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Chronic Myelomonocytic LeukemiaPhase 2NCT02666950

WEE1 Inhibitor AZD1775 With or Without Cytarabine in Treating Patients With Advanced Acute Myeloid Leukemia or Myelodysplastic Syndrome

A Phase 2 study testing Cytarabine, Laboratory Biomarker Analysis and Pharmacological Study in people with Chronic Myelomonocytic Leukemia and Myelodysplastic Syndrome With Isolated Del(5q), run by Mayo Clinic at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

This randomized phase II trial studies how well WEE1 inhibitor AZD1775 with or without cytarabine works in treating patients with acute myeloid leukemia or myelodysplastic syndrome that has spread to other places in the body and usually cannot be cured or controlled with treatment. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Cytarabine, Laboratory Biomarker Analysis and Pharmacological Study
Could I receive a placebo?
No, everyone receives an active treatment
How many people
3 participants
Where
1 siteUnited States
Study dates
5 May 2017to 17 Oct 2018
Phase
Phase 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

  • Patient population (histological or cytologically confirmed diagnosis):
  • Untreated elderly (> 60 years) AML if in the intermediate and poor-risk cytogenetic group and not candidates (as judged by treating doctor of medicine [MD]) for or willing to undergo standard induction therapy (i.e. elderly unfavorable cytogenetic AML) or any untreated AML age > 65 years
  • Note: previous therapy with a hypomethylating agent (HMA) for a diagnosis of MDS is allowed
  • Relapsed or refractory AML (>= 18 years)
  • Any MDS (>= 18 years) having failed or been intolerant to prior hypomethylating agent (HMA) treatment
  • Failure is defined as any disease progression while on HMA, relapse after HMA treatment or no response after 4 cycles of 5-Azacitidine or decitabine
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  • Patients with isolated 5q-/5q- syndrome must have failed, not tolerated, or lenalidomide in addition to having failed or been intolerant to HMA treatment
  • Note: patients with chronic myelomonocytic leukemia (CMML) and MDS/myeloproliferative neoplasms (MPN) overlap are allowed if meeting other study eligibility criteria
  • Note: for all patient groups, therapy as part of a plan as a bridge to transplant is allowed
  • Total bilirubin =< 1.5 mg/dL (except Gilbert's syndrome or known hemolysis or leukemic infiltration)
  • Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x upper limit normal (ULN) or < 5 x ULN if organ involvement
  • Alkaline phosphatase < 5 x ULN
  • Serum creatinine =< 2 x ULN or 24 hour creatinine (Cr) clearance > 30 ml/min
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
  • Ability to provide informed written consent and be able to adhere to the study visit schedule and other protocol requirements
  • Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
  • Willing to provide blood and bone marrow aspirate samples for correlative research purposes
  • Negative serum pregnancy test done =< 7 days prior to registration, for women of childbearing potential only
  • Men and women must be willing to use appropriate contraception throughout study and for 6 months after
  • Male patients who are sexually active with a female partner of childbearing potential must be either surgically sterilized or agree to use barrier contraception (ie, condoms) for the duration of study participation, and for 90 days after the final dose of study drug; cessation of birth control after this point should be discussed with a responsible physician
  • Patients who have undergone stem cell transplantation (SCT), autologous or allogeneic, are eligible provided that they are > 60 days from stem cell infusion, have graft-versus-host disease (GVHD) =< grade 1 and are off immunosuppressive agents for > 28 days at time of registration

Who cannot join

  • Uncontrolled intercurrent illness including, but not limited to, active uncontrolled infection, known positive for active infectious hepatitis, type A, B or C (past infection allowed), or psychiatric illness/social situations that would limit compliance with study requirements; Note: ongoing infection controlled on antibiotics/antifungal/antiviral medications are allowed
  • Any of the following prior therapies:
  • Cytotoxic chemotherapy =<14 days prior to registration
  • Immunotherapy =< 14 days prior to registration
  • Biologic therapy (i.e. antibody therapies) =< 14 days prior to registration
  • Radiation therapy =<14 days prior to registration
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  • Targeted therapies (i.e. kinase inhibitors, =< 7 days or 5 half-life's whichever is shorter)
  • For steroids or other non-cytotoxics given for blast count control, patient must be off for > 24 hours (hrs) before starting therapy; NOTE: hydroxyurea (HU) is allowed for blast count control throughout study
  • Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm =< 14 days prior to registration
  • Active uncontrolled central nervous system (CNS) leukemia; NOTE: positive (cyto)pathology is allowed and patient can receive intrathecal chemotherapy
  • Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy; NOTE: patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial
  • Any previous treatment with AZD1775 or allergic reactions to excipients of AZD1775
  • Acute promyelocytic leukemia (APL, M3) unless failed regimens that included tretinoin, arsenic trioxide, anthracyclines and cytarabine and currently NOT candidates for stem cell transplantation
  • Major surgery =< 28 days prior to registration
  • Clinically significant heart disease, including the following:
  • Active severe angina pectoris within 3 months prior to registration
  • Acute myocardial infarction within 3 months prior to registration
  • New York Heart Association classification IV cardiovascular disease or symptomatic class III disease
  • Note: patients with any of the above may be allowed after discussion amongst the investigators including the principal investigator
  • Any of the following:
  • Pregnant women
  • Nursing women
  • Men or women of childbearing potential who are unwilling to employ adequate contraception
  • Subject has had prescription or non-prescription drugs or other products known to be sensitive cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) substrates or CYP3A4 substrates with a narrow therapeutic index, or to be moderate to strong inhibitors/inducers of CYP3A4 which cannot be discontinued two weeks prior (alternatively 5 half lives if T1/2 is known) prior to day 1 of dosing and withheld throughout the study until 2 weeks after the last dose of study drug
  • NOTE: co-administration of aprepitant or fosaprepitant during this study is prohibited
  • Note: individual drugs exerting CYP interactions may be continued on a case by case basis if felt essential for patient management, after discussions and discretion of the treating physician
  • The preferred azole anti-fungal medication is fluconazole (alternatively posaconazole) which can be given during treatment with AZD1775 at the treating physician's discretion, however with dose reductions of AZD1775 by 25-75% (i.e. from AZD1775 200mg to 150 or 100mg)
  • Patients may not be on an inhibitor of breast cancer resistance protein (BCRP)
  • NOTE: AZD1775 is an inhibitor of breast cancer resistance protein (BCRP); the use of statins including atorvastatin which are substrates for BCRP are therefore prohibited and patients should be moved on to non-BCRP alternatives
  • Not willing to avoid grapefruit, grapefruit juices, grapefruit hybrids, Seville oranges, pummelos, and exotic citrus fruits from 7 days prior to the dose of study medication and during the entire study; NOTE: orange juice is allowed
  • Corrected QT interval (QTc) > 470 msec (as calculated per institutional standards) at study entry or congenital long QT syndrome

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Mayo Clinic in Arizona

    Scottsdale, Arizona, 85259

Other trials in United States

About this study

Official title: A Phase 2 Study of WEE1 Inhibition With AZD1775 Alone or Combined With Cytarabine in Patients With Advanced Acute Myeloid Leukemia and Myelodysplastic Syndrome

This randomized phase II trial studies how well WEE1 inhibitor AZD1775 with or without cytarabine works in treating patients with acute myeloid leukemia or myelodysplastic syndrome that has spread to other places in the body and usually cannot be cured or controlled with treatment. WEE1 inhibitor AZD1775 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving WEE1 inhibitor AZD1775 works better with or without cytarabine in treating patients with advanced acute myeloid leukemia or myelodysplastic syndrome.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To estimate the clinical efficacy of AZD1775 (WEE1 inhibitor AZD1775) in combination with AraC (cytarabine) in patients with newly diagnosed acute myeloid leukemia (AML) by assessing complete response (complete remission [CR] plus CR with incomplete blood count recovery [CRi]) rates.

II. To estimate the clinical efficacy of AZD1775 alone or in combination with AraC in patients with relapsed/refractory AML and hypomethylating agent failure myelodysplastic syndrome (MDS) by assessing complete response (CR plus CRi) rates.

SECONDARY OBJECTIVES:

  1. To determine the safety and tolerability of AZD1775 alone or combined with AraC in the study population.

II. To estimate additional measures of clinical benefit (i.e. hematological improvements, transfusion requirements).

III. To measure the duration of response of AZD1775 alone or combined with AraC.

IV. To measure time to response of AZD1775 alone or combined with AraC. V. To measure time to progression of AZD1775 alone or combined with AraC. VI. To measure overall survival of AZD1775 alone or combined with AraC. VII. To measure time to AML (for MDS subjects) of AZD1775 alone or combined with AraC.

TERTIARY OBJECTIVES:

  1. To determine the pharmacokinetics (PK) of AZD1775 alone or combined with AraC in the study population.

II. To conduct correlative research studies characterizing underlying molecular events and solidifying putative mechanism of action in vivo and to identify potential pharmacodynamic/biomarkers of response to AZD1775 alone or combined with AraC.

III. To evaluate quality of life (QOL) and patient-reported symptoms in subjects treated with AZD1775 alone or combined with AraC.

OUTLINE: Elderly newly diagnosed patients are assigned to arm A.

ARM A (ELDERLY NEWLY DIAGNOSED PATIENTS): Patients receive cytarabine subcutaneously (SC) twice daily (BID) on days 1-5 and 8-12 and WEE inhibitor AZD1775 orally (PO) daily on days 1-5 and 8-12.

Patients are randomized to 1 of 2 treatment arms.

ARM B: Patients receive cytarabine and WEE1 inhibitor AZD1775 as in Arm A.

ARM C: Patients receive WEE inhibitor AZD1775 PO daily on days 1-5, 8-12, 15-19, and 22-26.

In all arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3-6 months for 2 years.

Being tested
Cytarabine, Laboratory Biomarker Analysis, Pharmacological Study, Quality-of-Life Assessment, Questionnaire Administration
Medical subject headings
Leukemia, Myelomonocytic, Chronic, Chromosome 5q Deletion Syndrome, Myelodysplastic-Myeloproliferative Diseases, Leukemia, Myeloid, Acute

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • CytarabineDrug

    Also called .beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone

    Given SC

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • Pharmacological StudyOther

    Correlative studies

  • Quality-of-Life AssessmentOther

    Also called Quality of Life Assessment

    Ancillary studies

  • Questionnaire AdministrationOther

    Ancillary studies

  • WEE1 Inhibitor AZD1775Drug

    Also called AZD-1775, AZD1775, MK-1775, MK1775

    Given PO

Study groups in NCT02666950
Study groupRoleWhat they receive
Arm B (cytarabine and WEE1 inhibitor AZD1775ExperimentalPatients receive cytarabine and WEE1 inhibitor AZD1775 as in Arm A.
Receives: Drug: Cytarabine; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Other: Quality-of-Life Assessment; Other: Questionnaire Administration; Drug: WEE1 Inhibitor AZD1775
Arm C (WEE inhibitor AZD1775)ExperimentalPatients receive WEE inhibitor AZD1775 PO daily on days 1-5, 8-12, 15-19, and 22-26.
Receives: Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Other: Quality-of-Life Assessment; Other: Questionnaire Administration; Drug: WEE1 Inhibitor AZD1775

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Complete Response Rate (CR or CRi) Per the National Comprehensive Cancer Network (NCCN) Guidelines or According to Specific Criteria From Expert Panels

    Complete response rate will be evaluated over all courses of study treatment. The proportion of CR/CRi responses will be estimated by the number of CR/CRi responses divided by the total number of evaluable patients.

    Measured: Up to 17 months

Secondary outcomes (6)

  1. Clinical Benefit as Measured by the Number of Patients Who Were Not RBC Transfusion-dependent Post-Baseline

    Clinical benefit as measured by the number of patients who did not receive a RBC transfusion post-Baseline

    Measured: Up to 17 months

  2. Duration of Response

    Duration of response defined for all evaluable patients who have achieved a response as the date at which the patient's earliest best objective status is first noted to be a CR/CRi response to the earliest date progression is documented

    Measured: Up to 17 months

  3. Percentage of Participants With Grade 3 or Higher Adverse Events Considered At Least Possibly Related to Treatment

    The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns within patient groups. In addition, we will review all adverse event data that is graded as 3, 4, or 5 and classified as either "unrelated" or "unlikely to be related" to study treatment in the event of an actual relationship developing. The overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment are reported below.

    Measured: Up to 30 days post-treatment

  4. Overall Survival

    Overall survival time is defined as the time from registration to death due to any cause.

    Measured: From registration to death due to any cause, assessed up to 17 months

  5. Time to Progression, Defined as the Time From Registration to the Earliest Date of Documentation of Disease Progression

    Time to progression (TTP) is defined to be the length of time from study registration to a) date of disease progression as defined by section 11.0 of the protocol, or b) last follow-up. If a patient dies without documentation of disease progression, the patient will be considered to have had a tumor progression at the time of death unless there is sufficient documented evidence to conclude no progression occurred prior to death. Time to progression curves were compared via the log-rank test. Progression is defined as a >25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions or unequivocal increase in size of contrast enhancement or increase in mass effect as agreed upon independently by primary physician and quality control physicians: appearance of new lesions compared to pretreatment MRI and/or CT scan.

    Measured: Up to 17 months

  6. Time to Response, Defined as the Time From Registration to the Earliest Date of Documentation of Response

    Time to response, defined as the time from registration to the earliest date of documentation of response. The distribution of time to progression will be estimated using the method of Kaplan-Meier.

    Measured: Up to 17 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted28 Jan 2016 (estimated)
  2. Study start5 May 2017
  3. Primary completion25 Sep 2018
  4. Study completion17 Oct 2018

Resources

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 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
3 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02666950
Sponsor's protocol ID
MC1488
Other IDs
NCI-2015-02136, MC1488, P30CA015083
Status last verified
Nov 2018
First submitted
8 Jan 2016
Last updated
6 Sep 2019
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Cytarabine, Laboratory Biomarker Analysis and Pharmacological Study in people with Chronic Myelomonocytic Leukemia and Myelodysplastic Syndrome With Isolated Del(5q), run by Mayo Clinic at 1 site 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 21 inclusion and 31 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 6 Sep 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site 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 phase mean?

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 6 Sep 2019). 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?

Complete Response Rate (CR or CRi) Per the National Comprehensive Cancer Network (NCCN) Guidelines or According to Specific Criteria From Expert Panels (time frame: Up to 17 months). 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 NCT02666950.

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 6 Sep 2019.

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