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Protease Inhibitors

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)).

MLN9708

Ehab L Atallah, MD

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.

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.

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

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

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

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.

Ehab L Atallah

Associate Professor

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.

For patients without CNS involvement:

* Cytarabine 100 mg will be administered intrathecally on day 1 (+/-1 day) (cytarabine dose should be reduced to 50 mg if given through a central ommaya reservoir)
* Methotrexate 12 mg will be administered intrathecally on day 8 (+/-1 day)

For patients with CNS involvement:

-Cytarabine 100 mg will be 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)).

MLN9708

Vincristine

Doxorubicin

Dexamethasone

(Modified VXLD) Plus MLN9708

Age, Categorical

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

Ehab Atallah, MD

At dose level one, 3 patients who were enrolled. The protocol was amended to remove PEGaspargase from the regimen. Two additional patients were enrolled on dose level one.

Adverse Events.

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. Subsequent escalations will be to 3mg or 4 mg, respectively, on days 1, 8 and 15 based on the dosing schema.

For patients without CNS involvement:

* Cytarabine 100 mg will be administered intrathecally on day 1 (+/-1 day) (cytarabine dose should be reduced to 50 mg if given through a central ommaya reservoir)
* Methotrexate 12 mg will be administered intrathecally on day 8 (+/-1 day)

For patients with CNS involvement:

-Cytarabine 100 mg will be 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

All five subjects received the same 2.3 mg oral dose of MLN9708.

Optimal Dose of 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.

For patients without central nervous system (CNS) involvement:

* Cytarabine 100 mg will be administered intrathecally on day 1 (+/-1 day) (cytarabine dose should be reduced to 50 mg if given through a central ommaya reservoir)
* Methotrexate 12 mg will be administered intrathecally on day 8 (+/-1 day)

For patients with CNS involvement:

-Cytarabine 100 mg will be 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)).

Overall Study

Spots Global Cancer Trial Database for relapsed or refractory lymphoblastic lymphoma