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Efficacy and Safety of Ixazomib and Dexamethasone Refractory Autoimmune Cytopenia (Ixa-Cyto)
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 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 0 participants |
| Allocation: | N/A |
| 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.
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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
|
- 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
- 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
- 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.
- Gammablobulin level (and isotype) along the study [ Time Frame: Day 28, Day 56, Day 84, Day 112, 9 months and 12 months ]
- Number of infectious events along the study [ Time Frame: Up to 12 months ]
- 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. ]
- Protective antibody titers (measles, mumps, tetanus) (Ancillary Study) [ Time Frame: Day 0, Day 84, 6 months, 9 months and 12 months ]
- Number of pathogenic circulating plasmablasts (Ancillary study) [ Time Frame: Day 0, 28, 56, 84, 112 months 6, 9, 12 months ]
- Number and program of bone marrow pathogenic plasma cells for patients with refractory disease (Ancillary study). [ Time Frame: Day 0, 6 months ]
- Anti-platelets/red blood cells antibodies (Ancillary study) [ Time Frame: Day 0, Day 84, 6 months ]
- 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 ]
| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
ITP patients:
- Age >= 18 years
- Diagnosis of ITP according to the international definition (Rodeghiero et al Blood 2009)
- 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.
- 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
- Age >= 18 years
- Diagnosis of wAIHA , symptomatic anemia and a positive direct antiglobulin test
- 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;
- Absolute neutrophil count (ANC) >=1,000/mm3
- Gammablobulin level > 7 g/l
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3x ULN.
- Calculated creatinine clearance >=30 mL/min
- 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
- Major surgery within 14 days before enrollment.
- Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment.
- Female patients who are lactating or have a positive serum pregnancy test during the screening period.
- 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.
- 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.
- ) 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.
- Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
- Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
- Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib including difficulty swallowing.
- 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.
- Unable to comply with study and follow-up procedures due to psychiatric disorders or any other reason.
- Inflammatory central nervous system disorder.
- Patient has >=Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical examination during the screening period.
- 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.
- Patients that have previously been treated with ixazomib, or participated in a study with ixazomib whether treated with ixazomib or not.
- Total bilirubin ≥ 1.5 x the upper limit of the normal range (ULN).
| France | |
| Mahevas | |
| Créteil, France, 94000 | |
| Principal Investigator: | Matthieu Mahevas | Assistance Publique - Hôpitaux de Paris |
| Tracking Information | |||||
|---|---|---|---|---|---|
| First Submitted Date ICMJE | May 24, 2019 | ||||
| First Posted Date ICMJE | May 29, 2019 | ||||
| Last Update Posted Date | October 28, 2019 | ||||
| Estimated Study Start Date ICMJE | September 1, 2019 | ||||
| Estimated Primary Completion Date | March 1, 2023 (Final data collection date for primary outcome measure) | ||||
| Current Primary Outcome Measures ICMJE |
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
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| Original Primary Outcome Measures ICMJE | Same as current | ||||
| Change History | |||||
| Current Secondary Outcome Measures ICMJE |
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| Original Secondary Outcome Measures ICMJE | Same as current | ||||
| Current Other Pre-specified Outcome Measures | Not Provided | ||||
| Original Other Pre-specified Outcome Measures | Not Provided | ||||
| Descriptive Information | |||||
| Brief Title ICMJE | Efficacy and Safety of Ixazomib and Dexamethasone Refractory Autoimmune Cytopenia | ||||
| Official Title ICMJE | A Prospective Open-label Trial to Assess the Efficacy and Safety of Ixazomib and Dexamethasone in Patients With Refractory Autoimmune Cytopenia | ||||
| 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. |
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| Detailed Description | Not Provided | ||||
| Study Type ICMJE | Interventional | ||||
| Study Phase ICMJE | Phase 2 | ||||
| Study Design ICMJE | Allocation: N/A 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. Primary Purpose: Treatment |
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| Condition ICMJE |
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| Intervention ICMJE | 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
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| Study Arms ICMJE | 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.
Intervention: Drug: Ninlaro
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| Publications * | Not Provided | ||||
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* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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| Recruitment Information | |||||
| Recruitment Status ICMJE | Withdrawn | ||||
| Actual Enrollment ICMJE |
0 | ||||
| Original Estimated Enrollment ICMJE |
17 | ||||
| Estimated Study Completion Date ICMJE | September 1, 2023 | ||||
| Estimated Primary Completion Date | March 1, 2023 (Final data collection date for primary outcome measure) | ||||
| Eligibility Criteria ICMJE |
Inclusion Criteria: ITP patients:
wAIHA patients
For all patients;
Exclusion criteria
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| Sex/Gender ICMJE |
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| Ages ICMJE | 18 Years and older (Adult, Older Adult) | ||||
| Accepts Healthy Volunteers ICMJE | No | ||||
| Contacts ICMJE | Contact information is only displayed when the study is recruiting subjects | ||||
| Listed Location Countries ICMJE | France | ||||
| Removed Location Countries | |||||
| Administrative Information | |||||
| NCT Number ICMJE | NCT03965624 | ||||
| Other Study ID Numbers ICMJE | P171201J 2018-004556-38 ( EudraCT Number ) |
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| Has Data Monitoring Committee | Yes | ||||
| U.S. FDA-regulated Product |
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| IPD Sharing Statement ICMJE |
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| Responsible Party | Assistance Publique - Hôpitaux de Paris | ||||
| Study Sponsor ICMJE | Assistance Publique - Hôpitaux de Paris | ||||
| Collaborators ICMJE | Takeda Pharmaceuticals International, Inc. | ||||
| Investigators ICMJE |
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| PRS Account | Assistance Publique - Hôpitaux de Paris | ||||
| Verification Date | December 2018 | ||||
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ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |
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