Efficacy and Safety of Ixazomib and Dexamethasone Refractory Autoimmune Cytopenia

NCT ID: NCT03965624

Last Updated: 2019-10-28

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE2
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-09-01
• Study Completion Date: 2023-09-01

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.

Conditions

Immune Thrombocytopenia; Warm Autoimmune Hemolytic Anemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Ninlaro

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

Other Intervention Names

Ixazomib

Eligibility 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).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Takeda Pharmaceuticals International, Inc.

INDUSTRY

Sponsor Role: collaborator

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Matthieu Mahevas

Role: PRINCIPAL_INVESTIGATOR

Assistance Publique - Hôpitaux de Paris

Locations

Mahevas

Créteil, , France

Countries

France

Other Identifiers

2018-004556-38

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

P171201J

Identifier Type: -

Identifier Source: org_study_id