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

NCT03218683 | Terminated Phase 1 FDA Drug

• 1 other identifier: D6910C00001
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 10

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

Conditions

Relapsed or Refractory Acute Myeloid Leukemia (AML)

Keywords

relapsed; refractory; AZD5991; Acute Myeloid Leukemia (AML)

Outcome Measures

Primary Outcomes (3)

• Incidence of Adverse Events

  Number of subjects with adverse events as a measure of safety and tolerability including changes in vital signs, electrocardiograms (ECGs), safety and laboratory parameters

  At every treatment and follow up visit until disease progression. Expected to be for up to 12 months

• Dose limiting toxicities

  Minimum observation period is 28 days per cohort

• maximum tolerated dose

  Minimum observation period is 28 days for the maximum dose cohort

Secondary Outcomes (6)

• Maximum observed plasma concentration of AZD5991 monotherapy and AZD5991+venetoclax

  Predose and through 24 hours postdose

• Area under the concentration-time curve for plasma concentrations of AZD5991 monotherapy and AZD5991+venetoclax

  Predose and through 24 hours postdose

• Objective response rate (ORR)

  From time of first dose until discontinuation of AZD5991 monotherapy and AZD5991+venetoclax expected to be for up to 12 months

• Duration of response (DOR)

  From time of first dose until discontinuation of AZD5991 monotherapy and AZD5991+venetoclax expected to be for up to 12 months

• Progression-free survival (PFS)

  From time of first dose until first observation of progression expected to be for up to 12 months

Study Arms (3)

Monotherapy AZD5991

EXPERIMENTAL

Dose escalation - multiple dose levels

Drug: AZD5991

Monotherapy AZD5991 expansion

EXPERIMENTAL

Dose expansion

Drug: AZD5991

AZD5991 + venetoclax

EXPERIMENTAL

Dose escalation - multiple dose levels

Drug: AZD5991 + Venetoclax

Interventions

AZD5991 DRUG

AZD5991 will be administered intravenously for 9 cycles (each cycle 21 days) or until patient derives treatment benefit or progresses

Monotherapy AZD5991; Monotherapy AZD5991 expansion

AZD5991 + Venetoclax DRUG

Ascending oral doses of AZD5991 and/or venetoclax until no longer tolerated or disease progression

AZD5991 + venetoclax

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (10)

Research Site

Orange, California, 92868, United States

Location

Research Site

Aurora, Colorado, 80045, United States

Location

Research Site

Atlanta, Georgia, 30322, United States

Location

Research Site

Boston, Massachusetts, 02215, United States

Location

Research Site

St Louis, Missouri, 63110, United States

Location

Research Site

New York, New York, 10065, United States

Location

Research Site

Columbus, Ohio, 43210, United States

Location

Research Site

Portland, Oregon, 97239, United States

Location

Research Site

Nashville, Tennessee, 37203, United States

Location

Research Site

Houston, Texas, 77030, United States

Location

Related Publications (2)

• White MJ, Cheatham L, Wen S, Scarfe G, Cidado J, Reimer C, Hariparsad N, Jones RDO, Drew L, McGinnity DF, Vasalou C. A PKPD Case Study: Achieving Clinically Relevant Exposures of AZD5991 in Oncology Mouse Models. AAPS J. 2023 Jun 28;25(4):66. doi: 10.1208/s12248-023-00836-z.

  PMID: 37380821 DERIVED

• Tron AE, Belmonte MA, Adam A, Aquila BM, Boise LH, Chiarparin E, Cidado J, Embrey KJ, Gangl E, Gibbons FD, Gregory GP, Hargreaves D, Hendricks JA, Johannes JW, Johnstone RW, Kazmirski SL, Kettle JG, Lamb ML, Matulis SM, Nooka AK, Packer MJ, Peng B, Rawlins PB, Robbins DW, Schuller AG, Su N, Yang W, Ye Q, Zheng X, Secrist JP, Clark EA, Wilson DM, Fawell SE, Hird AW. Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia. Nat Commun. 2018 Dec 17;9(1):5341. doi: 10.1038/s41467-018-07551-w.

  PMID: 30559424 DERIVED

MeSH Terms

Conditions

Recurrence; Leukemia, Myeloid, Acute

Interventions

AZD5991; venetoclax

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: July 6, 2017
• First Posted: July 14, 2017
• Study Start: August 2, 2017
• Primary Completion: October 8, 2021
• Study Completion: October 8, 2021
• Last Updated: September 23, 2022

Record last verified: 2022-09

Data Sharing

• IPD Sharing: Will share
• 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.

Locations

US (10)