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Study of AZD5991 Alone or in Combination With Venetoclax in Relapsed or Refractory Haematologic Malignancies.

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ClinicalTrials.gov Identifier: NCT03218683
Recruitment Status : Suspended (The study has been put on hold to allow further evaluation of safety related information)
First Posted : July 14, 2017
Last Update Posted : October 19, 2021
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Brief Summary:
This study is a multicenter, open-label, nonrandomized, sequential group, dose-escalation study to assess safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of ascending doses of AZD5991 in subjects with relapsed or refractory hematologic malignancies Part 1 of the study is monotherapy dose escalation. Closed November 2020 Part 2 of the study is monotherapy expansion groups for relapsed/refractory chronic lymphocytic leukaemia (CLL), AML/ myelodysplastic syndromes (MDS), and multiple myeloma (MM). Closed November 2020 Part 3 is a sequential, dose-escalation study of the combination of AZD5991 and venetoclax in subjects with relapsed/refractory AML

Condition or disease Intervention/treatment Phase
Relapsed or Refractory Acute Myeloid Leukemia (AML) Drug: AZD5991 Drug: AZD5991 + Venetoclax Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 144 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: This study is a 3 part, multicenter, open-label, nonrandomized, sequential group, dose-escalation study to assess safety, tolerability,pharmacokinetics and preliminary anti-tumor activity of ascending doses of AZD5991 alone or in combination with venetoclax in subjects with relapsed or refractory hematologic malignancies.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/1b/2a, 3-Part, Open-Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Antitumor Activity of Ascending Doses of AZD5991 Monotherapy and in Combination With Venetoclax in Subjects With Relapsed or Refractory Haematologic Malignancies
Actual Study Start Date : August 14, 2017
Estimated Primary Completion Date : March 1, 2023
Estimated Study Completion Date : March 1, 2023


Arm Intervention/treatment
Experimental: Monotherapy AZD5991
Dose escalation - multiple dose levels
Drug: AZD5991
AZD5991 will be administered intravenously for 9 cycles (each cycle 21 days) or until patient derives treatment benefit or progresses

Experimental: Monotherapy AZD5991 expansion
Dose expansion
Drug: AZD5991
AZD5991 will be administered intravenously for 9 cycles (each cycle 21 days) or until patient derives treatment benefit or progresses

Experimental: AZD5991 + venetoclax
Dose escalation - multiple dose levels
Drug: AZD5991 + Venetoclax
Ascending oral doses of AZD5991 and/or venetoclax until no longer tolerated or disease progression




Primary Outcome Measures :
  1. Incidence of Adverse Events [ Time Frame: At every treatment and follow up visit until disease progression. Expected to be for up to 12 months ]
    Number of subjects with adverse events as a measure of safety and tolerability including changes in vital signs, electrocardiograms (ECGs), safety and laboratory parameters

  2. Dose limiting toxicities [ Time Frame: Minimum observation period is 28 days per cohort ]
  3. maximum tolerated dose [ Time Frame: Minimum observation period is 28 days for the maximum dose cohort ]

Secondary Outcome Measures :
  1. Maximum observed plasma concentration of AZD5991 monotherapy and AZD5991+venetoclax [ Time Frame: Predose and through 24 hours postdose ]
    To assess the pharmacokinetics of AZD5991 monotherapy and AZD5991+venetoclax

  2. Area under the concentration-time curve for plasma concentrations of AZD5991 monotherapy and AZD5991+venetoclax [ Time Frame: Predose and through 24 hours postdose ]
    To assess the pharmacokinetics of AZD5991 monotherapy and AZD5991+venetoclax

  3. Objective response rate (ORR) [ Time Frame: From time of first dose until discontinuation of AZD5991 monotherapy and AZD5991+venetoclax expected to be for up to 12 months ]
    To assess the antitumor activity of AZD5991 monotherapy and AZD5991+venetoclax. Response will be evaluated every 8-12 weeks during treatment until progression.

  4. Duration of response (DOR) [ Time Frame: From time of first dose until discontinuation of AZD5991 monotherapy and AZD5991+venetoclax expected to be for up to 12 months ]
    To assess the antitumor activity of AZD5991 monotherapy and AZD5991+venetoclax. Response will be evaluated every 8-12 weeks during treatment until progression.

  5. Progression-free survival (PFS) [ Time Frame: From time of first dose until first observation of progression expected to be for up to 12 months ]
    To assess the antitumor activity of AZD5991 monotherapy and AZD5991+venetoclax. Response will be evaluated every 8-12 weeks during treatment until progression.

  6. Complete remission rate (CRR) [ Time Frame: From time of first dose until discontinuation of AZD5991 monotherapy and AZD5991+venetoclax expected to be for up to 12 months ]
    To assess the antitumor activity of AZD5991 monotherapy and AZD5991+venetoclax. Response will be evaluated every 8-12 weeks during treatment until progression.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria (AZD5991 + venetoclax):

  • Provision of signed and dated, written informed consent prior to any study-specific procedures, sampling and analyses.
  • Men and women 18 to 85 years of age, inclusive.
  • Diagnosis of AML and histologically proven based on criteria established by the World Health Organisation (WHO) as documented by medical records. Must have a measurable blast infiltration in bone marrow which will serve as a response parameter
  • Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.
  • Must have received at least 1 prior line of therapy and there must be no treatment options available known to provide clinical benefit. Refer to National Comprehensive Cancer Network (NCCN) guidelines.
  • Documented active disease requiring treatment per respective NCCN guideline that is relapsed or refractory defined as:
  • Recurrence of disease after response to prior line(s) of therapy.
  • Or progressive disease after completion of the treatment regimen preceding entry into the study.
  • WBC ≤10,000 cells/mm3 (10 x 109/L); use of leukapheresis or hydroxyurea before study drug initiation is allowed to achieve this entry criterion.
  • Adequate hepatic and renal function at screening defined as:
  • Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0 x upper limit of normal (ULN).
  • Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin).
  • Serum creatinine ≤1.5 times ULN and creatinine clearance ≥50 mL/min (measured or calculated by Cockcroft and Gault equation [(140-Age) • Mass (kg)/(72 • creatinine mg/dL) • multiply by 0.85 if female]).
  • Lipase ≤1.5 x ULN and serum amylase ≤1.5 x ULN and no history of pancreatitis.
  • Women should be using adequate contraceptive measures, should not be breast feeding and must have a negative pregnancy test before start of dosing if of child-bearing potential or must have evidence of nonchildbearing potential.
  • Men should be willing to use barrier contraception (ie, condoms) and refrain from sperm donation during and after the conduct of the trial.

Exclusion Criteria (AZD5991 + venetoclax):

  • Treatment with any of the following:

    • Any investigational agents from a previous clinical study within 4 half-lives or 14 days, whichever is the greater, of said prior investigational agent(s) with regard to the first dose of study treatment on this protocol. Washout period not required in subjects with aggressive disease who require treatment sooner.
    • Any other chemotherapy, immunotherapy or anticancer agents within 2 weeks of the first dose of study treatment. Washout period not required in subjects with aggressive disease who require treatment sooner.
    • Any hematopoietic growth factors (eg, filgrastim [granulocyte colony-stimulating factor; G-CSF], sargramostin [granulocyte-macrophage colony-stimulating factor; GM-CSF]) within 7 days of the first dose of study drug or pegylated G-CSF (pegfilgrastim) or darbepoetin within 14 days of the first dose of study drug.
    • Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study treatment.
  • Except for alopecia, any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study treatment.
  • AML with known active central nervous system involvement.
  • As judged by the Investigator, any evidence of severe or uncontrolled systemic disease (eg, severe hepatic impairment, interstitial lung disease [bilateral, diffuse, parenchymal lung disease]), or current unstable or uncompensated respiratory or cardiac conditions, or uncontrolled hypertension, history of, or active, bleeding diatheses (eg, hemophilia or von Willebrand disease) or uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment), or intravenous anti-infective treatment within 2 weeks before first dose of study drug.
  • Malabsorption syndrome or other condition that precludes enteral route of administration.
  • Chronic respiratory disease that requires continuous oxygen use.
  • Known diagnosis of a hypercoagulable disorder other than malignancy
  • Undergone any of the following procedures or experienced any of the following conditions currently or in the preceding 6 months:

    • angina pectoris
    • supraventricular arrhythmias, including atrial fibrillation, which are uncontrolled
    • Myocarditis
    • heart failure NYHA Class I or above
  • Experienced any of the following conditions currently or at any previous timepoint

    • Myocardial infarction (MI)
    • coronary artery bypass graft
    • angioplasty
    • vascular stent
    • Heart failure NYHA Class ≥ 2
    • Ventricular arrhythmias requiring continuous therapy
  • Any of the following cardiac criteria:

    • Mean resting corrected QT interval (QTcF) ≥ 450 msec applicable to both genders obtained from 3 electrocardiograms (ECGs) (averaged)
    • Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG eg, complete left bundle branch block, second to third degree AV block, sinus node dysfunction with clinically significant sinus pause
    • Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age. Concomitant medications known to prolong QTc should be used with caution and cannot be used starting with the first dose of study drug and through the DLT review period.
    • ST-wave depression and T-wave changes (e.g. inversion or flattened) in recent or screening ECG
    • CPK assay reading ≥ ULN at screening
    • Subjects with any troponin assay reading of ≥ULN during screening
    • Left ventricular ejection fraction [LVEF] <55% with echocardiogram (ECHO) or multi-gated acquisition scan (MUGA). Appropriate correction to be used, if a MUGA is performed.
  • History of severe allergic or anaphylactic reactions to BH3 mimetics or history of hypersensitivity to active or inactive excipients of AZD5991.
  • Received the following within 7 days before initiation of venetoclax:
  • Strong or moderate cytochrome P450 3A (CYP3A) inducers
  • Strong or moderate CYP3A inhibitors
  • Pg-P inhibitors
  • Consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or star fruit within 3 days before the initiation of venetoclax.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03218683


Locations
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United States, California
Research Site
Orange, California, United States, 92868
United States, Colorado
Research Site
Aurora, Colorado, United States, 80045
United States, Georgia
Research Site
Atlanta, Georgia, United States, 30322
United States, Massachusetts
Research Site
Boston, Massachusetts, United States, 02215
United States, Michigan
Research Site
Ann Arbor, Michigan, United States, 48109
United States, Missouri
Research Site
Saint Louis, Missouri, United States, 63110
United States, New York
Research Site
New York, New York, United States, 10065
Research Site
New York, New York, United States, 10461
United States, Ohio
Research Site
Columbus, Ohio, United States, 43210
United States, Oregon
Research Site
Portland, Oregon, United States, 97239
United States, Pennsylvania
Research Site
Philadelphia, Pennsylvania, United States, 19107
Research Site
Pittsburgh, Pennsylvania, United States, 15232
United States, Tennessee
Research Site
Nashville, Tennessee, United States, 37203
United States, Texas
Research Site
Houston, Texas, United States, 77030
Sponsors and Collaborators
AstraZeneca
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03218683    
Other Study ID Numbers: D6910C00001
First Posted: July 14, 2017    Key Record Dates
Last Update Posted: October 19, 2021
Last Verified: October 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal.

All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
relapsed
refractory
AZD5991
Acute Myeloid Leukemia (AML)
Additional relevant MeSH terms:
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Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia
Neoplasms by Histologic Type
Neoplasms
Venetoclax
AZD5991
Antineoplastic Agents