Ixazomib (MLN9708) in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

• Sponsor: Steven E. Coutre (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02030405
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 4
• Location: 1
• Arm: 1
• Duration (Months): 20
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This phase 2 trial studies how well ixazomib(MLN9708) works in treating study participants with relapsed or refractory acute myeloid leukemia. Ixazomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Condition or Disease	Intervention/Treatment	Phase
Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Recurrent Adult Acute Myeloid Leukemia	Drug: Ixazomib	Phase 2

Detailed Description

PRIMARY OBJECTIVE:

Determine the best response including complete remission (CR), CR with incomplete recovery (CRi), and partial remission (PR) after 3 cycles of treatment with MLN9708 (ixazomib) in participants with nucleophosmin (NPM)1-mutated acute myeloid leukemia (AML) (following the LeukemiaNet1 guidelines for response criteria).

SECONDARY OBJECTIVES:

• Determine the duration of remission in all responders after treatment with MLN9708 defined as the time of documented remission until relapse.

• Determine the 1 year overall survival, which will be measured from time of study entry to the earlier of death from any cause or end of follow up at 1 year.

• Establish toxicity and tolerability of MLN9708 treatment in AML, including non-hematologic toxicities grade 3 or above as specified by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

OUTLINE:

Participants receive ixazomib orally (PO) on days 1, 4, 8, and 11. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Study Design

• Study Type: Interventional
• Actual Enrollment: 4 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study of Single-Agent MLN9708 for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia With Mutated Nucleophosmin-1
• Study Start Date: Mar 1, 2014
• Actual Primary Completion Date: Nov 1, 2015
• Actual Study Completion Date: Nov 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ixazomib (MLN9708) Participants receive ixazomib PO (orally) on days 1, 4, 8, and 11. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.	Drug: Ixazomib; Given orally (PO); Other Names: Ninlaro MLN9708 proteasome inhibitor

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate (ORR) [9 weeks]

   Overall response rate after 3 cycles of treatment (9 weeks) was assessed as complete remission (CR); CR with incomplete recovery (CRi); and partial remission (PR) with MLN9708, in participants with NPM1-mutated AML by LeukemiaNet1 guidelines: Although achievement of complete remission (CR) has unique clinical significance for improved overall survival (OS) and relapse-free survival (RFS) compared to achievement of CRi with incomplete platelet recovery, the latter is still a clinically meaningful response, as it is independently-superior to resistant disease. Partial remission (PR) is defined as meeting all hematologic criteria for CR with an allowance for 5% to 25% bone marrow blasts or decrease of pre-treatment bone marrow blast percentage by at least 50%. Stable disease is defined as a change in bone marrow aspirate blast count within 10% of baseline. Relapsed disease is defined as reappearance of blasts in the blood or bone marrow blasts

Secondary Outcome Measures

1. Duration of Response (DOR) [1 year]

   Duration of response (DOR) in participants with complete remission (CR) was defined as the period of time from documented complete remission through relapse or death, with relapse defined as reappearance of blasts in the blood or bone marrow blasts, after documented CR. DOR was to be assessed through at least 1 year follow-up.

2. Overall Survival (OS) [1 year]

   Overall survival (OS) from time of study entry to the earlier of death from any cause or end of follow up at 1 year

3. Serious Adverse Events Related to Ixazomib [1 year]

   Ixazomib toxicity and tolerability were assessed based on the non-hematologic toxicities ≥ Grade 3 determined to be possibly, probably, or definitely related to the study agent Ixazomib. Adverse events that are possibly, probably, or definitely related to the study agent are considered "toxicities." The outcome is reported as the overall number of non-hematologic toxicities ≥ Grade 3.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of relapsed or refractory AML of any French American British (FAB) subtype except M3 and NPM1 genetic mutation detected by molecular assay; AML patients treated at Stanford have NPM1 molecular mutation status checked routinely at time of diagnosis in a Clinical Laboratory Improvement Amendment (CLIA)-certified laboratory

• Male or female patients and no race-ethnic restrictions

• Patients are unwilling, or who are determined to be medically unfit for or resistant to standard intensive induction chemotherapy; patients who are medically unfit will be determined by the treating primary hematologist and the principal investigator (including but not limited to evaluation of co-morbidities, and response and complications to previous AML treatment strategy)

• Eastern Cooperative Oncology Group (ECOG) 0 to 2

• Ability to understand and the willingness to sign a written informed consent document

• 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)

• 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

Exclusion Criteria:

• Female patient who are lactating or have a positive serum pregnancy test during the screening period

• Major surgery within 14 days before enrollment

• Radiotherapy within 14 days before enrollment; if the involved field is small, 7 days will be considered a sufficient interval between treatment and administration of MLN9708

• Known active and uncontrolled central nervous system (CNS) involvement of leukemia (a lumbar puncture does not need to be performed as a part of screening)

• Have a significant uncontrolled infection active infection

• Have other severe concurrent disease or serious organ dysfunction involving the heart, kidney, liver or other organ system that may place the patient at undue risk to undergo treatment including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months

• Systemic treatment, within 14 days before the first dose of MLN9708, with strong inhibitors of cytochrome P450, family 1, subfamily A, polypeptide 2 (CYP1A2) (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of cytochrome P450, family 3, subfamily A (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

• Known ongoing or active systemic infection, active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive

• Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of MLN9708 including difficulty

• 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; this does not preclude previous diagnosis of acute myeloid leukemia or myelodysplastic syndrome

• Patient has ≥ grade 3 peripheral neuropathy, or grade 2 with pain on clinical examination during the screening

• Participation in other clinical trials, including those with other investigational agents not included in this trial, within 21 days of the start of this trial and throughout the duration of this trial

• Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University Cancer Institute	Stanford	California	United States	94305

Sponsors and Collaborators

• Steven E. Coutre
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Bruno de Medeiros, Stanford University Hospitals and Clinics

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Steven E. Coutre, Assistant Professor of Medicine, Stanford University
• ClinicalTrials.gov Identifier: NCT02030405
• Other Study ID Numbers: IRB-28771; NCI-2013-02231; P30CA124435; HEMAML0028
• First Posted: Jan 8, 2014
• Last Update Posted: Apr 5, 2019
• Last Verified: Apr 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia, Monocytic, Acute; Leukemia, Myelomonocytic, Acute; Leukemia, Megakaryoblastic, Acute; Leukemia, Erythroblastic, Acute; Ixazomib; Proteasome Inhibitors

Study Results

Participant Flow

Arm/Group Title	Ixazomib (MLN9708)
Arm/Group Description	Participants receive ixazomib (orally) PO on days 1, 4, 8, and 11. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	4
COMPLETED	2
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Ixazomib (MLN9708)
Arm/Group Description	Participants receive ixazomib (orally) PO on days 1, 4, 8, and 11. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Overall Participants	4
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	1 25%
>=65 years	3 75%
Sex: Female, Male (Count of Participants)
Female	4 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	4 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 25%
White	2 50%
More than one race	0 0%
Unknown or Not Reported	1 25%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate (ORR)
Description	Overall response rate after 3 cycles of treatment (9 weeks) was assessed as complete remission (CR); CR with incomplete recovery (CRi); and partial remission (PR) with MLN9708, in participants with NPM1-mutated AML by LeukemiaNet1 guidelines: Although achievement of complete remission (CR) has unique clinical significance for improved overall survival (OS) and relapse-free survival (RFS) compared to achievement of CRi with incomplete platelet recovery, the latter is still a clinically meaningful response, as it is independently-superior to resistant disease. Partial remission (PR) is defined as meeting all hematologic criteria for CR with an allowance for 5% to 25% bone marrow blasts or decrease of pre-treatment bone marrow blast percentage by at least 50%. Stable disease is defined as a change in bone marrow aspirate blast count within 10% of baseline. Relapsed disease is defined as reappearance of blasts in the blood or bone marrow blasts
Time Frame	9 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ixazomib (MLN9708)
Arm/Group Description	Participants receive ixazomib (orally) PO on days 1, 4, 8, and 11. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Measure Participants	2
Complete Remission (CR)	0 0%
Complete Remission with incomplete recovery (CRi)	0 0%
Partial Remission (PR)	0 0%
Stable Disease (SD)	0 0%
Relapsed Disease (RD)	0 0%
Progressive Disease (PD)	2 50%

2. Secondary Outcome

Title	Duration of Response (DOR)
Description	Duration of response (DOR) in participants with complete remission (CR) was defined as the period of time from documented complete remission through relapse or death, with relapse defined as reappearance of blasts in the blood or bone marrow blasts, after documented CR. DOR was to be assessed through at least 1 year follow-up.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

No participants met the criteria of complete remission (CR), and so duration of response (DOR) in those participants could not be assessed.

Arm/Group Title	Ixazomib (MLN9708)
Arm/Group Description	Participants receive ixazomib (orally) PO on days 1, 4, 8, and 11. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Measure Participants	0

3. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival (OS) from time of study entry to the earlier of death from any cause or end of follow up at 1 year
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ixazomib (MLN9708)
Arm/Group Description	Participants receive ixazomib (orally) PO on days 1, 4, 8, and 11. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Measure Participants	4
Count of Participants [Participants]	0 0%

4. Secondary Outcome

Title	Serious Adverse Events Related to Ixazomib
Description	Ixazomib toxicity and tolerability were assessed based on the non-hematologic toxicities ≥ Grade 3 determined to be possibly, probably, or definitely related to the study agent Ixazomib. Adverse events that are possibly, probably, or definitely related to the study agent are considered "toxicities." The outcome is reported as the overall number of non-hematologic toxicities ≥ Grade 3.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

All treated subjects are included.

Arm/Group Title	Ixazomib (MLN9708)
Arm/Group Description	Participants receive ixazomib PO (orally) on days 1, 4, 8, and 11. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Ixazomib: Given orally (PO)
Measure Participants	4
Number [Related adverse events]	3

Adverse Events

Time Frame	1 year
Arm/Group Title	Ixazomib (MLN9708)
Arm/Group Description	Participants receive ixazomib (orally) PO on days 1, 4, 8, and 11. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
All Cause Mortality
	Ixazomib (MLN9708)
	Affected / at Risk (%)	# Events
Total	4/4 (100%)
Serious Adverse Events
	Ixazomib (MLN9708)
	Affected / at Risk (%)	# Events
Total	4/4 (100%)
Blood and lymphatic system disorders
AML Disease progression	2/4 (50%)	2
Pancytopenia	1/4 (25%)	1
Cardiac disorders
Cardiopulmonary Arrest	1/4 (25%)	1
Gastrointestinal disorders
Diarrhea	2/4 (50%)	2
Nausea	1/4 (25%)	1
General disorders
Dehydration	1/4 (25%)	1
Infections and infestations
Febrile Neutropenia	1/4 (25%)	1
Renal and urinary disorders
Acute kidney injury	1/4 (25%)	1
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Distress Syndrome	1/4 (25%)	1
Other (Not Including Serious) Adverse Events
	Ixazomib (MLN9708)
	Affected / at Risk (%)	# Events
Total	4/4 (100%)
Gastrointestinal disorders
Vomiting	1/4 (25%)	1
Diarrhea	2/4 (50%)	2
Nausea	2/4 (50%)	2
Renal and urinary disorders
Rectal Pain	1/4 (25%)	1
Respiratory, thoracic and mediastinal disorders
Acute Pulmonary Edema	1/4 (25%)	1
Dysphagia	1/4 (25%)	1
Skin and subcutaneous tissue disorders
Skin Rash	2/4 (50%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.