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

• acalabrutinib (Drug), also known as ACP-196: Acalabrutinib is a selective, irreversible small molecule Bruton's tyrosine kinase (BTK) inhibitor.
• vistusertib (Drug), also known as AZD2014: Vistusertib is an inhibitor of mechanistic target of rapamycin (mTOR) kinase

Primary outcomes

• 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).

Sex: All, ages: 18 Years to 130 Years

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.

Participant flow

Outcome results

• Number of Participants With Treatment-Emergent Adverse Events (AEs) (Primary), Count of participants, Participants: Acalabrutinib 100 mg BID* Plus Vistusertib BID* Continuous 13; Acalabrutinib 100 mg BID* Plus Vistusertib BID* Intermittent 12

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.

Serious adverse events by term

Other adverse events by term

56 more terms not shown.

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

• Results publication: 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. PMID 34269152

• Study Protocol (PDF, 2019-03-29)
• Statistical Analysis Plan (PDF, 2018-08-16)

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