AZD2014 Plus Novel Anti-Cancer Agents in Relapsed or Refractory Diffuse Large B-Cell Lymphoma

• Status: Withdrawn
• Trial end date: 2019-04-01
• Target enrollment: 0
• Participant gender: All

Summary

This is a modular study of AZD2014 in combination with novel anti-cancer agents in patients with different subtypes of relapsed or refractory Diffuse Large B-Cell Lymphoma (DLBCL). Module 1, a combination with ibrutinib in patients with non-germinal centre B-cell-like (non-GCB) DLBCL, will consist of Part A, a Phase I dose-finding arm in which the safety and tolerability of the combination will be assessed, and Part B, a Phase II dose-expansion phase to assess the efficacy of the combination.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: AstraZeneca
• Treatments: Antineoplastic Agents

Criteria

Core Inclusion Criteria

1. Males and Females (M/F) ≥18

2. Histopathologically confirmed DLBCL

3. Progressive Disease (PD) after autologous stem cell transplantation (ASCT) or ineligible for ASCT

4. Relapsed/refractory de novo disease, defined as: i) recurrence of disease after complete response (CR), partial response (PR), or stable disease (SD); or ii) PD after completion of previous treatment regimen

5. ≥1 lesion on computerized tomography (CT) or magnetic resonance imaging (MRI) >1.5 cm

6. Adequate hematologic function

7. Adequate hepatic and renal function

8. Prothrombin time (PT)/international normalised ratio (INR) <1.5 x upper limit of normal (ULN) and activated partial thromboplastin time <1.5 x ULN

9. Serum potassium within normal limits (WNL)

10. ECOG perf. status of 0 or 1

11. Female patients willing to use 2 forms of contraception, not breast feeding

12. Male patients surgically sterile or willing to use effective barrier method of contraception

Core Exclusion Criteria

1. Previous allogenic stem cell transplant. Patients may have previous ASCT > 3 months prior

2. Prior standard anti-lymphoma therapy or radiation therapy ≤ 14 days

3. Concurrent systemic immunosuppressive therapy ≤ 28 days

4. Major surgery < 4 weeks or minor surgery < 14 days

5. Haemopoeitic growth factors < 7 days or pegylated G-CSF and darbepoetin < 14 days

6. History of severe allergic or anaphylactic reactions to kinase inhibitors or hypersensitivity to active or inactive excipients of vistusertib

7. Live, attenuated vaccine < 4 weeks

8. Unresolved toxicities from prior anti-cancer therapy with the exception of alopecia.

9. Bleeding disorders or haemophilia

10. History of stroke or intracranial haemorrhage < 6 months

11. Central nervous system (CNS) involvement by lymphoma or spinal cord compression

12. Corticosteroid use with the exception of control of symptoms relating to underlying disease and/or corticosteroid for other indications up to 20 mg/day prednisone

13. History of other malignancies

14. History of HIV, active or chronic hepatitis C, or hepatitis B

15. Have undergone any of the following procedures or experienced conditions currently or < 6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, angina pectoris, congestive heart failure [New York Heart Association (NYHA) grade ≥ 2], ventricular arrhythmias requiring continuous therapy, supraventricular arrhythmias, atrial fibrillation, haemorrhagic or thrombotic stroke, TIA or CNS bleeding.

16. Abnormal echo/MUGA at baseline

17. Mean resting QTc >450 msec obtained from 3 ECGs

18. Factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, or family history of sudden unexplained death <40 years-of-age

19. Type I or uncontrolled Type 2 diabetes mellitus.

20. Clinically significant pre-existing renal disease or high risk of developing renal impairment.

21. Refractory nausea and vomiting, malabsorption syndrome, disease significantly affecting GI function, resection of stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.

22. Concomitant use of therapeutic anticoagulants with the exception of short-acting heparins

23. Exposure to potent or moderate inhibitors or inducers of CYP 3A4/5, multi drug resistance 1 (MDR1) permeability glycoprotein (Pgp), or breast cancer resistance protein (BCRP)

24. Exposure to sensitive or narrow therapeutic range substrates of the drug metabolising enzymes CYP2C8, CYP2C9, CYP2C19, CYP2D6 or the drug transporters Pgp (MDR1), BCRP, OATP1B1, OATP1B3, OCT1 and OCT2.