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

Sponsor
Acerta Pharma BV (Industry)
Overall Status
Terminated
CT.gov ID
NCT03205046
Collaborator
(none)
25
Enrollment
11
Locations
2
Arms
28.7
Actual Duration (Months)
2.3
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
25 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 1/2 Proof-of-Concept Study of the Combination of Acalabrutinib and Vistusertib in Subjects With Relapsed/Refractory B-cell Malignancies
Actual Study Start Date :
Jun 29, 2017
Actual Primary Completion Date :
Nov 20, 2019
Actual Study Completion Date :
Nov 20, 2019

Arms and Interventions

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

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Number of Participants With Treatment-Emergent Adverse Events (AEs) [From first dose of study drug until 30 days post last dose]

      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).

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 130 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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).

    1. Men and women ≥18 years of age.

    2. 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.

    1. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.

    2. 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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Research Site Fairway Kansas United States 66205
    2 Research Site Bethesda Maryland United States 20892
    3 Research Site Rochester Minnesota United States 55902
    4 Research Site Omaha Nebraska United States 68198
    5 Research Site Hackensack New Jersey United States 07601
    6 Research Site Nashville Tennessee United States 37203
    7 Research Site Seattle Washington United States 98109
    8 Research Site Headington United Kingdom OX3 7LJ
    9 Research Site London United Kingdom EC1A 7BE
    10 Research Site Nottingham United Kingdom NG5 1PB
    11 Research Site Sutton United Kingdom SM2 5PT

    Sponsors and Collaborators

    • Acerta Pharma BV

    Investigators

    • Study Director: Acerta Clinical Trials, 1-888-292-9613; acertamc@dlss.com

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Acerta Pharma BV
    ClinicalTrials.gov Identifier:
    NCT03205046
    Other Study ID Numbers:
    • ACE-LY-110
    First Posted:
    Jul 2, 2017
    Last Update Posted:
    Jan 6, 2021
    Last Verified:
    Dec 1, 2020
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Acalabrutinib

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Acalabrutinib 100 mg BID Plus Vistusertib BID Continuous Acalabrutinib 100 mg BID Plus Vistusertib BID Intermittent
    Arm/Group Description Acalabrutinib daily + Vistusertib daily over the 28-day cycle Acalabrutinib daily + Vistusertib 2 days on/ 5 days off over the 28-day cycle
    Period Title: Overall Study
    STARTED 13 12
    COMPLETED 0 2
    NOT COMPLETED 13 10

    Baseline Characteristics

    Arm/Group Title Acalabrutinib 100 mg BID* Plus Vistusertib BID* Continuous Acalabrutinib 100 mg BID* Plus Vistusertib BID* Intermittent Total
    Arm/Group Description Acalabrutinib daily + Vistusertib daily over the 28-day cycle Acalabrutinib daily + Vistusertib 2 days on/ 5 days off over the 28-day cycle Total of all reporting groups
    Overall Participants 13 12 25
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    63.6
    (15.9)
    67.3
    (12.0)
    65.4
    (13.99)
    Sex: Female, Male (Count of Participants)
    Female
    4
    30.8%
    2
    16.7%
    6
    24%
    Male
    9
    69.2%
    10
    83.3%
    19
    76%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    1
    8.3%
    1
    4%
    Not Hispanic or Latino
    11
    84.6%
    11
    91.7%
    22
    88%
    Unknown or Not Reported
    2
    15.4%
    0
    0%
    2
    8%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    0
    0%
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    1
    7.7%
    0
    0%
    1
    4%
    White
    12
    92.3%
    11
    91.7%
    23
    92%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    1
    8.3%
    1
    4%
    Region of Enrollment (Count of Participants)
    United States
    5
    38.5%
    9
    75%
    14
    56%
    United Kingdom
    8
    61.5%
    3
    25%
    11
    44%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants With Treatment-Emergent Adverse Events (AEs)
    Description 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).
    Time Frame From first dose of study drug until 30 days post last dose

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Acalabrutinib 100 mg BID* Plus Vistusertib BID* Continuous Acalabrutinib 100 mg BID* Plus Vistusertib BID* Intermittent
    Arm/Group Description Acalabrutinib daily + Vistusertib daily over the 28-day cycle Acalabrutinib daily + Vistusertib 2 days on/ 5 days off over the 28-day cycle
    Measure Participants 13 12
    Count of Participants [Participants]
    13
    100%
    12
    100%

    Adverse Events

    Time Frame Serious Adverse Events and Other Adverse Events were assessed from first dose of study drug until 30 days post last dose; All-Cause Mortality was assessed from first dose of study drug until death, loss to follow up, sponsor decision to stop trial, or withdrawal of consent, whichever occurred first, an average of approximately 6 months.
    Adverse Event Reporting Description
    Arm/Group Title Acalabrutinib 100 mg BID* Plus Vistusertib BID* Continuous Acalabrutinib 100 mg BID* Plus Vistusertib BID* Intermittent
    Arm/Group Description Acalabrutinib daily + Vistusertib daily over the 28-day cycle Acalabrutinib daily + Vistusertib 2 days on/ 5 days off over the 28-day cycle
    All Cause Mortality
    Acalabrutinib 100 mg BID* Plus Vistusertib BID* Continuous Acalabrutinib 100 mg BID* Plus Vistusertib BID* Intermittent
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 10/13 (76.9%) 6/12 (50%)
    Serious Adverse Events
    Acalabrutinib 100 mg BID* Plus Vistusertib BID* Continuous Acalabrutinib 100 mg BID* Plus Vistusertib BID* Intermittent
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/13 (15.4%) 6/12 (50%)
    Blood and lymphatic system disorders
    Anaemia 0/13 (0%) 0 2/12 (16.7%) 2
    Lymph node pain 0/13 (0%) 0 1/12 (8.3%) 1
    General disorders
    Asthenia 0/13 (0%) 0 1/12 (8.3%) 1
    Pyrexia 1/13 (7.7%) 1 1/12 (8.3%) 1
    Infections and infestations
    Cellulitis 1/13 (7.7%) 2 0/12 (0%) 0
    Lower respiratory tract infection 0/13 (0%) 0 1/12 (8.3%) 1
    Pneumonia 0/13 (0%) 0 2/12 (16.7%) 2
    Investigations
    Computerised tomogram thorax abnormal 0/13 (0%) 0 1/12 (8.3%) 1
    Musculoskeletal and connective tissue disorders
    Pain in extremity 0/13 (0%) 0 1/12 (8.3%) 1
    Nervous system disorders
    Syncope 0/13 (0%) 0 1/12 (8.3%) 1
    Trigeminal neuralgia 0/13 (0%) 0 1/12 (8.3%) 1
    Respiratory, thoracic and mediastinal disorders
    Hypoxia 0/13 (0%) 0 1/12 (8.3%) 1
    Other (Not Including Serious) Adverse Events
    Acalabrutinib 100 mg BID* Plus Vistusertib BID* Continuous Acalabrutinib 100 mg BID* Plus Vistusertib BID* Intermittent
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 13/13 (100%) 12/12 (100%)
    Blood and lymphatic system disorders
    Anaemia 2/13 (15.4%) 2 5/12 (41.7%) 7
    Increased tendency to bruise 0/13 (0%) 0 1/12 (8.3%) 1
    Leukopenia 0/13 (0%) 0 2/12 (16.7%) 7
    Lymphopenia 0/13 (0%) 0 1/12 (8.3%) 1
    Neutropenia 1/13 (7.7%) 1 2/12 (16.7%) 3
    Thrombocytopenia 0/13 (0%) 0 3/12 (25%) 13
    Cardiac disorders
    Tachycardia 0/13 (0%) 0 1/12 (8.3%) 1
    Eye disorders
    Periorbital oedema 0/13 (0%) 0 1/12 (8.3%) 1
    Gastrointestinal disorders
    Abdominal pain 0/13 (0%) 0 2/12 (16.7%) 2
    Abdominal pain upper 1/13 (7.7%) 1 0/12 (0%) 0
    Aphthous ulcer 0/13 (0%) 0 1/12 (8.3%) 1
    Constipation 0/13 (0%) 0 6/12 (50%) 7
    Diarrhoea 6/13 (46.2%) 8 2/12 (16.7%) 5
    Dry mouth 2/13 (15.4%) 2 4/12 (33.3%) 4
    Dysphagia 0/13 (0%) 0 1/12 (8.3%) 1
    Gastrooesophageal reflux disease 0/13 (0%) 0 2/12 (16.7%) 2
    Nausea 1/13 (7.7%) 1 8/12 (66.7%) 10
    Stomatitis 0/13 (0%) 0 1/12 (8.3%) 1
    Vomiting 1/13 (7.7%) 2 5/12 (41.7%) 6
    General disorders
    Asthenia 0/13 (0%) 0 1/12 (8.3%) 1
    Chest pain 1/13 (7.7%) 1 0/12 (0%) 0
    Chills 0/13 (0%) 0 1/12 (8.3%) 1
    Fatigue 4/13 (30.8%) 4 8/12 (66.7%) 10
    Influenza like illness 1/13 (7.7%) 1 0/12 (0%) 0
    Injection site bruising 1/13 (7.7%) 1 0/12 (0%) 0
    Mucosal inflammation 0/13 (0%) 0 1/12 (8.3%) 1
    Non-cardiac chest pain 0/13 (0%) 0 1/12 (8.3%) 1
    Oedema 1/13 (7.7%) 1 0/12 (0%) 0
    Oedema peripheral 1/13 (7.7%) 1 1/12 (8.3%) 1
    Pain 0/13 (0%) 0 1/12 (8.3%) 1
    Peripheral swelling 1/13 (7.7%) 1 0/12 (0%) 0
    Pyrexia 2/13 (15.4%) 2 2/12 (16.7%) 4
    Immune system disorders
    Seasonal allergy 0/13 (0%) 0 1/12 (8.3%) 1
    Infections and infestations
    Candida infection 0/13 (0%) 0 1/12 (8.3%) 1
    Cellulitis 2/13 (15.4%) 2 0/12 (0%) 0
    Enterovirus infection 0/13 (0%) 0 1/12 (8.3%) 1
    Herpes zoster 0/13 (0%) 0 1/12 (8.3%) 1
    Lower respiratory tract infection 1/13 (7.7%) 1 0/12 (0%) 0
    Nasopharyngitis 0/13 (0%) 0 1/12 (8.3%) 1
    Oral candidiasis 1/13 (7.7%) 1 1/12 (8.3%) 1
    Pneumonia 1/13 (7.7%) 1 2/12 (16.7%) 3
    Respiratory tract infection 0/13 (0%) 0 1/12 (8.3%) 1
    Rhinovirus infection 0/13 (0%) 0 1/12 (8.3%) 1
    Sinusitis bacterial 0/13 (0%) 0 1/12 (8.3%) 1
    Tooth infection 0/13 (0%) 0 1/12 (8.3%) 1
    Urinary tract infection 1/13 (7.7%) 1 0/12 (0%) 0
    Injury, poisoning and procedural complications
    Fall 0/13 (0%) 0 1/12 (8.3%) 1
    Investigations
    Alanine aminotransferase increased 1/13 (7.7%) 1 1/12 (8.3%) 1
    Aspartate aminotransferase increased 1/13 (7.7%) 1 0/12 (0%) 0
    Bacterial test positive 0/13 (0%) 0 1/12 (8.3%) 1
    Blood alkaline phosphatase increased 1/13 (7.7%) 1 1/12 (8.3%) 1
    Blood creatinine increased 4/13 (30.8%) 5 7/12 (58.3%) 11
    Blood urea increased 0/13 (0%) 0 1/12 (8.3%) 1
    Ejection fraction decreased 0/13 (0%) 0 1/12 (8.3%) 1
    Electrocardiogram qt prolonged 0/13 (0%) 0 2/12 (16.7%) 2
    Electrocardiogram t wave abnormal 0/13 (0%) 0 1/12 (8.3%) 1
    Haemoglobin decreased 1/13 (7.7%) 1 0/12 (0%) 0
    Lymphocyte count decreased 0/13 (0%) 0 1/12 (8.3%) 3
    Platelet count decreased 1/13 (7.7%) 1 1/12 (8.3%) 3
    Weight decreased 1/13 (7.7%) 1 3/12 (25%) 3
    Metabolism and nutrition disorders
    Decreased appetite 0/13 (0%) 0 6/12 (50%) 6
    Dehydration 0/13 (0%) 0 2/12 (16.7%) 3
    Hypercalcaemia 0/13 (0%) 0 1/12 (8.3%) 4
    Hyperglycaemia 3/13 (23.1%) 5 5/12 (41.7%) 7
    Hypoalbuminaemia 0/13 (0%) 0 1/12 (8.3%) 5
    Hypoglycaemia 0/13 (0%) 0 1/12 (8.3%) 1
    Hypokalaemia 2/13 (15.4%) 2 2/12 (16.7%) 2
    Hypomagnesaemia 0/13 (0%) 0 1/12 (8.3%) 1
    Hyponatraemia 0/13 (0%) 0 3/12 (25%) 4
    Hypophosphataemia 0/13 (0%) 0 2/12 (16.7%) 5
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/13 (0%) 0 1/12 (8.3%) 1
    Back pain 0/13 (0%) 0 1/12 (8.3%) 1
    Joint swelling 0/13 (0%) 0 1/12 (8.3%) 1
    Muscle spasms 1/13 (7.7%) 1 1/12 (8.3%) 1
    Musculoskeletal chest pain 0/13 (0%) 0 2/12 (16.7%) 2
    Myalgia 2/13 (15.4%) 3 3/12 (25%) 3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour ulceration 0/13 (0%) 0 1/12 (8.3%) 1
    Nervous system disorders
    Disturbance in attention 0/13 (0%) 0 1/12 (8.3%) 1
    Dizziness 0/13 (0%) 0 1/12 (8.3%) 1
    Dysgeusia 0/13 (0%) 0 1/12 (8.3%) 1
    Headache 1/13 (7.7%) 1 4/12 (33.3%) 6
    Neuralgia 0/13 (0%) 0 2/12 (16.7%) 2
    Neuropathy peripheral 1/13 (7.7%) 1 0/12 (0%) 0
    Paraesthesia 0/13 (0%) 0 1/12 (8.3%) 1
    Peripheral sensory neuropathy 0/13 (0%) 0 1/12 (8.3%) 1
    Presyncope 0/13 (0%) 0 1/12 (8.3%) 1
    Trigeminal neuralgia 0/13 (0%) 0 1/12 (8.3%) 1
    Psychiatric disorders
    Agitation 1/13 (7.7%) 1 0/12 (0%) 0
    Anxiety 0/13 (0%) 0 1/12 (8.3%) 1
    Confusional state 0/13 (0%) 0 3/12 (25%) 3
    Depressed mood 1/13 (7.7%) 1 0/12 (0%) 0
    Insomnia 3/13 (23.1%) 3 0/12 (0%) 0
    Renal and urinary disorders
    Acute kidney injury 1/13 (7.7%) 1 1/12 (8.3%) 1
    Chronic kidney disease 1/13 (7.7%) 1 0/12 (0%) 0
    Pollakiuria 1/13 (7.7%) 1 0/12 (0%) 0
    Reproductive system and breast disorders
    Breast mass 0/13 (0%) 0 1/12 (8.3%) 1
    Respiratory, thoracic and mediastinal disorders
    Cough 2/13 (15.4%) 2 4/12 (33.3%) 4
    Dysphonia 0/13 (0%) 0 1/12 (8.3%) 1
    Dyspnoea 1/13 (7.7%) 1 2/12 (16.7%) 2
    Dyspnoea exertional 0/13 (0%) 0 1/12 (8.3%) 1
    Hypoxia 0/13 (0%) 0 1/12 (8.3%) 1
    Increased bronchial secretion 1/13 (7.7%) 1 0/12 (0%) 0
    Nasal congestion 1/13 (7.7%) 1 0/12 (0%) 0
    Oropharyngeal pain 0/13 (0%) 0 1/12 (8.3%) 1
    Pleural effusion 1/13 (7.7%) 1 1/12 (8.3%) 1
    Pneumonitis 0/13 (0%) 0 1/12 (8.3%) 1
    Sinus congestion 0/13 (0%) 0 1/12 (8.3%) 1
    Skin and subcutaneous tissue disorders
    Decubitus ulcer 0/13 (0%) 0 1/12 (8.3%) 1
    Dermatitis 0/13 (0%) 0 1/12 (8.3%) 2
    Erythema 1/13 (7.7%) 1 0/12 (0%) 0
    Pruritus 3/13 (23.1%) 3 2/12 (16.7%) 2
    Rash 3/13 (23.1%) 3 2/12 (16.7%) 4
    Rash maculo-papular 0/13 (0%) 0 1/12 (8.3%) 1
    Vascular disorders
    Hypotension 0/13 (0%) 0 5/12 (41.7%) 6
    Orthostatic hypotension 1/13 (7.7%) 1 0/12 (0%) 0
    Peripheral ischaemia 0/13 (0%) 0 1/12 (8.3%) 1

    Limitations/Caveats

    Enrollment to this study was stopped early by the sponsor and an abbreviated CSR was generated.

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Acerta Clinical Trials
    Organization Acerta Pharma B.V.
    Phone 1-888-292-9613
    Email acertamc@dlss.com
    Responsible Party:
    Acerta Pharma BV
    ClinicalTrials.gov Identifier:
    NCT03205046
    Other Study ID Numbers:
    • ACE-LY-110
    First Posted:
    Jul 2, 2017
    Last Update Posted:
    Jan 6, 2021
    Last Verified:
    Dec 1, 2020