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Phase I Study Of Vincristine, Doxorubicin, And Dexamethasone (VXD) Plus Ixazomib In Adults With Relapsed Or Refractory Acute Lymphoblastic Leukemia/Lymphoma, Lymphoblastic Lymphoma Or Mixed Phenotype Acute Leukemia

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ClinicalTrials.gov Identifier: NCT01887587
Recruitment Status : Terminated (SAE- risk of overall protocol treatment outweighs benefits)
First Posted : June 27, 2013
Last Update Posted : February 12, 2016
Sponsor:
Information provided by (Responsible Party):
Ehab L Atallah, Medical College of Wisconsin

Brief Summary:
This is a phase I study of vincristine, doxorubicin and dexamethasone (modified VXD) plus MLN9708 in adults with relapsed or refractory acute lymphoblastic leukemia/lymphoma, lymphoblastic lymphoma or mixed phenotype acute leukemia.

Condition or disease Intervention/treatment Phase
Relapsed or Refractory Acute Lymphoblastic Leukemia Relapsed or Refractory Lymphoblastic Lymphoma Mixed Phenotype Acute Leukemia Drug: MLN9708 Drug: Vincristine Drug: Doxorubicin Drug: Dexamethasone Phase 1

Detailed Description:
In this phase I study, escalating doses of MLN9708 will be combined with a fixed dose mVXD regimen. MLN 9708 will be administered on day 1, 8, and 15. If the patient experiences a DLT the dose of MLN maybe reduced to the next dose level on day 8 or day 15 in that patient. DLT would be any grade 3 or more toxicity which is thought to be probably or definitely related to MLN9708. Three patients will be treated per dose level unless dose limiting toxicity (DLT) is observed. The starting dose of MLN9708 will be 2.3 mg orally on days 1, 8 and 15. If toxicity is seen at this level then dose may be reduced to 1.5 mg (dose level -1) . If no DLT is seen in the first 3 patients, the dose will be increased to 3 mg and then to 4 mg orally on days 1, 8 and 15 in a classic 3 +3 phase I design. We will not attempt to increase the dose beyond 4 mg orally which, if achieved with acceptable toxicity, would be accepted as the recommended phase 2 dose (RP2D). 0 of 3 DLTs would allow escalation to the next dose level. 1 of 3 DLTs will require expanding to six patients; 1 of 6 DLTs will allow escalation again. 2 DLTs will require dose de-escalation. The maximum tolerated dose (MTD) will be the highest dose administered at which no more than 1 DLT was observed. All patients will be evaluated for hematopoetic stem cell transplantation. If patients achieve CR and are eligible for HSCT, they will proceed to HSCT. If they are not eligible, no donor is identified or if HSCT will be delayed, and the patient has achieved benefit, then treatment maybe repeated at the discretion of the investigator. A total of 9-18 patients will be enrolled on the study. The study duration would be about 2 years.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 18 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study Of Vincristine, Doxorubicin, And Dexamethasone (VXD) Plus Ixazomib In Adults With Relapsed Or Refractory Acute Lymphoblastic Leukemia/Lymphoma, Lymphoblastic Lymphoma Or Mixed Phenotype Acute Leukemia
Study Start Date : October 2013
Estimated Primary Completion Date : December 2017
Estimated Study Completion Date : August 2018


Arm Intervention/treatment
Experimental: (modified VXLD) plus MLN9708

Vincristine-1.5 mg/m2 to a max dose of 2 mg IV on days 1, 8, 15 and 22

Dexamethasone- 10 mg/m2 orally or IV on days 1-14

Doxorubicin- 60 mg/m2 on day 1 by IV bolus.

For patients without CNS involvement:

  • Cytarabine 100 mg will be administered intrathecally on day 1 (+/-1 day) (cytarabine dose should be reduced to 50 mg if given through a central ommaya reservoir)
  • Methotrexate 12 mg will be administered intrathecally on day 8 (+/-1 day)

For patients with CNS involvement:

-Cytarabine 100 mg will be administered intrathecally on day 1 (+/-1 day) (cytarabine dose should be reduced to 50 mg if given through a central ommaya reservoir) Triple intrathecal chemotherapy with cytarabine 30 mg, methotrexate 15 mg and hydrocortisone 15 mg on (Day 1, 8, 15 and 22 (+/-1 day)).

Drug: MLN9708
Drug: Vincristine
Other Name: Oncovin

Drug: Doxorubicin
Other Names:
  • Doxil
  • hydroxydaunorubicin

Drug: Dexamethasone



Primary Outcome Measures :
  1. To determine the number of patients with adverse events. [ Time Frame: At 8 weeks ]
    Safety, tolerability will be assessed by number of participants with adverse events.


Secondary Outcome Measures :
  1. To determine the optimal dose of MLN9708 [ Time Frame: Baseline and 8 weeks ]
    Optimal dose will be assessed by number of participants with adverse events.



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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

Each patient must meet all of the following inclusion criteria to be enrolled in the study:

Inclusion

  • Male or female patients 18 years or older
  • Have relapsed B or T-precursor acute lymphocytic leukemia/lymphoma, lymphoblastic lymphoma or mixed phenotype acute leukemia with increased bone marrow or peripheral blood blasts by morphology with or without CNS involvement
  • Prior therapy: At least two prior treatment attempts to induce remission with no limit on the number of prior treatment regimens.
  • Patients are eligible after allogeneic stem cell transplantation
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • Patients must meet the following clinical laboratory criteria:

    • Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN).
    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN.
    • Calculated creatinine clearance ≥ 30 mL/min
    • Absolute neutrophil count (ANC) > 1,000/cmm and platelets > 75,000/cmm unless the cytopenias are secondary to disease
  • Life expectancy reasonably adequate for evaluating the treatment effect
  • Patients must be at least 2 weeks from major surgery, radiation therapy, participation in other investigational trials and have recovered from clinically significant toxicities of these prior treatments
  • Female patients who:

    • Are postmenopausal for at least 1 year before the screening visit, OR
    • Are surgically sterile, OR
    • If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug, OR
    • Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)
  • Male patients, even if surgically sterilized (ie, status post-vasectomy), must agree to one of the following:

    • Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR
    • Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.).

Exclusion Criteria:

Patients meeting any of the following exclusion criteria are not to be enrolled in the study:

  • Patients who are Ph+ ALL who are naive to therapy with an approved tyrosine kinase inhibitor.
  • Prior exposure to ≥350 mg/m2 of anthracycline (in doxorubicin equivalent dosing), or left ventricular fractional shortening less than 50%.
  • Failure to have fully recovered (ie, ≤ Grade 2 toxicity) from the effects of prior chemotherapy regardless of the interval since last treatment.
  • Major surgery within 14 days before enrollment.
  • Chemotherapy in the last 14 days. (Steroids or Intrathecal chemotherapy will be allowed).
  • Systemic treatment, within 7 days before study enrollment, with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort.
  • Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, or psychiatric illness/social situations that would limit compliance with study requirements. Patients receiving intravenous antibiotics for infections that are under control may be included in this study.
  • Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
  • Inability to swallow oral medication, inability or unwillingness to comply with the drug administration requirements, or GI procedure that could interfere with the oral absorption or tolerance of treatment.
  • 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.
  • Patient has ≥ Grade 2 peripheral neuropathy.
  • Participation in clinical trials with other investigational agents not included in this trial, within 14 days of the start of this trial and throughout the duration of this trial.
  • Female patients who are breastfeeding or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 before first dose of study drug.

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): NCT01887587


Locations
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United States, Wisconsin
Froedtert Hospital and the Medical College of Wisconsin
Milwaukee, Wisconsin, United States, 53226
Sponsors and Collaborators
Ehab L Atallah
Investigators
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Principal Investigator: Ehab L Atallah, MD Medical College of Wisconsin

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Responsible Party: Ehab L Atallah, Associate Professor, Medical College of Wisconsin
ClinicalTrials.gov Identifier: NCT01887587     History of Changes
Other Study ID Numbers: PRO00020384
First Posted: June 27, 2013    Key Record Dates
Last Update Posted: February 12, 2016
Last Verified: February 2016
Additional relevant MeSH terms:
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Dexamethasone
Dexamethasone acetate
BB 1101
Lymphoma
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Lymphoma, Non-Hodgkin
Acute Disease
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Disease Attributes
Pathologic Processes
Doxorubicin
Liposomal doxorubicin
Vincristine
Ixazomib
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists