Trial Outcomes & Findings for Milademetan Tosylate and Low-Dose Cytarabine With or Without Venetoclax in Treating Participants With Recurrent or Refractory Acute Myeloid Leukemia (NCT NCT03634228)

Last Updated: 2023-06-15

Results Overview

As determined by dose limiting toxicity (DLT). MTD is defined the highest dose at which no more than one patient out of 6 patients experience DLTs in the first cycle. A 3+3 algorithm will be applied for dose escalation or dose de-escalation.

Recruitment status

TERMINATED

Study phase

PHASE1/PHASE2

Target enrollment

16 participants

Primary outcome timeframe

Up to 28 days

Results posted on

2023-06-15

Participant Flow

Participant milestones

Participant milestones
Measure	Phase I (Low Dose Cytarabine, MDM2 Inhibitor DS-3032b) Cohort 0 Patients receive low dose cytarabine SC BID on days 1-10 and milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cytarabine: Given SC Milademetan Tosylate: Given 120 mg PO	Phase I (Low Dose Cytarabine, MDM2 Inhibitor DS-3032b) Cohort 1 Patients receive low dose cytarabine SC BID on days 1-10 and milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cytarabine: Given SC Milademetan Tosylate: Given 200 mg PO	Phase I (Low Dose Cytarabine, MDM2 Inhibitor DS-3032b) Cohort 2 Patients receive low dose cytarabine SC BID on days 1-10 and milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cytarabine: Given SC Milademetan Tosylate: Given 260 mg PO
Overall Study STARTED	3	6	7
Overall Study COMPLETED	3	6	7
Overall Study NOT COMPLETED	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Milademetan Tosylate and Low-Dose Cytarabine With or Without Venetoclax in Treating Participants With Recurrent or Refractory Acute Myeloid Leukemia

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase I (Low Dose Cytarabine, MDM2 Inhibitor DS-3032b) Cohort 0 n=3 Participants Patients receive low dose cytarabine SC BID on days 1-10 and milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cytarabine: Given SC Milademetan Tosylate: Given 120 mg PO	Phase I (Low Dose Cytarabine, MDM2 Inhibitor DS-3032b) Cohort 1 n=6 Participants Patients receive low dose cytarabine SC BID on days 1-10 and milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cytarabine: Given SC Milademetan Tosylate: Given 200 mg PO	Phase I (Low Dose Cytarabine, MDM2 Inhibitor DS-3032b) Cohort 2 n=7 Participants Patients receive low dose cytarabine SC BID on days 1-10 and milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cytarabine: Given SC Milademetan Tosylate: Given 260 mg PO	Total n=16 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	1 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants	7 Participants n=4 Participants
Age, Categorical >=65 years	2 Participants n=5 Participants	4 Participants n=7 Participants	3 Participants n=5 Participants	9 Participants n=4 Participants
Age, Continuous	72 years n=5 Participants	70 years n=7 Participants	53 years n=5 Participants	70 years n=4 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	6 Participants n=7 Participants	4 Participants n=5 Participants	11 Participants n=4 Participants
Sex: Female, Male Male	2 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants	5 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	3 Participants n=4 Participants
Race (NIH/OMB) White	2 Participants n=5 Participants	4 Participants n=7 Participants	5 Participants n=5 Participants	11 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants
Region of Enrollment United States	3 participants n=5 Participants	6 participants n=7 Participants	7 participants n=5 Participants	16 participants n=4 Participants

PRIMARY outcome

Timeframe: Up to 28 days

Outcome measures

Outcome measures
Measure	Phase I (Low Dose Cytarabine, MDM2 Inhibitor DS-3032b) n=16 Participants Patients receive low dose cytarabine SC BID on days 1-10 and milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cytarabine: Given SC Milademetan Tosylate: Given PO	Phase I (Low Dose Cytarabine, MDM2 Inhibitor DS-3032b) Cohort 1 Patients receive low dose cytarabine SC BID on days 1-10 and milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cytarabine: Given SC Milademetan Tosylate: Given 200 mg PO	Phase I (Low Dose Cytarabine, MDM2 Inhibitor DS-3032b) Cohort 2 Patients receive low dose cytarabine SC BID on days 1-10 and milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cytarabine: Given SC Milademetan Tosylate: Given 260 mg PO
Maximum Tolerated Dose (MTD) (Phase I)	260 Milligrams	—	—

PRIMARY outcome

Timeframe: Up to 3 years, 4 months

Response is Complete Response (CR) + Complete Response with Incomplete Blood Count Recovery (CRi) + Partial Response (PR) + Morphologic Leukemia -Free State (MLFS: CR is Bone marrow blasts \< 5%; absence of circulating blasts and blasts with Auer rods; absence of extra-medullary disease; ANC \>/= 1.0 x 10\^9/L; platelet count \>/= 100 x 10\^9/L. CRi is CR except for ANC \< 1.0 x 10\^9 or platelet count , 100 x 10\^9/L. PR is decreased bone marrow blast % by at least 50% to a value of 5% to 25% and ANC \>/= 1.0 x 10\^9/L; platelet count \>/= 100 x 10\^9/L. MLFS is Bone marrow blasts \< 5%; abcence of blasts with Auer rods; absence of extra-medullary disease; no hematologic recovery required.

Outcome measures

Outcome measures
Measure	Phase I (Low Dose Cytarabine, MDM2 Inhibitor DS-3032b) n=3 Participants Patients receive low dose cytarabine SC BID on days 1-10 and milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cytarabine: Given SC Milademetan Tosylate: Given PO	Phase I (Low Dose Cytarabine, MDM2 Inhibitor DS-3032b) Cohort 1 n=6 Participants Patients receive low dose cytarabine SC BID on days 1-10 and milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cytarabine: Given SC Milademetan Tosylate: Given 200 mg PO	Phase I (Low Dose Cytarabine, MDM2 Inhibitor DS-3032b) Cohort 2 n=7 Participants Patients receive low dose cytarabine SC BID on days 1-10 and milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cytarabine: Given SC Milademetan Tosylate: Given 260 mg PO
Participants With a Response	0 Participants	1 Participants	1 Participants

SECONDARY outcome

Timeframe: Up to 3 years, 4 months

Time from date of treatment start until date of death due to any cause or last Follow-up.

Outcome measures

Outcome measures
Measure	Phase I (Low Dose Cytarabine, MDM2 Inhibitor DS-3032b) n=3 Participants Patients receive low dose cytarabine SC BID on days 1-10 and milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cytarabine: Given SC Milademetan Tosylate: Given PO	Phase I (Low Dose Cytarabine, MDM2 Inhibitor DS-3032b) Cohort 1 n=6 Participants Patients receive low dose cytarabine SC BID on days 1-10 and milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cytarabine: Given SC Milademetan Tosylate: Given 200 mg PO	Phase I (Low Dose Cytarabine, MDM2 Inhibitor DS-3032b) Cohort 2 n=7 Participants Patients receive low dose cytarabine SC BID on days 1-10 and milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cytarabine: Given SC Milademetan Tosylate: Given 260 mg PO
Overall Survival	2.1 Months Interval 1.6 to 2.5	4.3 Months Interval 0.6 to 28.4	7.6 Months Interval 1.5 to 21.4

SECONDARY outcome

Timeframe: Up to 3 years, 4 months

Time from date of treatment start until the date of first objective documentation of disease-relapse.

Outcome measures

Outcome measures
Measure	Phase I (Low Dose Cytarabine, MDM2 Inhibitor DS-3032b) n=3 Participants Patients receive low dose cytarabine SC BID on days 1-10 and milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cytarabine: Given SC Milademetan Tosylate: Given PO	Phase I (Low Dose Cytarabine, MDM2 Inhibitor DS-3032b) Cohort 1 n=6 Participants Patients receive low dose cytarabine SC BID on days 1-10 and milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cytarabine: Given SC Milademetan Tosylate: Given 200 mg PO	Phase I (Low Dose Cytarabine, MDM2 Inhibitor DS-3032b) Cohort 2 n=7 Participants Patients receive low dose cytarabine SC BID on days 1-10 and milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cytarabine: Given SC Milademetan Tosylate: Given 260 mg PO
Event Free Survival (EFS)	1.9 Months Interval 1.6 to 2.5	2.4 Months Interval 0.6 to 11.5	1.8 Months Interval 1.4 to 7.3

Adverse Events

Phase I (Low Dose Cytarabine, MDM2 Inhibitor DS-3032b) Cohort 0

Serious events: 3 serious events

Other events: 2 other events

Deaths: 2 deaths

Phase I (Low Dose Cytarabine, MDM2 Inhibitor DS-3032b) Cohort 1

Serious events: 6 serious events

Other events: 0 other events

Deaths: 4 deaths

Phase I (Low Dose Cytarabine, MDM2 Inhibitor DS-3032b) Cohort 2

Serious events: 7 serious events

Other events: 0 other events

Deaths: 1 deaths

Serious adverse events

Serious adverse events
Measure	Phase I (Low Dose Cytarabine, MDM2 Inhibitor DS-3032b) Cohort 0 n=3 participants at risk Patients receive low dose cytarabine SC BID on days 1-10 and milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cytarabine: Given SC Milademetan Tosylate: Given 120 mg PO	Phase I (Low Dose Cytarabine, MDM2 Inhibitor DS-3032b) Cohort 1 n=6 participants at risk Patients receive low dose cytarabine SC BID on days 1-10 and milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cytarabine: Given SC Milademetan Tosylate: Given 200 mg PO	Phase I (Low Dose Cytarabine, MDM2 Inhibitor DS-3032b) Cohort 2 n=7 participants at risk Patients receive low dose cytarabine SC BID on days 1-10 and milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cytarabine: Given SC Milademetan Tosylate: Given 260 mg PO
General disorders Chest Pain	33.3% 1/3 • Number of events 1 • Up to 3 years, 4 months	0.00% 0/6 • Up to 3 years, 4 months	0.00% 0/7 • Up to 3 years, 4 months
Gastrointestinal disorders Diarrhea	66.7% 2/3 • Number of events 2 • Up to 3 years, 4 months	0.00% 0/6 • Up to 3 years, 4 months	14.3% 1/7 • Number of events 1 • Up to 3 years, 4 months
Respiratory, thoracic and mediastinal disorders Dyspnea	33.3% 1/3 • Number of events 1 • Up to 3 years, 4 months	0.00% 0/6 • Up to 3 years, 4 months	14.3% 1/7 • Number of events 1 • Up to 3 years, 4 months
Eye disorders Eye Disorders	0.00% 0/3 • Up to 3 years, 4 months	0.00% 0/6 • Up to 3 years, 4 months	14.3% 1/7 • Number of events 1 • Up to 3 years, 4 months
General disorders Fatigue	33.3% 1/3 • Number of events 1 • Up to 3 years, 4 months	16.7% 1/6 • Number of events 1 • Up to 3 years, 4 months	0.00% 0/7 • Up to 3 years, 4 months
Blood and lymphatic system disorders Febrile Neutropenia	0.00% 0/3 • Up to 3 years, 4 months	33.3% 2/6 • Number of events 3 • Up to 3 years, 4 months	14.3% 1/7 • Number of events 1 • Up to 3 years, 4 months
Musculoskeletal and connective tissue disorders Generalized Muscle Weakness	0.00% 0/3 • Up to 3 years, 4 months	16.7% 1/6 • Number of events 1 • Up to 3 years, 4 months	0.00% 0/7 • Up to 3 years, 4 months
Vascular disorders Hypotension	0.00% 0/3 • Up to 3 years, 4 months	0.00% 0/6 • Up to 3 years, 4 months	14.3% 1/7 • Number of events 1 • Up to 3 years, 4 months
Infections and infestations Lung Infection	0.00% 0/3 • Up to 3 years, 4 months	50.0% 3/6 • Number of events 4 • Up to 3 years, 4 months	14.3% 1/7 • Number of events 1 • Up to 3 years, 4 months
Cardiac disorders Myocardial Infarction	33.3% 1/3 • Number of events 1 • Up to 3 years, 4 months	0.00% 0/6 • Up to 3 years, 4 months	0.00% 0/7 • Up to 3 years, 4 months
Gastrointestinal disorders Rectal Pain	33.3% 1/3 • Number of events 1 • Up to 3 years, 4 months	0.00% 0/6 • Up to 3 years, 4 months	0.00% 0/7 • Up to 3 years, 4 months
Infections and infestations Salivary Gland Infection	0.00% 0/3 • Up to 3 years, 4 months	0.00% 0/6 • Up to 3 years, 4 months	14.3% 1/7 • Number of events 1 • Up to 3 years, 4 months
Infections and infestations Sepsis	0.00% 0/3 • Up to 3 years, 4 months	66.7% 4/6 • Number of events 4 • Up to 3 years, 4 months	42.9% 3/7 • Number of events 4 • Up to 3 years, 4 months
Gastrointestinal disorders Vomiting	33.3% 1/3 • Number of events 1 • Up to 3 years, 4 months	0.00% 0/6 • Up to 3 years, 4 months	0.00% 0/7 • Up to 3 years, 4 months

Other adverse events

Other adverse events
Measure	Phase I (Low Dose Cytarabine, MDM2 Inhibitor DS-3032b) Cohort 0 n=3 participants at risk Patients receive low dose cytarabine SC BID on days 1-10 and milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cytarabine: Given SC Milademetan Tosylate: Given 120 mg PO	Phase I (Low Dose Cytarabine, MDM2 Inhibitor DS-3032b) Cohort 1 n=6 participants at risk Patients receive low dose cytarabine SC BID on days 1-10 and milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cytarabine: Given SC Milademetan Tosylate: Given 200 mg PO	Phase I (Low Dose Cytarabine, MDM2 Inhibitor DS-3032b) Cohort 2 n=7 participants at risk Patients receive low dose cytarabine SC BID on days 1-10 and milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cytarabine: Given SC Milademetan Tosylate: Given 260 mg PO
Metabolism and nutrition disorders Hypophosphatemia	66.7% 2/3 • Number of events 3 • Up to 3 years, 4 months	0.00% 0/6 • Up to 3 years, 4 months	0.00% 0/7 • Up to 3 years, 4 months
Metabolism and nutrition disorders Hypokalemia	33.3% 1/3 • Number of events 1 • Up to 3 years, 4 months	0.00% 0/6 • Up to 3 years, 4 months	0.00% 0/7 • Up to 3 years, 4 months

Additional Information

Courtney DiNardo, MD/ Associate Professor

The University of Texas MD Anderson Cancer Center

Phone: 713-794-1141

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place