Safety Study to Assess AFM11 in Patients With Relapsed or Refractory Adult B-precursor ALL

A Phase I Dose-escalation Study to Assess the Safety of AFM11 (CD19 x CD3 TandAb®) in Patients With Relapsed or Refractory Adult B-precursor Acute Lymphoblastic Leukemia

The purpose of the study is to determine the maximum tolerated dose (MTD) in patients with acute lymphoblastic leukemia (ALL) and to determine the safety and tolerability of increasing doses and different infusion times of AFM11 infusion in patients with adult B-precursor ALL

Acute lymphoblastic leukemia (ALL) is an aggressive type of leukemia characterized by an overproduction of lymphoblasts or lymphocytes in the bone marrow and the peripheral blood; it is frequently accompanied by suppression of normal hematopoiesis. It can spread to the lymph nodes, spleen, liver, the central nervous system (CNS), and other organs (sanctuary sites). Without treatment, ALL usually progresses quickly.

B- and T-cell lymphoblastic leukemia cells express surface antigens that parallel their respective developmental lineages. Precursor B-cell ALL cells typically express CD10, CD19, and CD34 on their surface, along with nuclear terminal deoxynucleotide transferase. About 20% of adult ALL patients have a cytogenetic abnormality that is indistinguishable from the Philadelphia chromosome (Ph1, t(9;22)), according to the National Cancer Institute (NCI).

The rationale for the use of AFM11 is based on its ability to bind to both malignant cells via its anti-CD19 domain and to T-cells via its anti-CD3 domains. This results in the formation of the "immunological synapse" and the subsequent T-cell activation on leading to killing of malignant cells. AFM11 has 2 binding sites for CD19 and 2 for CD3, its molecular weight is ~ 105kDa compared to diabodies like blinatumomab with one binding site for each target and a much lower molecular weight ~ 55kDa. In addition, preclinical experiments have shown that AFM11 has about a 100 fold higher affinity to CD3 compared to diabodies and is inducing higher cytotoxicity in vitro in the presence of low effector:target cell ratios. These differences might allow for a shortening of the infusion times and potentially higher clinical efficacy compared to blinatumomab.

Inclusion Criteria:

1. Patients with CD19+ B-precursor Philadelphia-chromosome negative ALL relapsed after at least induction and consolidation or having refractory disease and who are not candidates for bone marrow transplant (including both peripheral blood and hematopoietic stem cell transplant [HSCTs]) with a curative intent at time of screening

2. Patients with CD19+ Philadelphia-chromosome positive ALL who failed or were intolerant to therapy with at least 2 approved tyrosine kinase inhibitors

3. More than 5% blasts in bone marrow

4. In patients with high tumor burden (e.g., more than 50% blasts, or more than 15,000 blasts /µL blood, or elevated lactate dehydrogenase [LDH]) > 2 × upper limit of normal [ULN]), a pre treatment with 10 mg/m2 dexamethasone and 200 mg cyclophosphamide could be administered for up to 5 days.

5. Patients of both genders, age ≥ 18

6. Homogenous CD19 expression on leukemic blasts must be confirmed by either:

   1. Prior results from a CD19+ staining or flow cytometry at the most recent available diagnostic bone marrow biopsy or aspirate, or
   2. Submission of a recent bone marrow biopsy for staining for CD19 positivity. The results of this testing need to be available prior to start of AFM11 treatment.

7. Eastern Cooperative Oncology Group performance status ≤ 2

8. Life expectancy of at least 3 months

9. Ability to understand the patient information and informed consent form

10. Signed and dated written informed consent

Exclusion Criteria:

1. Autologous HSCT within 3 months prior to start of AFM11 treatment

2. Active acute or chronic graft-versus-host disease. All graft-versus-host disease medication should be omitted for at least 4 weeks prior to start of AFM11 treatment.

3. Allogeneic HSCT within 3 months prior to start of AFM11 treatment

4. Prior treatment with blinatumomab or any other CD19 targeting T-cell engager, including CD19 CAR-T cells

5. Treatment with donor-lymphocyte infusions within 4 weeks of start of AFM11 treatment or existing Graft versus Host Disease (GvHD)

6. Known or suspected central nervous system (CNS) involvement:

   1. Evidence for presence of malignant disease, inflammatory lesions, and/or vasculitis on cerebral magnetic resonance imaging (MRI)
   2. Infiltration of the cerebrospinal fluid by malignant B-cells, confirmed by lumbar puncture

7. History of or current relevant CNS pathology as epilepsy, seizure, paresis, aphasia, apoplexia, severe brain injuries, cerebellar disease, organic brain syndrome, psychosis

8. Cancer chemotherapy within 4 weeks prior to start of AFM11 treatment, or at least 4 times the respective half-lives, whichever is longer

9. Therapy with antibody, or antibody constructs within 4 weeks prior to the start of AFM11 treatment, or at least 4 half-lives, whichever is longer

10. Treatment with any investigational agent within 4 weeks prior to start of AFM11 treatment, or at least 4 times the respective half-life, whichever is longer

11. Contraindication for any of the concomitant medications

12. Abnormal renal or hepatic function as follows: aspartate aminotransferase (AST or SGOT) and/or alanine aminotransferase (ALT or SGPT) ≥ 2.5 × ULN; total bilirubin ≥ 1.5 × ULN; serum creatinine ≥ 2 × ULN; creatinine clearance < 50 mL/minute

13. History of malignancy other than B-cell lymphoma or B-precursor ALL within 5 years prior to study entry, with the exception of basal cell carcinoma of the skin or carcinoma in situ of the cervix

14. Uncontrolled infections; known bacteremia

15. Any concurrent disease or medical condition that is deemed to interfere with the conduct of the study as judged by the Investigator

16. Clinically relevant coronary artery disease (New York Heart Association [NYHA] functional angina classification III/IV), congestive heart failure (NYHA III/IV), high risk of or known uncontrolled arrhythmia

17. Regular dose of corticosteroids during the 4 weeks prior to start of AFM11 treatment of this study or anticipated need of corticosteroids exceeding prednisone 20 mg/day or equivalent, or any other immunosuppressive therapy within 4 weeks prior to study entry. Exception is the pre treatment of rapidly progressing disease

18. Known infection with human immunodeficiency virus or chronic or acute infection with hepatitis B or hepatitis C virus

19. Pregnant or nursing women or women of childbearing potential not willing to use an effective form of contraception during participation in the study and at least 3 months thereafter. Male patients not willing to ensure that during the study and at least 3 months thereafter no fathering takes place. Effective methods of contraception include intrauterine device (IUD), combined (estrogen- and progesterone-containing) hormonal contraception (oral, vaginal ring or transdermal patch) with an ethinylestradiol dose of at least 30 µg, plus use of male condoms (preferably with spermicides), female condoms, a female diaphragm, or a cervical cap.