A Study of Acalabrutinib and Vistusertib in Subjects With Relapsed/Refractory B-cell Malignancies

A Phase 1/2 Proof-of-Concept Study of the Combination of Acalabrutinib and Vistusertib in Subjects With Relapsed/Refractory B-cell Malignancies

This study evaluates the safety of acalabrutinib and vistusertib when taken in combination.

Study Overview

• Status: Terminated
• Conditions: DLBCL; Richter Syndrome
• Intervention / Treatment: Drug: acalabrutinib; Drug: vistusertib

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Headington, United Kingdom, OX3 7LJ
    • Research Site
  • London, United Kingdom, EC1A 7BE
    • Research Site
  • Nottingham, United Kingdom, NG5 1PB
    • Research Site
  • Sutton, United Kingdom, SM2 5PT
    • Research Site
• United States
  • Kansas
    • Fairway, Kansas, United States, 66205
      • Research Site
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Research Site
  • Minnesota
    • Rochester, Minnesota, United States, 55902
      • Research Site
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • Research Site
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Research Site
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Research Site
  • Washington
    • Seattle, Washington, United States, 98109
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 130 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Diagnosis of relapsed/refractory diffuse large B-cell lymphoma (DLBCL) as documented by medical records and with histology based on criteria established by The World Health Organization (WHO):

   • If a subject has de novo DLBCL, the diagnosis is confirmed by biopsy and is immunohistologically characterized as de novo germinal center B-cell-like (GCB) DLBCL or de novo non-GCB DLBCL.
   • If the subjects has Richter's Syndrome (RS), the diagnosis is confirmed by biopsy and is immunohistologically characterized as transformation to DLBCL.
   • If the subjects has transformed DLBCL, the diagnosis is confirmed by biopsy and is immunohistologically characterized as transformation to DLBCL from indolent lymphoma (eg, follicular lymphoma).
2. Men and women ≥18 years of age.

3. Prior treatment for lymphoid malignancy:

   • If the subject has DLBCL, there is no curative option with conventional therapy and the prior treatment included ≥ 1 prior combination chemoimmunotherapy regimen.
   • If the subject has RS, the subject must have had ≥1 prior treatment with a combination chemoimmunotherapy regimen.
4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.
5. Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy (defined as the presence of a ≥1.5 cm lesion, as measured in the longest dimension by computed tomography [CT] scan).

Exclusion Criteria:

1. 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.
2. Diagnosis of PMBCL.
3. Current refractory nausea and vomiting, malabsorption syndrome, disease significantly affecting gastrointestinal (GI) function, resection of the stomach, extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass.
4. History of central nervous system (CNS) lymphoma, leptomeningeal disease or spinal cord compression.
5. Any clinically significant pre-existing severe renal disease (eg, glomerulonephritis, nephritic syndrome, Fanconi Syndrome or renal tubular acidosis) or high risk of developing severe renal impairment.
6. Abnormal echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) at baseline (left ventricular ejection fraction [LVEF] <40% and shortening fraction <15%). Appropriate correction to be used, if a MUGA is performed.
7. Mean resting corrected QT interval (QTc) calculated using Fridericia's formula (QTcF) >450 msec obtained from 3 electrocardiograms (ECGs); family or personal history of long or short QT syndrome; Brugada syndrome or known history of QTc prolongation or torsade de pointes within 12 months of the subject entering the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Part 1 continuous dose for vistusertib; acalabrutinib daily + vistusertib daily	Drug: acalabrutinib; Acalabrutinib is a selective, irreversible small molecule Bruton's tyrosine kinase (BTK) inhibitor.; Other Names: ACP-196; Drug: vistusertib; Vistusertib is an inhibitor of mechanistic target of rapamycin (mTOR) kinase; Other Names: AZD2014
EXPERIMENTAL: Part 1 intermittent dose for vistusertib; acalabrutinib daily + vistusertib 5 days on and 2 days off	Drug: acalabrutinib; Acalabrutinib is a selective, irreversible small molecule Bruton's tyrosine kinase (BTK) inhibitor.; Other Names: ACP-196; Drug: vistusertib; Vistusertib is an inhibitor of mechanistic target of rapamycin (mTOR) kinase; Other Names: AZD2014

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (AEs)	Safety assessments comprised type, frequency, severity, and relationship to either or both study drug of any AEs or abnormalities of laboratory tests; serious adverse events (SAEs); dose-limiting toxicities (DLTs); or AEs that led to dose modification, dose delay, or discontinuation of study drug(s).	From first dose of study drug until 30 days post last dose

Collaborators and Investigators

• Sponsor: Acerta Pharma BV

Publications and helpful links

General Publications

• Collins GP, Clevenger TN, Burke KA, Yang B, MacDonald A, Cunningham D, Fox CP, Goy A, Gribben J, Nowakowski GS, Roschewski M, Vose JM, Vallurupalli A, Cheung J, Raymond A, Nuttall B, Stetson D, Dougherty BA, Schalkwijk S, Carnevalli LS, Willis B, Tao L, Harrington EA, Hamdy A, Izumi R, Pease JE, Frigault MM, Flinn I. A phase 1/2 study of the combination of acalabrutinib and vistusertib in patients with relapsed/refractory B-cell malignancies. Leuk Lymphoma. 2021 Nov;62(11):2625-2636. doi: 10.1080/10428194.2021.1938027. Epub 2021 Jul 16.

Helpful Links

• Related Info
• Related Info

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 29, 2017
• Primary Completion (ACTUAL): November 20, 2019
• Study Completion (ACTUAL): November 20, 2019

Study Registration Dates

• First Submitted: June 27, 2017
• First Submitted That Met QC Criteria: June 29, 2017
• First Posted (ACTUAL): July 2, 2017

Study Record Updates

• Last Update Posted (ACTUAL): January 6, 2021
• Last Update Submitted That Met QC Criteria: January 4, 2021
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Antineoplastic Agents; Acalabrutinib
• Other Study ID Numbers: ACE-LY-110

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD 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.

IPD Sharing 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.

• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No