other reason left up to investigator discretion within the months preceding inclusion.
  4. Multirefractory ITP defined as patients who have previously failed to maintain a response after rituximab (anti-CD20), splenectomy, and romiplostim and eltrombopag, except if patients have any contraindications or refused these treatments

wAIHA patients

  1. Age >= 18 years
  2. Diagnosis of wAIHA , symptomatic anemia and a positive direct antiglobulin test
  3. Refractory AIHA who have previously failed to maintain a sustained response after rituximab (anti-CD20) and splenectomy except if patients have any contraindications or refused these treatments.

For all patients;

  1. Absolute neutrophil count (ANC) >=1,000/mm3
  2. Gammablobulin level > 7 g/l
  3. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3x ULN.
  4. Calculated creatinine clearance >=30 mL/min
  5. Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.

Exclusion criteria

  1. Major surgery within 14 days before enrollment.
  2. Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment.
  3. Female patients who are lactating or have a positive serum pregnancy test during the screening period.
  4. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months.
  5. Systemic treatment, within 14 days before the first dose of ixazomib, with strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital, azathioprine), or use of St. John's wort.
  6. ) Positive HIV test and/or hepatitis virus C infection and/or positive hepatitis B virus surface antigen or core antibody (HbsAg or HBcAb) and/or Active Varicella or Herpes and zoster infection.
  7. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
  8. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
  9. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib including difficulty swallowing.
  10. Diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
  11. Unable to comply with study and follow-up procedures due to psychiatric disorders or any other reason.
  12. Inflammatory central nervous system disorder.
  13. Patient has >=Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical examination during the screening period.
  14. Participation in other clinical trials, including those with other investigational agents not included in this trial, within 30 days of the start of this trial and throughout the duration of this trial.
  15. Patients that have previously been treated with ixazomib, or participated in a study with ixazomib whether treated with ixazomib or not.
  16. Total bilirubin ≥ 1.5 x the upper limit of the normal range (ULN).

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): NCT03965624


Locations
Layout table for location information
France
Mahevas
Créteil, France, 94000
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Takeda Pharmaceuticals International, Inc.
Investigators
Layout table for investigator information
Principal Investigator: Matthieu Mahevas Assistance Publique - Hôpitaux de Paris

Layout table for additonal information
Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT03965624     History of Changes
Other Study ID Numbers: P171201J
2018-004556-38 ( EudraCT Number )
First Posted: May 29, 2019    Key Record Dates
Last Update Posted: October 28, 2019
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: DATAS ARE OWN BY ASSISTANCE PUBLIQUE - HOPITAUX DE PARIS, PLEASE CONTACT SPONSOR FOR FURTHER INFORMATION

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Assistance Publique - Hôpitaux de Paris:
MCNS
Rituximab
Complete remission
Additional relevant MeSH terms:
Layout table for MeSH terms
Hormones, Hormone Substitutes, and Hormone Antagonists
Thrombocytopenia
Purpura, Thrombocytopenic, Idiopathic
Anemia, Hemolytic
Anemia, Hemolytic, Autoimmune
Blood Platelet Disorders
Hematologic Diseases
Purpura, Thrombocytopenic
Purpura
Blood Coagulation Disorders
Thrombotic Microangiopathies
Hemorrhagic Disorders
Autoimmune Diseases
Immune System Diseases
Hemorrhage
Pathologic Processes
Skin Manifestations
Signs and Symptoms
Anemia
Dexamethasone
Dexamethasone acetate
Ixazomib
BB 1101
Glycine
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents