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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

Information source: Medical College of Wisconsin
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Relapsed or Refractory Acute Lymphoblastic Leukemia; Relapsed or Refractory Lymphoblastic Lymphoma; Mixed Phenotype Acute Leukemia

Intervention: MLN9708 (Drug); Vincristine (Drug); Doxorubicin (Drug); Dexamethasone (Drug)

Phase: Phase 1

Status: Suspended

Sponsored by: Ehab L Atallah

Official(s) and/or principal investigator(s):
Ehab L Atallah, MD, Principal Investigator, Affiliation: Medical College of Wisconsin

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.

Clinical Details

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 design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: To determine the number of patients with adverse events.

Secondary outcome: To determine the optimal dose of MLN9708

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.

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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.

Locations and Contacts

Froedtert Hospital and the Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States
Additional Information

Starting date: October 2013
Last updated: July 22, 2015

Page last updated: August 23, 2015

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