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Ixazomib in the Prophylaxis of Chronic Graft-versus-host Disease.

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: NCT03225417
Recruitment Status : Recruiting
First Posted : July 21, 2017
Last Update Posted : November 6, 2019
Sponsor:
Information provided by (Responsible Party):
Fundación Pública Andaluza para la gestión de la Investigación en Sevilla

Brief Summary:

Allogeneic hematopoietic stem cell transplantation (HTC) is the only curative option for many patients with hematologic malignancies but >50% of this patients will develop extensive chronic graft-versus-host disease (cGVHD), which remains the most important complication after HTC.

Classically, the most effective strategies to prevent GVHD have not improved survival; therefore, the new strategies are being sought.

This study is designed in two phases: the main objective for phase I study is the more suitable dose for ixazomib search. Phase II study is designed to evaluate the efficacy of ixazomib at the doses stablished in phase I.


Condition or disease Intervention/treatment Phase
Hematopoietic Stem Cell Transplantation Multiple Myeloma Drug: Ixazomib Drug: Tacrolimus Drug: Sirolimus Drug: Any prophylaxis for GVHD Phase 1 Phase 2

Detailed Description:

The study design is based on a phase I / II trial in eight Spanish hospitals.

In the phase I, a number of 3 to 12 patients will be included to evaluate the optimal dose of ixazomib in combination with sirolimus and tacrolimus.

In the phase II, a total number of 130 patients will be randomized to receive ixazomib or the best medical recommendation added in order to evaluate the efficacy of ixazomib. This patients who will receive any prophylaxis for GVHD, except those patients who received antithymocyte globulin , cyclophosphamide or any T depletion protocol in vitro or in vivo.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 142 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase Ib/II Trial to Evaluate Safety and Efficacy of Oral Ixazomib in the Prophylaxis of Chronic Graft-versus-host Disease.
Actual Study Start Date : May 16, 2017
Estimated Primary Completion Date : April 16, 2022
Estimated Study Completion Date : October 31, 2022


Arm Intervention/treatment
Experimental: Experimental group

Phase I: Ixazomib + Tacrolimus + Sirolimus. Ixazomib doses in this study is 3 to 4 mg of ixazomib on day +1, +8 and +15. Tacrolimus at a dose of 0.02 mg/kg/day and then 0.06 mg/kg/day. Sirolimus at a dose of 6 mg on day -5 and then 4 mg per day.

Phase II: Ixazomib+ any prophylaxis for GVHD, except antithymocyte globulin, cyclophosphamide or any T depletion protocol in vitro or in vivo.

Starting Dose of Ixazomib according to phase I.

Drug: Ixazomib
Ixazomib capsules. Phase I: Starting dose of Ixazomib: 3.0 or 4.0 mg by day +1, +8 and +15. Phase II: Starting Dose of Ixazomib: Maximum tolerated dose from Phase I.
Other Name: X16082

Drug: Tacrolimus
Tacrolimus at dose of 0.02 mg/kg/day and then 0.06 mg/kg/day.
Other Name: Prograf

Drug: Sirolimus
Sirolimus oral solution. Standing 6 mg orally on day -5 and continued 4mg per day. This drugs should be slowly tapered starting 3 months posttransplant in order to stop them at 9 to 12 months posttransplant according to physician criteria.
Other Name: Rapamune

Drug: Any prophylaxis for GVHD
Except antithymocyte globulin, cyclophosphamide or any T depletion protocol in vitro or in vivo.

Control group
Any prophylaxis for GVHD, except antithymocyte globulin, cyclophosphamide or any T depletion protocol in vitro or in vivo.
Drug: Tacrolimus
Tacrolimus at dose of 0.02 mg/kg/day and then 0.06 mg/kg/day.
Other Name: Prograf

Drug: Sirolimus
Sirolimus oral solution. Standing 6 mg orally on day -5 and continued 4mg per day. This drugs should be slowly tapered starting 3 months posttransplant in order to stop them at 9 to 12 months posttransplant according to physician criteria.
Other Name: Rapamune

Drug: Any prophylaxis for GVHD
Except antithymocyte globulin, cyclophosphamide or any T depletion protocol in vitro or in vivo.




Primary Outcome Measures :
  1. To identify the optimal dose and evaluate ixazomib tolerance used after transplantation for the phase I study [ Time Frame: 3 months after transplantation (a total of 3 cycles of 28 days length of study treatment) ]
    Identifying maximun tolerated dose

  2. Evaluate the immune recovery for the phase I study [ Time Frame: 9 months after transplantation. ]
    The 9-12 patients included in the safety cohort and compare it with a cohort of 9-12 patients receiving sirolimus and tacrolimus out of the trial.

  3. Efficacy of ixazomib for phase II study [ Time Frame: 9 months after transplantation (a total of 9 cycles of 28 days length of study treatment) ]
    Presence of moderate plus severe Chronic Graft-versus-host Disease according to NIH scale in patients receiving the maximum tolerated dose.


Secondary Outcome Measures :
  1. Event free survival for phase II study. [ Time Frame: Just after the time of transplantation and 1 and 2 years after transplantation ]
    Quantification of time of event free survival for patients receiving the maximum tolerated dose.

  2. Event immune recovery for phase II study. [ Time Frame: The post-transplant days +180, +270, +365, +545, +730 ]
    Quantification of time of event immune recovery in patients exposed and not exposed to ixazomib.

  3. Exposure to immunosuppressive treatment for phase II study. [ Time Frame: 1 and 2 years after transplantation. ]
    Evaluation of needs of additional permitted immunosuppressive treatment administered as concomitant medication

  4. Overall disease free survival for phase II study. [ Time Frame: 2 years after transplantation. ]
    Quantification of time of overall survival after study treatment

  5. Serious adverse event for phase II study. [ Time Frame: 1 and 2 years after transplantation. ]
    Describe the serious adverse event notified during the study.

  6. Risk of moderate or severe GVHD for phase II study. [ Time Frame: 2 years after transplantation ]
    To evaluate the risk of moderate or severe GVHD according to the NIH scale

  7. Differences among patients receiving a reduced-intensity and myeloablative conditioning regimen for phase II study. [ Time Frame: 1 and 2 years after transplantation. ]
    To evaluate differences in terms of chronic GVHD and treatment tolerance



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.


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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

Inclusion Criteria:

  1. Male or female patients 18 years or older.
  2. Patients on the day +100 +/- 20 days who have received an allogeneic transplant with myeloablative or reduced intensity conditioning peripheral blood allogeneic stem cell transplantation.
  3. Patients who have received a hematopoietic bone marrow transplant hematopoietic progenitors of peripheral blood from histo / compatible donor as definition accepted by protocol.
  4. Patients receiving any prophylaxis for GVHD, except for antithymocyte globulin, cyclophosphamide or any in vitro or in vivo depletion protocol.
  5. Voluntary written consent must be given before performance of any study related procedure.
  6. Female patients who accomplish with requisitions for not possibility of pregnancy (menopausal, effective methods of contraception), as detailed by protocol.
  7. Eastern Cooperative Oncology Group performance status and/or other performance status 0, 1, or 2.
  8. Patients must meet the following clinical laboratory criteria:

    • Absolute neutrophil count 1,000/mm3 and platelet count 75,000/mm3. Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before study enrollment.
    • Total bilirubin 1.5 the upper limit of the normal range .
    • Alanine aminotransferase and aspartate aminotransferase 3 upper limit of the normal range.
    • Calculated creatinine clearance 30 mL/min.
  9. Ability to swallow and tolerate oral medication.
  10. Absence of gastrointestinal symptoms that precludes oral intake and absorption.
  11. Off antibiotics and amphotericin B formulations, voriconazole or other anti-fungal therapy for the treatment of active proven, probable or possible infections.
  12. Ability to understand the nature of this study and give written informed consent.

Exclusion Criteria:

  1. Female patients who are lactating or have a positive serum pregnancy test during the screening period.
  2. Major surgery within 14 days before enrollment.
  3. Central nervous system involvement with malignant cells.
  4. Uncontrolled infection within 14 days before study enrollment.
  5. 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.
  6. Systemic treatment, within 14 days before the first dose of ixazomib, with strong Cytochrome P450, family 3, subfamily A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort.
  7. Ongoing or active systemic infection, active hepatitis B or C virus infection, or known human immunodeficiency virus positive.
  8. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
  9. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
  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. Patient has Grade 1 with pain or ≥ grade 2 with or without pain peripheral neuropathy.
  12. 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.
  13. Patients that have previously been treated with ixazomib, or participated in a study with ixazomib whether treated with ixazomib or not.
  14. Active Graft versus host disease at the time of inclusion: patients are allowed to be included if acute Graft-versus-host Disease is in complete remission and are receiving systemic steroids at < 0.25 mg / kg.
  15. Active hematologic malignancy at the time of inclusion.
  16. Active microangiopathy at the time of inclusion (according to International Working Group criteria).
  17. Gastrointestinal disease or procedure than can interfere with oral absorption , intolerance to the ixazomib or difficulty to swallow.

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): NCT03225417


Contacts
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Contact: Jose-Antonio Perez-Simon, MD-PhD 0034955013414 josea.perez.simon.sspa@juntadeandalucia.es
Contact: Clara Rosso, MD 0034955013414 claram.rosso.sspa@juntadeandalucia.es

Locations
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Spain
ICO- Hospital Germans Trias i Pujol Recruiting
Badalona, Spain
Contact: M. Christelle Ferra Coll, MD-PhD         
Principal Investigator: M. Christelle Ferra Coll, MD-PhD         
Hospital Clinic de Barcelona Not yet recruiting
Barcelona, Spain
Contact: Carmen Martínez, MD-Phd       CMARTI@clinic.cat   
Principal Investigator: Carmen Martínez, MD-Phd         
Hospital de la Santa Creu I Sant Pau Not yet recruiting
Barcelona, Spain
Contact: Jorge Sierra Gil, MD-Phd       jsierra@santpau.cat   
Principal Investigator: Jorge Sierra Gil, MD-Phd         
Hospital Universitario Vall D´Hebrón Recruiting
Barcelona, Spain
Contact: David Valcarcel Ferreira, MD-Phd       dvalcarcel.vhebron@me.com   
Principal Investigator: David Valcarcel Ferreira, MD-Phd         
Hospital Universitario Ramón y Cajal Not yet recruiting
Madrid, Spain, 28034
Contact: Anabelle Chinea Rodríguez, MD       anabellechip@hotmail.com   
Principal Investigator: Anabelle Chinea Rodríguez         
Hospital Clinico Universitario Salamanca Recruiting
Salamanca, Spain
Contact: Lucía Lopez del Corral, MD-PhD       lucialopezcorral@usal.es   
Principal Investigator: Lucía Lopez del Corral, MD-PhD         
Hospital Universitario Virgen del Rocío Recruiting
Sevilla, Spain, 41013
Contact: Jose-Antonio Perez-Simon, MD-PhD    0034955013260 ext 0034    josea.perez.simon.sspa@juntadeandalucia.es   
Contact: Clara M. Rosso, MD    0034955012144 ext 0034    claram.rosso.sspa@juntadeandalucia.es   
Principal Investigator: Jose-Antonio Perez-Simon, MD-PhD         
Hospital Clínico Universitario de Valencia Not yet recruiting
Valencia, Spain
Contact: Carlos Solano Vercet, MD-Phd       solano_car@gva.es   
Principal Investigator: Carlos Solano Vercet, MD-Phd         
Sponsors and Collaborators
Fundación Pública Andaluza para la gestión de la Investigación en Sevilla
Investigators
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Principal Investigator: Jose-Antonio Perez-Simon, MD-PhD Hospitales Universitarios Virgen del Rocío
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Responsible Party: Fundación Pública Andaluza para la gestión de la Investigación en Sevilla
ClinicalTrials.gov Identifier: NCT03225417    
Other Study ID Numbers: X16082
First Posted: July 21, 2017    Key Record Dates
Last Update Posted: November 6, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Anonymized data for primary and secondary variables is planned to be shared with all participants within 6 months of data completion.

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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 Fundación Pública Andaluza para la gestión de la Investigación en Sevilla:
Ixazomib
Additional relevant MeSH terms:
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Multiple Myeloma
Graft vs Host Disease
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
Sirolimus
Ixazomib
Tacrolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Protease Inhibitors