Vincristine, Doxorubicin, And Dexamethasone + Ixazomib in Acute Lymphoblastic Leukemia (ALL), Lymphoblastic Lymphoma Or Mixed Phenotype Acute Leukemia

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Brief Title

Vincristine, Doxorubicin, And Dexamethasone + Ixazomib in Acute Lymphoblastic Leukemia (ALL), Lymphoblastic Lymphoma Or Mixed Phenotype Acute Leukemia

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

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.
    

Detailed Description

      In this phase I study, escalating doses of MLN9708 will be combined with a fixed dose
      modified VXD regimen. The study drug, MLN9708, will be administered on day 1, 8, and 15. If
      the patient experiences a dose limiting toxicity (DLT) the dose of MLN9708 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 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 complete response (CR) and are eligible for
      hematopoietic stem cell transplantation (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.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

Adverse Events.


Condition

Relapsed or Refractory Acute Lymphoblastic Leukemia

Intervention

MLN9708

Study Arms / Comparison Groups

 (modified VXLD) plus MLN9708
Description:  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.
MLN9708 (Ixazomib)- 2.3 mg orally on days 1, 8 and 15. Escalations will be to 3mg or 4 mg, respectively, on days 1, 8 and 15 based on the dosing schema.
For patients without central nervous system (CNS) involvement:
Cytarabine 100 mg administered intrathecally on day 1 (cytarabine dose should be reduced to 50 mg if given through a central ommaya reservoir)
Methotrexate 12 mg administered intrathecally on day 8
For patients with CNS involvement:
-Cytarabine 100 mg 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)).

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

5

Start Date

June 2013

Completion Date

February 29, 2016

Primary Completion Date

February 29, 2016

Eligibility 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
             cytochrome P450 1A2 (CYP1A2) (e.g., fluvoxamine, enoxacin, ciprofloxacin), strong
             inhibitors of cytochrome P4503A (CYP3A) (e.g., 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.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Ehab L Atallah, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01887587

Organization ID

PRO00020384


Responsible Party

Sponsor-Investigator

Study Sponsor

Ehab L Atallah


Study Sponsor

Ehab L Atallah, MD, Principal Investigator, Medical College of Wisconsin


Verification Date

December 2019