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Phase I Study of Vincristine, Doxorubicin, PEG Asparaginase and Dexamethasone (Modified VXLD) Plus MLN9708 in Adults With Relapsed or Refractory Acute Lymphoblastic Leukemia/Lymphoma


Phase 1
18 Years
N/A
Not Enrolling
Both
Relapsed or Refractory Acute Lymphoblastic Leukemia, Relapsed or Refractory Lymphoma

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Trial Information

Phase I Study of Vincristine, Doxorubicin, PEG Asparaginase and Dexamethasone (Modified VXLD) Plus MLN9708 in Adults With Relapsed or Refractory Acute Lymphoblastic Leukemia/Lymphoma


In this phase I study, escalating doses of MLN9708 will be combined with a fixed dose mVXLD
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.

Inclusion 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-precursor acute lymphocytic leukemia/lymphoma with increased bone
marrow or peripheral blood blasts by morphology with or without CNS involvement

- Prior therapy: At least one prior treatment attempt 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, AND

- Must also adhere to the guidelines of any treatment-specific pregnancy
prevention program, if applicable, 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

- Must also adhere to the guidelines of any treatment-specific pregnancy
prevention program, if applicable, 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:

- Prior exposure to ≥350 mg/m2 of anthracycline (in doxorubicin equivalent dosing), or
left ventricular fractional shortening less than 50%.

- History of pancreatitis; serum amylase or lipase >2 times ULN

- 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. In case of allergy to PEGasparaginase, Erwinia
asparaginase would be used.

- 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.

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

To determine the number of patients with adverse events.

Outcome Description:

Safety, tolerability will be assessed by number of participants with adverse events.

Outcome Time Frame:

At 8 weeks

Safety Issue:

Yes

Principal Investigator

Ehab L Atallah, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Medical College of Wisconsin

Authority:

United States: Food and Drug Administration

Study ID:

PRO00020384

NCT ID:

NCT01887587

Start Date:

August 2013

Completion Date:

August 2018

Related Keywords:

  • Relapsed or Refractory Acute Lymphoblastic Leukemia
  • Relapsed or Refractory Lymphoma
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Lymphoma

Name

Location

Froedtert Hospital and the Medical College of WisconsinMilwaukee, Wisconsin  53226