An Evaluation AZD2014 Alone and in Combination With Rituximab in Relapsed/Refractory Diffuse Large B Cell Lymphoma

Inclusion Criteria:

1. Relapsed or refractory Diffuse Large B-Cell Lymphoma (DLBCL) relapsing after at least 1 course of potentially curative, anti-CD20 antibody containing regimen (e.g. RCHOP, GCHOP, RGCVP). High grade transformation from low grade lymphoma (e.g. follicular lymphoma, lymphoplasmacytic lymphoma, chronic lymphocytic leukaemia) is permitted. Patients must have relapsed post-ASCT or be considered not suitable for ASCT.
2. Tissue biopsy (or bone marrow trephine if no other tissue available) confirming histology within 3 months of enrolment.
3. Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses.
4. Aged at least 18 years.
5. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
6. Females should be using adequate contraceptive measures (as described in the protocol, different for patient receiving rituximab), should not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:

   * Post-menopausal defined as amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments
   * Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
7. Male patients should be willing to use barrier contraception (i.e. condoms) as described in the protocol, (different for patient receiving rituximab\*)
8. Ability to swallow and retain oral medication
9. CT measurable disease with at least 1 lesion having short axis ≥ 1.5cm or splenomegaly ≥ 14cm in cranio-caudal length attributable to relapsed lymphoma
10. Patients must have negative virology for HIV, hepatitis B and hepatitis C prior to trial entry. Patients with an isolated anti-hepatitis B sAg antibody may be entered as this indicates previous vaccination.. These patients MUST have HBV DNA tested.

Exclusion Criteria:

Patients must not enter the study if any of the following exclusion criteria are fulfilled:

1. Prior chemotherapy, biological therapy, radiation therapy, androgens, thalidomide, immunotherapy, other anticancer agents, and any investigational agents within 14 days of registration (not including palliative radiotherapy at focal sites). Corticosteroids are permitted during screening but should be weaned down to a maximum dose of prednisolone 10mg daily (or equivalent) by day 1 of cycle 1.

   \- With the exception of alopecia, any unresolved toxicities from prior chemotherapy should be no greater than CTCAE (Version 4.0) Grade 2 at the time of registration.
2. Major surgery within 4 weeks prior to entry to the study (excluding placement of vascular access), or minor surgery within 2 weeks of entry into the study.
3. Exposure to potent or moderate inhibitors or inducers of CYP3A4/5 if taken within the stated washout periods before the first dose of study treatment.
4. Exposure to potent or moderate inhibitors or inducers of CYP2C8 if taken within the stated washout periods before the first dose of study treatment.
5. 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 within the appropriate wash-out period (a minimum of 5 x the reported terminal elimination half-life of each drug) before the first dose of study treatment.
6. Previous treatment with any first generation mTORC1 inhibitors (rapamycin, sirolimus, temsirolimus, everolimus) or any dual mTORC1/2 inhibitors (e.g. AZD2014, AZD8055).
7. Patients who have experienced intolerable AEs prejudged by the treating Investigator due to other mTORC1 or mTORC1/2 inhibitors, PI3 kinase inhibitors, or AKT inhibitors.
8. Patients with proven central nervous system (CNS) involvement.
9. As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases (e.g., severe hepatic impairment, interstitial lung disease (e.g.bilateral, diffuse, parenchymal lung disease), uncontrolled chronic renal diseases (e.g. glomerulonephritis, nephritic syndrome, Fanconi Syndrome or Renal tubular acidosis) or current unstable or uncompensated respiratory or cardiac conditions, or uncontrolled hypertension, active bleeding diatheses or active infection. Screening for chronic conditions is not required.
10. Patients who have experienced any of the following procedures or conditions currently or in the preceding 12 months:

    * coronary artery bypass graft
    * angioplasty
    * vascular stent
    * myocardial infarction
    * angina pectoris
    * congestive heart failure New York Heart Association Grade ≥2
    * ventricular arrhythmias requiring continuous therapy
    * supraventricular arrhythmias including atrial fibrillation, which are uncontrolled
    * haemorrhagic or thrombotic stroke, including transient ischaemic attacks or any other central nervous system bleeding
11. Abnormal echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) at baseline (left ventricular ejection fraction \[LVEF\] \<50%).
12. Torsade's de Pointes within 12 months of study entry.
13. Mean (3 consequent ECGs 1 minute apart) resting QTcF and QTcB \>470 msec as per local reading.
14. Concomitant medications known to prolong QT interval, or with factors that increase the risk of QTc prolongation or risk of arrhythmic events (such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age).
15. Patients with Diabetes Type I or uncontrolled Type II (HbA1c \>7 mmol/L assessed locally) as judged by the local investigator.
16. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values unless due to underlying NHL infiltration.

    * Absolute neutrophil count \<1.5 x 10\^9/L (without GCSF / GMCSF support)
    * Platelet count \<100 x 10\^9/L
    * Haemoglobin \<90 g/L (transfusions permissible)
    * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>2.5 times the upper limit of normal (ULN) if no demonstrable liver involvement or \>5 times ULN in the presence of liver involvement
    * Total bilirubin \>1.5 times ULN unless in the presence of Gilbert's syndrome with an elevated indirect fraction
    * Serum creatinine \>1.5 times ULN concurrent with creatinine clearance ≤50 mL/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is only required when creatinine is \>1.5 times the ULN
17. Current refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD2014.
18. History of known hypersensitivity to active or inactive excipients of AZD2014 or drugs with a similar chemical structure or class to AZD2014.
19. Judgment by the Investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements.
20. Previous history of other active malignant disease other than fully excised basal or squamous cell carcinoma of the skin, carcinoma in situ of the uterine cervix or localised disease treated with curative intent using surgery alone, within the last 3 years.

    For the rituximab cohort only, patients must not enter the study if any of the above or below exclusion criteria are fulfilled:
21. Known hypersensitivity to recombinant proteins, murine proteins or to any excipients of rituximab infusions
22. Vaccination with live virus vaccine within the 4 weeks prior to study entry or intention to do so during the study treatment