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

NCT01887587 | Terminated Phase 1 Results DMC

• 1 other identifier: PRO00020384
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

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.

Conditions

Relapsed or Refractory Acute Lymphoblastic Leukemia; Relapsed or Refractory Lymphoblastic Lymphoma; Mixed Phenotype Acute Leukemia

Outcome Measures

Primary Outcomes (2)

• Adverse Events.

  Safety, tolerability will be assessed by counting the number of participants experiencing adverse events at 8 weeks post treatment.

  Baseline to 30 days post treatment; approximately 8 weeks

• Optimal Dose of MLN9708

  This measure will be the maximum tolerated dose (MTD) at which no more than 1 Dose Limiting Toxicity (DLT) is observed. The starting dose of MLN9708 will be 2.3 mg orally on days 1, 8 and 15. 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.

  8 Weeks

Study Arms (1)

(modified VXLD) plus MLN9708

EXPERIMENTAL

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)).

Drug: MLN9708; Drug: Vincristine; Drug: Doxorubicin; Drug: Dexamethasone

Interventions

MLN9708 DRUG

Also known as: Ixazomib

(modified VXLD) plus MLN9708

Vincristine DRUG

Also known as: Oncovin

(modified VXLD) plus MLN9708

Doxorubicin DRUG

Also known as: Doxil, hydroxydaunorubicin

(modified VXLD) plus MLN9708

Dexamethasone DRUG

Also known as: Decadron, Dexasone, Solurex, Baycadron

(modified VXLD) plus MLN9708

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Ehab L Atallah: lead

Study Sites (1)

Froedtert Hospital and the Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

MeSH Terms

Conditions

Recurrence; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Biphenotypic, Acute

Interventions

ixazomib; Vincristine; Doxorubicin; liposomal doxorubicin; Dexamethasone; Calcium Dobesilate

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Results Point of Contact

• Title: Ehab Atallah, MD
• Organization: Medical College of Wisconsin

eatallah@mcw.edu

414-805-8900

Study Officials

• Ehab L Atallah, MD

  Medical College of Wisconsin

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: June 5, 2013
• First Posted: June 27, 2013
• Study Start: June 1, 2013
• Primary Completion: February 29, 2016
• Study Completion: February 29, 2016
• Last Updated: January 22, 2020
• Results First Posted: January 22, 2020

Record last verified: 2019-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)