Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia, Myelodysplastic Syndrome, Myeloproliferative Neoplasm
Conditions
Keywords
myelodysplastic syndrome (MDS), TP53 mutant myelodysplastic syndrome, MDS/myeloproliferative neoplasm (MPN), chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML)
Brief summary
The main purpose of this study is to determine the safe and recommended dose of APR-246 in combination with azacitidine as well as to see if this combination of therapy improves overall survival.
Detailed description
Participants will be treated for a total of 6 cycles. For participants responding or who have stable disease following cycle 6, treatment may continue until one of the following criteria applies: * Inter-current illness that prevents further administration of treatment, * Unacceptable adverse event(s), * Participant decides to withdraw from the study, or * General or specific changes in the participant's condition render the participant unacceptable for further treatment in the judgment of the investigator. * Evidence of disease progression by the International Working Group (IWG) 2006 criteria. Participants who wish not to continue treatment at time of disease assessment at end of cycle 6 will complete their end of treatment visit upon completion of cycle 6.
Interventions
DRUGAPR-246
Phase 1b: Dose escalation of APR-246 via intravenous (IV) infusion, with starting dose of 50 mg/kg lean body weight (LBW). Phase 2: APR-246 at maximum tolerated dose (MTD).
DRUGAzacitidine
Azacitidine is administered subcutaneously (SC) or via IV at 75 mg/m\^2.
Sponsors
Aprea Therapeutics
H. Lee Moffitt Cancer Center and Research Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase 1b Dose Escalation followed by Phase 2 treatment. Participants will be evaluable for inclusion in the Phase 1b and Phase 2 portions of the study if they receive at least one dose of protocol therapy.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Has signed the Informed Consent (ICF) and is able to comply with protocol requirements. * Has adequate organ function according to study protocol guidelines. * Age ≥18 years at the time of signing the informed consent form. * Documented diagnosis of myelodysplastic syndrome (MDS), MDS/ myeloproliferative neoplasm (MPN), chronic myelomonocytic leukemia (CMML) or oligoblastic AML (20-30% myeloblasts) by World Health Organization (WHO) criteria. * Documentation of a TP53 gene mutation by NGS based on central or local evaluation. * For TP53 mutant patients with lower risk MDS (i.e., low or intermediate-1 risk by the International Prognostic Scoring System (IPSS)) and isolated deletion of 5q (del(5q)), failure of prior treatment with at least 4 full cycles of lenalidomide defined as no response to treatment, loss of response at any time point, progressive disease, or intolerance to therapy. * An Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 is required. * If of childbearing potential, negative pre-treatment urine or serum pregnancy test. * If of childbearing potential, willing to use an effective form of contraception such as hormonal birth control, intrauterine device or double barrier method during chemotherapy treatment and for at least six months thereafter.
Exclusion criteria
* Known history of HIV or active hepatitis B or active hepatitis C infection (testing not mandatory). * Has any of the following cardiac abnormalities (as determined by treating MD): a. Symptomatic congestive heart failure; b. Myocardial infarction less than or equal to 6 months prior to enrollment; c. Unstable angina pectoris; d. Serious uncontrolled cardiac arrhythmia; e. QTc ≥ 470 msec * Concomitant malignancies or previous malignancies with less than a 1-year disease free interval at the time of signing consent. Potential participants with adequately resected basal or squamous cell carcinoma of the skin, or adequately resected carcinoma in situ (e.g., cervix) may enroll irrespective of the time of diagnosis. * Use of cytotoxic chemotherapeutic agents, or experimental agents (agents that are not commercially available) for the treatment of MDS, MDS/MPN, CMML or AML within 14 days of the first day of study drug treatment. * No concurrent use of erythroid stimulating agents, G-CSF, GM-CSF is allowed during study except in cases of febrile neutropenia where G-CSF can be used for short term. Growth factors must be stopped 14 days prior to study. * Women who are pregnant or breastfeeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b: Maximum Tolerated Dose (MTD) | Up to 12 months | Maximum Tolerated Dose, defined as the dose level below which dose limiting toxicity (DLT) is manifested in ≥33% of the patients or at dose level 3 if DLT is manifested in \<33% of the patients. |
| Phase 2: Complete Response (CR) Rate | Up to 12 months | Complete Response Rate as defined by the 2006 International Working Group (IWG) criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: Duration of Response | Up to 24 months | Duration of response defined as the time between achieving response and progression of disease. |
| Overall Survival (OS) | Up to 24 months | OS:The length of time from the start of treatment until death by any cause. |
| Phase 2: Overall Response Rate | Up to 24 months | Proportion of participants achieving hematological improvement (HI), partial response (PR), complete response (CR), and/or marrow CR (mCR) by the IWG 2006 criteria. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 1B Dose Level 1 Participants treated at level 1: APR-246 50mg/kg lean body weight (LBW) + Azacitidine 75mg/m\^2 | 3 |
| Phase 1B Dos Level 2 Participants treated at dose level 2: APR-246 75mg/kg lean body weight (LBW) + Azacitidine 75mg/m\^2 | 3 |
| Phase 1B Dose Level 3/ MTD Participants treated at dose level 3/MTD : APR-246 100 mg/kg lean body weight (LBW) + Azacitidine 75mg/m\^2 | 49 |
| Total | 55 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 2 |
| Overall Study | Death | 0 | 0 | 3 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 4 |
Baseline characteristics
| Characteristic | Phase 1B Dose Level 1 | Phase 1B Dos Level 2 | Phase 1B Dose Level 3/ MTD | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 29 Participants | 33 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 1 Participants | 20 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 1 Participants | 45 Participants | 49 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 3 Participants | 4 Participants |
| Race (NIH/OMB) White | 2 Participants | 3 Participants | 42 Participants | 47 Participants |
| Region of Enrollment United States | 3 participants | 3 participants | 49 participants | 55 participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 24 Participants | 29 Participants |
| Sex: Female, Male Male | 1 Participants | 0 Participants | 25 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 1 / 3 | 36 / 49 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 47 / 49 |
| serious Total, serious adverse events | 3 / 3 | 1 / 3 | 30 / 49 |
Outcome results
Primary
Phase 1b: Maximum Tolerated Dose (MTD)
Maximum Tolerated Dose, defined as the dose level below which dose limiting toxicity (DLT) is manifested in ≥33% of the patients or at dose level 3 if DLT is manifested in \<33% of the patients.
Time frame: Up to 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b Dose Escalation | Phase 1b: Maximum Tolerated Dose (MTD) | 4500 mg/day |
Primary
Phase 2: Complete Response (CR) Rate
Complete Response Rate as defined by the 2006 International Working Group (IWG) criteria.
Time frame: Up to 12 months
Population: 45 participants were evaluable for response
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b Dose Escalation | Phase 2: Complete Response (CR) Rate | 53 percentage of patients |
Secondary
Overall Survival (OS)
OS:The length of time from the start of treatment until death by any cause.
Time frame: Up to 24 months
Population: All participants who received at least one dose of study drug
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b Dose Escalation | Overall Survival (OS) | 14.6 months |
| Phase 1B Dose Level 2 | Overall Survival (OS) | 11.6 months |
| Phase 1B: Dose Level 3 / Phase 2 MTD | Overall Survival (OS) | 10.4 months |
Secondary
Phase 2: Duration of Response
Duration of response defined as the time between achieving response and progression of disease.
Time frame: Up to 24 months
Population: 45 participants were evaluable for response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b Dose Escalation | Phase 2: Duration of Response | 8 months |
Secondary
Phase 2: Overall Response Rate
Proportion of participants achieving hematological improvement (HI), partial response (PR), complete response (CR), and/or marrow CR (mCR) by the IWG 2006 criteria.
Time frame: Up to 24 months
Population: 45 participants were evaluable for response
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b Dose Escalation | Phase 2: Overall Response Rate | 87 percent of participants |