Study of Betalutin for Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma (LYMRIT-37-05)

A Phase 1 Dose Finding Study of Lutetium (177Lu)-Lilotomab Satetraxetan (Betalutin®) in Patients With Relapsed/Refractory, Diffuse Large B-cell Lymphoma, Not Eligible for Autologous Stem Cell Transplant

This study is a phase 1, dose finding, open-label study in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). This is a dose escalating study to define the maximum tolerated dose (MTD) of lutetium (177Lu)-lilotomab satetraxetan (Betalutin®) in DLBCL patients who are not eligible for autologous stem cell transplant. The study will also assess safety and tolerability, pharmacokinetics, biodistribution and efficacy.

Inclusion Criteria:

1. Male or female aged ≥18 years.

2. Histologically confirmed DLBCL (WHO classification).

3. Received at least one prior line of therapy including immuno-chemotherapy.

4. In first or subsequent relapse, or refractory to the last treatment (defined as less than a complete metabolic response to the last treatment, or disease progression within 6 months from the last treatment).

5. Not suitable for, or declined/unwilling to undergo intensive therapy, including high dose chemotherapy and autologous stem cell transplantation (ASCT).

6. Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy (at least one objectively bi-dimensionally measurable (nodal) lesion (>1.5 cm in its largest dimension by CT scan).

7. Negative human anti-mouse antibody (HAMA) test.

8. Life expectancy of at least 3 months.

9. Bone marrow tumour infiltration <25% tumour cells.

10. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.

11. Normal organ and bone marrow function defined as:

    1. Absolute neutrophil count ≥1.5 x 109/L
    2. Platelet count ≥150 x 109/L;
    3. Haemoglobin ≥9 g/dL
    4. Total bilirubin ≤1.5 x upper limit of normal (ULN) (except patients with documented Gilbert's syndrome)
    5. Liver enzymes: Aspartate transaminase (AST); Alanine transaminase (ALT) or Alkaline phosphatase (ALP) ≤2.5 x ULN (or ≤5.0 x ULN if liver involvement by primary disease)
    6. Adequate renal function as demonstrated by a serum creatinine ≤1.5 mg/dL or a creatinine clearance >60 mL/min
    7. Normal coagulation parameters (elevated international normalized ratio (INR), prothrombin time or activated partial thromboplastin time (APTT) ≤1.3 ULN range acceptable)

12. Women of childbearing potential must:

    1. Understand that the study medication may have teratogenic risk

    2. Have a negative serum pregnancy test at screening and before Betalutin injection

    3. Commit to continued abstinence from heterosexual intercourse (excluding periodic abstinence or the withdrawal method) or begin two acceptable methods of birth control with a Pearl-Index ≤ 1%. without interruption from 4 weeks before starting study drug, throughout study drug therapy and for 12 months after end of study drug therapy, even if she has amenorrhoea. Apart from abstinence, acceptable methods of birth control are:

       • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)
       • Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
       • Intrauterine device (IUD)
       • Intrauterine hormone-releasing system (IUS)
       • Bilateral tubal occlusion
       • Vasectomised partner

13. Male patients must agree to use condoms during intercourse throughout study drug therapy and the following 12 months.

14. Ability to give written, informed consent prior to any study-specific screening procedures, with the understanding that the consent may be withdrawn by the patient at any time without prejudice.

15. Capable of understanding the protocol requirements, is willing and able to comply with the study protocol procedures, and has signed the informed consent document.

16. A negative Hepatitis B test (HBsAg and anti-HBc) and negative HIV test during screening

Exclusion Criteria:

1. Prior hematopoietic allogenic stem cell transplantation.

2. Prior autologous stem cell transplantation.

3. Previous total body irradiation.

4. Prior anti-lymphoma therapy (chemotherapy, immunotherapy or other investigational agent), excluding corticosteroids within 4 weeks prior to start of study treatment (i.e. rituximab) (G-CSF or GM-CSF are permitted up to 2 weeks prior to start of study treatment.)

5. Patients who are receiving any other investigational agents.

6. Patients with known or suspected central nervous system involvement of lymphoma.

7. History of a previous treated cancer except for the following:

   1. Adequately treated local basal cell or squamous cell carcinoma of the skin
   2. Cervical carcinoma in situ
   3. Superficial bladder cancer
   4. Localized prostate cancer undergoing surveillance or surgery
   5. Localised breast cancer treated with surgery and radiotherapy but not including systemic chemotherapy
   6. Other adequately treated Stage 1 or 2 cancer currently in complete remission

8. Pregnant or breastfeeding women.

9. Exposure to another CD37 targeting drug.

10. Allergy to X ray contrast agents.

11. A known hypersensitivity to rituximab, HH1, Betalutin or murine proteins or any excipient used in rituximab, lilotomab or Betalutin.

12. Has received a live attenuated vaccine within 30 days prior to enrolling in the study.

13. Evidence of severe or uncontrolled systemic diseases:

    1. Uncontrolled infection including evidence of ongoing systemic bacterial, fungal, or viral infection (excluding viral upper respiratory tract infections) at the time of initiation of study treatment

    2. Pulmonary conditions e.g. unstable or uncompensated respiratory disease

    3. Hepatic, renal neurological or metabolic conditions - which in the opinion of the investigator would compromise the protocol objectives

    4. Psychiatric conditions e.g. patients unlikely to comply with the protocol, e.g. mental condition rendering the patient unable to understand the nature, scope, and possible consequences of participating in the study

    5. History of erythema multiforme, toxic epidermal necrolysis or Stevens-Johnson syndrome

    6. Cardiac conditions, including:

       • history of acute coronary syndromes (including unstable angina)
       • class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system;
       • known uncontrolled arrhythmias (except sinus arrhythmia) in the past 24 weeks.