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

Phase 1

Terminated

Conditions: Mixed Phenotype Acute Leukemia
Relapsed or Refractory Acute Lymphoblastic Leukemia
Relapsed or Refractory Lymphoblastic Lymphoma

Interventions: Drug: MLN9708
Drug: Vincristine
Drug: Doxorubicin
Drug: Dexamethasone

Registration Number: NCT01887587

Lead Sponsor: Ehab L Atallah

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 5

Inclusion Criteria

Not provided

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
(modified VXLD) plus MLN9708	MLN9708	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)).
(modified VXLD) plus MLN9708	Vincristine	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)).
(modified VXLD) plus MLN9708	Doxorubicin	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)).
(modified VXLD) plus MLN9708	Dexamethasone	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)).

Primary Outcome Measures

Name	Time	Method
Adverse Events.	Baseline to 30 days post treatment; approximately 8 weeks	Safety, tolerability will be assessed by counting the number of participants experiencing adverse events at 8 weeks post treatment.
Optimal Dose of MLN9708	8 Weeks	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.

Secondary Outcome Measures