DLBCL, Richter Syndrome
Conditions
Brief summary
This study evaluates the safety of acalabrutinib and vistusertib when taken in combination.
Interventions
DRUGacalabrutinib
Acalabrutinib is a selective, irreversible small molecule Bruton's tyrosine kinase (BTK) inhibitor.
DRUGvistusertib
Vistusertib is an inhibitor of mechanistic target of rapamycin (mTOR) kinase
Sponsors
Acerta Pharma BV
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
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). 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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). |
Countries
United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Acalabrutinib 100 mg BID* Plus Vistusertib BID* Continuous Acalabrutinib daily + Vistusertib daily over the 28-day cycle | 13 |
| Acalabrutinib 100 mg BID* Plus Vistusertib BID* Intermittent Acalabrutinib daily + Vistusertib 2 days on/ 5 days off over the 28-day cycle | 12 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 10 | 6 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Study terminated by sponsor | 2 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Acalabrutinib 100 mg BID* Plus Vistusertib BID* Intermittent | Total | Acalabrutinib 100 mg BID* Plus Vistusertib BID* Continuous |
|---|---|---|---|
| Age, Continuous | 67.3 Years STANDARD_DEVIATION 12 | 65.4 Years STANDARD_DEVIATION 13.99 | 63.6 Years STANDARD_DEVIATION 15.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 22 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 11 Participants | 23 Participants | 12 Participants |
| Region of Enrollment United Kingdom | 3 Participants | 11 Participants | 8 Participants |
| Region of Enrollment United States | 9 Participants | 14 Participants | 5 Participants |
| Sex: Female, Male Female | 2 Participants | 6 Participants | 4 Participants |
| Sex: Female, Male Male | 10 Participants | 19 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 10 / 13 | 6 / 12 |
| other Total, other adverse events | 13 / 13 | 12 / 12 |
| serious Total, serious adverse events | 2 / 13 | 6 / 12 |
Outcome results
Primary
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).
Time frame: From first dose of study drug until 30 days post last dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Acalabrutinib 100 mg BID* Plus Vistusertib BID* Continuous | Number of Participants With Treatment-Emergent Adverse Events (AEs) | 13 Participants |
| Acalabrutinib 100 mg BID* Plus Vistusertib BID* Intermittent | Number of Participants With Treatment-Emergent Adverse Events (AEs) | 12 Participants |