Avelumab in Relapsed and Refractory Peripheral T-cell Lymphoma

A Phase 2a Trial of Avelumab, an Anti-PDL1 Antibody, in Relapsed and Refractory Peripheral T-cell Lymphoma

The AVAIL-T trial is a trial to find out how effective avelumab is at treating patients with primary T-cell lymphoma that is refractory to or has relapsed following initial treatment.

The AVAIL-T trial is designed to find out how effective avelumab is at treating patients with primary T-cell lymphoma that is refractory to or has relapsed following initial treatment. Up to 36 people will be taking part in the AVAIL-T trial at hospitals across the United Kingdom. All patients on the trial will be recruited over 2 years and receive up to 8 cycles of avelumab treatment. Avelumab is an anti-PDL1 (programmed cell death receptor ligand 1) antibody that will be given as an infusion once every 2 weeks in cycles lasting 28 days. The trial will be looking at the response to avelumab, by measuring the change in the tumour size using CT scans, and seeing how long that response is maintained. The trial will also look at toxicity, overall survival, and progression free survival.

In addition we will analyse blood samples and samples of the cancer to understand better how the cancer behaves. This may guide the investigators in developing better treatments in the future.

Inclusion Criteria:

• Male or female patients aged ≥ 16 years

• Life expectancy > 12 weeks

• ECOG (eastern oncology cooperative group) performance status ≤ 2

• Relapsed or refractory* peripheral T-cell lymphoma including the following histologies: peripheral T-cell lymphoma not otherwise specified (PTCL NOS) , angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (ALCL), enteropathy associated T-cell lymphoma (EATL), extranodal NK (natural killer)/T- cell lymphoma (ENKL), transformed mycosis fungoides (LCT MF), hepatosplenic T-cell lymphoma (HSTCL) * For all relapsed patients, relapse must be confirmed by tissue biopsy (or bone marrow trephine if no other tissue available). For refractory patients, a biopsy must have been obtained within the last 3 months

• Failed at least 1 prior therapy (but no upper limit of prior regimens)

• Adequate haematological function defined by at registration:

  • absolute neutrophil count (ANC) ≥ 1.0 × 109/L, (unsupported)
  • platelet count ≥ 75 × 109/L, (unsupported)
  • haemoglobin ≥ 9 g/dL (may have been transfused)

• Adequate hepatic function defined by:

  • total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range
  • AST (aspartate aminotransferase) or ALT (alanine aminotransferase) levels ≤ 2.5 × ULN for all patients, or AST and ALT levels ≤ 5 x ULN (for subjects with documented metastatic disease to the liver)

• Adequate renal function defined by an estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method)

• CT measurable disease with at least 1 lesion having short axis > 1.5cm or splenomegaly > 14cm in cranio-caudal length attributable to relapsed/non responding lymphoma

• Negative serum pregnancy test at screening for women of childbearing potential.

• Highly effective contraception for both male and female patients if the risk of conception exists. (Note: women of childbearing potential and men able to father a child must agree to use 2 highly effective contraception, defined as methods with a failure rate of less than 1 % per year. Highly effective contraception is required from consent, throughout and for at least 60 days after avelumab treatment.

• Ability to give informed consent

Exclusion Criteria:

Patients are not eligible for the trial if they fulfill any of the following exclusion criteria:

• All patients with active central nervous system (CNS) involvement of lymphoma

• Prior organ transplantation, including allogeneic stem cell transplantation

• Significant acute or chronic infections including, among others:

  • Known history of testing positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS),
  • Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)

• Current use of immunosuppressive medication, EXCEPT for the following:

  • intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); Systemic corticosteroids at a maximum dose of ≤ 1 mg/kg of prednisone or equivalent during screening (to be stopped by day 1 of trial treatment); Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).

• Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible

• Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade ≥ 3)

• Persisting toxicity related to prior therapy of Grade >1 NCI-CTCAE v 4.03; however, alopecia and sensory neuropathy Grade ≤ 2 or other Grade ≤ 2 not constituting a safety risk based on investigator's judgment are acceptable are acceptable

• Pregnancy or lactation

• Known alcohol or drug abuse

• Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to registration), myocardial infarction (< 6 months prior to registration), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.

• Other severe acute or chronic medical conditions including colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behaviour; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study

• Vaccination within 4 weeks of the first dose of avelumab and while on trial is prohibited except for administration of inactivated vaccines

• Active infection requiring systemic therapy

• Major surgery within 4 weeks of trial entry

• Patients and partners of childbearing potential not willing to use two methods of effective contraception during and for 60 days after therapy