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