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Study of AZD5991 in Relapsed or Refractory Haematologic Malignancies.

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ClinicalTrials.gov Identifier: NCT03218683
Recruitment Status : Recruiting
First Posted : July 14, 2017
Last Update Posted : November 8, 2019
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. Part 2 of the study is monotherapy expansion groups for relapsed/refractory chronic lymphocytic leukaemia (CLL), AML/ myelodysplastic syndromes (MDS), and multiple myeloma (MM) Part 3 is a sequential, dose-escalation study of the combination of AZD5991 and venetoclax in subjects with relapsed/refractory AML/MDS


Condition or disease Intervention/treatment Phase
Relapsed or Refractory Hematologic Malignancies Non-Hodgkin Lymphoma Richter Syndrome Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma T-cell Lymphoma Multiple Myeloma Acute Myeloid Leukemia (AML) Acute Lymphocytic Leukemia (ALL) Myelodysplastic Syndrome (MDS) Cutaneous T-cell Lymphoma Drug: AZD5991 Drug: AZD5991 + Venetoclax Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 228 participants
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 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 in Subjects With Relapsed or Refractory Haematologic Malignancies
Actual Study Start Date : August 2, 2017
Estimated Primary Completion Date : January 19, 2021
Estimated Study Completion Date : January 19, 2021


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 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: Dose limiting toxicity (DLT) period is 21 days per cohort ]
  3. maximum tolerated dose [ Time Frame: After completion of dose limiting toxicity (DLT) period (21 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:

  • 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 any of the following hematologic malignancies:

    • non-Hodgkin lymphoma
    • Richter syndrome
    • Chronic lymphocytic leukemia/small lymphocytic lymphoma (SLL)
    • T-cell lymphoma
    • multiple myeloma (MM)
    • Acute Myeloid Leukemia (AML)
    • Acute Lymphocytic Leukemia (ALL)
    • Myelodysplastic Syndrome (MDS)
  • Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.
  • Must have received at least 2 prior lines of therapy for the treatment of current histology; there are no treatment options available known to provide clinical benefit. Refer to National Comprehensive Cancer Network (NCCN) guidelines of each respective histology for guidance.
  • 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.

Inclusion criteria for expansion cohorts in CLL and MM (Part 2 only):

  • To be eligible for the CLL expansion cohort, subjects must have received at least 2 prior lines of therapy for CLL including a Bruton tyrosine kinase (BTK) inhibitor and venetoclax.
  • To be eligible for the MM expansion cohort, subjects must have received at least 2 prior lines of therapy for MM including an immunomodulatory agent (eg, lenalidamide), a proteasome inhibitor and daratumumab.

Inclusion for AZD5991+venetoclax:

  • Must have received at least 2 prior lines of therapy for the treatment of AML or MDS; there are 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 ≤25,000 cells/mm3 (25 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.

Exclusion Criteria:

  • Treatment with any of the following:

    • Any investigational agents from a previous clinical study within 4 half-lives 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.
  • Presence of, or history of, central nervous system (CNS) lymphoma, leptomeningeal disease or spinal cord compression.
  • 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.

Exclusion AZD5991 + venetoclax

  • AML with known active central nervous system involvement.
  • 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
  • High risk of developing renal impairment, per investigator discretion.
  • Hyperuricemia (defined as uric acid above laboratory normal range) present at screening or hyperphosphatemia (defined as phosphate/phosphorus levels above laboratory normal range) present at screening.
  • Any of the following cardiac criteria:

    • Mean resting corrected QT interval (QTcF) ≥ 450 msec obtained from 3 electrocardiograms (ECGs)
    • Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG eg, complete left bundle branch block, third degree heart block
    • 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.
    • Abnormal echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) at baseline (left ventricular ejection fraction [LVEF] <40%). 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


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

Locations
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United States, California
Research Site Recruiting
Orange, California, United States, 92868
United States, Colorado
Research Site Recruiting
Aurora, Colorado, United States, 80045
United States, District of Columbia
Research Site Withdrawn
Washington, District of Columbia, United States, 20007
United States, Georgia
Research Site Recruiting
Atlanta, Georgia, United States, 30322
United States, Massachusetts
Research Site Recruiting
Boston, Massachusetts, United States, 02215
United States, Missouri
Research Site Recruiting
Saint Louis, Missouri, United States, 63110
United States, New Jersey
Research Site Withdrawn
Hackensack, New Jersey, United States, 07601-2191
United States, New York
Research Site Not yet recruiting
New Hyde Park, New York, United States, 11042
Research Site Recruiting
New York, New York, United States, 10065
United States, Ohio
Research Site Recruiting
Columbus, Ohio, United States, 43210
United States, Oregon
Research Site Recruiting
Portland, Oregon, United States, 97239
United States, Tennessee
Research Site Recruiting
Nashville, Tennessee, United States, 37203
United States, Texas
Research Site Recruiting
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     History of Changes
Other Study ID Numbers: D6910C00001
First Posted: July 14, 2017    Key Record Dates
Last Update Posted: November 8, 2019
Last Verified: November 2019

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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
Non-Hodgkin lymphoma
Richter syndrome
Chronic lymphocytic leukemia
Small lymphocytic lymphoma
T-cell lymphoma, Multiple myeloma
Acute Myeloid Leukemia (AML)
Acute Lymphocytic Leukemia (ALL)
Myelodysplastic Syndrome (MDS)
Cutaneous T-cell Lymphoma
Additional relevant MeSH terms:
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Venetoclax
Lymphoma
Leukemia
Leukemia, Myeloid, Acute
Multiple Myeloma
Preleukemia
Lymphoma, Non-Hodgkin
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, T-Cell
Lymphoma, T-Cell, Cutaneous
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Myelodysplastic Syndromes
Syndrome
Neoplasms
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Disease
Pathologic Processes
Leukemia, Myeloid
Neoplasms, Plasma Cell
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases