Myelodysplastic SyndromePhase 1/2NCT03072043
Phase 1b/2 Safety and Efficacy of APR-246 w/Azacitidine for tx of TP53 Mutant Myeloid Neoplasms
A Phase 1/2 study testing APR-246 and Azacitidine in people with Myelodysplastic Syndrome and Acute Myeloid Leukemia, run by H. Lee Moffitt Cancer Center and Research Institute at 6 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Myelodysplastic Syndrome, Acute Myeloid Leukemia, Myeloproliferative Neoplasm
- What is being tested?
- APR-246 and Azacitidine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 55 participants
- Where
- 6 sitesUnited States
- Study dates
- 18 May 2017to 8 Dec 2021
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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.
Trial locations and contacts
6 sites in 1 country.
6 sites in 1 country
United States6 sites
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, 21231
Dana-Farber Cancer Institute
Boston, Massachusetts, 02215
Cleveland Clinic Taussig Cancer Center
Cleveland, Ohio, 44195
University of Texas M.D. Anderson Cancer Center
Houston, Texas, 77030
Weill Medical College of Cornell University
New York, New York, 10065
H. Lee Moffitt Cancer Center and Research Institute
Tampa, Florida, 33612
About this study
Official title: A Phase 1b/2 Study to Evaluate the Safety and Efficacy of APR-246 in Combination With Azacitidine for the Treatment of TP53 Mutant Myeloid Neoplasms
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.
Read the 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.
- Conditions
- Myelodysplastic Syndrome, Acute Myeloid Leukemia, Myeloproliferative Neoplasm, Chronic Myelomonocytic Leukemia
- Being tested
- APR-246, Azacitidine
- Keywords
- myelodysplastic syndrome (MDS), TP53 mutant myelodysplastic syndrome, MDS/myeloproliferative neoplasm (MPN), chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML)
- Medical subject headings
- Myelodysplastic Syndromes, Leukemia, Myeloid, Acute, Myeloproliferative Disorders, Leukemia, Myelomonocytic, Chronic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
APR-246Drug
Also called PRIMA-1MET, Methylated analogue to PRIMA-1
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).
AzacitidineDrug
Also called Mylosar, Vidaza
Azacitidine is administered subcutaneously (SC) or via IV at 75 mg/m^2.
| Study group | Role | What they receive |
|---|---|---|
| Phase 1b Dose Escalation | Experimental | Participants will receive intravenous infusions of APR-246 as a lead-in phase on days -14 to -11 starting at Dose Level 1 prior to starting cycle #1 of combination therapy with azacitidine. Combination therapy will consist of APR-246 on days 1-4 and azacitidine on days 4-10 (or days 4-5 and 8-12) of a 28 day cycle. Receives: Drug: APR-246; Drug: Azacitidine |
| Phase 2 Treatment | Experimental | Participants will be treated with APR-246 administered at the maximum tolerated dose (MTD) with azacitidine on a 28 day cycle utilizing the same dosing schedule as in Phase 1b. Receives: Drug: APR-246; Drug: Azacitidine |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Up to 12 months
Phase 2: Complete Response (CR) Rate
Complete Response Rate as defined by the 2006 International Working Group (IWG) criteria.
Measured: Up to 12 months
Secondary outcomes (3)
Phase 2: Duration of Response
Duration of response defined as the time between achieving response and progression of disease.
Measured: Up to 24 months
Overall Survival (OS)
OS:The length of time from the start of treatment until death by any cause.
Measured: Up to 24 months
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.
Measured: Up to 24 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Mar 2017
- Study start18 May 2017
- Primary completion15 Nov 2019
- Study completion8 Dec 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Myelodysplastic SyndromeStudies of the same condition, open and under way.
- More trials run by H. Lee Moffitt Cancer Center and Research InstituteThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- 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.
- Masking
- None (open label)
- Enrolment
- 55 participants (actual)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Collaborators
- Aprea Therapeutics
- Responsible party
- Sponsor
- Investigators
- David Sallman, M.D., Principal investigator, H. Lee Moffitt Cancer Center and Research Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03072043
- Sponsor's protocol ID
- MCC-18973
- Status last verified
- Jan 2022
- First submitted
- 2 Mar 2017
- Last updated
- 24 Jan 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Sallman DA, DeZern AE, Garcia-Manero G, Steensma DP, Roboz GJ, Sekeres MA, Cluzeau T, Sweet KL, McLemore A, McGraw KL, Puskas J, Zhang L, Yao J, Mo Q, Nardelli L, Al Ali NH, Padron E, Korbel G, Attar EC, Kantarjian HM, Lancet JE, Fenaux P, List AF, Komrokji RS. Eprenetapopt (APR-246) and Azacitidine in TP53-Mutant Myelodysplastic Syndromes. J Clin Oncol. 2021 May 10;39(14):1584-1594. doi: 10.1200/JCO.20.02341. Epub 2021 Jan 15.
PubMed 33449813
Study at a glance
From the registry record, last updated by the sponsor on 24 Jan 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1b/2 Study to Evaluate the Safety and Efficacy of APR-246 in Combination With Azacitidine for the Treatment of TP53 Mutant Myeloid Neoplasms
- ClinicalTrials.gov ID
- NCT03072043
- Acronym / sponsor ID
- MCC-18973
- Conditions
- Myelodysplastic Syndrome, Acute Myeloid Leukemia, Myeloproliferative Neoplasm, Chronic Myelomonocytic Leukemia
- Keywords
- myelodysplastic syndrome (MDS), TP53 mutant myelodysplastic syndrome, MDS/myeloproliferative neoplasm (MPN), chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML)
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 55 participants (actual)
- Lead sponsor
- H. Lee Moffitt Cancer Center and Research InstituteUniversity, hospital or other
- Collaborators
- Aprea Therapeutics
- Study start
- 18 May 2017 (actual)
- Primary completion
- 15 Nov 2019 (actual)
- Study completion
- 8 Dec 2021 (actual)
- First posted
- 7 Mar 2017 (actual)
- Results
- Posted 25 Feb 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 2
- 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.
| Arm | Type | Receives |
|---|---|---|
| Phase 1b Dose Escalation | Experimental | Drug: APR-246, Drug: AzacitidineParticipants will receive intravenous infusions of APR-246 as a lead-in phase on days -14 to -11 starting at Dose Level 1 prior to starting cycle #1 of combination therapy with azacitidine. Combination therapy will consist of APR-246 on days 1-4 and azacitidine on days 4-10 (or days 4-5 and 8-12) of a 28 day cycle. |
| Phase 2 Treatment | Experimental | Drug: APR-246, Drug: AzacitidineParticipants will be treated with APR-246 administered at the maximum tolerated dose (MTD) with azacitidine on a 28 day cycle utilizing the same dosing schedule as in Phase 1b. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- 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.
Key exclusion criteria (6 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| APR-246Also: PRIMA-1MET, Methylated analogue to PRIMA-1Phase 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). | Drug | Phase 1b Dose Escalation, Phase 2 Treatment |
| AzacitidineAlso: Mylosar, VidazaAzacitidine is administered subcutaneously (SC) or via IV at 75 mg/m^2. | Drug | Phase 1b Dose Escalation, Phase 2 Treatment |
Primary outcome
Phase 1b: Maximum Tolerated Dose (MTD)
Time frame: 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
Time frame: Up to 12 months
Complete Response Rate as defined by the 2006 International Working Group (IWG) criteria.
3 secondary outcomes
Phase 2: Duration of Response
Time frame: Up to 24 months
Overall Survival (OS)
Time frame: Up to 24 months
Phase 2: Overall Response Rate
Time frame: Up to 24 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Jan 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 33449813Sallman DA, DeZern AE, Garcia-Manero G, Steensma DP, Roboz GJ, Sekeres MA, Cluzeau T, Sweet KL, McLemore A, McGraw KL, Puskas J, Zhang L, Yao J, Mo Q, Nardelli L, Al Ali NH, Padron E, Korbel G, Attar EC, Kantarjian HM, Lancet JE, Fenaux P, List AF, Komrokji RS. Eprenetapopt (APR-246) and Azacitidine in TP53-Mutant Myelodysplastic Syndromes. J Clin Oncol. 2021 May 10;39(14):1584-1594. doi: 10.1200/JCO.20.02341. Epub 2021 Jan 15.
- Moffitt Cancer Center Clinical Trials websiteLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
David Sallman, M.D. principal investigator
H. Lee Moffitt Cancer Center and Research Institute
6 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing APR-246 and Azacitidine in people with Myelodysplastic Syndrome and Acute Myeloid Leukemia, run by H. Lee Moffitt Cancer Center and Research Institute at 6 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 24 Jan 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 25 Feb 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Phase 1b: Maximum Tolerated Dose (MTD) (time frame: Up to 12 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03072043, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Jan 2022.