Part 1: De novo Diffuse large B-cell lymphoma (DLBCL), Transformed DLBCL and Richter syndrome (RS). Part 2: De novo Germinal center B-cell (GCB) DLBCL and De novo non-GCB DLBCL MedDRA version: 20.0 Level: PT Classification code 10012822 Term: Diffuse large B-cell lymphoma refractory System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) Med
Conditions
Sponsors
Acerta Pharma BV
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Diagnosis of relapsed/refractory DLBCL as documented by medical records and with histology based on criteria established by WHO: a. If a subject has de novo DLBCL, the diagnosis is confirmed by biopsy and is immunohistologically characterized as de novo non-GCB DLBCL or de novo GCB DLBCL. Note that PMBCL is excluded from this protocol. Tumor tissue must also be available for sending to the sponsor for central cell of origin testing. b. If the subjects has RS, the diagnosis is confirmed by biopsy and is immunohistologically characterized as transformation to DLBCL. Tumor tissue must also be available for sending to the sponsor for central pathology testing. This histology applies to Part 1 only. c. 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). Tumor tissue must also be available for sending to the sponsor for central pathology testing. This histology applies to Part 1 only. 2. Men and women =18 years of age. 3. Prior treatment for lymphoid malignancy: a. If the subject has DLBCL, there is no curative option with conventional therapy and the prior treatment included = 1 prior combination chemoimmunotherapy regimen (eg, anthracycline based therapy with rituximab such R-CHOP). Also subjects should have relapsed after ASCT or should be noncandidates for ASCT. b. If the subject has RS, the subject must have had =1 prior treatment with a combination chemoimmunotherapy regimen. 4. 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 CT scan for all histologies). 5. Documented active disease that is relapsed or refractory defined as: a. Relapse: disease progression after completion of the treatment regimen preceding entry into the study. b. Refractory: progressive disease or stable disease as best response at any point during chemotherapy (>4 cycles of first-line or 2 cycles of later-line therapy) or relapsed at =12 months from autologous stem cell transplantation (Crump et al 2017). 6. ECOG performance status of =2. 7. Adequate hematologic function, independent of transfusion and growth factor support for =14 days before screening, defined as: a. ANC >1000 cells/mm3 (1.0 x 109/L) b. Platelet count >75,000 cells/mm3 (75 x 109/L) or >50,000 cells/mm3 with bone marrow involvement c. Hemoglobin >8.0 g/dL 8. Adequate hepatic and renal function at screening defined as: a. Serum AST and ALT =2.5 x ULN if no demonstrable liver involvement or =3 x ULN in the presence of liver metastases b. Bilirubin =1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin) c. Serum creatinine =1.5 times ULN and creatinine clearance >30 mL/min (measured or calculated by Cockcroft and Gault equation [(140-Age) • Mass (kg)/(72 • creatinine mg/dL) • multiply by 0.85 if female]) 9. PT/INR <1.5 x ULN and aPTT <1.5 x ULN.
Exclusion criteria
Exclusion criteria: 1. History of prior malignancy except for the following: a) Malignancy treated with curative intent and with no evidence of active disease present for more than 2 years before screening and felt to be at low risk for recurrence by treating physician. b) Adequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled nonmelanomatous skin cancer. c) Adequately treated carcinoma in situ without current evidence of disease. 2. As judged by the Investigator, any evidence of severe or uncontrolled systemic disease, or current unstable or uncompensated respiratory or cardiac conditions, or uncontrolled hypertension, history of, or active, bleeding diatheses or uncontrolled active systemic fungal, bacterial, viral, or other infection, or intravenous anti-infective treatment within 2 weeks before first dose of study drug. 3. Diagnosis of PMBCL. 4. Known history of infection with HIV. 5. Serologic status reflecting active hepatitis B or C infection. 6. Active CMV infection 7. Undergone any of the following procedures or experienced any of the following conditions currently or in the preceding 6 months: a) coronary artery bypass graft b) angioplasty c) vascular stent d) myocardial infarction e) angina pectoris f) congestive heart failure (NYHA Grade =2) g) ventricular arrhythmias requiring continuous therapy h) supraventricular arrhythmias, including atrial fibrillation, which are uncontrolled i) hemorrhagic or thrombotic stroke, including transient ischemic attacks or any other central nervous system bleeding. 8. Current refractory nausea and vomiting, malabsorption syndrome, disease significantly affecting 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. 9. History of CNS lymphoma, leptomeningeal disease or spinal cord compression. 10. History of severe allergic or anaphylactic reactions to kinase inhibitors or history of hypersensitivity to active or inactive excipients of vistusertib or acalabrutinib or drugs with a similar chemical structure or class to vistusertib or acalabrutinib. 11. Presence of a GI ulcer diagnosed by endoscopy within 3 months before screening. 12. Uncontrolled Type 1 or Type 2 diabetes mellitus. 13. Any clinically significant pre-existing renal disease or high risk of developing renal impairment. 14. Major surgical procedure within 28 days before first dose of study drug. . 15. Unresolved toxicities from prior anticancer therapy, defined as having not resolved to CTCAE, Version 4.03 Grade 0 or 1, or to the levels dictated in the inclusion/exclusion criteria, with the exception of alopecia. 16. Any hematopoietic growth factors 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. 17. Vaccinated with live, attenuated
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Part 1 Primary Objective: To determine a dose and schedule for vistusertib in combination with acalabrutinib 100 mg bid for evaluation in Part 2 Part 2 Primary Objectives: To evaluate the safety of acalabrutinib and vistusertib when coadministered ; Secondary Objective: -To evaluate the PK of acalabrutinib and vistusertib when coadministered -To evaluate the clinical activity of acalabrutinib and vistusertib, when coadministered, as measured by ORR, including CR rate, DOR, DRR, PFS and OS ; Primary end point(s): - Safety Verbatim descriptions of AEs will be mapped according to the MedDRA thesaurus terms and graded according to NCI CTCAE, v4.03 or higher. ; Timepoint(s) of evaluation of this end point: Extent of exposure to study drug(s), all AEs, SAEs, any adverse events leading to study drug(s) discontinuation, and study drug(s) related-adverse events will be summarized. The frequency of AEs will be summarized by system organ class and preferred terms according to MedDRA, as well as per severity per NCI CTCAE grade. Treatment-emergent AEs will be summarized, unless otherwise specified. For events with varying severity, the worst reported grade will be used. Laboratory abnormalities will be defined based on laboratory normal ranges (universal normal ranges, if central lab). Selected laboratory parameters may be analyzed with shift tables and summaries of changes from baseline to worst post-treatment value. Vital sign assessments will be tabulated and summarized. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Analysis of Efficacy Parameters - Overall Response Rate (ORR) and Complete Response (CR)Rate - Progression-free Survival (PFS) - Duration of Response (DOR) - Durable Response Rate (DRR) - Overall Survival (OS) ; Timepoint(s) of evaluation of this end point: -The ORR is defined as the rate of subjects who achieve either a PR or CR, according to the revised response criteria for malignant lymphoma, as assessed by investigators before receiving any other anticancer therapy. - PFS is defined as the time from first dose date to documented disease progression, or death from any cause, whichever occurs first. -DOR is defined as the time from the first objective response of CR or PR to the time of documented disease progression or death due to any cause, whichever occurs first. -OS is defined as the time from first dose until the date of death from any cause. -The DRR is defined as the percentage of subjects who have a complete or partial response lasting =8 weeks. | — |
Countries
United Kingdom, United States
Contacts
Public ContactMedical Director (Ahmed Hamdy)
Acerta Pharma LLC
Outcome results
None listed