| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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 |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10012822 |
| E.1.2 | Term | Diffuse large B-cell lymphoma refractory |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10058728 |
| E.1.2 | Term | Richter's syndrome |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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 |
|
| E.2.2 | Secondary objectives of the trial |
-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 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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.
10. Serum potassium within normal range.
11. Women should be using adequate contraceptive measures, should not be breast feeding and must have a
negative pregnancy test before start of dosing if of child-bearing potential or must have evidence of nonchildbearing potential by fulfilling one of the following criteria at screening:
a. Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following
cessation of all exogenous hormonal treatments
b. Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral
salpingectomy but not tubal ligation
12. Men should be willing to use barrier contraception (ie, condoms) and refrain from sperm donation during and after the conduct of the trial. If not done previously, storage of sperm before receiving vistusertib will be advised to male subjects with a desire to have children.
13. Willing and able to participate in all required evaluations and procedures in this study protocol including
swallowing capsules without difficulty.
14. Willing to follow sunlight protection measures while taking vistusertib (eg, using sunscreen and avoiding
excessive sun exposure) and for 90 days after the last dose of vistusertib.
15. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local patient privacy regulations). |
|
| E.4 | Principal 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 vaccines within 4 weeks of first dose of study drug.
18. Abnormal ECHO or MUGA at baseline (LVEF <40% and shortening fraction SF <15%).
19. Mean resting QTc calculated using Fridericia's formula (QTcF) >450 msec obtained from 3 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.
20. Factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, or family history of sudden unexplained death under 40 years of age. Concomitant medications known to prolong QTc should be used with caution and cannot be used during the first 28 days on study.
21. Any therapeutic antibody within 4 weeks of first dose of study drugs.
22.Prior use of standard antilymphoma therapy or radiation therapy within 14 days of receiving the first dose of study drug
23. Ongoing immunosuppressive therapy, including systemic corticosteroids for treatment of lymphoid cancer or other conditions.
24. Exposure to strong or moderate inhibitors or inducers of CYP3A4/5, P-gp, or BCRP, if taken within the stated washout periods before the first dose of study drug.
26. Requires or receiving therapeutic anticoagulants, with the exception of short-acting heparins, within 7 days of first dose of study drug.
27. Requires treatment with proton-pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).
28. Concurrent participation in another therapeutic clinical trial |
|
| E.5 End points |
| E.5.1 | 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. |
|
| E.5.1.1 | 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. |
|
| E.5.2 | 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) |
|
| E.5.2.1 | 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. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| This is a controlled trial with no randomization in Part 2, and randomization in Part 1 |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of study for this protocol is when the last subject on the study has either discontinued the study or been transitioned to a roll over protocol. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 7 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 7 |
Print
